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Conclusions SC therapy is effective for PAH in pre clinical studies . These results may help to st and ardise pre clinical animal studies and provide a theoretical basis for clinical trial design in the future .

Background Despite significant progress in drug treatment , the prognosis of patients with advanced pulmonary arterial hypertension ( PAH ) remains extremely poor . Many pre clinical studies have reported the efficacy of stem cell ( SC ) therapy for PAH ; however , this approach remains controversial . The aim of this systematic review and meta- analysis is to assess the potential efficacy of SC therapy for PAH .

Although transplantation of adult bone marrow mesenchymal stem cells ( BM-MSCs ) holds promise in the treatment for pulmonary arterial hypertension ( PAH ) , the poor survival and differentiation potential of adult BM-MSCs have limited their therapeutic efficiency . Here , we compared the therapeutic efficacy of human embryonic stem cell-derived MSCs ( hESC-MSCs ) with adult BM-MSCs for the treatment of PAH in an animal model . One week following monocrotaline (MCT)-induced PAH , mice were r and omly assigned to receive phosphate-buffered saline ( MCT group ) ; 3.0 × 106 human BM-derived MSCs ( BM-MSCs group ) or 3.0 × 106 hESC-derived MSCs ( hESC-MSCs group ) via tail vein injection . At 3 weeks posttransplantation , the right ventricular systolic pressure ( RVSP ) , degree of RV hypertrophy , and medial wall thickening of pulmonary arteries were lower= , and pulmonary capillary density was higher in the hESC-MSC group as compared with BM-MSC and MCT groups ( all p < 0.05 ) . At 1 week posttransplantation , the number of engrafted MSCs in the lungs was found significantly higher in the hESC-MSC group than in the BM-MSC group ( all p < 0.01 ) . At 3 weeks posttransplantation , implanted BM-MSCs were undetectable whereas hESC-MSCs were not only engrafted in injured pulmonary arteries but had also undergone endothelial differentiation . In addition , protein profiling of hESC-MSC- and BM-MSC-conditioned medium revealed a differential paracrine capacity . Classification of these factors into bioprocesses revealed that secreted factors from hESC-MSCs were preferentially involved in early embryonic development and tissue differentiation , especially blood vessel morphogenesis . We concluded that improved cell survival and paracrine capacity of hESC-MSCs provide better therapeutic efficacy than BM-MSCs in the treatment for PAH Abstract We investigated the effect of adipose-derived stem cells ( ADSCs ) transplantation effects on structural remodeling and pulmonary artery pressure in monocrotaline (MCT)-induced pulmonary hypertensive rats . In the first experiment , 32 male Sprague-Dawley ( SD ) rats were r and omly divided into four groups ( n = 8/group ) : 3 ADSCs treated groups and normal control ( Ctrl ) . ADSCs were administered through the left jugular vein at 105 , 106 and 107 cells , respectively , and a cell density of 106cells/ml was shown to be optimal . The GFP-tagged ADSCs were identified in the lungs and differentiated into endothelial-like cells . In the second experiment , 96 male SD rats were r and omly divided into three groups ( n = 32/group ) : Ctrl , MCT-induced pulmonary arterial hypertension ( PAH ) , and PAH treated with ADSCs ( ADSCs ) . Two weeks post-MCT administration , the ADSCs group received 1 × 106 ADSCs via the external jugular vein . Compared to PAH rats , mean pulmonary arterial pressure was decreased in rats at 1 , 2 , and 3 weeks after ADSCs-treatment ( 18.63 ± 2.15 mmHg versus 24.53 ± 2.90 mmHg ; 23.07 ± 2.84 mmHg versus 33.18 ± 2.30 mmHg ; 22.98 ± 2.34 mmHg versus 36.38 ± 3.28 mmHg , p < 0.05 ) . Meanwhile , the right heart hypertrophy index ( 36.2 1 ± 4.27 % versus 41.01 ± 1.29 % ; 39.47 ± 4.02 % versus 48.75 ± 2 .13 % ; 41.02 ± 0.9 % versus 50.52 ± 1.49 % , p < 0.05 , respectively ) , ratio of wall/lumen thickness , as well as the wall/lumen area were significantly reduced in PAH rats at these time points following ADSCs-treatment , as compared with untreated PAH rats . In summary , ADSCs may colonize the pulmonary arteries , attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling The aim of the present study was to investigate the effect of bone marrow mesenchymal stem cell ( BMSC ) transp1antation on lung and heart damage in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension ( PAH ) . The animals were r and omly divided into 3 groups : control , PAH and BMSC implantation groups . Structural changes in the pulmonary vascular wall , such as the pulmonary artery lumen area ( VA ) and vascular area ( TAA ) were measured by hematoxylin and eosin ( H&E ) staining , and the hemodynamics were detected by echocardiography . Two weeks post-operation , our results demonstrated that sublingual vein injection of BMSCs significantly attenuated the pulmonary vascular structural and hemodynamic changes caused by pulmonary arterial hypertension . The mechanism may be executed via paracrine effects OBJECTIVE To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival . DESIGN Registry with prospect i ve follow-up . SETTING Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart , Lung , and Blood Institute . PATIENTS Patients ( 194 ) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988 . MEASUREMENTS At diagnosis , measurements of hemodynamic variables , pulmonary function , and gas exchange variables were taken in addition to information on demographic variables , medical history , and life-style . Patients were followed for survival at 6-month intervals . MAIN RESULTS The estimated median survival of these patients was 2.8 years ( 95 % Cl , 1.9 to 3.7 years ) . Estimated single-year survival rates were as follows : at 1 year , 68 % ( Cl , 61 % to 75 % ) ; at 3 years , 48 % ( Cl , 41 % to 55 % ) ; and at 5 years , 34 % ( Cl , 24 % to 44 % ) . Variables associated with poor survival included a New York Heart Association ( NYHA ) functional class of III or IV , presence of Raynaud phenomenon , elevated mean right atrial pressure , elevated mean pulmonary artery pressure , decreased cardiac index , and decreased diffusing capacity for carbon monoxide ( DLCO ) . Drug therapy at entry or discharge was not associated with survival duration . CONCLUSIONS Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables : mean pulmonary artery pressure , mean right atrial pressure , and cardiac index . Such an equation , once vali date d prospect ively , could be used as an adjunct in planning treatment strategies and allocating medical re sources BACKGROUND Sildenafil inhibits phosphodiesterase type 5 , an enzyme that metabolizes cyclic guanosine monophosphate , thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells , including those in the lung . METHODS In this double-blind , placebo-controlled study , we r and omly assigned 278 patients with symptomatic pulmonary arterial hypertension ( either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts ) to placebo or sildenafil ( 20 , 40 , or 80 mg ) orally three times daily for 12 weeks . The primary end point was the change from baseline to week 12 in the distance walked in six minutes . The change in mean pulmonary-artery pressure and World Health Organization ( WHO ) functional class and the incidence of clinical worsening were also assessed , but the study was not powered to assess mortality . Patients completing the 12-week r and omized study could enter a long-term extension study . RESULTS The distance walked in six minutes increased from baseline in all sildenafil groups ; the mean placebo-corrected treatment effects were 45 m ( + 13.0 percent ) , 46 m ( + 13.3 percent ) , and 50 m ( + 14.7 percent ) for 20 , 40 , and 80 mg of sildenafil , respectively ( P<0.001 for all comparisons ) . All sildenafil doses reduced the mean pulmonary-artery pressure ( P=0.04 , P=0.01 , and P<0.001 , respectively ) , improved the WHO functional class ( P=0.003 , P<0.001 , and P<0.001 , respectively ) , and were associated with side effects such as flushing , dyspepsia , and diarrhea . The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo . Among the 222 patients completing one year of treatment with sildenafil monotherapy , the improvement from baseline at one year in the distance walked in six minutes was 51 m. CONCLUSIONS Sildenafil improves exercise capacity , WHO functional class , and hemodynamics in patients with symptomatic pulmonary arterial hypertension BACKGROUND Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point . We assessed the efficacy of macitentan , a new dual endothelin-receptor antagonist , using a primary end point of morbidity and mortality in a long-term trial . METHODS We r and omly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily , macitentan at a once-daily dose of 3 mg , or macitentan at a once-daily dose of 10 mg . Stable use of oral or inhaled therapy for pulmonary arterial hypertension , other than endothelin-receptor antagonists , was allowed at study entry . The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death , atrial septostomy , lung transplantation , initiation of treatment with intravenous or subcutaneous prostanoids , or worsening of pulmonary arterial hypertension . RESULTS A total of 250 patients were r and omly assigned to placebo , 250 to the 3-mg macitentan dose , and 242 to the 10-mg macitentan dose . The primary end point occurred in 46.4 % , 38.0 % , and 31.4 % of the patients in these groups , respectively . The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 ( 97.5 % confidence interval [ CI ] , 0.52 to 0.96 ; P=0.01 ) , and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 ( 97.5 % CI , 0.39 to 0.76 ; P<0.001 ) . Worsening of pulmonary arterial hypertension was the most frequent primary end-point event . The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline . Adverse events more frequently associated with macitentan than with placebo were headache , nasopharyngitis , and anemia . CONCLUSIONS Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study . ( Funded by Actelion Pharmaceuticals ; SERAPHIN Clinical Trials.gov number , NCT00660179 . ) Our previous studies have shown that bone marrow mesenchymal stem cells ( BMSCs ) can inhibit the progression of pulmonary artery hypertension ( PAH ) in the monocrotaline ( MCT ) model in the short term . The aim of this study was to further investigate the long-term effect of BMSCs on PAH and to explore the mechanism of the protective effect including the pulmonary vascular remodeling and cell differentiation . PAH model was established by subcutaneous injection of 50 mg/kg MCT as previously study . Postoperatively , the animals were r and omly divided into three groups ( n = 10 in each group ) : control , PAH group , and BMSCs implantation group . Six months after injection , immunology and immunohistochemistry analysis indicated the MCT-induced intima-media thickness in muscular arteries was reduced ( P < 0.05 ) ; the area of collagen fibers in lung tissue was lower ( P < 0.05 ) , and the proliferating cell nuclear antigen level in pulmonary artery smooth muscle cells was decreased ( P < 0.05 ) . Immunofluorescence showed that the cells have the ability to differentiate between von Willebr and factor and vascular endothelial growth factor . Six months after intravenous injection , BMSCs could significantly improve pulmonary function by inhibiting the ventricular remodeling and the effect of cell differentiation Experimental data suggest that transplantation of EPCs attenuates monocrotaline-induced pulmonary hypertension in rats and dogs . In addition , our previous studies suggested that autologous EPC transplantation was feasible , safe , and might have beneficial effects on exercise capacity and pulmonary hemodynamics in adults with IPAH . Thus , we hypothesized that transplantation of EPCs would improve exercise capacity and pulmonary hemodynamics in children with IPAH . Thirteen children with IPAH received intravenous infusion of autologous EPCs . The right-sided heart catheterization and 6-MWD test were performed at baseline and at the time of 12 wk after cell infusion . At the time of 12 wk , mPAP decreased by 6.4 mmHg from 70.3 + /- 19.0 to 63.9 + /- 19.3 mmHg ( p = 0.015 ) . PVR decreased by approximately 19 % from 1118 + /- 537 to 906 + /- 377 dyn s/cm(5 ) ( p = 0.047 ) . CO increased from 3.39 + /- 0.79 to 3.85 + /- 0.42 L/min ( p = 0.048 ) . The 6-MWD increased by 39 m from 359 + /- 82 to 399 + /- 74 m ( p = 0.012 ) . NYHA functional class also improved . There were no severe adverse events with cell infusion . The small pilot study suggested that intravenous infusion of autologous EPCs was feasible , safe , and associated with significant improvements in exercise capacity , NYHA functional class , and pulmonary hemodynamics in children with IPAH . Confirmation of these results in a r and omized controlled trial are essential BACKGROUND Uncontrolled studies suggested that aerosolized iloprost , a stable analogue of prostacyclin , causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension . METHODS We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost ( six or nine times per day ; median inhaled dose , 30 microg per day ) with inhalation of placebo . A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension ( New York Heart Association [ NYHA ] functional class III or IV ) were included . The primary end point was met if , after week 12 , the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent , respectively , in the absence of clinical deterioration according to predefined criteria and death . RESULTS The combined clinical end point was met by 16.8 percent of the patients receiving iloprost , as compared with 4.9 percent of the patients receiving placebo ( P=0.007 ) . There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole ( P=0.004 ) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension . Overall , 4.0 percent of patients in the iloprost group ( including one who died ) and 13.7 percent of those in the placebo group ( including four who died ) did not complete the study ( P=0.024 ) ; the most common reason for withdrawal was clinical deterioration . As compared with base-line values , hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation ( P<0.001 ) , were largely unchanged when measured before iloprost inhalation , and were significantly worse in the placebo group . Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class ( P=0.03 ) , dyspnea ( P=0.015 ) , and quality of life ( P=0.026 ) . Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group , although this adverse effect was not associated with clinical deterioration . CONCLUSIONS Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension BACKGROUND High pulmonary vascular resistance ( PVR ) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients . Furthermore , PVR may increase long after the Fontan operation . Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined . METHODS AND RESULTS This was a prospect i ve , multicenter study . Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units · ㎡ ( WU ) were enrolled . Cardiac catheterization was performed before and after administration of sildenafil in all patients . After the Fontan operation , a six minute walk test ( 6MWT ) was also performed . A total of 42 patients were enrolled . PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration : from 4.3±1.5WU to 2.1±0.6WU ( p<0.01 ) in patients before a Glenn shunt , from 3.2±0.5WU to 1.6±0.6WU ( p<0.001 ) in patients after a Glenn shunt , and from 3.9±1.7WU to 2.3±0.8WU ( p<0.001 ) in patients after Fontan . In patients after Fontan , the 6MWT increased from 416±74 m to 485±72 m ( p<0.01 ) , and NYHA functional class improved significantly ( p<0.05 ) after sildenafil administration . No major side effects were observed in any patients . CONCLUSIONS Sildenafil reduced PVR in patients with single ventricle physiology . Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation . This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology . Long-term clinical significance warrants further study OBJECTIVES The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan , an oral endothelin type A receptor-selective antagonist , in patients with pulmonary arterial hypertension ( PAH ) . BACKGROUND Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options . Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH . METHODS In this double-blind , dose-ranging study , 64 patients with idiopathic PAH or PAH associated with collagen vascular disease , anorexigen use , or human immunodeficiency virus infection were r and omized to receive 1 , 2.5 , 5 , or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan . The primary end point was an improvement from baseline in 6-min walk distance ( 6MWD ) ; secondary end points included Borg dyspnea index , World Health Organization ( WHO ) functional class , a subject global assessment , and cardiopulmonary hemodynamics . RESULTS At 12 weeks , ambrisentan increased 6MWD ( + 36.1 m , p < 0.0001 ) with similar and statistically significant increases for each dose group ( range , + 33.9 to + 38.1 m ) . Improvements were also observed in Borg dyspnea index , WHO functional class , subject global assessment , mean pulmonary arterial pressure ( -5.2 mm Hg , p < 0.0001 ) , and cardiac index ( + 0.33 l/min/m2 , p < 0.0008 ) . Adverse events were mild and unrelated to dose , including the incidence of elevated serum aminotransferase concentrations > 3 times the upper limit of normal ( 3.1 % ) . CONCLUSIONS Ambrisentan appears to improve exercise capacity , symptoms , and hemodynamics in patients with PAH . The incidence and severity of liver enzyme abnormalities appear to be low UNLABELLED Pulmonary arterial hypertension ( PAH ) is characterized by functional and structural changes in the pulmonary vasculature , and despite the drug treatment that made significant progress , the prognosis of patients with advanced PH remains extremely poor . In the present study , we investigated the early effect of bone marrow mesenchymal stem cells ( BMSCs ) on experimental high blood flow-induced PAH model rats and discussed the mechanism . BMSCs were isolated , cultured from bone marrow of Sprague-Dawley ( SD ) rat . The animal model of PAH was created by surgical methods to produce a left-to-right shunt . Following the successful establishment of the PAH model , rats were r and omly assigned to three groups ( n=20 in each group ) : sham group ( control ) , PAH group , and BMSC group ( received a sublingual vein injection of 1 - 5 × 10(6 ) BMSCs ) . Two weeks after the administration , BMSCs significantly reduced the vascular remodeling , improved the hemodynamic data , and deceased the right ventricle weight ratio to left ventricular plus septal weight ( RV/LV+S ) ( P<0.05 ) . Real-time reverse transcription-polymerase chain reaction ( RT-PCR ) and immunohistochemistry analysis results indicated that the inflammation factors such as interleukin-1β ( IL-1β ) , IL-6 , and tumor necrosis factor-α ( TNF-α ) were reduced ( P<0.05 ) ; the expression of matrix metallo proteinase-9 ( MMP-9 ) was lower ( P<0.05 ) ; vascular endothelial growth factor ( VEGF ) was higher in BMSC group than those in PAH group ( P<0.05 ) . CONCLUSION Sublingual vein injection of BMSCs for 2 weeks , significantly improved the lung and heart injury caused by left-to-right shunt-induced PAH ; decreased pulmonary vascular remodeling and inflammation ; and enhanced angiogenesis Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective . However , this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis , thromboembolism , or syncope . Treprostinil , a stable prostacyclin analogue , can be administered by a continuous subcutaneous infusion , avoiding these risks . We conducted a 12-week , double-blind , placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension , either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts . Exercise capacity improved with treprostinil and was unchanged with placebo ; the between treatment group difference in median six-minute walking distance was 16 m ( p = 0.006 ) . Improvement in exercise capacity was greater in the sicker patients and was dose-related , but independent of disease etiology . Concomitantly , treprostinil significantly improved indices of dyspnea , signs and symptoms of pulmonary hypertension , and hemodynamics . The most common side effect attributed to treprostinil was infusion site pain ( 85 % ) leading to premature discontinuation from the study in 8 % of patients . Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage . We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension BACKGROUND Endothelin 1 , a powerful endogenous vasoconstrictor and mitogen , might be a cause of pulmonary hypertension . We describe the efficacy and safety of bosentan , a dual endothelin-receptor antagonist that can be taken orally , in patients with severe pulmonary hypertension . METHODS In this double-blind , placebo-controlled study , 32 patients with pulmonary hypertension ( primary or associated with scleroderma ) were r and omly assigned to bosentan ( 62.5 mg taken twice daily for 4 weeks then 125 mg twice daily ) or placebo for a minimum of 12 weeks . The primary endpoint was change in exercise capacity . Secondary endpoints included changes in cardiopulmonary haemodynamics , Borg dyspnoea index , WHO functional class , and withdrawal due to clinical worsening . Analysis was by intention to treat . FINDINGS In patients given bosentan , the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline , whereas it worsened by 6 m in those on placebo ( difference 76 m [ 95 % CI 12 - 139 ] , p=0.021 ) . The improvement was maintained for at least 20 weeks . The cardiac index was 1.0 L min(-1 ) m(-2 ) ( 95 % CI 0.6 - 1.4 , p<0.0001 ) greater in patients given bosentan than in those given placebo . Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5 ) with bosentan , but increased by 191 dyn s cm(-5 ) with placebo ( difference -415 [ -608 to -221 ] , p=0.0002 ) . Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class . All three withdrawals from clinical worsening were in the placebo group ( p=0.033 ) . The number and nature of adverse events did not differ between the two groups . INTERPRETATION Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension , suggesting that endothelin has an important role in pulmonary hypertension Background Systematic Review s ( SRs ) of experimental animal studies are not yet common practice , but awareness of the merits of conducting such SRs is steadily increasing . As animal intervention studies differ from r and omized clinical trials ( RCT ) in many aspects , the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies . The Cochrane Collaboration developed a Risk of Bias ( RoB ) tool to establish consistency and avoid discrepancies in assessing the method ological quality of RCTs . A similar initiative is warranted in the field of animal experimentation . Methods We provide an RoB tool for animal intervention studies ( SYRCLE ’s RoB tool ) . This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies . To enhance transparency and applicability , we formulated signalling questions to facilitate judgment . Results The result ing RoB tool for animal studies contains 10 entries . These entries are related to selection bias , performance bias , detection bias , attrition bias , reporting bias and other biases . Half these items are in agreement with the items in the Cochrane RoB tool . Most of the variations between the two tools are due to differences in design between RCTs and animal studies . Shortcomings in , or unfamiliarity with , specific aspects of experimental design of animal studies compared to clinical studies also play a role . Conclusions SYRCLE ’s RoB tool is an adapted version of the Cochrane RoB tool . Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies . This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the method ological quality of animal studies

There was a trend for endothelin receptor antagonists to reduce mortality ( OR 0.48 ; 95 % CI 0.21 to 1.09 ) , and limited data suggest that endothelin receptor antagonists improve Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients . Hepatic toxicity was not common , and endothelin receptor antagonists were well tolerated in this population . Endothelin receptor antagonists can increase exercise capacity , improve WHO/NYHA functional class , prevent WHO/NYHA functional class deterioration , reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III . However , there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension . Efficacy data are strongest in those with idiopathic pulmonary hypertension

BACKGROUND Pulmonary arterial hypertension is a devastating disease , which leads to right heart failure and premature death . Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension . OBJECTIVES To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension .

BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospect i ve , r and omized trial to improve survival . METHODS We conducted a 12-week prospect i ve , r and omized , multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol ( formerly called prostacyclin ) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension ( New York Heart Association functional class III or IV ) . RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol ( median distance walked in six minutes , 362 m at 12 weeks vs. 315 m at base line ) , but it decreased in the 40 patients treated with conventional therapy alone ( 204 m at 12 weeks vs. 270 m at base line ; P < 0.002 for the comparison of the treatment groups ) . Indexes of the quality of life were improved only in the epoprostenol group ( P < 0.01 ) . Hemodynamics improved at 12 weeks in the epoprostenol-treated patients . The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and + 3 percent , respectively ( difference in mean change , -6.7 mm Hg ; 95 percent confidence interval , -10.7 to -2.6 mm Hg ; P < 0.002 ) , and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and + 9 percent , respectively ( difference in mean change , -4.9 mm Hg/liter/min ; 95 percent confidence interval , -7.6 to -2.3 mm Hg/liter/min ; P < 0.001 ) . Eight patients died during the study , all of whom had been r and omly assigned to conventional therapy ( P = 0.003 ) . Serious complications included four episodes of catheter-related sepsis and one thrombotic event . CONCLUSIONS As compared with conventional therapy , the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement , as well as improved survival in patients with severe primary pulmonary hypertension BACKGROUND Patients with precapillary pulmonary hypertension ( PH ) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries . By causing the pulmonary artery to dilate , inhaled nitric oxide ( NO ) may allow an increase in exercise capacity in patients with PH . METHODS AND RESULTS On 2 separate days , 3 days apart , 14 patients with precapillary PH ( 10 primary PH , 4 residual PH after correction of an intracardiac shunt ; age , 40+/-12 years ; mean pulmonary artery pressure , 60+/-23 mm Hg ) performed exercise , with and without inhalation of 20 ppm NO , on a cycle ergometer . The work rate was increased 15 W/min until their symptom-limited maximum , with breath-by-breath gas analysis . Patients were r and omly and blindly selected to inhale NO on either their first or second test . Peak exercise load and anaerobic threshold tended to increase , but not significantly . Peak oxygen consumption ( f1.gif " BORDER="0" > O(2 ) ) and Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio increased significantly , by 18 % and 22 % , respectively ( peak f1.gif " BORDER="0" > O(2 ) , 13.6+/-3.6 to 16.0+/-4 . 1 mL. kg(-1 ) . min(-1 ) ; Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio , 5 . 8+/-2.4 to 7.1+/-2.3 mL. kg(-1 ) . min(-1 ) . W(-1 ) ; both P<0.01 ) . Peak f1.gif " BORDER="0" > O(2 ) increased > 10 % in 12 of the 14 patients . However , respiratory quotient at peak exercise decreased from 1 . 22+/-0.15 to 1.09+/-0.15 ( P<0.01 ) . CONCLUSIONS Inhaled NO substantially increases oxygen consumption at the same workload during exercise . This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH After the approval of bosentan for the treatment of pulmonary arterial hypertension ( PAH ) , European authorities required the introduction of a post-marketing surveillance system ( PMS ) to obtain further data on its safety profile . A novel , prospect i ve , internet-based PMS was design ed , which solicited reports on elevated aminotransferases , medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation . Data captured included demographics , PAH aetiology , baseline functional status and concomitant PAH-specific medications . Safety signals captured included death , hospitalisation , serious adverse events , unexpected adverse events and elevated aminotransferases . Within 30 months , 4,994 patients were included , representing 79 % of patients receiving bosentan in Europe . In total , 4,623 patients were naïve to treatment ; of these , 352 had elevated aminotransferases , corresponding to a crude incidence of 7.6 % and an annual rate of 10.1 % . Bosentan was discontinued due to elevated aminotransferases in 150 ( 3.2 % ) bosentan-naïve patients . Safety results were consistent across subgroups and aetiologies . The novel post-marketing surveillance captured targeted safety data ( “ potential safety signals ” ) from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials . These data complement those from r and omised controlled clinical trials and provide important additional information on the safety profile of bosentan Background : Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases ( CTDs ) such as systemic sclerosis ( SSc ) , leading to vasoconstriction , fibrosis , hypertrophy and inflammation . A frequent complication of CTD is pulmonary arterial hypertension ( PAH ) , which has a major effect on functioning and quality of life , and is associated with a particularly poor prognosis . Objective : To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist bosentan in patients with PAH and CTD , mostly SSc and lupus erythematosus . Methods : 66 patients with PAH secondary to CTD , in World Health Organization functional class III or IV , were r and omised to two double-blind , placebo-controlled studies and followed up for 12 and 16 weeks , respectively . The primary end point was change in exercise capacity , assessed using the 6-min walk test . In both studies and their extensions , survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan – Meier estimates . Results : 44 patients with PAH secondary to CTD who were treated with bosentan were stable in 6-min walk distance at the end of the study ( + 19.5 m , 95 % confidence interval ( CI ) −3.2 to 42.2 ) , whereas patients treated with placebo deteriorated ( −2.6 m , 95 % CI −54.0 to 48.7 ) . 64 patients subsequently received bosentan in an open-label long-term extension study . Mean ( st and ard deviation ( SD ) ) exposure to bosentan was 1.6 ( 0.9 ) years , and duration of observation was 1.8 ( 0.8 ) years . 8 ( 16 % ) patients received epoprostenol as add-on treatment and 7 ( 14 % ) after discontinuation of bosentan . Survival in those receiving bosentan was 85.9 % after 1 year and 73.4 % after 2 years . Conclusion : Short-term bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo . The long-term follow-up of these patients suggests that first-line bosentan , with the subsequent addition of other PAH treatments if required , is safe for long-term treatment and may have a positive effect on outcome Pulmonary hypertension is characterized by progressive elevation of pulmonary artery pressure and vascular resistance , often leading to right ventricular failure and death ( 1 - 3 ) . Continuous intravenous infusion of epoprostenol improves prognosis and symptoms in patients with primary ( idiopathic ) pulmonary hypertension ( 4 - 8 ) . R and omized , controlled clinical trials of epoprostenol for secondary pulmonary hypertension have not been conducted . Pulmonary hypertension frequently complicates the scleroderma spectrum of disease , which includes diffuse scleroderma , limited scleroderma ( the CREST syndrome [ calcinosis cutis , the Raynaud phenomenon , esophageal dysfunction , sclerodactyly , and telangectasia ] ) , and the overlap syndrome . These multisystem diseases are characterized by connective tissue and vascular abnormalities ; vascular lesions are prominent in all affected tissues ( 9 ) . Pulmonary hypertension occurs in up to 33 % of patients with diffuse scleroderma and 10 % to 50 % of those with the CREST syndrome ( 10 , 11 ) , in which it is one of the leading causes of death ( 12 , 13 ) . Pulmonary hypertension in the scleroderma spectrum of disease may be associated with interstitial pulmonary fibrosis or may consist of a direct involvement of small and medium-sized pulmonary arteries and arterioles with smooth-muscle hyperplasia , medial hypertrophy , and intimal proliferation ( 10 , 13 , 14 ) . Principal involvement of the pulmonary vasculature is more common in the CREST syndrome , whereas patients with pulmonary hypertension and diffuse scleroderma more often have interstitial lung disease ( 13 ) . No therapies have been proven effective for pulmonary hypertension secondary to the scleroderma spectrum of disease . Small numbers of patients have responded to captopril ( 15 ) , nifedipine ( 16 - 20 ) , and prazosin . In a short-term study of intravenous epoprostenol in seven patients with scleroderma ( two with diffuse scleroderma and five with limited scleroderma ) , six had a decrease in mean pulmonary artery pressure and pulmonary vascular resistance ( 21 ) . In a small study of pulmonary hypertension secondary to connective tissue disease , long-term infusion therapy with a prostacyclin analogue , iloprost , result ed in improvement in New York Heart Association ( NYHA ) functional class and quality of life but a variable hemodynamic response ( 22 ) . Results from a single-center , uncontrolled study suggest that long-term , continuously infused epoprostenol therapy can produce hemodynamic and symptomatic responses in patients with connective tissue disease who have severe pulmonary hypertension that is refractory to conventional medical therapy ( 23 ) . The rationale for using continuous epoprostenol infusion to treat pulmonary hypertension secondary to the scleroderma spectrum of disease was based on the efficacy of this therapy for primary pulmonary hypertension ( 4 - 8 ) and recognition that scleroderma is a disease characterized by vasospasm and structural changes in the walls of blood vessels . Prostacyclin is a naturally occurring substance produced by vascular endothelium that has vasodilating , antiplatelet aggregation , and cytoprotective effects ( 24 - 33 ) . Endogenous production of prostacyclin is decreased in an animal model of neonatal pulmonary hypertension ( 34 ) and in adult humans with pulmonary hypertension ( 35 ) . Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in patients with primary pulmonary hypertension ( 36 ) . Endothelial dysfunction also plays an important role in the vascular manifestations of the scleroderma spectrum of disease ( 37 , 38 ) , including the Raynaud phenomenon and digital ischemia , which cause considerable morbidity . Calcium-channel blockers ( 39 - 45 ) , enalapril ( 46 ) , and intermittent intravenous infusions of prostacyclin ( 47 - 49 ) and iloprost ( 50 - 54 ) improve the Raynaud phenomenon in some patients . Mixed results have been obtained with oral prostacyclin analogues ( 55 , 56 ) , and a recent multicenter trial of oral iloprost showed no benefit ( 57 ) . The effect of long-term , continuously infused epoprostenol on the severity of the Raynaud phenomenon and on digital ulcer counts has not been previously evaluated . Our 12-week multicenter , open-label , r and omized study was design ed to determine whether the beneficial effect of epoprostenol seen in patients with primary pulmonary hypertension could be extended to patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . Our objective was to evaluate the effects of continuous infusion of epoprostenol on exercise capacity in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . A secondary objective was assessment of the effects of long-term continuous epoprostenol infusion on cardiopulmonary hemodynamics , Borg Dyspnea Score , Dyspnea-Fatigue Rating , NYHA functional class , survival , and safety . Vasospastic manifestations , such as the Raynaud phenomenon and digital ulcerations , were also followed . Methods Patient Selection Eligible patients had pulmonary hypertension secondary to the scleroderma spectrum of disease in accordance with the inclusion and exclusion criteria summarized in Table 1 . For the purpose s of this study , the scleroderma spectrum of disease was defined as systemic sclerosis with diffuse or limited scleroderma ( 58 ) ; systemic sclerosis that overlapped with another connective tissue disease ; or the presence of definite features of systemic sclerosis , including the Raynaud phenomenon and positive test result for antinuclear antibody , plus positive test results for anticentromere antibody , anti-Scl 70 antibody , or nailfold capillary abnormalities . Systemic sclerosis with limited cutaneous involvement ( the CREST syndrome ) was defined as the presence of any three of the following conditions : subcutaneous calcinosis , the Raynaud phenomenon , esophageal dysfunction ( defined clinical ly ) , sclerodactyly , or telangectasia . Patients with interstitial lung disease of a more than mild degree were not included in the study because such patients were thought to be less likely to show benefit . Table 1 . Key Inclusion and Exclusion Criteria On the basis of a previous 12-week study of the effects of epoprostenol infusion in patients with severe primary pulmonary hypertension ( 6 ) and using the 6-minute walk test as the primary outcome measure , we calculated that 50 patients per treatment group would provide 80 % power to detect a difference of 50 meters in the average change from baseline , at an level of 0.05 ( two-tailed t-test ) . R and omization and Treatment The protocol was approved by the institutional review boards of the 17 participating centers . After giving informed consent , 111 eligible patients were r and omly assigned ( 1:1 ) to receive continuous epoprostenol infusion ( Flolan , Glaxo Wellcome , Inc. , Research Triangle Park , North Carolina ) plus conventional therapy or to receive conventional therapy alone . Investigators contacted a central r and omization center to obtain treatment assignment , which was based on a stratified r and omized block design . Assignments were stratified on the basis of vasodilator use at baseline ( yes or no ) and exercise capacity at baseline ( 50 to<200 m or 200 m ) and were r and omized within blocks . Fifty-six patients were assigned to receive epoprostenol plus conventional therapy , and 55 patients were assigned to receive conventional therapy alone . Investigators were not blinded to treatment group assignment ; however , independent blinded observers assessed the primary efficacy measure , exercise capacity . Patients taking calcium-channel blockers at study entry continued to take them during the study period . Adjustments in concomitant medications were allowed during the study on the basis of clinical judgment . Patients in both groups were to receive oral anticoagulants during the study ; 94 of the 111 enrolled patients took warfarin . Venous access for epoprostenol infusion ( in the epoprostenol group only ) was obtained by insertion of a permanent indwelling central venous catheter . Epoprostenol was infused continuously by a portable infusion pump ( CADD-1 Model 5100 HF , SIMS Deltec , St. Paul , Minnesota ) . Patients were instructed in sterile technique , catheter care , and drug preparation and administration . Epoprostenol therapy was initiated at a low dose ( usually 2 ng/kg of body weight per minute ) . During the 12-week study , doses were adjusted on the basis of signs or symptoms consistent with persistent pulmonary hypertension in the absence of intolerable adverse effects ( Figure 1 ) . Figure 1 . Epoprostenol dosing . Outcome Measures The primary measure of efficacy was exercise capacity , as defined by the distance a patient could walk in 6 minutes . Trained observers at each site who were not otherwise involved in patient care administered the 6-minute walk test . All patients wore an ambulatory infusion pump and a hospital gown over their clothes to mask the presence or absence of a long-term indwelling catheter , thereby blinding testers to the patients ' treatment groups . Each patient performed one practice walk test . A st and ardized , unencouraged 6-minute walk test was performed as described elsewhere ( 59 ) at baseline and at 1 , 6 , and 12 weeks . The 6-minute walk test has been shown to provide meaningful outcome data in assessing potential therapy for patients with pulmonary hypertension ( 6 ) . Secondary measures of efficacy were cardiopulmonary hemodynamics measured by performing right-heart catheterization using st and ard techniques at baseline and week 12 ; the Borg Dyspnea Score ( 60 ) , obtained immediately after completion of the 6-minute walk test at baseline and 1 , 6 , and 12 weeks ( 6 , 59 ) ; the Dyspnea-Fatigue Rating , obtained before the 6-minute walk test at baseline and weeks 1 , 6 , and 12 ( 61 ) ; NYHA functional class ( 62 ) , measured at baseline and weeks 1 , 6 , and 12 ; digital ulcer counts , done at baseline and weeks 6 and 12 ; and the severity of the Raynaud phenomenon ,

This present meta- analysis suggests that statin pretreatment might be effective in improving myocardial perfusion in STEMI patients

BACKGROUND To achieve sufficient myocardial perfusion in ST-segment elevation myocardial infa rct ion ( STEMI ) patients receiving primary percutaneous coronary intervention ( PPCI ) , many adjunctive therapies have been proposed . Previous trials have reported variances in myocardial perfusion improvement for statin pretreatment , which made it inconvincible to confirm the beneficial effects of statins . Therefore , we performed a systematic review and meta- analysis to determine whether statin pretreatment was effective in improving myocardial perfusion . HYPOTHESIS Statin pretreatment could improve myocardial perfusion in STEMI patients undergoing PPCI .

BACKGROUND Although improved epicardial blood flow ( as assessed with either TIMI flow grade s or TIMI frame count ) has been related to reduced mortality after administration of thrombolytic drugs , the relationship of myocardial perfusion ( as assessed on the coronary arteriogram ) to mortality has not been examined . METHODS AND RESULTS A new , simple angiographic method , the TIMI myocardial perfusion ( TMP ) grade , was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI ( Thrombolysis In Myocardial Infa rct ion ) 10B trial , and its relationship to mortality was examined . TMP grade 0 was defined as no apparent tissue-level perfusion ( no ground-glass appearance of blush or opacification of the myocardium ) in the distribution of the culprit artery ; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature ( blush or a stain was present on the next injection ) ; TMP grade 2 blush clears slowly ( blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase ) ; and TMP grade 3 indicates that blush begins to clear during washout ( blush is minimally persistent after 3 cardiac cycles of washout ) . There was a mortality gradient across the TMP grade s , with mortality lowest in those patients with TMP grade 3 ( 2.0 % ) , intermediate in TMP grade 2 ( 4.4 % ) , and highest in TMP grade s 0 and 1 ( 6.0 % ; 3-way P=0.05 ) . Even among patients with TIMI grade 3 flow in the epicardial artery , the TMP grade s allowed further risk stratification of 30-day mortality : 0.73 % for TMP grade 3 ; 2.9 % for TMP grade 2 ; 5.0 % for TMP grade 0 or 1 ( P=0.03 for TMP grade 3 versus grade s 0 , 1 , and 2 ; 3-way P=0.066 ) . TMP grade 3 flow was a multivariate correlate of 30-day mortality ( OR 0.35 , 95 % CI 0.12 to 1.02 , P=0.054 ) in a multivariate model that adjusted for the presence of TIMI 3 flow ( P = NS ) , the corrected TIMI frame count ( OR 1.02 , P=0.06 ) , the presence of an anterior myocardial infa rct ion ( OR 2.3 , P=0.03 ) , pulse rate on admission ( P = NS ) , female sex ( P = NS ) , and age ( OR 1.1 , P<0.001 ) . CONCLUSIONS Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery . Patients with both normal epicardial flow ( TIMI grade 3 flow ) and normal tissue level perfusion ( TMP grade 3 ) have an extremely low risk of mortality Background —We hypothesized that preserved microvascular integrity in the area at risk would favorably influence left ventricular ( LV ) remodeling and long-term outcome after acute myocardial infa rct ion . Methods and Results —Before and after successful primary angioplasty ( percutaneous transluminal coronary angioplasty [ PTCA ] ) , 124 patients with acute myocardial infa rct ion underwent intracoronary myocardial contrast echo ( MCE ) . An MCE score index ( MCESI ) was derived by averaging the single-segment score ( 0=not visible , 1=patchy , 2=homogeneous contrast effect ) within the area at risk . An MCESI ≥1 was considered adequate reperfusion . Mean follow-up was 46±32 months . After PTCA , 100 patients showed adequate reperfusion ( no microvascular dysfunction , NoMD ) , whereas 24 did not ( MD ) . MD patients had a higher mean creatine kinase ( 4153±2422 versus 2743±1774 U/L ; P = 0.002 ) and baseline wall-motion score index ( 2.61±0.31 versus 2.25±0.42 ; P < 0.001 ) and a lower baseline ejection fraction ( 33±8 % versus 40±7 % ; P < 0.001 ) . From day 1 on , LV volumes progressively increased in the MD patients ( n=19 ) and were larger than those of NoMD patients ( n=85 ) at 6 months ( end-diastolic volume 170±55 versus 115±29 mL ; P < 0.001 ) . MCESI was the most important independent predictor of LV dilation ( OR 0.61 , 95 % CI 0.52 to 0.71 , P < 0.000001 ) . By Cox analysis , MD represented the only predictor of cardiac death ( OR 0.26 , 95 % CI 0.09 to 0.72 , P = 0.010 ) and combined events ( cardiac death , reinfa rct ion , and heart failure ; OR 0.44 , 95 % CI 0.23 to 0.85 , P = 0.014 ) . MD patients showed worse survival in terms of cardiac death ( P < 0.0001 ) and combined events ( P < 0.0001 ) . Conclusions —In reperfused acute myocardial infa rct ion , MD within the risk area is an important predictor of both LV remodeling and unfavorable long-term outcome Increased neutrophil counts have been associated with an increased risk of adverse clinical events after acute myocardial infa rct ion ( AMI ) . We examined the association of neutrophil counts on admission with degree of microvascular injury and left ventricular functional recovery after primary coronary angioplasty in AMI . We studied 116 patients with a first anterior wall AMI who underwent primary coronary angioplasty within 12 hours of onset . Patients were categorized into 3 groups based on initial neutrophil count : low ( < 5,000/mm(3 ) ) , intermediate ( 5,000 to 10,000/mm(3 ) ) , and high ( > 10,000/mm(3 ) ) . Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire . We defined severe microvascular injury as the presence of systolic flow reversal and a diastolic deceleration time < 600 ms . Echocardiographic wall motion was analyzed before revascularization and 4 weeks after revascularization . In patients with a high neutrophil count , systolic flow reversal was more frequently observed , diastolic deceleration time was shorter , and coronary flow reserve was lower . By regression analysis , neutrophil count significantly correlated with diastolic deceleration time ( r = -0.38 , p < 0.0001 ) , coronary flow reserve ( r = -0.33 , p = 0.0004 ) , and score for change in wall motion ( r = -0.36 , p = 0.0004 ) . Multivariate analysis showed that neutrophil count on admission was an independent predictor of severe microvascular injury ( odds ratio 2.94 , p = 0.02 ) . In conclusion , neutrophilia on admission is associated with impaired microvascular reperfusion and poor functional recovery after primary coronary angioplasty Objective : The aim of this pilot study was to determine whether early atorvastatin treatment will reduce left ventricle ( LV ) remodeling , infa rct size , and improve microvascular perfusion . Background : In animal studies , early statin therapy reduces reperfusion injury after a percutaneous coronary intervention ( PCI ) for acute myocardial infa rct ion ( AMI ) . Methods : Forty‐two consecutive patients ( 82 % male , mean age 61.2 ± 9.8 ) who underwent a primary PCI for a first ST‐elevated AMI were r and omized for pretreatment with atorvastatin 80 mg ( n = 20 ) or placebo ( n = 22 ) and continued with the same dosage daily for 1 week . All patients received atorvastatin 80 mg once daily 7 days after primary PCI . The LV function and infa rct size were measured by magnetic resonance imaging within 1 day , at 1 week , and 3 months follow up . The primary endpoint was the end‐systolic volume index ( ESVI ) at 3 months . Secondary endpoints were global LV function measurements , myocardial infa rct size , biochemical cardiac markers , TIMI flow , and ST‐T elevation resolution . Results : ESVI 3 months after AMI was 25.1 mL/m2 in the atorvastatin arm and 25.0 mL/m2 in the placebo arm ( P = 0.74 ) . The differences in change from baseline to 3 months follow up in global LV function and myocardial infa rct size did not differ between both treatment arms . Furthermore , biochemical markers , TIMI flow , and ST‐T elevation resolution did not differ between atorvastatin and placebo arm . Conclusions : In this pilot study , pretreatment with atorvastatin in an acute myocardial infa rct ion does not result in an improved cardiac function , microvascular perfusion , or decreased myocardial infa rct size . © 2012 Wiley Periodicals Primary and secondary prevention with statins reduce major cardiac events in patients with coronary artery disease . The impact of pretreatment with statins prior to percutaneous coronary intervention ( PCI ) is not well established . The objective of this study was to determine if pretreatment with statins prior to PCI reduce myonecrosis and improve clinical outcome . One hundred nineteen consecutive patients with acute coronary syndrome who underwent PCI were identified . We compared the incidence of myonecrosis defined as peak elevation of CK‐MB or CK three time above upper limit of normal within 24 hr and the 6‐month cardiovascular event rate ( death , nonfatal myocardial infa rct ion unrelated to PCI , target vessels revascularization , and unstable angina requiring hospitalization ) among patients who received statins prior to PCI ( n = 63 ) to those who did not ( n = 56 ) . Pretreated patients were more likely to have history of myocardial infa rct ion or revascularization ( 63 % vs. 43 % ; P = 0.015 ) , hyperlipidemia ( 80 % vs. 48 % ; P = 0.001 ) , hypertension ( 83 % vs. 49 % ; P = 0.02 ) , and use of angiotensin‐converting enzyme inhibitor ( 62 % vs. 38 % ; P = 0.008 ) . The rest of baseline characteristics were similar between the two groups , including use of glycoprotein IIb/IIIa inhibitors , number of diseased vessels , and type of lesions . Patients pretreated with statins had a significantly lower incidence of myonecrosis ( 2 % vs. 10 % ; P = 0.04 ) at 24 hr and a significantly lower clinical event ( CE ) rate at 6 months ( 17 % vs. 21 % ; P = 0.015 ) . Of patients not pretreated with statins , 72 % were taking statins at 6 months as compared to 98 % of pretreated patients . After adjusting for all baseline characteristics , use of statins prior to PCI was associated with a marked decrease in risk of all CEs ( OR = 0.2 ; CI = 0.06–0.63 ; P = 0.006 ) . Statin therapy prior to PCI may reduces peri‐PCI myonecrosis and late cardiac events . These results need to be confirmed in large prospect i ve r and omized trials . Catheter Cardiovasc Interv 2004;62:193–197 . © 2004 Wiley‐Liss , OBJECTIVES This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) undergoing primary percutaneous coronary intervention ( PCI ) . BACKGROUND Previous r and omized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events ( MACEs ) in patients with stable angina pectoris and acute coronary syndrome . However , no r and omized studies have been carried out with STEMI patients in a primary PCI setting . METHODS A total 171 patients with STEMI were r and omized to 80-mg atorvastatin ( n = 86 ) or 10-mg atorvastatin ( n = 85 ) arms for pre-treatment before PCI . All patients were prescribed clopidogrel ( 600 mg ) before PCI . After PCI , both groups were treated with atorvastatin ( 10 mg ) . The primary end point was 30-day incidence of MACE including death , nonfatal MI , and target vessel revascularization . Secondary end points included corrected thrombolysis in myocardial infa rct ion frame count , myocardial blush grade , and ST-segment resolution at 90 min after PCI . RESULTS MACE occurred in 5 ( 5.8 % ) and 9 ( 10.6 % ) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms , respectively ( p = 0.26 ) . Corrected thrombolysis in myocardial infa rct ion frame count was lower in the 80-mg atorvastatin arm ( 26.9 + /- 12.3 vs. 34.1 + /- 19.0 , p = 0.01 ) . Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm ( 2.2 + /- 0.8 vs. 1.9 + /- 0.8 , p = 0.02 and 61.8 + /- 26.2 vs. 50.6 + /- 25.8 % , p = 0.01 ) . CONCLUSIONS High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI . High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion . ( Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infa rct ion [ STATIN STEMI ] ; NCT00808717 ) Background Recent data have demonstrated a lower mortality in acute ST-elevation myocardial infa rct ion ( STEMI ) patients with previous treatment with statins , especially in patients with high risk profiles . Moreover , a significant reduction in enzymatic infa rct size in non-STEMI patients could be observed . However , systematic data of the impact of chronic statin pre-treatment on myocardial damage and reperfusion injury assessed with the gold st and ard cardiac magnetic resonance imaging ( CMR ) are lacking . The aim of our prospect i ve study was therefore to assess the effects of a chronic statin pre-treatment on myocardial damage as assessed by CMR in patients with acute reperfused STEMI . BACKGROUND Atorvastatin pretreatment has been reported to reduce myocardial damage in patients undergoing percutaneous coronary intervention ( PCI ) . We sought to investigate the effect of atorvastatin pretreatment on infa rct size in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) . METHODS Patients undergoing primary PCI for ST-segment elevation myocardial infa rct ion within 12 hours after symptom onset were r and omized to an atorvastatin group ( 80 mg before PCI and for 5 days after PCI [ n = 89 ] ) or a control group ( 10 mg daily after PCI [ n = 84 ] ) . The primary end point was infa rct size measured by technetium Tc 99 m tetrofosmin single-photon emission computed tomography between days 5 and 14 . RESULTS Baseline clinical , angiographic , and procedural characteristics were not significantly different between groups except for age and current smoking status . There was no significant difference in infa rct size ( as a percentage of the left ventricle ) between groups ( 22.2 % ± 15.5 % in the atorvastatin group vs 21.6 % ± 15.4 % in the control group , P = .79 ) . The median infa rct size was 19.0 % ( interquartile range 9.0 - 32.0 ) in the atorvastatin group and 18.0 % ( 9.3 - 32.5 ) in the control group ( P = .76 ) . Achievement of myocardial blush grade 2/3 and complete ST-segment resolution at 60 minutes after PCI occurred with similar frequency ( 72.8 % vs 81.9 % , P = .33 and 43.2 % vs 47.5 % , P = .57 , respectively ) . CONCLUSIONS Pretreatment with high-dose atorvastatin followed by further treatment for 5 days did not reduce infa rct size measured by single-photon emission computed tomography in patients undergoing primary PCI BACKGROUND Studies have reported an association between receipt of statin therapy and a reduction in complications after elective percutaneous coronary intervention ( PCI ) . However , there are limited data on the effects of chronic statin therapy before the occurrence of an acute myocardial infa rct ion ( AMI ) . OBJECTIVE This study investigated whether administration of chronic statin therapy before AMI was associated with a reduction in reperfusion injury in AMI patients undergoing PCI . METHODS This was a retrospective study of consecutive patients with a first AMI who underwent successful reperfusion therapy with PCI within 24 hours after the onset of AMI between April 1998 and October 2003 . Patients were stratified according to whether they had or had not been receiving chronic statin therapy for > or = 1 month before the onset of AMI . The following end points were compared after PCI : electrocardiographic resolution of ST segment elevation , defined as a reduction of > or = 50 % from the initial value ; achievement of Thrombolysis in Myocardial Infa rct ion ( TIMI ) grade 3 flow ; corrected TIMI frame count ( cTFC ) ; maximum serum creatine kinase ( CK ) level ; and the type and frequency of ventricular arrhythmias . RESULTS The study enrolled 386 patients , 40 of whom had been receiving statin therapy before the onset of AMI . The clinical characteristics of the 2 groups were similar at baseline , with the exceptions of a significantly higher rate of hyperlipidemia in the statin group compared with the nonstatin group ( P < 0.001 ) , significantly greater chronic use of aspirin therapy ( P < 0.001 ) , and significantly greater chronic use of antihypertensive medications ( beta-blockers : P = 0.004 ; angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers : P = 0.007 ; calcium channel blockers : P = 0.006 ) . Electrocardiographic ST segment resolution after PCI was observed in 87.5 % and 69.9 % of the statin and nonstatin groups , respectively ( hazard ratio [ HR ] : 3.01 ; 95 % CI , 1.15 - 7.90 ; P = 0.025 ) . Achievement of TIMI grade 3 flow after PCI was seen in 95.0 % of the statin group and 83.5 % of the nonstatin group ( HR : 3.75 ; 95 % CI , 0.88 - 16.0 ; P = NS ) . Patients treated with a statin had a significantly lower mean ( SD ) maximum CK level compared with the nonstatin group ( 2300 [ 1449 ] vs 3538 [ 3170 ] IU/mL , respectively ; P = 0.015 ) and a lower cTFC after PCI ( 18.8 [ 4.0 ] vs 24.2 [ 14.2 ] ; P = 0.017 ) . The difference in reperfusion arrhythmias between groups was not statistically significant . After adjustment for baseline covariates , pretreatment with a statin was found to be an independent predictor of ST segment resolution after PCI ( HR : 2.95 ; 95 % CI , 1.08 - 8.09 ; P = 0.035 ) and prevention of impaired coronary flow ( HR : 3.00 ; 95 % CI , 1.63 - 5.55 ; P < 0.001 ) . CONCLUSION In this study , receipt of chronic statin therapy before the onset of AMI was associated with improvement in epicardial perfusion and a reduction in myocardial necrosis after PCI Recent studies emphasized the non-lipid-lowering effects of hydroxymethylglutaryl coenzyme A reductase inhibitors on endothelial function , inflammation , and platelet activation in patients with stable atherosclerosis . This study sought to evaluate the impact of statin pretreatment in patients with acute myocardial infa rct ion ( AMI ) on level of systemic inflammation and myocardial perfusion . A total of 253 consecutive patients undergoing primary angioplasty on a native vessel within 12 hours of AMI were divided into a group with statin pretreatment ( n = 86 ) and control patients ( n = 167 ) . Angiographic myocardial blush grade ( MBG ) after revascularization of the infa rct -related artery was determined to evaluate myocardial perfusion . Statin pretreatment was associated with a lower frequency of increased C-reactive protein ( > or=5 mg/L ) on admission compared with the control group ( 48 % vs 64 % ; p = 0.019 ) . The frequency of normal perfusion ( MBG 3 ) was higher in the statin-pretreatment group than the control group ( 45 % vs 26 % , respectively ; p < 0.001 ) . Statin pretreatment was an independent predictor of normal myocardial perfusion ( MBG 3 ; odds ratio 2.53 , 95 % confidence interval 1.15 to 9.53 , p = 0.022 ) in addition to age < or=70 years and C-reactive protein < 5 mg/L. In conclusion , statin pretreatment in patients with AMI was associated with decreased systemic inflammation and better perfusion after primary angioplasty of the infa rct -related artery

In conclusion , there is a lack of evidence of effectiveness for most waterpipe interventions .

Waterpipe tobacco smoking is growing in popularity despite adverse health effects among users . We systematic ally review ed the literature , search ing MEDLINE , EMBASE and Web of Science , for interventions targeting prevention and cessation of waterpipe tobacco smoking .

INTRODUCTION We explored the differential effect of cessation interventions ( behavioral support sessions with [ BSS+ ] and without [ BSS ] bupropion ) between hookah and cigarette smokers . METHODS We reanalyzed the data from a major cluster-r and omized controlled trial , ASSIST ( Action to Stop Smoking In Suspected Tuberculosis ) , which consisted of 3 conditions : ( a ) behavioral support sessions ( BSS ) , ( b ) behavioral support sessions plus 7 weeks of bupropion therapy ( BSS+ ) , and ( c ) controls receiving usual care . The trial originally recruited 1,955 adult smokers with suspected tuberculosis from 33 health centers in the Jhang and Sargodha districts of Pakistan between 2010 and 2011 . The primary endpoint was continuous 6-month smoking abstinence , which was determined by carbon monoxide levels . Subgroup-specific relative risks ( RRs ) of smoking abstinence were computed and tested for differential intervention effect using log binomial regression ( generalized linear model ) between 3 subgroups ( cigarette-only : 1,255 ; mixed : 485 ; and hookah-only : 215 ) . RESULTS The test result for homogeneity of intervention effects between the smoking forms was statistically significant ( p-value for BSS+ : .04 and for BSS : .02 ) . Compared to the control , both interventions appeared to be effective among hookah smokers ( RR = 2.5 ; 95 % CI = 1.3 - 4.7 and RR = 2.2 ; 95 % CI = 1.3 - 3.8 , respectively ) but less effective among cigarette smokers ( RR = 6.6 ; 95 % CI = 4.6 - 9.6 and RR = 5.8 ; 95 % CI = 4.0 - 8.5 ) , respectively . CONCLUSIONS The differential intervention effects on hookah and cigarette smokers were seen ( a ) because the behavioral support intervention was design ed primarily for cigarette smokers ; ( b ) because of differences in demographic characteristics , behavioral , and sociocultural determinants ; or ( c ) because of differences in nicotine dependency levels between the 2 groups INTRODUCTION Tobacco use in low- to middle-income countries is a major public health concern for both smokers and those exposed to environmental tobacco smoke ( ETS ) . Egypt has made important strides in controlling tobacco use , but smoking and ETS remain highly prevalent . This r and omized intervention sought to improve the target population 's knowledge regarding the hazards of smoking and ETS and to change attitudes and smoking behaviors within the community and the household . METHODS In this 2005 - 2006 study in Egypt 's Qalyubia governorate , trained professionals visited schools , households , mosques , and health care centers in rural villages r and omly selected for the intervention to discuss the adverse effects of smoking and ETS exposure and ways to reduce one 's ETS exposure . Data collected in interviewer-facilitated surveys before and after the intervention period were analyzed in pairwise comparisons with data from control villages to assess the effectiveness of the intervention in achieving its aims . RESULTS The intervention group showed a greater increase in underst and ing the dangers associated with smoking cigarettes and waterpipes and became more proactive in limiting ETS exposure by asking smokers to stop , avoiding areas with ETS , and enacting smoking bans in the home . However , the intervention had little to no impact on the number of smokers and the amount of tobacco smoked . CONCLUSIONS Results are consistent with previous studies showing that changing smokers ' behavior can be difficult , but community-wide efforts to reduce ETS exposure through smoking bans , education , and empowering people to ask smokers to stop are effective . The method can be generalized to other setting In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias INTRODUCTION Tobacco use remains a major public health problem worldwide . Water-pipe smoking is spreading rapidly and threatening to undermine the successes achieved in tobacco control . METHODS A school-based longitudinal study in the city of Irbid , Jordan , was performed from 2008 to 2010 . All seventh- grade students in 19 r and omly selected schools , out of a total of 60 schools in the city , were enrolled at baseline and surveyed annually . RESULTS Of the 1781 students enrolled at baseline 1,701 ( 95.5 % ) were still in the study at the end of the second year of follow-up ( 869 boys , median age at baseline 13 years ) . Ever and current water-pipe smoking were higher than those of cigarette smoking at baseline ( ever smoking : 25.9 % vs. 17.6 % and current smoking : 13.3 % vs. 5.3 % for water-pipe and cigarette smoking , respectively ; p < .01 for both ) but cigarette smoking caught up by the second year of follow-up ( ever smoking : 46.4 % vs. 44.7 % ; p = .32 and current smoking : 18.9 % vs. 14.9 % ; p < .01 ) . Water pipe-only smokers at baseline were twice as likely to become current cigarette smokers after 2 years compared with never smokers ( relative risk ( RR ) = 2.1 ; 95 % CI = 1.2 , 3.4 ) . A similar pattern was observed for cigarette-only smokers at baseline ( RR = 2.0 ; 95 % CI = 0.9 , 4.8 ) . CONCLUSIONS Prevalence of water-pipe and cigarette smoking increased dramatically over the 2-year follow-up period with similar patterns in boys and girls , although girls had lower prevalence in all categories . Water-pipe smoking at baseline predicted the progress to cigarette smoking in the future and vice versa Background Involving children in research studies requires obtaining parental permission . A school-based intervention to delay/prevent waterpipe use for 7th and 8th grade rs in Qatar was developed , and parental permission requested . Fifty three percent ( 2308/4314 ) of the parents returned permission forms ; of those 19.5 % of the total ( 840/4314 ) granted permission . This paper describes the challenges to obtaining parental permission . No research to date has described such challenges in the Arab world . Methods A r and om sample of 40 schools in Doha , Qatar was selected for inclusion in the original intervention . Permission forms were distributed to parents for approval of their child ’s participation . The permission forms requested that parents indicate their reasons for non-permission if they declined . These were categorized into themes . In order to underst and reasons for non-permission , interviews with parents were conducted . Phone numbers of parents were requested from the school administration ; 12 of the 40 schools ( 30 % ) agreed to provide the contact information . A r and om sample of 28 parents from 12 schools was interviewed to reach data saturation . Thematic analysis was used to analyze their responses . Results Reasons for non-permission documented in both the forms and interviews included : poor timing ; lack of interest ; the child not wanting to participate ; and the child living in a smoke-free environment . Interviews provided information on important topics to include in the consent forms , parents ’ decision-making processes regarding their child ’s participation , and considerations for communicating with parents . Many parents also indicated that this was the first time they had been asked to give an informed consent for their child ’s participation in a study . Conclusions Results indicate that more attention needs to be given to the informed parental consent process . Research ers should consider enhancing both the methods of communicating information as well the specific information provided . Before embarking on recruitment of children for studies , formative research on the parental consent process is suggested Background Among Arab citizens in Israel , cigarette and nargila ( hookah , waterpipe ) smoking is a serious public health problem , particularly among the young adult population . With the dramatic increase of Internet and computer use among Arab college and university students , a Web-based program may provide an easy , accessible tool to reduce smoking rates without heavy re source dem and s required by traditional methods . Objective The purpose of this research was to examine the acceptability and feasibility of a pilot Web-based program that provides tailored feedback to increase smoking knowledge and reduce cigarette and nargila smoking behaviors among Arab college/university students in Israel . Methods A pilot Web-based program was developed , consisting of a self-administered question naire and feedback system on cigarette and nargila smoking . Arab university students were recruited to participate in a mixed- methods study , using both quantitative ( pre-/posttest study design ) and qualitative tools . A posttest was implemented at 1 month following participation in the intervention to assess any changes in smoking knowledge and behaviors . Focus group sessions were implemented to assess acceptability and preferences related to the Web-based program . Results A total of 225 participants —response rate of 63.2 % (225/356)—completed the intervention at baseline and at 1-month post study , and were used for the comparative analysis . Statistically significant reductions in nargila smoking among participants ( P=.001 ) were found . The intervention did not result in reductions in cigarette smoking . However , the tailored Web intervention result ed in statistically significant increases in the intention to quit smoking ( P=.021 ) . No statistically significant increases in knowledge were seen at 1-month post study . Participants expressed high satisfaction with the intervention and 93.8 % ( 211/225 ) of those who completed the intervention at both time intervals reported that they would recommend the program to their friends , indicating excellent acceptability and feasibility of the intervention . This was further emphasized in the focus group sessions . Conclusions A tailored Web-based program may be a promising tool to reduce nargila smoking among Arab university students in Israel . The tailored Web intervention was not successful at significantly reducing cigarette smoking or increasing knowledge . However , the intervention did increase participants ’ intention to quit smoking . Participants considered the Web-based tool to be an interesting , feasible , and highly acceptable strategy . Trial Registration Trial Registration : IS RCT N registry IS RCT N59207794 ; http://www.is rct n.com/IS RCT N59207794 ( Archived by WebCite at http://www.webcitation.org/6VkYOBNOJ ) Objectives : This research was undertaken with the aim of assessing the indoor air quality in popular hospitality venues , as also to evaluate the effectiveness of the nationwide comprehensive public smoking ban . The analysis was split into two halves – baseline study taken up prior to implementation of the said ban on 2nd October 2008 , and the follow-up study after it came into effect . Material s and Methods : Twenty-five venues including five restaurants , fourteen resto-bars , two hookah ( smoking water-pipe ) cafes and four pubs were selected using a mix of r and om , convenience and purpose ful sampling . Particulate matter ( PM2.5 ) measurements at these venues were made using TSI SidePak AM510 Personal Aerosol Monitor . Results : The average PM2.5 level in venues where smoking was permitted prior to implementation of ban was found to be 669.95 μg/m3 in the baseline study . Post ban , the average PM2.5 level in same test venues reduced to 240.8 μg/m3 . The hookah cafes were an exception as the average PM2.5 levels exceeded the permissible limits before as well as post ban . Conclusion : The baseline study showed that the hospitality venues had hazardous levels of PM2.5 particles arising from second-h and smoke prior to smoking ban . These decreased by a maximum of 64 % after the law took effect . A substantial improvement in air quality at these venues post implementation of the smoking ban indicated the effectiveness of the law BACKGROUND Waterpipe use has increased dramatically in the Middle East and other parts of the world . Many users exhibit signs of dependence , including withdrawal and difficulty quitting , but there is no evidence base to guide cessation efforts . METHODS We developed a behavioral cessation program for willing-to-quit waterpipe users , and evaluated its feasibility and efficacy in a pilot , two arm , parallel group , r and omized , open label trial in Aleppo , Syria . Fifty adults who smoked waterpipe ≥3 times per week in the last year , did not smoke cigarettes , and were interested in quitting were r and omized to receive either brief ( 1 in-person session and 3 phone calls ) or intensive ( 3 in-person sessions and 5 phone calls ) behavioral cessation treatment delivered by a trained physician in a clinical setting . The primary efficacy end point of the developed interventions was prolonged abstinence at three months post-quit day , assessed by self-report and exhaled carbon monoxide levels of < 10 ppm . Secondary end points were 7 day point-prevalent abstinence and adherence to treatment . RESULTS Thirty percent of participants were fully adherent to treatment , which did not vary by treatment group . The proportions of participants in the brief and intensive interventions with prolonged abstinence at the 3-month assessment were 30.4 % and 44.4 % , respectively . Previous success in quitting ( OR=3.57 ; 95 % CI=1.03 - 12.43 ) predicted cessation . Higher baseline readiness to quit , more confidence in quitting , and being unemployed predicted a better adherence to treatment ( all p-values < 0.05 ) . CONCLUSIONS Brief behavioral cessation treatment for waterpipe users appears to be feasible and effective OBJECTIVE To determine the feasibility of implementing cessation interventions in Syria . METHODS We r and omized 50 smokers to either a brief or intensive behavioral cessation intervention . Adherence to treatment and cessation through 3 months postcessation were calculated . RESULTS Adherence in the intensive group was only moderate and was associated with smoking for more years and higher self-efficacy . Cessation rates in the brief and intensive intervention groups were 16 % and 4 % , respectively . Nicotine dependence predicted abstinence at 3 months . CONCLUSION Important barriers to cessation included perceived dependence , lack of access to pharmacotherapy , poor social support , and water pipe smoking INTRODUCTION Waterpipe tobacco smoking is highly prevalent among young people in some setting s. There is an absence of nationally representative prevalence studies of waterpipe tobacco use and dual use with other tobacco products in young people . METHODS We conducted a secondary analysis of the Global Youth Tobacco Survey , a nationally representative cross-sectional study of students aged 13 - 15 years . Of 180 participating countries , 25 included optional waterpipe tobacco smoking questions : 15 Eastern Mediterranean and 10 Eastern European countries . We calculated the prevalence of current ( past 30-day ) waterpipe tobacco use , including dual waterpipe and other tobacco use , and used logistic regression models to identify sociodemographic correlates of waterpipe tobacco smoking . Individual country results were combined in a r and om effects meta- analysis . RESULTS Waterpipe tobacco smoking prevalence was highest in Lebanon ( 36.9 % ) , the West Bank ( 32.7 % ) and parts of Eastern Europe ( Latvia 22.7 % , the Czech Republic 22.1 % , Estonia 21.9 % ) . These countries also recorded greater than 10 % prevalence of dual waterpipe and cigarette use . In a meta- analysis , higher odds of waterpipe tobacco smoking were found among males ( Adjusted odds ratio [ AOR ] = 1.37 , 95 % confidence interval [ CI ] = 1.18 % to 1.59 % ) , cigarette users ( AOR = 6.95 , 95 % CI = 5.74 % to 8.42 % ) , those whose parents ( AOR = 1.54 , 95 % CI = 1.31 % to 1.82 % ) or peers smoked ( AOR = 3.53 , 95 % CI = 2.97 % to 4.20 % ) and those whose parents had higher educational attainment ( Father , AOR = 1.47 , 95 % CI = 1.14 % to 1.89 % ; Mother , AOR = 1.62 , 95 % CI = 1.07 % to 2.46 % ) . We report on regional- and country income-level differences . CONCLUSIONS Waterpipe tobacco smoking , including dual waterpipe and cigarette use , is alarmingly high in several Eastern Mediterranean and Eastern European countries . Ongoing waterpipe tobacco smoking surveillance is warranted

Several PROMs have been identified to evaluate sexual function in neurologic patients . Strong evidence was found only for the Multiple Sclerosis Intimacy and Sexuality Question naire-15 and Multiple Sclerosis Intimacy and Sexuality Question naire-19 for patients with MS , although evidence was lacking for certain measurement properties as well .

CONTEXT Impaired sexual function has a significant effect on quality of life . Various patient-reported outcome measures ( PROMs ) are available to evaluate sexual function . The quality of the PROMs to be used for neurologic patients remains unknown . OBJECTIVE To systematic ally review which vali date d PROMs are available to evaluate sexual function in neurologic patients and to critically assess the quality of the validation studies and measurement properties for each identified PROM .

INTRODUCTION Cultural sensitivities tend to limit assessment s of sexual dysfunction ( SD ) in Parkinson 's disease ( PD ) . OBJECTIVE To assess the validity and reliability of the Thai translation ( ASEX-Thai ) of the Arizona Sexual Experiences Scale ( ASEX ) . METHOD The validity and reliability of ASEX-Thai were assessed with a r and om sample of 40 PD patients . Back translation and cross-cultural modifications assured content validity . Criterion validity used DSM-IV-TR criteria and receiver operating characteristics ( ROC ) analysis was calculated for cutoff points plus sensitivity and specificity . Internal consistency was assessed with Cronbach 's alpha coefficient . Test-retest reliability was assessed by Pearson 's correlation at baseline and at a 2-month follow-up . RESULT Criterion validity was conducted with a positive correlation between the clinical diagnosis of SD and DSM-IV-TR ( r = 0.601 ; p < 0.001 ) . The ROC analysis differentiated between SD and non-SD patients ( p < 0.001 ) . The cutoff point of ASEX-Thai at ≥16 points effectively screened for SD ( sensitivity 96.2 % , specificity 92.9 % ) . Reliability was documented with the Cronbach 's alpha of all items at baseline and at a 2-month follow-up with values of 0.948 and 0.962 respectively . The Pearson 's correlation also showed highly significant test-retest reliability [ Item 1 ( r = 0.959 , p < 0.001 ) , Item 2 ( r = 0.914 , p < 0.001 ) , Item 3 ( r = 0.944 , p < 0.001 ) , Item 4 ( r = 0.992 , p < 0.001 ) , Item 5 ( r = 0.930 , p < 0.001 ) , and total ASEX-Thai score ( r = 0.883 , p < 0.001 ) ] . CONCLUSION ASEX-Thai is a valid and reliable instrument for the assessment of sexual dysfunction in Thai PD patients Study design : Two r and omized , double-blind , placebo-controlled trials . Objective : To evaluate the efficacy and safety of fampridine sustained-release tablets ( fampridine-SR ) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury ( SCI ) . Setting : United States and Canada . Methods : Patients with incomplete chronic SCI were r and omized to twice daily fampridine-SR 25 mg or placebo , with a 2-week single-blind placebo run-in , a 2-week titration , 12 weeks of stable dosing , 2 weeks of downward titration and 2 weeks of untreated follow-up . Co- primary end points were the change from baseline , averaged over the double-blind treatment period , for Ashworth score ( bilateral knee flexors and extensors ) and a 7-point Subject Global Impression of treatment ( SGI ; 1 , terrible ; 7 , delighted ) . Secondary end points were : Penn Spasm Frequency Scale ; the motor/sensory score from the International St and ards for Neurological Classification of SCI ; Clinician ’s Global Impression of Change of neurological status ; and the International Index of Erectile Function ( men ) or the Female Sexual Function Index ( women ) . Results : The population s were 212 and 203 patients in the two studies , respectively . Changes from baseline in Ashworth score were −0.15 ( placebo ) and −0.19 ( fampridine-SR ) in the first study , and −0.16 ( placebo ) and −0.28 ( fampridine-SR ) in the second study . The between-treatment difference was not significant for either the Ashworth score or the SGI and , with few exceptions , neither were the secondary end points . Fampridine-SR was generally well tolerated ; treatment-emergent adverse events ( TEAEs ) and serious TEAEs were reported with similar frequency between treatments . Conclusion : Fampridine-SR was well tolerated . No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI Introduction and hypothesisThe objective of this study was to create a valid , reliable , and responsive sexual function measure in women with pelvic floor disorders ( PFDs ) for both sexually active ( SA ) and inactive ( NSA ) women . Methods Expert review identified concept gaps and generated items evaluated with cognitive interviews . Women underwent Pelvic Organ Prolapse Quantification ( POPQ ) exams and completed the Incontinence Severity Index ( ISI ) , a prolapse question from the Epidemiology of Prolapse and Incontinence Question naire ( ISI scores ) , the Pelvic Floor Distress Inventory-20 ( PFDI-20 ) , and the Female Sexual Function Index ( FSFI ) . Principle components and orthogonal varimax rotation and principle factor analysis with oblique rotation identified item grouping . Cronbach ’s alpha measured internal consistency . Factor correlations evaluated criterion validation . Change scores compared to change scores in other measures evaluated responsiveness among women who underwent surgery . Results A total of 589 women gave baseline data , 200 returned surveys after treatment , and 147 provided test-retest data . For SA women , 3 subscales each in 2 domains ( 21 items ) and for NSA women 2 subscales in each of 2 domains ( 12 items ) emerged with robust psychometric properties . Cronbach ’s alpha ranged from .63 to .91 . For SA women , correlations were in the anticipated direction with PFDI-20 , ISI , and FSFI scores , POPQ , and EPIQ question # 35 ( all p < .05 ) . PFDI-20 , ISI , and FSFI subscale change scores correlated with Pelvic Organ Prolapse/Urinary Incontinence Sexual Question naire International Urogynecological Association-revised ( PISQ-IR ) factor change scores and with mean change scores in women who underwent surgery ( all p < .05 ) . For NSA women , PISQ-IR scores correlated with PFDI-20 , ISI scores , and with EPIQ question # 35 ( all p < .05 ) . No items demonstrated differences between test and retest ( all p ≥ .05 ) , indicating stability over time . Conclusions The PISQ-IR is a valid , reliable , and responsive measure of sexual function OBJECTIVE To identify determinants of sexual adjustment by persons with spinal cord injury ( SCI ) and quality of the relationship compared with persons in the general population . DESIGN Controlled survey . SETTING Postdischarge community setting . PARTICIPANTS A consecutive series of 252 persons admitted to our spinal unit between November 1982 and July 1991 with traumatic SCI were contacted , 85 of whom persons were excluded : 36 were dead , 37 had recovered , 5 could not be located , 4 were younger than 18 years , 2 had language difficulties , and 1 had a psychiatric illness . Of the remaining 167 persons with SCI , 85 had a stable partner relationship , 75 of whom ( 88 % ) completed and returned the question naires ( median age , 33 years ; range 19 to 76 ) . An age- and sex-matched control group was r and omly selected from the general population . Of the 264 respondents , 155 ( 59 % ) had a stable partner relationship . MAIN OUTCOME MEASURES The 80-item question naire addressed experiences concerning sexual functioning , desire , and activity , sexual behavior , satisfaction with sex life , and aspects of the emotional quality of the relationship . RESULTS Sexual activity and satisfaction was lower among persons with SCI compared with the controls ; the emotional quality of the relationship did not differ . The most important correlates for sexual fulfillment in both groups were found to be the use of a varied repertoire of sexual behaviors and the perception that the partner enjoys and is satisfied with the sexual part of the relationship . CONCLUSION Psychosocial rather than physical factors were important for a satisfying sexual life and relationship . A qualitative study should be undertaken to further explore the complexity of sexual adjustment after SCI OBJECTIVE To describe sexual life in women with spinal cord injury . DESIGN Controlled cross-sectional , question naire . PARTICIPANTS AND METHODS Women , 18 - 65 years , treated at spinal cord centres in Sweden , Denmark , Norway , Finl and and Icel and . 545 women ( 57 % ) completed the question naires . The age-matched control group consisted of 507 women . The 104-item Spinal Cord Injury Women Question naire , was design ed to assess different dimensions of sexuality . RESULTS 80 % of the women with spinal cord injury had engaged in sex after the injury . Reasons for not wanting or not having the courage to be intimate and sexual were physical problems , low sexual desire , low self-esteem and feelings of being unattractive . The motivations of both the women with spinal cord injury and controls to engage in sexual activity were intimacy-based rather than primarily sexual . Being in the right mood both before and during sex to become receptive to sexual stimulation was important . CONCLUSION For women who are able to overcome the physical restrictions and mental obstacles due to injury , it is possible to regain an active and positive sexual life together with a partner . Sexual information and counselling should be available both during initial rehabilitation and later when the women have returned to their homes

Preoperative carbohydrate drinks significantly improved insulin resistance and indices of patient comfort following surgery , especially hunger , thirst , malaise , anxiety and nausea . No definite conclusions could be made regarding preservation of muscle mass . Following ingestion of carbohydrate drinks , no adverse events such as apparent or proven aspiration during or after surgery were reported . Administration of oral carbohydrate drinks before surgery is probably safe and may have a positive influence on a wide range of perioperative markers of clinical outcome .

INTRODUCTION Surgical stress in the presence of fasting worsens the catabolic state , causes insulin resistance and may delay recovery . Carbohydrate rich drinks given preoperatively may ameliorate these deleterious effects . A systematic review was undertaken to analyse the effect of preoperative carbohydrate loading on insulin resistance , gastric emptying , gastric acidity , patient wellbeing , immunity and nutrition following surgery .

The effect on gastric pH and volume of 0 , 6 and 10 ml · kg−1 , of apple juice given 2.5 hours before surgery to children aged five to ten years was investigated in this prospect i ve , r and omized , single-blind study . Gastric contents were aspirated after induction of anaesthesia , and the volume measured . The pH of the gastric aspirate was then assessed using pH paper . Neither gastric volume nor pH immediately following the induction of general anaesthesia were significantly different among the three groups . Gastric volumes after 0 , 6 and 10 ml · kg−1 , of juice averaged ( mean ±SD ) 0.45 ±0.31 , 0.66 ±0.79 and 0.71 ±0.76 ml · kg−1 , respectively ; gastric pH averaged 1.7 ±0.6 , 1.7 ±0.6 and 1.8 ±0.8 , respectively . On the basis of questions asked immediately before induction of anaesthiesia , patients who drank 6 ml · kg−1 of apple juice had decreased thirst and were less irritable and upset before anaesthesia than those who had not ( P < 0.05 ) . It is concluded that drinking large volumes of clear apple juice 2.5 hours before scheduled surgery does not have a measurable effect on gastric volume and pH and may offer benefits such as improved patient comfort . RésuméL’effet sur le volume et le pH gastrique de 0,6 et 10 ml · kg−1 de jus de pomme donné 2.5 heures avant la chirurgie aux enfants âgés de cinq à dix ans a été investigué dans cette étude prospect i ve r and omisée et a simple insu . Le contenu gastrique fut aspiré après induction de l’anesthésie et le volume mesuré . Le pH du sue gastrique aspiré a par la suite été évalué par un papier à pH. Ni le volume gastrique ni son pH n’était significativement différent pour les trois groupes après l’induction de l’anesthesie générale . Le volume gastrique après 0,6 et 10 ml · kg−1 de jus de pomme était en moyenne ( moyenne ±SD ) respectivement 0,45 ±0,31 , 0,66 ±0,79 et 0,71 ±0,76 ml · kg−1 , en moyenne le pH gastrique était de 1,7 ±0,6 , 1,7 ±0,6 et 1,8 ±0,8 . Pour les avoir question né immédiatement avant l’induction de l’anesthésie les patients ayant bu 6 ml · kg−1 de jus de pomme avaient moins soif et étaient moins irritables avant l’anesthésie que ceux qui n’en ont pas eu ( P < 0.05 ) . On conclut que l’ingestion dun large volume de jus de pomme 2.5 heures avant la chirurgie n’a pas d’effet mesurable sur le volume et le pH gastrique et peut offrir des bénéfices tel que l’amélioration du confort du patient The effect of preoperative glucose infusion on preoperative alterations in hepatic glycogen content , the activity of key hepatic glucoregulatory enzymes ( fructose 1,6-diphosphatase [ FDPase ] ) , pyruvate kinase ( PK ) , hormonal developments , and plasma levels of free fatty acids ( FFA ) were investigated in 16 patients undergoing open cholecystectomy . Patients were r and omized to receive ( group G ) or not receive ( group C ) overnight glucose infusion ( 5 mg.kg-1.d-1 ) preoperatively . Infusion of glucose overnight result ed in preoperative elevations of insulin and c-peptide ( P < 0.05 ) and lower plasma levels of FFA , while the same glucose levels were found in both groups , 4.6 mmol/L. During and after surgery , only minor changes in the plasma levels of insulin , c-peptide , catecholamines , glucagon , cortisol , growth hormone , and FFA were found , with minimal differences between groups . The hepatic glycogen content was 65 % higher in group G and a significant reduction was confirmed only in this group of patients during surgery . The higher glycogen content was associated with a higher FDPase activity ratio ( P < 0.05 ) , which remained unchanged during surgery . In contrast , a significant ( P < 0.05 ) increase in the activity of this enzyme was found in group C. The PK activity ratio did not differ between groups and remained unchanged during surgery . The finding of enhanced FDPase activity suggests that the indirect route ( via gluconeogenesis ) represents an important contributor to the increased glycogen formation during glucose infusion . Additionally , surgery in the overnight fasted patient induces enzymatic changes favoring gluconeogenesis . Lastly , preoperative high-dose glucose infusion has only minor effects on the endocrine response , plasma levels of FFA , and glycogen depletion during elective open cholecystectomy The effect of 3 ml·kg-1 of apple juice given 2.6 ± 0.4 hours preoperatively was investigated in 80 healthy children of ages five to ten years in this prospect i ve , r and omized , single blind study . The children who drank apple juice preoperatively had decreased gastric volume , thirst , and hunger ( p < 0.05 ) . The gastric volume in the control group was 0.43 ± 0.46 ml·kg-1 and in the patients who received apple juice the gastric volume was 0.24 ± 0.31 ml·kg-1 . The gastric pH was not significantly different , with the control group ’s gastric pH being 1.7 ± 0.6 and the treated group ’s pH was 2.2 ± 1.2 . Further studies of the effects of different volumes and timing of preoperative clear fluids are indicated in paediatric patients .RésuméNous avons entrepris une étude prospect i ve , r and omisée et à ľaveugle pour déterminer ľeffet de 3 ml · kg-1 de jus de pomme donné 2.6 ± 0.4 h. avant ľopération à 80 enfants agés de 5 à 10 ans . Les enfants qui avaient bu du jus avant ľopération avaient moins f aim et soif et leurs volumes gastriques étaient moindres ( p < 0.05 ) . Le volume gastrique était de 0.43 ± 0.46 ml · kg-1 chez le groupe contrôle , et de 0.24 ± 0.31 ml · kg-1 chez le groupe “ jus de pomm ” . Le pH du liquide se chiffrait à 1.7 ± 0.6 pour les contrôles et à 2.2 ± 1.2 pour les buveurs de jus , écart non significatif . On aura besoin ďautres études pour préciser ľimpact du volume et de ľintervalle ďadministration des liquides clairs chez les enfants Background : Post‐operative insulin resistance and hyperglycaemia are associated with an impaired outcome after surgery . Pre‐operative oral carbohydrate loading ( CHO ) reduces post‐operative insulin resistance with a reduced risk of hyperglycaemia during post‐operative nutrition . Insulin‐resistant diabetic patients have not been given CHO because the effects on pre‐operative glycaemia and gastric emptying are unknown BACKGROUND AND AIMS Preoperative intake of a clear carbohydrate-rich drink reduces insulin resistance after surgery . In this study , we evaluated whether this could be related to increased insulin sensitivity at the onset of surgery . Furthermore , we aim ed to establish the optimal dose-regimen . METHODS Six healthy volunteers underwent hyperinsulinaemic ( 0.8 mU/kg/min ) , normoglycaemic ( 4.5 mmol/l ) clamps and indirect calorimetry on four occasions in a crossover-r and omised order ; after overnight fasting ( CC ) , after a single evening dose ( 800 ml ) of the drink ( LC ) , after a single morning dose ( 400 ml , CL ) and after intake of the drink in the evening and in the morning before the clamp ( LL ) . Data are presented as mean+/-SD . Statistical analysis was performed using the Student 's t-test and ANOVA . RESULTS Insulin sensitivity was higher in CL and LL ( 9.2+/-1.5 and 9.3+/-1.9 mg/kg/min , respectively ) compared to CC and LC ( 6.1+/-1.6 and 6.6+/-1.9 mg/kg/min , P<0.01 vs. CL and LL ) . CONCLUSIONS A carbohydrate-rich drink enhances insulin action 3 h later by approximately 50 % . Enhanced insulin action to normal postpr and ial day-time level at the time of onset of anaesthesia or surgery is likely to , at least partly , explain the effects on postoperative insulin resistance Background Studies showing the improvement of insulin sensitivity by reducing the term of preoperative fasting are mostly done in patients undergoing major operations . More information about the role of shortened preoperative fasting in perioperative metabolism is needed for such elective minor/moderate abdominal procedures as laparoscopic cholecystectomy . We investigated the influence of a carbohydrate-rich drink given 2 h before laparoscopic cholecystectomy on insulin resistance and the metabolic response to trauma . Methods A group of 21 female c and i date s ( 18–65 years old ) for elective laparoscopic cholecystectomy were r and omized to either an 8 h fasting group ( control group : n = 10 ) or to a group receiving 200 ml of a carbohydrate beverage containing 12.5 % ( 25 g , 50 kcal per 100 ml and approximately 285 mOsm ) of maltodextrine 2 h before operation ( CHO group : n = 11 ) . Blood sample s for various biochemical assays were collected both at induction of anesthesia and after the 10th postoperative hour . Insulin resistance was assessed by the HOMA-IR equation ( Insulin ( μU/ml ) × blood glucose (mg/dl)/405 ) . Results There were no postoperative complications . Seventy percent ( 7/10 ) of the controls and 27.3 % ( 3/11 ) of the CHO group experienced at least one episode of vomiting ( RR = 2.42 , 95 % Confidence Interval [ CI ] = 0.88–6.68 ; P = 0.08 ) . Biochemical analysis showed that serum glucose ( P < 0.01 ) , insulin ( P < 0.01 ) , lactate/pyruvate ratio ( P = 0.03 ) , and triglycerides ( P < 0.01 ) for the control group were higher than for the CHO group . The value of HOMA-IR was significantly greater ( P = 0.03 ) in the conventionally fasted patients than in the CHO group . Conclusions Abbreviation of the period of preoperative fasting and administration of a carbohydrate beverage diminishes insulin resistance and the organic response to trauma BACKGROUND Diabetes mellitus is a risk factor for deep sternal wound infection after open heart surgical procedures . We previously showed that elevated postoperative blood glucose levels are a predictor of deep sternal wound infection in diabetic patients . Therefore , we hypothesized that aggressive intravenous pharmacologic control of postoperative blood glucose levels would reduce the incidence of deep sternal wound infection . METHODS In a prospect i ve study of 2,467 consecutive diabetic patients who underwent open heart surgical procedures between 1987 and 1997 , perioperative blood glucose levels were recorded every 1 to 2 hours . Patients were classified into two sequential groups : the control group included 968 patients treated with sliding-scale-guided intermittent subcutaneous insulin injections ( SQI ) ; the study group included 1,499 patients treated with a continuous intravenous insulin infusion in an attempt to maintain a blood glucose level of less than 200 mg/dL. There were no differences between these groups with respect to age , sex , procedure , bypass time , antibiotic prophylaxis , or skin preparation methods . RESULTS Compared with subcutaneous insulin injections , continuous intravenous insulin infusion induced a significant reduction in perioperative blood glucose levels , which led to a significant reduction in the incidence of deep sternal wound infection in the continuous intravenous insulin infusion group ( 0.8 % [ 12 of 1,499 ] ) versus the intermittent subcutaneous insulin injection group ( 2.0 % [ 19 of 968 ] , p = 0.01 by the chi2 test ) . Multivariate logistic regression revealed that continuous intravenous insulin infusion induced a significant decrease in the risk of deep sternal wound infection ( p = 0.005 ; relative risk , 0.34 ) , whereas obesity ( p < 0.03 ; relative risk , 1.06 ) and use of an internal thoracic artery pedicle ( p = 0.1 ; relative risk , 2.0 ) increased the risk of deep sternal wound infection . CONCLUSIONS Use of perioperative continuous intravenous insulin infusion in diabetic patients undergoing open heart surgical procedures significantly reduces major infectious morbidity and its associated socioeconomic costs Glucose metabolism is adversely affected in patients following major surgery . Patients may develop hyperglycemia due to a combination of surgical stress and postoperative insulin resistance . A r and omized trial was conducted to eluci date the effect of preoperative supplementation with carbohydrates and branched-chain amino acids on postoperative insulin resistance in patients undergoing hepatic resection . A total of 26 patients undergoing a hepatectomy for the treatment of a hepatic neoplasm were r and omly assigned to receive a preoperative supplement of carbohydrate and branched-chain amino acid-enriched nutrient mixture or not . The postoperative blood glucose level and the total insulin requirement for normoglycemic control during the 16 h following hepatic resection were determined using the artificial pancreas STG-22 . Postoperative insulin requirements for normoglycemic control in the group with preoperative nutritional support was significantly lower than that in the control group ( P = 0.039 ) . There was no incidence of hypoglycemia ( < 40 mg/dL ) observed in patients , including those with diabetes mellitus , when the STG-22 was used to control blood glucose levels . STG-22 is a safe and reliable tool to control postoperative glucose metabolism and evaluate insulin resistance . The preoperative oral administration of carbohydrate and branched-chain amino acid-enriched nutrient is of clinical benefit and reduces postoperative insulin resistance in patients undergoing hepatic resection Background and objective We studied the effect of three different fasting protocol s on preoperative discomfort and glucose and insulin levels . Methods Two hundred and ten ASA I – III patients undergoing general or gastrointestinal surgery were r and omly assigned to three groups : overnight intravenous 5 % glucose infusion ( 1000 ml ) , carbohydrate-rich drink ( 400 ml ) at 6–7 a.m. , or overnight fasting . The subjective feelings of thirst , hunger , mouth dryness , weakness , tiredness , anxiety , headache and pain of each patient were question ed preoperatively using a visual analogue scale . Serum glucose and insulin levels were measured at predetermined time points preoperatively . Results During the waiting period before surgery , the carbohydrate-rich drink group was less hungry than the fasting group ( P = 0.011 ) . No other differences were seen in visual analogue scale scores among the study groups . Trend analysis showed increasing thirst , mouth dryness and anxiety in the intravenous glucose group ( P < 0.05 ) . The carbohydrate-rich drink group experienced decreasing thirst but increasing hunger and mouth dryness ( P < 0.05 ) . In the fasting group , thirst , hunger , mouth dryness , weakness , tiredness and anxiety increased ( P < 0.05 ) . Both intravenous and oral carbohydrate caused a significant increase in glucose and insulin levels . Conclusion Intravenous glucose infusion does not decrease the sense of thirst and hunger as effectively as a carbohydrate-rich drink but does alleviate the feelings of weakness and tiredness compared with fasting AIM Recent evidence suggests that the provision of energy-containing fluids is safe and may impact positively on markers of recovery . The aims of this study were to assess the tolerance of preoperative carbohydrate fluid administration and to determine its effect on postoperative metabolic and clinical responses . METHODS Patients admitted to the Royal Infirmary of Edinburgh for major , elective abdominal surgery were recruited to this double-blind , r and omised study and received either a placebo drink or carbohydrate ( 12.6g/100ml ) drink ( CHOD ) . Patients consumed 800 ml of their drink on the evening before surgery and 400 ml on the day of surgery 2 - 3 h before the induction of anaesthesia . Nutritional status was determined using body mass index ( BMI ) and upper arm anthropometry ; all measurements were taken preoperatively , postoperatively and at discharge . Blood glucose and insulin concentrations were also measured preoperatively and on the first post operative day . Length of hospital stay ( LOS ) and postoperative complications were recorded . RESULTS Seventy-two patients were recruited and 65 ( 34 male:31 female ) completed this study . Thirty-four patients were r and omised to receive the placebo drink ( control group ) and 31 patients to receive the carbohydrate drink ( CHOD group ) . Groups were well-matched in terms of gender and age . There were no differences between the two groups at baseline for BMI ( control : -25.1+/-1.7 kg/m2 ; CHOD -25.2+/-1.2 kg/m2 ) , upper arm anthropometry or surgical procedure . At discharge loss of muscle mass ( arm muscle circumference ) was significantly greater in the control group when compared with the CHOD group ( control : -1.1+/-0.15 cm ; CHOD : -0.5+/-0.16 cm ; P<0.05 ) . Baseline insulin ( control : 20.7+/-4.9 mU/l ; CHOD : 24.6+/-6.2 mU/l ) and glucose ( control : 6.0+/-1.4 mmol/l ; CHOD 5.7+/-1.4 mmol/l ) were comparable in the two groups and did not differ postoperatively . No complications were recorded as a result of preoperative fluid consumption . Postoperative morbidity occurred in six patients from each group . Median LOS in the control group was 10 days ( IQR=6 ) , and 8 days ( IQR=4 ) in the CHOD group . CONCLUSION Preoperative consumption of carbohydrate-containing fluids is safe . Provision of a carbohydrate energy source prior to surgery may attenuate depletion of muscle mass after surgery . Further studies are required to determine if this preservation of muscle mass is reflected in improved function and reduced rehabilitation time UNLABELLED Infusions of carbohydrates before surgery have been shown to reduce postoperative insulin resistance . Presently , we investigated the effects of a carbohydrate drink , given shortly before surgery , on postoperative insulin sensitivity . METHODS Insulin sensitivity and glucose turnover ( [ 6 , 6,(2)H(2)]-D-glucose ) were measured using hyper-insulinemic , normoglycemic clamps before and after elective surgery . Sixteen patients undergoing total hip replacement were r and omly assigned to preoperative oral carbohydrate administration ( CHO-H , n = 8) or the same amount of a placebo drink ( placebo , n = 8) before surgery . Insulin sensitivity was measured before and immediately after surgery . Patients undergoing elective colorectal surgery were studied before surgery and 24 h postoperatively ( CHO-C ( n = 7 ) , and fasted ( n = 7 ) , groups ) . The fasted group underwent surgery after an overnight fast . In both studies , the CHO groups received 800 ml of an isoosmolar carbohydrate rich beverage the evening before the operation ( 100 g carbohydrates ) , as well as another 400 ml ( 50 g carbohydrates ) 2 h before the initiation of anesthesia . RESULTS Immediately after surgery , insulin sensitivity was reduced 37 % in the placebo group ( P < 0.05 vs. preoperatively ) while no significant change was found in the CHO-H group ( -16 % , p = NS ) . During clamps performed 24h postoperatively , insulin sensitivity and whole-body glucose disposal was reduced in both groups , but the reduction was greater compared to that in the CHO-C group ( -49 + /- 6 % vs. -26 + /- 8 % , P > > 0.05 fasted vs. CHO-C ) . CONCLUSIONS Patients given a carbohydrate drink shortly before elective surgery displayed less reduced insulin sensitivity after surgery as compared to patients undergoing surgery after an overnight fast We studied the effects of different preoperative oral fluid protocol s on preoperative discomfort , residual gastric fluid volumes , and gastric acidity . Two-hundred-fifty-two elective abdominal surgery patients ( ASA physical status I – II ) were r and omized to preparation with a 12.5 % carbohydrate drink ( CHO ) , placebo ( flavored water ) , or overnight fasting . The CHO and Placebo groups were double-blinded and were given 800 mL to drink on the evening before and 400 mL on the morning of surgery . Visual analog scales were used to score 11 different discomfort variables . CHO did not increase gastric fluid volumes or affect acidity , and there were no adverse events . The visual analog scale scores in a control situation were not different between groups . During the waiting period before surgery , the CHO-treated group was less hungry and less anxious than both the other groups ( P ≤ 0.05 ) . CHO reduced thirst as effectively as placebo ( P < 0.0001 versus Fasted ) . Trend analysis showed consistently decreasing thirst , hunger , anxiety , malaise , and unfitness in the CHO group ( P < 0.05 ) . The Placebo group experienced decreasing unfitness and malaise , whereas nausea , tiredness , and inability to concentrate increased ( P < 0.05 ) . In the Fasted group , hunger , thirst , tiredness , weakness , and inability to concentrate increased ( P < 0.05 ) . In conclusion , CHO significantly reduces preoperative discomfort without adversely affecting gastric contents OBJECTIVE To assess the effect of an intensive glucose management protocol in a heterogeneous population of critically ill adult patients . PATIENTS AND METHODS This study consisted of 800 consecutive patients admitted after institution of the protocol ( treatment group , between February 1 , 2003 , and January 10 , 2004 ) and 800 patients admitted immediately preceding institution of the protocol ( baseline group , between February 23 , 2002 , and January 31 , 2003 ) . The setting was a 14-bed medical-surgical intensive care unit ( ICU ) in a university-affiliated community teaching hospital . The protocol involved intensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL. Continuous intravenous insulin was used if glucose values exceeded 200 mg/dL on 2 successive occasions . RESULTS The 2 groups of patients were well matched , with similar age , sex , race , prevalence of diabetes mellitus , Acute Physiology and Chronic Health Evaluation II scores , and distribution of diagnoses . After institution of the protocol , the mean glucose value decreased from 152.3 to 130.7 mg/dL ( P<.001 ) , marked by a 56.3 % reduction in the percentage of glucose values of 200 mg/dL or higher , without a significant change in hypoglycemia . The development of new renal insufficiency decreased 75 % ( P=-.03 ) , and the number of patients undergoing transfusion of packed red blood cells decreased 18.7 % ( P=.04 ) . Hospital mortality decreased 29.3 % ( P=.002 ) , and length of stay in the ICU decreased 10.8 % ( P=.01 ) . CONCLUSION The protocol result ed in significantly improved glycemic control and was associated with decreased mortality , organ dysfunction , and length of stay in the ICU in a heterogeneous population of critically ill adult patients . These results support the adoption of this low-cost intervention as a st and ard of care for critically ill patients A carbohydrate‐rich drink ( CHO ) has been shown to reduce preoperative discomfort . It was hypothesized that it may also reduce postoperative nausea and vomiting ( PONV ) Preoperative oral carbohydrate can attenuate postoperative insulin resistance and catabolism , and may have the potential to improve postoperative recovery . There are no data from r and omized studies on postoperative clinical outcome after specific surgical procedures . This study evaluated the clinical effects of a preoperative carbohydrate beverage in patients undergoing laparoscopic cholecystectomy Major surgery is associated with postoperative insulin resistance which is attenuated by preoperative carbohydrate ( CHO ) treatment . The effect of this treatment on clinical outcome after major abdominal surgery has not been assessed in a double‐blind r and omized trial Background : Surgery is succeeded by long‐lasting state of relative peripheral insulin resistance , which is reduced by giving glucose infusion or oral carbohydrate‐rich drinks immediate before operating instead of fasting . The aim of the present study was to investigate whether oral carbohydrate or carbohydrate with peptide drinks preoperatively instead of fasting would improve postoperative voluntary muscle strength , nutritional intake and ambulation , decrease postoperative fatigue , anxiety and discomfort , and reduce the endocrine response to surgery Preoperative oral carbohydrate ( CHO ) reduces postoperative insulin resistance . In this r and omized trial , the effect of CHO on postoperative whole‐body protein turnover was studied

Conclusions — In observational studies , reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence .

Background and Purpose — The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage ( ICH ) remain unclear . We performed a systematic review and meta- analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism .

Background : For patients who survive intracerebral haemorrhage ( ICH ) during treatment with oral anticoagulation ( OAC ) , the balance between the benefits and risks of restarting OAC is unclear . The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved . We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH . Methods : We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period . Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through question naires and patient files . The primary outcome was recurrent fatal or non-fatal stroke . Secondary outcomes were the occurrence of other haemorrhagic , thrombotic or thromboembolic events . With patients without antithrombotic treatment as reference , we calculated incidence ratios with corresponding 95 % confidence intervals ( CI ) for treatment with OAC and for treatment with antiplatelet therapy . Results : We included 38 patients , of whom 21 ( 55 % ) died during a mean follow-up of 3.5 years . The medication regime changed frequently during follow-up , illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time . Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication , 7 during 63.8 patient-years on antiplatelet medication ( incidence ratio 1.9 ; 95 % CI , 0.4 - 9.4 ) , and 3 during 19.5 patient-years on OAC ( incidence ratio 2.7 ; 95 % CI , 0.5 - 16.3 ) . There was only 1 recurrent ICH , which occurred during treatment with OAC . Conclusion : In this observational study , no significant difference in the primary outcome measure was found between the treatment groups , but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy . However , based on these results it is difficult to draw any concrete conclusions or make any strong recommendations . A r and omized trial to assess the optimal long-term strategy after OAC-related ICH is warranted . Based on the point estimates of our study , such a trial should involve at least 300 patient-years of follow-up BACKGROUND While warfarin-related intracranial hemorrhage ( ICH ) occurs in 0.25%-1.1 % patients per year , little is known about the practice and outcomes of anticoagulant reinitiation . METHODS We studied a cohort of consecutive patients with warfarin-related ICH ( intracerebral or subarachnoid ) admitted to 13 stroke centres in the Registry of the Canadian Stroke Network between July 2003 and March 2008 . We examined patterns of warfarin reinitiation and variables associated with 30-day and 1-year outcomes . RESULTS Among the 284 patients studied ( mean age 74 ± 12 years ) , warfarin was restarted in-hospital in 91 patients ( 32 % ) . Factors associated with restarting warfarin were lower stroke severity ( adjusted odds ratio [ aOR ] 2.07 , 95 % confidence interval [ CI ] ; 1.20 - 3.57 , P = 0.009 ) or presence of valve prosthesis ( aOR 3.07 , 95 % CI ; 1.29 - 7.27 , P = 0.011 ) . Mortality rates were not higher in those who restarted warfarin in-hospital : 31.9 % vs 54.4 % ( 30-day , P < 0.001 ) and 48 % vs 61 % ( 1-year , P = 0.04 ) , and bleeding was not increased . Multivariable predictors of mortality included initial international normalized ratio > 3.0 ( aOR , 3.28 [ 30-day , P < 0.001 ] and 3.32 [ 1-year , P = 0.003 ] ) , greater stroke severity ( aOR , 6.04 [ 30-day ] and 4.22 [ 1-year ] ; both P < 0.001 ) , and intraventricular hemorrhage ( aOR , 2.19 [ 30-day ; P = 0.03 ] and 2.04 [ 1-year ; P = 0.04 ] ) . In selected patients who reinitiated warfarin , there was no increase in 30-day ( aOR , 0.49 ; P = 0.03 ) or 1-year mortality ( aOR , 0.79 ; P = 0.43 ) . CONCLUSIONS In selected patients at high thrombosis risk , reinitiation of warfarin after ICH did not confer increased mortality or bleeding events OBJECT Aneurysmal subarachnoid hemorrhage ( aSAH ) predisposes to delayed neurological deficits , including stroke and cognitive and neuropsychological abnormalities . Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH . METHODS The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus . Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion ( Maryl and low-dose intravenous heparin infusion protocol : 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr ) beginning 12 hours after surgery and continuing until Day 14 after the ictus . Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis . RESULTS Patients in the 2 groups were balanced in terms of baseline characteristics . In the heparin group , activated partial thromboplastin times were normal to mildly elevated ; no clinical ly significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered . In the control group , the incidence of clinical vasospasm requiring rescue therapy ( induced hypertension , selective intraarterial verapamil , and angioplasty ) was 20 ( 47 % ) of 43 patients , and 9 ( 21 % ) of 43 patients experienced a delayed infa rct on CT scanning . In the heparin group , the incidence of clinical vasospasm requiring rescue therapy was 9 % ( 4 of 43 , p = 0.0002 ) , and no patient suffered a delayed infa rct ( p = 0.003 ) . CONCLUSIONS In patients with Fisher Grade 3 aSAH whose aneurysm is secured , postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial Abstract Purpose s : Intracranial haemorrhage ( ICH ) is a rare but potentially devastating complication of oral anticoagulants ( OAC ) . This raises the difficult clinical choice between either permanent cessation of OAC , or continuing OAC and if so , when to restart . To make this choice , one needs to balance the thrombo-embolic risk after cessation of OAC against the risk of recurrent intracranial haemorrhage when OAC are restarted . There are few published data to base this difficult clinical decision on . Methods : We present an observational study of a consecutive series of 108 patients , collected prospect ively and admitted to our department , with an OAC-related intracranial haemorrhage , in whom we assessed the thrombotic event rate and the recurrent intracranial bleeding rate during follow-up . Results : In the 25 patients in whom OAC were reinstituted no new thrombo-embolic events occurred ( 0/506 unprotected patient-days ) . In the group of patients in whom OAC were not restarted ( n = 81 ) , the thrombo-embolic event rate was 8/11590 unprotected patient-days , of which only 2 were cerebrovascular thrombo-embolisms . The overall risk of a thrombo-embolic complication can be estimated to be 0.66 events/1000 patient-days at risk ( 95 % exact confidence limits of 0.3 to 1.3 events/1000 patient-days at risk ) . In three patients the thrombo-embolic event was fatal . We saw recurrent intracranial bleeding in eight patients , 2 of which were fatal . Seven of these occurred before the restarting of the OAC . Conclusions : In OAC-related intracranial haemorrhages , OAC can be stopped safely for a considerable period , with a very low overall thrombotic event rate . The recurrent bleeding risk after restarting OAC is low . Recurrent bleeding mostly occurred before restarting OAC and is probably caused by insufficient or unsustained correction of the initial coagulation deficit . Immediate reversal of anticoagulation provides the patient with the best possible treatment options including surgery . OAC-related intracranial haemorrhages can therefore be actively treated IMPORTANCE Although use of oral anticoagulants ( OACs ) is increasing , there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage ( ICH ) . OBJECTIVE To assess the association of anticoagulation reversal and blood pressure ( BP ) with hematoma enlargement and the effects of OAC resumption . DESIGN , SETTING , AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers ( 2006 - 2012 ) including 1176 individuals for analysis of long-term functional outcome , 853 for analysis of hematoma enlargement , and 719 for analysis of OAC resumption . EXPOSURES Reversal of anticoagulation during acute phase , systolic BP at 4 hours , and reinitiation of OAC for long-term treatment . MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio ( INR ) and BP . Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption . Factors associated with favorable ( modified Rankin Scale score , 0 - 3 ) vs unfavorable functional outcome . RESULTS Hemorrhage enlargement occurred in 307 of 853 patients ( 36.0 % ) . Reduced rates of hematoma enlargement were associated with reversal of INR levels < 1.3 within 4 hours after admission ( 43/217 [ 19.8 % ] ) vs INR of ≥1.3 ( 264/636 [ 41.5 % ] ; P < .001 ) and systolic BP < 160 mm Hg at 4 hours ( 167/504 [ 33.1 % ] ) vs ≥160 mm Hg ( 98/187 [ 52.4 % ] ; P < .001 ) . The combination of INR reversal < 1.3 within 4 hours and systolic BP of < 160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement ( 35/193 [ 18.1 % ] vs 220/498 [ 44.2 % ] not achieving these values ; OR , 0.28 ; 95 % CI , 0.19 - 0.42 ; P < .001 ) and lower rates of in-hospital mortality ( 26/193 [ 13.5 % ] vs 103/498 [ 20.7 % ] ; OR , 0.60 ; 95 % CI , 0.37 - 0.95 ; P = .03 ) . OAC was resumed in 172 of 719 survivors ( 23.9 % ) . OAC resumption showed fewer ischemic complications ( OAC : 9/172 [ 5.2 % ] vs no OAC : 82/547 [ 15.0 % ] ; P < .001 ) and not significantly different hemorrhagic complications ( OAC : 14/172 [ 8.1 % ] vs no OAC : 36/547 [ 6.6 % ] ; P = .48 ) . Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 ( 95 % CI , 0.125 - 0.534 ; P < .001 ) for long-term mortality . Functional long-term outcome was unfavorable in 786 of 1083 patients ( 72.6 % ) . CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH , reversal of INR < 1.3 within 4 hours and systolic BP < 160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement , and resumption of OAC therapy was associated with lower risk of ischemic events . These findings require replication and assessment in prospect i ve studies . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01829581

This meta- analysis found no evidence of an increased risk of suicide or attempted suicide , suicidal ideation , depression , or death with varenicline . These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline . There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams .

OBJECTIVE To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in r and omised controlled trials .

Abstract Alcohol and nicotine dependence are common in schizophrenia . Varenicline is effective in smoking cessation and has also been shown to decrease alcohol consumption in smokers . The present pilot study assessed the safety and effectiveness of varenicline for treatment of concurrent nicotine and alcohol dependence in schizophrenia . Out patients with schizophrenia or schizoaffective disorder and concurrent alcohol and nicotine dependence were enrolled in this 8-week , double-blind , r and omized , placebo-controlled trial . Alcohol use and smoking were assessed using self-report ( Timeline Follow-Back ) and biological measures . Adverse events were recorded . Changes in the number of st and ard drinks per week and cigarettes per week were compared in the 2 groups . Because of safety concerns or loss to follow-up , of 55 patients enrolled , only 10 started study medication , 5 each on varenicline and placebo . Gastrointestinal adverse effects , such as severe abdominal pain , limited study completion to only 4 subjects . Number of st and ard alcoholic drinks consumed per week decreased by [ mean ( SD ) ] 16.6 ( 20.1 ) in the varenicline group and by 2.4 ( 27.4 ) in the placebo group . Mean ( SD ) number of cigarettes smoked per week decreased by 66 ( 65 ) in the varenicline group and by 47 ( 77 ) in the placebo group . Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia may be problematic because of safety concerns limiting recruitment and poor tolerability ( gastrointestinal adverse effects ) limiting retention . There was no increased number of serious neuropsychiatric adverse events in the varenicline group . Based on this small sample , concurrent alcohol and nicotine dependence in schizophrenia may present special obstacles to successful treatment with varenicline BACKGROUND Varenicline is approved as an aid to smoking cessation in adults aged > or = 18 years . OBJECTIVE The goal of this study was to characterize the multiple-dose pharmacokinetics , safety , and tolerability of varenicline in adolescent smokers . METHODS This multicenter , r and omized , double-blind , placebo-controlled , parallel-group study enrolled healthy 12- to 16-year-old smokers ( > or =3 cigarettes daily ) into high-body-weight ( > 55 kg ) and low-body-weight ( < or = 55 kg ) groups . Subjects were r and omized to receive 14 days of treatment with a high dose of varenicline , a low dose of varenicline , or placebo . The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID ; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily . The apparent renal clearance ( CL/F ) and volume of distribution ( V/F ) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling . RESULTS The high-body-weight group consisted of 35 subjects ( 65.7 % male ; 77.1 % white ; mean age , 15.2 years ) . The low-body-weight group consisted of 37 subjects ( 37.8 % male ; 48.6 % white ; mean age , 14.3 years ) . The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d . The CL/F for a 70-kg adolescent was 10.4 L/h , comparable to that in a 70-kg adult . The estimated varenicline V/F was decreased in individuals of small body size , thus predicting a varenicline C(max ) approximately 30 % greater in low-body-weight subjects than in high-body-weight subjects . In high-body-weight subjects , steady-state varenicline exposure , as represented by the AUC(0 - 24 ) , was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID , consistent with values reported previously in adult smokers at the equivalent doses . In low-body-weight subjects , varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily , values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID , respectively . Among high-body-weight subjects , adverse events ( AEs ) were reported by 57.1 % of subjects in both the high- and low-dose varenicline groups and by 14.3 % of subjects in the placebo group ; among low-body-weight subjects , AEs were reported by 64.3 % , 73.3 % , and 12.5 % of subjects in the high-dose varenicline , low-dose varenicline , and placebo groups , respectively . The most common AEs were nausea , headache , vomiting , and dizziness . Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild , transient anger in 1 subject . Of the AEs reported by > or = 1 subject in any treatment group , > or = 92 % were mild in intensity . No subject discontinued the study because of an AE . CONCLUSIONS Varenicline steady-state exposure in study subjects weighing > 55 kg was similar to that observed previously in adults . The body-weight effect on varenicline pharmacokinetics , which result ed in higher exposure in individuals of smaller body size ( < or = 55 kg ) , was adequately offset by administration of half the varenicline dose recommended in adults . Varenicline was generally well tolerated during the 14-day treatment period . Clinical Trials Identification Number : NCT00463918 Background — Smoking cessation is a key component of secondary cardiovascular disease prevention . Varenicline , a partial & agr;4&bgr;2 nicotinic acetylcholine receptor agonist , is effective for smoking cessation in healthy smokers , but its efficacy and safety in smokers with cardiovascular disease are unknown . Methods and Results — A multicenter , r and omized , double-blind , placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease . Participants received varenicline ( 1 mg twice daily ) or placebo , along with smoking-cessation counseling , for 12 weeks . Follow-up lasted 52 weeks . The primary end point was carbon monoxide – confirmed continuous abstinence rate for weeks 9 through 12 ( last 4 weeks of treatment ) . The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 ( 47.0 % versus 13.9 % ; odds ratio , 6.11 ; 95 % confidence interval [ CI ] , 4.18 to 8.93 ) and weeks 9 through 52 ( 19.2 % versus 7.2 % ; odds ratio , 3.14 ; 95 % CI , 1.93 to 5.11 ) . The varenicline and placebo groups did not differ significantly in cardiovascular mortality ( 0.3 % versus 0.6 % ; difference , −0.3 % ; 95 % CI , −1.3 to 0.7 ) , all-cause mortality ( 0.6 % versus 1.4 % ; difference , −0.8 % ; 95 % CI , −2.3 to 0.6 ) , cardiovascular events ( 7.1 % versus 5.7 % ; difference , 1.4 % ; 95 % CI , −2.3 to 5.0 ) , or serious adverse events ( 6.5 % and 6.0 % ; difference , 0.5 % ; 95 % CI , −3.1 to 4.1 ) . As a result of adverse events , 9.6 % of varenicline and 4.3 % of placebo participants discontinued study drug . Conclusions — Varenicline is effective for smoking cessation in smokers with cardiovascular disease . It was well tolerated and did not increase cardiovascular events or mortality ; however , trial size and duration limit definitive conclusions about safety . Clinical Trial Registration Information— URL : http://www . clinical trials.gov/ct2/show/NCT00282984 . Unique identifier : NCT00282984 BACKGROUND Currently available smoking cessation therapies have limited success rates . Varenicline tartrate is a novel , selective nicotinic receptor partial agonist developed specifically for smoking cessation . This study evaluated the efficacy , tolerability , and safety of 3 varenicline doses for smoking cessation . Bupropion hydrochloride was included as an active control . METHODS A phase 2 , multicenter , r and omized , double-blind , placebo-controlled study of healthy smokers ( 18 - 65 years old ) . Subjects were r and omized to varenicline tartrate , 0.3 mg once daily ( n = 128 ) , 1.0 mg once daily ( n = 128 ) , or 1.0 mg twice daily ( n = 127 ) , for 6 weeks plus placebo for 1 week ; to 150-mg sustained-release bupropion hydrochloride twice daily ( n = 128 ) for 7 weeks ; or to placebo ( n = 127 ) for 7 weeks . RESULTS During the treatment phase , the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate , 1.0 mg twice daily ( 48.0 % ; P<.001 ) and 1.0 mg once daily ( 37.3 % ; P<.001 ) , than for placebo ( 17.1 % ) . The bupropion rate was 33.3 % ( P = .002 vs placebo ) . The carbon monoxide-confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate , 1.0 mg twice daily , group compared with the placebo group ( 14.4 % vs 4.9 % ; P = .002 ) . The bupropion rate was 6.3 % ( P = .60 vs placebo ) . Discontinuation owing to treatment-emergent adverse events was 15.9 % for bupropion , 11.2 % to 14.3 % for varenicline , and 9.8 % for placebo . No dose-related increases occurred in adverse events for varenicline . CONCLUSIONS Varenicline tartrate demonstrated both short-term ( 1 mg twice daily and 1 mg once daily ) and long-term efficacy ( 1 mg twice daily ) vs placebo . Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation Objective : The objective of this double-blind , placebo-controlled , r and omized study was to evaluate the efficacy of varenicline ( Chantix ) , a partial agonist at α4β2 neuronal nicotinic acetylcholine receptors used for smoking cessation , in patients with spinocerebellar ataxia ( SCA ) 3 . Methods : Patients with genetically confirmed SCA3 were r and omly assigned to receive either varenicline ( 4 weeks for titration and 4 weeks at a dose of 1 mg twice daily ) or placebo . Outcome measures included changes in the Scale for the Rating and Assessment of Ataxia ( SARA ) scores at endpoint ( 8 weeks ) compared with baseline , a timed 25-foot walk and 9-hole peg test , measurements of mood and anxiety , and adverse events . Results : Twenty patients with SCA3 ( mean age = 51 ± 10.98 years ; mean disease duration = 14 ± 9.82 years ; mean SARA score = 16.13 ± 4.67 ) were enrolled in the study , and data on 18 patients were analyzed in period I. The most common side effect associated with varenicline was nausea . Improvements were noted in the SARA subsections for gait ( p = 0.04 ) , stance ( p = 0.03 ) , rapid alternating movements ( p = 0.003 ) , and timed 25-foot walk ( p = 0.05 ) and Beck Depression Inventory scores ( p = 0.03 ) in patients taking varenicline compared with those taking placebo at endpoint , with a trend toward improvement in the SARA total score ( p = 0.06 ) in the varenicline group . Conclusions : In this controlled study , varenicline significantly improved axial symptoms and rapid alternating movements in patients with SCA3 as measured by SARA subscores and was fairly well tolerated . Classification of evidence : This study provides Class II evidence that varenicline improved the axial functions of gait , stance , and timed 25-foot walk but did not improve appendicular function , except for rapid alternating movements , in adult patients with genetically confirmed SCA3 BACKGROUND The selective nicotinic acetylcholine receptor partial agonist , varenicline tartrate , represents a novel type of therapy for smoking cessation . This study evaluated the efficacy , safety , and tolerability of 4 varenicline dose regimens , 2 with progressive dosing over the first week ( eg , titrated ) and 2 with a fixed dosing schedule ( eg , non-titrated ) , for promoting smoking cessation . METHODS This multicenter , double-blind , placebo-controlled study r and omized healthy smokers ( aged 18 - 65 years ) to varenicline tartrate , 0.5 mg twice daily nontitrated ( n = 129 ) , 0.5 mg twice daily titrated ( n = 130 ) , 1.0 mg twice daily nontitrated ( n = 129 ) , 1.0 mg twice daily titrated ( n = 130 ) , or placebo ( n = 129 ) for 12 weeks to aid in smoking cessation . A 40-week follow-up period assessed long-term efficacy . The primary efficacy measures were the carbon monoxide-confirmed 4-week continuous quit rates by pooled dosage group for weeks 4 through 7 and 9 through 12 and the continuous abstinence rates for weeks 9 through 52 . RESULTS Weeks 9 through 12 continuous quit rates were greater in the 1.0-mg group ( 49.4 % ) and the 0.5-mg group ( 44.0 % ) vs placebo ( 11.6 % ; P<.001 vs both doses ) . Weeks 9 through 52 abstinence rates were greater in the 1.0-mg group ( 22.4 % ; P<.001 ) and the 0.5-mg group ( 18.5 % ; P<.001 ) vs placebo ( 3.9 % ) . Varenicline was generally well tolerated , with nausea occurring in 16 % to 42 % of varenicline-treated subjects . Reports of nausea were lower for the titrated vs nontitrated dosing and infrequently led to medication discontinuation . CONCLUSION Varenicline tartrate , 0.5 mg and 1.0 mg twice daily , is efficacious for smoking cessation INTRODUCTION This study evaluated the effect of varenicline in combination with counseling to assist long-term nicotine replacement therapy ( NRT ) users to quit NRT . METHODS This was a double-blind , placebo-controlled , r and omized trial of varenicline or placebo for 12 weeks , with 52-week follow-up , performed in 1 hospital-based smoking cessation specialist clinic . At the first visit , 139 ex-smokers and long-term NRT users were allocated to treatment according to a computer-generated list with r and om numbers . Visits were scheduled at Weeks 0 , 2 , 4 , 6 , 9 , 12 , and 52 . At each visit , nurse-led counseling was delivered , carbon monoxide in expired air , plasma cotinine , and body weight were assessed , and subjects were asked about craving , nausea , and dreams . The primary outcome was 12-week point prevalence quit rate ( PPR ) of nicotine replacement therapy use . RESULTS At all time points , the PPR was superior for varenicline versus placebo , although the difference was only statistically significant at 12 and 36 weeks . The PPR was 64.3 % ( varenicline ) versus 40.6 % ( placebo ) at 12 weeks ( p = .006 ) , and 42.9 % ( varenicline ) versus 36.2 % ( placebo ) at 52 weeks ( NS ) . The continuous abstinence rate from Week 9 to Week 12 was 48.6 % ( varenicline ) versus 30.4 % ( placebo ) ( p = .03 ) . Withdrawal symptoms were statistically significantly lower in the varenicline group than the placebo group . CONCLUSION Varenicline for 12 weeks combined with supportive visits was superior to placebo to get long-term NRT users to quit NRT . A larger study is needed to evaluate long-term efficacy OBJECTIVE Virtually no clinical trials for smoking cessation have been undertaken in bipolar disorder . Varenicline has shown efficacy for smoking cessation , but warnings about neuropsychiatric adverse events have been issued . We assessed the efficacy and safety of varenicline in euthymic bipolar subjects motivated to quit smoking . METHOD Clinical ly stable adult patients with DSM-IV bipolar disorder ( n = 60 ) who smoked ≥ 10 cigarettes per day were r and omized to a 3-month , double-blind , placebo-controlled varenicline trial and a 3-month follow-up . Study enrollment was completed from February 2010 through March 2013 . Varenicline was dosed using st and ard titration , and smoking cessation counseling was provided to all patients . The primary outcome was defined as a 7-day point prevalence of self-reported no smoking verified by expired carbon monoxide level < 10 ppm at 12 weeks . Psychopathology and side-effects were assessed at each visit . RESULTS At 3 months ( end of treatment ) , significantly more subjects quit smoking with varenicline ( n/n = 15/31 , 48.4 % ) than with placebo ( n/n = 3/29 , 10.3 % ) ( OR = 8.1 ; 95 % CI , 2.03 - 32.5 ; P < .002 ) . At 6 months , 6 of 31 varenicline-treated subjects ( 19.4 % ) remained abstinent compared to 2 of 29 ( 6.90 % ) assigned to placebo ( OR = 3.2 ; 95 % CI , 0.60 - 17.6 ; P = .17 ) . Psychopathology scores remained stable . Ten serious adverse events occurred ( n = 6 , varenicline ; n = 4 , placebo ) . Abnormal dreams occurred significantly more often in varenicline-treated subjects ( n/n = 18/31 , 61.3 % ) than in those receiving placebo ( n/n = 9/29 , 31 % ; Fisher exact test , P = .04 ) . Eight varenicline-treated and 5 placebo-assigned subjects expressed fleeting suicidal ideation , a nonsignificant difference . CONCLUSIONS Varenicline shows efficacy for initiating smoking cessation in bipolar patients , but medication trials of longer duration are warranted for maintaining abstinence . Vigilance for neuropsychiatric adverse events is prudent when initiating varenicline for smoking cessation in this patient population . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01010204 Background : The efficacy of perioperative tobacco interventions on long-term abstinence and the safety of smoking cessation less than 4 weeks before surgery is unclear . Our objective was to determine the efficacy and safety of a perioperative smoking cessation intervention with varenicline to reduce smoking in elective surgical patients . Methods : In a prospect i ve , multicenter , double-blind , placebo-controlled trial , 286 patients were r and omized to receive varenicline or placebo . Both groups received in-hospital and telephone counseling during 12 months . The primary outcome was the 7-day point prevalence abstinence rate 12 months after surgery . Secondary outcomes included abstinence at 3 and 6 months after surgery . Multivariable logistic regression was used to identify independent variables related to abstinence . Results : The 7-day point prevalence abstinence at 12 months for varenicline versus placebo was 36.4 % versus 25.2 % ( relative risk : 1.45 ; 95 % : CI : 1.01–2.07 ; P = 0.04 ) . At 3 and 6 months , the 7-day point prevalence abstinence was 43.7 % versus 31.9 % ( relative risk : 1.37 ; 95 % CI : 1.01 to 1.86 ; P = 0.04 ) , and 35.8 % versus 25.9 % ( relative risk : 1.43 ; 95 % : CI 1.01–2.04 ; P = 0.04 ) for varenicline versus placebo , respectively . Treatment with varenicline ( odds ratio : 1.76 ; 95 % CI : 1.03–3.01 ; P = 0.04 ) , and preoperative nicotine dependence ( odds ratio : 0.82 , 95 % CI : 0.68 to 0.98 ; P = 0.03 ) predicted abstinence at 12 months . The adverse events profile in both groups was similar except for nausea , which occurred more frequently for varenicline versus placebo ( 13.3 % vs. 3.7 % , P = 0.004 ) . Conclusions : A perioperative smoking cessation intervention with varenicline increased abstinence from smoking 3 , 6 , and 12 months after elective noncardiac surgery with no increase in serious adverse events The aim of this study is to examine the effects of treatment with varenicline , a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor , on cognitive impairments in people with schizophrenia . In all , 120 clinical ly stable people with schizophrenia participated in r and omized , double-blind , placebo-controlled 8-week trial . Antipsychotic and concomitant medication doses remained fixed throughout the study . Varenicline was titrated up to 1 mg twice daily for weeks 2–8 . Neuropsychological , clinical , and safety assessment s were administered at baseline and weeks 1 , 2 , 4 , and 8 . In the primary analyses of neurocognitive differences at week 8 , no varenicline – placebo differences were significant . In secondary longitudinal analyses , varenicline improved compared with placebo on the Digital Symbol Substitution Test ( p=0.013 ) and the Wisconsin Card Sorting Test non-perseverative errors ( p=0.043 ) . Some treatment effects were different between smokers and non-smokers . In smokers , Continuous Performance Test hit reaction time ( p=0.008 ) and Stroop Interference ( p=0.004 ) were reduced for varenicline compared with placebo , while there were no treatment differences in non-smokers . No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms . Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia . In some cases , effects of treatment varied between smokers and non-smokers . Further study is required to assess the functional significance of these changes IMPORTANCE Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release ( SR ) on neurobiological targets related to affect and reward , it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness . OBJECTIVE To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning . DESIGN AND SETTING Placebo-controlled r and omized clinical trial at a university medical center . PARTICIPANTS In total , 294 community volunteers who wanted to quit smoking . INTERVENTIONS Twelve weeks of varenicline , bupropion SR , or placebo plus intensive smoking cessation counseling ( 10 sessions , for a total of approximately 240 minutes of counseling ) . MAIN OUTCOME MEASURES Prolonged abstinence from smoking and weekly measures of depression , negative affect , and other symptoms of nicotine withdrawal . RESULTS Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit , favoring both active medications compared with placebo . At the 6-month postquit follow-up visit , only the varenicline vs placebo comparison remained significant . Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments , while both active medications improved concentration , reduced craving , and decreased negative affect and sadness compared with placebo , while having little effect ( increase or decrease ) on anxiety and anger . No differences were noted in self-reported rates of neuropsychiatric adverse events . CONCLUSIONS AND RELEVANCE In a community sample , varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable ( suppressive ) effect on symptoms of depression and other affective measures , with no clear unfavorable effect on neuropsychiatric adverse events . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00507728 Rationale Emerging evidence suggests that the α4β2 form of the nicotinic acetylcholine receptor ( nAChR ) modulates the rewarding effects of alcohol . The nAChR α4β2 subunit partial agonist varenicline ( Chantix ™ ) , which is approved by the Food and Drug Administration for smoking cessation , also decreases ethanol consumption in rodents ( Steensl and et al. , Proc Natl Acad Sci U S A 104:12518–12523 , 2007 ) and in human laboratory and open-label studies ( Fucito et al. , Psychopharmacology ( Berl ) 215:655–663 , 2011 ; McKee et al. , Biol Psychiatry 66:185–190 2009 ) . Objectives We present a r and omized , double-blind , 16-week study in heavy-drinking smokers ( n = 64 r and omized to treatment ) who were seeking treatment for their smoking . The study was design ed to determine the effects of varenicline on alcohol craving and consumption . Outcome measures included number of alcoholic drinks per week , cigarettes per week , amount of alcohol craving per week , cumulative cigarettes and alcoholic drinks consumed during the treatment period , number of abstinent days , and weekly percentage of positive ethyl glucuronide and cotinine screens . Results Varenicline significantly decreases alcohol consumption ( χ2 = 35.32 , p < 0.0001 ) in smokers . Although varenicline has previously been associated with suicidality and depression , side effects were low in this study and declined over time in the varenicline treatment group . Conclusions Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke . Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking Objective To assess the efficacy and safety of varenicline ( a licensed cigarette smoking cessation aid ) in helping users of smokeless tobacco to quit . Design Double blind , placebo controlled , parallel group , multicentre , r and omised controlled trial . Setting Medical clinics ( mostly primary care ) in Norway and Sweden . Participants Men and women aged ≥18 who used smokeless tobacco at least eight times a day , with no abstinence period over three months within one year before screening , who wanted to quit all tobacco use . Participants were excluded if they used any other form of tobacco ( except smokeless tobacco ) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition . Interventions Varenicline 1 mg twice daily ( titrated during the first week ) or placebo for 12 weeks , with 14 weeks ’ follow-up after treatment . Main outcome measures The primary end point was the four week continuous abstinence rate at the end of treatment ( weeks 9 - 12 ) confirmed with cotinine concentration . A secondary end point was continuous abstinence rate for weeks 9 - 26 . Safety and tolerability were also evaluated . Results 431 participants ( 213 varenicline ; 218 placebo ) were r and omised and received at least one dose of study drug . Participants ’ demographics and baseline use of smokeless tobacco were similar ( 89 % ( 189 ) and 90 % ( 196 ) , respectively , were men ; mean age in both groups was 43.9 ; participants used smokeless tobacco products about 15 times a day , and about 80 % first used smokeless tobacco within 30 minutes after awakening ) . Continuous abstinence rate at week 9 - 12 was higher in the varenicline group than the placebo group ( 59 % ( 125 ) v 39 % ( 85 ) ; relative risk 1.60 , 95 % confidence interval 1.32 to 1.87 , P<0.001 ; risk difference 20 % ; number needed to treat 5 ) . The advantage of varenicline over placebo persisted through 14 weeks of follow-up ( continuous abstinence rate at week 9 - 26 was 45 % ( 95 ) v 34 % ( 73 ) ; relative risk 1.42 , 1.08 to 1.79 , P=0.012 ; risk difference 11 % ; number needed to treat 9 ) . The most common adverse events in the varenicline group compared with the placebo group were nausea ( 35 % ( 74 ) v 6 % ( 14 ) ) , fatigue ( 10 % ( 22 ) v 7 % ( 15 ) ) , headache ( 10 % ( 22 ) v 9 % ( 20 ) ) , and sleep disorder ( 10 % ( 22 ) v 7 % ( 15 ) ) . Few adverse events led to discontinuation of treatment ( 9 % ( 19 ) and 4 % ( 9 ) , respectively ) , and serious adverse events occurred in two ( 1 % ) and three ( 1 % ) participants , respectively . Conclusion Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile . The response rate in the placebo group in this study was high , suggesting a population less resistant to treatment than smokers . Trial Registration NCT00717093 Introduction : Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy . However , providing flexibility in the date of quitting may be more acceptable to some smokers . The objective of this study was to compare varenicline 1 mg twice daily ( b.i.d . ) with placebo in subjects using a flexible quit date paradigm after starting medication . Methods : In this double-blind , r and omized , placebo-controlled international study , smokers of ≥10 cigarettes/day , aged 18–75 years , and who were motivated to quit were r and omized ( 3:1 ) to receive varenicline 1 mg b.i.d . or placebo for 12 weeks . Subjects were followed up through Week 24 . Subjects were instructed to quit between Days 8 and 35 after starting medication . The primary endpoint was carbon monoxide – confirmed continuous abstinence during Weeks 9–12 , and a key secondary endpoint was continuous abstinence during Weeks 9–24 . Results : Overall , 493 subjects were r and omized to varenicline and 166 to placebo . Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment ( Weeks 9–12 : 53.1 % vs. 19.3 % ; odds ratio [ OR ] 5.9 ; 95 % CI , 3.7–9.4 ; p < .0001 ) and through 24 weeks follow-up ( Weeks 9–24 : 34.7 % vs. 12.7 % ; OR 4.4 ; 95 % CI , 2.6–7.5 ; p < .0001 ) . Serious adverse events occurred in 1.2 % varenicline ( none were psychiatric ) and 0.6 % placebo subjects . Fewer varenicline than placebo subjects reported depression-related adverse events ( 2.3 % vs. 6.7 % , respectively ) . Conclusions : Varenicline 1 mg b.i.d . using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies BACKGROUND Alcohol use , abuse and dependence remain a pressing public health problem . Based on its mechanism of action , varenicline seemed to be a likely c and i date for treating alcohol dependence . METHODS Alcohol dependent subjects ( n=40 ) were enrolled in a 13-week double-blind placebo controlled clinical trial . Subject visits were once per week . At each visit , subjects were tested for breath alcohol levels , provided self-report data on alcohol and nicotine use , and on mood and craving . In addition , subjects received once a week medical management ( MM ) . RESULTS There was no difference between varenicline and placebo treated groups on any of the drinking outcomes . Compared to placebo-treated subjects , varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking , as well as greater mood improvements during the later part of the study ( weeks 6 - 13 ) . In addition , among subjects who were cigarette smokers , those treated with varenicline were significantly less likely to report heavy drinking during the trial . CONCLUSIONS Although varenicline was not significantly more effective than placebo at reducing drinking during the trial , its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline , as well as additional clinical studies may be warranted . In particular , the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies OBJECTIVE In 2009 , the U.S. Food and Drug Administration issued a black box warning for varenicline regarding neuropsychiatric events . The authors used data from r and omized controlled trials and from a large Department of Defense ( DOD ) observational study to assess the efficacy and safety of varenicline . METHOD The authors reanalyzed data from the 17 placebo-controlled r and omized controlled trials ( N=8,027 ) of varenicline conducted by Pfizer , using complete intent-to-treat person-level longitudinal data to assess smoking abstinence and reports of suicidal thoughts and behavior , depression , aggression/agitation , and nausea and to compare effects in patients with ( N=1,004 ) and without ( N=7,023 ) psychiatric disorders . The authors also analyzed a large DOD data set to compare acute ( 30-day and 60-day ) rates of neuropsychiatric adverse events in patients receiving varenicline or nicotine replacement therapy ( N=35,800 ) and to assess reports of anxiety , mood , and psychotic symptoms and disorders , other mental disorders , and suicide attempt . RESULTS In the r and omized controlled trials , varenicline increased the risk of nausea ( odds ratio=3.69 , 95 % CI=3.03 - 4.48 ) but not rates of suicidal events , depression , or aggression/agitation . It significantly increased the abstinence rate , by 124 % compared with placebo and 22 % compared with bupropion . Having a current or past psychiatric illness increased the risk of neuropsychiatric events equally in treated and placebo patients . In the DOD study , after propensity score matching , the overall rate of neuropsychiatric disorders was significantly lower for varenicline than for nicotine replacement therapy ( 2.28 % compared with 3.16 % ) . CONCLUSIONS This analysis revealed no evidence that varenicline is associated with adverse neuropsychiatric events . The evidence supports the superior efficacy of varenicline relative to both placebo and bupropion , indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events , in individuals with and without a recent history of a psychiatric disorder BACKGROUND Prevalence rates of smoking are rising in developing countries . Previous trials evaluating the efficacy and tolerability of the smoking-cessation medication varenicline have used largely participants of Caucasian origin . OBJECTIVE This study was conducted to evaluate the efficacy and tolerability of varenicline in population s of participants from Latin America , Africa , and the Middle East to investigate potential differences in the therapeutic response to varenicline . METHODS This multinational , r and omized , double-blind , placebo-controlled trial was conducted at 42 centers in 11 countries ( Latin America : Brazil , Colombia , Costa Rica , Mexico , and Venezuela ; Africa : Egypt and South Africa ; Middle East : Jordan , Lebanon , Saudi Arabia , and the United Arab Emirates ) . Participants were male and female smokers aged 18 to 75 years who were motivated to stop smoking ; smoked ≥10 cigarettes/d , with no cumulative period of abstinence > 3 months in the previous year ; and who had no serious or unstable disease within the previous 6 months . Subjects were r and omized in a 2:1 ratio to receive varenicline 1 mg or placebo , BID for 12 weeks , with a 12-week nontreatment follow-up . Brief smoking-cessation counseling was provided . The main outcome measures were carbon monoxide-confirmed continuous abstinence rate ( CAR ) at weeks 9 to 12 and weeks 9 to 24 . Adverse events ( AEs ) were recorded for tolerability assessment . RESULTS Overall , 588 subjects ( varenicline , 390 ; placebo , 198 ) were r and omized and treated . The mean ( SD ) ages of subjects in the varenicline and placebo groups were 43.1 ( 10.8 ) and 43.9 ( 10.8 ) years , respectively ; 57.7 % and 65.7 % were male ; and the mean ( SD ) weights were 75.0 ( 16.0 ) and 76.7 ( 16.3 ) kg ( range , 40.0 - 130.0 and 45.6 - 126.0 kg ) . CAR at weeks 9 to 12 was significantly higher with varenicline than with placebo ( 53.59 % vs 18.69 % ; odds ratio [ OR ] = 5.76 ; 95 % CI , 3.74 - 8.88 ; P < 0.0001 ) , and this rate was maintained during weeks 9 to 24 ( 39.74 % vs 13.13 % ; OR = 4.78 ; 95 % CI , 2.97 - 7.68 ; P < 0.0001 ) . Nausea , headache , and insomnia were the most commonly reported AEs with varenicline and were reported numerically more frequently in the varenicline group compared with the placebo group . Serious AEs ( SAEs ) were reported in 2.8 % of varenicline recipients compared with 1.0 % in the placebo group , with 6 subjects reporting psychiatric SAEs compared with none in the placebo group . CONCLUSION Based on these data , varenicline was apparently efficacious and generally well tolerated as a smoking-cessation aid in smokers from selected sites in Latin America , Africa , and the Middle East . Clinical Trials.gov identifier : NCT00594204 OBJECTIVE Effective smoking cessation treatments are needed for patients with schizophrenia , who , compared with the general population , have high rates of cigarette smoking and more difficulty quitting . We evaluated the safety and efficacy of varenicline for smoking cessation in out patients with stable schizophrenia or schizoaffective disorder . METHOD In this 12-week , r and omized , double-blind , multicenter trial ( May 8 , 2008 , to April 1 , 2010 ) , 127 smokers ( ≥ 15 cigarettes/d ) with DSM-IV-confirmed schizophrenia or schizoaffective disorder received varenicline or placebo ( 2:1 ratio ) . The primary outcome was safety and tolerability of varenicline assessed by adverse events frequency and changes in ratings on the Positive and Negative Syndrome Scale and other psychiatric scales from baseline to 24 weeks . Abstinence was defined as no smoking 7 days prior to weeks 12 and 24 , verified by carbon monoxide level . RESULTS Eighty-four participants received varenicline ; 43 , placebo . At 12 weeks ( end of treatment ) , 16/84 varenicline-treated patients ( 19.0 % ) met smoking cessation criteria versus 2/43 ( 4.7 % ) for placebo ( P = .046 ) . At 24 weeks , 10/84 ( 11.9 % ) varenicline-treated and 1/43 ( 2.3 % ) placebo-treated patients , respectively , met abstinence criteria ( P = .090 ) . Total adverse event rates were similar between groups , with no significant changes in symptoms of schizophrenia or in mood and anxiety ratings . Rates of suicidal ideation adverse events were 6.0 % ( varenicline ) and 7.0 % ( placebo ) ( P = 1.0 ) . There was 1 suicide attempt by a varenicline patient with a lifetime history of similar attempts and no completed suicides . CONCLUSIONS Varenicline was well tolerated , with no evidence of exacerbation of symptoms , and was associated with significantly higher smoking cessation rates versus placebo at 12 weeks . Our findings suggest varenicline is a suitable smoking cessation therapy for patients with schizophrenia or schizoaffective disorder . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00644969 CONTEXT The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder . It is not yet clear which nicotinic acetylcholine receptor ( nAChR ) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder . OBJECTIVE Because α4β2 is a key nAChR subtype for nicotinic actions , we investigated the effect of varenicline tartrate , a relatively specific α4β2 partial agonist and antagonist , on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans . DESIGN A double-blind , parallel , r and omized , placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks ( short-term treatment ) and 8 weeks ( long-term treatment ) , using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects . SETTING Outpatient clinics . PARTICIPANTS A total of 69 smoking and nonsmoking patients ; 64 patients completed week 2 , and 59 patients completed week 8 . Intervention Varenicline . MAIN OUTCOME MEASURES Prepulse inhibition , sensory gating , antisaccade , spatial working memory , eye tracking , processing speed , and sustained attention . RESULTS A moderate dose of varenicline ( 1 ) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment ( P = .006 ) , ( 2 ) reduced startle reactivity ( P = .02 ) regardless of baseline smoking status , and ( 3 ) improved executive function by reducing the antisaccadic error rate ( P = .03 ) regardless of smoking status . A moderate dose of varenicline had no significant effect on spatial working memory , predictive and maintenance pursuit measures , processing speed , or sustained attention by Conners ' Continuous Performance Test . Clinical ly , there was no evidence of exacerbation of psychiatric symptoms , psychosis , depression , or suicidality using a gradual titration ( 1-mg daily dose ) . CONCLUSIONS Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers . Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits CONTEXT The majority of cigarette smokers who achieve abstinence relapse within the first year and require many attempts before achieving permanent abstinence . Evidence to support pharmacological treatment for relapse prevention is insufficient . OBJECTIVE To determine whether smokers who quit after 12 weeks of treatment with varenicline , a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist , maintain greater continuous abstinence rates ( defined as not a single " puff " of a cigarette ) than placebo controls during an additional 12 weeks of treatment and until 52 weeks after treatment initiation . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at multiple medical clinics in 7 countries with follow-up to 52 weeks after study baseline . Of 1927 cigarette smokers recruited between April 2003 and February 2004 and treated for 12 weeks with open-label varenicline titrated to 1 mg twice per day , 1236 ( 64.1 % ) did not smoke , use tobacco , or use nicotine replacement therapy during the last week of treatment and 62.8 % ( n = 1210 ) were r and omized to additional treatment or placebo . INTERVENTION Participants were r and omly assigned to receive either double-blind varenicline , 1 mg twice per day ( n = 603 ) , or placebo ( n = 607 ) for an additional 12 weeks . MAIN OUTCOME MEASURES Carbon monoxide-confirmed continued abstinence during weeks 13 to 24 and weeks 13 to 52 of the study . RESULTS The carbon monoxide-confirmed continuous abstinence rate was significantly higher for the varenicline group than for the placebo group for weeks 13 to 24 ( 70.5 % vs 49.6 % ; odds ratio [ OR ] , 2.48 ; 95 % confidence interval [ CI ] , 1.95 - 3.16 ; P<.001 ) as well as for weeks 13 to 52 ( 43.6 % vs 36.9 % ; OR , 1.34 ; 95 % CI , 1.06 - 1.69 ; P = .02 ) . Adverse events reported in the open-label period were mostly mild ; no difference in adverse events between varenicline and placebo was observed during the double-blind period . CONCLUSIONS Smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment and were r and omized to receive an additional 12 weeks of varenicline treatment showed significantly greater continuous abstinence in weeks 13 to 24 compared with placebo . This advantage was maintained through the nontreatment follow-up to week 52 . Varenicline may be an efficacious , safe , and well-tolerated agent for maintaining abstinence from smoking . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00143286 INTRODUCTION Long-term smokeless tobacco ( ST ) use is known to increase the risk for oropharyngeal cancer , heart attack , and stroke . Varenicline has recently been demonstrated to increase ST abstinence rates among Swedish snus users . We have conducted a pilot study to obtain preliminary evidence of efficacy of varenicline for the treatment of ST users in Midwestern United States . METHODS We conducted a r and omized , placebo-controlled Phase II clinical trial to evaluate the potential efficacy of 12 weeks of varenicline for the treatment of ST users with an a priori decision rule that a 1-tailed p < .20 for the comparison of the primary endpoint was evidence to conclude that future studies were warranted . Subjects were followed for 6 months after r and omization . RESULTS We r and omized 76 subjects ( 38 varenicline and 38 placebo ) . Subjects were similar at baseline with a mean age of 41 years , and all were male . The biochemically confirmed point prevalence tobacco abstinence rates at end of treatment were 55.3 % for varenicline and 42.1 % for placebo ( p = .126 ) and 47.4 % and 31.6 % ( p = .080 ) , respectively , at 6 months . Point prevalence ST abstinence rates at end of treatment for varenicline were 57.9 % and 42.1 % for placebo ( p = .084 ) and 57.9 % and 31.6 % ( p = .011 ) , respectively , at 6 months . Varenicline was associated with significantly less craving compared with placebo . Varenicline was well tolerated with nausea and sleep disturbance being the most common side effects . CONCLUSIONS Varenicline decreases craving and may be effective for increasing tobacco abstinence rates among ST users . Larger trials may be warranted to confirm these results The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this r and omized , double‐blind , placebo‐controlled , multicenter trial ( Australia , Belgium , Canada , the Czech Republic , France , Germany , the United Kingdom , and the United States ) . Participants were generally healthy adult smokers ( ≥10 cigarettes/day ) with ≥1 prior quit attempt ( ≥2 weeks ) using varenicline and no quit attempts in ≤3 months ; they were r and omly assigned ( 1:1 ) to 12 weeks ' varenicline ( n = 251 ) or placebo ( n = 247 ) treatment , with individual counseling , plus 40 weeks ' nontreatment follow‐up . The primary efficacy end point was the carbon monoxide – confirmed ( ≤10 ppm ) continuous abstinence rate for weeks 9–12 , which was 45.0 % ( varenicline ; n = 249 ) vs. 11.8 % ( placebo ; n = 245 ; odds ratio : 7.08 ; 95 % confidence interval : 4.34 , 11.55 ; P < 0.0001 ) . Common varenicline group adverse events were nausea , abnormal dreams , and headache , with no reported suicidal behavior . Varenicline is efficacious and well tolerated in smokers who have previously taken it . Abstinence rates are comparable with rates reported for varenicline‐naive smokers Varenicline is an effective and increasingly prescribed drug for smoking cessation , but has been associated with depressive symptoms and suicidal behavior . However , it remains unclear whether those changes in mood and behavior are directly related to varenicline use , or caused by smoking cessation itself or reflects depression and suicidality rates in smokers , independent of treatment . To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation , we assessed the effects of varenicline on emotional processing ( a biomarker of depressogenic effects ) , emotion-potentiated startle reactivity , impulsivity ( linked with suicidal behavior ) , and cognitive performance in non-smoking subjects . We used a r and omized , double-blind design , in which we administered varenicline or placebo to healthy subjects over 7 days ( 0.5 mg/day first 3 days , then 1 mg/day ) . Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response . A total of 41 subjects were r and omized , with 38 subjects included in the analysis . The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood . However , compared with placebo , the varenicline group scored higher on working and declarative memory . In conclusion , short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects , thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects . In contrast , varenicline may have cognitive-enhancing effects BACKGROUND With smoking rates far exceeding the general population , methadone-maintained ( MMT ) opiate-dependent smokers experience high rates of tobacco-related health consequences . Previous treatment studies have used nicotine replacement and produced low quit rates . METHODS We test , using a three-group r and omized design , the efficacy of varenicline versus placebo , in comparison with nicotine replacement therapy ( NRT ) that combines nicotine patch prescription plus ad libitum nicotine rescue , for smoking cessation . We recruited methadone-maintained smokers from nine treatment centers in southern New Engl and and provided six months of treatment , and a minimal behavioral intervention at baseline ( NCI 's 5A 's ) . Outcomes included carbon monoxide ( CO ) confirmed 7-day point smoking cessation prevalence at 6 months and self-reported change in mean cigarettes per day . RESULTS The 315 participants had a mean age of 40 , with 50 % male and 79 % non-Hispanic White , smoked an average of 19.6 ( ± 10.4 ) cigarettes/day , and had a mean daily methadone dose of 109 mg . Intent-to-treat analyses , with missing considered to be smoking , showed the rate of CO-confirmed 7-day abstinence at 6-months was 5.4 % overall , with varenicline 3.7 % compared to placebo 2.2 % , and NRT 8.3 % ( p>.05 ) . Adherence rates during the 7-days immediately prior to 6-month assessment were 34.2 % in varenicline , 34.4 % in placebo , and 48.8 % in NRT . Between baseline and 6-months there was an overall self-reported mean reduction of 8.3 cigarettes/day . CONCLUSION Varenicline did not increase quit rates over placebo . Smoking cessation rates in methadone-maintained smokers are low and novel treatment strategies are required Objective To compare the risk of suicide , self harm , and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy . Design Prospect i ve cohort study within the Clinical Practice Research Data link . Setting 349 general practice s in Engl and . Participants 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011 . There were 81 545 users of nicotine replacement products ( 68.2 % of all users of smoking cessation medicines ) , 6741 bupropion ( 5.6 % ) , and 31 260 varenicline ( 26.2 % ) users . Main outcome measures Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription , determined from linkage with mortality data from the Office for National Statistics ( for suicide ) and Hospital Episode Statistics data ( for hospital admissions relating to non-fatal self harm ) . Hazard ratios or risk differences were estimated using Cox multivariable regression models , propensity score matching , and instrumental variable analysis using physicians ’ prescribing preferences as an instrument . Sensitivity analyses were performed for outcomes at six and nine months . Results We detected 92 cases of fatal and non-fatal self harm ( 326.5 events per 100 000 person years ) and 1094 primary care records of treated depression ( 6963.3 per 100 000 person years ) . Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm ( hazard ratio 0.88 , 95 % confidence interval 0.52 to 1.49 ) or treated depression ( 0.75 , 0.65 to 0.87 ) compared with those prescribed nicotine replacement therapy . There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm ( 0.83 , 0.30 to 2.31 ) or of treated depression ( 0.63 , 0.46 to 0.87 ) compared with patients prescribed nicotine replacement therapy . Similar findings were obtained using propensity score methods and instrumental variable analyses . Conclusions There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy . These findings should be reassuring for users and prescribers of smoking cessation medicines OBJECTIVE We assessed the safety of long-term varenicline administration for smoking cessation . METHODS In this r and omized , double-blind , multicenter trial , eligible adult smokers ( 18 - 75 years ) who smoked an average of > or = 10 cigarettes/day were r and omized to either varenicline 1 mg twice daily ( BID ) or placebo for 52 weeks . Subjects made weekly clinic visits until week 8 , and then every 4 weeks until week 52 , with a follow-up visit at week 53 . The target quit date was the morning of the week 1 clinic visit . Brief counseling was provided at each visit , and vital signs , adverse events ( AEs ) , and smoking status were documented . Other laboratory measures were collected at specified visits . RESULTS A total of 251 subjects were r and omized to varenicline and 126 to placebo . Approximately half of the subjects in each arm completed the study ( 53.8 % varenicline ; 46.8 % placebo ) . Treatment-emergent AEs were observed in 96.4 % of varenicline- and 82.5 % of placebo-treated subjects during the study . Common varenicline-associated AEs were nausea ( 40.2 % ) , abnormal dreams ( 22.7 % ) , and insomnia ( 19.1 % ) . Most AEs were considered mild or moderate in intensity . AEs leading to discontinuation of varenicline treatment included nausea ( 7.6 % ) , insomnia ( 3.2 % ) , and abnormal dreams ( 2.4 % ) . A single varenicline-related serious AE , bilateral subcapsular cataracts , was observed . At week 52 , 7-day point prevalence abstinence rates were 36.7 % ( varenicline ) and 7.9 % ( placebo ) . CONCLUSIONS Varenicline 1 mg BID can be safely administered for up to 1 year . Varenicline was also a more effective smoking cessation aid than placebo throughout the study , supporting both its short- ( 12-week ) and long-term ( 52-week ) efficacy BACKGROUND AND OBJECTIVE Varenicline tartrate , a novel , selective , nicotinic acetylcholine receptor partial agonist , has been developed specifically as a smoking cessation drug . This study evaluated the efficacy of a st and ard regimen of varenicline compared with placebo for smoking cessation in 333 subjects in China , Singapore and Thail and . METHODS This 24-week , r and omized , double-blind , placebo-controlled trial of varenicline , 1 mg bd , consisted of a 12-week treatment period followed by a 12-week non-treatment follow-up period . The primary study end-point was the 4-week continuous abstinence rate defined as the proportion of subjects who reported total abstinence from smoking and other nicotine products from weeks 9 - 12 . A key secondary end-point was the continuous abstinence rate from weeks 9 - 24 , defined as the proportion of subjects who achieved the primary end-point as well as total abstinence from all tobacco products from weeks 13 - 24 . RESULTS Both end-points were achieved by a significantly higher proportion of subjects in the varenicline group than in the placebo group . The 4-week continuous abstinence end-point was achieved by 50.3 % and 31.6 % in the varenicline and placebo groups , respectively ( P = 0.0003 ) , while continuous abstinence from weeks 9 - 24 was achieved by 38.2 % and 25.0 % of subjects , respectively ( P = 0.0080 ) . The treatment effect was generalizable by treatment centre and country . Varenicline was safe and appeared to be well tolerated by most subjects . CONCLUSION Varenicline was significantly more efficacious for smoking cessation than placebo over a 12-week treatment period and a further 12-week non-treatment follow-up period in smokers from China , Singapore and Thail and . No significant side-effects were noted Objectives : To assess the efficacy and safety of varenicline ( Chantix ) for the treatment of alcohol dependence . Varenicline is a partial & agr;4&bgr;2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation . It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers . This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence . Methods : Men and women ( n = 200 ) meeting the criteria for alcohol dependence were recruited across 5 clinical sites . Patients received double-blind varenicline or placebo and a computerized behavioral intervention . Varenicline was titrated during the first week to 2 mg/d , which was maintained during weeks 2 to 13 . Results : The varenicline group had significantly lower weekly percent heavy drinking days ( primary outcome ) ( adjusted mean difference = 10.4 ) , drinks per day , drinks per drinking day , and alcohol craving compared with the placebo group ( P < 0.05 ) . The average treatment effect on alcohol use was similar for smokers and nonsmokers . Varenicline was well-tolerated ; adverse events were expected and mild . Conclusions : Varenicline significantly reduced alcohol consumption and craving , making it a potentially viable option for the treatment of alcohol dependence In this double-blind , placebo-controlled trial , we compared varenicline ( 2 mg ) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects . Subjects received weekly counseling during the 12-week study participation . Our results indicate that varenicline is safe to give to this subject population , as there were no adverse events related to medication during this study . Varenicline was no more effective than placebo for abstinence from cocaine . Treatment with varenicline was associated with a reduced number of cigarettes smoked per day , even though subjects received only a brief education for smoking cessation . The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence . However , self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group , although this appears to be due to r and omization differences related to lifetime depression diagnosis . These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone BACKGROUND Varenicline , a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist , has been developed specifically for smoking cessation . In Japan , 39.3 % of men smoke and this is a major public health concern . OBJECTIVE The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers . METHODS In this double-blind , placebo-controlled , r and omized , parallel-group study , subjects were r and omized to receive varenicline at 0.25 mg BID , 0.5 mg BID , 1 mg BID , or placebo for 12 weeks followed by a 40-week , nontreatment follow-up phase . The primary efficacy variable was the continuous abstinence rate ( CAR ) , defined as no reported smoking ( not even a puff ) or other nicotine use and confirmed by end-expiratory carbon monoxide level < or=10 ppm , during the last 4 weeks of treatment ( weeks 9 - 12 ) . Secondary end points included CARs for weeks 9 - 24 and 9 - 52 . Craving , withdrawal , and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale , the Brief Question naire on Smoking Urges , and the modified Cigarette Evaluation Question naire . The tolerability of varenicline was also evaluated . RESULTS Of 618 subjects who received treatment , 515 ( 83.3 % ) were classified as nicotine dependent ( scoring > or=5 on the Tobacco Dependence Screener ) , and constituted the primary analysis group . Of these , 385 ( 74.8 % ) subjects were male , and the mean age was within the range of 39.0 to 40.2 years . Across treatment groups , subjects cl aim ed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days , and the mean score on the Fagerström Test for Nicotine Dependence was within the range from 5.4 to 5.7 . The CAR for weeks 9 - 12 was significantly higher for all doses of varenicline compared with placebo ( 39.5 % [ 51/129 ] ) . The highest CAR of 65.4 % ( 85/130 ) was achieved with varenicline 1 mg BID ( odds ratio [ OR ] [ 95 % CI ] = 2.98 [ 1.78 - 4.99 ] ; P < 0.001 ) . The CAR for weeks 9 - 52 was significantly greater for varenicline 1 mg BID than placebo ( 34.6 % [ 45/130 ] vs 23.3 % [ 30/129 ] ; OR [ 95 % CI ] = 1.81 [ 1.04 - 3.17 ] ; P = 0.036 ) . The CARs for weeks 9 - 24 at 0.25 , 0.5 , and 1 mg BID were 33.6 % ( 43/128 ) , 35.2 % ( 45/128 ) , 37.7 % ( 49/130 ) , and for weeks 9 - 52 at 0.25 and 0.5 mg BID were 27.3 % ( 35/128 ) and 28.9 % ( 37/128 ) but failed to reach significance versus the placebo ( 29.5 % [ 38/129 ] for weeks 9 - 24 and 23.3 % [ 30/129 ] for weeks 9 - 52 ) . Treatment-emergent adverse events ( AEs ) were more prevalent among varenicline-treated subjects ( 79.1 % [ 121/153 ] at 0.25 mg BID , 80.6 % [ 125/155 ] at 0.5 mg BID , and 80.1 % [ 125/156 ] at 1 mg BID ) than placebo subjects ( 71.4 % [ 110/154 ] ) . The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis ( 35.9 % [ 56/156 ] ) , nausea ( 24.4 % [ 38/156 ] ) , and headache ( 10.3 % [ 16/156 ] ) , all of which were of mild or moderate intensity . Nausea was the only AE that appeared dose related ( 7.2 % [ 11/153 ] at 0.25 mg BID , 9.7 % [ 15/155 ] at 0.5 mg BID , and 24.4 % [ 38/156 ] at 1 mg BID ) versus placebo ( 7.8 % [ 12/154 ] ) . CONCLUSIONS Varenicline was associated with dose-dependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up . The dose associated with the highest efficacy was varenicline 1 mg BID OBJECTIVE To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation . RESEARCH DESIGN AND METHODS 320 healthy , motivated-to-quit smokers ( > or = 10 cigarettes/day ) aged 18 - 65 years , entered a multicenter , r and omized , double-blind , placebo-controlled study - conducted between December 26 , 2001 and June 24 , 2003 - with a 12-week treatment phase and 40-week , double-blind , non-treatment follow-up . Treatment consisted of varenicline or placebo in fixed doses ( Week 1 : titrated from 0.5 to 1.0 mg/day ) followed by a self-regulated flexible schedule ( Weeks 2 - 12 : 0.5 - 2.0 mg/day ) . MAIN OUTCOME MEASURES Primary outcomes included carbon monoxide-confirmed continuous abstinence rate ( CAR ) from smoking for Weeks 4 through 7 , 9 through 12 , and 9 through 52 . Secondary outcomes included CAR from Weeks 9 through 24 , 7-day point prevalence of abstinence , safety assessment s , and measures of craving , withdrawal , and smoking reward . RESULTS Superior CARs were observed in varenicline-treated ( n = 157 ) versus placebo participants ( n=155 ) for Weeks 4 through 7 ( 38.2 vs. 11.6 % ) , 9 through 12 ( 40.1 vs. 11.6 % ) , 9 through 24 ( 28.0 vs. 9.0 % ) , and 9 through 52 ( 22.3 vs. 7.7 % ) ( all p<0.001 ) . Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 ( 46.5 vs. 14.2 % ; p<0.001 ) , 24 ( 32.5 vs. 13.5 % ; p<0.001 ) , and 52 ( 28.0 vs. 13.5 % ; p=0.001 ) . Overall , medication compliance was high , although varenicline-treated , but not placebo , participants tended to taper down their dosage over time . Total treatment-emergent AEs were 77.1 % ( varenicline : 121/157 ) and 65.8 % ( placebo : 102/155 ) . Few AEs led to treatment discontinuation ( varenicline : 11/157 , 7.0 % and placebo : 7/155 , 4.5 % ) . Participants were primarily healthy Caucasians , so more research is necessary to determine how applicable these findings are to other population s. CONCLUSIONS A self-regulated , flexible dosing regimen of varenicline is well tolerated , with superior effectiveness versus placebo for smoking cessation OBJECTIVE The hospital can be an important opportunity for smoking cessation interventions . This is the first r and omized , double-blinded , placebo-controlled pilot trial utilizing varenicline and post-discharge , in-person behavioral treatment for hospitalized smokers . METHOD Seventy-nine smokers admitted to a university-based hospital with various diagnoses were enrolled from 2007 to 2009 . The primary outcome was biochemically confirmed abstinence at 24 weeks following discharge . Secondary outcomes included withdrawal symptoms , motivation , utilization of treatment , and medical events . RESULTS Overall abstinence at 24 weeks was 27 % with no difference between varenicline and placebo treatment groups ( 23 % vs. 31 % ) . There were no significant differences in motivation to stop smoking or withdrawal symptoms . Over 40 % of all subjects utilized post-discharge behavioral treatment with significantly higher abstinence rates compared with those who did not ( 53.1 % vs. 8.5 % , p<0.01 ) . Overall adverse events were similar in both treatment groups with the only significant difference being more nausea in the varenicline group ( 25 % vs. 5 % ; p<0.01 ) . Twenty-three subjects were re-hospitalized with no significant differences between treatment groups ( 13 varenicline vs. 10 placebo ) . CONCLUSION This pilot trial of varenicline in hospitalized smokers demonstrated feasibility of implementation , produced some hypothesis-generating findings , and suggested the potential benefit of face-to-face treatment following discharge BACKGROUND Smoking is the most important risk factor for COPD and accelerates its progression . Despite the health implication s , a large proportion of patients with COPD continue to smoke , so finding effective smoking cessation interventions for this population is paramount . To our knowledge , this is the first r and omized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD . METHODS In a 27-center , double-blind , multinational study , 504 patients with mild to moderate COPD ( postbronchodilator FEV1/FVC , < 70 % ; FEV1 percent predicted normal value , ≥50 % ) and without known psychiatric disturbances were r and omized to receive varenicline ( n=250 ) or placebo ( n=254 ) for 12 weeks , with a 40-week nontreatment follow-up . The primary end point was carbon monoxide-confirmed continuous abstinence rate ( CAR ) for weeks 9 to 12 . A secondary end point was CAR for weeks 9 to 52 . RESULTS CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group ( 42.3 % ) than for those in the placebo group ( 8.8 % ) ( OR , 8.40 ; 95 % CI , 4.99 - 14.14 ; P<.0001 ) . CAR in the patients treated with varenicline remained significantly higher than in those treated with placebo through weeks 9 to 52 ( 18.6 % vs 5.6 % ) ( OR , 4.04 ; 95 % CI , 2.13 - 7.67 ; P<.0001 ) . Nausea , abnormal dreams , upper-respiratory tract infection , and insomnia were the most commonly reported adverse events ( AEs ) for patients in the varenicline group . Serious AEs were infrequent in both treatment groups . Two patients in the varenicline group and one patient in the placebo group died during the study . Reports of psychiatric AEs were similar for both treatment groups . CONCLUSIONS Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00285012 ; URL : www . clinical trials.gov BACKGROUND Rates of smoking in East Asian men range from > 35 % to > 60 % , and are increasing in women and the young . OBJECTIVE This study evaluated the efficacy and tolerability of 1 mg BID varenicline , a novel alpha4beta2 nicotinic acetylcholine receptor partial agonist , for smoking cessation in smokers in Taiwan and Korea . METHODS A r and omized , double-blind , placebo-controlled , 12-week treatment , 12-week follow-up trial was conducted at 5 sites each in Korea and Taiwan . Eligible subjects , smoking > or=10 cigarettes/d , received brief smoking-cessation counseling and were r and omly assigned in a 1:1 ratio to varenicline 1 mg BID ( titrated during the first week ) or placebo . Smoking status was established by self-report and confirmed at clinic visits by end-expiratory carbon monoxide < or=10 ppm . The primary end point was continuous abstinence rate ( CAR ) during the last 4 weeks of treatment . Secondary end points included CAR from weeks 9 to 24 and 7-day point prevalence ( PP ) of abstinence at weeks 12 and 24 . Craving , withdrawal , and smoking satisfaction were determined by the Minnesota Nicotine Withdrawal Scale , the Brief Question naire of Smoking Urges , and the modified Cigarette Evaluation Question naire . Observed or volunteered adverse-event data were recorded at clinic visits . RESULTS Overall , 126 subjects ( 84.9 % male ) received varenicline , and 124 ( 92.7 % male ) received placebo , Subjects were aged 21 to 73 years ( mean age , 39.7 and 40.9 years for varenicline and placebo groups , respectively ) , and the mean ( range ) body weights were 69.0 ( 44.8 - 110.0 ) kg and 71.4 ( 45.5 - 102.0 ) kg , respectively . Subjects had smoked for 3 to 52 years ( mean , 20.2 and 22.1 years in the varenicline and placebo groups , respectively ) . Subjects had smoked a mean of 23 cigarettes/d over the past month , with 51.6 % ( varenicline ) and 46.0 % ( placebo ) having made 1 or more prior serious quit attempts . Smoking-cessation rates at the end of treatment were 59.5 % with varenicline versus 32.3 % with placebo ( P < 0.001 ) . CARs through 12 weeks post-treatment ( weeks 9 - 24 ) were 46.8 % with varenicline and 21.8 % with placebo ( P < 0.001 ) . The 7-day PP was 67.5 % with varenicline versus 36.3 % with placebo at week 12 , and 57.1 % versus 29.0 % with placebo at week 24 ( both , P < 0.001 ) . Treatment-emergent , all-causality adverse events with an incidence > or= 5 % for varenicline were nausea ( 43.7 % for varenicline vs 11.3 % placebo ) , insomnia ( 15.1 % vs 13.7 % ) , increased appetite ( 7.9 % vs 6.5 % ) , constipation ( 7.1 % vs 2.4 % ) , anxiety ( 5.6 % vs 2.4 % ) , and abnormal dreams ( 5.6 % vs 0.8 % ) . Adverse events result ed in < 10 % treatment discontinuations overall . CONCLUSION Varenicline was an efficacious and well-tolerated pharmacotherapy for smoking cessation in this group of Asian smokers over a 12-week treatment period , and its effects persisted for a further 12-week follow-up period BACKGROUND Varenicline is an α4β2 partial nicotinic agonist approved for smoking cessation . There have been spontaneous postmarketing reports of neuropsychiatric adverse events ( NPAEs ) in smokers without a history of psychiatric illness quitting with varenicline . METHODS One hundred ten smokers without history of psychiatric illness ( screened by Structured Clinical Interview for DSM-IV ) were r and omized to 12 weeks of varenicline 1 mg twice daily ( n = 55 ) or placebo . Adverse events were solicited systematic ally . Depressive symptoms , anxiety , aggression , and irritability were measured at baseline and weekly using the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , the Hamilton Anxiety Scale ( HAM-A ) , and the Overt Aggression Scale-Modified ( OAS-M ) . The Profile of Mood States ( POMS ) was administered daily . Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods . RESULTS Participants ' mean baseline characteristics were 33 years of age , 22 cigarettes/day and Fagerström Test for Nicotine Dependence score > 7 . Reported NPAEs were similar between groups . No suicidal events were reported . There were no significant differences between groups for the MADRS ( treatment difference vs. placebo = .03 , 95 % confidence interval [ CI ] -.68-.73 ; NS ) , HAM-A ( treatment difference [ TD ] = .14 , 95 % CI -.62-.90 ; NS ) , OAS-M Aggression subscale ( TD = .5 , 95 % CI -1.18 - 2.18 ; NS ) , OAS-M Irritability subscale ( TD = .08 , 95 % CI -.17-.34 ; NS ) , and the POMS total scores ( TD = .5 , 95 % CI -.52 - 1.53 ; NS ) . CONCLUSIONS There were no significant differences between groups on measures of depressive symptoms , anxiety , or aggression/hostility . Systematic ally solicited NPAEs were similar between the varenicline and placebo groups OBJECTIVES This study examined the relation between smoking and suicide , controlling for various confounders . METHODS More than 50,000 predominantly White , middle-aged and elderly male health professionals were followed up prospect ively with biennial question naires from 1986 through 1994 . The primary end point was suicide . Characteristics controlled for included age , marital status , body mass index , physical activity , alcohol intake , coffee consumption , and history of cancer . RESULTS Eighty-two members of the cohort committed suicide during the 8-year follow-up period . In age-adjusted analyses with never smokers as the comparison group , the relative risk of suicide was 1.4 ( 95 % confidence interval [ CI ] = 0.8 , 2.3 ) among former smokers , 2.6 ( 95 % CI = 0.9 , 7.5 ) for light smokers ( < 15 cigarettes/day ) , and 4.5 ( 95 % CI = 2.3 , 8.8 ) among heavier smokers . After adjustment for potential confounders , the relative risks were 1.4 ( 95 % CI = 0.9 , 2.4 ) , 2.5 ( 95 % CI = 0.9 , 7.3 ) , and 4.3 ( 95 % CI = 2.2 , 8.5 ) , respectively . CONCLUSION We found a positive , dose-related association between smoking and suicide among White men . Although inference about causality is not justified , our findings indicate that the smoking-suicide connection is not entirely due to the greater tendency among smokers to be unmarried , to be sedentary , to drink heavily , or to develop cancers INTRODUCTION Varenicline ( Chantix ® ) is an efficacious first-line medication for smoking cessation . Studies suggest that one mechanism by which varenicline facilitates sustained smoking abstinence is by reducing the likelihood of relapse to smoking when a lapse , or slip , occurs during a quit attempt . The present study extends this line of research by conducting a prospect i ve laboratory study to examine the relapse prevention effects of varenicline following a programmed lapse . METHODS Daily smokers ( N = 47 ) completed a 5-week outpatient study in which they were r and omized to receive varenicline or placebo . The first week was a medication induction period that was immediately followed by a 4-week quit attempt . A programmed lapse ( 2 cigarettes smoked in the laboratory ) occurred on the second day of the quit attempt . RESULTS Participants receiving varenicline were slower to relapse and had greater total abstinence rates following lapse exposure . Participants in the varenicline group rated lapse cigarettes lower on measures of reward and intoxication and showed increased behavioral economic dem and elasticity for cigarettes ( reduced cigarette purchasing at higher prices ) compared with those receiving placebo . CONCLUSIONS These results demonstrate a relapse prevention effect of varenicline following smoking lapse exposure and suggest that an attenuation of reward from smoking and the blunting of subjective effects of smoking may underlie and /or contribute to this effect The authors examined the relation between cigarette smoking and suicide by conducting a cohort study of 300,000 male US Army personnel followed prospect ively from January 1987 through December 1996 for 961,657 person-years . They found that the risk of suicide increased significantly with the number of cigarettes smoked daily ( p for trend < 0.001 ) . In multivariable-adjusted analyses , smokers of more than 20 cigarettes a day , compared with never smokers , were more than twice as likely to commit suicide . For male active-duty army personnel , the dose-related association between smoking and suicide was not entirely explained by the greater tendency of smokers to be White , drink heavily , have less education , and exercise less often UNLABELLED Chinese translation BACKGROUND Depression is overrepresented in smokers . OBJECTIVE To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo . DESIGN Phase 4 , multicenter , parallel , 1:1 allocation , double-blind , r and omization trial . R and omization , stratified by antidepressant use and depression score at baseline , was blocked in sizes of 4 . ( Clinical Trials.gov : NCT01078298 ) . SETTING 38 centers in 8 countries . PARTICIPANTS 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events . INTERVENTION Varenicline , 1 mg twice daily , or placebo for 12 weeks , with 40-week nontreatment follow-up . MEASUREMENTS Primary outcome was carbon monoxide-confirmed continuous abstinence rate ( CAR ) for weeks 9 to 12 . Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood , anxiety , and suicidal ideation or behavior . RESULTS 68.4 % versus 66.5 % of the varenicline and placebo groups , respectively , completed the study . Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 ( 35.9 % vs. 15.6 % ; odds ratio [ OR ] , 3.35 [ 95 % CI , 2.16 to 5.21 ] ; P < 0.001 ) , 9 to 24 ( 25.0 % vs. 12.3 % ; OR , 2.53 [ CI , 1.56 to 4.10 ] ; P < 0.001 ) , and 9 to 52 ( 20.3 % vs. 10.4 % ; OR , 2.36 [ CI , 1.40 to 3.98 ] ; P = 0.001 ) . There were no clinical ly relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group . The most frequent adverse event was nausea ( varenicline , 27.0 % ; placebo , 10.4 % ) . Two varenicline-group participants died during the nontreatment phase . LIMITATIONS Some data were missing , and power to detect differences between groups was low in rare events . Smokers with untreated depression , with co-occurring psychiatric conditions , or receiving mood stabilizers and antipsychotics were not included . CONCLUSION Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety . PRIMARY FUNDING SOURCE Pfizer IMPORTANCE It is estimated that more than half of those with serious mental illness smoke tobacco regularly . St and ard courses of pharmacotherapeutic cessation aids improve short-term abstinence , but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy . OBJECTIVE To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with st and ard treatment . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , parallel-group , relapse-prevention clinical trial conducted in 10 community mental-health centers . Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012 , 203 received 12-weeks ' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention . INTERVENTIONS Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were r and omly assigned to receive cognitive behavioral therapy and double-blind varenicline ( 1 mg , 2 per day ) or placebo from weeks 12 to 52 . Participants then discontinued study treatment and were followed up to week 76 . MAIN OUTCOMES AND MEASURES Seven-day rate of continuous abstinence at study week 52 , the end of the relapse-prevention phase , confirmed by exhaled carbon monoxide . Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76 , based on self-reported smoking behavior . RESULTS Sixty-one participants completed the relapse-prevention phase ; 26 discontinued participation ( 7 varenicline , 19 placebo ) and were considered to have relapsed for the analyses ; 18 of these had relapsed prior to dropout . At week 52 , point-prevalence abstinence rates were 60 % in the varenicline group ( 24 of 40 ) vs 19 % ( 9 of 47 ) in the placebo group ( odds ratio [ OR ] , 6.2 ; 95 % CI , 2.2 - 19.2 ; P < .001 ) . From weeks 12 through 64 , 45 % ( 18 of 40 ) among those in the varenicline group vs 15 % ( 7 of 47 ) in the placebo group were continuously abstinent ( OR , 4.6 ; 95 % CI , 1.5 - 15.7 ; P = .004 ) , and from weeks 12 through 76 , 30 % ( 12 of 40 ) in the varenicline group vs 11 % ( 5 of 47 ) in the placebo group were continuously abstinent ( OR , 3.4 ; 95 % CI , 1.02 - 13.6 ; P = .03 ) . There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events . CONCLUSIONS AND RELEVANCE Among smokers with serious mental illness who attained initial abstinence with st and ard treatment , maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00621777 INTRODUCTION Nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking . We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts . METHODS This r and omized , placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month . Participants used varenicline ( 2 mg/day ) or placebo for 2 - 8 weeks plus received brief counseling on methods to reduce cigarettes/day . The primary measure was the incidence of a quit attempt within 6 months of study entry . Secondary measures were point prevalence abstinence , motivation to stop smoking , and reduction in cigarettes/day . RESULTS Varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site ( 73 % vs. 41 % ; p < .001 ) but not at the Vermont site ( 45 % vs. 51 % ; p = .45 ) . Varenicline increased most other measures of quit attempts , motivation and abstinence , independent of site . The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day , dependence , craving , and cigarette satisfaction . Varenicline had a greater effect on quit attempts in less-dependent smokers , in minority smokers , and in those who had less prior cessation or reduction activity . Adverse events were minimal . CONCLUSIONS Varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site . This appeared to be due to decreasing cigarettes/day and level of dependence This study was design ed to investigate the multiple-dose pharmacokinetics , safety , and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist , varenicline , in elderly ( 65 - 85 years old ) nonsmokers . Fifty male and female subjects with normal renal function for their age were r and omized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design . Treatment regimens included weekly titration ( n = 14 ; days 1 - 7 , 0.5 mg once daily ; days 8 - 14 , 0.5 mg twice daily ; days 15 - 21 , 1 mg twice daily ) ; 2-week twice-daily titration ( n = 13 ; days 1 - 14 , 0.5 mg once daily ; days 15 - 21 , 0.5 mg twice daily ) ; 2-week once-daily titration ( n = 13 ; days 1 - 14 , 0.5 mg once daily ; days 15 - 21 , 1 mg once daily ) ; and placebo ( n = 10 ) . Approximate dose-proportional increases in systemic exposure of varenicline at steady state , based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state , were observed across the dose range of 0.5 to 2 mg/d . Median time to maximum concentration was 3 hours . Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose . Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population

Overall , the 5-year complication rates were low . The most frequent complications were secondary caries , endodontic problems , ceramic fractures , ceramic chipping , and loss of retention . CONCLUSION This systematic review showed that all-ceramic restorations fabricated using the correct clinical protocol have an adequate clinical survival for at least 5 years of clinical service with very low complication rates . Minor ceramic chipping and debonding did not affect the longevity of the restorations . CLINICAL RELEVANCE Long-term clinical performance of all-ceramic restorations manufactured using various ceramic systems provides clinical evidence of complications and long-term management of these restorations . Available evidence indicates the effectiveness of many ceramic systems for numerous clinical applications . Correct planning and a rigorous technical execution protocol increase clinical success . Studies of ceramic prostheses indicate more problems with ceramic failure and debonding

OBJECTIVE The purpose of this systematic review was to compare the survival and complication rates of all-ceramic restorations after a minimum follow-up time of 5 years .

This study prospect ively evaluated the clinical performance of computer-assisted design and computer-assisted manufacturing (CAD/CAM)-generated In-Ceram Alumina core crowns in Japanese patients for up to 5 years . A total of 101 In-Ceram crowns with aluminium copings fabricated using the GN-I system were placed in Japanese patients . The crowns were evaluated using a California Dental Association ( CDA ) quality assessment system at baseline and at all follow-up examinations . Gingival condition was assessed using plaque and bleeding scores . The survival of anterior and posterior crowns was analysed according to the Kaplan-Meier method . The scores of gingival condition were compared between restored crowns and contralateral teeth using a t-test . During the observation period , six crowns were lost to follow-up . Five crowns were fractured from the copings and removed , and four crowns were removed for other reasons . Chipping within the porcelain was detected in three crowns , which were then polished . The cumulative survival rates after 60 months were 96·9 % for anterior crowns and 87·7 % for posterior ones , and there were no significant differences between anterior and posterior crowns . According to the CDA criteria , most of the crowns were rated as satisfactory during the observation period . There were significant differences in soft tissue conditions between In-Ceram crowns and control teeth at 2- and 5-year examinations . Despite the five fractures from copings , In-Ceram Alumina crowns with copings fabricated using the CAD/CAM ( GN-I system ) for replacing both anterior and posterior teeth showed predictable results during a 5-year observation period Objectives The purpose of this prospect i ve study was to evaluate the clinical outcome of anterior and posterior crowns made of a lithium-disilicate glass – ceramic framework material ( IPS e.max Press , Ivoclar Vivadent ) . Material s and methods A total of 104 single crowns were placed in 41 patients ( mean age , 34 ± 9.6 years ; 15 male , 26 female ) . Eighty-two anterior and 22 posterior crowns were inserted . All teeth received a 1-mm-wide chamfer or rounded shoulder preparation with an occlusal/incisal reduction of 1.5–2.0 mm . The minimum framework thickness was 0.8 mm . Frameworks were laminated by a prototype of a veneering material combined with an experimental glaze . Considering the individual abutment preconditions , the examined crowns were either adhesively luted ( 69.2 % ) or inserted with glass – ionomer cement ( 30.8 % ) . Follow-up appointments were performed 6 months after insertion , then annually . Replacement of a restoration was defined as failure . Results Four patients ( 10 crowns ) were defined as dropouts . For the remaining 94 crowns , the mean observation time was 79.5 months ( range , 34–109.7 months ) . The cumulative survival rate according to Kaplan – Meier was 97.4 % after 5 years and 94.8 % after 8 years . Applying log rank test , it was shown that the location of the crown did not significantly have an impact on the survival rate ( p = 0.74 ) and that the cementation mode did not significantly influence the occurrence of complications ( p = 0.17 ) . Conclusions The application of lithium-disilicate framework material for single crowns seems to be a reliable treatment option . Clinical relevance Crowns made of a lithium-disilicate framework material can be used clinical ly in the anterior and posterior region irrespective of an adhesive or conventional cementation when considering abutment preconditions PURPOSE This study aim ed to prospect ively analyze the outcomes of 304 feldspathic porcelain veneers prepared by the same operator , in 100 patients , that were in situ for up to 16 years . MATERIAL S AND METHODS A total of 304 porcelain veneers on incisors , canines , and premolars in 100 patients completed by one prosthodontist between 1988 and 2003 were sequentially included . Preparations were design ed with chamfer margins , incisal reduction , and palatal overlap . At least 80 % of each preparation was in enamel . Feldspathic porcelain veneers from refractory dies were etched ( hydrofluoric acid ) , silanated , and cemented ( Vision 2 , Mirage Dental Systems ) . Outcomes were expressed as percentages ( success , survival , unknown , dead , repair , failure ) . The results were statistically analyzed using the chi-square test and Kaplan-Meier survival estimation . Statistical significance was set at P < .05 . RESULTS The cumulative survival for veneers was 96 % + /- 1 % at 5 to 6 years , 93 % + /- 2 % at 10 to 11 years , 91 % + /- 3 % at 12 to 13 years , and 73 % + /- 16 % at 15 to 16 years . The marked drop in survival between 13 and 16 years was the result of the death of 1 patient and the low number of veneers in that period . The cumulative survival was greater when different statistical methods were employed . Sixteen veneers in 14 patients failed . Failed veneers were associated with esthetics ( 31 % ) , mechanical complications ( 31 % ) , periodontal support ( 12.5 % ) , loss of retention > 2 ( 12.5 % ) , caries ( 6 % ) , and tooth fracture ( 6 % ) . Statistically significantly fewer veneers survived as the time in situ increased . CONCLUSIONS Feldspathic porcelain veneers , when bonded to enamel substrate , offer a predictable long-term restoration with a low failure rate . The statistical methods used to calculate the cumulative survival can markedly affect the apparent outcome and thus should be clearly defined in outcome studies The aim of this prospect i ve clinical study was to investigate the long-term survival of Procera AllCeram all-ceramic crowns in the anterior and posterior regions . Between 1997 and 2005 , 155 Procera crowns with aluminum oxide cores were placed in 50 patients . Patients were recalled in 2005 for a clinical assessment . Thirty-nine patients with 135 crowns attended the recall examination . Of the 135 total crowns , 103 were located in the posterior region and 32 were located in the anterior region . The cumulative survival rate was 100 % in the anterior region and 98.8 % in the posterior region ( 1 crown fracture ) after 5 and 7 years . Clinical success was achieved irrespective of the tooth position , cement used ( resin composite or glass-ionomer cement ) , or the core design with reduced or conventional margins . Procera AllCeram seems to be a predictable technique for esthetic all-ceramic single crown restorations in the anterior and posterior regions OBJECTIVE Ceramic inlays and onlays are a tooth colored alternative to metallic restorations . Clinical long-term data are scarce though , especially about inlays and onlays having proximal margins in dentin . The present prospect i ve controlled clinical study evaluated the clinical performance of IPS Empress inlays and onlays with cuspal replacements and proximal margins below the cementoenamel junction over eight years . METHODS Ninety six ceramic restorations were placed in 34 patients by six dentists . The restorations were bonded with an enamel/dentin bonding system ( Syntac Classic ) and four different resin composite systems . The restorations were assessed after placement by two calibrated investigators using modified USPHS codes and criteria at the following time periods : baseline , 1,2,4,6 and 8 years . RESULTS Eight of the 96 restorations investigated had to be replaced ( failure rate 8 % ; Kaplan-Meier ) : Six inlays suffered cohesive bulk fractures , two teeth required endodontic treatment . After eight years of clinical service , significant deterioration ( Friedman 2-way ANOVA ; P < 0.05 ) was found for marginal adaptation of the remaining restorations . 98 % of the surviving restorations exhibited marginal deficiencies , independent of the luting composite . CONCLUSIONS IPS Empress inlays and onlays demonstrated to be successful even in large defects . Neither the absence of enamel margins , nor cuspal replacement significantly affected the quality of the restorations Procera AllCeram crowns were prospect ively evaluated clinical ly in both anterior and posterior regions in Japanese . One-hundred and one crowns were fabricated for 57 patients at the Tsurumi University Dental Hospital from August 2001 to October 2002 and evaluated according to the California Dental Association ( CDA ) quality evaluation system at baseline and annually at all follow-up examinations for 5 years . The plaque index ( PI ) and gingival index ( GI ) were recorded , and chipping and fracture were checked at the same time as well . A total of 75 Procera AllCeram crowns were evaluated , and the cumulative survival rate was 90.2 % over the 5-year clinical trial . Six crowns experienced fractures within the veneering porcelain and from aluminium oxide coping , all of which occurred on the premolar and molar regions , and they had to be removed . Small chipping was observed on three crowns . According to the CDA criteria , 98 % of Procera AllCeram crowns were rated as satisfactory , and PI and GI were comparable to those of control teeth during the observation period PURPOSE The aim of this prospect i ve study was to evaluate the clinical efficacy and long-term survival rate of three-unit fixed partial dentures ( FPDs ) made from lithium disilicate-based core ceramic . MATERIAL S AND METHODS Twenty-one three-unit FPDs were placed in 19 patients to replace single lost teeth in the esthetic area , following a study protocol that took clinical , esthetic , and radiologic aspects into consideration . Each case was review ed at 1 week following placement , at 6 months , and then annually for 10 years . Statistical analysis was performed using Kaplan-Meier survival analysis . RESULTS Out of the 19 patients , 14.3 % presented reversible postoperative sensitivity . Recession was observed in 24 % of dental posts , and 7.1 % presented marginal discoloration . Treatment did not increase either Bleeding or Plaque Index scores at prepared teeth ; secondary caries did not appear either . The restorations ' survival rate at the 10-year follow-up was 71.4 % ; six FPDs had fractured and one debonded . CONCLUSIONS Fracture failure rate was 28.6 % after 10 years ; a high percentage corresponded to connector fractures and occurred during the first 5 years . Lithium disilicate glass-ceramic FPDs present a higher risk of fracture than st and ard therapies ( metal-ceramic ) or other more recently developed ceramic material s. The prognosis for survival improves for Class I occlusion and nonparafunctional patients The purpose of this prospect i ve cohort study was to assess the performance of tooth-supported , long-span , zirconia fixed dental prostheses ( FDPs ) . Thirty FDPs with span lengths from 36 to 46 mm ( mean 40·33 mm ) , with 4 - 7 units and with connector dimensions ∼9 mm(2 ) were inserted ( 19 in the posterior region , 11 including anterior teeth ) using glass-ionomer cement . The performance of the FDPs was assessed ( aesthetic evaluation , failures , hypersensitivity/tooth vitality , secondary caries , pocket depth , decementation , and chipping ) at baseline and after 5 years . Cox regression analysis was performed to identify risk factors . There were 16 failures after 5 years . Framework fracture occurred for two FDPs , four FDPs had to be re-cemented , one abutment tooth had to be treated endodontically , one abutment tooth fractured and cohesive failure of the veneer occurred for eight . Four FDPs had to be replaced , so survival was 82 % . The aesthetics were rated as excellent by the patients at baseline and good at the 5-year recall . Cox regression analysis showed that both length [ P = 0·05 , exp(B ) = 1·22 ] and location [ P = 0·019 , exp(B ) = 4·09 ] of the FDP were risk factors for failure . Compared with the previously published 2-year results , the incidence of complications increased dramatically . Additionally , it was shown that long-span FDPs in the molar region are at greater risk of failure than FDPs in the anterior region PURPOSE The aim of the present study was to clinical ly evaluate the effect of two different adhesive/resin composite combinations for luting IPS Empress inlays with a special focus on luting gap wear and marginal adaptation . MATERIAL S AND METHODS In the course of a controlled prospect i ve clinical split-mouth study , 94 IPS Empress restorations were placed in 31 patients . The inlays were luted with EBS Multi + Compolute ( EC ; 3 M ESPE ) or with Syntac + Variolink II low ( SV ; Ivoclar Vivadent ) . At baseline and after 0.5 , 1 , 2 , 4 , and 8 years , the ceramic restorations were examined according to modified USPHS codes and criteria . Thirty-five selected sample s were investigated under an SEM regarding morphological changes ; marginal quality analysis was carried out using a stereo light microscope , and luting composite wear was scanned with a profilometer . RESULTS Eight patients ( including 25 restorations ) missed the recalls ; the recall rate at the last investigation was 72 % . After 96 months of clinical service , seven restorations in five patients ( six EC , one SV ) had to be replaced due to hypersensitivities ( n = 5 ) or inlay fractures ( n = 2 ) result ing in a survival rate of 90 % . Over the 8-year period , the restorations revealed no statistically significant differences in terms of surface roughness , color matching , proximal contact , sensitivity , or complaints ( p > 0.05 , Friedman test ) . Significant deteriorations were found for marginal integrity ( p < 0.05 ) . No significant differences were observed for the different luting systems ( p = 0.096 , Log rank test/ Mantel Cox ) . Marginal analysis revealed no statistical difference among the material s ( p > 0.05 ; Mann-Whitney U-test ) , however , the scans of the luting gap showed that Compolute was more prone to wear ( p < 0.05 ) . CONCLUSION For luting of ceramic inlays , no difference between the two luting systems was detectable . The overall failure rate after 8 years was 10 % OBJECTIVES The purpose of this study was to investigate the durability of extensive dentin-enamel-bonded posterior ceramic coverages in a 15 years follow-up . METHODS All extensive dentin-enamel-bonded posterior partial and complete all-ceramic coverages placed during the period November 1992-December 1998 were included . In 121 patients , 252 coverages ( IPS Empress ) were placed . The adhesive bonding to dentin and enamel was performed with three 3-step and one 2-step etch and rinse bonding . In 106 restorations the classic Syntac was used in combination with the dual-cured resin composite Variolink . The other restorations were luted with the chemically cured resin composite Bisfil 2B and bonded with 3-step etch and rinse systems , classic Gluma ( 37 ) , Allbond 2 ( 57 ) , Syntac ( 32 ) or the 2-step etch and rinse system , One step ( 20 ) . The ceramics were evaluated yearly by modified USPHS criteria during 15 years . RESULTS Postoperative sensitivity was registered in 4 patients during bite forces lasting for 2 - 4 weeks . Fifty-five of 228 coverages ( 24.1 % ) failed . The mean observation period of the acceptable coverages was 12.6 years ( range 11 - 15 years ) . The main reasons for failure were lost restorations ( 18 ) , ceramic fracture ( 16 ) , and secondary caries ( 11 ) . Significant differences in failure rate were observed between the dentin bonding agents but not between the two luting agents . Ceramic coverages placed on non-vital teeth failed in 39 % and on vital teeth in 20.9 % ( p=0.014 ) . Logistic regression indicated three significant predictors for failure of the coverages : gender and parafunctional habits of the patient and non-vitality of the tooth . SIGNIFICANCE The technique investigated showed advantages like less destruction of healthy tissue , and avoiding of endodontic treatment and /or deep cervical placement of restoration margins to obtain retention OBJECTIVES Midterm-evaluation of a prospect i ve 5-year clinical study on long-term performance and success rate of pressed-ceramic veneers with two extended preparation design s. METHODS Anterior teeth of 25 patients were restored with 66 extended veneers . Forty-two overlap veneers ( OV ) ( incisal-edge-reduction 0.5 - 1.5 mm , butt-joint ) and 24 full veneers ( FV ) were inserted . Both veneer design s were similar in buccal ( 0.5 mm ) and proximal ( 0.5 - 0.7 mm ) chamfer preparation , but differed in palatal extension . Ceramic veneers were fabricated with IPS Empress * and adhesively luted with dual-polymerizing composite Variolink II * ( * Ivoclar Vivadent ) . Clinical reevaluations were performed 6 , 12 , 25 , 39 , 45 , and 62 months after insertion of the veneers according to the modified USPHS- criteria . Absolute failures were recorded as survival-rate , relative failures demonstrated by Kaplan-Meier success-rate . RESULTS After an observation time up to 5 years , survival-rate of full veneers was 100 % , of overlap veneers 97.5 % due to one severe fracture . Kaplan-Meier- analysis of relative failures result ed in a success-rate of 85 % for FV and 72 % for OV . Reasons for relative failures were cracks , ceramic-cohesive-fractures , and loss-of-adhesion . No significant differences were found between the two veneer groups . Secondary caries and endodontic complications did not occur . Increased clinical service time result ed in enhanced marginal discoloration and decrease of marginal adaptation . SIGNIFICANCE Extended pressed-ceramic veneers ( both OV and FV ) proved to be reliable procedures to restore larger deficits in anterior teeth . Pronounced palatal extension of full veneers was not linked to a higher failure probability . Reliable adhesive bonding , as well as ceramic fatigue and fracture resistance are considered key factors for long-term success of extended-veneer restorations The aim of this r and omized controlled trial was to evaluate the clinical performance of lithium disilicate fixed partial dentures ( FPDs ) . Eighteen patients received lithium disilicate FPDs ( study group ) , and 19 patients received porcelain-fused-to-metal FPDs ( control ) . After 6 years , the survival probabilities were found to be 63 % in the study group and 95 % in the control group ( log-rank test , P = .028 ) . The data suggest that strict conditions should be considered before the use of lithium disilicate glass-ceramic for FPDs OBJECTIVES The purpose of this prospect i ve study was to evaluate the clinical outcome of crown-retained fixed dental prostheses ( FDPs ) made from a lithium-disilicate glass-ceramic ( IPS e.max Press , Ivoclar-Vivadent ) . METHODS Thirty-six three-unit FDPs were placed in 28 patients . The FDPs replaced teeth in the anterior ( 16 % ) and posterior ( 84 % ) regions . All teeth were prepared following a st and ardized protocol . The size of the proximal connector of the FDPs was 12 mm2 ( anterior ) or 16 mm2 ( posterior ) . FDPs were cemented either with glass-ionomer cement ( n=19 ) or composite resin ( n=17 ) . The following parameters were evaluated at baseline , 6 months after cementation and then annually ( at abutment and contralateral teeth ) : probing pocket depth , plaque index , bleeding on probing , and tooth vitality . RESULTS Three FDPs were defined as drop-out . The mean observation period of the remaining 33 FDPs was 86 months ( range : 67 - 98 months ) : two FDPs in two patients had to be replaced ( 6 % ) because of fractures . The 8-year survival rate according to Kaplan-Meier was 93 % . In addition , chipping of the veneering material was found in two FDPs ( 6 % ) . Two abutments ( 3 % ) of two restorations had to be treated endodontically ; and two FDPs ( 6 % ) lost retention and had to be recemented . These complications did not affect the function of the involved restorations clinical ly . There were no significant differences between the periodontal parameters of the test and control teeth . SIGNIFICANCE Short-span crown-retained three-unit FDPs made from lithium-disilicate glass-ceramic can be used clinical ly irrespective of an adhesive or conventional cementation PURPOSE The aim of this prospect i ve clinical cohort study was to determine the success rate of 3- to 5-unit zirconia frameworks for posterior fixed partial dentures ( FPDs ) after 5 years of clinical observation . MATERIAL S AND METHODS Forty-five patients who needed at least 1 FPD to replace 1 to 3 posterior teeth were included in the study . Fifty-seven 3- to 5-unit FPDs with zirconia frameworks were cemented with 1 of 2 resin cements ( Variolink or Panavia TC ) . The following parameters were evaluated at baseline , after 6 months , and 1 to 5 years after cementation at test ( abutments ) and control ( contralateral ) teeth : probing pocket depth , probing attachment level , Plaque Index , bleeding on probing , and tooth vitality . Intraoral radiographs of the FPDs were taken . Statistical analysis was performed using descriptive statistics , Kaplan-Meier survival analysis , and the McNemar test . RESULTS Twenty-seven patients with 33 zirconia FPDs were examined after a mean observation period of 53.4 + /- 13 months . Eleven patients with 17 FPDs were lost to follow-up . After the 3-year recall visit , 7 FPDs in 7 patients were replaced because they were not clinical ly acceptable due to biologic or technical complications . After 5 years of clinical observation , 12 FPDs in 12 patients had to be replaced . One 5-unit FPD fractured as a result of trauma after 38 months . The success rate of the zirconia frameworks was 97.8 % ; however , the survival rate was 73.9 % due to other complications . Secondary caries was found in 21.7 % of the FPDs , and chipping of the veneering ceramic in 15.2 % . There were no significant differences between the periodontal parameters of the test and control teeth . CONCLUSIONS Zirconia offers sufficient stability as a framework material for 3- and 4-unit posterior FPDs . The fit of the frameworks and veneering ceramics , however , should be improved OBJECTIVE The aim of this prospect i ve clinical study was to evaluate the survival rates of IPS Empress 2 ( Ivoclar Vivadent ) all-ceramic crowns and fixed partial dentures ( FPDs ) after an observation period of up to 5 years . METHOD AND MATERIAL S Forty-three patients ( 19 women and 24 men ) were included in this study . The patients were treated with a total of 58 adhesive bonded IPS Empress 2 restorations . A total of 27 single crowns were placed on molars and premolars , and 31 three-unit FPDs were placed in the anterior and premolar regions . Clinical follow-up examinations took place at 6 , 12 , 24 , 36 , 48 , and 60 months after insertion . Statistical analysis of the data was calculated using the Kaplan-Meier method . RESULTS Results of the 50-month analysis ( interquartile range , 33 to 61 months ) showed that the survival rate was 100 % for crowns and 70 % for FPDs . Six failures that occurred exclusively in the three-unit FPDs were observed . Framework fractures were recorded in three FPD units where the connector dimensions did not meet the manufacturer specifications . Only one FPD exhibited an irreparable partial veneer fracture , and 2 FPDs showed evidence of biologic failures . The accuracy of fit and esthetic parameters were clinical ly satisfactory for crowns and FPDs . CONCLUSION The results of this 5-year clinical evaluation suggest that IPS Empress 2 ceramic is an appropriate material for the fabrication of single crowns . Because of the reduced survival rates , strict conditions should be considered before the use of IPS Empress 2 material for the fabrication of three-unit FPDs Objectives This prospect i ve , r and omized clinical split-mouth study investigated the 5-year performance of InCeram Alumina posterior crowns cemented with three different luting cements . 4-META- and MDP-based cements were used for adhesive luting . Glass ionomer cement served as control . Material s and Methods Sixty patients were treated with 149 ( n = 62 Panavia F/MDP ; n = 59 SuperBond-C&B/4-META ; n = 28 Ketac Cem/glass ionomer ) InCeram Alumina crowns on vital molars and premolars in a comparable position . Follow-up examinations were performed annually up to 5 years after crown placement using the modified United States Public Health Service ( USPHS ) criteria . Kaplan – Meier survival analysis comprised secondary caries , clinical ly unacceptable fractures , root canal treatment and debonding . Kaplan – Meier success rate included restorations with minimal crevices , tolerable color deviations ( < 1 Vitashade ) , and clinical ly acceptable fractures . Logistic regression models with a r and om intercept were fitted . Results The 5-year Kaplan – Meier survival probabilities were : SuperBond-C&B 88.7 % , Panavia F 82.8 % , Ketac Cem 80.1 % with no significant difference ( p = .813 ) . Endodontical treatment was carried out on 7.4 % of all abutment teeth , and 5.4 % revealed secondary caries . Unacceptable ceramic fractures were observed in 7.4 % . Debonding was a rare complication ( 1.3 % ) . The 5 year Kaplan – Meier success rate was 91.6 % for SuperBond-C&B- , 87.4 % for Ketac Cem- and 86.3 % for Panavia F-bonded restorations with no significant difference ( p = .624 ) . All cement types showed significant marginal deterioration over time ( p < .0001 ) . Conclusions Posterior InCeram Alumina crowns showed acceptable long-term survival and success rates independent of luting agent used . Ceramic fractures , endodontical treatments and secondary caries were the most frequent failures . Clinical relevance Glass-infiltrated Alumina crowns in combination with adhesive as well as conventional cementation can be considered as a reliable treatment option in posterior teeth This prospect i ve study evaluated the clinical outcome of three-unit posterior fixed dental prostheses ( FDPs ) made of In-Ceram Zirconia . All 65 FDPs were inserted at the Department of Prosthodontics , School of Dentistry , Kiel , Germany , and cemented with glass-ionomer cement . Follow-ups were performed annually . During a mean observation time of 54.4 months , two FDPs failed ( one technical and one biologic failure ) . Two FDPs debonded and the veneering ceramic fractured in four cases . Three abutment teeth needed endodontic treatment and two additional abutment teeth exhibited secondary caries . Results suggest that posterior three-unit all-ceramic FDPs made from In-Ceram Zirconia may be a viable prosthetic treatment option with an outcome comparable to metal-ceramic FDPs BACKGROUND The authors conducted a prospect i ve study to evaluate the long-term outcome of crown-retained fixed dental prostheses ( FDPs ) made from monolithic lithium disilicate ceramic ( IPS e.max Press , Ivoclar Vivadent , Schaan , Liechtenstein ) . METHODS Faculty dentists at the Department of Prosthodontics , Propaedeutics and Dental Material s , School of Dentistry , Christian-Albrechts University at Kiel , Germany , placed 36 three-unit FDPs in 28 patients to replace six anterior and 30 posterior teeth . The proximal connector size ( height and width ) was 4 × 3 millimeters for anterior FDPs and 4 × 4 mm for posterior FDPs . FDPs were cemented either conventionally with glass ionomer cement ( n = 19 ) or adhesively with resin-based composite ( n = 17 ) . Patients made annual recall visits . RESULTS The mean ( st and ard deviation ) observation period was 121 ( 12.8 ) months . FDPs ' survival rate ( survival being defined as remaining in place either with or without complications ) was 100 percent after five years and 87.9 percent after 10 years , and their success rate ( success being defined as remaining unchanged and free of complications ) was 91.1 percent after five years and 69.8 percent after 10 years . The cementation method did not affect the outcome . CONCLUSION Three-unit FDPs made from monolithic lithium disilicate ceramic showed five- and 10-year survival and success rates that were similar to those of conventional metal-ceramic FDPs . CLINICAL IMPLICATION S If the manufacturer 's recommendations are followed , three-unit FDPs made from monolithic lithium disilicate ceramic may be a safe alternative to metal-ceramic FDPs regardless of the cementation method used This prospect i ve clinical trial aim ed at evaluating the clinical performance of three-unit posterior zirconia fixed dental prostheses ( FDPs ) after 5 years of clinical function . Thirty-seven patients received 48 three-unit zirconia-based FDPs . The restorations replaced either a premolar or a molar . Specific inclusion criteria were needed . Tooth preparation was st and ardized . Computer-aided design /computer-assisted manufacturing frameworks with a 9-mm2 cross section of the connector and a 0.6-mm minimum thickness of the retainer were made . The restorations were luted with resin cement . The patients were recalled after 1 , 6 , 12 , 24 , 36 , 48 , and 60 months . The survival and success of the ceramics and zirconia were evaluated . The technical and aesthetic outcomes were examined using the United States Public Health Service criteria . The biologic outcomes were analyzed at abutment and contralateral teeth . Descriptive statistics were performed . All FDPs completed the study , result ing in 100 % cumulative survival rate and 91.9 % and 95.4 % cumulative success rates for patients wearing one and two FDPs , respectively . No losses of retention were recorded . Forty-two restorations were rated alpha in all measured parameters . A minor chipping of the ceramics was detected in three restorations . No significant differences between the periodontal parameters of the test and control teeth were observed . Five-year clinical results proved that three-unit posterior zirconia-based FDPs were successful in the medium term for both function and aesthetic . Zirconia can be considered a promising substitute of metal frameworks for the fabrication of short-span posterior prostheses PURPOSE The aim of this prospect i ve study was to evaluate the clinical performance of fully sintered hot isostatic pressed yttria-partially-stabilized zirconia ( Denzir ) 3-unit fixed partial dentures ( FPDs ) . MATERIAL S AND METHODS Nineteen 3-unit FPDs were placed in 18 patients . Ten FPDs were placed in the maxilla and 9 in the m and ible . Two calibrated examiners evaluated the FPDs independently 1 week ( baseline ) , 1 year , 3 years , and 5 years after placement using the California Dental Association quality evaluation system . RESULTS All FPDs were intact at the 5-year examination . One FPD lost retention after 12 months but remained intact ; it was recemented and is still in function after 5 years . All FPDs were rated satisfactory over 5 years . No changes were seen in terms of color and anatomic form . The number of slightly rough or pitted occlusal surfaces increased approximately 30 % over 5 years . Visible evidence of ditching along the margin increased over time , but only for those FPDs luted with zinc phosphate cement . CONCLUSION The 5-year results indicate that yttria-partially-stabilized zirconia 3-unit FPDs with anatomically design ed frameworks are promising prosthetic alternatives , even in the premolar and molar regions . However , for all-ceramic FPDs with more units in function , further studies are necessary The aim of this prospect i ve clinical study was to investigate the long-term performance of all-ceramic veneers with overlap ( OV ) and full veneer ( FV ) preparation design s. Twenty-five patients were restored using 42 OV restorations ( incisal/palatal butt-joint margin ) and 24 FV restorations ( palatal rounded shoulder margin ) . All restorations were leucite-reinforced glass-ceramic anterior veneers . The 7-year Kaplan-Meier survival rate was 100 % for FV restorations and 97.6 % for OV restorations . The all-ceramic veneers revealed significant deterioration over time according to United States Public Health Service criteria , irrespective of the preparation design . Based on the 7-year results of this study , both preparation design s can be considered reliable treatment options for anterior teeth with extended deficits OBJECTIVES The aim of this prospect i ve clinical study was to assess the long-term clinical survival rate and the technical and biological complication rates of zirconia-based posterior FDPs . MATERIAL S AND METHODS Forty-five patients in need of one or more posterior FDPs received 57 three- to five-unit zirconia-based FDPs . The frameworks were fabricated by means of a prototype computer-aided manufacturing ( CAM ) system ( direct ceramic machining , DCM ) , first processing zirconia in the white stage . The frameworks were veneered with a prototype veneering ceramic . The FDPs were adhesively placed . At baseline , 6 months , and 1,2 , 3 , 5 , 8 and 10 years of function , the FDPs were examined for technical and /or biological complications . Furthermore , the periodontal health of the abutment teeth ( test ) and untreated control teeth was analyzed . Statistical analysis was performed applying descriptive statistics , Kaplan-Meier survival and multiple mixed effects regression tests . RESULTS Twenty-one patients with 26 FDPs were examined at a mean observation time of 10.7 + /- 1.3 years . A total of 16 FDPs were lost to follow-up . Fifteen FDPs had to be replaced due to technical/biological complications ; hence , the 10-year survival rate of the FDPs was 67 % . Three framework fractures occurred , result ing in a 10-year survival rate for the zirconia frameworks of 91.5 % . Chipping/fracture of the veneering ceramic was detected in 16 FDPs over 10 years ( complication rate 32 % ) . A significant correlation of the span of the FDPs and the incidence of chipping was observed : 4- and 5-unit FDPs had a 4.9 times higher probability for chipping than 3-unit FDPs . Marginal discrepancy/degradation was found in 90.7 % of the FDPs over 10 years . At 11 of the FDPs ( complication rate 27 % ) , secondary caries occurred . No difference of the periodontal health was found around test and control teeth . CONCLUSION The zirconia frameworks exhibited very good long-term stability . However , the zirconia-based FDPs frequently exhibited problems such as marginal deficiency or chipping of the veneering ceramic . Both problems may be associated with the prototype status of the system OBJECTIVE The purpose of this study was to evaluate the clinical performance of Procera AllCeram crowns placed over a 5-year period at three different private dental practice s. METHOD AND MATERIAL S Two hundred five Procera AllCeram crowns ( 50 anterior and 155 posterior ) were evaluated in a prospect i ve study from a minimum of 6 months to a maximum of 60 months , with a mean of 23.52 months . RESULTS A restoration was considered to be a failure when it impaired esthetic quality or function , thus necessitating remake of the crown . The survival rate was determined with the use of the Kaplan-Meier survival rate , which gave an overall survival rate of 96.7 % ( 100 % for the anterior crowns and 95.15 % for the posterior crowns ) . CONCLUSION The Procera AllCeram system seems to have a good prognosis for the posterior teeth and an excellent one for the anterior teeth The aim of this prospect i ve clinical split-mouth study was to investigate the longterm performance of pressed and computer-aided design /computer-assisted manufacture ( CAD/CAM ) all-ceramic partial-coverage restorations ( PCRs ) . Twentyfive patients were restored with 40 lithium disilicate pressed PCRs ( IPS e.max-Press , Ivoclar Vivadent ) and 40 leucite-reinforced glass-ceramic CAD/CAM PCRs ( ProCAD , Ivoclar Vivadent ) . All restorations were placed in vital first or second molars . The 7-year Kaplan-Meier survival rate was 100 % for pressed PCRs and 97 % for CAD/ CAM PCRs . Both systems showed significant deterioration over time in all modified United States Public Health Service criteria . Increased surface roughness and impaired color match were significantly more prevalent with pressed PCRs . Based on the 7-year data , both all-ceramic systems can be considered reliable treatment options for posterior PCRs PURPOSE This controlled clinical trial aim ed to evaluate IPS Empress inlays and onlays over 12 years . The null hypothesis was that different luting resins would have no influence on clinical outcome . MATERIAL S AND METHODS In the course of a prospect i ve clinical long-term trial , 96 ceramic inlays and onlays were placed in 34 patients using one adhesive ( Syntac ) and four different luting composites ( Tetric , Variolink Low , Variolink Ultra , Dual Cement ) . Recalls were carried out by two calibrated investigators using modified USPHS codes and criteria at baseline , 1 , 2 , 4 , 6 , 8 , and 12 years . RESULTS Fifteen of the 96 restorations had to be replaced ( failure rate 16 % ; Kaplan-Meier ) ; 12 of them suffered bulk fractures . After twelve years of clinical service , significantly more bulk fractures were found when light-curing composite was used for luting ( p < 0.05 ) . Fractures were noticed between 3 and 4 years of clinical service and later after 11 to 12 years ; aside from those times , no single fracture occurred . Secondary caries was not observed . CONCLUSION IPS Empress inlays and onlays exhibited satisfactory clinical outcomes over a 12-year clinical period . Restorations luted with dual-cured resin composites revealed significantly fewer bulk fractures OBJECTIVES Midterm-evaluation of a 5-year prospect i ve clinical splitmouth-investigation on survival rate and long-term behavior of all-ceramic partial coverage restorations ( PCRs ) on molars . Pressed ceramic and CAD/CAM fabricated PCRs were compared . METHODS 80 vital molars of 25 patients were restored with all-ceramic PCRs ( 40 IPS e.max Press*[IP ] and 40 ProCAD*[PC ] ) . IP-PCRs were heat pressed following the lost-wax method . PC-PCRs were fabricated with Cerec 3 * * and Cerec InLab * * CAD/CAM system ( * * Sirona Dental Systems , Bensheim , Germany ) . All PCRs were adhesively luted with a light-polymerizing composite ( Syntac*/Tetric * ) ( * Ivoclar Vivadent , Schaan , Liechtenstein ) . Clinical reevaluations were performed at baseline and 13 , 25 , and 36 months after insertion of the PCRs according to the modified United States Public Health Services ( USPHS ) criteria . Absolute failures were demonstrated by Kaplan-Meier survival rate . RESULTS After an observation time up to 3 years , survival rate of IP-PCRs was 100 % and 97 % for PC-PCRs due to one severe fracture . The PC-PCR had to be replaced after 9 months . Secondary caries and endodontic complications did not occur . Increased clinical service time result ed in significant decrease of marginal adaptation ( p=0.031 ) and enhanced marginal discoloration ( p<0.0001 ) . Both PCR ceramic material s demonstrated significant deteriorations in color match ( p<0.0001 ) and surface roughness ( p<0.0001 ) , IP-PCRs were significantly more affected ( p < or = 0.005 ) . Regarding anatomic form IP-PCRs performed significantly better ( p=0.0012 ) . CONCLUSION Pressed ceramic and CAD/CAM fabricated partial coverage restorations exhibited a reliable treatment option to restore larger defects in posterior teeth . Marginal degradation of the resin cement and deterioration of the all-ceramic material s during clinical function determine the clinical long-term performance of partial coverage restorations

Because of insufficient method ological quality of most prognostic studies , the predictive value of many clinical determinants for outcome of ADL remains unclear .

BACKGROUND AND PURPOSE Knowledge about robust and unbiased factors that predict outcome of activities of daily living ( ADL ) is paramount in stroke management . This review investigates the method ological quality of prognostic studies in the early poststroke phase for final ADL to identify variables that are predictive or not predictive for outcome of ADL after stroke .

Background and Purpose — Several prognostic factors have been identified for outcome after stroke . However , there is a need for empirically derived models that can predict outcome and assist in medical management during rehabilitation . To be useful , these models should take into account early changes in recovery and individual patient characteristics . We present such a model and demonstrate its clinical utility . Methods — Data on functional recovery ( Barthel Index ) at 0 , 2 , 4 , 6 , and 12 months after stroke were collected prospect ively for 299 stroke patients at 2 London hospitals . Multilevel models were used to model recovery trajectories , allowing for day-to-day and between-patient variation . The predictive performance of the model was vali date d with an independent cohort of 710 stroke patients . Results — Urinary incontinence , sex , prestroke disability , and dysarthria affected the level of outcome after stroke ; age , dysphasia , and limb deficit also affected the rate of recovery . Applying this to the validation cohort , the average difference between predicted and observed Barthel Index was −0.4 , with 90 % limits of agreement from −7 to 6 . Predicted Barthel Index lay within 3 points of the observed Barthel Index on 49 % of occasions and improved to 69 % when patients ’ recovery histories were taken into account . Conclusions — The model predicts recovery at various stages of rehabilitation in ways that could improve clinical decision making . Predictions can be altered in light of observed recovery . This model is a potentially useful tool for comparing individual patients with average recovery trajectories . Patients at elevated risk could be identified and interventions initiated Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items Although visual neglect is a predictor of poor outcome after stroke , some patients regain independence , whilst others take up considerable rehabilitation re sources . Intensive treatment of visual neglect is available and a knowledge of the predictive features in the recovery of these patients would be helpful in the early selection of patients for treatment . A study was therefore carried out to determine the prognosis of patients presenting with visual neglect at two to three days after stroke . Linear logistic regression showed that the initial degree of paralysis ( measured by the Motricity Index ) , the severity of neglect ( measured by the Visual Neglect Recovery Index ) and the patient 's age were the significant predictors of independence ( Barthel score 20 ) , mild dependence ( Barthel 15 - 19 ) , and moderate/severe dependence ( Barthel 0 - 14 ) in surviving patients at three months and at six months . Regression equations correctly predicted 78 % of outcomes , and had a sensitivity and specificity for " independence " of 84 % and 90 % respectively , and a sensitivity and specificity for " moderate/severe dependence " of 89 % and 80 % . It is suggested that these equations may be useful in selecting comparable groups of patients for r and omised controlled trials of treatment of visual neglect A cohort study tracks two or more groups forward from exposure to outcome . This type of study can be done by going ahead in time from the present ( prospect i ve cohort study ) or , alternatively , by going back in time to comprise the cohorts and following them up to the present ( retrospective cohort study ) . A cohort study is the best way to identify incidence and natural history of a disease , and can be used to examine multiple outcomes after a single exposure . However , this type of study is less useful for examination of rare events or those that take a long time to develop . A cohort study should provide specific definitions of exposures and outcomes : determination of both should be as objective as possible . The control group ( unexposed ) should be similar in all important respects to the exposed , with the exception of not having the exposure . Observational studies , however , rarely achieve such a degree of similarity , so investigators need to measure and control for confounding factors . Reduction of loss to follow-up over time is a challenge , since differential losses to follow-up introduce bias . Variations on the cohort theme include the before-after study and nested case-control study ( within a cohort study ) . Strengths of a cohort study include the ability to calculate incidence rates , relative risks , and 95 % CIs . This format is the preferred way of presenting study results , rather that with p values Background and Purpose — Prediction models for ischemic stroke outcome have the potential to contribute prognostic information in the clinical and /or research setting . The importance of diffusion-weighted magnetic resonance imaging ( DWI ) in the prediction of clinical outcome , however , is unclear . The purpose of this study was to combine acute clinical data and DWI lesion volume for ischemic stroke patients to determine whether DWI improves the prediction of clinical outcome . Methods — Patients ( N=382 ) with baseline DWI data from the Glycine Antagonist In Neuroprotection and citicoline ( 010 and 018 ) trials were used to develop the prediction models by multivariable logistic regression . Data from prospect ively collected patients ( N=266 ) from the Acute Stroke Accurate Prediction Study were used to externally vali date the model equations . The models predicted either full recovery or nursing home – level disability/death , as defined by the National Institutes of Health Stroke Scale , Barthel Index , or modified Rankin Scale . Results — The full-recovery models with DWI lesion volume had areas under the receiver operating characteristic curves ( AUCs ) of 0.799 to 0.821 , and those without DWI lesion volume had AUCs of 0.758 to 0.798 . The nursing home – level disability/death models with DWI had AUCs of 0.832 to 0.882 , and those without DWI had AUCs of 0.827 to 0.867 . All models had mean absolute errors ≤0.4 for calibration . Conclusions — All 12 models had excellent discrimination and calibration , with 8 of 12 meeting prespecified performance criteria ( AUC ≥0.8 , mean absolute error ≤0.4 ) . Although DWI lesion volume significantly increased model explanatory power , the magnitude of increase was not large enough to be clinical ly important Background and Purpose — Longitudinal conducted studies show that neurologic and functional recovery show faster recovery in the first weeks poststroke . The aim of the present study was to study the effects of progress of time on observed improvements in motor strength , synergisms , and activities during the first 16 weeks poststroke . Methods — Based on data from a previous study , 101 patients with first-ever ischemic middle cerebral artery strokes were prospect ively investigated during the first 16 weeks after stroke . Progress of time was categorized into 8 biweekly time intervals and was used as the independent covariate in a first-order longitudinal regression model . The biweekly time change ( progress of time ) was related to improvement in upper and lower limb motor recovery assessed with Fugl-Meyer score and Motricity Index , reduction in visuospatial inattention based on the letter cancellation task , and improvement in walking ability , dexterity , and activities of daily living measured with the Functional Ambulation Categories , Action Research Arm test , and Barthel Index . Results — Time explained a significant change of 8.4 ( 42 % ) measurement units on the Barthel Index for the first 10 weeks poststroke , 1.1 ( 22 % ) measurement units on Functional Ambulation Categories , and 19 % on the Action Research Arm test for the first 6 and 8 weeks poststroke . Approximately 25 % ( for Fugl-Meyer – arm ) to 26 % ( for Motricity Index – arm ) of the significant change in measurements units was explained by time alone for the upper limb compared with 33 % for Fugl-Meyer – leg and 39 % for Motricity Index – leg of the lower limb . Time accounted for a reduction of 16 % in the letter cancellation task . Observed associations did not change after controlling for covariates such as age , gender , hemisphere of stroke , type of stroke , or intervention . Conclusion — Progress of time is an independent covariate that reflects spontaneous recovery of body functions and activities explaining ≈16 % to 42 % of the observed improvements in the first 6 to 10 weeks after stroke onset BACKGROUND AND PURPOSE Previous studies suggest that undernourished patients with acute stroke do badly . The data , however , are not robust . We aim ed to reliably assess the importance of baseline nutritional status as an independent predictor of long-term outcome after stroke in a large prospect i ve cohort enrolled in the Feed Or Ordinary Diet ( FOOD ) trial , a multicenter r and omized trial evaluating various feeding policies . METHODS Patients admitted to hospital with a recent stroke were enrolled in the FOOD trial . Data on nutritional status and other clinical predictors of outcome were collected at trial entry . At 6 months , the coordinating center collected data on survival and functional status ( modified Rankin Scale ) . Outcome assessment was done by research ers blinded to baseline assessment s and treatment allocation . RESULTS Between November 1996 and November 2001 , 3012 patients were enrolled , and 2955 ( 98 % ) were followed up . Of the 275 undernourished patients , 102 ( 37 % ) were dead by final follow-up compared with only 445 ( 20 % ) of 2194 patients of normal nutritional status ( odds ratio [ OR ] , 2.32 ; 95 % CI , 1.78 to 3.02 ) . After adjustment for age , prestroke functional state , and stroke severity , this relationship , although weakened , still held ( OR , 1.82 ; 95 % CI , 1.34 to 2.47 ) . Undernourished patients were more likely to develop pneumonia , other infections , and gastrointestinal bleeding during their hospital admission than other patients . CONCLUSIONS These data provide reliable evidence that nutritional status early after stroke is independently associated with long-term outcome . It supports the rationale for the FOOD trial , which continues to recruit and aims to estimate the effect of different feeding regimes on outcome after stroke and thus determine whether the association observed in this study is likely to be causal In a prospect i ve study , the prognostic value of clinical characteristics in 157 consecutive patients with spontaneous supratentorial intracerebral haemorrhage were examined by means of multivariate analysis . Two days after the event 37 ( 24 % ) patients had died . Factors independently contributing to the prediction of two day mortality were pineal gl and displacement on CT of 3 mm or more ( p less than 0.001 ) , blood glucose level on admission of 8.0 mmol/l or more ( p = 0.01 ) , eye and motor score on the Glasgow Coma Scale of eight out of 10 or less ( p = 0.022 ) and haematoma volume of 40 cm3 or more ( p = 0.037 ) . Between the third day and one year after the event another 46 of the 120 two day survivors had died ; the independent prognostic indicators for death during that period were : age 70 years or more ( p less than 0.001 ) and severe h and icap ( Rankin grade five ) on the third day ( p less than 0.001 ) . Functional independence ( Rankin grade two or less ) at one year was most common not only with the converse features of age less than 70 years ( p less than 0.01 ) and Rankin grade four or less on the third day ( p = 0.002 ) , but also with an eye and motor score on the Glasgow Coma Scale of nine or 10 on the third day ( p less than 0.001 ) . The 120 patients with intracerebral haemorrhage who were still alive two days after the event were matched with 120 patients with cerebral infa rct ion , according to age , level of consciousness on the third day after stroke ( Glasgow Coma Scale ) and h and icap ( Rankin grade ) . Survival and h and icap after one year did not differ between these two groups . The conclusion drawn is that it is not the cause ( intracerebral haemorrhage or cerebral infa rct ion ) but the extent of the brain lesion that determines the outcome in patients who survive the first two days BACKGROUND AND PURPOSE The great variability of outcome seen in stroke patients has led to an interest in identifying predictors of outcome . The combination of clinical and imaging variables as predictors of stroke outcome in a multivariable risk adjustment model may be more powerful than either alone . The purpose of this study was to determine the multivariable relationship between infa rct volume , 6 clinical variables , and 3-month outcomes in ischemic stroke patients . METHODS Included in the study were 256 eligible patients from the R and omized Trial of Tirilazad Mesylate in Acute Stroke ( RANTTAS ) . Six clinical variables and 1-week infa rct volume were the prespecified predictor variables . The National Institutes of Health Stroke Scale , Barthel Index , and Glasgow Outcome Scale were the outcomes . Multivariable logistic regression techniques were used to develop the model equations , and bootstrap techniques were used for internal validation . Predictive performance of the models was assessed for discrimination with receiver operator characteristic ( ROC ) curves and for calibration with calibration curves . RESULTS The predictive models had areas under the ROC curve of 0.79 to 0.88 and demonstrated nearly ideal calibration curves . The areas under the ROC curves were statistically greater ( P<0.001 ) with both clinical and imaging information combined than with either alone for predicting excellent recovery and death or severe disability . CONCLUSIONS Combined clinical and imaging variables are predictive of 3-month outcome in ischemic stroke patients . Demonstration of this relationship with acute clinical variables and 1-week infa rct information supports future attempts to predict 3-month outcome with all acute variables Two hundred and six patients with acute stroke admitted consecutively to District General Hospitals , were studied for a period of six months . Significance tests conducted singly detected 21 factors present during the first 48 h of stroke , which were related to outcome six months later in terms of both mortality and functional recovery . Among these significant factors were various measures of perceptual dysfunction , including Albert 's Test . Multivariate statistical analysis which included discriminant analysis and linear logistic modelling , revealed six factors ( Albert 's Test Score , leg function , level of consciousness , arm power , weighted mental score and ECG changes ) which were significantly and independently related to outcome . A statistical model based on these factors predicted functional outcome with an overall accuracy of 67 per cent and mortality with an accuracy of 83 per cent . This model provides a useful basis for stratification in future r and omized controlled trial in stroke , and may have a role in the management of the individual stroke patient The prognosis of supratentorial haematomas is based on clinical signs and radiological features . The role of evoked potentials has not been evaluated systematic ally . In a prospect i ve study of supratentorial haemorrhage a number of clinical ( 17 ) , radiological ( 3 ) and evoked potential ( 2 ) parameters were evaluated employing univariate logistic regression analysis in 69 patients and multivariate logistic regression stepdown analysis in 51 patients . The outcome was grade d on the basis of the Barthel index ( BI ) score at 3 months as good ( BI ≥ 12 ) or poor ( death or BI < 12 ) recovery . Employing univariate analysis the significant prognostic variables were Glasgow Coma Scale , Canadian Neurological Scale , tendon reflex , associated medical complications , urinary incontinence , ventricular extension of the haematoma and motor evoked potentials . Using multivariate logistic regression analysis the best set of parameters in relation to outcome inlcuded Glasgow Coma Scale ( P < 0.05 ) , Canadian Neurological Scale ( P < 0.05 ) , tendon reflex ( P < 0.1 ) , ventricular extent ( P < 0.01 ) and motor evoked potentials ( P < 0.05 ) . From this study it is concluded that , in addition to clinical and radiological parameters , motor evoked potentials also have an important role in predicting outcome Background and Purpose — Increased circulating endothelial progenitor cells ( EPC ) have been associated with a low cardiovascular risk and may be involved in endothelial cell regeneration . The present study was design ed to evaluate the prognostic value of EPC in acute ischemic stroke . Methods — Forty-eight patients with a first-ever nonlacunar ischemic stroke were prospect ively included in the study within 12 hours of symptoms onset . Stroke severity was evaluated by the National Institutes of Health Stroke Scale , and functional outcome was assessed at 3 months by the modified Rankin Scale ( mRS ) . Infa rct volume growth between admission and days 4 to 7 was measured on multiparametric MRI . EPC colonies were defined as early outgrowth colony-forming unit-endothelial cell ( CFU-EC ) . The increment of CFU-EC was quantified during the first week and defined as the absolute difference between the number of CFU-EC at day 7 and admission . The influence of CFU-EC increase on good functional outcome ( mRS ≤2 ) and infa rct growth was analyzed by logistic regression and linear models . Results — Patients with good outcome ( n=25 ) showed a higher CFU-EC increment during the first week ( median [ quartiles ] , 23 [ 11 , 36 ] versus −3 [ −7 , 1 ] , P<0.0001 ) compared with patients with poor outcome . CFU-EC increment ≥4 during the first week was associated with good functional outcome at 3 months ( odds ratio , 30.7 ; 95 % CI , 2.4 to 375.7 ; P=0.004 ) after adjustment for baseline stroke severity , ischemic volume and thrombolytic treatment . For each unit increase in the CFU-EC the mean reduction in the growth of infa rct volume was 0.39 ( 0.03 to 0.76 ) mL ( P=0.033 ) . Conclusions — The increase of circulating EPC after acute ischemic stroke is associated with good functional outcome and reduced infa rct growth . These findings suggest that EPC might participate in neurorepair after ischemic stroke Objective : The NIH Stroke Scale ( NIHSS ) may not appropriately assess the spectrum of posterior circulation (PC)–related neurologic deficits . We determined the cutoff baseline NIHSS score that predicts independent daily life activity during the chronic stage in anterior circulation ( AC ) vs PC ischemic strokes . Methods : A total of 310 consecutive patients hospitalized within 3 days after the onset of an ischemic stroke were prospect ively enrolled in the study . Patients on thrombolytic therapy were excluded . In all patients , infa rcts and vascular lesions were identified primarily using magnetic resonance techniques . A favorable outcome was defined as a modified Rankin Scale score of ≤2 at 3 months poststroke . Results : In 101 patients with PC stroke , the total baseline NIHSS score was lower ( p < 0.001 ) , and the subscores of ataxia ( p < 0.001 ) and visual fields ( p = 0.043 ) were higher than in 209 patients with AC stroke . Multivariate-adjusted OR for the favorable outcome in patients with PC vs AC stroke was 2.339 ( 95 % CI 1.331–4.109 , p = 0.003 ) . A low baseline NIHSS score was independently predictive of a favorable outcome in both patients with PC ( OR 1.547 , 95 % CI 1.232–1.941 ) and AC ( 1.279 , 1.188–1.376 ) stroke . The optimal cutoff scores of the baseline NIHSS for the favorable outcome were ≤5 for patients with PC stroke ( sensitivity , 84 % ; specificity , 81 % ) and ≤8 for patients with AC stroke ( sensitivity , 80 % ; specificity , 82 % ) . Conclusions : The cutoff score of the baseline NIH Stroke Scale ( NIHSS ) for a favorable chronic outcome was relatively low in patients with PC stroke compared to patients with AC stroke . The NIHSS appears to have limitations with respect to its use when comparing the neurologic severity of PC and AC stroke Background and Purpose The purpose of this study was to analyze recovery of motor function in a cohort of patients presenting with an acute occlusion in the carotid distribution . Analysis of recovery patterns is important for estimating patient care needs , establishing therapeutic plans , and estimating sample sizes for clinical intervention trials . Methods We prospect ively measured the motor deficits of 104 stroke patients over a 6-month period to identify earliest measures that would predict subsequent motor recovery . Motor function was measured with the Fugl-Meyer Assessment . Fifty-four patients were r and omly assigned to a training set for model development ; 50 patients were assigned to a test set for model validation . In a second analysis , patients were stratified on basis of time and stroke severity . The sample size required to detect a 50 % improvement in residual motor function was calculated for each level of impairment and at three points in time . Results At baseline the initial Fugl-Meyer motor scores accounted for only half the variance in 6-month motor function ( r2=0.53 , p<0.001 ) . After 5 days , both the 5-day motor and sensory scores explained 74 % of the variance ( p<0.001 ) . After 30 days , the 30-day motor score explained 86 % of the variance ( p<0.001 ) . Application of these best models to the test set confirmed the results obtained with the training set . Sample -size calculations revealed that as severity and time since stroke increased , sample sizes required to detect a 50 % improvement in residual motor deficits decreased . Conclusions Most of the variability in motor recovery can be explained by 30 days after stroke . These findings have important implication s for clinical practice and research Background and Purpose — Intracerebral hemorrhage ( ICH ) is the most fatal and disabling stroke subtype . Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not design ed to predict functional recovery . We developed an acute clinical score to predict likelihood of functional independence . Methods — We prospect ively characterized 629 consecutive patients with ICH at hospital presentation . Predictors of functional independence ( Glasgow Outcome Score ≥4 ) at 90 days were used to develop a logistic regression-based risk stratification scale in a r and om subset of two thirds and vali date d in the remaining one third of the cohort . Results — At 90 days , 162 ( 26 % ) patients achieved independence . Age , Glasgow Coma Scale , ICH location , volume ( all P<0.0001 ) , and pre-ICH cognitive impairment ( P=0.005 ) were independently associated with Glasgow Outcome Score ≥4 . The FUNC score was developed as a sum of individual points ( 0–11 ) based on strength of association with outcome . In both the development and validation cohorts , the proportion of patients who achieved Glasgow Outcome Score ≥4 increased steadily with FUNC score . No patient assigned a FUNC score ≤4 achieved functional independence , whereas > 80 % with a score of 11 did . The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only , consistent with absence of confounding by early withdrawal of care . Conclusions — FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus , can provide guidance in clinical decision-making and patient selection for clinical trials Abstract . Objective : Disability and mortality represent the most relevant clinical outcome after acute ischemic stroke . However , vali date d and comprehensive prognostic models for recovery have not been developed . An accurate model including all previously suggested independent outcome predictors could improve the design and analysis of clinical trials . We therefore developed prognostic models for functional dependence and death after 100 days in a large cohort of stroke patients . Methods : From the German Stroke Data base , 1754 prospect ively collected records of patients with acute ischemic stroke were used for the development of prognostic models . Intubated patients and patients with low functional status before stroke were excluded . Functional independence was defined as a Barthel Index ≥95 after 100 days . Prognostic factors assessable within 72 hours after admission were identified by a systematic literature review . The final models of binary logistic regression analyses were internally vali date d and calibrated . Results : The result ing cross-vali date d and calibrated models correctly classified more than 80 % of the patients and yielded the following prognostic factors for functional independence : Age , right and left arm paresis at admission , NIH-Stroke Scale at admission , Rankin Scale 48–72 hours later , gender , prior stroke , diabetes , fever , lenticulostriate infa rct ion , neurological complications . The following variables were identified as prognostic factors for death : Age , NIH-Stroke Scale at admission , and fever . Conclusions : Our work gives an important insight into prognostic factors after acute ischemic stroke and presents predictive models with high prognostic accuracy . Together with a prospect i ve validation study , currently underway , we hence hope to improve the prediction of functional outcome after ischemic stroke Using death and functional status as end points , we prospect ively analyzed the outcome 6 months after spontaneous intracerebral hemorrhage in 166 patients admitted to an acute-care stroke unit on the first day of their stroke . Seventy-one patients ( 43 % ) died , 69 ( 42 % ) had a satisfactory outcome , and 26 ( 16 % ) had a poor functional outcome . Early ( 30-day ) survival was correlated with morphologic parameters on the initial computed tomogram ( hemorrhage size , midline shift , and intraventricular spread of the hemorrhage ) , while later ( 6-month ) survival was correlated with age . Using logistic regression , we found five independent predictors of satisfactory outcome at 6 months : age , hemorrhage size , intraventricular spread of the hemorrhage , limb paresis , and communication disorders . Of these , age was the most important predictor by far PURPOSE This study examined the relationship between depressive symptoms and time courses in achieving independence in basic activities of daily living ( BADL ) and instrumental activities of daily living ( IADL ) . METHODS At baseline , 1 , 3 , and 6 months after stroke , 459 stroke patients were prospect ively assessed . We used the Geriatric Depression Scale to determine depressive status . Outcomes were times to achieve independence in BADL ( Barthel > 95 ) and independ-ence in at least three IADL . We used the Kaplan-Meier method and time-dependent Cox proportional hazards regression to examine the relationship between depression and stroke recovery . RESULTS Depressed patients were 0.3 times less likely than nondepressed patients to achieve BADL of > 95 and 0.4 times less likely to be independent in three or more IADL . The cumulative percentages for the nondepressed patients to achieve a BADL of > 95 at 1 , 3 , and 6 months after stroke were 47 % , 63 % , and 72 % , and for the depressed patients , they were 19 % , 34 % , and 52 % , respectively . Similarly , the cumulative percentages for nondepressed patients to achieve complete independence in three or more IADL at 1 , 3 , and 6 months after stroke were 56 % , 72 % , and 85 % , and for the depressed patients , they were 32 % , 47 % , and 72 % , respectively . Depressed patients had poorer recovery patterns and took longer to achieve the outcomes . CONCLUSION Stroke patients with depressive symptoms progressed slower in achieving independence of BADL and IADL compared to patients without depressive symptoms OBJECTIVE To determine whether changes in nutritional status in the first week after acute ischemic stroke and undernutrition predicts poor clinical outcomes . DESIGN Prospect i ve observational study . SETTING Tertiary university hospital . PATIENTS We included 131 acute ischemic stroke patients who underwent nutritional assessment s within 24 hours and at 1 week after symptom onset . MAIN OUTCOME MEASURES Undernutrition was diagnosed when 1 or more of the following 5 parameters were present : ( 1 ) weight loss 10 % or more during the past 3 months or 6 % or more during the week after admission , ( 2 ) a weight index less than 80 % , ( 3 ) a serum albumin level less than 3.0 g/dL , ( 4 ) a transferrin level less than 150 mg/dL , or ( 5 ) a prealbumin level less than 10 mg/dL. We assessed poststroke complications and 3-month outcome using modified Rankin Scale responder analysis . RESULTS Of 131 patients included in this study , undernutrition was observed in 16 ( 12.2 % ) patients at admission and in 26 ( 19.8 % ) at 1 week . Multiple logistic regression analysis showed that baseline undernutrition independently predicted 1-week undernutrition ( odds ratio [ OR ] , 14.85 ; 95 % confidence interval [ CI ] , 3.52 - 62.76 ; P < .001 ) and poststroke complications ( OR , 6.72 ; 95 % CI , 1.09 - 41.56 ; P= .04 ) , and that 1-week undernutrition ( OR , 4.49 ; 95 % CI , 1.07 - 18.94 ; P= .04 ) and 1-week National Institutes of Health Stroke Scale score ( OR , 1.76 ; 95 % CI , 1.31 - 2.37 ; P < .001 ) independently predicted poor 3-month outcomes . CONCLUSIONS These findings suggest that acute ischemic stroke patients with baseline undernutrition are being undernourished during hospitalization . Strategic nutritional support , particularly in patients with baseline undernutrition , may improve clinical outcomes Objective : To compare the baseline National Institutes of Health Stroke Scale ( NIHSS ) score and the Trial of Org 10172 in Acute Stroke Treatment ( TOAST ) stroke subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke . Methods : Using data collected from 1,281 patients enrolled in a clinical trial , subtype of stroke was categorized using the TOAST classification , and neurologic impairment at baseline was quantified using the NIHSS . Outcomes were assessed at 7 days and 3 months using the Barthel Index ( BI ) and the Glasgow Outcome Scale ( GOS ) . An outcome was rated as excellent if the GOS score was 1 and the BI was 19 or 20 ( scale of 0 to 20 ) . Analyses were adjusted for age , sex , race , and history of previous stroke . Results : The baseline NIHSS score strongly predicted outcome , with one additional point on the NIHSS decreasing the likelihood of excellent outcomes at 7 days by 24 % and at 3 months by 17 % . At 3 months , excellent outcomes were noted in 46 % of patients with NIHSS scores of 7 to 10 and in 23 % of patients with scores of 11 to 15 . After multivariate adjustment , lacunar stroke had an odds ratio of 3.1 ( 95 % CI , 1.5 to 6.4 ) for an excellent outcome at 3 months . Conclusions : The NIHSS score strongly predicts the likelihood of a patient ’s recovery after stroke . A score of ≥16 forecasts a high probability of death or severe disability whereas a score of ≤6 forecasts a good recovery . Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score Background and Purpose : Models are used to adjust for case mix and to stratify treatment allocation in clinical trials and can , if accurate enough , be used to aid decision-making in individual patients . We aim ed to vali date , in patients assessed within 6 hours of onset , a previously described six simple variable ( SSV ) model that was developed in stroke patients who were assessed sub-acutely . The explanatory variables in the model are age , living alone , independent pre-stroke , Glasgow Coma Scale verbal score , ability to lift arms and ability to walk . Methods : The six variables were collected at r and omisation in the Third International Stroke Trial ( IST3 ) trial of recombinant tissue plasminogen activator in ischaemic stroke . We assessed survival to 30 days and functional status at 6 months using the Oxford H and icap Scale . We constructed receiver operator characteristic ( ROC ) curves to establish the model ’s discriminatory performance and tested its calibration by charting predicted versus actual outcomes . Results : 537 patients ( mean age , 74 years ) were included , of whom 422 ( 79 % ) survived 30 days and 179 ( 33 % ) were alive and independent at 6 months . The SSV model had an area under the ROC curve of 0.73 for 30-day survival and 0.82 for independent survival at 6 months . Calibration was satisfactory . Conclusions : This study confirms the external validity of the SSV model in an ischaemic stroke population assessed within 6 hours of symptom onset . The SSV model comprising easily collected variables can therefore be used to stratify patients in hyper-acute stroke trials , but probably is not accurate enough for decision-making in individual patients Objectives : ( I ) To obtain biomechanical parameters and assessment scores applied at a very early stage after stroke that predict best the functional outcome after rehabilitation . ( II ) To evaluate the predictive value of changes ( i.e. increase or decrease ) of these parameters during the first week in relation to the predictive value of their absolute scores . Design : Prospect i ve outcome study . Subjects : Forty-one stroke patients , admitted to the stroke unit within 24 hours . Main outcome measures : Barthel Index , Rivermead Motor Assessment , Motor Club Assessment and Functional movement activities , NIH-Stroke scale ( NIH-SS ) , Grip strength . Results : Parameters assessed within the first hours after stroke correlated only weakly with the outcome . The best model predicting functional outcome and independence in activities of daily living of stroke patients after 6 months was that including NIH-SS , grip strength , age and previous stroke explaining 79 % of the variance . These parameters assessed on day 7 post-stroke are more predictive than the difference between stroke onset and day 7 post-stroke . Conclusion : Parameters for predicting outcome should not be assessed before day 7 post-stroke OBJECTIVE To develop a model for predicting outcome in the first few hours after the onset of an ischemic stroke on the basis of the clinical findings obtained during a rapid bedside examination . DESIGN Clinical records were retrieved from the data bank of a r and omized multicenter trial . The result ing case series was split into two subgroups that served as a " training set " and a " test set . " Logistic regression was applied to the training set to select the prognostic predictors among baseline clinical findings . The performances of the model based on independent prognostic predictors were then vali date d in the test set . SETTING Eleven primary care institutions ( either hospitals or university clinics ) participating in the Italian Acute Stroke Study on the efficacy of hemodilution and monosialoganglioside in acute ischemic stroke . PATIENTS Consecutive noncomatose patients ( N = 300 ) observed within the first 6 hours after the onset of a first supratentorial ischemic stroke . MAIN OUTCOME MEASURE Death or disablement 4 months after the index stroke . Disablement was defined as a score of 3 or higher on the Rankin Scale . RESULTS Age and CNS score defined six risk groups with a predicted 4-month poor outcome rate ranging from 10 % ( patients aged 70 years or younger and with an initial CNS score of 7 or higher ) to 89 % ( patients older than 70 years and with a CNS score of 4.5 or lower ) . When a risk of poor outcome of 60 % was taken as a cutoff , the accuracy of the prediction was 78 % + /- 6 % in the training set and 72 % + /- 9 % in the test set . CONCLUSION Long-term outcome can be predicted in the first few hours following an acute ischemic stroke by means of a simple model based on age and CNS score OBJECTIVE To determine whether physical function before stroke is an independent predictor of physical function and institutionalization 6 months after discharge from hospital in elderly stroke patients . DESIGN Population -based prospect i ve cohort design where incidence of stroke was monitored from 1982 through 1988 . Baseline demographic and health information including prestroke function was collected prospect ively . Eligible subjects who had a stroke were interviewed 6 months after discharge from hospital to assess outcomes . SETTING New Haven , Connecticut . PATIENTS Subjects were recruited from an initial sample of 2,812 older adults . Of 79 subjects who survived a first stroke at 6 months postdischarge , complete follow-up data were obtained on 63 subjects . MAIN OUTCOME MEASURE Physical function as measured by the Katz scale and institutionalization . RESULTS Fewer limitations in activities of daily living before stroke were associated with fewer limitation in physical function after stroke controlling for stroke severity and other relevant health and sociodemographic conditions ( p < .01 ) . Fewer limitations in gross mobility function before stroke were also independently associated with a lower risk of institutionalization ( p < .05 ) . CONCLUSION This study provides useful information in assessing the prognosis of elderly stroke patients upon admission to hospital . It also supports the concept of general frailty being a risk factor for poorer health and institutionalization overall in aged persons . Studies have shown that factors related to physical frailty , such as decline in muscle function , can be reversed . The effect of interventions aim ed at improving the physical function of the elderly on stroke incidence , stroke outcomes , and all-cause mortality , however , needs to be determined In a prospect i ve observational study , we assessed the relative value of conventional stroke risk factors and emerging markers in the prediction of functional outcome of patients surviving the acute phase of an ischemic non-embolic stroke . All available eligible patients consecutively admitted due to a first-ever acute ischemic non-embolic stroke during a 2-year period were evaluated . In a total of 105 patients ( 54 males , 51 diabetic ) a series of clinical , biochemical and imaging characteristics were recorded , including demographic data , blood pressure , serum glucose , insulin , lipids , inflammatory markers , intima-media thickness of the carotid arteries ( IMT ) , brain damage location and size of the infa rct volume . Barthel Activities of Daily Living Index ( BI ) scale was used to assess the severity of neurological deficit on admission and the functional outcome 6 months after discharge . Brain infa rct volume , stroke location in the anterior circulation , age , diabetes mellitus , IMT and plasma interleukin-1beta levels proved to be significant determinants of long-term functional outcome , assessed by BI disability score . ROC curve analyses indicated that the infa rct volume is superior to other predictors in the diagnosis of patients with unfavorable functional outcome ( BI<95 ) at 6 months post-discharge ( area under the curve , AUC=0.80 , 95 % confidence interval 0.64 - 0.95 ; p=0.003 ) . Significant differences in the mean infa rct volume were noted among age tertiles , with the diabetic patients in the 3rd tertile of age experiencing the worst outcome ( LSD test , p=0.019 ) . Taken together , the assessment of infa rct volume seems to have a significant predictive value regarding long-term functional outcome , especially in the elderly diabetic patients Abstract : Few well‐ design ed descriptive studies focus exclusively on patients after motor stroke . This study describes a cohort of participants after motor stroke and assesses the extent to which five key variables explain the variation in functional recovery 3 months after stroke . Prospect i ve data were collected ( N = 100 ) on age , lesion volume , motor strength , cognition , and poststroke function during the acute care hospital admission . Instruments included magnetic resonance imaging ( MRI ) to provide a measure of lesion volume , the Mini‐Mental State Examination ( MMSE ) and the Neurobehavioral Cognitive Status Examination ( NCSE ) to measure cognitive status , and the National Institutes of Health Stroke Scale ( NIHSS ) to measure motor strength . The Functional Independence Measure ( FIMTM ) was used to measure baseline function and functional recovery 3 months after stroke . Descriptive and hierarchical multiple regression analyses were used to describe the cohort and predict functional recovery . The means for key variables during acute care were 65 ( ±15 ) years of age , lesion volume 21.5 ( ±44.7 ) cm3 , NIHSS 6.34 ( ±3.55 ) , MMSE 24.38 ( ±4.82 ) , NCSE 64.33 ( ±13 ) , and FIMTM 94.05 ( ±19.31 ) . Age , cognitive status , and initial function accounted for 42 % of the variance in functional recovery 3 months after stroke . Results indicate that neuroscience nurses need to add cognition to their focus during the fast‐paced acute phase of care following motor stroke OBJECTIVE To compare the acute Allen 's Prognostic Score , Canadian Neurological Score , and subacute Barthel Index as predictors of outcome functional status and infa rct size at 3 months in patients with acute cortical infa rct ion . DESIGN A prospect i ve study of acute stroke predictors and outcome measurements in a cohort of sequential hospitalized patients . PATIENTS Fifty-one patients with acute cortical infa rct ion and without previous disability assessed 24 hours after onset with Allen 's Prognostic Score and the Canadian Neurological Score and at 7 days with the Barthel Index . MAIN OUTCOME MEASURES Mortality , Barthel Index , and volumetric measurement of infa rct size on computed tomography 3 months after stroke . RESULTS There were seven deaths . The outcome Barthel Index was measured in all 44 survivors , of whom 29 had computed tomography at the time outcome was determined . In a multivariate analysis , functional outcome was best predicted by Allen 's Prognostic Score , a score of less than -15 having a sensitivity of 82 % and specificity of 97 % in predicting a poor outcome ( Barthel Index , < or = 12 or death ) . Volumetric tissue loss was predicted only by Allen 's Prognostic Score ( r = .62 , P < .001 ) . CONCLUSIONS Allen 's Prognostic Score is a robust predictor of both functional outcome and tissue loss in acute cortical infa rct ion and has a potentially important role in the analysis of the results of acute stroke intervention trials Background : Common carotid artery intima – media thickness ( CCA-IMT ) is an independent and early marker of generalised atherosclerosis . Brain affected by atherosclerosis may be more vulnerable to an ischaemic insult . Objective : To investigate the association between CCA-IMT and functional outcome after an acute ischaemic stroke . Design : Prospect i ve cohort analysis . Methods : 284 consecutive patients ( mean ( SD ) age , 68.7 ( 12.7 ) years , 126 ( 44 % ) female ) with an acute ischaemic stroke had carotid ultrasonography , carried out by a single operator . Demographic data , vascular risk factors , initial stroke severity , and brain imaging findings were recorded . Outcome was assessed at seven days from stroke onset , at discharge from hospital , and at one year post-stroke . Results : CCA-IMT was not significantly associated with adverse short or long term functional outcome in univariate analysis , or after adjustment in a multivariate logistic regression analysis for demographic data , initial stroke severity , conventional vascular risk factors , and the characteristics of the ischaemic lesion . Age and initial stroke severity were the only independent predictors of outcome . Conclusions : CCA-IMT was not associated with adverse functional outcome after an ischaemic stroke . Adding CCA-IMT in a prediction model for stroke outcome would probably not improve the power of the model OBJECTIVE Establish the relation between age , gender , initial neurologic deficit , stroke location , prior stroke , hemisphere of stroke , and functional outcome in ischemic stroke . DESIGN Single group , multivariate , repeated measures design with 327 persons having ischemic stroke recruited from 20 participating centers . SETTING Twenty European stroke centers . PATIENTS Consecutive admissions of men and women between the ages of 40 and 85 yrs with a hemispheric stroke caused by middle cerebral artery ischemia and a Unified Neurological Stroke Scale score of 5 to 24 . INTERVENTIONS In patients enrolled in the trial received traditional rehabilitation therapies including physical therapy , occupational therapy , and speech therapy when appropriate . MAIN OUTCOME MEASURES Barthel Index computed at 7 to 10 days and 3 months poststroke . RESULTS Positive functional outcomes were significantly related to the absence of prior strokes , a younger age , a less severe initial neurologic deficit , stroke involving cortical structures , and dominant ( left hemisphere ) lesions . CONCLUSIONS Despite some inconsistencies in existing literature , st and ardized prospect i ve examination of outcome after stroke clearly demonstrated the effect of age , initial severity of stroke , and lesion location as predictors of functional outcome Objective : To externally vali date two prognostic models predicting functional outcome and survival 100 days after acute ischemic stroke . Methods : Using prospect ively collected data from 1,470 patients , the authors evaluated two previously developed models . Model I predicts incomplete functional recovery ( Barthel Index < 95 ) vs complete functional recovery with 11 variables , whereas model II predicts mortality vs survival with 3 variables . On admission to a participating hospital , patients were registered prospect ively and included according to defined criteria . Within 72 hours , predictive variables under investigation were assessed . Follow-up was performed 100 days after the event . Results : Model I correctly predicted 68.1 % of the patients who had incompletely recovered or had died and 85.7 % of the completely recovered patients , model II 46.9 % of the patients who had died and 95.9 % of the surviving patients . Both models performed better than the treating physicians ’ predictions made within 72 hours after admission . Conclusion : The result ing prognostic models are useful to correctly stratify treatment groups in clinical trials and to accurately predict the distribution of endpoint variables The aim of this study was to evaluate prospect ively early predictors for ambulation and motor outcome 6~months after stroke occurrence . Sixty-eight consecutive , first-ever , stroke survivors were prospect ively studied from the second week to the sixth month post stroke . Sex , age , stroke type , urinary incontinence , National Institutes of Health Stroke Scale ( NIHSS ) , and Trunk Control Test ( TCT ) scores were taken as independent variables . Gait ability and motor functional outcome at 6 months post-stroke were assessed . Age , sex , urinary incontinence , TCT and NIHSS were significantly related to final modified Rankin Scale ( mRS ) , motor portion of the Functional Independence Measure ( FIM ) and Berg Balance Scale ( BBS ) . Age and early TCT alone accounted for 61.1 % of the variance in the motor FIM rating ( at 6 months post-stroke ) . TCT < or= 50 on day 14 predicts non-independent walkers ( Functional Ambulation Categories ( FAC ) < 4 ) : sensitivity 83.3 % , specificity 85.7 % ) , OR : 30.0 , 95 % CI : 4.7 - 247.3 . In conclusion , early administered TCT predicts independent walking ability and motor functional outcome at six months post-stroke

There are likely to be considerable collateral benefits of ITN roll out on cutaneous leishmaniasis where this disease is co-endemic with malaria . Nonetheless , it is clear that insecticide-treated material s such as ITNs have the potential to reduce pathogen transmission and morbidity from VBDs where vectors enter houses

INTRODUCTION Insecticide-treated nets ( ITNs ) are one of the main interventions used for malaria control . However , these nets may also be effective against other vector borne diseases ( VBDs ) . We conducted a systematic review and meta- analysis to estimate the efficacy of ITNs , insecticide-treated curtains ( ITCs ) and insecticide-treated house screening ( ITS ) against Chagas disease , cutaneous and visceral leishmaniasis , dengue , human African trypanosomiasis , Japanese encephalitis , lymphatic filariasis and onchocerciasis .

Visceral leishmaniasis ( VL ) is a deadly vector-borne disease that causes an estimated 500 000 new cases a year . In India , Nepal and Bangladesh , VL is caused by Leishmania donovani , which is transmitted from man to man by the s and fly Phlebotomus argentipes . In 2005 , these three countries signed a memor and um of underst and ing to eliminate VL from the region . Integrated vector management is one of the pillars of this elimination strategy , alongside early case detection and treatment . We review ed the evidence of effectiveness of different vector control methods , to examine the potential role of insecticide treated bednets ( ITNs ) . Indoor residual spraying has shown poor impact for various reasons and resistance to DDT is emerging in Bihar . Environmental management performed poorly compared to insecticide based methods . ITNs could give individual protection but this still needs to be proven in r and omized trials . Given the constraints of indoor residual spraying , it is worthwhile to further explore the use of ITNs , in particular long lasting ITNs , as an additional tool in the VL elimination initiative INTRODUCTION American cutaneous leishmaniasis is endemic in Colombia , where approximately 6.000 new cases are reported every year . Current prevention and control measures are restricted to the diagnosis and treatment of cases . OBJECTIVE To evaluate the efficacy of a multifaceted intervention to prevent the transmission of Leishmania in the endemic focus of Tumaco , on the Pacific Coast of Colombia . MATERIAL S AND METHODS A group-r and omized trial was conducted . Twenty villages were matched according to prevalence of Leishmania infection , number of inhabitants and level of community participation , and then r and omly assigned to intervention or control . The intervention included deltamethrin-impregnated bednets , repellent ( 20 % diethyltoluamide and 0.5 % permethrin ) , modification of s and fly resting sites , and health education . Villages were under surveillance for one year and the use of the intervention measures monitored . The incidence of American cutaneous leishmaniasis and Leishmania infection in the two groups were compared , adherence to the intervention and adverse events were monitored , and the results were adjusted for village intraclass correlation . RESULTS Ten cases of American cutaneous leishmaniasis were confirmed in the intervention and 23 in the control group , OR = 0.42 , 95 % CI 0.14 - 1.26 . The intervention had a greater effect in children < 10 years old , in people living on the periphery of the village and in villages with a prevalence of infection in small children > 1 % . Adverse events associated with the use of the bednets and the repellent were reported in 2 % of the participants and were always mild . CONCLUSION Incident cases of American cutaneous leishmaniasis were reduced by 58 % in the intervention group . However , the small number of cases renders the effect estimate imprecise and precludes us to cl aim a protective effect for the intervention . Specific population s could be the targets of simpler and more cost-effective interventions in the future A large-scale intervention field trial of the effect of Olyset long-lasting insecticide-treated bednets on transmission of cutaneous leishmaniasis was carried out in 2 cities in the Islamic Republic of Iran from October 2003 to July 2005 . We enrolled 8620 individuals in 3000 households in 6 pairs of sectors in each city . Epidemiological and entomological surveys were carried out pre- and post-intervention . In both cities a statistically significant reduction was found in the incidence of new cases in intervention sectors who received bednets compared with control areas . Entomological surveys showed a reduction in numbers of female Phlebotomus sergenti captured indoors in intervention sectors Objective To test the effectiveness of large scale distribution of longlasting nets treated with insecticide in reducing the incidence of visceral leishmaniasis in India and Nepal . Design Paired cluster r and omised controlled trial design ed to detect a 50 % reduction in incidence of Leishmania donovani infection . Setting Villages in Muzaffarpur district in India and Saptari , Sunsari , and Morang districts in Nepal . Participants 13 intervention and 13 control clusters . 12 691 people were included in the analysis of the main outcome ( infection ) , and 19 810 were enrolled for the secondary ( disease ) end point . Intervention Longlasting insecticidal nets ( treated with deltamethrin ) were distributed in the intervention clusters in December 2006 . Main outcome measures Infection was determined by direct agglutination test at 12 and 24 months after the intervention in those who had negative results ( titre < 1:1600 ) at baseline . The effect estimate was computed as the geometric mean of the risk ratios for seroconversion for each cluster pair ( net/no net ) , with its 95 % confidence interval . Formal tests of effect of no intervention were obtained with a paired t test . Results There was no significant difference in the risk of seroconversion over 24 months in intervention ( 5.4 % ; 347/6372 ) compared with control ( 5.5 % ; 345/6319 people ) clusters ( risk ratio 0.90 , 95 % confidence interval 0.49 to 1.65 ) nor in the risk of clinical visceral leishmaniasis ( 0.99 , 0.46 to 1.40 ) . Adjustment for covariates did not alter these conclusions . Conclusions There is no evidence that large scale distribution of longlasting insecticidal nets provides additional protection against visceral leishmaniasis compared with existing control practice in the Indian subcontinent . The observed effect was small and not significant , though the confidence intervals did not exclude a 50 % change in either direction . Trial registration Clinical Trials NCT 2005 - 015374 Abstract Objective : To measure the impact on transmission of leishmaniasis of curtains impregnated with insecticide . Design : Cluster r and omised controlled trial : household interview survey , observational study of people 's behaviour , entomological study with light trap captures of s and flies inside houses . Setting : 14 urban sectors in Trujillo , Venezuela . Participants : 2913 inhabitants of 569houses . Intervention : Sectors were paired according to their 12month cumulative incidence of cutaneous leishmaniasis , one sector in each pair was r and omly allocated to receive polyester curtains impregnated with lambdacyhalothrin ( intervention group ) while the other sector received curtains without insecticide or no curtains ( control groups ) . After 12 months a follow up household survey was conducted . Main outcome measures : Reduction in abundance of s and flies indoors and 12 month incidence of clinical cases of cutaneous leishmaniasis . Results : Transmission of cutaneous leishmaniasis occurred mainly in the domestic setting , with the incidence over 12 months of 4 % . The mean number of s and flies per trap per night was 16.After follow up the 12 month incidence of cutaneous leishmaniasis was 0 % in the intervention group and 8 % in the six pairs in the control group that received unimpregnated curtains ( mean difference 8 , 95 % confidence interval 4.22 to 11.78 ; P=0.001 ) . There were significantly fewer s and flies in the intervention group ( 2 v 15,mean difference 13 s and flies per trap ; 9 to 17 ; P<0.001 ) . Conclusion : Curtains impregnated with insecticide provide a high degree of protection against indoor transmission of cutaneous leishmaniasis Background Bangladesh , India and Nepal are working towards the elimination of visceral leishmaniasis ( VL ) by 2015 . In 2005 the World Health Organization/Training in Tropical Diseases launched an implementation research programme to support integrated vector management for the elimination of VL from Bangladesh , India and Nepal . The programme is conducted in different phases , from proof-of-concept to scaling up intervention . This study was design ed in order to evaluate the efficacy of the three different interventions for VL vector management : indoor residual spraying ( IRS ) ; long-lasting insecticide treated nets ( LLIN ) ; and environmental modification ( EVM ) through plastering of walls with lime or mud . Methods Using a cluster r and omized controlled trial we compared three vector control interventions with a control arm in 96 clusters ( hamlets or neighbourhoods ) in each of the 4 study sites : Bangladesh ( one ) , India ( one ) and Nepal ( two ) . In each site four villages with high reported VL incidences were included . In each village six clusters and in each cluster five households were r and omly selected for s and fly collection on two consecutive nights . Control and intervention clusters were matched with average pre-intervention vector densities . In each site six clusters were r and omly assigned to each of the following interventions : indoor residual spraying ( IRS ) ; long-lasting insecticide treated nets ( LLIN ) ; environmental management ( EVM ) or control . All the houses ( 50 - 100 ) in each intervention cluster underwent the intervention measures . A reduction of intra-domestic s and fly densities measured in the study households by overnight US Centres for Disease Prevention and Control light trap captures ( that is the number of s and flies per trap per night ) was the main outcome measure . Results IRS , and to a lesser extent EVM and LLINs , significantly reduced s and fly densities for at least 5 months in the study households irrespective of type of walls or whether or not people shared their house with cattle . IRS was effective in all sites but LLINs were only effective in Bangladesh and India . Mud plastering did not reduce s and fly density ( Bangladesh study ) ; lime plastering in India and one Nepali site , result ed in a significant reduction of s and fly density but not in the second Nepali site . ConclusionS and fly control can contribute to the regional VL elimination programme ; IRS should be strengthened in India and Nepal but in Bangladesh , where vector control has largely been ab and oned during the last decades , the insecticide treatment of existing bed nets ( coverage above 90 % in VL endemic districts ) could bring about an immediate reduction of vector population s ; operational research to inform policy makers about the efficacious options for VL vector control and programme performance should be strengthened in the three countries The efficacy of insecticide-treated window curtains ( ITCs ) for dengue vector control was evaluated in Thail and in a cluster-r and omized controlled trial . A total of 2,037 houses in 26 clusters was r and omized to receive the intervention or act as control ( no treatment ) . Entomological surveys measured Aedes infestations ( Breteau index , house index , container index , and pupae per person index ) and oviposition indices ( mean numbers of eggs laid in oviposition traps ) immediately before and after intervention , and at 3-month intervals over 12 months . There were no consistent statistically significant differences in entomological indices between intervention and control clusters , although oviposition indices were lower ( P < 0.01 ) in ITC clusters during the wet season . It is possible that the open housing structures in the study reduced the likelihood of mosquitoes making contact with ITCs . ITCs deployed in a region where this house design is common may be unsuitable for dengue vector control Abstract Objectives To measure the impact on the dengue vector population ( Aedes aegypti ) and disease transmission of window curtains and water container covers treated with insecticide . Design Cluster r and omised controlled trial based on entomological surveys and , for Trujillo only , serological survey . In addition , each site had a non-r and omised external control . Setting 18 urban sectors in Veracruz ( Mexico ) and 18 in Trujillo ( Venezuela ) . Participants 4743 inhabitants ( 1095 houses ) in Veracruz and 5306 inhabitants ( 1122 houses ) in Trujillo . Intervention Sectors were paired according to entomological indices , and one sector in each pair was r and omly allocated to receive treatment . In Veracruz , the intervention comprised curtains treated with lambdacyhalothrin and water treatment with pyriproxyfen chips ( an insect growth regulator ) . In Trujillo , the intervention comprised curtains treated with longlasting deltamethrin ( PermaNet ) plus water jar covers of the same material . Follow-up surveys were conducted at intervals , with the final survey after 12 months in Veracruz and nine months in Trujillo . Main outcome measures Reduction in entomological indices , specifically the Breteau and house indices . Results In both study sites , indices at the end of the trial were significantly lower than those at baseline , though with no significant differences between control and intervention arms . The mean Breteau index dropped from 60 % ( intervention clusters ) and 113 % ( control ) to 7 % ( intervention ) and 12 % ( control ) in Veracruz and from 38 % to 11 % ( intervention ) and from 34 % to 17 % ( control ) in Trujillo . The pupae per person and container indices showed similar patterns . In contrast , in nearby communities not in the trial the entomological indices followed the rainfall pattern . The intervention reduced mosquito population s in neighbouring control clusters ( spill-over effect ) ; and houses closer to treated houses were less likely to have infestations than those further away . This created a community effect whereby mosquito numbers were reduced throughout the study site . The observed effects were probably associated with the use of material s treated with insecticide at both sites because in Veracruz , people did not accept and use the pyriproxyfen chips . Conclusion Window curtains and domestic water container covers treated with insecticide can reduce densities of dengue vectors to low levels and potentially affect dengue transmission Background Visceral leishmaniasis ( VL ) control in the Indian subcontinent is currently based on case detection and treatment , and on vector control using indoor residual spraying ( IRS ) . The use of long-lasting insecticidal nets ( LN ) has been postulated as an alternative or complement to IRS . Here we tested the impact of comprehensive distribution of LN on the density of Phlebotomus argentipes in VL-endemic villages . Methods A cluster-r and omized controlled trial with household P. argentipes density as outcome was design ed . Twelve clusters from an ongoing LN clinical trial — three intervention and three control clusters in both India and Nepal — were selected on the basis of accessibility and VL incidence . Ten houses per cluster selected on the basis of high pre-intervention P. argentipes density were monitored monthly for 12 months after distribution of LN using CDC light traps ( LT ) and mouth aspiration methods . Ten cattle sheds per cluster were also monitored by aspiration . Findings A r and om effect linear regression model showed that the cluster-wide distribution of LNs significantly reduced the P. argentipes density/house by 24.9 % ( 95 % CI 1.80%–42.5 % ) as measured by means of LTs . Interpretation The ongoing clinical trial , design ed to measure the impact of LNs on VL incidence , will confirm whether LNs should be adopted as a control strategy in the regional VL elimination programs . The entomological evidence described here provides some evidence that LNs could be usefully deployed as part of the VL control program . Trial registration Clinical Trials.gov CT-2005 - ABSTRACT Screening homes is an effective way of reducing house entry by mosquitoes . Here , we assess how important blocking the eaves is for reducing house entry by anopheline and culicine mosquitoes for houses that have screened doors and no windows . Twelve houses , with two screened doors and no windows , in which a single adult male slept , were included in a simple crossover design . In the first period , six houses were r and omly selected and had the eaves blocked using a mixture of rubble and mortar ; the other six were left with open eaves . Mosquitoes were sample d using CDC light traps from each house twice a week for 4 wk . Mosquito control activities and the number and type of domestic animals within the compound was recorded on each sampling occasion . Before beginning the second sampling period , homes with blocked eaves had them opened , and those with open eaves had them closed . Mosquitoes were then sample d from each house for a further 4 wk . When houses had their eaves closed , a three-fold reduction in Anopheles gambiae s.l . Giles caught indoors was observed . However , there was no reduction in total culicine numbers observed . This study demonstrates that the eaves are the major route by which An . gambiae enters houses . By contrast , culicine mosquitoes enter largely through doors and windows . Sealing the eave gap is an important method for reducing malaria transmission in homes where doors and windows are screened OBJECTIVES Insecticide-treated bednets ( ITNs ) are effective in preventing nocturnally transmitted vector-borne diseases , but their effect on diurnally active dengue vectors has never been studied . We investigated the efficacy of ITNs in reducing Aedes aegypti population s and dengue transmission . METHODS A cluster-r and omized trial was carried out in Leogane , Haiti between July 2003 and July 2004 . The study area ( 1017 houses ) was divided into 18 sectors ( clusters ) : nine received ITNs ( Olyset(R ) long-lasting insecticidal bednets ) and nine were untreated controls . Entomological surveys [ measuring Breteau ( BI ) , house ( HI ) , container ( CI ) and pupae per person ( PPI ) indices and oviposition activity ] were undertaken at baseline and at 1 and 5 months post-intervention . All houses were georeferenced to enable spatial analysis . Control sectors received ITNs at 6 months , and a final entomological and attitudinal survey was undertaken at 12 months after baseline . Anti-dengue IgM seropositivity rates were measured at baseline and after 12 months . Efficacy of ITNs was assessed by WHO cone bioassays . RESULTS At 1-month post-intervention , entomological indices fell in all sectors , with HI and BI in the bednet sectors reduced by 6.7 ( 95 % CI -10.6 , -2.7 ; P < 0.01 ) and 8.4 ( 95 % CI -14.1 , -2.6 ; P < 0.01 ) respectively . Moreover at 1 month , ovitraps in control sectors were significantly more likely to be positive than in bednet sectors ( P < 0.01 ) . By 5 months , all indices remained low and HI , CI and BI were also significantly lower than that of baseline in the control arm . Curiously , at 5 months , HI , CI and BI were lower in the control arm than that in the bednet arm . A final survey , 12 months after the initial baseline study ( 5 months after bednets had been given to all households ) indicated that all indices were significantly lower than that at baseline ( P < 0.001 ) . Control houses located within 50 m of a bednet house had significantly lower CI ( Z = -2.67 , P = 0.008 ) and PPI ( Z = -2.19 , P = 0.028 ) at 1 month , an effect that extended to 100 m by 5 months ( Z = -2.03 , P = 0.042 and Z = -2.37 , P = 0.018 respectively ) , suggesting a spill-over effect of the bednets . An IgM serosurvey showed a 15.3 % decrease ( 95 % CI 5.0 - 25.5 % , P < 0.01 ) in the number of IgM-positive individuals from baseline to12 months later . CONCLUSIONS Insecticide-treated bednets had an immediate effect on dengue vector population s after their introduction , and over the next 5 - 12 months , the presence of ITNs may have continued to affect vector population s and dengue transmission Anthroponotic cutaneous leishmaniasis ( ACL ) is a significant public health problem in many towns and cities of south central Asia and the Middle East , result ing in disfigurement and disability which warrants preventive action . A r and omized controlled trial was conducted in 1997/98 amongst a non-immune study population of 3666 people in Kabul , Afghanistan , to compare the efficacy of insecticide-treated nets ( ITNs ) , insecticide-treated Islamic cloth wraps ( chaddars ) used to sleep in , and residual pyrethroid spraying of individual houses for the prevention of ACL . Dosages of insecticide were : ITNs with permethrin , 0.5 g/m2 ; chaddars with permethrin , 1 g/m2 ; rooms with lambdacyhalothrin , 30 mg/m2 . Cases of ACL were diagnosed on clinical criteria . At the end of the trial period ( 15 months ) the incidence of ACL amongst controls was 7.2 % , amongst ITN users 2.4 % ( OR 0.31 , 95 % CI 0.2 - 0.5 ) , amongst impregnated chaddar users 2.5 % ( OR 0.33 , 95 % CI 0.2 - 0.6 ) and amongst residents of sprayed houses 4.4 % ( OR 0.60 , 95 % CI 0.3 - 0.95 ) . ITNs and impregnated chaddars were equally effective , providing about 65 % protective efficacy , with approximately 40 % protective efficacy attributable to individual house spraying . No significant differences for age or sex were found between new cases in the intervention and control groups . No serious side-effects were reported and interventions were generally popular ; ITNs were the most popular , followed by residual spraying and then impregnated chaddars The prevalence of bedbugs ( Cimex hemipterus L. ) , chicken ticks ( Argas persicus Oken ) and headlice ( Pediculus capitis De Geer ) was surveyed in a rural area of The Gambia . At the beginning of the study 37.5 % of children 's beds were infested with bedbugs and 3.9 % with chicken ticks , whilst the prevalence rate of pediculosis in children under 10 years old was 28.8 % . Both bedbugs and headlice were clustered within compounds . Headlice prevalence increased with hair length and they were more common on girls than boys . Following this cross-sectional survey all bednets in the sixteen hamlets were either dipped in permethrin or a placebo . About 4 months later it was found that bedbugs and chicken ticks had disappeared from homes in which the bednets had been impregnated with permethrin . There was no reduction in hamlets with placebo-treated bednets . The rate of acquiring headlice between the two surveys was reduced by 91.1 % in children who slept under insecticide-treated bednets compared with children with placebo-treated bednets . There were also significantly fewer day-flying and crawling insects , except earwigs , in homes of children who slept under insecticide-treated bednets compared with those with placebo-treated nets . These additional benefits of permethrin-treated bednets should contribute to their widespread acceptance and utilization by the community for personal protection Prior to implementation of a r and omized controlled trial of insecticide (permethrin)-treated bed nets ( ITNs ) in western Kenya , ethnographic studies were conducted to underst and local perceptions of disease , sleeping patterns , and other factors that might affect use of ITNs . Educational activities took place prior to distribution , but immediately after distribution in Asembo only approximately half of the ITNs were in use . A qualitative study was then conducted to identify the community 's perceptions about ITNs and the ITN project . While participants ranked malaria as important and recognized that malaria prevention could be beneficial , they believed ITNs would be only partly effective due to the perception that malaria has multiple causes . Concerns expressed included fear of the insecticide , thought by some to be a toxic family planning aid , the taking of blood during clinical studies , and the mixing up of family ITNs during net re-treatment , which would violate cultural taboos . Attempts were made to allay fears by improved communication on these subjects and modification of the study design The effectiveness of bednets and curtains ( nylon mesh 64 per cm2 ) impregnated with deltamethrin at 26 mg a.i./m2 in reducing the biting nuisance caused by three phlebotomine s and fly species : Lutzomyia columbiana , Lu.lichyi and the predominant Lu.youngi ( Diptera : Psychodidae ) , was evaluated at La Guaira , a rural settlement in Valle de Cauca near Cali , Colombia . Pairs of volunteers collected s and flies under impregnated bednets , in rooms protected by impregnated curtains or in unprotected rooms in a r and omized matched design . Collection s were made in three houses per night on three consecutive nights , so that each house was sample d under each of the three treatments . This routine was repeated at 2-week intervals for 6 months . There was no significant difference between the overall numbers of s and flies collected in rooms with or without impregnated curtains . Only 0.14 s and flies/man-hour were caught on human bait under impregnated bednets , significantly fewer than the numbers collected on human bait outside the nets in the same room ( 1.91 ) or in unprotected rooms ( 3.29 ) . In a second set of experiments carried out in La Guaira and the neighbouring community of Jiguales , the effect of deltamethrin impregnation was evaluated by comparing numbers of s and flies collected on human bait under treated and untreated nets . Significantly fewer were collected under the impregnated nets ( 0.25 v. 0.69/man-hour ) . Wild-caught female Lu.youngi exposed to treated netting for 2 min in the laboratory all died with 24 h. The impact of deltamethrin-impregnated bednets was considered to be useful against Lu.youngi and other potential vectors of leishmaniasis in such communities

We did not pool data for other outcomes due to either heterogeneity in outcome measures or differing interventions .There was no evidence that glycerine gel dressings or breast shells with lanolin significantly improved nipple pain . However , this beneficial effect was not maintained after six to seven days of treatment . There were no group differences in nipple pain perceptions at any assessment between women who applied expressed breast milk and women who applied nothing . Women who applied an " all- purpose nipple ointment " , in comparison to women who applied lanolin , had no improvement in nipple pain after seven days of treatment . There was insufficient evidence that glycerine gel dressings , lanolin with breast shells , lanolin alone , expressed breast milk , or all- purpose nipple ointment improved maternal perceptions of nipple pain . Overall , there was insufficient evidence to recommend any intervention for the treatment of nipple pain . However , one important finding was that regardless of the treatment used , for most women nipple pain reduced to mild levels after approximately seven to 10 days ' postpartum . The provision of anticipatory guidance regarding usual time to pain reduction may be a useful strategy in assisting women to continue to breastfeed and to do so exclusively . There was insufficient evidence that glycerine gel dressings , breast shells with lanolin , lanolin alone , or the all- purpose nipple ointment significantly improved maternal perceptions of nipple pain . The results from these four trials of good method ological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin .

BACKGROUND Leading health authorities all recommend exclusive breastfeeding to six months ' postpartum . While most women initiate breastfeeding , many discontinue due to difficulties encountered rather than maternal choice . One common breastfeeding difficulty is painful nipples . Research has identified poor infant positioning or latch as a common cause of painful nipples . While many different interventions design ed to reduce nipple pain in breastfeeding women have been evaluated , it is unclear which intervention is the most effective treatment . An underst and ing of nipple pain and treatment options are needed to improve breastfeeding duration and exclusivity rates and to address systematic ally one of the most frequent difficulties encountered by breastfeeding women . OBJECTIVES To assess the effects of all interventions in the resolution or reduction of nipple pain and the impact of the interventions on other outcomes such as nipple trauma , nipple infections , breast mastitis , breastfeeding duration , breastfeeding exclusivity , and maternal satisfaction . Nipple pain in women who are feeding with expressed breast milk ( i.e. women of infants in neonatal units ) is associated with other methods of removing milk from the mother 's breast such as manual expression and various types of breast pumps . Nipple pain and subsequent treatment is different in this unique maternal population and thus we excluded women solely feeding with expressed breast milk from this review .

Background A small , non-blinded , RCT ( r and omised controlled trial ) had reported that oral antibiotics reduced the incidence of mastitis in lactating women with Staphylococcus aureus ( S. aureus)- colonized cracked nipples . We aim ed to replicate the study with a more rigorous design and adequate sample size . Methods Our intention was to conduct a double-blind placebo-controlled trial to determine if an antibiotic ( flucloxacillin ) could prevent mastitis in lactating women with S. aureus-colonized cracked nipples . We planned to recruit two groups of 133 women with S. aureus-colonized cracked nipples . Results We spent over twelve months su bmi tting applications to five hospital ethics committees and seven funding bodies , before commencing the trial . Recruitment to the trial was very slow and only ten women were r and omized to the trial after twelve months , and therefore the trial was stopped early . Conclusions In retrospect we should have conducted a feasibility study , which would have revealed the low number of women in these Melbourne hospitals ( maternity wards and breastfeeding clinics ) with damaged nipples . The appropriate use of antibiotics for breastfeeding women with cracked nipples still needs to be tested Trial design A r and omised , parallel group , pragmatic trial . Setting A large UK maternity hospital . Participants Term infants < 2 weeks old with a mild or moderate degree of tongue-tie , and their mothers who were having difficulties breastfeeding . Objectives To determine if immediate frenotomy was better than st and ard breastfeeding support . Interventions Participants were r and omised to an early frenotomy intervention group or a ‘ st and ard care ’ comparison group . Outcomes Primary outcome was breastfeeding at 5 days , with secondary outcomes of breastfeeding self-efficacy and pain on feeding . Final assessment was at 8 weeks ; 20 also had qualitative interviews . Research ers assessing outcomes , but not participants , were blinded to group assignment . Results 107 infants were r and omised , 55 to the intervention group and 52 to the comparison group . Five-day outcome measures were available for 53 ( 96 % ) of the intervention group and 52 ( 100 % ) of the comparison group , and intention-to-treat analysis showed no difference in the primary outcome —Latch , Audible swallowing , nipple Type , Comfort , Hold score . Frenotomy did improve the tongue-tie and increased maternal breastfeeding self-efficacy . At 5 days , there was a 15.5 % increase in bottle feeding in the comparison group compared with a 7.5 % increase in the intervention group . After the 5-day clinic , 44 of the comparison group had requested a frenotomy ; by 8 weeks only 6 ( 12 % ) were breastfeeding without a frenotomy . At 8 weeks , there were no differences between groups in the breastfeeding measures or in the infant weight . No adverse events were observed . Conclusions Early frenotomy did not result in an objective improvement in breastfeeding but was associated with improved self-efficacy . The majority in the comparison arm opted for the intervention after 5 days BACKGROUND : Ankyloglossia has been associated with a variety of infant-feeding problems . Frenotomy commonly is performed for relief of ankyloglossia , but there has been a lack of convincing data to support this practice . OBJECTIVES : Our primary objective was to determine whether frenotomy for infants with ankyloglossia improved maternal nipple pain and ability to breastfeed . A secondary objective was to determine whether frenotomy improved the length of breastfeeding . METHODS : Over a 12-month period , neonates who had difficulty breastfeeding and significant ankyloglossia were enrolled in this r and omized , single-blinded , controlled trial and assigned to either a frenotomy ( 30 infants ) or a sham procedure ( 28 infants ) . Breastfeeding was assessed by a preintervention and postintervention nipple-pain scale and the Infant Breastfeeding Assessment Tool . The same tools were used at the 2-week follow-up and regularly scheduled follow-ups over a 1-year period . The infants in the sham group were given a frenotomy before or at the 2-week follow-up if it was desired . RESULTS : Both groups demonstrated statistically significantly decreased pain scores after the intervention . The frenotomy group improved significantly more than the sham group ( P < .001 ) . Breastfeeding scores significantly improved in the frenotomy group ( P = .029 ) without a significant change in the control group . All but 1 parent in the sham group elected to have the procedure performed when their infant reached 2 weeks of age , which prevented additional comparisons between the 2 groups . CONCLUSIONS : We demonstrated immediate improvement in nipple-pain and breastfeeding scores , despite a placebo effect on nipple pain . This should provide convincing evidence for those seeking a frenotomy for infants with signficant ankyloglossia BACKGROUND The negative outcomes associated with painful and damaged nipples have been widely documented in the breastfeeding literature . Numerous studies have been conducted evaluating topical preparations to treat nipple pain and damage with equivocal findings . No studies have evaluated the effectiveness of the increasingly popular all- purpose nipple ointment ( APNO ) . The purpose of this trial is to evaluate the effect of the APNO versus lanolin on nipple pain among breastfeeding women with damaged nipples . SUBJECTS AND METHODS A double-blind , r and omized controlled trial was conducted in a large single-site , tertiary-care hospital in Toronto , ON , Canada . Breastfeeding women ( n=151 ) identified as having damage to one or both nipples were r and omized to apply either APNO ( intervention group ) or lanolin ( control group ) to their nipples according to the trial protocol . The primary outcome was nipple pain at 1 week after r and omization measured using the Short Form McGill Pain Question naire . Additional outcomes at 1 week after r and omization and 12 weeks postpartum included nipple yeast symptoms and /or mastitis , rates of breastfeeding duration and exclusivity , and maternal satisfaction with infant feeding method and treatment ointment . RESULTS There were no significant group differences in mean pain scores at 1 week after r and omization . Women in the lanolin group reported significantly greater satisfaction with their infant feeding method and had nonsignificantly higher breastfeeding duration and exclusivity rates at 12 weeks postpartum . CONCLUSION Results suggest that APNO is not superior to lanolin in treating painful , damaged nipples Painful and /or damaged nipples associated with breastfeeding are common and represent a challenge for both the persons experiencing nipple pain and /or trauma and for those providing treatment . However , evidence -based data has been insufficient to demonstrably minimize these common reasons for failure to initiate or continue successful breastfeeding . The aim of this study was to evaluate the efficacy of specific- grade highly purified anhydrous ( HPA ) lanolin versus expressed breastmilk ( EBM ) for the treatment of painful and damaged nipples associated with breastfeeding in a prospect i ve controlled clinical trial evaluating 84 lactating mothers . Nipple trauma and healing rates were rated by the Nipple Trauma Score . Nipple pain intensity was assessed on a visual analog scale . Outcome parameters were in favor of the HPA lanolin group , reaching statistical significance for healing rates , nipple trauma and nipple pain . In our study , we found HPA lanolin more effective than EBM , inducing faster healing of nipple trauma ( absolute risk reduction of 0.43 ) and reducing nipple pain ( absolute risk reduction of 0.61 on day 3 ) . We concluded that HPA lanolin , combined with breastfeeding education , was more effective than EBM , combined with breastfeeding education , in reducing nipple pain and promoting healing of nipple trauma Pre- and perinatal variables commonly found to predict breast-feeding duration were examined to see whether they also predicted breast-feeding problems in the first week postpartum . One hundred and twenty-eight families who prenatally committed to breast-feeding for at least 6 weeks comprised the sample . The families were r and omly assigned to one of two groups : a group in which bottle feedings would be avoided in Weeks 2–6 postpartum and a group in which approximately one bottle per day would be given during the same period . Breastfeeding events most commonly experienced as problems in previous studies were also reported by mothers in this sample . Multiple regression analyses revealed that bottle use in the hospital , lower satisfaction with first breastfeeding , and group assignment were weakly predictive of the Breast-feeding Problem Score at 1 week , R2 = .154 , p = .0004 . The negative effect of hospital bottle use was greater for women in the bottle-restricted group than for women in the planned-bottle group The research undertaken in this study utilized a case-control group nested within a prospect i ve cohort which was followed for the first 3 months postpartum . Mothers with mastitis and their controls were requested to complete a self-report question naire design ed to investigate the association between the potential risk factors , identified from the literature , and lactation mastitis . Logistic regression analyses of the possible risk factors were performed separately for mothers who had not breastfed Obviously and those mothers who had breastfed at least one infant prior to this lactation/nalysis showed blocked duct(s ) and increased levels of stress were the significant pre icors for mastitis in mothers who had breastfed a previous infant and blocked duct(s ) , restriction from a tight bra , attachment difficulties , and nipple pain during a feed were the significant predictors for mastitis in first time breastfeeding mothers AIM This study investigated if a maternally reported , immediate improvement in breastfeeding following division of tongue-tie is due to a placebo effect . METHODS This r and omized controlled trial was conducted at Southampton General Hospital , Southampton , UK , in 2003 - 2004 . Sixty breastfed babies 5 - 115 days old ( mean , 32 days ; median , 23 days ) were r and omized to division ( Group A ) or non-division ( Group B ) . The mother and a trained observer were blinded and assessed breastfeeding before the intervention . Fifty-seven babies were analyzed because blinding failed in three of the babies in Group A. Following the intervention , the mother 's and observer 's views were noted , and then those infants allocated to non-division had their tongue-tie divided . RESULTS Seventy-eight percent ( 21 of 27 ) of mothers in Group A reported an immediate improvement in feeding following the intervention , compared with 47 % ( 14 of 30 ) in Group B ( two-tailed χ(2 ) p<0.02 ; 95 % confidence interval , 6 - 51 % ) . At 1-day follow-up , 90 % ( 54 of 60 ) reported improved feeding following division . At 3-month follow-up , 92 % ( 54 of 59 ) still reported improved feeding , with 51 % ( 30 of 59 ) continuing to breastfeed . CONCLUSIONS There is a real , immediate improvement in breastfeeding , detectable by the mother , which is sustained and does not appear to be due to a placebo effect BACKGROUND Sore nipples are common during lactation and remain the major reason for failing to establish successful breastfeeding . To formulate a peppermint gel and to evaluate its effect on the prevention of nipple crack associated with breast-feeding , a r and omized double-blinded clinical trial comparing the above formulation with modified lanolin and a neutral ointment was carried out . MATERIAL / METHODS Two hundred and sixteen primiparous participants were assigned r and omly to three groups . Each group applied only one of the above three preparations on both breasts for 14 days . Each group consisted of 72 primiparous mothers and was seen for a maximum of four follow-up visits within 14 days and a final visit at week 6 . The rate of nipple and areola crack and pain was evaluated . RESULTS The study groups were comparable in mean age and route of delivery . Nipple crack were less in mothers who received peppermint gel than in those who received lanolin ointment or placebo ( chi(2)=16.8 , df=6 , P=0.01 ) . Relative risk of nipple crack in the lanolin group ( RR : 2.41 , 95%CI : 1.20 - 3.01 ) was higher than in the peppermint group ( RR : 1.85 , 95%CI : 1.64 - 3.10 ) . CONCLUSIONS Prophylactic peppermint gel in breastfeeding lactating women is associated with fewer nipple cracks and is more effective than lanolin and placebo . It could be recommended for preventing of nipple crack along with teaching better breastfeeding technique at the initiation of breastfeeding PURPOSE Ankyloglossia ( " tongue-tie " ) occurs in nearly 5 % of neonates , but its clinical significance relating to breast-feeding difficulties is controversial . We tested the hypothesis that in infants with ankyloglossia referred because of breast-feeding difficulties , frenotomy alleviates the symptoms . METHODS Twenty-five mothers of healthy infants with ankyloglossia were recruited because of sore nipples . Infants were r and omized to either of 2 sequences : ( 1 ) frenotomy , breast-feeding , sham , breast-feeding ( n = 14 ) or ( 2 ) sham , breast-feeding , frenotomy , breast-feeding ( n = 11 ) . The mothers as well as all personnel taking care of the child after each sham or frenotomy procedure were masked as to the study sequence . In every sequence , and after each sham or frenotomy procedure , a st and ardized latch score and pain score were obtained from the mother . RESULTS There was a significant decrease in pain score after frenotomy than after sham ( P = .001 ) . There was also a nearly significant improvement in latch after the frenotomy in these mothers ( P = .06 ) . CONCLUSION Frenotomy appears to alleviate nipple pain immediately after frenotomy . We speculate that ankyloglossia plays a significant role in early breast-feeding difficulties , and that frenotomy is an effective therapy for these difficulties Background Nipple pain and damage in breastfeeding mothers are common causes of premature breastfeeding cessation . Peppermint water is popularly used for the prevention of nipple cracks in the North West of Iran . The aim of this study was to determine the effectiveness of peppermint water in the prevention of nipple cracks during breastfeeding in comparison with the application of expressed breast milk ( EBM ) . Methods One hundred and ninety-six primiparous breastfeeding women who gave birth between February and May 2005 in a teaching hospital in Tabriz , Iran , were r and omized to receive either peppermint water or EBM . Each woman was followed for up to three visits or telephone calls within 14 days and then by telephone call at week six postpartum . Results Women who were r and omized to receive peppermint water were less likely to experience nipple and areola cracks ( 9 % ) compared to women using EBM ( 27 % ; p < 0.01 ) . Women who used the peppermint water on a daily basis were less likely to have a cracked nipple than women who did not use peppermint water ( relative risk 3.6 , 95%CI : 2.9 , 4.3 ) . Nipple pain in the peppermint water group was lower than the expressed breast milk group ( OR 5.6 , 95 % CI : 2.2 , 14.6 ; p < 0.005 ) . Conclusion This study suggests that peppermint water is effective in the prevention of nipple pain and damage . Further studies are needed to assess the usefulness of peppermint water in conjunction with correct breastfeeding techniques . Trial registration number : BACKGROUND Sore nipples in breast-feeding mothers are a common cause of premature weaning , and are difficult to treat owing to recurrent trauma and exposure to the infant 's oral flora . OBJECTIVE To compare the safety and efficacy of a hydrogel moist wound dressing ( Elasto-gel , Southwest Technologies Inc , Baltimore , Md ) with the use of breast shells and lanolin cream in the treatment of maternal sore nipples associated with breast-feeding . DESIGN R and omized controlled trial comparing the above treatments for sore nipples . Patients were seen for a maximum of 3 follow-up visits within 10 days , or until the resolution of symptoms . SETTING The Maternal-Infant Lactation Center at the Mercy Hospital of Pittsburgh , Pittsburgh , Pa , a tertiary care teaching hospital in inner-city Pittsburgh . PATIENTS A referred sample of 42 breast-feeding women who presented to the Maternal-Infant Lactation Center for the treatment of sore nipples . All patients with breast infection or chronic unrelated pain conditions were excluded from the study . INTERVENTION After informed consent , patients were r and omized to receive either a hydrogel wound dressing or breast shells and lanolin . All patients underwent a history , physical examination of the infant and the mother 's breasts , assessment of breast-feeding technique , and breast-feeding instruction . MAIN OUTCOME MEASURES The degree of pain on self-report question naires and the change in scores for physical examination , breast-feeding technique , and pain behaviors during breast-feeding . RESULTS Although both treatments , in association with instruction in breast-feeding technique , were effective , greater improvement was seen in the group using breast shells and lanolin . This reached statistical significance for physician-rated healing ( P<.01 ) and self-reported pain ( P<.05 ) . There were significantly more infections in the dressing group ( P<.05 ) , which result ed in early discontinuation of the study . CONCLUSIONS Prevention of sore nipples by teaching proper technique on the initiation of breast-feeding should be instituted . For those cases in which sore nipples do develop , breast shells and lanolin in association with instruction in breast-feeding technique are more effective than moist wound dressings . Lanolin and shells should remain first-line therapy OBJECTIVE To determine the demographic , behavioral , and clinical factors associated with breastfeeding termination in the first 12 weeks postpartum . STUDY DESIGN This was a prospect i ve cohort study . POPULATION Breastfeeding women in Michigan and Nebraska were interviewed by telephone at 3 , 6 , 9 , and 12 weeks postpartum or until breastfeeding termination . OUTCOMES MEASURED We measured associations of demographic , clinical , and breastfeeding variables with weaning during the first 12 weeks postpartum . RESULTS A total of 946 women participated ; 75 % breastfed until 12 weeks . Women older than 30 years and women with at least a bachelor 's degree were more likely to continue breastfeeding in any given week . Mastitis , breast or nipple pain , bottle use , and milk expression in the first 3 weeks were all associated with termination . Beyond 3 weeks , women who expressed breast milk were 75 % less likely to discontinue breastfeeding than women who did not . Women who used a bottle for some feedings during weeks 4 to 12 were 98 % less likely to discontinue breastfeeding than women who did not use a bottle . " Not enough milk " was the most common reason given for termination in weeks 1 through 3 ( 37 % ) and weeks 4 through 6 ( 35 % ) ; " return to work " was the most common reason given in weeks 7 through 9 ( 53 % ) and weeks 10 through 12 ( 58 % ) . CONCLUSIONS Younger women and less educated women need additional support in their breastfeeding efforts . Counseling and assistance should be provided to women with pain and mastitis . Exclusive breastfeeding for the first 3 weeks should be recommended . After the first 3 weeks , bottles and manual expression are not associated with weaning and may improve the likelihood of continuing breastfeeding , at least until 12 weeks Sore , cracked nipples are commonly experienced by breastfeeding mothers . We have previously reported a strong correlation between sore , cracked nipples and S. aureus colonization . A prospect i ve , r and omized clinical trial was performed to compare four treatmnent regimes for S. aureus infected sore nipples . Eighty-four breastfeeding mothers were enrolled in the study . After 5 days to 7 days of treatment , only 8 % of mothers showed improvement in the " optimal breastfeeding technique alone " group , 16 % improved with topical mupiricin , 29 % improved with topical fusidic acid , yet 79 % improved with oral antibiotics ( p<.0001 ) . Optimal breastfeeding techniques and topical antibiotics ointment failed to heal most infected , sore , cracked nipples . Mastitis developed in 12 % to 35 % of mothers not treated with systemic antibiotics compared to 5 % of mothers treated with systemic antibiotics ( p<.005 ) . In conclusion , S. aureus infected sore , cracked nipples should be diagnosed as a potentially widespread impetigo vulgaris and treated aggressively with systemic antibiotics in order to improve healing and decrease the risk of developing mastitis due to an ascending lactiferous duct bacterial infection Health-promotion goals include increasing the duration of breastfeeding because of its irrefutable advantages to the mother and baby , society , and the environment . However , many mothers experience painful , sore nipples during breastfeeding and stop nursing before they intended ( Livingstone & Stringer , 1999 ) . The experimental trial described in this paper r and omized 94 breastfeeding women with sore nipples into three treatment groups . Midwives practicing in hospitals in Latvia assessed the participants ' breastfeeding practice s , then gave the mothers individualized education and corrective interventions using a guided documentation form , the Lactation Assessment Tool ( LATtrade mark ) . In addition , two groups were instructed to use commercial products on their breasts and nipples : breast shells and lanolin cream for one group , and glycerin gel therapy for the other . Nipple pain during breastfeeding was rated by the mothers on a 5-point verbal descriptor scale at each visit , and pain at the start of treatment was compared to pain at the last visit . Analysis of variance ( using Fisher 's Exact Test ) determined that no significant differences existed between the groups : F(2 , 86 ) = 1.34 , p > .05 . Almost all of the mothers experienced nipple healing , as assessed by the midwife . Mothers in the glycerin gel group were more satisfied with their treatment method , but this finding was not statistically significant . The results of this study indicate that effective care and perinatal education for nursing mothers with sore nipples should include assessment of breastfeeding positioning and latch-on , as well as education and corrective interventions using a guidance tool , whether or not commercial preparations are used BACKGROUND Nipple soreness is one reason why breastfeeding women wean their infants . This study examined the effectiveness of three topical agents -- USP-modified lanolin , warm water compresses , and expressed breast milk with air drying -- in alleviating nipple pain , and if early predictors of breastfeeding at six weeks could be determined . METHODS One hundred seventy-seven breastfeeding , primiparous women were r and omly assigned to one of four groups . All women received education about breastfeeding technique . Numeric rating scales were used to discriminate levels of pain intensity , pain affect , and strength of sucking on day 1 . Participants were interviewed by telephone on postpartum days 4 , 7 , and 14 , and during week 6 using the same scales . RESULTS No significant differences were found among groups for pain intensity , pain affect , or duration of breastfeeding . Results of a logistic regression indicated that older mothers and those who were exclusively breastfeeding ( no supplemental feeding ) were most likely to be breastfeeding six weeks postpartum . Raw scores supported the use of warm compresses . CONCLUSION Further investigation is required into ways of supporting young mothers and how caregivers provide support to breastfeeding mothers in the early weeks after childbirth OBJECTIVE To evaluate the use of hydrogel dressings for the prevention and treatment of nipple soreness in lactating women as compared with the common intervention of lanolin ointment . The hypothesis was as follows : Participants using hydrogel dressings as a preventive measure for nipple soreness will experience greater pain relief and a lower rate of nipple wounds as compared with the control group . The secondary hypothesis was that the reduction of nipple soreness in the treatment group would produce a longer duration of breastfeeding as compared with the control group . DESIGN A multicentered , prospect i ve , r and omized controlled clinical trial evaluating a sample of 106 lactating mothers . SETTING Study sites were the University of Alabama Medical Center at Birmingham ( an inner-city teaching hospital ) and Northeast Health System ( a community hospital in Beverly , Massachusetts ) . PARTICIPANTS Participants were older than age 18 , fluent in English , and had an operational telephone in the residence . Other inclusion criteria were singleton , vaginal deliveries ; no prior breastfeeding experience ; and written informed consent . INTERVENTIONS Participants were r and omized to either the lanolin ointment or the hydrogel dressings group and received instructions specific to their assignment . All participants received breastfeeding education provided by a board-certified lactation consultant . MAIN OUTCOME MEASURES During the initial 12 study days , participants identified pain intensity using a numeric pain intensity scale and verbal descriptor scale . Subjective data were collected via self-reported skin assessment s of the bilateral breasts , nipples , and areolae . Breastfeeding duration was established by a follow-up telephone call at 2 months . RESULTS The hydrogel dressings group had significantly greater reduction in pain score mean values at baseline , on study Day 10 , and on study Day 12 in comparison to the control group . Participants using the hydrogel dressings discontinued treatment sooner than participants in the lanolin ointment group . The lanolin ointment group had eight breast infections , whereas the hydrogel dressings group had none . CONCLUSION Hydrogel dressings are a safe , available treatment that provided more effective pain management for nipple soreness than the common intervention of lanolin ointment OBJECTIVE To evaluate effectiveness of water versus tea bag compresses in treatment of sore nipples during breastfeeding . DESIGN Prospect i ve , r and omized trial . SETTING Mother-infant care wards in a tertiary care teaching hospital . PARTICIPANTS Sixty-five primiparae with sore nipples who were breastfeeding after a vaginal delivery at 37 or more weeks gestation , who were 36 hours or less postpartum , and had combined mother-infant care . INTERVENTIONS Participants were assigned r and omly to one of six treatment groups with one of three regimens ( tea bag compress , water compress , or no compress ) r and omly assigned to right or left sides . Participants applied the treatments at least four times a day , from Days 1 to 5 postpartum . MAIN OUTCOME MEASURE Reduction of nipple pain . RESULTS Tea bag and water compresses were more effective than no treatment , with no statistically significant difference between the two types of compresses . CONCLUSION Warm water or tea bag compresses are an inexpensive , equally effective treatment for sore nipples during the early postpartum period The objective of this study was to prospect ively explore the influence ofwomen ’s experiences in preparing for and establishing breastfeeding on the duration of breastfeeding . A cohort of 490 women was surveyed at intervals during pregnancy and after giving birth . Data were collected on breastfeeding outcomes and experiences and analyzed using multiple logistic regression . After controlling for sociodemographic variables , women were less likely to be still fully breastfeeding at 6 to 10 weeks postpartum if they believed they needed more breastfeeding information prior to delivery or had experienced breastfeeding problems . Women were less likely to be fully breastfeeding at 4 months postpartum if they had experienced breastfeeding problems . This prospect i ve study demonstrated the influence ofwomen ’s preparedness for breastfeeding and their experiences in establishing breastfeeding on breastfeeding duration . Improvements in prenatal education about breastfeeding and management of breastfeeding problems are likely to increase breastfeeding duration This exploratory study compared the effect of two methods of breast feeding on breast engorgement , mastitis , infantile colic and duration of breast feeding . An opportunity sample of subjects was assigned either to the experimental group ( prolonged emptying of one breast at each feed ) ( n = 150 ) or to the control group ( both breasts equally drained at each feed ) in= 152 ) and both groups were followed prospect ively to 6 months after delivery . The experimental group had a lower incidence of breast engorgement in the first week ( 61.4 % versus 74.3 % ; p < 0.02 ) and colic over the first 6 months ( 12 % versus 23.4 % ; p < 0.02 ) . There was no significant difference between the two groups in the incidence of mastitis over 6 months and the length of breast feeding ( 16.510.3 weeks versus 17.510 weeks experimental versus control group ) . The majority of mothers in the experimental group ( 63 % ) felt it necessary to offer the second breast at the end of a feed to satisfy their infant 's hunger . The “ perceived insufficient milk supply syndrome ” was the main reason given for cessation of breast feeding in both groups . This study provides data to advise nursing mothers about these two methods of breast feeding . Breast engorgement , breast feeding methods , foremilk , hindmilk , infantile colic , BACKGROUND Most mothers stop breast-feeding before the recommended 6 months post partum . A systematic review showed that breast-feeding support programs by health care professionals did not substantially improve breast-feeding outcomes beyond 2 months post partum . We conducted a r and omized controlled trial to evaluate the effect of peer ( mother-to-mother ) support on breast-feeding duration among first-time breast-feeding mothers . METHODS We recruited 256 breast-feeding mothers from 2 semi-urban community hospitals near Toronto and r and omly assigned them to a control group ( conventional care ) or a peer support group ( conventional care plus telephone-based support , initiated within 48 hours after hospital discharge , from a woman experienced with breast-feeding who attended a 2.5-hour orientation session ) . Follow-up of breast-feeding duration , maternal satisfaction with infant feeding method and perceptions of peer support received was conducted at 4 , 8 and 12 weeks post partum . RESULTS Significantly more mothers in the peer support group than in the control group continued to breast-feed at 3 months post partum ( 81.1 % v. 66.9 % , p = 0.01 ) and did so exclusively ( 56.8 % v. 40.3 % , p = 0.01 ) . Breast-feeding rates at 4 , 8 and 12 weeks post partum were 92.4 % , 84.8 % and 81.1 % respectively among the mothers in the peer support group , as compared with 83.9 % , 75.0 % and 66.9 % among those in the control group ( p < or = 0.05 for all time periods ) . The corresponding relative risks were 1.10 ( 95 % confidence interval [ CI ] 1.01 - 2.72 ) at 4 weeks , 1.13 ( 95 % CI 1.00 - 1.28 ) at 8 weeks and 1.21 ( 95 % CI 1.04 - 1.41 ) at 12 weeks post partum . In addition , when asked for an overall rating of their feeding experience , significantly fewer mothers in the peer support group than in the control group were dissatisfied ( 1.5 % v. 10.5 % ) ( p = 0.02 ) . Of the 130 mothers who evaluated the peer support intervention , 81.6 % were satisfied with their peer volunteer experience and 100 % felt that all new breast-feeding mothers should be offered this peer support intervention . INTERPRETATION The telephone-based peer support intervention was effective in maintaining breast-feeding to 3 months post partum and improving satisfaction with the infant feeding experience . The high satisfaction with and acceptance of the intervention indicates that breast-feeding peer support programs , in conjunction with professional health services , are effective OBJECTIVE To examine various comfort measures and evaluate their effects in alleviating nipple soreness . DESIGN Prospect ively r and omized , experimental study . SETTING Postpartum unit of a community teaching hospital . PATIENTS Seventy-three primiparous , postpartum , breastfeeding women . INTERVENTIONS Subjects were r and omly assigned to four groups , with all women receiving instruction about breastfeeding and using one of the following treatments : warm moist tea bag compress , warm water compress , expressed milk massaged into the nipple and areola and air dried , instruction only ( control group ) . The subjects completed a question naire each morning for 7 days regarding nipple soreness . MAIN OUTCOME MEASURE Effect of treatments on postpartum nipple pain . RESULTS Subjects in the warm water compress group demonstrated significantly less pain on Day 3 than did the tea or breast milk group . CONCLUSIONS Anticipatory guidance by obstetric nurses may assist breastfeeding women in treating their pain nonpharmacologically Sore and cracked nipples are common and may represent an obstacle to successful breastfeeding . In Italy , it is customary for health professionals to prescribe some type of ointment to prevent or treat sore and cracked nipples . The efficacy of these ointments is insufficiently documented . The incidence of sore and cracked nipples was compared between mothers given routine nipple care , including an ointment ( control group ) , and mothers instructed to avoid the use of nipple creams and other products ( intervention group ) . Breastfeeding duration was also compared between the two groups . Eligible mothers were r and omly assigned , after informed consent , to one of the two groups . No difference was found between the control ( n=96 ) and the intervention group ( n=123 ) in the incidence of sore and cracked nipples and in breastfeeding duration . However , several factors were associated with sore nipples and with breastfeeding duration . The use of a pacifier and of a feeding bottle in the hospital were both associated with sore nipples at discharge ( p=0.02 and p=0.03 , respectively ) . Full breastfeeding up to 4 months postpartum was significantly associated with the following early practice s : breastfeeding on dem and , rooming-in at least 20 hours/day , non-use of formula and pacifier , no test-weighing at each breastfeed . The incidence of sore and cracked nipples and the duration of breastfeeding were not influenced by the use of a nipple ointment . Other interventions , such as providing the mother with guidance and support on positioning and latching , and modifications of hospital practice s may be more effective in reducing nipple problems OBJECTIVE To compare the effect of rubbing breast milk versus lanolin in the treatment of symptoms of sore nipples . METHODS We carried out this r and omized clinical trial on 225 mothers with sore nipples in the Neonatal Intensive Care Unit of Imam Reza Hospital in Mashhad , Iran from April 2001 for 2 years . We r and omly divided the patients into 3 groups . The first group rubbed the hind milk on their nipples at the end of each breast-feeding session , and the second group used lanolin locally on the nipple 3 times a day , and cleaned the nipple with a wet cloth before infant feeding . The third group did not use anything ( control group ) . We corrected the breast-feeding technique of all mothers throughout the study . After the first visit , we reexamined the patient on the third , fifth , seventh and tenth days . We obtained information with interviewing and physical examination by using a question naire . We based the sore nipple improvement on absence of irritation according to mothers opinions . We analyzed the obtained information using the SPSS version 11.5 software , and the used tests were Chi-Square test , Mann-Whitney test , and Kruskal-Wallis test . RESULTS The first group ( breast milk users ) included 78 patients , the second group ( lanolin users ) included 74 patients , and the third group ( control group ) included 73 patients . The 3 groups were similar in gravidity , delivery method , pre-delivery breast feeding education , the beginning time of the first breast feeding , prior success breast feeding experiences , detergent agents usage for nipples , use of formula , and pacifier . Clinical manifestations , such as appearance time of symptoms , irritation and breast wound were not significantly different . The healing time was different in these 3 groups ( p=0.038 ) according to the mean ranking in the groups . The healing time in the lanolin group was longer than the breast milk group ( p=0.029 ) and the control group ( p=0.028 ) . No side effects were noted during the study . CONCLUSION This study suggests that , due to the better healing of the sore nipple with breast milk , its availability , without payment and side effect , breast milk is recommended for the treatment of sore nipples OBJECTIVE To determine whether , in infants with a tongue-tie and a feeding problem , the current medical treatment ( referral to a lactation consultant ) or immediate division works best and enables the infants to feed normally . METHODS Between March and July 2002 , all the babies in the district of Southampton with tongue-ties were followed in order to see if they had any feeding problems . If they developed problems , the mothers gave written consent and were enrolled in an ethics committee approved , r and omized , controlled trial , comparing 48 h of intensive lactation consultant support ( control ) with immediate division . RESULTS A total of 201 babies had tongue-tie , of whom 88 had breast-feeding or bottle-feeding problems . Thirty-one were not enrolled , so 57 were r and omized . Of the 29 controls , one improved ( 3 % ) and breast-fed for 8 months , but 28 did not . At 48 h , these 28 were offered division , which all accepted , and 27 improved ( 96 % ) and fed normally . Of the 28 babies who had immediate division , 27 improved and fed normally but one remained on a nipple shield ( P < 0.001 ) . Twenty-four mothers breast-fed for 4 months ( 24/40 , 60 % ) . Overall , division of the tongue-tie babies result ed in improved feeding in 54/57 ( 95 % ) babies . CONCLUSIONS This r and omized , controlled trial has clearly shown that tongue-ties can affect feeding and that division is safe , successful and improved feeding for mother and baby significantly better than the intensive skilled support of a lactation consultant OBJECTIVE To assess whether an antenatal teaching session on position and attachment of the baby on the breast had an effect on postnatal nipple pain , nipple trauma and breast feeding duration . The study was planned as a pilot study to allow an adequate sample size to be calculated for a larger study . DESIGN An observer blind experimental design was used . Women were r and omly assigned to either the experimental group teaching session or the control group . SETTING One public hospital in Western Australia . PARTICIPANTS 70 primiparae who intended to breast feed their baby were recruited from the antenatal clinic of the study hospital at 36 weeks ' gestation . INTERVENTION Antenatal group sessions on position and attachment of the baby on the breast were conducted by a lactation consultant . MEASUREMENTS AND FINDINGS During the first four postnatal days , position and attachment was measured by LATCH ( Latch on , Audible swallow , Type of nipple , Comfort and Help ) ( Jensen et al 1994 ) , nipple pain was measured by the Visual Analogue Scale ( VAS ) and nipple trauma was measured by the Nipple Trauma Index ( NTI ) . The analysis of variance ( ANOVA ) results indicated that the women in the experimental group were better able to attach the baby on the breast and had significantly less nipple pain and trauma than the control group . At six weeks postnatally , 31 of the 35 women in the experimental group were breast feeding compared to 10 of the 35 in the control group . CONCLUSIONS AND IMPLICATION S These initial findings suggest that midwives can make the best use of decreasing re sources by using practical ' h and s on ' antenatal group teaching as an effective strategy to increase breast feeding rates BACKGROUND Although lactation experts suggest that a correct positioning and attachment technique reduces breastfeeding problems and enhances long-term breastfeeding , evidence from r and omized trials is lacking . The objective of this study was to evaluate the effect of postpartum positioning and attachment education on breastfeeding outcomes in first-time mothers . METHOD A r and omized trial was performed in a public hospital in Adelaide , South Australia , where 160 first-time mothers were r and omly allocated to receive either structured one-to-one education ( experimental group ) or usual postpartum care ( control group ) within 24 hours of birth . The primary outcome was breastfeeding at 6 weeks and 3 and 6 months postpartum ; other outcomes were nipple pain and trauma in hospital and at 6 weeks and 3 and 6 months , and satisfaction with breastfeeding . RESULTS No significant differences occurred in breastfeeding rates between the groups at each endpoint , although a trend in the direction of lower rates was seen at each endpoint in the experimental group . This group reported less nipple pain on days 2 ( p = 0.004 ) and 3 ( p = 0.04 ) , but this was not sustained on follow-up . No differences were observed in nipple trauma in hospital or in self-reported nipple pain and /or trauma at the three endpoints . Experimental group women were less satisfied with breastfeeding at 3 and 6 months postpartum when using a one-item measure ; however , a multiple-item measure showed no significant differences at the three endpoints . CONCLUSIONS The intervention did not increase breastfeeding duration at any assessment time or demonstrate any differences between the groups on secondary outcomes . The trend toward lower breastfeeding rates in the experimental group suggests a need for a larger trial to evaluate whether or nor postpartum positioning and attachment education may negatively affect breastfeeding The purpose of the present prospect i ve study was to compare incision and drainage against needle aspiration for the treatment of breast abscesses in lactating women . During the 3-year study period , patients with breast abscesses were r and omized 1:1 to undergo either incision and drainage ( 23 patients ) or needle aspiration ( 22 patients ) . Ultrasound guidance was not used for any of these patients . Age , parity , localization of abscess , whether or not nipples were cracked , duration of symptoms and lactation , abscess diameter , pus culture results , breast infection history during any previous period of lactation , healing time , recurrence , cosmetic outcome in the case of incision and drainage , and volume of pus removed and number of aspirations needed in the case of aspiration were recorded . The treatment value of each of these techniques was investigated . Student 's t-test , Fisher 's exact test , a Chi-square test and the Mann-Whitney U-test were used for statistical analysis . In the incision and drainage group all patients were treated successfully , but 1 patient ( 4 % ) had a recurrence 2 months after complete healing and 16 patients ( 70 % ) in this group were not pleased with the cosmetic outcome . In the needle aspiration group , overall 3 patients were treated with a single aspiration and 10 patients ( 45 % ) with multiple aspirations , but 9 patients ( 41 % ) did not heal following needle aspiration and subsequently required incision and drainage in addition . No recurrences were observed in the needle aspiration group during the follow-up period . The risk factors for failure of needle aspiration for breast abscesses were abscesses larger than 5 cm in diameter , unusually large volume of aspirated pus , and delay in treatment . In conclusion , breast abscesses smaller than 5 cm in diameter on physical examination can be treated with repeated aspirations with good cosmetic results . Incision and drainage should be reserved for use in patients with larger abscesses

VEGF-A level is a reasonable c and i date biomarker for bevacizumab in the treatment of breast cancer .

Abstract Bevacizumab may improve outcomes of patients with breast cancer , but the absence of an established biomarker hampers patient selection and research ers ´ ability to demonstrate a clear survival benefit . Its putative target , circulating VEGF-A , emerged as the main c and i date and we sought to identify the relationship between VEGF-A levels and outcomes through systematic review .

PURPOSE This r and omized , open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent st and ard-of-care ( SOC ) chemotherapy in patients with previously treated advanced triple-negative breast cancer ( TNBC ) . METHODS Patients with advanced TNBC , relapsed after anthracycline- and taxane-based chemotherapy , were r and omized to receive either sunitinib ( 37.5 mg/day ) or the investigator 's choice of SOC therapy . Progression-free survival was the primary endpoint . RESULTS Median progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy ( one-sided P = 0.888 ) . Median overall survival was not prolonged with sunitinib ( 9.4 months ) compared with SOC chemotherapy ( 10.5 months ; one-sided P = 0.839 ) . The objective response rate was 3 % with sunitinib and 7 % with SOC chemotherapy ( one-sided P = 0.962 ) . CONCLUSIONS Sunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC , for which identification of effective treatments and therapeutic targets remains an urgent need . TRIAL REGISTRATION NCT00246571 BACKGROUND Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer . The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel , followed by doxorubicin plus cyclophosphamide , would increase the rates of pathological complete response in the breast in women with operable , human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response . METHODS We r and omly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel ( 100 mg per square meter of body-surface area on day 1 ) , docetaxel ( 75 mg per square meter on day 1 ) plus capecitabine ( 825 mg per square meter twice a day on days 1 to 14 ) , or docetaxel ( 75 mg per square meter on day 1 ) plus gemcitabine ( 1000 mg per square meter on days 1 and 8) for four cycles , with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles . Patients were also r and omly assigned to receive or not to receive bevacizumab ( 15 mg per kilogram of body weight ) for the first six cycles of chemotherapy . RESULTS The addition of capecitabine or gemcitabine to docetaxel therapy , as compared with docetaxel therapy alone , did not significantly increase the rate of pathological complete response ( 29.7 % and 31.8 % , respectively , vs. 32.7 % ; P=0.69 ) . Both capecitabine and gemcitabine were associated with increased toxic effects -- specifically , the h and -foot syndrome , mucositis , and neutropenia . The addition of bevacizumab significantly increased the rate of pathological complete response ( 28.2 % without bevacizumab vs. 34.5 % with bevacizumab , P=0.02 ) . The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups . The addition of bevacizumab increased the rates of hypertension , left ventricular systolic dysfunction , the h and -foot syndrome , and mucositis . CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response , which was the primary end point of this study . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00408408 . ) BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting . Micrometastases are dependent on angiogenesis , suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting . We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer . METHODS For this open-label , r and omised phase 3 trial we recruited patients with central ly confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries . We r and omly allocated patients aged 18 years or older ( 1:1 with block r and omisation ; stratified by nodal status , chemotherapy [ with an anthracycline , taxane , or both ] , hormone receptor status [ negative vs low ] , and type of surgery ) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab ( equivalent of 5 mg/kg every week for 1 year ) . The primary endpoint was invasive disease-free survival ( IDFS ) . Efficacy analyses were based on the intention-to-treat population , safety analyses were done on all patients who received at least one dose of study drug , and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample . This trial is registered with Clinical Trials.gov , number NCT00528567 . FINDINGS Between Dec 3 , 2007 , and March 8 , 2010 , we r and omly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy . Most patients received anthracycline-containing therapy ; 1638 ( 63 % ) of the 2591 patients had node-negative disease . At the time of analysis of IDFS , median follow-up was 31·5 months ( IQR 25·6 - 36·8 ) in the chemotherapy-alone group and 32·0 months ( 27·5 - 36·9 ) in the bevacizumab group . At the time of the primary analysis , IDFS events had been reported in 205 patients ( 16 % ) in the chemotherapy-alone group and in 188 patients ( 14 % ) in the bevacizumab group ( hazard ratio [ HR ] in stratified log-rank analysis 0·87 , 95 % CI 0·72 - 1·07 ; p=0·18 ) . 3-year IDFS was 82·7 % ( 95 % CI 80·5 - 85·0 ) with chemotherapy alone and 83·7 % ( 81·4 - 86·0 ) with bevacizumab and chemotherapy . After 200 deaths , no difference in overall survival was noted between the groups ( HR 0·84 , 95 % CI 0·64 - 1·12 ; p=0·23 ) . Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab ( Cox interaction test p=0·029 ) . Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension ( 154 patients [ 12 % ] vs eight patients [ 1 % ] ) , severe cardiac events occurring at any point during the 18-month safety reporting period ( 19 [ 1 % ] vs two [ < 0·5 % ] ) , and treatment discontinuation ( bevacizumab , chemotherapy , or both ; 256 [ 20 % ] vs 30 [ 2 % ] ) ; we recorded no increase in fatal adverse events with bevacizumab ( four [ < 0·5 % ] vs three [ < 0·5 % ] ) . INTERPRETATION Bevacizumab can not be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer . Further follow-up is needed to assess the potential effect of bevacizumab on overall survival Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists INTRODUCTION A multicenter , open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival ( PFS ) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2(- ) advanced breast cancer . PATIENTS AND METHODS Patients with HER2(- ) advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were r and omized ( 1:1 ; planned enrollment 740 patients ) to receive intravenous ( I.V. ) paclitaxel 90 mg/m(2 ) every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks . [ corrected ] RESULTS The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis . At data cutoff , 242 patients had been r and omized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel . Median PFS was shorter with sunitinib-paclitaxel ( 7.4 vs. 9.2 months ; hazard ratio [ HR ] 1.63 [ 95 % confidence interval ( CI ) , 1.18 - 2.25 ] ; 1-sided P = .999 ) . At a median follow-up of 8.1 months , with 79 % of sunitinib-paclitaxel and 87 % of bevacizumab-paclitaxel patients alive , overall survival analysis favored bevacizumab-paclitaxel ( HR 1.82 [ 95 % CI , 1.16 - 2.86 ] ; 1-sided P = .996 ) . The objective response rate was 32 % in both arms , but median duration of response was shorter with sunitinib-paclitaxel ( 6.3 vs. 14.8 months ) . Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel . This was primarily due to a high frequency of grade 3/4 , treatment-related neutropenia with sunitinib-paclitaxel ( 52 % ) precluding delivery of the prescribed doses of both drugs . CONCLUSION The sunitinib-paclitaxel regimen evaluated in this study was clinical ly inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer In February 2008 , the U.S. Food and Drug Administration ( FDA ) granted accelerated approval to bevacizumab ( Avastin ) in combination with paclitaxel as first-line treatment for HER-2 negative metastatic breast cancer . Approval was based on the results of E2100 , a cooperative-group r and omized trial that showed a 5.5-month increase in progression-free survival associated with the addition of bevacizumab to paclitaxel therapy.1,2 Confirmatory studies by Genentech , the manufacturer , however , showed that bevacizumab 's benefits for progression-free survival may be appreciably smaller than those shown in E2100 and have demonstrated convincingly that the addition of bevacizumab to the chemotherapy agents they have tested offers no . . PURPOSE The AVAGAST study showed that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response rate but not overall survival . To examine the hypothesis that angiogenic markers may have predictive value for bevacizumab efficacy in gastric cancer , AVAGAST included a prospect i ve , m and atory biomarker program . PATIENTS AND METHODS Patients with previously untreated , locally advanced or metastatic gastric cancer were r and omly assigned to bevacizumab ( n = 387 ) or placebo ( n = 387 ) in combination with chemotherapy . Blood and tumor tissue sample s were collected at baseline . Prespecified biomarkers included plasma vascular endothelial growth factor-A ( VEGF-A ) , protein expression of neuropilin-1 , and VEGF receptors-1 and -2 ( VEGFR-1 and VEGFR-2 ) . Correlations between biomarkers and clinical outcomes were assessed by using a Cox proportional hazards model . RESULTS Plasma was available from 712 patients ( 92 % ) , and tumor sample s were available from 727 patients ( 94 % ) . Baseline plasma VEGF-A levels and tumor neuropilin-1 expression were identified as potential predictors of bevacizumab efficacy . Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival ( hazard ratio [ HR ] , 0.72 ; 95 % CI , 0.57 to 0.93 ) versus patients with low VEGF-A levels ( HR , 1.01 ; 95 % CI , 0.77 to 1.31 ; interaction P = .07 ) . Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival ( HR , 0.75 ; 95 % CI , 0.59 to 0.97 ) versus patients with high neuropilin-1 expression ( HR , 1.07 ; 95 % CI , 0.81 to 1.40 ; interaction P = .06 ) . For both biomarkers , subgroup analyses demonstrated significance only in patients from non-Asian regions . CONCLUSION Plasma VEGF-A and tumor neuropilin-1 are strong biomarker c and i date s for predicting clinical outcome in patients with advanced gastric cancer treated with bevacizumab BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor A , has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer . We evaluated the efficacy , measured according to the rate of pathological complete response ( absence of invasive and intraductal disease in the breast and the axillary lymph nodes ) , and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer . METHODS We r and omly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel , with or without concomitant bevacizumab . Patients with untreated HER2-negative breast cancer were eligible if they had large tumors , hormone-receptor-negative disease , or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy , and no increased cardiovascular or bleeding risk . RESULTS Overall , the rates of pathological complete response were 14.9 % with epirubicin and cyclophosphamide followed by docetaxel and 18.4 % with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab ( odds ratio with addition of bevacizumab , 1.29 ; 95 % confidence interval , 1.02 to 1.65 ; P=0.04 ) ; the corresponding rates of pathological complete response were 27.9 % and 39.3 % among 663 patients with triple-negative tumors ( P=0.003 ) and 7.8 % and 7.7 % among 1262 patients with hormone-receptor-positive tumors ( P=1.00 ) . Breast-conserving surgery was possible in 66.6 % of the patients in both groups . The addition of bevacizumab , as compared with neoadjuvant therapy alone , was associated with a higher incidence of grade 3 or 4 toxic effects ( febrile neutropenia , mucositis , the h and -foot syndrome , infection , and hypertension ) but with a similar incidence of surgical complications . CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer . Efficacy was restricted primarily to patients with triple-negative tumors , in whom the pathological complete response is considered to be a reliable predictor of long-term outcome . ( Funded by Sanofi-Aventis and Roche , Germany ; Clinical Trials.gov number , NCT00567554 . )

There were no clear effects on bleeding , shivering or length of stay in post-anaesthetic care for either comparison . No other adverse effects were reported . There is no clear benefit of extra thermal insulation compared with st and ard care . Forced air warming does seem to maintain core temperature better than extra thermal insulation , by between 0.5 ºC and 1 ºC , but the clinical importance of this difference is unclear

BACKGROUND Inadvertent perioperative hypothermia occurs because of interference with normal temperature regulation by anaesthetic drugs and exposure of skin for prolonged periods . A number of different interventions have been proposed to maintain body temperature by reducing heat loss . Thermal insulation , such as extra layers of insulating material or reflective blankets , should reduce heat loss through convection and radiation and potentially help avoid hypothermia . OBJECTIVES To assess the effects of pre- or intraoperative thermal insulation , or both , in preventing perioperative hypothermia and its complications during surgery in adults .

We have investigated the role of aluminized metal foil ( space blanket , UN 320 ) , used pre-emptively , in post-anaesthetic shivering and patients ' subjective perception of cold after general anaesthesia of short duration . Sixty-eight ASA I and II patients undergoing orthopaedic and plastic surgery on the peripheries were allocated r and omly to two groups : those in group 1 were wrapped ( not less than 60 % of body surface area ) in the space blanket before induction of anaesthesia . In group 2 patients had st and ard surgical draping . In all subjects , anaesthesia was induced with fentanyl and propofol , and maintained with nitrous oxide and enflurane in oxygen , after a laryngeal mask airway was positioned . Patients were asked to grade their perception of cold on a visual analogue scale , before induction and on recovery . Skin ( dorsum of h and ) and core ( nasopharyngeal ) temperatures were recorded at 15-min intervals . Occurrence of shivering and cold scores were recorded by blinded observers . Groups were similar in age and gender ; duration of anaesthesia was also similar ( mean 41.6 ( SEM 4.8 ) vs 47.5 ( 3.3 ) min , respectively ) . The incidences of shivering were 15 % and 63 % in groups 1 and 2 , respectively ( P < 0.001 ) . Cold scores were 2.4 ( 0.4 ) and 5.7 ( 0.5 ) , respectively ( P < 0.001 ) . Skin temperatures increased with increasing duration of anaesthesia in both groups but were greater at 15 , 30 and 45 min in group 1 ( 33.38 ( 0.25 ) vs 31.56 ( 0.31 ) , 34.46 ( 0.25 ) vs 32.45 ( 0.31 ) and 35.22 ( 0.36 ) vs 33.13 ( 0.34 ) , respectively ; P < 0.001 each comparison ) . Core temperature increased slightly in group 1 and decreased in group 2 ( P = 0.11 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Background Keeping abdominal surgery patients warm is common and warming methods are needed in power outages during natural disasters . We aim ed to evaluate the efficacy of low-cost , low-power warming methods for maintaining normothermia in abdominal surgery patients . Methods Patients ( n = 160 ) scheduled for elective abdominal surgery were included in this prospect i ve clinical study . Five warming methods were applied : heated blood transfusion/fluid infusion vs. unheated ; wrapping patients vs. not wrapping ; applying moist dressings , heated or not ; surgical field rinse heated or not ; and applying heating blankets or not . Patients ’ nasopharyngeal and rectal temperatures were recorded to evaluate warming efficacy . Significant differences were found in mean temperatures of warmed patients compared to those not warmed . Results When we compared temperatures of abdominal surgery patient groups receiving three specific warming methods with temperatures of control groups not receiving these methods , significant differences were revealed in temperatures maintained during the surgeries between the warmed groups and controls . Discussion The value of maintaining normothermia in patients undergoing abdominal surgery under general anesthesia is accepted . Three effective economical and practically applicable warming methods are combined body wrapping and heating blanket ; combined body wrapping , heated moist dressings , and heating blanket ; combined body wrapping , heated moist dressings , and warmed surgical rinse fluid , with or without heating blanket . These methods are practically applicable when low-cost method is indeed needed BACKGROUND Mild perioperative hypothermia , which is common during major surgery , may promote surgical-wound infection by triggering thermoregulatory vasoconstriction , which decreases subcutaneous oxygen tension . Reduced levels of oxygen in tissue impair oxidative killing by neutrophils and decrease the strength of the healing wound by reducing the deposition of collagen . Hypothermia also directly impairs immune function . We tested the hypothesis that hypothermia both increases susceptibility to surgical-wound infection and lengthens hospitalization . METHODS Two hundred patients undergoing colorectal surgery were r and omly assigned to routine intraoperative thermal care ( the hypothermia group ) or additional warming ( the normothermia group ) . The patient 's anesthetic care was st and ardized , and they were all given cefam and ole and metronidazole . In a double-blind protocol , their wounds were evaluated daily until discharge from the hospital and in the clinic after two weeks ; wounds containing culture-positive pus were considered infected . The patients ' surgeons remained unaware of the patients ' group assignments . RESULTS The mean ( + /- SD ) final intraoperative core temperature was 34.7 + /- 0.6 degrees C in the hypothermia group and 36.6 + /- 0.5 degrees C in the normothermia group ( P < 0.001 ) Surgical-wound infections were found in 18 of 96 patients assigned to hypothermia ( 19 percent ) but in only 6 of 104 patients assigned to normothermia ( 6 percent , P = 0.009 ) . The sutures were removed one day later in the patients assigned to hypothermia than in those assigned to normothermia ( P = 0.002 ) , and the duration of hospitalization was prolonged by 2.6 days ( approximately 20 percent ) in hypothermia group ( P = 0.01 ) . CONCLUSIONS Hypothermia itself may delay healing and predispose patients to wound infections . Maintaining normothermia intraoperatively is likely to decrease the incidence of infectious complications in patients undergoing colorectal resection and to shorten their hospitalizations Changes in mean body temperature and muscle protein metabolism were studied in elderly patients undergoing large bowel surgery . Two groups were studied : in one , efforts were made to maintain the patients normothermic during and after surgery by warming the fresh gases , the i.v . fluids , by placing warmed cotton padding around the exposed parts of the body and by covering the patients with a metallized plastic sheet in the recovery period . The other group received routine management . Otherwise the anaesthetic technique was comparable . The excretion of the amino acid 3-methylhistidine ( 3-MeH ) , an indicator of muscle protein breakdown , and urea nitrogen loss were measured in the urine collected the day before , and on the 2nd and 4th postoperative days . Prevention of heat loss during and after surgery caused a significant decrease in muscle protein degradation and nitrogen loss UNLABELLED Perioperative hypothermia poses a challenge because of its deleterious effects on patient recovery . The current practice of applying two cotton blankets on patients during surgery is thought to be less ideal than using reflective insulation or forced-air warming . We studied 300 patients who underwent unilateral total knee replacement and were r and omized equally to three groups : ( a ) the two-cotton-blanket group , ( b ) the one-reflective-blanket with one-cotton-blanket group , and ( c ) the forced-air-warming with one-cotton-blanket group . Tympanic temperature readings were taken before surgery in the induction room , on arrival at the recovery room , and at 10-min intervals until discharge from the recovery room . On arrival at the recovery room , the forced-air-warming group had significantly higher temperatures ( adjusted for sex , age , and patient 's induction room temperature ) of 0.577 degrees C + /- 0.079 degrees C ( 95 % confidence interval [ CI ] , 0.427 - 0.726 ; P < 0.001 ) and 0.510 degrees C + /- 0.08 degrees C ( 95 % CI , 0.349 - 0.672 ; P < 0.001 ) more than the reflective-blanket and two-cot-ton-blanket groups , respectively . The forced-air-warming group took a significantly ( P < 0.001 ) shorter time of 18.75 min ( 95 % CI , 13.88 - 23.62 ) to achieve a temperature of 36.5 degrees C in the recovery room as compared with 41.78 min ( 95 % CI , 36.86 - 46.58 ) and 36.43 min ( 95 % CI , 31.23 - 41.62 ) for the reflective-blanket and two-cotton-blanket groups , respectively . The reflective technology was less effective than using two cotton blankets , and the forced-air warming was most efficient in maintaining perioperative normothermia . IMPLICATION S Perioperative hypothermia has deleterious effects on patient recovery . We found in patients having knee surgery that reflective technology was less effective than using two cotton blankets , whereas active surface warming with the forced-air method was most effective in maintaining normothermia Mild intraoperative hypothermia is common . We therefore studied the effects of mild hypothermia on propofol pharmacokinetics , hepatic blood flow , and atracurium duration of action in healthy volunteers . Six young volunteers were studied on two r and omly assigned days , at either 34 degrees C or 37 degrees C. Anesthesia was induced with thiopental , 3 mg/kg , and maintained with 70 % N2 O and 0.6 % isoflurane . Core hypothermia was induced by conductive and convective cooling . On the other study day , normothermia was maintained by a Bair Hugger Registered Trademark ( Augustine Medical , Inc. , Eden Prairie , MN ) forced-air warmer . Propofol , 1 mg/kg lean body mass ( LBM ) , then was given , followed by a 4-h infusion at 5 mg centered dot kg-1 centered dot h-1 . After 2 h , atracurium 0.5 mg/kg was administered as an intravenous bolus . Indocyanine green was administered for estimation of hepatic blood flow . Arterial blood was assayed for propofol and indocyanine green concentration . Pharmacokinetic analysis was performed using NONMEM . Results are reported as means + /- SEM . Propofol blood concentrations averaged approximate equals 28 % more at 34 degrees C than at 37 degrees C ( P < 0.05 ) . Hepatic blood flow decreased 23 % + /- 11 % in normothermic volunteers during the propofol infusion , and 33 % + /- 11 % in hypothermic volunteers ( P = not significant ) . A three-compartment mamillary model fitted the data best . Inclusion of hepatic blood flow change from the prepropofol baseline as a covariate for total body clearance significantly improved the fit . The intercompartmental clearances were decreased in the presence of hypothermia . Core hypothermia prolonged the time to recovery of the first twitch in the train-of-four to 10 % of its control value ( T1 = 10 % ) after atracurium administration by approximate equals 60 % ( P < 0.05 ) , from 44 + /- 4 min to 68 + /- 7 min . In contrast , T1 = 25%-75 % remained unchanged . We conclude that 3 degrees C of core hypothermia increased propofol blood concentrations and prolonged atracurium duration of action . Hepatic blood flow was decreased during propofol administration , and this change was a significant predictor of propofol clearance , indicating that the effect of propofol on hepatic blood flow impairs the clearance of propofol itself . ( Anesth Analg 1995;80:1007 - 14 Background and objective Unintentional hypothermia of a patient is a common adverse effect during surgical procedures . Many strategies can be used to reduce heat loss . The aim of this prospect i ve , r and omised , controlled study was to determine whether the use of the thermal suit ( T-Balance ) could prevent surgical patients from experiencing thermal loss better than conventional measures . Methods We examined a group of consecutive patients undergoing transurethral resection of the prostate under spinal anaesthesia . Forty patients were r and omised to receive the special textile clothing , thermal suit ( group 1 ) or the conventional clothing ( group 2 , control ) . Heated blankets and a forced-air warming device ( Bair-Hugger ) were used when any patient felt cold or body temperature decreased below 35 ° C . Body temperatures were measured via mouth using an infrared thermometer and recorded at given points ( T1–T10 ) during the procedure . Results The mean temperatures were higher ( about 0.5 ° C ) in group 1 than in group 2 at the entrance to the recovery room ( P = 0.03 ) . The mean maximal decrease in temperature was 0.56 ° C in group 1 and 1.31 ° C in group 2 ( P = 0.000 between groups ) . One patient in group 1 and seven patients in group 2 needed warming with a Bair-Hugger , and 15 out of 20 patients in group 2 needed extra blankets during surgery or recovery . Conclusion The use of the thermal suit is a good alternative to conventional measures of warming in reducing heat loss during surgical procedure under regional anaesthesia Hypothermia is one of the common complications in the perioperative period . Currently , normothermia is maintained with forced air warming ( FAW ) or passive heat retention methods . We compared the efficacy of the Mediwrap blanket with FAW in maintaining normothermia during intra-operative period in thoracic surgery in a prospect i ve r and omised controlled trial on 30 patients . Core temperature was measured at 30-min intervals in the perioperative period and the time taken to attain baseline in the postoperative periods in the two groups was compared . There was no difference in core temperatures between the groups during pre- and intra-operative period , with mean+/-S.D. final core temperatures of 36.2+/-0.6 degrees C with Mediwrap and 36+/-0.9 degrees C with the FAW blanket . However , the postoperative core temperatures were significantly higher in the Mediwrap group . The time required to reach baseline temperature was lower in the Mediwrap group with a mean+/-S.D. of 66+/-66 min as compared to 161+/-108 min in the FAW group . The Mediwrap blanket is as effective as the FAW blanket in maintaining core body temperature during thoracotomy when applied thirty minutes before the surgery OBJECTIVE Perioperative hypothermia might be detrimental to the patient undergoing off-pump coronary artery bypass surgery . We assessed the efficacy of the Allon thermoregulation system ( MTRE Advanced Technologies Ltd , Or-Akiva , Israel ) compared with that of routine thermal care in maintaining normothermia during and after off-pump coronary artery bypass surgery . METHODS Patients undergoing off-pump coronary artery bypass surgery were perioperatively and r and omly warmed with the 2 techniques ( n = 45 per group ) . Core temperature , hemodynamics , and troponin I , interleukin 6 , interleukin 8 , and interleukin 10 blood levels were assessed . RESULTS The mean temperature of the patients in the Allon thermoregulation system group ( AT group ) was significantly ( P < .005 ) higher than that of the patients receiving routine thermal care ( the RTC group ) ; less than 40 % of the latter reached 36 degrees C compared with 100 % of the former . The cardiac index was higher and the systemic vascular resistance was lower ( P < .05 ) by 16 % and 25 % , respectively , in the individuals in the AT group compared with in the individuals in the RTC group during the 4 postoperative hours . End-of-surgery interleukin 6 levels and 24-hour postoperative troponin I levels were significantly ( P < .01 ) lower in the patients in the AT group than in the RTC group . The RTC group 's troponin levels closely correlated with their interleukin 6 levels at the end of the operation ( R = 0.51 , P = .002 ) . CONCLUSIONS Unlike routine thermal care , the Allon thermoregulation system maintains core normothermia in more than 80 % of patients undergoing off-pump coronary artery bypass surgery . Normothermia is associated with better cardiac and vascular conditions , a lower cardiac injury rate , and a lower inflammatory response . The close correlation between the increased interleukin 6 and troponin I levels in the routine thermal care group indicates a potential deleterious effect of lowered temperature on the patient 's outcome We have studied the ability of reflective blankets to reduce net loss of body heat during regional anaesthesia for total hip arthroplasty . Thirty patients were allocated r and omly to either the study group ( insulated with reflective blankets ) or the control group ( no reflective blankets ) . Surgical and operation room draping , theatre temperature and i.v . fluid administration were st and ardized for all patients . Total body heat was deduced from core temperature ( aural canal ) and mean skin temperature ( four measuring sites ) . After 2 h of surgery , loss of body heat was reduced significantly in patients wrapped in reflective blankets ( 26 kJ ) compared with those in the control group ( 95 kJ ) OBJECTIVES To evaluate the efficacy of two different nursing interventions regarding control of body heat loss , using blankets during the intraoperative period of elderly patients . METHODS This was an experimental , comparative , applied , longitudinal prospect i ve study with a quantitative approach . Eighty-one elderly patients undergoing elective surgery with a surgical time frame of at least one hour were selected by systematic probability sampling into two Experimental and one Control Group . Informed consent was obtained from participants . Data was collected by biophysiological measurement , using a tympanic thermometer . RESULTS After the homogeneity of variables - gender , surgical duration , age , BMR , anesthesia , room humidity and temperature , drugs and liquid infusion- had been demonstrated , the interventions were confronted . Incidence of hypothermia ( 59.3 % ) and body heat loss ( E1=-0.6 degrees C , E2=-0.6 degrees C and C=-0.7 degrees C ) were not significantly different between the groups ( p=0.85 and p=0.7 respectively ) . CONCLUSIONS Results show the need for associated extra body warming methods to maintain normothermia Purpose To determine the effect of covering the patient ’s head and face on the prevention of intraoperative hypothermia ( < 35.5 ° C ) . Methods This r and omized , prospect i ve trial included 44 adults undergoing elective abdominal surgery . After the induction of anesthesia with thiopental , in 44 patients their extremities and trunk were covered with towels and sheets . In addition , 22 patients ( covered group ) had their face and head fully covered . Anesthesia was maintained with N2O 50–66 % ( 2–3 L·min−1 ) and isoflurane ( < IMAC ) in oxygen combined with thoracic epidural anesthesia . Core temperature was measured at the tympanic membrane continuously and was recorded at 15 min intervals from the induction of anesthesia . Heat and moisture exchangers were used in their anesthetic circuit . Ambient temperature was maintained near 25 ° C . Results Neither group demonstrated intraoperative hypothermia . However , tympanic membrane temperature at 75 , 90 , 105 min in the covered group were higherthan those of control group ( 36.7 ± 0.4 ° C vs 36.5 ± 0.4 ° C , 36.8 ± 0.5 ° C vs 36.4 ± 0.5 ° C , 36.8 ± 0.5 ° C vs 36.4 ± 0.5 ° C , respectively , P < 0.05 ) . Conclusion Covering the patient ’s head and face maintains intraoperative core temperature . RésuméObjectifDéterminer si le fait de couvrir la tête et le visage des patients contribue à prévenir l’hypothermie peropératoire ( < 35,5 ° C).MéthodeLessai r and omisé et prospect if a porté sur 44 adultes subissant une intervention abdominale élective . Après l’induction de l’anesthésie avec du thiopental , on a couvert les extrémités et le tronc des 44 patients de serviettes et de draps . De plus , pour 22 d’entre eux ( le groupe couvert ) , on a aussi couvert complètement le visage et la tête . On a maintenu l’anesthésie avec du N2O 50–66 % ( 2 - 3 L·min−1 ) et de l’isoflurane ( < ICAM ) mêlé à de l’oxygène , combiné à une anesthésie péridurale thoracique . On a procédé à une mesure continue de la température central e , à la membrane tympanique , et on l’a notée aux 15 min depuis l’induction de l’anesthésie . Les échangeurs de chaleur et d’humidité ont été intégrés au circuit anesthésique . La température ambiante a été maintenue autour de 25 ° C.RésultatsAucun des patients n’a présenté d’hypothermie peropératoire . Cependant , la température prélevée à la membrane tympanique à 75 , 90 et 105 min dans le groupe couvert était plus élevée que dans le groupe témoin ( 36,7 ± 0,4 ° C vs 36,5 ± 0,4 ° C , 36,8 ± 0,5 ° C vs 36,4 ± 0,5 ° C , 36,8 ± 0,5 ° C vs 36,4 ± 0,5 ° C , respectivement , P < 0,05 ) . Conclusion Couvrir la tête et le visage maintient la température central e peropératoire Hypothermia is a common problem for surgical patients and can result in many complications . Because few studies compare methods of passive warming , we used an unblinded , prospect i ve , experimental , r and omized design to compare the effectiveness of two passive methods of normothermia management in the postanesthesia care unit ( PACU ) . We assigned a total of 578 adult ambulatory surgery patients to either a control group that was given two folded , warmed cotton blankets or a treatment group that was given a warmed , unfolded cotton sheet and cotton blanket . We recorded patients ' temperatures on their arrival in the PACU and at 30 minutes after arrival . The treatment group had temperatures that were significantly higher than those of the control group 30 minutes after arrival in the PACU , and the treatment group experienced a greater change in temperature from baseline measurements to those taken at 30 minutes . The treatment group also used fewer warmed blankets , result ing in cost savings for the PACU STUDY OBJECTIVE To compare the ability of forced-air warming and reflective insulation to maintain intraoperative normothermia . DESIGN Prospect i ve , r and omized clinical trial . SETTING Operating rooms of a general hospital . PATIENTS 20 ASA physical status I and II patients undergoing elective total hip arthroplasty . INTERVENTIONS Patients were r and omly assigned to be warmed intraoperatively using forced-air or reflective insulation . Inspired gases were conditioned using a heat- and -moisture exchanger in both groups , and infused intravenous fluids were warmed to 37 degrees C. MEASUREMENTS AND MAIN RESULTS Distal esophageal ( core ) temperatures decreased approximately 0.5 degrees C in both groups during the first 45 minutes of anesthesia . Subsequently , core temperatures increased slightly in the patients given forced-air warming . In contrast , core temperatures continued to decrease in patients covered with reflective insulation . After 135 minutes of anesthesia , core temperatures were 36.4 + /- 0.6 degrees C ( mean + /- SD ) in the forced-air group but only 35.4 + /- 0.6 degrees C in the insulated group ( p < 0.01 , unpaired t-test ) . These data indicate that forced-air warming is superior to reflective insulation . CONCLUSION Reflective insulation was unable to maintain intraoperative normothermia during total hip arthroplasty . Active warming , such as that provided by forced air , was required to prevent hypothermia We have measured aural canal ( core ) and skin temperatures , and body heat content in 45 patients undergoing elective hip arthroplasty . They received general anaesthesia which included thiopentone , vecuronium and enflurane and nitrous oxide in oxygen . Patients were allocated r and omly to three groups : group 1 , control ( n = 15 ) , received no intraoperative warming device ; group 2 had passive skin surface warming ( metallized plastic sheet , Thermolite ( n = 15 ) ; and group 3 had active skin surface warming ( forced heated air , Bair-Hugger ) ( n = 15 ) . Duration of surgery , fluid administration and the temperature and relative humidity of the operating theatre were similar for the three groups . Core temperature and mean body heat content decreased significantly during surgery in groups 1 and 2 ( aural canal temperature 1.5 and 1.0 degrees C , and mean body heat content 287 and 189 kJ , respectively ) , while in group 3 these variables remained near preoperative values ( P = 0.001 ) . Mean skin and h and temperatures decreased in the control group , increased in the active warming group and were unchanged in the passive warming group ( P < 0.005 ) , indicating that the forced heated air system was very efficient in providing thermal homeostasis during surgery , while the metallized plastic sheet was able to insulate the skin only from radiant and convective heat losses , without attenuating the reduction in core temperature BACKGROUND To compare passive thermal insulation by reflective blankets with forced-air active warming on the efficacy of normothermia maintenance and time for discharging from the recovery room after combined spinal/epidural anesthesia for total hip arthroplasty . METHODS DESIGN Prospect i ve , r and omized study . SETTING Inpatient anesthesia at three University Departments of orthopedic surgery . PATIENTS 50 ASA physical status I-III patients , who were scheduled for elective total hip arthroplasty . INTERVENTIONS Patients received combined spinal/epidural anesthesia ( CSE ) with intrathecal injection of 15 mg of 0.5 % hyperbaric bupivacaine . All procedures started 8 - 10 a.m. , and operating room temperature was maintained between 21 - 23 degrees C , with relative humidity ranging between 40 - 45 % . As warming therapy patients received either passive thermal insulation of the trunk , the two upper limbs and the unoperated lower limb with reflective blankets ( group passive , n = 25 ) , or forced-air active warming of the two upper limbs ( group active , n = 25 ) . Core temperature was measured before CSE placement ( baseline ) , and then every 30 min until recovery of normothermia . RESULTS Demographic data , duration of surgery , intraoperative blood losses , and crystalloid infusion were similar in the two groups . Arterial blood pressure decreased in both groups compared with baseline values , while no differences in heart rate were observed during the study . Core temperatures in passive group patients decreased more markedly than in actively warmed patients , with a 1 degree C difference between the two groups at the end of surgery ( p < 0.0005 ) . At recovery room entry seven patients in group active ( 24 % ) and 16 patients in group passive ( 64 % ) showed a core temperature < 36 degrees C ( p < 0.01 ) . Achievement of both discharging criteria and normothermia required 32 + /- 18 min in active group and 74 + /- 52 min in passive group ( p < 0.0005 ) . CONCLUSIONS Forced-air cutaneous warming allows the anesthesiologist to maintain normothermia during combined spinal/epidural anesthesia for total hip replacement even if the convective blanket is placed on a relatively small skin surface with reflex vasoconstriction . Maintaining core normothermia decreased the duration of postanesthesia recovery and may , therefore , reduce costs of care PURPOSE Adverse outcomes apparently associated with hypothermia led us to examine patients undergoing elective abdominal aortic aneurysm ( AAA ) repairs to test the hypothesis that hypothermia ( temperature less than 34.5 degrees C ) is associated with increased morbidity and excess mortality rates . METHODS Two hundred sixty-two elective AAA repairs were retrospectively review ed for preoperative and intraoperative risk factors . Core temperature , age , Acute Physiology and Chronic Health Evaluation ( APACHE ) II and APACHE III scores ( raw and temperature-adjusted ) , fluid resuscitation , and perioperative organ dysfunction were recorded prospect ively . Outcome measures included lengths of stay in the intensive care unit and in the hospital , and hospital mortality rates . RESULTS Except for a higher risk of hypothermia in women ( p < 0.05 ) , by univariate analysis , preoperative risk factors were similar in patients in the hypothermic and normothermic groups . After operation , patients with hypothermia had significantly greater APACHE scores ( p < 0.0001 ) , and patients in the hypothermic nonsurvivor group took significantly longer to rewarm ( p < 0.05 ) , suggesting marked hypoperfusion . Patients with hypothermia had significantly greater fluid ( p < 0.05 ) , transfusion ( p < 0.01 ) , vasopressor ( p < 0.05 ) , and inotrope ( p < 0.05 ) requirements , result ing in significantly higher incidences of organ dysfunction ( 53.0 % vs 28.7 % , p < 0.01 ) and death ( 12.1 % vs 1.5 % , p < 0.01 ) and markedly prolonged lengths of stay in the unit ( 9.2 + /- 2.0 vs 5.3 + /- 0.6 , p < 0.05 ) and in the hospital ( 24.3 + /- 2.9 vs 15.0 + /- 0.08 , p < 0.01 ) . By multivariate analysis , female gender ( p = 0.004 ) was the only predictor of intraoperative hypothermia , whereas initial hypothermia was significantly predictive of both prolonged hypothermia and development of organ failure ( p < 0.05 ) . Organ failure ( p < 0.05 ) and acute myocardial infa rct ion ( p < 0.01 ) were independent predictors of death . CONCLUSIONS After AAA repair , patients with hypothermia have multiple physiologic derangements associated with adverse outcomes . Although multiple etiologic factors are interacting , body temperature is one variable that should be controlled during aortic surgery BACKGROUND Wound infection after clean surgery is an expensive and often underestimated cause of patient morbidity , and the benefits of using prophylactic antibiotics have not been proven . Warming patients during colorectal surgery has been shown to reduce infection rates . We aim ed to assess whether warming patients before short duration , clean surgery would have the same effect . METHODS 421 patients having clean ( breast , varicose vein , or hernia ) surgery were r and omly assigned to either a non-warmed ( st and ard ) group or one of two warmed groups ( local and systemic ) . We applied warming for at least 30 min before surgery . Patients were followed up and masked outcome assessment s made at 2 and 6 weeks . FINDINGS Analysis was done on an intention-to-treat basis . We identified 19 wound infections in 139 non-warmed patients ( 14 % ) but only 13 in 277 who received warming ( 5 % ; p=0.001 ) . Wound scores were also significantly lower ( p=0.007 ) in warmed patients . There was no significant difference in the development of haematomas or seromas after surgery but the non-warmed group were prescribed significantly more postoperative antibiotics ( p=0.002 ) . INTERPRETATION Warming patients before clean surgery seems to aid the prevention of postoperative wound infection . If applied according to the manufacturers guidelines these therapies have no known side-effects and might , with the support of further studies , provide an alternative to prophylactic antibiotics in this type of surgery Hypothermia is experienced by all patients undergoing major surgical procedures . Hypothermia can lead to postoperative complications affecting oxygenation with neurologic , immunologic , and metabolic consequences . Current methods of heat conservation used in the operating room include blanket warmers , fluid warmers , and anesthesia circuit warmers . These methods are often inadequate at maintaining a patient 's body temperature . The current study used a post-test-only control group design . Subjects in the treatment group had an insulated head cover applied within 1 minute of arrival in the operating room , while those in the control group did not . All subjects had routine heat conservation measures ( blanket warmers , fluid warmers , and anesthesia circuit humidifiers ) . Following induction of anesthesia , subjects ' temperatures were measured using an esophageal stethoscope with thermistor probe at 10 and 70 minutes . Results showed no significant differences between groups at either time point Twenty-six patients requiring orthopaedic surgery were anaesthetized and oesophageal and rectal temperature were monitored continuously . Twenty patients requiring a pneumatic tourniquet were allocated prospect ively to one of two groups : passive group ( Pg ) with reflective insulation on all available skin surface ( n = 10 ) and forced group ( Fg ) , with active warming by a forced air system ( n = 10 ) . Six patients without a tourniquet were used as a reference group ( Rg ) . The pneumatic tourniquet time was similar in the tourniquet groups . During tourniquet inflation , oesophageal temperature increased with time . The difference was significant compared with the reference group at approximately 20 min . At about 30 min , oesophageal temperature in group Fg was significantly higher than that in group Pg . After tourniquet deflation , temperature decreased transiently . Changes in rectal temperature were similar but delayed significantly . A mechanism to explain the increase in core temperature during pneumatic tourniquet use remains unclear . A redistribution mechanism by cooling of the blood in a cold and vasodilated limb could explain the decrease of temperature after tourniquet deflation STUDY OBJECTIVE to compare passive heat retention by low-flow anesthesia , alone and with additional thermal insulation by reflective blankets , with forced-air warming preventing intraoperative hypothermia during combined epidural-general anesthesia . DESIGN R and omized , controlled study . SETTING Inpatient anesthesia at a university department of orthopedic surgery . PATIENTS 30 ASA physical status I and II patients , who were scheduled for elective hip or knee arthroplasty and were free from systemic disease . INTERVENTIONS Patients received epidural block up to T10 by alkalinized lidocaine 2 % , and then were administered st and ard general anesthesia by means of low-flow rebreathing system ( fresh gas flow = 1 L/min ) . All procedures started between 8 and 10 AM , and operating room ( OR ) temperature was maintained between 21 degrees and 23 degrees C , with relative humidity ranging between 40 % and 45 % . For heat retention or warming therapy , patients received either low-flow anesthesia only ( control , n = 10 ) , low-flow anesthesia with additional reflective blankets ( blanket , n = 10 ) , or low-flow anesthesia with active forced-air warming ( forced-air , n = 10 ) . Tympanic temperature was measured at OR arrival ( baseline ) ; immediately following general anesthesia induction ; 30 , 60 , 90 , and 120 minutes from general anesthesia induction ; and at the end of surgery . MEASUREMENTS AND MAIN RESULTS Duration of anesthesia , invasiveness of surgery , and baseline core temperature were similar in the three groups . Core temperature decreased in all the three groups 30 minutes after general anesthesia induction compared with baseline ( p < 0.01 ) ; afterwards , it progressively decreased in the control and blankets groups ( p = 0.004 ) , with a reduction from baseline values measured at the end of surgery of 2.0 degrees C and 1.6 degrees C , respectively . In the forced-air group , after the initial significant decrease ( p = 0.01 vs. baseline ) , core temperature progressively increased to 35.8 + /- 0.6 degrees C , which was similar to preoperative values and significantly higher than either the control or blankets groups ( p = 0.004 ) . CONCLUSIONS During combined epidural-general anesthesia for elective hip and knee arthroplasty , passive heat retention by means of low-flow anesthesia alone and in combination with reflective blankets is ineffective in maintaining intraoperative normothermia and definitely inferior to active forced-air warning Hypothermia during prolonged surgery may be prevented by active and passive warming methods . We have compared r and omly two types of occlusive body wraps in groups of 20 patients . One wrap had additional reflective properties which , by reducing radiative in addition to convective and evaporative heat loss , was expected to improve heat conservation . Patients were studied during hepatopancreatobiliary surgery and both groups were similar in characteristics . Skin and core body temperatures increased and core temperature exceeded 37 degrees C in 40 % of patients in both groups . This continuous increase in temperature was unexpected and the observed heat gain may have been stimulated endogenously by the type of surgery rather than that supplied externally . Overall , mean hourly heat gain was similar in both groups : 71 ( SD 28 ) kJ h-1 in the reflective group and 67 ( 33 ) kJ h-1 in the other group BACKGROUND Most patients undergoing coronary artery bypass surgery demonstrate perioperative mild-to-moderate hypothermia ( < 36 degrees C ) . Patients undergoing off-pump coronary artery bypass ( OPCAB ) grafting may become even more severely hypothermic for want of cardiopulmonary bypass rewarming . One consequence is increased circulating catecholamine levels that induce an elevated systemic vascular resistance ( SVR ) , which causes a subsequent deterioration in cardiac output . MATERIAL S AND METHODS We assessed the ability of the Allon thermoregulatory ( AT ) system to maintain normothermia and its impact on hemodynamics and myocardial function in patients undergoing OPCAB surgery . In this study , the first 60 of 120 suitable patients were assigned to AT ( n = 40 ) or routine thermal care ( RTC ) ( n = 20 ) . Core body temperature , cardiac index ( CI ) , SVR , and cardiac-specific troponin I ( cTnI ) were analyzed perioperatively for patients in both groups . RESULTS Core body temperature was significantly higher in the AT group ( from 36.1 degrees C + /- 0.5 degrees C at induction of anesthesia to 37 degrees C + /- 0.5 degrees C during surgery ) than in the RTC group ( from 35.8 degrees C + /- 0.4 degrees C to 35.2 degrees C + /- 0.8 degrees C , respectively ; P < .01 ) . SVR was significantly lower , and CI was greater ( at comparable time points ) , whereas cTnI levels in the AT group were lower than in the RTC group from the end of surgery until 24 hours postoperatively ( 7.4 + /- 17.7 g/L versus 31.9 + /- 47.4 g/L ; P = .03 ) . These findings indicate the possibility for less ischemic damage sustained intraoperatively in the AT group . CONCLUSIONS Maintenance of perioperative normothermia ( 36.5 degrees C-37.5 degrees C ) during OPCAB procedures can be efficiently achieved with the Allon thermoregulation system . The system was found to be superior to other routinely used methods of temperature maintenance . Benefits may include lowering afterload ( as expressed by reduced SVR ) , an improved CI , and attenuation of myocardial injury ( as assessed by cTnI levels ) Background : Intraoperative hypothermia initially results from internal redistribution of heat facilitated by anesthesia-induced vasodilatlon . Preinductlon skin-surface warming minimizes postinduction hypothermia in anesthetized volunteers . However , its efficacy might be reduced in surgical situations , because of multiple sources of heat loss . Methods : Intraoperative core and mean skin temperatures were measured during total hip arthroplasty in 16 patients , r and omly assigned to be covered preoperatlvely with a warming blanket for ≥90 min ( prewarmed group ) or not covered ( unwarmed group ) . Results : During the first hour of anesthesia , core temperature decreased more than twice as much in the unwarmed group ( −0.7 ± 0.1 ° C ; mean ± SE ) than in the prewarmed patients ( −0.3 ± 0.1 ° C ) . At the end of surgery , core temperature was 36.3 ± 0.1 ° C in the prewarmed group and 35.2 ± 0.2 ° C in the unwarmed group . During recovery , seven patients obviously shivered in the unwarmed group and none in the prewarmed group . Conclusions : Preanesthetic skin-surface warming reduces the initial postinductlon hypothermia in surgical patients , preventing intraoperative hypothermia and postoperative shivering even for procedures lasting 3 h or longer Background : Intraoperative hypothermia is common and persists for several hours after surgery . Hypothermia may prolong immediate recovery by augmenting anesthetic potency , delaying drug metabolism , producing hemodynamic instability , or depressing cognitive function . Accordingly , the authors tested the hypothesis that intraoperative hypothermia prolongs postoperative recovery . Methods : Patients undergoing elective major abdominal surgery ( n = 150 ) were anesthetized with isoflurane , nitrous oxide , and fentanyl . They were r and omly assigned to routine thermal management ( hypothermia ) or extra warming ( normothermia ) . Postoperative surgical pain was treated with patient‐controlled analgesia . Fitness for discharge from the post‐anesthesia care unit was evaluated at 20‐min intervals by investigators blinded to group assignment and postoperative core temperatures . Scoring was based on a modification of a previously published system that included activity , ventilation , consciousness , and hemodynamic responses . Patients were considered fit for discharge when they sustained a score of 80 % ( 13 points ) for at least two consecutive measurement periods . Results : Morphometric characteristics and anesthetic management were similar in each group . Final intraoperative core temperatures differed by [ nearly = ] 2 [ degree sign ] Celsius : 34.8 + /‐ 0.6 versus 36.7 + /‐ 0.6 [ degree sign ] Celsius ( mean + /‐ SD , P < 0.001 ) . Postoperative pain scores and postoperative use of patient‐controlled opioid were similar . Hypothermic patients required [ nearly = ] 40 min longer ( 94 + /‐ 65 vs. 53 + /‐ 36 min ) to reach fitness for discharge , even when return to normothermia was not a criterion ( P < 0.001 ) . Duration of recovery in the two groups differed by [ nearly = ] 90 min when a core temperature > 36 [ degree sign ] Celsius was also required ( P < 0.001 ) . Conclusion : Maintaining core normothermia decreases the duration of postanesthetic recovery and may , therefore , reduce costs of care BACKGROUND We evaluated the performance of a new temperature management system ( Allon Thermowrap , MTRE , Israel ) in maintaining normothermia during OPCAB ( Off-Pump Coronary Artery Bypass ) procedures and Zeus-robotic IMA ( internal mammary artery ) takedowns . MATERIAL / METHODS One hundred patients were prospect ively r and omized to either a conventional temperature management method ( thick blanket , warm intravenous fluids , operating room temperature 25 degrees C ) , or the new Allon Thermowrap system ( pads with temperature-controlled water circulation placed on the patient 's back , legs , and arms ) . The mean age , body surface area , total operating time , and OR air temperature were similar in both groups . RESULTS The Allon Thermowrap system maintained a higher bladder and nasopharyngeal temperature ( p<0.05 ) . The SVR decreased ( p<0.05 ) and the cardiac index increased ( p<0.05 ) in patients with a body temperature>35.80 degrees C. Without reaching a significant level , the postoperative blood loss was lower in the Allon Thermowrap group . CONCLUSIONS The Allon Thermowrap system significantly out-performed conventional techniques in achieving and maintaining normothermia during off-pump and robotic procedures Peroperative thermal losses were studied in 28 patients ( mean age 64 years ) operated for a total hip prosthesis under controlled hypotension . The patients were split into four groups according to the method of hypothermia prevention used : reflective blanket , heating humidifier of inhaled gases , combination of both techniques or no prevention at all . The thermal loss was quicker and more intense in the last group . The superiority of one prevention method over another could not be demonstrated , but the urgency of its implementation proved to be essential Assessment was made of whether a cold-room environment prior to surgical draping affected patient temperature or the incidence of shivering in the recovery room in patients undergoing major vascular surgery when warming blankets and warmed fluids were used to maintain intraoperative temperature . Forty-two patients scheduled to undergo major vascular surgery were r and omly assigned in equal numbers to a “ cold ” or “ warm ” room . Temperatures in the “ warm ” rooms were 22.2 C or above ( range 22.8–25.6 C ) until draping , and in “ cold ” rooms , 18.9 C or below ( range 13.9–17.8 C ) . Once surgical drapes were placed , the room temperature control was set at its minimum , 17 C. All intravenous fluids and blood were warmed to 37.5 C , and a heating blanket was maintained at 37.8 C before and during the operative procedure . Patient temperatures initially did not differ between groups . Despite significantly greater heat loss prior to draping in the cold-room group ( 0.63 ± 0.14 C ) than in the warm-room group ( 0.32 ± 0.10 C)(p < 0.01 ) , there were no differences in temperature in the recovery room , shivering , myocardial , renal , CNS , pulmonary , or graft morbidity in the two groups . In major intra-abdominal vascular operations the use of warming blankets and the practice of warming all fluids for infusion allow a comfortable room temperature without detriment to patient care BACKGROUND Perioperative hypothermia is a common complication of general anesthesia and occurs in up to 50 % of patients during ear , nose and throat ( ENT ) surgery . In this prospect i ve , r and omized controlled study the hypothesis that a new conductive warming blanket ( Barrier ® EasyWarm ® , Mölnlycke Health Care Erkrath , Germany ) is better in reducing the incidence of perioperative hypothermia in ENT surgery than insulation with a conventional hospital duvet alone was tested . MATERIAL S AND METHODS After approval of the local ethics committee and written informed consent 80 patients with a planned procedure time between 1 and 3 h were recruited . Anesthesia was induced and maintained using propofol , remifentanil and rocuronium and the core temperature was measured using an esophageal temperature probe . Patients in the study group were warmed at least 30 min prior to induction of anesthesia using the novel warming blanket ( Barrier ® EasyWarm ® ) and patients in the control group were insulated with a st and ard hospital duvet . Data were tested using Fisher 's exact test , Student 's t-test or the Mann-Whitney U-test as appropriate . Time-dependent changes in core temperature were evaluated using repeated measures analysis of variance ( ANOVA ) and post hoc Scheffé 's test . Results are expressed as mean ± SD or as median and interquartile range ( IQR ) as appropriate . A p < 0.05 was considered to be statistically significant . RESULTS The ANOVA did not identify a significantly higher core temperature in the study group at any time point . Furthermore , Fisher 's exact test showed no differences in the incidence of intraoperative ( 12 out of 29 versus 10 out of 32 patients , p = 0.44 ) or postoperative hypothermia ( 12 out of 29 versus 9 out of 32 patients , p = 0.30 ) between the groups . No adverse effects were observed . CONCLUSIONS In the studied patient group the new conductive warming blanket ( Barrier ® EasyWarm ® ) showed no superiority compared to conventional thermal insulation alone

None of the RCTs with altered WBRT dose-fractionation schemes as compared to st and ard ( 3000 cGy in 10 daily fractions or 2000 cGy in 4 or 5 daily fractions ) found a benefit in terms of overall survival , neurologic function , or symptom control . Radiosurgery boost with WBRT may improve local disease control in selected participants as compared to WBRT alone , although survival remains unchanged for participants with multiple brain metastases . The addition of WBRT to radiosurgery improves local and distant brain control but there is no difference in overall survival . It may be that supportive care alone , without WBRT , is appropriate for some participants , particularly those with advanced disease and poor performance status

BACKGROUND Brain metastases represent a significant healthcare problem . It is estimated that 20 % to 40 % of patients with cancer will develop metastatic cancer to the brain during the course of their illness . The burden of brain metastases impacts on quality and length of survival . Presenting symptoms include headache ( 49 % ) , focal weakness ( 30 % ) , mental disturbances ( 32 % ) , gait ataxia ( 21 % ) , seizures ( 18 % ) , speech difficulty ( 12 % ) , visual disturbance ( 6 % ) , sensory disturbance ( 6 % ) and limb ataxia (6%).Brain metastases may spread from any primary site . The most common primary site is the lung , followed by the breast then gastrointestinal sites . Eighty-five per cent of brain metastases are found in the cerebral hemispheres , 10 % to 15 % in the cerebellum and 1 % to 3 % in the brainstem . Brain radiotherapy is used to treat cancer participants who have brain metastases from various primary malignancies . This is an up date to the original review published in Issue 3 , 2006 . OBJECTIVES To assess the effectiveness and adverse effects of whole brain radiotherapy ( WBRT ) in adult participants with multiple metastases to the brain .

BACKGROUND To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy ( WBRT ) . METHODS Adult patients with brain metastases received WBRT and were r and omized to receive placebo or memantine ( 20 mg/d ) , within 3 days of initiating radiotherapy for 24 weeks . Serial st and ardized tests of cognitive function were performed . RESULTS Of 554 patients who were accrued , 508 were eligible . Grade 3 or 4 toxicities and study compliance were similar in the 2 arms . There was less decline in delayed recall in the memantine arm at 24 weeks ( P = .059 ) , but the difference was not statistically significant , possibly because there were only 149 analyzable patients at 24 weeks , result ing in only 35 % statistical power . The memantine arm had significantly longer time to cognitive decline ( hazard ratio 0.78 , 95 % confidence interval 0.62 - 0.99 , P = .01 ) ; the probability of cognitive function failure at 24 weeks was 53.8 % in the memantine arm and 64.9 % in the placebo arm . Superior results were seen in the memantine arm for executive function at 8 ( P = .008 ) and 16 weeks ( P = .0041 ) and for processing speed ( P = .0137 ) and delayed recognition ( P = .0149 ) at 24 weeks . CONCLUSIONS Memantine was well tolerated and had a toxicity profile very similar to placebo . Although there was less decline in the primary endpoint of delayed recall at 24 weeks , this lacked statistical significance possibly due to significant patient loss . Overall , patients treated with memantine had better cognitive function over time ; specifically , memantine delayed time to cognitive decline and reduced the rate of decline in memory , executive function , and processing speed in patients receiving WBRT . RTOG 0614 , Clinical Trials.gov number CT00566852

This is not yet the case for off-pump surgery

BACKGROUND Reports from animal studies indicate that volatile anaesthetics protect the myocardium against the effects of acute ischaemia – reperfusion injury by reducing infa rct size . This cardioprotective effect in the clinical setting of coronary artery bypass graft ( CABG ) surgery , where the heart is subjected to global ischaemia – reperfusion injury , remains controversial . OBJECTIVE The objective was to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics on cardiac troponins in CABG are no longer warranted . We also investigated the effect of volatile anaesthetics on cardiac enzymes in off-pump cardiac surgery .

BACKGROUND Recent clinical and experimental data indicate that volatile anaesthetics may precondition myocardium against ischaemia and infa rct ion . The present clinical trial was design ed to verify the cardioprotective effects of desflurane in patients undergoing elective coronary artery bypass surgery . It was hypothesized that desflurane preconditioning would decrease postoperative release of troponin I and brain natriuretic peptide ( NT-proBNP ) . Besides , we have hypothesized that desflurane preconditioning would preserve the myocardium from the dysfunction following cardioplegic arrest . METHODS Twenty-eight patients were r and omly divided into two groups : Control group ( 14 patients ) and Desflurane group ( 14 patients ) . In Desflurane group ( DS ) patients , preconditioning was elicited after the onset of cardiopulmonary bypass via a 5-min exposure to desflurane ( 2.5 minimum alveolar concentration ) , followed by a 10-min washout before aortic cross-clamping and cardioplegic arrest . The control group ( C ) patients underwent an equivalent period ( 15 min ) of pre-arrest desflurane-free bypass . Haemodynamic measurements were obtained at six different times . The biochemistry markers of cellular damage and myocardial dysfunction ( troponin I , NT-proBNP ) were determined . Left ventricular ( LV ) function was assessed using tissue Doppler imaging ( TDI ) of mitral annulus . Two-factor repeated- measures analysis of variance was used to evaluate differences over time between groups for all parameters determined in plasma sample s and for all TDI-derived variables . RESULTS After surgery , both the troponin I values ( 2.04+/-1.09 ng/ml vs 1.44+/-0.77 ng/ml , p<0.01 after 24h and 1.62+/-0.96 ng/ml vs 1.00+/-0.24 ng/ml , p<0.01 after 72 h respectively ) and those of the NT-proBNP ( 2187+/-282.9 ng/l vs 885.4+/-117.35 ng/l , p<0.01 after 24h and 3097.9+/-226.2 vs 1393.6+/-312.07 ng/l , p<0.01 after 72 h respectively ) were less in the desflurane-treated patients . The values of TDI of mitral annulus were constantly better in desflurane-treated patients . CONCLUSIONS We can conclude that the use of desflurane in these patients provides a pharmacological preconditioning so as to reduce myocardial necrosis and improve the cardiac performance in the postoperative period Background The present study investigated the effects of propofol , desflurane , and sevoflurane on recovery of myocardial function in high-risk coronary surgery patients . High-risk patients were defined as those older than 70 yr with three-vessel disease and an ejection fraction less than 50 % with impaired length-dependent regulation of myocardial function . Methods Coronary surgery patients ( n = 45 ) were r and omly assigned to receive either target-controlled infusion of propofol or inhalational anesthesia with desflurane or sevoflurane . Cardiac function was assessed perioperatively and during 24 h postoperatively using a Swan-Ganz catheter . Perioperatively , a high-fidelity pressure catheter was positioned in the left and right atrium and ventricle . Response to increased cardiac load , obtained by leg elevation , was assessed before and after cardiopulmonary bypass ( CPB ) . Effects on contraction were evaluated by analysis of changes in dP/dtmax . Effects on relaxation were assessed by analysis of the load-dependence of myocardial relaxation . Postoperative levels of cardiac troponin I were followed for 36 h. Results After CPB , cardiac index and dP/dtmax were significantly lower in patients under propofol anesthesia . Post-CPB , leg elevation result ed in a significantly greater decrease in dP/dtmax in the propofol group , whereas the responses in the desflurane and sevoflurane groups were comparable with the responses before CPB . After CPB , load dependence of left ventricular pressure drop was significantly higher in the propofol group than in the desflurane and sevoflurane group . Troponin I levels were significantly higher in the propofol group . Conclusions Sevoflurane and desflurane but not propofol preserved left ventricular function after CPB in high-risk coronary surgery patients with less evidence of myocardial damage postoperatively Background : Two preconditioning stimuli should induce a more consistent overall cell protection . We hypothesized that remote ischemic preconditioning ( RIPC , second preconditioning stimulus ) applied during isoflurane inhalation ( first preconditioning stimulus ) would provide more protection to the myocardium of patients undergoing on-pump coronary artery bypass grafting . Methods : In this placebo-controlled r and omized controlled study , patients in the RIPC group received four 5-min cycles of 300 mmHg cuff inflation/deflation of the leg before aortic cross-clamping . Anesthesia consisted of opioids and propofol for induction and isoflurane for maintenance . The primary outcome was high-sensitivity cardiac troponin T release . Secondary endpoints were plasma levels of N-terminal pro-brain natriuretic peptide , high-sensitivity C-reactive protein , S100 protein , and short- and long-term clinical outcomes . Gene expression profiles were obtained from atrial tissue using microarrays . Results : RIPC ( n = 27 ) did not reduce high-sensitivity cardiac troponin T release when compared with placebo ( n = 28 ) . Likewise , N-terminal pro-brain natriuretic peptide , a marker of myocardial dysfunction ; high-sensitivity C-reactive protein , a marker of perioperative inflammatory response ; and S100 , a marker of cerebral injury , were not different between the groups . The incidence for the perioperative composite endpoint combining new arrhythmias and myocardial infa rct ions was higher in the RIPC group than the placebo group ( 14/27 vs. 6/28 , P = 0.036 ) . However , there was no difference in the 6-month cardiovascular outcome . N-terminal pro-brain natriuretic peptide release correlated with isoflurane-induced transcriptional changes in fatty-acid metabolism ( P = 0.001 ) and DNA-damage signaling ( P < 0.001 ) , but not with RIPC-induced changes in gene expression . Conclusions : RIPC applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass grafting OBJECTIVE The purpose of this study was to evaluate the effects of volatile anesthesia versus total intravenous anesthesia on cardiac troponin release in off-pump coronary artery bypass grafting ( OPCAB ) . DESIGN The authors performed a multicenter r and omized controlled study to compare cardiac troponin release in patients receiving either volatile anesthetics or total intravenous anesthesia for cardiac surgery on the beating heart , which is an excellent model of human myocardial ischemia . SETTING Three university hospitals . PARTICIPANTS The authors r and omly assigned 57 patients to desflurane ( volatile anesthetic ) and 55 patients to propofol ( intravenous anesthetic ) in addition to an opiate-based anesthesia for OPCAB . INTERVENTIONS The 2 groups of patients received either desflurane ( volatile anesthetic ) or propofol in addition to an opiate-based anesthesia for OPCAB . Peak postoperative troponin I release was measured as a marker of myocardial necrosis . Prolonged hospitalization was considered as a secondary outcome . MEASUREMENTS AND MAIN RESULTS Patient mean age was 69 years , and 82 % were men . There was a significant ( p < 0.001 ) reduction in postoperative median ( 25th-75th percentiles ) peak of troponin I in patients receiving volatile anesthetics , 1.2 ( 0.9 - 1.9 ) ng/dL , compared with patients receiving total intravenous anesthesia , 2.7 ( 2.1 - 4.0 ) ng/dL. This myocardial protection result ed in a reduced ( p = 0.04 ) number ( percentage ) of patients requiring postoperative inotropes , 20 ( 35 % ) versus 31 ( 56 % ) , and a reduced number ( percentage ) of patients su bmi tted to prolonged hospitalization ( > or = 7 days ) , 7 ( 12 % ) versus 20 ( 36 % ) in the 2 groups ( p = 0.005 ) . One patient receiving total intravenous anesthesia died within 30 days of surgery . CONCLUSIONS Myocardial damage measured by cardiac troponin release could be reduced by volatile anesthetics during OPCAB . Because patients underwent cardiac surgery on the beating heart , these results could have implication s for cardiac patients undergoing noncardiac surgery Background The value of postoperative cardiac troponin I ( cTnI ) has been shown to indicate a higher risk of in-hospital death after cardiac surgery . The authors therefore assessed the long-term prognostic value of cTnI in patients undergoing elective coronary artery bypass grafting . Methods Consecutive patients ( n = 202 ) were included and divided into two groups according to the postoperative value of cTnI ( < or ≥ 13 ng/ml ) . In-hospital mortality and nonfatal cardiac events ( delayed extubation > 24 h ; postoperative requirement of inotropic agent ; ventricular and supraventricular arrhythmia ; postoperative myocardial infa rct ion ) were recorded . Survivors were then followed up over a 2-yr period . Data are median and odds ratio ( 95 % confidence interval ) . Results Of all patients , 174 ( 86 % ) had a low cTnI ( 4.1 ng/ml ; range , 1.1–12.6 ) and 28 ( 14 % ) had a high cTnI ( 23.8 ng/ml ; range , 13.4–174.6 ) . In-hospital mortality was not significantly different ( 4 vs. 2 % ) , whereas long-term mortality ( 18 vs. 3 % , P = 0.006 ) and mortality from cardiac cause ( 18 vs. 1 % , P < 0.001 ) was greater in patients with a high cTnI. A high cTnI was a significant factor predicting death ( odds ratio , 7.3 [ 2.0–27.1 ] ) or death from cardiac causes ( odds ratio , 37.4 [ 4.2–334.4 ] ) . Nonfatal cardiac events were also more frequent in the hospital ( 64 vs. 41 % , P = 0.02 ) and within the 2-yr follow-up period ( 39%vs . 16 % , P = 0.03 ) in patients with high cTnI. Conclusion A high postoperative peak of cTnI is associated with increased risk of death , death from cardiac causes , and nonfatal cardiac events within 2 yr after coronary artery bypass grafting BACKGROUND Activation of the kinase cascade ( protein kinase C ( PKC ) , tyrosine kinase ( TK ) , and mitogen-activated protein kinase ( MAPK ) is a key feature of the transduction pathway , elicited by preconditioning signals and mediating their cardioprotective effects . We assessed whether such an activation occurred during cardiac operations and could thus represent a target for cardioprotective strategies . METHODS A total of 20 patients undergoing coronary artery bypass grafting surgery were studied . During the first 10 minutes of cardiopulmonary bypass ( CPB ) , 10 were treated with sevoflurane ( 2.5 minimum alveolar concentration ) , an inhalational anesthetic that mimics preconditioning through a similar activation of the kinase cascade . Ten case-matched patients undergoing 10 minutes of sevoflurane-free CPB served as controls . Right atrial biopsies were taken before and 10 minutes after CPB and were then processed for the measurement of PKC , TK , and p38 MAPK activities by enzyme assay techniques . Troponin I was also monitored over the first 2 postoperative days . RESULTS Compared with pre-CPB values , PKC and p38 MAPK activities ( in nanomoles per milligram of protein per minute and arbitrary units , respectively ) increased significantly and to the same extent in both groups : PKC , from 20.7+/-0.7 to 29.9+/-3.9 in controls ( p = 0.037 ) and from 18.4+/-1.1 to 23.9+/-1.8 in sevoflurane ( p = 0.016 ) ; p38 MAPK , from 88.6+/-8.5 to 312.9+/-66.2 in controls ( p = 0.005 ) and from 114.6+/-14.7 to 213.4+/-51.8 in sevoflurane ( p = 0.045 ) . Conversely , sevoflurane triggered a significant increase in TK activity ( from 68.5+/-1.4 to 83.7+/-2.9 picomoles per milligram of protein per minute p = 0.0015 ) which did not occur in controls ( from 67.5+/-1.9 to 76.8+/-4.2 picomoles per milligram of protein per minute , p = 0.09 ) . Likewise , the peak postoperative value of troponin I was not different between controls and sevoflurane-treated patients ( 3.4+/-0.6 vs 2.4+/-0.4 , p = 0.21 ) . CONCLUSIONS Cardiopulmonary bypass triggers an activation of the kinase cascade that is mechanistically linked to opening of potassium channels . The direct opening of these channels by the anesthetic sevoflurane does not increase kinase activation further , nor does it improve markers of cell necrosis , thus suggesting that pharmacologically targeting potassium channels may overlap the preconditioning-like effects of CPB alone Background : Experimental studies have related the cardioprotective effects of sevoflurane both to preconditioning properties and to beneficial effects during reperfusion . In clinical studies , the cardioprotective effects of volatile agents seem more important when administered throughout the procedure than when used only in the preconditioning period . The authors hypothesized that the cardioprotective effects of sevoflurane observed in patients undergoing coronary surgery with cardiopulmonary bypass are related to timing and duration of its administration . Methods : Elective coronary surgery patients were r and omly assigned to four different anesthetic protocol s ( n = 50 each ) . In a first group , patients received a propofol based intravenous regimen ( propofol group ) . In a second group , propofol was replaced by sevoflurane from sternotomy until the start of cardiopulmonary bypass ( SEVO pre group ) . In a third group , propofol was replaced by sevoflurane after completion of the coronary anastomoses ( SEVO post group ) . In a fourth group , propofol was administered until sternotomy and then replaced by sevoflurane for the remaining of the operation ( SEVO all group ) . Postoperative concentrations of cardiac troponin I were followed during 48 h. Cardiac function was assessed perioperatively and during 24 h postoperatively . Results : Postoperative troponin I concentrations in the SEVO all group were lower than in the propofol group . Stroke volume decreased transiently after cardiopulmonary bypass in the propofol group but remained unchanged throughout in the SEVO all group . In the SEVO pre and SEVO post groups , stroke volume also decreased after cardiopulmonary bypass but returned earlier to baseline values than in the propofol group . Duration of stay in the intensive care unit was lower in the SEVO all group than in the propofol group . Conclusion : In patients undergoing coronary artery surgery with cardiopulmonary bypass , the cardioprotective effects of sevoflurane were clinical ly most apparent when it was administered throughout the operation Background Sevoflurane has been shown to protect against myocardial ischemia and reperfusion injury in animals . The present study investigated whether these effects were clinical ly relevant and would protect left ventricular ( LV ) function during coronary surgery . Methods Twenty coronary surgery patients were r and omly assigned to receive either target-controlled infusion of propofol or inhalational anesthesia with sevoflurane . Except for this , anesthetic and surgical management was the same in all patients . A high-fidelity pressure catheter was positioned in the left ventricle and the left atrium . LV response to increased cardiac load , obtained by leg elevation , was assessed before and after cardiopulmonary bypass ( CPB ) . Effects on contraction were evaluated by analysis of changes in dP/dtmax . Effects on relaxation were assessed by analysis of the load dependence of myocardial relaxation ( R = slope of the relation between time constant & tgr ; of isovolumic relaxation and end-systolic pressure ) . Postoperative concentrations of cardiac troponin I were followed during 36 h. Results Before CPB , leg elevation slightly increased dP/dtmax in the sevoflurane group ( 5 ± 3 % ) , whereas it remained unchanged in the propofol group ( 1 ± 6 % ) . After CPB , leg elevation result ed in a decrease in dP/dtmax in the propofol group ( −5 ± 4 % ) , whereas the response in the sevoflurane group was comparable to the response before CPB ( 5 ± 4 % ) . Load dependence of LV pressure fall ( R ) was similar in both groups before CPB . After CPB , R was increased in the propofol group but not in the sevoflurane group . Troponin I concentrations were significantly lower in the sevoflurane than in the propofol group . Conclusions Sevoflurane preserved LV function after CPB with less evidence of myocardial damage in the first 36 h postoperatively . These data suggest a cardioprotective effect of sevoflurane during coronary artery surgery Background and objectives : To evaluate the effects of total intravenous anaesthesia vs. volatile anaesthesia on cardiac troponin release in coronary artery bypass grafting with cardiopulmonary bypass , we performed a multicentre r and omized controlled study to compare postoperative cardiac troponin release in patients receiving two different anaesthesia plans . Methods : We r and omly assigned 75 patients to propofol ( intravenous anaesthetic ) and 75 patients to desflurane ( volatile anaesthetic ) in addition to an opiate‐based anaesthesia for coronary artery bypass grafting . Peak postoperative troponin I release was measured as a marker of myocardial necrosis . Results : There was a significant ( P < 0.001 ) difference in the postoperative median ( 25th‐75th percentiles ) peak of troponin I in patients receiving propofol 5,5 ( 2,3‐9,5 ) ng dL−1 when compared to patients receiving desflurane 2,5 ( 1,1‐5,3 ) ng dL−1 . The median ( interquartile ) troponin I area under the curve analysis confirmed the results : 68 ( 30.5‐104.8 ) vs. 36.3 ( 17.9‐86.6 ) h ng dL−1 ( P = 0.002 ) . Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support ( 24/75 , 32.0 % vs. 31/75 , 41.3 % , P = 0.04 ) , and tends toward a reduction in number of Q‐wave myocardial infa rct ion , time on mechanical ventilation , intensive care unit and overall hospital stay . Conclusions : Myocardial damage measured by cardiac troponin release could be reduced by volatile anaesthetics in coronary artery bypass surgery OBJECTIVE To evaluate changes in cardiac troponin-I levels after major vascular surgery and their association with early and late postoperative cardiac complications . DESIGN Prospect i ve , observational investigation . SETTING University teaching hospital . PATIENTS 75 consecutive patients undergoing major vascular surgery . INTERVENTIONS All patients received a st and ard sevoflurane-fentanyl anesthesia during the procedure . Blood levels of creatine kinase with MB subtype and cardiac troponin-I were assessed before surgery and then everyday for the first 3 days after surgery . At the same time , 12-lead electrocardiography was also performed , and occurrence of any cardiac adverse event was recorded . Patients were then followed up for 1 month after surgery . MEASUREMENT AND MAIN RESULTS Troponin-I levels increased in 25 patients ( 33 % ) during the first 3 days after surgery ; 9 of these patients ( 12 % ) had myocardial infa rct ion . At univariate analysis , uncontrolled hypertension was the only risk factor for perioperative infa rct ion ( odds ratio , 16 ; ( 95 % confidence interval , 3 - 74 ) ; however , multivariate logistic regression analysis failed to show statistically significant associations . Increases in troponin-I had a 100 % sensitivity and 75 % specificity in detecting myocardial ischemia with a 36 % positive and 100 % negative predictive values . Severe cardiac complication 1 month after surgery was reported in 5 patients ( 6.6 % ) . The increase of cardiac troponin-I levels during the first 3 postoperative days was associated with an increased frequency of major cardiac complication at 1-month follow-up ( P = 0.003 ) , with a 100 % sensitivity , 71 % specificity , and 100 % negative predictive value . CONCLUSIONS Myocardial infa rct ion after major noncardiac vascular surgery occurs in up to 12 % of cases . Perioperative monitoring of troponin-I plasma levels may help to identify patients at increased risk for cardiac morbidity not only early after surgery but also during the first postoperative month Objective —To investigate whether administration of isoflurane prior to cardiopulmonary bypass ( CPB ) could partly account for the observed protection of the myocardial function and to decrease myocardial injury in patients undergoing coronary artery bypass grafting ( CABG ) . Methods —Thirty‐four patients with stable angina who were scheduled for isolated elective CABG operations were r and omized into the control group or isoflurane ( ISO ) group . In the ISO group , isoflurane was inhaled for 5 min followed by another 5‐min washout period before commencing CPB . The control group did not receive isoflurane . Hemodynamic data and biochemical markers of myocardial injury were measured perioperatively . Results —There were no adverse effects related to isoflurane . Cardiac index ( CI ) increased postoperatively as compared with the baseline . In the ISO group , there was a tendency for a greater increase of CI than that in the control group ( p = 0.054 , ANOVA for repeated measurements ) . At 1 h after CPB , the change of CI was much higher in the ISO group than that in the controls ( p = 0.001 ) . Both the creatine kinase cardiac isoenzyme ( CK‐MB ) and troponin I ( TnI ) reached peak value at 6 h after CPB . Isoflurane patients released slightly less CK‐MB than the controls postoperatively , but the difference was not significant ( p = 0.16 , ANOVA for repeated measurements ) . The release of TnI was similar in both groups ( p = 0.65 , ANOVA for repeated measurements ) . Conclusions —Administration of isoflurane prior to commencing CPB may bring an improvement in early hemodynamic performance after CABG operations BACKGROUND In experimental and clinical studies , volatile anaesthesia has proven to possess cardioprotective properties . However , no r and omized controlled trials on the use of isoflurane during the entire cardiac surgical procedure are available . We therefore compared isoflurane-sufentanil vs propofol-sufentanil anaesthesia in patients undergoing coronary artery bypass grafting . METHODS One hundred patients were r and omly assigned to receive isoflurane-sufentanil ( I ) ( n = 51 ) or propofol-sufentanil ( P ) ( n = 49 ) anaesthesia , aim ed at the same hypnotic depth . Postoperative concentrations of cardiac troponin I ( cTnI ) were followed for 72 h. Secondary outcome variables were length of stay ( LOS ) in the intensive care unit ( ICU ) and in hospital , and 30 day and 1 yr mortality and morbidity , defined as acute myocardial infa rct ion , arrhythmias , and cardiac dysfunction . Groups were compared by an on-treatment analysis , using linear mixed models for repeated measures . RESULTS Eighty-four patients completed the protocol ( I : 41 vs P : 43 ) . Postoperative cTnI concentrations increased to a maximum of I : 2.72 ng ml(-1 ) ( 1.78 - 5.85 ) and P : 2.64 ng ml(-1 ) ( 1.67 - 4.83 ) , but did not differ between groups ( P=0.11 ) . LOS in the ICU and in hospital was similar [ ICU I : 18 ( 17.0 - 21.5 ) vs P : 19 ( 17.0 - 22.0 ) h ; hospital I : 9 ( 6.5 - 8.0 ) vs P : 8 ( 6.0 - 9.0 ) days ] . Cardiac morbidity and mortality in hospital and 30 days after surgery did not differ between groups . One year after surgery , two patients had died of non-cardiac causes . No between-group differences in cardiac morbidity were found . CONCLUSIONS In this study , the use of isoflurane-sufentanil in comparison with propofol-sufentanil anaesthesia does not afford additional reduction of postoperative cTnI levels Background and objectives Peroperative myocardial infa rct ion ( MI ) is the most common cause of morbidity and mortality . What is the role of general anesthesia in this process ? Is general anesthesia a risk for myocardial infa rct ion ? The present study was design ed to determine whether the measurement of serum levels of cardiac troponin I ( cTnI ) , a highly sensitive and specific marker for cardiac injury , would help establish the diagnosis of myocardial infa rct ion in two different types of anesthesia . Method Elective abdominal hysterectomy was planned with the permission of the ethic committee in 40 patients who were 20–45 years range , in ASA-I group , and have a Goldman Cardiac Risk Index-0 . The patients were divided into two groups . Isoflurane + N2O was administrated to first group , and Propofol + Fentanyl to second group . cTnI levels were determined before anesthesia , after induction before surgery and 9 hours after the second period respectively . Results There was no significant difference between the groups by the means of demographic properties , hemodynamic parameters and cTnI levels , and the cTnI levels were determined under the basal levels in all sample s. Conclusion General anesthesia is not a risk for myocardial infa rct ion to state eliminating risk factors and protection hemodynamia cardiac OBJECTIVES To analyze the hemodynamic effects and myocardial injury using troponin-T and creatine phosphokinase ( CPK-MB ) with isoflurane and compare it with a control group in patients undergoing off-pump coronary artery bypass ( OPCAB ) surgery . DESIGN This prospect i ve , r and omized study was performed in patients scheduled for elective OPCAB surgery during February 2007 to February 2009 . SETTING Tertiary care , university teaching hospital . PARTICIPANTS Forty-five patients undergoing elective OPCAB surgery . INTERVENTIONS Patients were r and omly allotted to receive either isoflurane ( inspired concentration between 1.0 % and 2.5 % ) or propofol ( 1.5 to 3.5 mg/kg/h ) during OPCAB surgery . The concentration of these agents was titrated such that the BIS value was maintained between 50 and 60 . MEASUREMENTS AND MAIN RESULTS The hemodynamic data were measured and recorded after induction of anesthesia ( baseline ) , during the distal anastomosis of each coronary artery , and 5 and 30 minutes after giving protamine . In addition , blood sample s for troponin-T and CPK-MB were obtained after induction ( baseline ) , after 6 hours and 24 hours postoperatively . The cardiac index was significantly higher in the isoflurane group at all stages , except during distal anastomosis of the diagonal branch of the left anterior descending artery ( p < 0.05 ) . There was a significant increase in troponin-T levels at 6 and 24 hours after surgery in the propofol group ( from 0.037 ± 0.013 ng/mL to 0.098 ± 0.045 ng/mL and 0.081 ± 0.025 ng/mL , respectively , p < 0.05 ) . Significant increases in the troponin-T levels were observed at 6 hours ( from 0.033 ± 0.011 ng/mL to 0.052 ± 0.025 ng/mL , ( p < 0.05 ) in the isoflurane group , and the levels in the propofol group were significantly higher than the isoflurane group at 6 and 24 hours after surgery ( p < 0.05 ) . The CPK-MB levels increased in both groups , but were not statistically different . CONCLUSIONS Isoflurane provides protection against myocardial damage in a clinical ly used dosage as documented by lower levels of troponin-T in patients undergoing OPCAB surgery BACKGROUND This study was undertaken to compare the in vivo effects of isoflurane , sevoflurane , and propofol anesthesia on ischemia- and reperfusion-mediated free-radical injury and oxidative stress during coronary artery bypass graft surgery . We also compared the effects of these anesthetic agents on levels of end products of lipid peroxidation and nitric oxide ( NO ) in human right atrial tissue and blood . METHODS Sixty patients scheduled to undergo elective coronary surgery with cardiopulmonary bypass ( CPB ) were enrolled . Patients were r and omly allocated to receive 1 of 3 different anesthetic protocol s : propofol ( group A ) , isoflurane ( group B ) , or sevoflurane ( group C ) . We recorded global hemodynamic data ( mean arterial pressure , mean pulmonary artery pressure , central venous pressure , pulmonary capillary wedge pressure , cardiac output , cardiac index , and systemic vascular resistance index ) just before the start of surgery , before the start of CPB , 15 minutes after the end of CPB , at the end of the operation , 6 hours after installation in the intensive care unit , and 12 and 24 hours later . Sample s of the right atrial appendage were harvested before and after exposure of the heart to blood cardioplegia and short-term reperfusion under conditions of CPB . Biochemical and oxidative stress parameters were analyzed in both blood and tissue . RESULTS Hemodynamic parameters were kept stable throughout in all groups . Troponin I increased transiently with all used anesthetic regimens , but this increase was significantly lower in groups B and C. After clamp removal , lipid peroxidation in patients who received propofol ( group A ) was less than in patients who received isoflurane ( group B ) or sevoflurane ( group C ) ( P= .001 , P= .005 , respectively ) . Although the 3 groups showed no statistically significant differences in tissue levels of thiobarbituric acid-reactive substances and superoxide dismutase , propofol significantly lowered NO production in atrial tissue after clamp removal and induced less NO production than sevoflurane ( P < .05 ) . CONCLUSION Inhalation anesthetics such as isoflurane and sevoflurane preserved cardiac function in coronary surgery patients after CPB with less evidence for myocardial damage than propofol . Furthermore , propofol induced lower blood levels of lipid peroxidation than isoflurane and sevoflurane . Propofol also increased glutathione peroxidase activity but induced less NO production compared to sevoflurane . These findings also support the cardioprotective properties that are demonstrated by hemodynamic parameters A r and omised study of 414 patients undergoing coronary artery surgery with cardiopulmonary bypass was conducted to compare the effects of a volatile anaesthetic regimen with either deesflurane or sevoflurane , and a total intravenous anaesthesia ( TIVA ) regimen on postoperative troponin T release . The primary outcome variable was postoperative troponin T release , secondary outcome variables were hospital length of stay and 1‐year mortality . Maximal postoperative troponin T values did not differ between groups ( TIVA : 0.30 [ 0.00–4.79 ] ng.ml−1 ( median [ range ] ) , sevoflurane : 0.33 [ 0.02–3.68 ] ng.ml−1 , and desflurane : 0.39 [ 0.08–3.74 ] ng.ml−1 ) . The independent predictors of hospital length of stay were the EuroSCORE ( p < 0.001 ) , female gender ( p = 0.042 ) and the group assignment ( p < 0.001 ) . The one‐year mortality was 12.3 % in the TIVA group , 3.3 % in the sevoflurane group , and 6.7 % in the desflurane group . The EuroSCORE ( p = 0.003 ) was the only significant independent predictor of 1‐year mortality Volatile anesthetics exert cardioprotective properties in experimental and clinical studies . We design ed this study to investigate the effects of sevoflurane on left ventricular ( LV ) performance during minimally invasive direct coronary artery bypass grafting ( MIDCAB ) without cardiopulmonary bypass . Fifty-two patients scheduled for MIDCAB surgery were r and omly assigned to a propofol or a sevoflurane group . Apart from the anesthetics used , there was no difference in surgical and anesthetic management . After determination of cardiac troponin T , creatine kinase , and creatine kinase MB , electrocardiographic ( ECG ) data and echocardiography variables ( myocardial performance index and early to atrial filling velocity ratio ) the left anterior descending coronary artery ( LAD ) was clamped until anastomosis with the left internal mammary artery was completed . During LAD occlusion and during reperfusion , echocardiography measurements were repeated . Blood sample s were obtained repeatedly for up to 72 h. After LAD occlusion , myocardial performance index and early to atrial filling velocity ratio in the propofol group deteriorated significantly from 0.40 ± 0.12 and 1.29 ± 0.35 to 0.49 ± 0.10 and 1.13 ± 0.22 , respectively , whereas there was no change in the sevoflurane group . In the propofol group myocardial performance index remained increased ( 0.47 ± 0.11 ) compared with baseline during reperfusion . There were no significant differences in ECG and laboratory values between groups . In conclusion , during a brief period of ischemia in patients undergoing MIDCAB surgery , sevoflurane preserved myocardial function better than propofol Background Cardiac surgery is associated with some degree of myocardial injury . Preconditioning first described in 1986 was pharmacologic and non- pharmacologic . Among the long list of anesthetic drugs , isoflurane as an inhaling agent along with midazolam and propofol as injectable substances have been documented to confer some preconditioning effects on myocardium . Objectives In this study cardiac Troponin T ( cTnT ) , as a reliable marker , was used for evaluating myocardial injury . Methods This prospect i ve double blind study was comprised of 60 patients scheduled for CABG and were r and omly assigned into three groups who received infusion of propofol or midazolam or isoflorane . Surgical procedures and anesthetics were similar for 3 groups . cTnT measured preoperatively and at 12 , 24 and 36hr after arrival in ICU . Results There were no statistically significant differences in mean cTnT levels between three groups in the preoperative period and 12 - 24 hours after arrival in ICU . However , mean cTnT in 3 groups at 36 hours after arrival in ICU were different ( P < 0.013 ) and cTnT level was significantly higher in midazolam group ( P<0.001 ) and lowest in isoflurane group ( P=0.002 ) . Conclusion There were significant differences on cTnT levels between anesthetic groups of isofluran , midazolam and propofol at 36 hr after surgery . Preconditioning effect of isoflurane was higher than the other two groups BACKGROUND Several studies have highlighted that volatile anaesthetics improve myocardial protection in cardiopulmonary bypass coronary surgery . However , the haemodynamic effect of desflurane in off-pump coronary surgery has not been clarified yet . Our study hypothesis was that desflurane-fentanyl anaesthesia could decrease myocardial injury markers and improve haemodynamics compared to propofol-fentanyl in patients undergoing off-pump coronary surgery . METHODS DESIGN Prospect i ve , r and omised open-lable study . Sixty elective patients with left ventricular ejection fraction above 30 % received either desflurane ( group D , n = 32 ) or propofol ( group P , n = 28 ) , in addition to fentanyl and vecuronium bromide anaesthesia for off-pump coronary surgery . Assessment of haemodynamic function included thermodilution continuous cardiac output and right ventricular end diastolic volume . RESULTS No significant differences in cardiac output , stroke volume and mean arterial pressure were noted between groups . The only observed difference in haemodynamic profile was that group D demonstrated improved stability , expressed as left ventricular stroke work index ( LVSWI ) . Decrease in LVSWI after performing distal anastomoses was smaller in D compared to P ( median value : -14.3 and -19.8 [ g m m⁻² beat⁻¹ ] ) , respectively ( P = 0.029 ) . Oxygen uptake index ( VO₂I ) and oxygen extraction ratio ( OER ) after skin incision were lower in D , while blood lactate concentration was slightly higher after surgery in D compared to P. The groups did not differ with respect to CK-MB and troponin I concentration . CONCLUSIONS This study demonstrated no difference between desflurane and propofol anaesthesia for off-pump coronary surgery in major haemodynamic parameters , as well as in myocardial injury markers and the long-term outcome . However , the study indicated that desflurane might accelerate recovery of myocardial contractility , as assessed by LVSWI . Lower oxygen uptake and elevated lactate under desflurane anaesthesia indicated a discrete shift towards anaerobic metabolism . CLINICAL TRIAL REGISTRATION INFORMATION NCT00528515 ( http://www . clinical trials.gov/ ct2/show/NCT00528515?term = NCT00528515&rank = 1 ) Background The relationship between cardiac enzyme ( CE ) release following coronary artery bypass surgery ( CABG ) and medium term outcome is unclear . We sought to determine the relationship between post-operative CE release and one-year survival following isolated CABG . Methods Over three years 3,024 consecutive patients underwent isolated CABG . Patient characteristics were prospect ively recorded in a cardiac surgical data base . CE release , taken as the highest single measurement recorded in the first 24 hours post-op , was abstract ed from an electronic archive . All cause mortality was taken from a national registry of deaths . Results Data were complete for 2,860 ( 94.6 % ) patients . CK-MB isoenzyme ( reference range 5–24 U/l ) was recorded in 2,568 ( 89.8 % ) , total CK in 292 (10.2%).CE release three or more times the upper limit of the reference range ( ULR ) were recorded in 498 ( 17.4 % ) patients , 163 ( 5.7 % ) patients had CE more than six times ULR . There were 122 deaths ( 4.3 % ) . Cox proportional hazards analysis showed that CE release 3–6 times ULR ( adjusted HR 2.1 [ 95 % CI : 1.6 to 2.6 ] , p = 0.002 ) and CE release six or more times the ULR ( adjusted HR 5.0 [ 95 % CI : 4.5 to 5.4 ] , p < 0.001 ) were independently associated with increased one-year mortality . Conclusion Cardiac enzyme release following CABG is associated with increased one-year all-cause mortality . The definition of peri-operative myocardial infa rct ion following CABG should include elevation of CK-MB three or more times the upper limit of normal Background Preconditioning by volatile anesthetics is a promising therapeutic strategy to render myocardial tissue resistant to perioperative ischemia . It was hypothesized that sevoflurane preconditioning would decrease postoperative release of brain natriuretic peptide , a biochemical marker for myocardial dysfunction . In addition , several variables associated with the protective effects of preconditioning were evaluated . Methods Seventy-two patients scheduled for coronary artery bypass graft surgery under cardioplegic arrest were r and omly assigned to preconditioning during the first 10 min of complete cardiopulmonary bypass with either placebo ( oxygen – air mixture only ) or sevoflurane 4 vol% ( 2 minimum alveolar concentration ) . No other volatile anesthetics were administered at any time during the study . Treatment was strictly blinded to anesthesiologists , perfusionists , and surgeons . Biochemical markers of myocardial dysfunction and injury ( brain natriuretic peptide , creatine kinase – MB activity , and cardiac troponin T ) , and renal dysfunction ( cystatin C ) were determined . Results of Holter electrocardiography were recorded perioperatively . Translocation of protein kinase C was assessed by immunohistochemical analysis of atrial sample s. Results Sevoflurane preconditioning significantly decreased postoperative release of brain natriuretic peptide , a sensitive biochemical marker of myocardial contractile dysfunction . Pronounced protein kinase C & dgr ; and & egr ; translocation was observed in sevoflurane-preconditioned myocardium . In addition , postoperative plasma cystatin C concentrations increased significantly less in sevoflurane-preconditioned patients . No differences between groups were found for perioperative ST-segment changes , arrhythmias , or creatine kinase – MB and cardiac troponin T release . Conclusions Sevoflurane preconditioning preserves myocardial and renal function as assessed by biochemical markers in patients undergoing coronary artery bypass graft surgery under cardioplegic arrest . This study demonstrated for the first time translocation of protein kinase C isoforms & dgr ; and & egr ; in human myocardium in response to sevoflurane AIM The cardioprotective effects afforded by volatile anesthetics , i.e. isoflurane , during heart surgery may be due to preconditioning of the myocardium through the activation of KATP channels . The aims of this study were to establish whether glibenclamide prevents the isoflurane-induced cardioprotection in diabetic patients undergoing coronary surgery ( CABG ) and whether this cardioprotective effect can be restored by preoperative shift from glibenclamide to insulin therapy . METHODS We enrolled 60 patients undergoing CABG . Twenty consecutive non-diabetic patients were r and omized to receive conventional anesthesia ( CA ) or conventional anesthesia plus isoflurane ( ISO ) ( added to the inspired oxygen before starting cardiopulmonary bypass ) ; 40 consecutive diabetic patients in chronic treatment with oral glibenclamide were r and omized to conventional anesthesia ( G-CA ) , conventional anesthesia plus isoflurane ( G-ISO ) , conventional anesthesia after shifting to insulin ( I-CA ) or conventional anesthesia plus isoflurane after shifting to insulin ( I-ISO ) . Serum levels of cardiac troponin I ( CTnI ) and CK-MB , as markers of ischemic injury , were obtained 1 , 24 , 48 and 96 hours , postoperatively . RESULTS Postoperative peak levels of CTnI and CK-MB were lower in ISO than in CA ( 0.5+/-0.3 vs 2.8+/-2.2 ng/ml , p<0.05 and 61+/-27 vs 79+/-28 U/L , p<0.05 , respectively ) , as well as in I-CA and I-ISO than G-CA and G-ISO groups ( 0.5+/-0.7 and 0.7+/-0.9 vs 3.5+/-3 and 2.7+/-2.5 ng/ml , p<0.05 ; 47+/-7 and 41+/-5 vs 85+/-28 and 50+/-23 U/L , p<0.05 , respectively ) . No significant differences were detected in postoperative hemodynamic variables or in-hospital outcome . CONCLUSION This prospect i ve r and omized study shows a cardioprotective effect of preoperative administration of isoflurane during CABG . Such an effect is prevented by glibenclamide , but can be restored in diabetic patients by preoperative shift from glibenclamide to insulin We investigated if increasing propofol 's dosage to augment its antioxidant capacity during cardiopulmonary bypass ( CPB ) could confer cardiac protection . Fifty-four coronary artery bypass graft surgery patients were r and omly assigned to small-dose propofol ( Group P ; n = 18 ) , large-dose propofol ( Group HiP ; n = 18 ) , or isoflurane Group ( Group I ; n = 18 ) . After the induction , anesthesia was maintained with an inspired concentration of isoflurane 1%–3.5 % ( Group I ) or a continuous infusion of propofol 60 & mgr;g · kg−1 · min−1 ( Group P ) throughout the surgery . In Group HiP , this dose of propofol was increased to 120 & mgr;g · kg−1 · min−1 for 10 min before the onset of CPB until 15 min after aortic unclamping and then decreased to 60 & mgr;g · kg−1 · min−1 until the end of surgery . The duration of aortic cross-clamping was 83 ± 24 , 88 ± 22 , and 81 ± 20 min in Group P , Group HiP , and Group I , respectively ( P > 0.1 ) . Plasma malondialdehyde , a marker of oxidative stress , was significantly lower at 8 h after CPB , and Troponin I was lower at 24 h after CPB in Group HiP compared with Group P and Group I ( P < 0.05 ) . There was a significant reduction in inotropic requirements for separation from CPB in Group HiP compared with Group I. Postoperative systemic vascular resistance was significantly reduced in Group HiP as compared with Group I. Mean cardiac index was significantly higher at 24 h after CPB in Group HiP compared with Group P and Group I ( P < 0.05 ) ( Group I , 2.2 ± 0.1 ; Group P , 2.3 ± 0.2 ; and Group HiP , 2.8 ± 0.3 L · min−1 · m−2 , respectively ) . The duration of intensive care unit stay was significantly shorter in Group Hi-P compared with Group I. We conclude that administration of a large dose of propofol during CPB attenuates postoperative myocardial cellular damage as compared with isoflurane or small-dose propofol anesthesia The aim of the study was to evaluate the effects of sevoflurane and propofol on the activity of mitochondrial function related to ischemia-reperfusion injury , myocardial damage biomarkers release and clinical parameters in the postoperative period . Seventy-two patients scheduled for elective coronary artery bypass graft surgery with cardiopulmonary bypass were r and omized into two groups : 36 patients received sevoflurane during anesthesia ( Group S ) and 36 patients received propofol ( Group P ) . To investigate the functional activity of mitochondria , we used skinned fibers prepared from biopsies of right atrial tissue before cardioplegia and after the aorta cross-clamp removal ( within 10 - 15 minutes after reperfusion ) . Patients ’ clinical data ( length of stay in ICU , hemodynamic parameters , duration of mechanical ventilation ( MV ) and the amount of lactate and troponin I in the blood serum ) were evaluated postoperatively . The results showed that , before cardioplegia and after reperfusion , there was no significant difference in the mitochondrial routine and State 3 respiration rates between the groups . The effect of cytochrome c was higher in Group P. Troponin I concentration at the 12th hour after the surgery was 2.2 ± 0.8 ng/mL in Group S and 3.5 ± 1.1 ng/mL in Group P ( p<0.001 ) . There were no significant differences in the duration of mechanical ventilation , hemodynamic parameters and length of stay in the ICU between the groups . We conclude that sevoflurane slightly protects the mitochondrial outer membrane from ischemia-reperfusion injury and the loss of cytochrome c , yet has the similar effect on clinical parameters in the postoperative period when compared to propofol Myocardial ischemic damage is reduced by volatile anaesthetics in patients undergoing low‐risk coronary artery bypass graft surgery ; few and discordant results exist in other setting s. We therefore performed a r and omised controlled trial ( sevoflurane vs. propofol ) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery OBJECTIVE To investigate the effect of long-term sevoflurane anesthesia on markers of myocardial damage or toxicity . METHODS Forty adult patients scheduled for upper abdominal surgery with general anesthesia for 4 hours or more were r and omly divided into Group S and PR ( n=20 each ) . After anesthesia induction , patients of Group S were maintained with only sevoflurane , and patients of Group PR with target-controlled infusion of propofol 2 - 4 microg/ml and remifentanil 4 - 8 ng/ml . Anesthesia was titrated to control blood pressure and heart rate change at less than 20 percent of baseline values . Blood sample s were draw at pre-induction , 4 h and 24 h post-induction respectively . Serum level of cardiac troponin I , creatine kinase MB and myoglobin were analyzed . RESULTS There were no significant changes of troponin I , creatine kinase MB and myoglobin in Group S between pre-induction and 4 h or 24 h post-induction ( P > 0.05 ) . And there was also no significant differences as compared with Group PR ( P > 0.05 ) . CONCLUSION At the concentration range of 1.6%-3 % , long-term sevoflurane anesthesia does not cause detectable changes of markers of myocardial damage or toxicity BACKGROUND Experimental evidence suggests that the inhalational anesthetic sevoflurane has a cardioprotective effect . Our objective was to determine if sedation with sevoflurane will reduce infa rct size in patients with acute myocardial infa rct ion ( MI ) who are treated with primary percutaneous coronary intervention ( PCI ) . METHODS We r and omized 50 patients presenting with a first acute ST-elevation MI treated by primary PCI within 6 hours from symptom onset to sedation with sevoflurane inhalation or st and ard sedation ( control ) . Coronary flow at the end of PCI was assessed by corrected Thrombolysis In Myocardial Infa rct ion frame count . Myocardial reperfusion was assessed by ST-segment resolution 60 minutes post-PCI . Infa rct size was assessed by release of creatinine kinase ( CK ) and troponin T. RESULTS There was no difference in the primary end point : troponin T or CK release adjusted to the area at risk , between groups . However , among patients with anterior MI , there was a trend toward lower CK ( P = .05 ) and nonsignificant decrease in troponin ( P = .11 ) levels in the sevoflurane group . Corrected Thrombolysis In Myocardial Infa rct ion frame count was 12.3 ± 1.5 in the sevoflurane group and 15.6 ± 9.1 in the control group ( P = .16 ) . There was more ST resolution in patients treated by sevoflurane 80.7 % ± 25.8 % versus 56.6 % ± 35.7 % ( P = .01 ) . Sevoflurane had no significant adverse effect during administration . CONCLUSIONS Sevoflurane administration during primary PCI did not reduce infa rct size . There was a trend toward a reduction in infa rct size among patients with anterior MI . Sevoflurane administration was associated with improvement in ST-segment resolution Background Sevoflurane , like other halogenated anesthetics , has been shown to have a protective effect on the myocardium at risk after an ischemic injury . The current study tested the hypothesis that such beneficial effects , so far mainly seen in the laboratory , are reproducible in humans . Methods After institutional review board approval , 20 patients scheduled to undergo elective off-pump coronary artery bypass surgery were r and omized to receive general anesthesia with either sevoflurane or propofol . Except for this , anesthetic and surgical management was the same in both groups . For assessing myocardial injury , troponin I and myocardial fraction of creatine kinase were determined during the first 24 postoperative hours . Systemic hemodynamic variables were measured before , during , and after completion of coronary artery bypass . Results Troponin I concentrations increased significantly more in propofol-anesthetized patients than in patients anesthetized with sevoflurane . Conclusion Patients receiving sevoflurane for off-pump coronary artery surgery had less myocardial injury during the first 24 postoperative hours than patients receiving propofol . The results further support cardioprotective effects of sevoflurane Either isoflurane preconditioning or high-dose propofol treatment has been shown to attenuate myocardial IRI ( ischaemia/reperfusion injury ) in patients undergoing CABG ( coronary artery bypass graft ) surgery . It is unknown whether isoflurane and propofol may synergistically attenuate myocardial injury in patients . The present study investigated the efficacy of IsoPC ( isoflurane preconditioning ) , propofol treatment ( postconditioning ) and their synergy in attenuating postischaemic myocardial injury in patients undergoing CABG surgery using CPB ( cardiopulmonary bypass ) . Patients ( n = 120 ) selected for CABG surgery were r and omly assigned to one of four groups ( n = 30 each ) . After induction , anaesthesia was maintained either with fentanyl and midazolam ( control ; group C ) ; with propofol at 100 μg x kg(-1 ) of body weight x min(-1 ) before and during CPB followed by propofol at 60 μg x kg(-1 ) of body weight x min(-1 ) for 15 min after aortic declamping ( group P ) ; with isoflurane 1 - 1.5 % end tidal throughout the surgery ( group I ) or with isoflurane 1 - 1.5 % end tidal before CPB and switching to propofol at 100 μg x kg(-1 ) of body weight x min(-1 ) during CPB followed by propofol at 60 μg x kg(-1 ) of body weight x min(-1 ) for 15 min after aortic declamping ( group IP , i.e. IsoPC plus propofol postconditioning ) . A joint isoflurane and propofol anaesthesia regimen synergistically reduced plasma levels of cTnI ( cardiac troponin I ) and CK-MB ( creatine kinase MB ) and f-FABP ( heart-type fatty acid-binding protein ) ( all P < 0.05 compared with control , group P or group I ) and facilitated postoperative myocardial functional recovery . During reperfusion , myocardial tissue eNOS ( endothelial NO synthase ) protein expression in group IP was significantly higher , whereas nitrotyrosine protein expression was lower than those in the control group . In conclusion , a joint isoflurane preconditioning and propofol anaesthesia regimen synergistically attenuated myocardial reperfusion injury in patients OBJECTIVE To investigate the value of cardiac troponin I ( cTnI ) levels in assessing myocardial protection by remifentanil precondition against myocardial injury induced by off-pump coronary artery bypass ( OPCAB ) . METHODS Twenty-four patients undergoing OPCAB were r and omized into control and remifentanil preconditioning group ( n=12 ) . All the patients received pretreatment with oral diazepam ( 10 mg ) , intramuscular morphine ( 10 mg ) and hyosine ( 0.3 mg ) . General anesthesia was induced with midazolam ( 0.08 mg/kg ) , etomi date ( 0.1 - 0.3 mg/kg ) , fentanyl ( 5 - 10 microg/kg ) , and rocuronium ( 1 mg/kg ) , and maintained with isoflurane inhalation and propofol infusion . Intermittent fentanyl and pipecuronium were given intravenously . In remifentanil preconditioning group , remifentanil ( 5 microg/kg in 50 ml normal saline ) was infused in 10 min after anesthesia induction , and only NS was administered in the control group . Blood sample s were obtained before and at 0 , 2 , 6 , 24 , and 48 h after the operation to determine serum cTnI levels . RESULTS In both of the two groups , the cTnI levels increased significantly at the postoperative time points ( 0 , 2 , 6 , 24 , and 48 h ) as compared with those before the operation ( P<0.05 ) . The cTnI levels of remifentanil preconditioning group were markedly decreased after the operation in comparison with those of the control group ( P<0.05 ) . CONCLUSION Remifentanil preconditioning decreases the cTnI levels and reduces myocardial injury induced by OPCAB Context Volatile anaesthetics may have direct cardioprotective properties due to effects similar to ischaemic preconditioning and postconditioning . Clinical results in cardiac surgery patients are controversial and may be related to the timing of administration of anaesthetics intraoperatively . Objective We hypothesised that the cardioprotective effect of sevoflurane in coronary bypass graft surgical patients would be greater if administration during anaesthesia continued in the ICU for at least 4 h postoperatively until weaning from mechanical ventilation . Design Double-blind , double-dummy , prospect i ve , r and omised and controlled clinical trial . Setting In a single centre between June 2006 and June 2007 . Patients Seventy-five adult patients were assigned r and omly to receive anaesthesia and postoperative sedation either with propofol ( control , n = 37 ) or sevoflurane ( n = 36 ) . Interventions Myocardial biomarkers were measured before surgery , at the time of admission to the intensive care unit and at 6 , 24 , 48 and 72 h. The need for inotropic support , and lengths of stay in the intensive care unit and hospital were also recorded . Main outcome measures Elevation of myocardial biomarkers was the primary endpoint . The secondary endpoints were haemodynamic events and lengths of stay in the intensive care unit and hospital . Results Necrosis biomarkers increased significantly in the postoperative period in both groups with no significant differences at any time . Inotropic support was needed in 72.7 and 54.3 % of patients in the propofol and sevoflurane groups , respectively ( P = 0.086 ) . There were no significant differences in haemodynamic variables , incidence of arrhythmias , myocardial ischaemia or and lengths of stay in the ICU and hospital between the two groups . Conclusion In patients undergoing coronary bypass graft surgery , continuous administration of sevoflurane as a sedative in the ICU for at least 4 h postoperatively did not yield significant improvements in the extent and time course of myocardial damage biomarkers compared to propofol OBJECTIVE Myocardial ischemic damage is reduced by volatile anesthetics in patients undergoing coronary artery bypass graft surgery , but it is unknown whether this benefit exists in patients undergoing valvular surgery with ischemia-reperfusion injury related to cardioplegic arrest and cardiopulmonary bypass . This study compared cardiac troponin release in patients receiving either volatile anesthetics or total intravenous anesthesia for mitral valve surgery . DESIGN R and omized controlled study . SETTING University hospital . PARTICIPANTS One hundred twenty patients undergoing mitral valve surgery . INTERVENTIONS Fifty-nine patients received the volatile anesthetic desflurane for 30 minutes before cardiopulmonary bypass , whereas 61 patients received a total intravenous anesthetic with propofol . All patients had an opioid-based anesthetic for the mitral valve surgery . MEASUREMENTS AND MAIN RESULTS Peak postoperative troponin I release was measured as a marker of myocardial necrosis after mitral valve surgery . Patient mean age was 60 years , and 54 % were men . There was no significant ( p = 0.7 ) reduction in median ( 25th-75th percentiles ) postoperative peak troponin , 11.0 ( 7.5 - 17.4 ) ng/dL in the desflurane group versus 11.5 ( 6.9 - 18.0 ) ng/dL in the propofol group . A subgroup of patients with concomitant coronary artery disease had the expected reduction ( p = 0.02 ) of peak troponin I in those receiving desflurane , 14.0 ( 9.7 - 17.3 ) ng/dL , when compared with patients receiving total intravenous anesthesia , 31.6 ( 15.7 - 52.0 ) ng/dL. CONCLUSIONS Myocardial damage measured by cardiac troponin release was not reduced by volatile anesthetics in patients undergoing mitral valve surgery , whereas it was reduced in patients with concomitant coronary artery disease OBJECTIVE The aim of this prospect i ve r and omized study was to compare the myocardial protective effects of sevoflurane and isoflurane during coronary bypass surgery . METHODS After induction of general anesthesia with etomi date 0.3 mg/kg , a bolus dose of pancuronium 0.1 mg/kg and remifentanil 1 mcg/kg was administered . For the maintenance of anesthesia , patients received either sevoflurane ( n=20 ) at 2 - 4 % or isoflurane ( n=20 ) at 1 - 2 % . Arterial blood sample s were obtained as follows : before induction of anesthesia , after aortic unclamping , at postoperative period . Troponin-T , creatine kinase ( CK ) , and creatine kinase-MB ( CKMB ) values were measured in all obtained sample s. Statistical analysis was performed using two-way ANOVA analysis and Mann-Whitney test . RESULTS Heart rate was significantly higher in the sevoflurane group during the aortic side-clamp period , at the 10th minute and 20th minute after cardiopulmonary bypass ( CPB ) ending . The CK-MB values at 24th postoperative hour in the sevoflurane group were found to be significantly lower from the isoflurane group . The troponin-T values following the removal of the cross-clamp ( 1.015 ( 0.935 - 1.850 ) ng/ml vs 1.469 ( 1.290 - 1.645 ) ng/ml , p<0.001 ) and those at the 24th postoperative hour ( 5.345±0.654 ng/ml vs 8.715±1.020 ng/ml , p<0.001 ) were significantly lower in the sevoflurane group when compared to those in the isoflurane group . CONCLUSION Sevoflurane provides a better myocardial protection than isoflurane , as may be inferred by the lower levels of the myocardial injury markers troponin-T and CK-MB observed with sevoflurane Ischaemic damage to the myocardium inevitably occurs during coronary artery surgery . However , the extent of the damage may be influenced by the anaesthetic technique used . The most sensitive and reliable marker of myocardial damage is currently thought to be troponin T. We conducted a prospect i ve , r and omised , single‐blind pilot study to determine the baseline values of troponin T release after off‐pump coronary artery bypass surgery in 30 patients r and omly allocated to receive either propofol , isoflurane or isoflurane and high thoracic epidural analgesia . All other treatment was st and ardised . Patients undergoing emergency surgery and those with unstable angina were excluded . Blood sample s were taken at 0 , 3 , 6 , 12 , 24 and 48 h after surgery for troponin T analysis . Mean troponin T levels at 24 h were not significantly different between the groups ( p = 0.41 ) . These data allows appropriate power calculations for further , large‐scale studies to determine the anaesthetic technique that provides optimal myocardial protection This r and omised controlled trial compared the effect of equipotent anaesthetic doses of sevoflurane ( S group ) versus propofol ( P group ) , during remifentanil-based anaesthesia for off-pump coronary artery bypass surgery , on myocardial injury . Either sevoflurane or propofol was titrated to maintain bispectral index values between 40 and 50 . In both groups , a targeted concentration of remifentanil 20 ng.ml-1 was maintained during anaesthesia . The concentrations of creatine kinase MB and troponin I were measured before the start of surgery , on admission to the intensive care unit , and at 12 and 24 hours after intensive care unit admission . The postoperative values of creatine kinase MB ( S group : 15.08±18.97 , 20.78±20.92 , 12.76±12.82 vs 2.09±1.54 ng.ml-1 ; P group : 10.99±13.15 , 27.16±56.55 , 11.88±18.80 vs 1.84±1.67 ng.ml-1 ) and troponin I ( S group : 3.56±5.19 , 5.66±7.89 , 3.35±4.55 vs 0.52±1.90 ng.ml-1 ; P group : 2.42±3.33 , 4.11±6.01 , 3.04±5.31 vs 0.43±1.28 ng.ml-1 ) were significantly higher than preoperative values in both groups but there were no significant differences between the two groups . There were no significant differences in time to extubation ( S group , 476±284 minutes ; P group , 450±268 minutes ) and intensive care unit length of stay ( S group , 2775±1449 minutes ; P group , 2797±1534 minutes ) between the two groups . In conclusion , sevoflurane and propofol at equipotent doses guided by bispectral index with remifentanil 20 ng.ml-1 had similar creatine kinase MB and troponin I values UNLABELLED The aim of the study is to investigate cardioprotective properties of sevoflurne during coronary bypass surgery with extracorporeal circulation . METHODS 60 patients with coronary heart disease ( left ventricular ejection fraction 61,3 + 1,0 % ) underwent surgery with extracorporeal circulation . Inhalation anesthesia with Sevoflurane and TIVA were performed . Hemodynamic , troponin level , KFK , protein of heart shock in plasma ( PHS 70 ) and PHS in myocard were monitored . RESULTS patients who were administrated with Sevoflurane had lower level of troponin than patients of second group . In postperfusion period the amount of PHS 70 in myocard increased in 1.6 times than in preperfusion period in comparison to TIVA method this figure did not change . There was negative correlation in level of PHS 70 in plasma and troponin in first day after the operation ( r = -0,61 p < 0,05 ) and second day ( r = - 0,76 , p < 0,05 ) . In conclusion Sevoflurane had affected hemodynamic less than TIVA . Increased level of PHS has cardioprotective effects Perioperative myocardial ischemia contributes to postoperative morbidity and mortality . Remote intermittent ischemia ( RI ) has been shown to benefit patients undergoing coronary artery bypass graft ( CABG ) surgery by decreasing postoperative cardiac troponin levels . In addition , there is evidence that volatile anesthetics may provide myocardial protection . In this prospect i ve r and omized controlled trial we tested the hypothesis that RI is cardioprotective under a strict anesthetic regime with volatile anesthesia until cardiopulmonary bypass ( CPB ) . We also assessed whether RI modulates postoperative cytokine and growth factor concentrations . Fifty-four patients referred for elective CABG surgery without concomitant valve or aortic surgery were r and omized to three 5-min cycles of left upper limb ischemia by cuff inflation ( RI ) or placebo without cuff inflation ( Plac ) . All patients received the volatile anesthetic isoflurane ( 1.15–1.5 vol% ) before CPB and the intravenous anesthetic propofol ( 3–4 mg/kg/h ) thereafter until the end of surgery . Cardiac arrest during CPB was induced by intermittent cross-clamp fibrillation , or by blood cardioplegia . We excluded patients older than 85 years , with unstable angina , significant renal disease , and those taking sulfonylureas . Troponin I ( cTnI ) was measured preoperatively and after 6 , 12 , 24 and 48 h. In addition , brain natriuretic peptide ( BNP ) , creatine kinase ( CKMB ) and a panel of cytokines and growth factors were analyzed perioperatively . Although cTnI , BNP and CKMB all increased post-CABG , there were no significant differences between RI and Plac groups ; area under the curve for cTnI 189.4 ( 183.6 ) ng/mL/48 h and 183.0 ( 155.2 ) ng/mL/48 h mean ( SD ) , p = 0.90 , respectively , despite a tendency to a shorter ( p < 0.07 ) cross-clamp time in the treatment group . Similarly , there were no differences between groups in the central venous concentrations of numerous cytokines and growth factors . In patients undergoing CABG surgery RI does not provide myocardial protection under a strict anesthetic regime with volatile anesthesia until CPB , and RI was not associated with changes in cytokines OBJECTIVE Anesthetic preconditioning may contribute to the cardioprotective effects of sevoflurane in patients having coronary artery bypass surgery . We investigated whether 2 different sevoflurane administration protocol s can induce preconditioning in patients having coronary artery bypass . METHODS Thirty patients were r and omly allocated to 1 of 3 groups . All patients received a total intravenous anesthesia with sufentanil ( 0.3 microg(-1 ) x kg x h(-1 ) ) and propofol as target controlled infusion ( 2.5 microg/mL ) . The control group had no further intervention ; 10 minutes prior to establishing the extracorporeal circulation , patients of the sevoflurane-I group received 1 minimum alveolar concentration of sevoflurane for 5 minutes . Patients of the sevoflurane-II group received ( 2 times ) 5 minutes of sevoflurane , interspersed by 5-minute washout 10 minutes prior to extracorporeal circulation . Troponin I was measured as marker of cardiac cellular damage . RESULTS Peak levels of troponin I release were observed at 4 hours after cardiopulmonary bypass and were not affected by 1 cycle of sevoflurane administration ( controls : 14 + /- 3 ng/mL vs sevoflurane-I group , 14 + /- 3 ng/mL ) . Two periods of sevoflurane preconditioning significantly reduced cellular damage compared with controls ( peak troponin I level sevoflurane-II group , 7 + /- 2 ng/mL ) . CONCLUSION These data show that sevoflurane-induced preconditioning is reproducible in patients having coronary artery bypass but depends on the preconditioning protocol used OBJECTIVE To examine the role of sevoflurane in myocardial protection in patients undergoing coronary artery bypass graft ( CABG ) surgery . DESIGN Prospect i ve , r and omized , controlled , double-blinded study . SETTING Veterans Administration Medical Center ( VAMC ) , Buffalo , New York . SUBJECTS Twenty-one patients undergoing CABG were included in the study . Eleven patients were r and omized to receive sevoflurane , and 10 patients served as controls . INTERVENTION Total intravenous anesthesia was provided for both study and control groups by infusion of propofol , fentanyl , and midazolam . Sevoflurane 2 % was added to the cardioplegia solution in the experimental group . MEASUREMENTS AND MAIN RESULTS Neutrophil beta-integrins ( CD11b/CD18 ) , tumor necrosis factor alpha ( TNF-alpha ) , and interleukin (IL)-6 were measured as indicators of the inflammatory response to myocardial ischemia-reperfusion injury . Blood sample s were obtained from the aorta and coronary sinus before ( T1 ) and immediately after cardiopulmonary bypass ( CPB ) ( T2 ) and , in addition , from a peripheral artery 6 hours ( T3 ) after CPB . Myocardial function was determined in all patients at each time point . Left ventricular stroke work index ( LVSWI ) was calculated as an estimation of left ventricular function . Left ventricular regional wall motion abnormality ( RWMA ) was assessed by transesophageal echocardiography at T1 and T2 time points . TNF-alpha was detectable only in the control group in arterial sample s at T3 . IL-6 levels ( pg/mL ) were found to be lower in the sevoflurane group compared with controls at T2 arterial circulation ( 38.2 + /- 21.1 v 60.6 + /- 19.1 , p < 0.05 ) as well as in the coronary circulation ( 38.4 + /- 19.9 v 118.2 + /- 23.5 , p < 0.01 ) at T2 . CD11b/CD18 increased 79 % after CPB in the control group while only increasing 36 % in the sevoflurane group ( p < 0.05 ) . The post-CPB LVSWI was back to its baseline values in the sevoflurane group , whereas it was still significantly depressed in the control group . Eight of 10 patients in the control group showed a transient new-onset RWMA in either the septal or anteroseptal regions . Only 2 of 11 patients in the sevoflurane group showed transient RWMA of the LV . CONCLUSIONS Sevoflurane decreases the inflammatory response after CPB , as measured by the release of IL-6 , CD11b/CD18 , and TNF-alpha . Myocardial function after CPB , as assessed by RWMA and LVSWI , was also improved with sevoflurane . The role of sevoflurane in myocardial protection and the inflammatory response to myocardial reperfusion should be considered PURPOSE The benefits of intraoperative administration of halogenated agents in patients undergoing cardiac surgery have been shown by numerous studies . The mechanisms of preconditioning and postconditioning appear to be the cause of these benefits . The possibility of maintaining the early postoperative sedation with halogenated agents , after its intraoperative administration , can increase their benefits . PATIENTS AND METHODS This is a prospect i ve trial with 60 patients undergoing coronary artery bypass graft surgery divided into 3 groups according to the administration of hypnotic drugs in the intraoperative and postoperative periods ( sevoflurane , sevoflurane : SS , sevoflurane-propofol : SP , propofol-propofol : PP ) . For the first 48 hours , hemodynamic parameters , the need for inotropic drugs , N-terminal pro-brain natriuretic peptide , and troponin I plasmatic concentrations were obtained . RESULTS There were significant differences between group SS and the other 2 groups in the levels of N-terminal pro-brain natriuretic peptide ( SS [ 501±280 pg/mL ] compared with SP [ 1270±498 pg/mL ] and PP [ 1775±527 pg/mL ] [ P<.05 ] ) and troponin I ( SS [ 0.5±0.4 ng/mL ] compared with SP [ 1.61±1.30 ng/mL ] and PP [ 2.27±1.5 ng/mL ] [ P<.05 ] ) and a lower number of inotropic drugs . CONCLUSION Sevoflurane administration in patients undergoing off-pump coronary artery bypass graft , in the operating room and the intensive care unit , decreases myocardial injury markers compared with patients who only received sevoflurane in the intraoperative period , but both were a better option to decrease levels of myocardial markers when compared with the propofol group OBJECTIVE Cardioprotective properties have been shown with halogenated volatile agents . It was hypothesized that low-dose isoflurane administered before aortic cross-clamping may reduce the amount of dobutamine required to improve impaired postoperative cardiac function after various types of cardiac surgery . DESIGN A prospect i ve , r and omized trial . SETTING An anesthesia and intensive care unit , university hospital . PARTICIPANTS Two hundred eighty cardiac surgery patients . INTERVENTIONS All patients allocated to either isoflurane treatment ( T ) or no treatment ( control group [ C ] ) received total intravenous anesthesia . In the treatment group , isoflurane was administered at a 0.5 minimum alveolar concentration ( MAC ) from tracheal intubation to initiation of cardiopulmonary bypass ( CPB ) . During weaning from CPB , dobutamine was introduced by using a hemodynamically driven decision tree . MEASUREMENTS AND MAIN RESULTS The number of patients receiving dobutamine was comparable ( 66 v 78 , p = 0.07 , in T and C groups , respectively ) . The total amount of postoperative dobutamine indexed to patient weight , considered as the primary endpoint , was reduced in the isoflurane-treated group ( 4.2 + /- 8 v 7.2 + /- 15 , p < 0.02 , in T and C , respectively ) . Isoflurane was identified as an independent variable significantly ( odds ratio [ confidence interval ] ) influencing the total amount of postoperative dobutamine ( 0.53 [ 0.31 - 0.92 ] , p < 0.02 ) . Postoperative troponin I release at 20 hours was not affected by isoflurane treatment . CONCLUSIONS This study revealed that exposure to 0.5 MAC isoflurane before CPB reduced the total amount of dobutamine required to normalize postoperative cardiac dysfunction in various types of cardiac surgical patients OBJECTIVE To determine whether sevoflurane , because of its lower blood/gas partition coefficient , compared with isoflurane as the primary anesthetic agent , allows earlier tracheal extubation and assessment of cognitive function after off-pump coronary artery bypass ( OPCAB ) surgery . DESIGN Prospect ively , patients were r and omly assigned to receive sevoflurane or isoflurane as their primary anesthetic . Intraoperative opioids were limited to 5 microg/kg of fentanyl . SETTING Two university hospitals with active cardiac surgery programs . PARTICIPANTS One hundred one OPCAB surgery patients who met inclusion ary and exclusionary criteria participated with institutional review board approval . INTERVENTIONS Mini-Mental Status Examination , Memory Recall Test , and Observer Assessment of Anxiety and Sedation scales were administered preoperatively , postextubation , at 90 minutes , and between 12 to 24 hours . Pain scores were obtained every 15 minutes after extubation for 90 minutes . MEASUREMENTS AND MAIN RESULTS Sevoflurane patients were extubated earlier than isoflurane patients ( Sevo , 176 + /- 217 minutes and Iso , 257 + /- 279 min , p = 0.02 ) . Although both agents produced similar postanesthetic cognitive profiles , cognitive testing occurred approximately 90 minutes earlier in the sevoflurane group . Verbal rating scale for pain scores > 5 were more frequent for sevoflurane than isoflurane patients ( p = 0.03 ) . CONCLUSIONS Both sevoflurane and isoflurane may be safely used as maintenance agents in OPCAB . Sevoflurane has the advantage of allowing earlier extubation and evaluation of cognitive and neurologic function after OPCAB Background : Volatile anesthetics protect the myocardium during coronary surgery . This study hypothesized that the use of a volatile agent in the anesthetic regimen would be associated with a shorter intensive care unit ( ICU ) and hospital length of stay ( LOS ) , compared with a total intravenous anesthetic regimen . Methods : Elective coronary surgery patients were r and omly assigned to receive propofol ( n = 80 ) , midazolam ( n = 80 ) , sevoflurane ( n = 80 ) , or desflurane ( n = 80 ) as part of a remifentanil-based anesthetic regimen . Multiple logistic regression analysis was used to identify the independent variables associated with a prolonged ICU LOS . Results : Patient characteristics were similar in all groups . ICU and hospital LOS were lower in the sevoflurane and desflurane groups ( P < 0.01 ) . The number of patients who needed a prolonged ICU stay ( > 48 h ) was also significantly lower ( propofol : n = 31 ; midazolam : n = 34 ; sevoflurane : n = 10 ; desflurane : n = 15 ; P < 0.01 ) . Occurrence of atrial fibrillation , a postoperative troponin I concentration greater than 4 ng/ml , and the need for prolonged inotropic support ( > 12 h ) were identified as the significant risk factors for prolonged ICU LOS . Postoperative troponin I concentrations and need for prolonged inotropic support were lower in the sevoflurane and desflurane group ( P < 0.01 ) . Postoperative cardiac function was also better preserved with the volatile anesthetics . The incidence of other postoperative complications was similar in all groups . Conclusions : The use of sevoflurane and desflurane result ed in a shorter ICU and hospital LOS . This seemed to be related to a better preservation of early postoperative myocardial function Objectives . To compare the cardioprotective effects of anesthetic preconditioning by isoflurane with ischemic preconditioning . Methods . A total of 45 patients scheduled for elective coronary artery bypass graft ( CABG ) surgery were r and omized to preconditioning either by 3 episodes of 1-minute aortic cross-clamping followed by 4 minutes of reperfusion after each episode , a 10-minute exposure to isoflurane 2.5 % followed by 5 minutes of washout , or no preconditioning technique ( control group ) . Hemodynamic data , cardiac troponin I ( cTnI ) , creatine kinase isoenzyme MB ( CK-MB ) release , need for inotropic support , hospital stay , and adverse cardiac events were measured and recorded . Results . Preconditioned patients showed marked improvement in hemodynamic data , less need for inotropic support , and less postoperative increase in the serum levels of CK-MB and cTnI. No significant difference in hospital stay was found . Also , 4 patients in the control group had adverse cardiac events versus 1 patient in the isoflurane and ischemic groups in 1 year of follow-up . Conclusions . Based on this very small sample size , these data support a cardioprotective effect of isoflurane and ischemic preconditioning during CABG surgery Abstract Objective . We investigated the myocardial protective effect of sevoflurane in patients receiving off-pump coronary artery bypass grafting ( OPCABG ) and the role of brain natriuretic peptide ( BNP ) . Design . Forty-eight patients receiving elective OPCABG were r and omly assigned to a control group , and to 0.75 MAC , 1.0 MAC and 1.5 MAC sevoflurane groups . Blood sample s were collected and levels of BNP and cardiac troponin I ( cTnI ) were measured before anesthesia , and immediately , 24 , 48 and 72 h after surgery . Results . Dopamine was necessary to maintain blood pressure in the sevoflurane groups , but not in the control group ( p < 0.002 ) . 1.0 MAC sevoflurane significantly decreased post-surgical cTnI levels ( p < 0.001 ) . 0.75 MAC had no significant effect , and increasing sevoflurane concentrations to 1.5 MAC caused no further decrease in cTnI concentrations . There was no significant difference in BNP level among the groups ( p = 0.227 ) or between any two groups , although values of BNP showed a significant correlation with cTnI values in control subjects immediately after ( r = 0.847 ) and 24 h after ( r = 0.661 ) surgery . Conclusions . Our results demonstrated that 1.0 MAC and 1.5 MAC sevoflurane can exert a significant myocardial protective effect . BNP can not be used to predict the myocardial protective effect of sevoflurane in OPCABG AIMS AND OBJECTIVES The objective of the study was to evaluate the myocardial protective effect of volatile agents-sevoflurane and desflurane versus total intravenous anesthesia ( TIVA ) with propofol in offpump coronary artery bypass surgery ( OPCAB ) by measuring cardiac troponin-T ( cTnT ) as a marker of myocardial cell death . MATERIAL S AND METHODS The study was conducted on 139 patients scheduled to undergo elective OPCAB surgery . The patients were r and omly allocated to receive anesthesia with sevoflurane , desflurane or TIVA with propofol . The cTnT levels were measured preoperatively , at arrival in postoperative intensive care unit , at 8 , 24 , 48 and 96 hours thereafter . RESULTS The changes in cTnT levels at all time intervals were comparable in the three groups . CONCLUSION The study did not reveal any difference in myocardial protection after OPCAB with either sevoflurane or desflurane or TIVA using propofol as assessed by measuring serial cTnT values Background and objectives : Ischaemic preconditioning is commonly regarded as one of the most powerful protective mechanisms against a subsequent lethal ischaemic injury during coronary artery bypass graft surgery but is not practice d routinely . Experimentally , isoflurane , a commonly used volatile anaesthetic agent , provides myocardial protection through a signal transduction cascade that is remarkably similar to the pathways identified in ischaemic preconditioning . The aim of our study was to investigate whether pre‐ischaemic administration of isoflurane exerted protection against prolonged ischaemia with functional recovery and reduced necrosis among patients undergoing coronary artery bypass graft surgery . Methods : Forty patients scheduled for elective coronary artery bypass graft operations were prospect ively r and omized into the control or isoflurane groups . In the isoflurane group , isoflurane 2.5 minimum alveolar concentration was administered for 15 min followed by a 5‐min washout period before aortic cross‐clamping . The control group received a time‐matched period of isoflurane‐free cardiopulmonary bypass . The conduction of anaesthesia and surgery were st and ardized in all patients . Haemodynamic data , troponin I release and inotropic support were measured and recorded perioperatively . Results : There were no adverse effects related to isoflurane administration . In the isoflurane group , the mean cardiac index after cardiopulmonary bypass was significantly higher than the pre‐bypass value ( P < 0.05 ) , whereas no difference was found in the control group . At 15 min after cardiopulmonary bypass and 6 h after surgery , the changes in cardiac index and stroke volume index were significantly higher in the isoflurane group than in the control group ( P < 0.05 ) . There was a consistently lower release of troponin I in the isoflurane group compared to the control group . Compared to the controls , the mean troponin I level was significantly reduced in the isoflurane group at 24 h after surgery ( P = 0.042 ) . Conclusions : The present results support the preconditioning effect of isoflurane in patients undergoing coronary artery bypass graft surgery as clinical ly feasible and providing optimal cardiac protection OBJECTIVE Volatile anesthetics reduce the risk of myocardial infa rct ion and mortality in coronary artery surgery . Recently , the American College of Cardiology/American Heart Association Guidelines suggested the use of volatile anesthetic agents for the maintenance of general anesthesia during noncardiac surgery in patients at risk for perioperative myocardial ischemia , but no r and omized experience to document the cardioprotective effects of these agents exists in this setting . Therefore , the authors performed a prospect i ve , r and omized , controlled trial to compare the effects of sevoflurane versus total intravenous anesthesia , in terms of postoperative cardiac troponin I release in patients undergoing noncardiac surgery . DESIGN A r and omized , controlled trial . SETTING A teaching hospital . PARTICIPANTS Eighty-eight consecutive patients undergoing noncardiac surgery . INTERVENTIONS Patients were allocated r and omly to receive either volatile anesthetic ( 44 patients ) as the main anesthetic agent or total intravenous anesthesia ( TIVA ) ( 44 patients ) . MEASUREMENTS Postoperative cardiac troponin I release was measured as a marker of myocardial necrosis . Patients with detectable postoperative troponin I in the sevoflurane group ( 12/44 , 27.3 % ) were similar to those in the propofol group ( 9/44 , 20.5 % ; p = 0.6 ) . There was no significant reduction of postoperative median peak cTnI release ( 0.16 ± 0.71 ng/mL in the sevoflurane group compared with the TIVA group , 0.03 ± 0.08 ng/mL ; p = 0.4 ) . Three patients died at the 1-year follow-up for noncardiac causes ( 2 in the TIVA group ) . CONCLUSIONS In the authors ' experience , patients undergoing noncardiac surgery did not benefit from anesthesia based on halogenated anesthetics . Further studies are necessary to evaluate the cardioprotective effects of volatile agents in noncardiac surgery A RECURRING decision that has to be made in planning a controlled clinical trial of a new treatment is the size of the patient sample necessary . In this decision , a major determinant is ethical , fo ... Volatile anaesthetics have been shown to exert cardioprotective properties in experimental and clinical studies . However , the mode of administration may influence these cardioprotective effects . The present study was design ed to compare the effect of interrupted administration of sevoflurane before cardiopulmonary bypass with continuous sevoflurane administration and with propofol‐only anaesthesia , on cardioprotection as assessed by left ventricular performance and myocardial cell damage during coronary artery bypass grafting . Forty‐two patients scheduled for coronary bypass surgery were r and omly assigned to one of three groups : propofol‐only ( P ; n = 14 ) , continuous ( SevoC ; n = 14 ) and interrupted sevoflurane administration ( SevoI ; n = 14 ) . Myocardial cell damage as assessed by Troponin T ( cTNT ) and creatine kinase MB ( CK‐MB ) were chosen as the primary endpoints and echocardiographic myocardial performance index ( MPI ) measurements were also performed . Up to 48 h postoperatively , in group SevoI , postoperative cTNT values ( mean ( SD ) 0.13 ( 0.04 ) ng.ml−1 ) were significantly ( p < 0.05 ) lower than both the P ( 0.26 ( 0.31 ) ng.ml−1 ) and SevoC ( 0.25 ( 0.17 ) ng.ml−1 ) groups . CK‐MB levels were also significantly ( p < 0.05 ) lower in the SevoI group at 24 h after surgery and MPI significantly improved compared with both the P and SevoC groups . There was , however , no difference with respect to cytokine release and length of stay in either the intensive care unit or in the hospital . We conclude that prior interrupted sevoflurane administration confers some cardioprotection as compared with continuous sevoflurane administration or propofol‐based anaesthesia The purpose of the investigation was to study whether isoflurane and sevoflurane might be used for pharmacological myocardial preconditioning ( PMP ) in patients with coronary heart disease during myocardial revascularization on the working ( Part I ) and arrested ( Part II ) heart and to develop a possible procedure for PMP . Part I deals with the study of the effect of PMP with halogen-containing anesthetics during myocardial revascularization on the working heart . The study included 66 patients who were divided into 4 groups ; 1 ) sevoflurane feeding was started just after anesthesia induction and it lasted until some coronary arteries were ligated ; 2 ) sevoflurane was fed for 15 min ; 3 ) isoflurane was used ; 4 ) controls . The markers of myocardial lesion ( troponin T , I ) were measured and the incidence of perioperative myocardial ischemia and needs for inotropic support were also analyzed . Part II was dedicated to the study of the effect of PMP during myocardial revascularization under extracorporeal circulation ( EC ) . The study covered 65 patients who were divided into 4 groups ; 1 ) sevoflurane was administered throughout the anesthesia until the aorta was ligated ; 2 ) it was used for 15 min before aortic ligation ; 3 ) sevoflurane was employed only to induce anesthesia ; 4 ) controls . The variables similar to those in Part I of the investigation were chosen to assess the results of this study . The use of sevoflurane and isoflurane reduces a risk for myocardial ischemic lesion during myocardial revascularization both under EC and on the working heart . Short-term ( 15-min ) use of an agent before myocardial ischemia suffices for PMP to develop its effect . The effect of PMP has its duration that is 76 min , as shown by our findings BACKGROUND Experimental studies indicate that isoflurane , a commonly used volatile anesthetic , mimics the cardioprotective effects of ischemic preconditioning , probably through ATP-sensitive K+ ( KATP ) channel activation . The aim of this study was to evaluate the impact of isoflurane during coronary bypass surgery ( CABG ) on troponin I release . MATERIAL AND METHODS Forty consecutive patients with chronic stable angina and multivessel disease undergoing isolated CABG were r and omized to a control ( 16 men and 4 women , aged 51 to 73 years , mean 62 ) or isoflurane ( 15 men and 5 women , aged 51 to 77 years , mean 65 ) group before aortic cross-clamping and cardioplegia . Serum levels of troponin I and creatine kinase (CK)-MB , as markers of ischemic injury , were obtained at 24 hours after CABG . Regional wall motion score and left ventricular ejection fraction ( LVEF ) at transthoracic echocardiography were assessed 5 days postoperatively . Comparisons between groups were performed in the entire population and , subsequently , in those patients with preoperative LVEF < 50 % . RESULTS There were no significant differences between isoflurane-treated patients and controls in cross-clamp time ( 49 + /- 14 vs 51 + /- 13 min , p = ns ) , peak values of troponin I ( 0.9 + /- 0.7 vs 1.4 + /- 1.3 ng/ml , p = ns ) and CK-MB ( 62 + /- 27 vs 64 + /- 27 U/l , p = ns ) , or postoperative echocardiographic score ( 26 + /- 7 vs 22 + /- 5 , p = ns ) and LVEF ( 53 + /- 10 vs 55 + /- 7 % , p = ns ) . When the comparisons were restricted to those patients with preoperative LVEF < 50 % , at 24 hours the isoflurane-treated patients exhibited a smaller release of troponin I and of CK-MB than controls ( 1.1 + /- 0.7 vs 2.3 + /- 1.3 ng/ml , p = 0.03 , and 39 + /- 10 vs 57 + /- 22 U/l , p = 0.04 , respectively ) . CONCLUSIONS Isoflurane reduces myocardial injury in patients with impaired left ventricular function undergoing CABG ; thus , it can be safely used as an additional cardioprotective tool during routine CABG in high-risk patients with poor left ventricular function In several recent clinical trials on cardiac surgery patients , remote ischaemic preconditioning ( RIPC ) showed a powerful myocardial protective effect . However , the effect of RIPC has not been studied in patients undergoing off-pump coronary artery bypass graft surgery . We evaluated whether RIPC could induce myocardial protection in off-pump coronary artery bypass graft surgery patients . Patients undergoing elective off-pump coronary artery bypass graft surgery were r and omly allocated to the RIPC ( n=65 ) or control group ( n=65 ) . After induction of anaesthesia , RIPC was induced by four cycles of five-minute ischaemia and reperfusion on the upper limb using a pneumatic cuff . Anaesthesia was maintained with sevoflurane , remifentanil and vecuronium . Myocardial injury was assessed by troponin I before surgery and 1 , 6 , 12 , 24 , 48 and 72 hours after surgery . There were no statistical differences in troponin I levels between RIPC and control groups ( P=0.172 ) . Although RIPC reduced the total amount of troponin I ( area under the curve of troponin increase ) by 26 % , it did not reach statistical significance ( RIPC group 53.2∓72.9 hours.ng/ml vs control group 67.4∓97.7 hours.ng/ml , P=0.281 ) . In this study , RIPC by upper limb ischaemia reduced the postoperative myocardial enzyme elevation in offpump coronary artery bypass graft surgery patients , but this did not reach statistical significance . Further study with a larger number of patients may be needed to fully evaluate the clinical effect of RIPC in off-pump coronary artery bypass graft surgery patients OBJECTIVE The effects of sevoflurane on proinflammatory cytokines related to ischemic-reperfusion injury are not clear . The hypothesis was tested that sevoflurane decreases myocardial ischemic-reperfusion injury by suppressing proinflammatory cytokines . DESIGN Prospect i ve , r and omized study . SETTING A medical university heart center . PARTICIPANTS Twenty-three patients undergoing coronary artery bypass surgery allocated r and omly into 2 groups . INTERVENTIONS Anesthesia for 23 patients undergoing coronary artery bypass surgery was maintained using either fentanyl ( 30 microg/kg ) with propofol ( 2 - 8 mg/kg/h ) in the control group ( n = 10 ) or fentanyl ( 30 microg/kg ) with 0.5 % to 1.0 % sevoflurane in the sevoflurane group ( n = 13 ) . MEASUREMENTS AND MAIN RESULTS Interleukin (IL)-6 , IL-8 , IL-10 , and IL-1 receptor antagonist ( IL-1ra ) were measured by enzyme-linked immunosorbent assay . Troponin-T and creatine kinase-MB isoenzyme ( CK-MB ) were measured by enzyme immunoassay and ultraviolet absorption spectrophotometry , respectively . Serum IL-6 and IL-8 concentrations in both groups increased significantly over baseline from 60 minutes after declamping the aorta ( p < 0.001 ) . The increases were greater in the control group than in the sevoflurane group ( p < 0.05 ) . Serum IL-10 and IL-1ra concentrations in both groups increased significantly over baseline from 60 minutes after declamping the aorta ( p < 0.001 ) . There were no differences between the two groups . Serum troponin-T and CK-MB concentrations increased significantly in both groups from 60 minutes after declamping the aorta ( p < 0.001 ) ; the increases were greater in the control group ( p < 0.05 ) . CONCLUSION Sevoflurane suppressed the production of IL-6 and IL-8 , but not IL-10 and IL-1ra . Changes in the balance between pro- and anti-inflammatory cytokines may be one of the most important mechanisms of myocardial protection caused by sevoflurane BACKGROUND Whether remote ischaemic preconditioning , an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia , is beneficial for patients undergoing coronary artery bypass graft surgery is unknown . We did a single-blinded r and omised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients . METHODS 57 adult patients undergoing elective coronary artery bypass graft surgery were r and omly assigned to either a remote ischaemic preconditioning group ( n=27 ) or to a control group ( n=30 ) after induction of anaesthesia . Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia , induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg , with an intervening 5 min of reperfusion during which the cuff was deflated . Serum troponin-T concentration was measured before surgery and at 6 , 12 , 24 , 48 , and 72 h after surgery . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00397163 . FINDINGS Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6 , 12 , 24 , and 48 h after surgery . The total area under the curve was reduced by 43 % , from 36.12 microg/L ( SD 26.08 ) in the control group to 20.58 microg/L ( 9.58 ) in the remote ischaemic preconditioning group ( mean difference 15.55 [ SD 5.32 ] ; 95 % CI 4.88 - 26.21 ; p=0.005 ) . INTERPRETATION We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning , using transient upper limb ischaemia BACKGROUND Volatile agents can mimic ischaemic preconditioning leading to a decrease in myocardial infa rct size . The present study investigated if a 15 min sevoflurane administration before cardiopulmonary bypass ( CPB ) has a cardioprotective effect in patients undergoing coronary surgery . METHODS Seventy-two patients were r and omized in two centres . The intervention group ( S ) received 1 MAC sevoflurane administrated via the ventilator for 15 min followed by a 15 min washout before CPB , the control group did not . The primary outcome was the postoperative troponin Ic peak . A biopsy of the atrium was taken during canulation for enzyme dosages . Results are expressed as mean ( SD ) . RESULTS Neither troponin Ic nor tissular enzyme measurement exhibited any difference between the groups : peak of troponin Ic was 4.4 ( 5.6 ) in S group vs 5.2 ( 6.6 ) ng ml(-1 ) in control group ( ns ) . Intratissular ecto-5'-nucleotidase activity was 7.1 ( 4.3 ) vs 8.5 ( 11.9 ) , protein kinase C activity was 27.1 ( 15.7 ) vs 29.2 ( 28.7 ) , tyrosine kinase activity was 101 ( 54.1 ) vs 98.5 ( 63.3 ) , and P38 MAPKinase activity was 131.1 ( 76.1 ) vs 127.1 ( 86.8 ) nmol mg protein(-1 ) min(-1 ) in S group and control group , respectively ( ns ) . However there were fewer patients with low postoperative cardiac index in S group ( 11 % in S vs 35 % in control group , P < 0.05 ) when considering the per protocol population . In S group , 25 % of patients required an inotropic support during the postoperative period , vs 36 % of patients in control group ( ns ) . CONCLUSIONS This study did not show a significant preconditioning signal after 15 min of sevoflurane administration . The 15 min duration might be too short or the concentration of sevoflurane too low to induce cardioprotection detected by troponin I levels Background / Aims : Study eluci date s and compares the mitochondrial bioenergetic-related molecular basis of sevoflurane and propofol cardioprotection during aortic valve replacement surgery due to aortic valve stenosis . Methods : Twenty-two patients were prospect ively r and omized in two groups regarding the anesthetic regime : sevoflurane and propofol . Hemodynamic parameters , biomarkers of cardiac injury and brain natriuretic peptide ( BNP ) were measured preoperatively and postoperatively . In tissue sample s , taken from the interventricular septum , key mitochondrial molecules were determined by Western blot , real time PCR , as well as confocal microscopy and immunohisto- and immunocyto-chemical analysis . Results : The protein levels of cytochrome c oxidase and ATP synthase were higher in sevoflurane than in propofol group . Nevertheless , cytochrome c protein content was higher in propofol than sevoflurane receiving patients . Propofol group also showed higher protein level of connexin 43 ( Cx43 ) than sevoflurane group . Besides , immunogold analysis showed its mitochondrial localization . The mRNA level of mtDNA and uncoupling protein ( UCP2 ) were higher in propofol than sevoflurane patients , as well . On the other h and , there were no significant differences between groups in hemodynamic assessment , intensive care unit length of stay , troponin I and BNP level . Conclusions : Our data indicate that sevoflurane and propofol lead to cardiac protection via different mitochondrially related molecular mechanisms . It appears that sevoflurane acts regulating cytochrome c oxidase and ATP synthase , while the effects of propofol occur through regulation of cytochrome c , Cx43 , mtDNA transcription and UCP2 Background and objectives : Volatile anaesthetics have gained more popularity recently due to the potential for cardiac protection . Ultra‐fast‐track anaesthesia implies the immediate extubation after cardiac surgery . The purpose of this prospect i ve r and omized double‐blind controlled study is to compare the cardioprotective effects of sevoflurane and isoflurane in off‐pump cardiac bypass surgery . Methods : Forty patients undergoing elective off‐pump cardiac bypass surgery with high thoracic epidural analgesia and immediate extubation at the end of surgery were r and omized into two groups . During surgery , anaesthesia was provided with either 1 minimum alvelolar anaesthetic concentration of sevoflurane or 1 minimum alvelolar anaesthetic concentration of isoflurane . Troponin‐T , creatine kinase‐MB , left ventricular wall motion anomalies , time to extubation , respiratory functions and haemodynamic parameters were compared between the two groups by analysis of variance . Results : All patients were successfully extubated in the operating theatre with minimal postoperative pain . Serial creatine kinase‐MB and troponin‐T concentrations were not significantly different between the two volatile agents . Haemodynamic stability throughout surgery and contractility was not different between groups . However , extubation time was significantly shorter with sevoflurane ( 10 ± 5 min ) compared to isoflurane ( 18 ± 4 min ) . Conclusion : This study indicates that during off‐pump cardiac bypass surgery , sevoflurane and isoflurane provide the same ischaemic cardioprotective effects . There is no difference for heart contractility and haemodynamic values during and after off‐pump cardiac bypass surgery between the two agents . Sevoflurane allows a more rapid recovery from anaesthesia , but this does not translate into better pulmonary function or haemodynamics . Both agents are similar in ultra‐fast‐track off‐pump cardiac bypass surgery In coronary surgery patients the use of a volatile anesthetic regimen with sevoflurane was associated with a better recovery of myocardial function and less postoperative release of troponin I. In the present study we investigated whether these cardioprotective properties were also apparent in the cardiac surgical setting of aortic valve replacement ( AVR ) surgery for the correction of aortic stenosis . Thirty AVR surgery patients were r and omly assigned to receive either target-controlled infusion of propofol or inhaled anesthesia with sevoflurane . Cardiac function was assessed perioperatively using a pulmonary artery catheter . Perioperatively , a high-fidelity pressure catheter was positioned in the left ventricle . Postoperative concentrations of cardiac troponin I were followed for 48 h. After cardiopulmonary bypass ( CPB ) , stroke volume and dP/dtmax were significantly higher in the patients with sevoflurane . Post-CPB , the effects of an increase in cardiac load on dP/dtmax were similar to pre-CPB in the sevoflurane group ( 1.0 % ± 5.4 % post-CPB versus 1.3 % ± 8.6 % pre-CPB ) but more depressed in the propofol group ( −8.2 % ± 4.4 % post-CPB versus 0.1 % ± 4.9 % pre-CPB ) . The rate of relaxation was significantly slower post-CPB in the propofol group . Postoperative levels of troponin I were significantly lower in the sevoflurane group . Our data indicate that the use of a volatile anesthetic regimen in AVR surgery was associated with better preservation of myocardial function and a reduced postoperative release of troponin OBJECTIVE Myocardial ischemic damage is reduced by volatile anesthetics in patients undergoing coronary artery bypass graft surgery . The authors tested the hypothesis that low-dose sevoflurane could decrease perioperative myocardial damage , as measured by cTnI release , when compared with placebo , in patients undergoing interventional cardiology procedures . DESIGN A single-blind , r and omized controlled trial . SETTING A university hospital . PARTICIPANTS Thirty patients undergoing stenting procedures ( May 2005 ) were included in the present study . INTERVENTIONS The authors r and omly assigned 16 patients to breathe sevoflurane ( expired end-tidal concentration 1 % ) and 14 patients to breathe a placebo oxygen/air mix before stenting procedures . MEASUREMENTS AND MAIN RESULTS Postprocedural cardiac troponin I release was measured as a marker of myocardial necrosis . Sixteen patients had detectable cardiac troponin I levels after stenting procedures , with no difference between groups : 10 in the sevoflurane group ( 16 patients ) versus 6 in the placebo group ( 14 patients ) ( p = 0.3 ) . No difference in the amount of postprocedural median ( interquartile range ) cardiac troponin I release was noted between the sevoflurane group , 0.15 ( 0 - 4.73 ) ng/mL , and the placebo group , 0.14 ( 0 - 0.87 ) ng/mL ( p = 0.4 ) . CONCLUSIONS Myocardial damage measured by cardiac troponin release was not reduced by the volatile anesthetic sevoflurane during interventional cardiology procedures in this study

Weight-based and high fixed-dose chemoprophylaxis regimens achieved target anti-Xa concentrations more frequently than st and ard fixed-dose regimens but were not associated with a reduction in VTE . Additionally , high fixed-dose approaches are associated with increased bleeding complications .

BACKGROUND Venous thromboembolism ( VTE ) continues to be a devastating source of morbidity and mortality in obese patients who suffer traumatic injuries or obese surgery patients . High incidence rates in VTE despite adherence to prevention protocol s have stirred interest in new dosing regimens . The purpose of this study was to systematic ally review the literature and present the existing VTE chemoprophylaxis regimens for obese trauma and surgical patients in terms of efficacy and safety as measured by the incidence of VTE , anti-factor Xa levels , and the occurrence of bleeding events .

BACKGROUND Prophylaxis for venous thromboembolism is routinely performed for all patients undergoing bariatric surgery . However , there is disagreement regarding the optimal dosing and duration of anticoagulant therapy . Furthermore , there is little data regarding the incidence of asymptomatic deep venous thrombosis ( DVT ) in this population . Our objective was to conduct a pilot r and omized double blind study to evaluate the pharmacodynamic parameters of 2 different anticoagulation medications ( enoxaparin and fondaparinux ) administered to patients undergoing bariatric surgery . METHODS From July 2010 to August 2013 , 198 consecutive bariatric surgery patients from an academic institution were r and omized in a double blinded manner to receive either 40 mg enoxaparin twice daily or 5 mg fondaparinux sodium once daily . Antifactor Xa activity was measured on all patients in both study arms , 3 hours after the first dose ( on the day of the operation ) , immediately before the second dose ( postoperative day one ) , and 3 hours after the second dose . At the routine 2 week postoperative visit , patients underwent magnetic resonance venography ( MRV ) to detect DVT . The primary outcome was attainment of therapeutic antifactor Xa levels . The secondary outcome was DVT , as detected by MRV . Safety outcomes were perioperative bleeding , perioperative complications , and death . RESULTS Of 198 patients r and omized , 177 underwent MRV and 137 had interpretable antifactor Xa levels . Nearly half of the patients ( 47.4 % ) did not attain target prophylactic antifactor Xa levels . Adequate antifactor Xa levels were more common with fondaparinux ( 74.2 % ) than with enoxaparin ( 32.4 % ) . Antifactor Xa levels were also associated with preoperative D-dimer level . 4 of the 175 patients who underwent MRV developed DVT , 2 in each arm of the study . No major adverse events occurred in either arm . CONCLUSION Fondaparinux was much more likely to produce target prophylactic antifactor Xa levels than enoxaparin . Both regimens appear to be equally effective at reducing the risk of DVT . Further prospect i ve studies are needed to determine the optimal DVT prophylaxis regimen in the bariatric surgical population Background The incidence of venous thromboembolism ( VTE ) after bariatric surgery is uncertain . Methods Using the re sources of the Rochester Epidemiology Project and the Mayo Bariatric Surgery Registry , we identified all residents of Olmsted County , Minnesota , with incident VTE after undergoing bariatric surgery from 1987 through 2005 . Using the date s of bariatric surgery and VTE events , we determined the cumulative incidence of VTE after bariatric surgery by using the Kaplan – Meier estimator . Cox proportional hazards modeling was used to assess patient age , sex , weight , and body mass index as potential predictors of VTE after bariatric surgery . Results We identified 396 residents who underwent 402 bariatric operations . The most common operation was an open Roux-en-Y gastric bypass ( n = 228 ) . Eight patients had VTE that developed within 6 months ( 7 within 1 month ) after surgery ; five events occurred after hospital discharge but within 1 month after bariatric surgery . The cumulative incidence of VTE at 7 , 30 , 90 , and 180 days was 0.3 , 1.9 , 2.1 , and 2.1 % , respectively ( 180-day 95 % confidence interval ( CI ) , 0.7–3.6 % ) . Patient age was a predictor of postoperative VTE ( hazard ratio , 1.89 per 10-year increase in age ; 95 % CI , 1.01–3.55 ; P = 0.05 ) . Conclusions In our population -based study , bariatric surgery had a high risk of VTE , especially for older patients . Because most VTE events occurred after hospital discharge , a r and omized controlled trial of extended outpatient thromboprophylaxis is warranted in patients undergoing open Roux-en-Y gastric bypass for medically complicated obesity Background Obese patients have a higher risk of venous thromboembolism when immobilized due to surgery . The objective of this study was to assess anti-factor Xa activity in adolescent bariatric surgical patients receiving prophylactic enoxaparin . Methods Four morbidly obese adolescents undergoing laparoscopic sleeve gastrectomy were enrolled . Enoxaparin was administered ( 40 mg subcutaneous ( SC ) if BMI ≤50 kg/m2 or 60 mg SC if BMI > 50 kg/m2 ) for prevention of venous thromboembolism every 12 h starting after induction of anesthesia until discharge . Plasma anti-factor Xa activity was assessed over 12 h after the first dose and used as a surrogate marker for enoxaparin levels . Non-compartmental analysis of anti-factor Xa activity levels was performed and compared with previously published studies . Results Patients recruited were 16 to 18 years of age with a mean BMI of 52.6 ± 5.8 kg/m2 ( > 99th BMI percentile ) . Peak anti-factor Xa activity ranged from 0.20 to 0.23 IU/mL in our study population , compared to 0.38 to 0.53 IU/mL in the cited lean comparator groups . Conclusions Our current dosing practice of 40 mg SC for individuals with a BMI ≤50 kg/m2 and 60 mg for individuals with a BMI ≥50 kg/m2 result ed in anti-factor Xa activity that was sufficient for adequate thromboprophylaxis in adolescent bariatric surgical patients . Our data also demonstrates lower drug exposures in the obese when compared to lean patients . Therefore , r and omized controlled efficacy and safety studies are urgently needed to guide the use of low-molecular-weight heparins in the pediatric and adolescent obese population BACKGROUND Venous thromboembolism ( VTE ) after laparoscopic bariatric surgery is a significant cause of morbidity and mortality . The objective of the present study was to study the incidence of symptomatic VTE in extended thromboprophylaxis regimens using dalteparin at an independent hospital in Engl and , United Kingdom . METHODS A prospect i ve data base of all patients undergoing bariatric surgery was retrospectively analyzed . All patients underwent VTE prophylaxis regimen using perioperative and extended postoperative low-molecular-weight heparin ( dalteparin 2500 IU preoperatively , followed by 5000 IU daily postoperatively ) . The treatment period was 1 week for laparoscopic gastric b and ing or 3 weeks for all other procedures . Inferior vena cava filters were used in selected patients with thrombophilia , a history of pulmonary embolism , or > 1 episode of deep vein thrombosis . The endpoint was the incidence of symptomatic VTE . RESULTS A total of 735 patients underwent laparoscopic bariatric surgery , all of whom received dalteparin . The postoperative VTE incidence was 0 % . The 30-day and 90-day all-cause mortality rate was 0 % . A total of 3 adverse bleeding events occurred . CONCLUSION An extended VTE prophylaxis regimen using low-molecular-weight heparin is simple and effective and was associated with a low incidence of bleeding complications BACKGROUND The optimal scheme of thromboprophylaxis in bariatric surgery remains uncertain , because clinical practice is different between countries and r and omized trials are lacking . OBJECTIVES The primary objective of this r and omized multicenter study was to determine the optimal regimen of enoxaparin providing an antifactor Xa peak activity between .3 and .5 IU/mL at equilibrium and to evaluate the course of procoagulant microparticles ( MPs ) . SETTING University hospital . METHODS A total of 164 patients scheduled for gastric bypass were allocated to 3 groups ( A , B , and C ) of enoxaparin treatment ( 4000 , 6000 , or 2 × 4000 IU , respectively ) . Antifactor Xa activity was measured before and 4 hours after each injection from D0 to D2 . Doppler screening of the lower limbs was performed at D1 , D9 , and D30 . Bleeding ( BE ) and thrombotic events ( TE ) were recorded during the first postoperative month . Total MPs were measured at D0 , D9 , and D30 . MPs of leucocyte , platelet , and granulocyte origin were assessed in one third of the patients from each group . The 3 groups were compared by ANOVA . RESULTS A total of 135 patients were analyzed . The equilibrium of antifactor Xa peak levels was obtained 52 hours after the presurgery injection and 12.8 % , 56.4 % , and 27.3 % of the patients reached the target in groups A , B , and C , respectively ( P<.001 ) . No TE was detected . BE occurred in 1 , 2 , and 6 patients in groups A , B , and C , respectively ) . Total MPs remained unchanged over time . While no significant variation was observed in the other groups , platelet GP1 b(+)-MPs increased ( P = .01 ) at D9 in group C , suggesting an incomplete control of anticoagulation leading to cell activation and procoagulant MP release that was confirmed by the higher MP levels measured at D30 ( P = .04 ) . CD66(+)-MPs were also highly elevated at J9 and D30 in group C indicating a granulocyte contribution . CONCLUSIONS This study shows that a single dose of enoxaparin 6000 IU/d allowed most of the patients to reach the target range of antifactor Xa activity without increasing the bleeding risk , with the most likely efficient reduction of procoagulant MPs . ( Surg Obes Relat Dis 2015;0:000 - 000 . ) © 2015 American Society for Metabolic and Bariatric Surgery . All rights reserved Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Objective : To compare two enoxaparin dosing strategies at achieving prophylactic anti-Xa levels in women with a body mass index ( BMI ) ⩾35 ( kg m−2 ) postcesarean delivery . Study Design : Women with BMI ⩾35 were r and omized to receive prophylactic enoxaparin at a fixed dose of 40 mg daily or weight-based dosing of 0.5 mg kg−1 twice daily . The primary outcome was the proportion of subjects with peak anti-Xa levels in the prophylactic range of 0.2 to 0.6 IU ml−1 . Result : From August 2013 through February 2014 , 84 demographically similar women completed the protocol . In the weight-based group , 88 % ( 37/42 ) of the women reached prophylactic anti-Xa levels versus 14 % ( 6/42 ) in the fixed dose group ( odds ratio 44.4 , 95 % confidence interval 12.44 , 158.48 , P<0.001 ) . No anti-Xa level exceeded 0.48 IU ml−1 . There were no venous thromboembolic or bleeding events requiring reoperation or transfusion in either group . Conclusion : Compared with fixed dosing daily , weight-based dosing twice daily more effectively achieved prophylactic anti-Xa levels without reaching the therapeutic range Background The optimal dose of low molecular weight heparin ( LMWH ) to prevent venous thromboembolism ( VTE ) after bariatric surgery remains controversial . The aim of this multicentre , open-label , pilot study was to evaluate the efficacy and safety of two different doses of the LMWH parnaparin administered to patients undergoing bariatric surgery . Methods Patients were r and omised to receive 4,250 IU/day ( group A ) or 6,400 IU/day ( group B ) of parnaparin s.c . for 7–11 days . Bilateral colour Doppler ultrasound of the lower limb was performed before surgery and at the end of the treatment period . The primary efficacy outcome was a composite of asymptomatic and symptomatic deep vein thrombosis , symptomatic pulmonary embolism and death from any cause during treatment . The primary safety endpoint was major and clinical ly relevant non-major bleeding . Results A total of 258 patients underwent r and omization ; 8 subjects were excluded following the safety analysis . One hundred thirty-one patients [ 106 females ; mean age , 40.3 years ( st and ard deviation ( SD ) ±9.6 ) ; mean body mass index ( BMI ) , 44.6 kg/m2 ( SD ±5.4 ) ] were assigned to group A and 119 patients [ 93 females ; mean age , 41.5 years ( SD ±9.9 ) ; mean BMI , 44.2 kg/m2 ( SD ±5.4 ) ] were assigned to group B. The rate of the primary efficacy outcome was 1.5 % ( two cases ; 95 % confidence interval ( CI ) , 0.2–6.0 % ) in group A as compared with 0.8 % ( one case ; 95 % CI , 0.4–5.3 % ) in group B ( p = ns ) . The composite incidence of major bleeding and clinical ly relevant non-major bleeding was 6.1 % ( eight cases ; 95 % CI , 2.9–12.1 % ) in group A and 5.0 % ( six cases ; 95 % CI , 2.1–11.1 % ) in group B ( p = ns ) . Conclusions A parnaparin dose of 4,250 IU/day seems suitable for VTE prevention in patients undergoing bariatric surgery OBJECTIVE : To compare the adequacy of venous thromboembolism prophylaxis based on anti-Xa concentrations between weight-based enoxaparin dosing and body mass index ( BMI ) –stratified dosing in morbidly obese women after cesarean delivery . METHODS : A prospect i ve sequential cohort study of women with BMI s of 40 or greater who underwent cesarean delivery was conducted . Participants received either weight-based or BMI -stratified enoxaparin dosing to prevent venous thromboembolism formation . The weight-based regimen was 0.5 mg/kg of enoxaparin every 12 hours . In the BMI -stratified regimen , women with BMI s of 40–59.9 received 40 mg enoxaparin every 12 hours and women with BMI s of 60 or greater received 60 mg every 12 hours . The primary outcome was an anti-Xa concentration in the adequate thromboprophylaxis range ( 0.2–0.6 international units/mL ) . Secondary outcomes included enoxaparin dosage , timing of dosing and anti-Xa concentration , estimated surgical blood loss , postoperative changes in hemoglobin and platelets , wound hematoma , and adverse reactions to enoxaparin . Univariate analysis was used to compare dosing regimens . RESULTS : Forty-two morbidly obese women received weight-based enoxaparin , and 43 received BMI -stratified dosing . Anti-Xa concentrations were significantly higher in the weight-based group compared with the BMI -stratified group ( 0.29±0.08 international units/mL compared with 0.17±0.07 international units/mL , P<.001 ) . Thirty-six participants ( 86 % ) on weight-based dosing had anti-Xa concentrations within the prophylactic range compared with 11 ( 26 % ) on BMI -stratified dosing ( P<.001 ) . No participant had an anti-Xa concentration of 0.6 international units/mL or greater , the therapeutic threshold for venous thromboembolism prophylaxis . CONCLUSION : In morbidly obese women after cesarean delivery , weight-based dosing of enoxaparin for venous thromboembolism prophylaxis is significantly more effective than BMI -stratified dosing in achieving adequate anti-Xa concentrations . LEVEL OF EVIDENCE : BACKGROUND We report our experience dosing and monitoring enoxaparin with anti-factor Xa activity ( anti-FXaA ) levels for venous thromboembolism prophylaxis in trauma patients ( TP ) . MATERIAL S AND METHODS TP receiving st and ard , non-weight-based dosed enoxaparin administered every 12 h for venous thromboembolism prophylaxis with peak anti-FXaA levels measured were prospect ively monitored and evaluated and those whose first anti-FXaA levels ≥ or < 0.2 IU/mL were compared . Anti-FXaA levels and enoxaparin dose ( mg/kg actual body weight ) were evaluated for correlation . RESULTS Of the fifty-one TP included , initial anti-FXaA levels were < 0.2 IU/mL in 37 ( 72.5 % ) whose dose was lower than those within target range ( 0.38 [ 0.32 - 0.42 ] mg/kg versus 0.45 [ 0.39 - 0.48 ] mg/kg , P = 0.003 ) . Thirty-seven TP achieved anti-FXaA level ≥0.2 IU/mL ( 23 requiring dose increases ) at a dose of 0.49 [ 0.44 - 0.54 ] mg/kg . Correlation between dose and anti-FXaA levels for the initial 51 anti-FXaA levels ( r = 0.360 , P = 0.009 ) and for all 103 anti-XaA levels ( r = 0.556 , P < 0.001 ) was noted . CONCLUSIONS Non-weight-based enoxaparin dosing did not achieve target anti-FXaA levels in most TP . Higher anti-FXaA levels correlated with larger weight-based enoxaparin doses . Weight-based enoxaparin dosing ( i.e. , 0.5 mg/kg subcutaneously every 12 h ) would better achieve target anti-FXaA levels BACKGROUND Morbidly obese patients undergoing gastric bypass surgery are at risk for postoperative venous thromboembolism . Evidence -based recommendations regarding the dosing and duration of thromboprophylaxis are lacking for morbidly obese surgical patients . The aims of this study were to evaluate the safety and efficacy of an extended duration , body mass index ( BMI ) -stratified enoxaparin thromboprophylaxis regimen in patients undergoing Roux-en-Y gastric bypass and to determine the result ant antifactor Xa ( AFXa ) activity in morbidly obese surgical patients . METHODS In this prospect i ve open trial , 223 patients ( 75 % female , mean BMI 50.4 kg/m2 ) undergoing Roux-en-Y gastric bypass were assigned to receive enoxaparin 40 mg ( BMI < or=50 kg/m2 ) , n = 124 ) or 60 mg ( BMI > 50 kg/m2 ) , n = 99 ) every 12 hours during hospitalization and once daily for 10 days after discharge . The AFXa levels were monitored serially , and dose adjustments were made for results outside the target prophylactic range ( .2-.4 IU/mL + /- 10 % ) after the third dose . The safety and efficacy outcomes were major bleeding and venous thromboembolism . RESULTS Roux-en-Y gastric bypass was performed laparoscopically in 208 subjects ( 93 % ) . The duration of surgery averaged 99.5 + /- 31 minutes , and the median length of hospitalization was 3 days . Target prophylactic AFXa concentration was achieved by 74 % of patients after the third enoxaparin dose ; none reached the full anticoagulation concentration . One patient developed nonfatal venous thromboembolism ( .45 % ) . Four patients required transfusion ( 1.79 % ) . Bleeding was not associated with a high AFXa concentration . CONCLUSION This BMI -stratified , extended enoxaparin dosing regimen provided well-tolerated , effective prophylaxis against venous thromboembolism in patients undergoing gastric bypass surgery BACKGROUND The optimal amount of thromboembolic prophylaxis to use in bariatric surgery is still unresolved . OBJECTIVE The aim of this study was to determine the optimal pharmacologic prophylaxis with minimal bleeding complications for bariatric patients . SETTING A nonr and omized clinical study of 400 consecutive bariatric patients surgically treated between 2008 and 2013 at Peijas Hospital . METHODS The patients , who either underwent mainly a sleeve gastrectomy or a Roux-en-Y gastric bypass , were divided consecutively into 3 subgroups with different approaches to pharmacologic enoxaparin prophylaxis . For the first 100 operated patients ( high-dose group ) , enoxaparin was given at a dose of 40 mg twice daily , starting 1 day before the operation . The next 100 patients ( intermediate-dose group ) received 40 mg of enoxaparin twice daily , without the dose on the morning of the operation . The last 200 patients ( low-dose group ) received enoxaparin 40 mg once daily , starting 1 day before the operation and without the dose on the morning of the operation . The primary endpoints in this study were a major bleeding complication and a venous thromboembolism . RESULTS There were no thromboembolic complications in this study . The difference in bleeding complications between the high-dose group and low-dose group was -10.5 % ( 95 % CI from -18.1 % to -3.0 % ) , and the difference between high-dose group and intermediate-dose group was -9 % ( 95 % CI from -17.4 % to -.6 % ) . Age and preoperative weight had no effect on bleeding complications , but hypertension significantly increased the amount of bleeding complications ( P = .01 , 95 % CI from 1.55 % to 29.7 % ) . CONCLUSION Thromboembolic complications are avoidable . Enoxaparin ( 40 mg ) given once daily was the safest with regard to bleeding complications . High blood pressure elevates the risk for bleeding Background There are limited data on appropriate dosing of low-molecular-weight heparins ( LMWHs ) for venous thromboembolism ( VTE ) prophylaxis in bariatric surgery . The primary objective of this preliminary study was to evaluate the preoperative effects of increasing doses of the LMWH parnaparin on coagulation in severely obese patients undergoing bariatric surgery . Methods Severely obese patients ( BMI > 50 kg/m2 ) were administered three increasing single doses of parnaparin ( 3200 , 4250 , and 6400 IU ) on the three consecutive days leading up to biliointestinal bypass surgery . Activated partial thromboplastin time ( APTT ) , anti-factor IIa and anti-factor Xa levels were measured 1 h before and 4 h after dosing . The highest dose ( 6400 IU/day ) was continued from the day of surgery until day 30 ( recovery period ) . Intermittent pneumatic compression and stockings were applied during surgery and the recovery period , respectively . Lower limb echoDoppler and phleboscintigraphy , and pulmonary scintigraphy were used for VTE detection . Results Ten patients ( mean BMI 52.4 kg/m2 ) were recruited into this study . During the preoperative dosing phase , parnaparin dose-dependently prolonged APTT , with the 6400 IU dose significantly prolonging APTT versus the lower doses . Meanwhile , anti-factor Xa and anti-factor IIa activity was increased by the 4250 and 6400 IU doses . After surgery , one patient with heparin resistance experienced pulmonary embolization . No bleeding complications were observed . Conclusion The dose – response data reported in this preliminary study suggest that parnaparin doses of 4250 and 6400 IU may provide effective prophylaxis for VTE in patients undergoing bariatric surgery . However , given the small number of patients , larger , well-controlled trials are required to confirm these findings Background : Obese patients undergoing bariatric surgery are at a high risk of developing fatal pulmonary embolism or post-thrombotic syndrome . The prophylactic use of low molecular weight heparins ( LMWHs ) is correlated with a significant reduction in post-operative venous thrombosis in patients undergoing orthopedic or general surgery . In morbidity obese patients , the limited number of comparative trials are too sparse to allow a consensus on the effective dose and dosing schedule . Methods : In a prospect i ve study to evaluate the effect of two doses of nadroparin as prophylaxis for venous thromboembolism following bariatric surgery , 60 consecutive patients undergoing Rouxen-Y gastric bypass were r and omized to receive either 0.6 ml ( 5700 IU ) or 1.0 ml ( 9500 IU ) of nadroparin started pre-operatively and then given once daily post-operatively until discharge . Results : No statistically significant differences between the two groups were detected in any of the measured coagulation parameters either preoperatively or at days 1 , 3 and 5 postoperatively . No thrombotic events were observed pre- or post- operatively , and no patient developed meta-thrombotic syndrome at the 3 and 6 months follow-up . No bleeding events occurred in the patients given the lower dose compared with two major hemorrhages in those given the higher dose . Conclusion : Our results indicate that 0.6 ml ( 5700 IU ) of nadroparin once daily is safe and well-tolerated , and it is as effective in prophylaxis of venous thromboembolism as the higher dose of 1 ml ( 9500 IU ) , in such high risk patients BACKGROUND St and ard venous thromboembolism ( VTE ) prophylaxis with enoxaparin results in inadequate protection in certain patients , with subtherapeutic plasma anti-Xa levels associated with elevated VTE rates . We hypothesized that many trauma patients would be subtherapeutic on the st and ard prophylactic dose of enoxaparin . Our goal was to adjust the enoxaparin dose to achieve target anti-Xa levels to take advantage of the drug based on its pharmacologic properties . METHODS Patients admitted to the trauma service were included if they received at least three doses of prophylactic enoxaparin and underwent at least two screening venous duplex . Peak plasma anti-Xa levels of 0.2 IU/mL or less were considered low , and the dose was increased by 10 mg twice daily until adequate anti-Xa levels were obtained . A strict screening venous duplex protocol was followed . Patients were excluded if they were diagnosed with a deep venous thrombosis before beginning enoxaparin or did not have correctly timed anti-Xa levels . RESULTS Sixty-one trauma patients met inclusion criteria . There were three patients diagnosed with VTE ( 4.9 % ) . Patients had a mean age of 45.9 years and were predominantly male ( 70.5 % ) . Of the 61 patients , 18 ( 29.5 % ) had therapeutic anti-Xa levels on st and ard enoxaparin 30 mg twice daily . Compared with patients who had therapeutic anti-Xa levels on enoxaparin 30 mg twice daily , the 43 patients ( 70.5 % ) who were subtherapeutic were more likely to be male , have greater body weight , and larger body surface area . There were no significant bleeding events in the group that received an enoxaparin dose adjustment . CONCLUSION Most patients had subtherapeutic anti-Xa levels while on enoxaparin 30 mg twice daily , suggesting inadequate VTE prophylaxis . The need for routine use of a higher dose of prophylactic enoxaparin in trauma patients and the effects of routinely dose adjusting enoxaparin on VTE rates should be the study of future prospect i ve , r and omized trials . LEVEL OF EVIDENCE Therapeutic study , level IV BACKGROUND Morbidly obese patients undergoing bariatric surgery are at risk for developing venous thromboembolic events . Data regarding the appropriate dosing strategy in this special population is limited . OBJECTIVE To evaluate 2 different dosing regimens of enoxaparin in a prospect i ve cohort of patients undergoing laparoscopic sleeve gastrectomy . SETTING University hospital , Israel METHODS : The study cohort consisted of 54 patients divided into 2 groups . Group I received 40 mg enoxaparin every 24 hours , and group II received 60 mg enoxaparin every 24 hours . Anti-factor Xa ( FXa ) levels from each patient were obtained 3 to 4 hours after administration of the third dose of enoxaparin . Levels between .2 and 0.5 U/mL were considered appropriate . Five additional patients were selected as controls . RESULTS There were 31 patients in group I and 23 patients in group II . There was a statistically significant difference between anti-FXa levels achieved in each group : .247 U/mL in group I ( range , .15-.39 ) versus .346 U/mL ( range , .24-.8 ) in group II . Both groups achieved mean anti-FXa levels in the range design ated appropriate with a high proportion of patients achieving appropriate levels ( group I : 80.6 % ; group II : 91.3 % ) . Univariate analyses found that total weight and sex were significantly correlated with anti-FXa levels . However , a multivariate analysis including enoxaparin dose found that only enoxaparin dose remained significantly correlated with anti-FXa levels . CONCLUSION In the absence of sufficient data regarding clinical efficacy and safety of different dosing regimens both dosing regimens studied are reasonable choices for venous thromboembolic events prophylaxis after bariatric surgery INTRODUCTION We prospect ively evaluated 30-day thromboembolic and bleeding events in 2 groups of laparoscopic gastric bypass patients receiving different anticoagulation regimens . METHODS The first cohort of patients received enoxaparin 40 mg subcutaneously preoperatively , 40 mg subcutaneously on postoperative day 0 , and twice daily until discharge . The second cohort of patients received unfractionated heparin 5,000 units subcutaneously preoperatively , nothing on postoperative day 0 , and 5,000 units 3 times per day until discharge . RESULTS The incidence of deep venous thrombosis in both cohorts was 0 . There was 1 pulmonary embolism in the heparin cohort ( P = .999 ) . Fourteen patients ( 5.9 % ) in the enoxaparin cohort required postoperative transfusions compared with 3 patients ( 1.3 % ) in the heparin cohort ( P = .011 ) . Four patients ( 1.7 % ) in the enoxaparin cohort required re-exploration for bleeding . CONCLUSION Both enoxaparin and heparin are effective at preventing thromboembolic events following laparoscopic gastric bypass . Heparin is the preferred agent due to the excessive bleeding complications encountered with enoxaparin Recent reports confirm that the st and ard dose of enoxaparin in obese patients is often subtherapeutic , leading to a higher incidence of venous thromboembolism . All patients receiving subcutaneous enoxaparin 30 mg twice a day ( b.i.d . ) for venous thromboembolism prophylaxis were prospect ively enrolled in this study . Trough antiXa levels were obtained and any level less than 0.1 IU/mL was considered subtherapeutic and the final dosage requirement was recorded . Body mass index ( BMI ) , abdominal wall thickness , and fluid balance were collected . Thirty-four patients were prospect ively enrolled in the study , 14 ( 50 % ) of which had a BMI > 30 . Sixty-five per cent of obese patients were initially nontherapeutic , compared with 53 per cent of the nonobese ( P = 0.73 ) . However , elevated BMI ( P < 0.05 ) and abdominal wall thickness ( P < 0.05 ) correlated to an increased final dose required to attain an anti Xa ≥0.1 when not initially therapeutic , whereas fluid balance demonstrated no correlation ( P = 0.232 ) . Subcutaneous enoxaparin dosing of 30 mg b.i.d . is not sufficient for the majority adult trauma patients in the intensive care unit , regardless of BMI . When enoxaparin 30 mg b.i.d . is initially subtherapeutic , obese patients may require a larger dose necessary to achieve necessary anticoagulation BACKGROUND Women undergoing caesarean section are at higher risk for thromboembolic complications following delivery than other parturients . The aim of this study was to determine whether higher doses of enoxaparin based on body weight are safe and more likely to achieve plasma anti-Xa levels within the accepted thromboprophylactic range . METHODS We undertook a prospect i ve cohort study of 80 women undergoing caesarean section in a tertiary obstetric hospital with > 6000 deliveries per year . Enoxaparin was administered after caesarean section using the Royal College of Obstetricians and Gynaecologists weight-adjusted dosing guidelines . Plasma anti-Xa levels were measured at baseline and 3 - 4 h after enoxaparin administration on days one and three postoperatively . The main outcomes of interest were plasma anti-Xa levels and the proportion of patients with plasma anti-Xa levels in the range of 0.2 - 0.4 IU/mL. RESULTS The proportion of women with anti-Xa levels between 0.2 and 0.4 IU/mL was 72 % ( 95 % CI 60 - 81 % ) . Unadjusted mean anti-Xa levels were 0.26 ± 0.09 IU/mL and 0.28 ± 0.08 IU/mL on day one and day three respectively . No woman had levels > 0.48 IU/mL. CONCLUSION The majority of women receiving weight-based enoxaparin thromboprophylaxis following caesarean section achieved plasma anti-Xa levels within the putative thromboprophylactic range . No woman achieved levels associated with an increased risk of bleeding ( > 0.8 IU/mL ) . These findings provide a safety basis for a large prospect i ve study using this regimen Background Morbidly obese patients are at increased risk to develop venous thromboembolism ( VTE ) , especially after bariatric surgery . Adequate postoperative thrombosis prophylaxis is of utmost importance . It is assumed that morbidly obese patients need higher doses of low molecular weight heparin ( LMWH ) compared to normal-weight patients ; however , current guidelines based on relative efficacy in obese population s are lacking . Objectives First , we will evaluate the relationship between body weight descriptors and anti-Xa activity prospect ively . Second , we will determine the dose-linearity of LMWH in morbidly obese patients . Setting This study was performed in a general hospital specialized in bariatric surgery . Methods Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight ( TBW ) of ≥ 140 kg . Patients ( n = 50 , 64 % female ) received a daily postoperative dose of 5700 IU of nadroparin for 4 weeks . Anti-Xa activity was determined 4 h after the last nadroparin administration . To determine the dose linearity , anti-Xa was determined following a preoperative dose of 2850 IU nadroparin in another 50 patients ( 52 % ) . Results TBW of the complete group was 148.5 ± 12.6 kg . Mean anti-Xa activity following 5700 IU nadroparin was 0.19 ± 0.07 IU/mL. Of all patients , 32 % had anti-Xa levels below the prophylactic range . Anti-Xa activity inversely correlated with TBW ( correlation coefficient − 0.410 ) and lean body weight ( LBW ; correlation coefficient − 0.447 ) ; 67 % of patients with a LBW ≥ 80 kg had insufficient anti-Xa activity concentrations . No VTE events occurred . Conclusions In morbidly obese patients , a postoperative dose of 5700 IU of nadroparin result ed in subprophylactic exposure in a significant proportion of patients . Especially in patients with LBW ≥ 80 kg , a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels BACKGROUND One risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification . OBJECTIVES The objectives of this study were to identify antiXa goal attainment with the institutional st and ard chemoprophylaxis , analyze discordance between antiXa and thrombin generation assay ( TGA ) in terms of adequacy of anticoagulation , and to identify correlations between patient characteristics or covariates and markers of coagulation status . SETTING Large academic medical center in Northeastern United States . METHODS A total of 60 sleeve gastrectomy patients were enrolled in this institutional review board-approved , prospect i ve cohort study . Patients received the institutional st and ard prophylactic therapy ( subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [ UFH ] ) . The UFH dose was weight based , 5000 units ( < 120 kg ) or 7500 units ( ≥120 kg ) every 8 hours . Various measures of coagulation status were measured at or near steady state . RESULTS Patients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group , and statistical significance was demonstrated ( 93.8 % versus 4.5 % , respectively ; P < .0001 ) . Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH ( 50 % versus 27.7 % , respectively ; P = .12 ) . AntiXa was below the limit of detection for the majority of UFH patients ; while TGA suggested patients did experience anticoagulation at some level of effectiveness . Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition . CONCLUSIONS Patients receiving enoxaparin achieved goal antiXa more often versus UFH . There was discordance between antiXa and TGA-based assessment of coagulation status . TGA may provide a more robust assessment of the adequacy of chemoprophylaxis Introduction There is lack of data on the pharmacodynamics of low-molecular-weight heparins in obese patients . Background The aims of this study are to investigate the correlation between anti-factor Xa ( anti-Xa ) levels and body weight with fixed-dose enoxaparin after bariatric surgery and to investigate the percentage of patients that reach the desired prophylactic range for anti-Xa levels . Methods Blood for anti-Xa peak levels measurement was drawn 3–5 h after administration of enoxaparin at the planned visit 8–16 days after surgery . Patients were included in three categories : < 110 kg ( group 1 ) , 110–150 kg ( group 2 ) , and > 150 kg ( group 3 ) . Results Fifty-one patients were included ( 43.9 ± 9.9 years , 75 % women ) . Mean anti-Xa level was 0.37 ± 0.14 IU/ml . This level was the highest in group 1 ( 0.47 ± 0.13 IU/ml ) and lowest in group 3 ( 0.23 ± 0.07 ) . No subprophylactic ( < 0.2 IU/ml ) anti-Xa levels were detected in group 1 , whereas this was observed in 38 % in patients in group 3 . Supraprophylactic levels ( > 0.5 IU/ml ) were most often present in group 1 ( 36 % ) . With multivariable regression analysis , body weight ( β −0.720 ( 95 % confidence interval −.717 ; −.993 ) , p < 0.001 ) was an independent predictor of anti-Xa levels , whereas lean body was not independently associated . This was confirmed in a non-linear mixed effects analysis of the data . Conclusions Patients with excessive body weight may not be adequately treated with fixed-dose enoxaparin thromboprophylaxis while patients with lower body weight may have an increased bleeding risk . Body weight is a better predictor of anti-Xa levels compared to lean body weight

LET could lead to worse anterior instability than with ALL reconstruction when these two approaches were combined with single-bundle ACL reconstruction . However , rotational stability and patient-reported outcomes were similar between the techniques

Anterolateral augmentation procedures can be divided into traditional lateral extra-articular tenodesis ( LET ) and modern anterolateral ligament ( ALL ) reconstruction . Nevertheless , no studies have compared the clinical results between LET and ALL reconstruction , when combined with intra-articular ACL reconstruction . This study was therefore design ed to compare the clinical results , including the anterior translation , rotational laxity , and patient-reported outcomes , in a group of patients who underwent ACL reconstruction combined with LET or ALL reconstruction .

Background : The individual kinematic roles of the anterolateral ligament ( ALL ) and the distal iliotibial b and Kaplan fibers in the setting of anterior cruciate ligament ( ACL ) deficiency require further clarification . This will improve underst and ing of their potential contribution to residual anterolateral rotational laxity after ACL reconstruction and may influence selection of an anterolateral extra-articular reconstruction technique , which is currently a matter of debate . Hypothesis/ Purpose : To compare the role of the ALL and the Kaplan fibers in stabilizing the knee against tibial internal rotation , anterior tibial translation , and the pivot shift in ACL-deficient knees . We hypothesized that the Kaplan fibers would provide greater tibial internal rotation restraint than the ALL in ACL-deficient knees and that both structures would provide restraint against internal rotation during a simulated pivot-shift test . Study Design : Controlled laboratory study . Methods : Ten paired fresh-frozen cadaveric knees ( n = 20 ) were used to investigate the effect of sectioning the ALL and the Kaplan fibers in ACL-deficient knees with a 6 degrees of freedom robotic testing system . After ACL sectioning , sectioning was r and omly performed for the ALL and the Kaplan fibers . An established robotic testing protocol was utilized to assess knee kinematics when the specimens were subjected to a 5-N·m internal rotation torque ( 0 ° -90 ° at 15 ° increments ) , a simulated pivot shift with 10-N·m valgus and 5-N·m internal rotation torque ( 15 ° and 30 ° ) , and an 88-N anterior tibial load ( 30 ° and 90 ° ) . Results : Sectioning of the ACL led to significantly increased tibial internal rotation ( from 0 ° to 90 ° ) and anterior tibial translation ( 30 ° and 90 ° ) as compared with the intact state . Significantly increased internal rotation occurred with further sectioning of the ALL ( 15 ° -90 ° ) and Kaplan fibers ( 15 ° , 60 ° -90 ° ) . At higher flexion angles ( 60 ° -90 ° ) , sectioning the Kaplan fibers led to significantly greater internal rotation when compared with ALL sectioning . On simulated pivot-shift testing , ALL sectioning led to significantly increased internal rotation and anterior translation at 15 ° and 30 ° ; sectioning of the Kaplan fibers led to significantly increased tibial internal rotation at 15 ° and 30 ° and anterior translation at 15 ° . No significant difference was found when anterior tibial translation was compared between the ACL/ALL- and ACL/Kaplan fiber – deficient states on simulated pivot-shift testing or isolated anterior tibial load . Conclusion : The ALL and Kaplan fibers restrain internal rotation in the ACL-deficient knee . Sectioning the Kaplan fibers led to greater tibial internal rotation at higher flexion angles ( 60 ° -90 ° ) as compared with ALL sectioning . Additionally , the ALL and Kaplan fibers contribute to restraint of the pivot shift and anterior tibial translation in the ACL-deficient knee . Clinical Relevance : This study reports that the ALL and distal iliotibial b and Kaplan fibers restrain anterior tibial translation , internal rotation , and pivot shift in the ACL-deficient knee . Furthermore , sectioning the Kaplan fibers led to significantly greater tibial internal rotation when compared with ALL sectioning at high flexion angles . These results demonstrate increased rotational knee laxity with combined ACL and anterolateral extra-articular knee injuries and may allow surgeons to optimize the care of patients with this injury pattern Background : Rotational instability of the knee remains an issue after anterior cruciate ligament ( ACL ) reconstruction . Hypothesis/ Purpose : The purpose was to evaluate the subjective and objective outcomes of combined reconstruction of the ACL and anterolateral ligament ( ALL ) of the knee . The hypothesis was that favorable outcomes can be achieved with this surgical procedure compared with isolated anatomic reconstruction of the ACL . Study Design : R and omized controlled trial ; Level of evidence , 2 . Methods : One hundred ten patients with a unilateral ACL injury and high- grade pivot shift were r and omly assigned to undergo either combined ACL and ALL reconstruction ( group A ) or isolated ACL reconstruction ( group B ) . Preoperative and postoperative evaluations of the patients were conducted by obtaining history details , recording physical examination findings , measuring knee laxity using the KT-1000 arthrometer , and using vali date d outcome scores for the knee . P < .05 was considered as the cut-off level of statistical significance . The Fisher exact and Mann-Whitney U tests were used to assess statistical significance . Results : At a mean follow-up of 27 months , 53 and 50 patients in groups A and B , respectively , were available for analysis . No statistically different outcomes were found between the 2 groups except for the KT-1000 arthrometer values . The median KT-1000 arthrometer result for combined ACL and ALL reconstruction was 1.3 mm , while the median result for isolated ACL reconstruction was 1.8 mm ( P < .001 ) . None of the patients ( n = 0 ; 0.0 % ) who underwent combined ACL and ALL reconstruction had anterior translation of greater than 5 mm at maximum pulling strength compared with their normal knees at final follow-up . On the other h and , 3 ( 6.0 % ) patients who underwent isolated ACL reconstruction had anterior translation of more than 5 mm . No serious complications were found in both groups . Conclusion : Combined ACL and ALL reconstruction was found to be effective in improving subjective and objective outcomes . Nevertheless , these findings were not significantly superior to isolated ACL reconstruction except for the instrumented knee laxity testing results . This might indicate that ALL reconstruction should not be performed routinely for patients undergoing ACL reconstruction PURPOSE The purpose of the current paper was to report the surgical technique of combined anatomic anterior cruciate ligament ( ACL ) and anterolateral ligament ( ALL ) reconstruction as well as the short term clinical results after this surgical procedure . MATERIAL AND METHODS The current prospect i ve study included 32 patients ( 5 females and 27 males ) with combined ACL and ALL reconstruction performed between December 2015 and July 2016 . The patients were included in the study taking into consideration the following criteria : chronic ACL lesion , high grade rotational instability ( pivot shift grade II and III ) and participation in high grade pivoting sports . Patient evaluation followed an established clinical and imaging protocol both preoperatively and at 6 and 12 weeks postoperatively . This included clinical knee stability testing ( Lachman test , Pivot shift test ) , Rolimeter differential laxity testing , subjective and objective IKDC scores and Lysholm score and Tegner score . RESULTS Postoperative stability at 6 weeks and 12 weeks as tested with Lachman test ( p=0.02 and 0.01 , respectively ) , pivot shift test ( p=0.03 and 0.01 , respectively ) and the Rolimeter arthrometer ( p=0.008 and 0.006 , respectively ) showed a statistically significant difference as compared to preoperative values . Postoperative scores at 6 weeks and 12 weeks as measured using objective IKDC form ( p=0.008 and 0.006 , respectively ) , subjective IKDC form ( p=0.04 and 0.03 , respectively ) and Lysholm form ( p=0.02 and 0.01 , respectively ) were statistically significant improved as compared to preoperative values . All patients had a negative Lachman test at 6 and 12 weeks postoperatively . One patient had a positive grade I pivot shift test at 6 weeks postoperatively and two patients had a positive grade I pivot shift test at 12 weeks postoperatively . Differential anteroposterior laxity as measured with the Rolimeter arthrometer improved from 7.19±1.96 mm preoperatively to 0.28±0.45 mm and 0.13±0.34 mm , at 6 weeks and 12 weeks postoperatively , respectively . According to the objective IKDC form , 29 patients were normal or nearly normal ( grade A and B ) at 6 weeks postoperatively and 31 patients were normal or nearly normal at 12 weeks postoperatively . Subjective IKDC score improved from 47.72±17.18 preoperatively to 56.52±11.74 and 73.38±14.28 at 6 and 12 weeks postoperatively , respectively . Lysholm score improved from 63.44±23.01 preoperatively to 80.41±11.94 and 90.47±8.22 at 6 and 12 weeks postoperatively , respectively . Improved Tegner activity scores were present at 12 weeks postoperatively as compared with 6 weeks postoperatively , but still lower as compared to pre-traumatic scores . No significant complications were present in the current study group . CONCLUSIONS Combined ACL and ALL reconstruction is an effective surgical procedure , with improved postoperative clinical results and no significant short term complications . Longer follow-up is necessary in order to better evaluate the results of this procedure INTRODUCTION Lateral tenodesis ( LT ) is performed to limit the risk of iterative tear following anterior cruciate ligament ( ACL ) reconstruction in at-risk patients . By adding an extra procedure to isolated ACL graft , LT reconstruction increases operating time and may complicate postoperative course . The objective of the present study was to evaluate the rate of early complications . The study hypothesis was that associating ALL reconstruction to ACL reconstruction does not increase the complications rate found with isolated ACL reconstruction . MATERIAL AND METHODS A prospect i ve multicenter study included 392 patients : 70 % male ; mean age , 29.9 years ; treated by associated ACL and LT reconstruction . All adverse events were inventoried . RESULTS Mean hospital stay was 2 days , with 46 % day-surgery . Walking was resumed at a mean 27 days , with an advantage for patients treated by the hamstring technique . The early postoperative complications rate was 12 % , with 1.7 % specifically implicating LT reconstruction : pain , hematoma , stiffness in flexion and extension , and infection . There was a 5 % rate of surgical revision during the first year , predominantly comprising arthrolysis for extension deficit . The 1-year recurrence rate was 2.8 % . DISCUSSION The complications rate for combined intra- and extra-articular reconstruction was no higher than for isolated intra-articular ACL reconstruction , with no increase in infection or stiffness rates . The rate of complications specific to ALL reconstruction was low , at 1.7 % , and mainly involved fixation error causing lateral soft-tissue impingement . LEVEL OF EVIDENCE IV , prospect i ve multicenter study

: Several interventions have been developed to improve health for people with low literacy .

Abstract OBJECTIVE : To perform a systematic review of interventions design ed to improve health outcomes for persons with low literacy skills .

PURPOSE A comprehensive worksite health promotion program design ed to reduce risk factors for cardiovascular disease among 4000 city of Birmingham employees was used to develop and implement a tailored antihypertensive educational intervention . The mean age of the underlying population was 36 years , 89 % were blue-collar or unskilled workers , 50 % were African Americans and 20 % were female . METHODS First , we identified barriers to hypertension control : low literacy , difficulty underst and ing the need for treatment of asymptomatic disease , and wide variability of health beliefs and priorities . We then tailored an educational program , which offered employees health education sessions on a variety of different topics , including heart disease , cancer , sleep disorders and back injury . All program material s focused on lifestyle changes and the need to seek medical care . This program was offered to all hypertensive workers ; 130 chose to enroll , and 81 completed the program . These 81 participants were matched by age , sex , race and baseline BP with nonparticipating hypertensive workers ( controls ) . Changes in SBP and DBP from before to after the educational program were used to evaluate the program . RESULTS Overall , intervention participants had a decrease of 4.5 mm Hg in mean SBP ( different from zero , [ p = 0.03 ] ) . African American participants showed a significant decrease ( 7.4 mm Hg , [ p = 0.004 ] ) , as did unskilled intervention participants ( SBP changes = 7.7 mm Hg , [ p = 0.004 ] ) . Although not statistically significant , controls showed decreases in BP in the same direction . CONCLUSION An educational intervention tailored to the specific health perceptions and working conditions of a low literacy population is feasible , and may have a significant effect on hypertension control A nutrition intervention focused on low-fat eating pattern changes was conducted among low-literacy participants in a Twin Cities Metropolitan area Exp and ed Food and Nutrition Education Program ( EFNEP ) . A total of 134 EFNEP participants who participated in the intervention were compared to 70 comparison participants who received EFNEP nutrition education material s. Associations between changes in outcome variables specific to the intervention were evaluated using mixed-model regression analyses . The principal effects seen for this program were related to changes in eating pattern scales . More modest effects were seen in scales related to attitudes of low-fat eating , and although changes in dietary fat intake as measured by 24-hour dietary interviews suggested a positive intervention effect , this did not approach statistical significance We used a r and omized trial to compare two polio vaccine pamphlets written on a sixth grade level -- the vaccine information statement prepared by the Centers for Disease Control ( CDC ) and an easy-to-read pamphlet we developed (LSU)--for reading ability , comprehension and preference among 610 parents with a broad range of demographic characteristics . Parents at all reading levels and incomes preferred LSU ( 76 % vs. 21 % , P < 0.001 ) . Although readers of LSU achieved significantly higher comprehension ( 65 % vs. 60 % , P < 0.05 ) this difference may not be clinical ly significant . The information items presented with instructional graphics were the only items on which differences in comprehension levels achieved both clinical and statistical significance . Comprehension was lowest for the CDC m and ated information on risks and the National Injury Compensation . Our findings demonstrate that simplifying written immunization material and making it more suitable will increase appeal , but such modification may not raise comprehension to an acceptable level without use of instructional graphics . Health education material s intended for general parent population s , which are written on a sixth grade reading level , may not adequately educate parents or prepare them for a discussion with their physicians CONTEXT Pneumococcal immunization rates for elderly and high-risk patients are only one third to one half the target rate of 60 % established by the US Public Health Service . Limited or marginal literacy , which affects nearly 100 million Americans , especially the elderly , may contribute to these low rates of immunization . OBJECTIVE To determine whether the use of a simple , low-literacy educational tool enhances patient-physician dialogue about pneumococcal vaccination and increases rates of immunization . DESIGN A r and omized controlled trial conducted between May and June of 1998 . SETTING Ambulatory care clinic of a 900-bed public teaching hospital serving a predominantly indigent , low-literate , African American , inner-city population . PARTICIPANTS Of 433 patients who presented for routine primary care , had vaccine indications ( age > or = 65 years or chronic disease ) , and had not been previously vaccinated , 221 were r and omly assigned to the intervention group and 212 to the control group . Of the total patient population ( mean age , 63 years ) , 280 ( 64.7 % ) had less than a high school education , 401 ( 92.6 % ) were African American , and 300 ( 69.3 % ) were female . INTERVENTION One-page , low-literacy ( below fifth- grade level ) educational h and out encouraging patients to " ask your doctor about the pneumonia shot " vs a control group ( 1 -page , low-literacy educational h and out conveying information about nutrition ) . MAIN OUTCOME MEASURES Vaccination rates ( documented by chart audit ) of patients who received pneumococcal vaccination and rates of patients who self-reported having discussed vaccination with their physicians . RESULTS Patients in the intervention group were 4 times more likely to have discussed the pneumococcal vaccine with their physicians than patients in the control group ( 87/221 [ 39.4 % ] vs 21/212 [ 9.9 % ] ; relative risk [ RR ] , 3.97 [ 95 % confidence interval [ CI ] , 2.71 - 5.83 ] ) , and were more than 5 times as likely to have received the pneumococcal vaccine than the control group ( 44/221 [ 19.9 % ] vs 8/212 [ 3.8 % ] ; RR , 5.28 [ 95 % CI , 2.80 - 9.93 ] ) . In a multivariate analysis controlling for race , sex , education , insurance status , age , level of physician training , health status , and vaccine indication , only assignment to the intervention group was statistically significantly related to the probability of being immunized or discussing the issue with their physicians ( P<.001 for both trends ) . CONCLUSIONS A simple , low-literacy educational tool increased pneumococcal vaccination rates and patient-physician discussion s about the vaccine in an elderly , low-literate , indigent , minority population OBJECTIVES This study was undertaken to test the effectiveness of the Stanford Nutrition Action Program , an experimental trial to reduce dietary fat intake among low-literacy , low-income adults . METHODS Twenty-four paired adult education classes ( 351 participants , 85 % women , mean age = 31 years ) were r and omly assigned to receive a newly developed dietary fat curriculum ( the Stanford Nutrition Action Program ) or an existing general nutrition curriculum . Food frequency and nutrition-related data , body mass index , and capillary blood cholesterol were collected at baseline and at two postintervention follow-ups . RESULTS The Stanford Nutrition Action Program classes showed significantly greater net improvements in nutrition knowledge ( + 7.7 ) , attitudes ( /0.2 ) , and self-efficacy ( -0.2 ) than the general nutrition classes ; they also showed significantly greater reductions in the percentage of calories from total ( -2.3 % ) and saturated ( -0.9 % ) fat . There were no significant differences in body mass index or blood cholesterol . All positive intervention effects were maintained for 3 months postintervention . CONCLUSIONS The Stanford Nutrition Action Program curriculum , tailored to the cultural , economic , and learning needs of low-literacy , low-income adults , was significantly more effective in achieving fat-related nutritional changes than the general nutrition curriculum The effect of the readability level of patient drug information material s on patient comprehension of and attitude toward the information was studied . The reading level of 108 out patients at a Veterans Administration hospital who could read English , read type of normal size , and who were not receiving warfarin sodium was measured . Patients then were given , on a r and om basis , a warfarin drug monograph written on either the 5th- or 10th- grade level . To test comprehension , all subjects took a true-false test of recall written at the 5th- grade level . A significant relationship was found between comprehension and reading ability ( p less than 0.001 ) . Patients receiving the 5th- grade level monograph exhibited significantly better comprehension than those receiving the 10th- grade level material ( p less than 0.001 ) . As compared with those getting 10th- grade material , the group receiving the 5th- grade material had a more favorable perception of the level of difficulty , underst and ability , and clarity of the material . The study indicates that comprehension of written patient drug information can be improved by adjusting the readability of informational material s to the reading level of the patients We investigated whether printed or videotaped information is more effective in enhancing colon cancer knowledge . Subjects ( n = 1100 ) were r and omized into three groups : to receive a booklet , view a videotape , or receive no intervention . Subjects receiving the intervention showed increased knowledge compared with control subjects ( booklet = 23 % and videotape = 26 % vs no intervention = 3 % ) . Findings suggest that personalized educational material s are effective in enhancing colon cancer knowledge A r and omized controlled trial was conducted to determine whether an education program specifically design ed for patients with non-insulin-dependent diabetes and limited literacy could improve and sustain glucose and weight control . From a referral clinic , 120 obese ( > 130 per cent of ideal body weight ) diabetic patients who were not taking insulin were recruited . Of these , 55 per cent were female and 49 per cent were black ; the mean age was 53 years . Mean glycosylated hemoglobin ( HbA1 % ) was 10.2 per cent . Each subject was assigned to one of three groups : 1 ) monthly group sessions with videotapes for diabetic persons with low literacy skills ; 2 ) monthly group sessions without videotapes ; or 3 ) no monthly sessions . After seven months , there had been 16 dropouts ( 13 per cent ) . Differences in weight changes between groups were significant ( p<0.05 ) ; group 1 lost a median of 1 kg of weight ( p<0.05 ) compared with a 0.1-kg loss and no change in groups 2 and 3 , respectively . This weight loss was not sustained at 11 months . There was no significant change in HbA1 % . Age , education , and compliance beliefs did not predict outcome . The authors conclude that the patient education programs did not result in sustained glucose or weight control Research suggests that much of the available health education literature requires a level of reading ability that makes it inaccessible to a large proportion of the population in greatest need of health information . The present study tested the value of illustrations and a narrative text style as means of improving the readability of a brochure design ed to provide information on cervical cancer and condyloma . Two versions of the brochure were design ed , one that had only text presented as simple sentences in bullet-type format ( SMOG reading level score of 7.7 ) , and a second version that had somewhat more difficult text formatted in a narrative style ( SMOG grade level score of 8.4 ) together with drawings design ed to complement the text . A r and omized study design was used to test for comprehension , perceived ease of underst and ing , and overall rating of the two brochures . Women selected from one private and three public health primary -care clinics were r and omly assigned to read one of the two brochures . The brochure with illustrations and narrative text was given a significantly higher overall rating than the one with bullet-type text and no illustrations , while no difference was found in perceived ease of reading . Among poor readers , comprehension was significantly greater for women who read the brochure with illustrations and narrative text , with no difference in comprehension of the two brochures for better readers . The results suggest that the use of aids such as illustrations and text style can make health education literature more accessible to high-risk population s , while remaining interesting enough to appeal to individuals at all levels of reading ability The authors explored changes in dietary behavior , nutrition knowledge , and parental support among inner-city , low-income , Hispanic American families . Thirty-eight families were r and omly assigned to receive a 12-week , culture-specific dietary intervention or be in a control group . Results showed that parental support was related to changes in diet , nutrition knowledge , and attendance for both mothers and children . Dietary behavior changes ( e.g. , reduction in dietary fat ) were seen only in the treatment group . Distribution of health-related pamphlets to the control group may have promoted cognitive changes ( e.g. , increased nutrition knowledge ) seen in this low-literacy sample . Further research is needed to document behavioral changes after ethnic-specific interventions and the maintenance of those changes over time BACKGROUND Medication adherence by older adults who are discharged from the emergency department ( ED ) is an essential attribute of effective treatment . Research ers have demonstrated that delivery of well-structured instructions increases the knowledge of discharge regimens and increases adherence among ED population s. OBJECTIVES This study compared the level of medication knowledge of elderly ED patients receiving instruction by one of two teaching methods : the usual preprinted discharge instructions with h and written medication information and individualized computer-generated discharge instructions design ed within a geragogy framework . METHOD The geragogy intervention included large-print , easily readable , specific information ordered within the elderly memory schema . This schema consists of purpose , administration , and emergency information in that order . The Knowledge of Medication Subtest by Horn and Swain ( 1977 ) was administered by telephone 48 to 72 hours after discharge . Sixty patients ( 38 women , 22 men ) with a mean age of 76 years were r and omly assigned to groups and completed the study at three rural ED sites . RESULTS Subjects in the geragogy-based intervention group demonstrated significantly more knowledge of medications than did subjects experiencing the usual discharge teaching method ( t = 2.19 , p = .016 ) . CONCLUSIONS These findings suggest that a medication teaching intervention geared to the special needs of the elderly can be effective in increasing medication knowledge The purpose of this project was to develop and test culturally appropriate , low literacy , smoking cessation intervention material s design ed to increase quit rates and prevent relapse postpartum for low-income African American and Hispanic women . A quasi-experimental , pretest-posttest design was used . Four Women , Infants , and Children ( WIC ) clinic sites in south and central Los Angeles were identified , pair-matched based on ethnic mix , and r and omized to intervention ( 2 sites ) or control status ( 2 sites ) . Participants were 18 years of age or older and either current or exsmokers ( stopped smoking in the past year ) . The intervention group received the " Time for a Change : A Program for Healthy Moms and Babies " program including a 15-minute one-to-one counseling session and self-help guide , incorporating behavior-change strategies , booster postcard , and incentive contest . All material s were design ed to match the cultural , language , and literacy needs of the target population . The smoking cessation intervention had a positive impact on both quit-smoking behavior during pregnancy and relapse prevention postpartum . Almost twice as many smokers in the intervention group ( 43 % ) reported quitting smoking at 9 months , compared to the control group ( 25 % ) ( P < 0.01 ) . At 6 weeks postpartum , 25 % of the intervention baseline smokers were abstinent , compared to 12 % of the control group ( P < 0.01 ) . Although no significant differences were observed for relapse during pregnancy among exsmokers at 6 weeks postpartum , a significantly higher proportion of intervention exsmokers were still abstinent ( 79 % ) , compared to control exsmokers ( 62 % ) ( P < 0.01 ) . For the exsmokers , relapse prevention rates remained significant when adjusted for cotinine vali date d abstinence . ( ABSTRACT TRUNCATED AT 250 WORDS Changes after 2 years in a Head Start Family Service Center Demonstration Project were assessed through pre-implementation and postimplementation interviews with 80 parents of Head Start children to evaluate changes during the project noted for the children 's parents . Compared with parents in regular Head Start , parents in the supplementary Family Service Center project reported more contact with staff , increased their functional literacy scores , and increased their family incomes . The percentage of these parents with high depression scores decreased . These changes encourage implementation of more intensive social services within Head Start programs as a means of effectively assisting Head Start parents Medication knowledge and compliance among the elderly was examined using a color-coded method , which was design ed to tailor the medication regimen to the person 's daily schedule . Data were collected from 80 elderly , predominantly indigent , and individuals of low literacy . Group 1 of the study received verbal teaching only , whereas Group 2 received verbal teaching and a color-coded medication schedule . Knowledge increased significantly among both groups . Compliance to the medication schedule increased in Group 2 , among those subjects whose pretest compliance scores were low . These results suggest that a method that considers the characteristics of the individual can significantly increase knowledge and compliance UNLABELLED Development and pilot testing of a disease management program for low literacy patients with heart failure . BACKGROUND R and omized trials have shown that disease management programs can reduce hospitalizations and improve symptoms for patients with congestive heart failure . We sought to create and pilot test such a program for patients with low literacy skills . METHODS We used focus groups and individual cognitive response interviews ( CRIs ) to develop an educational booklet for low literacy patients with heart failure . We incorporated the booklet into a disease management intervention that also included an initial individualized 1-h educational session and scheduled supportive phone calls that were tapered over 6 weeks . We then conducted a 3-month before-after study on patients with low literacy skills ( < 9th grade literacy level ) in a university internal medicine clinic to test the acceptability and efficacy of our program . Outcomes of interest included heart failure-related knowledge , self-care behavior and heart failure-related symptoms measured on the Minnesota Living with Heart Failure ( MLwHF ) scale . RESULTS Twenty-five patients were enrolled and 23 ( 92 % ) completed 3-month follow-up . Mean age was 60 years ( range 35 - 74 ) , 60 % were men , 60 % were African-American , and 74 % had household income under $ 15,000 per year . The median reading level was fifth grade with 32 % reading at or below the third grade level . Mean knowledge score at baseline was 67 % and did not improve after the intervention . The proportion of patients reporting weighing themselves daily increased from 32 % at baseline to 100 % at 12 weeks . Mean improvement on the MLwHF scale was 9.9 points over the 3-month trial ( 95 % CI : 0.5 , 19.2 ) , which corresponds to an improvement in one class on the New York Heart Association heart failure scale . CONCLUSION A heart failure disease management program design ed specifically for patients with low literacy skills is acceptable and is associated with improvement in self-care behavior and heart failure related symptoms PURPOSE / OBJECTIVES To develop and test an interactive multimedia module prototype design ed to accommo date adults with limited literacy and without computer skills . DESIGN Experimental , r and omized , controlled , pretest , post-test . SETTING Cancer treatment centers in California , Louisiana ( pilot ) . New Hampshire , Pennsylvania , and Texas . SAMPLE Out patients who were at least 18 years old with a minimum fifth- grade reading level ; 86 experimental treatment , 88 control . METHODS Experimental treatment involved use of the interactive multimedia module ; the control group received customary Instruction . FINDINGS As compared to the control group , subjects in the experimental group had significant improvement ( p = 0.0001 ; 257 % gain ) in self-care ability regardless of age , sex race , education , geographic location , reading ability , computer experience , or preferred learning style ; a 6.515 % increase in fatigue content covered and 16.775 % Increase in instructional duration ; and significantly greater benefit from sleep-related activities and a consistent , positive pattern of self-care behavior . CONCLUSIONS The program is instructionally effective , appropriate for a wide and geographically diverse audience , and feasible for use in the ambulatory setting . IMPLICATION S FOR NURSING PRACTICE The interactive multimedia module is an effective , self-directed re source for individualized patient fatigue education OBJECTIVE To evaluate a cardiovascular nutrition education package design ed for African-American adults with a wide range of literacy skills . DESIGN Comparison of a self-help group and a full-instruction group ; each group received nutrition counseling and clinical monitoring every 4 months . SUBJECTS Three hundred thirty African-American adults , aged 40 to 70 years , with elevated cholesterol level or high blood pressure were r and omly assigned to the self-help or full-instruction group ; 255 completed the 12-month follow-up . INTERVENTIONS Counseling to reduce intake of dietary fat , cholesterol , and sodium was based on Cardiovascular Dietary Education System ( CARDES ) material s , which included food-picture cards , a nutrition guide ( self-help and full-instruction group ) , a video and audiotape series , and 4 classes ( full-instruction group only ) . MAIN OUTCOME MEASURES Changes in lipid levels and blood pressure after 12 months . STATISTICAL ANALYSES PERFORMED Primary analyses consisted of repeated- measures analysis of variance to examine effects of time and r and omization group on outcomes . RESULTS Total cholesterol and low-density lipoprotein cholesterol level decreased by 7 % to 8 % in the self-help and full-instruction groups of men and women ( P < .01 ) . The ratio of total cholesterol to high-density lipoprotein cholesterol ( HDL-C ) decreased in both groups of women and in the men in the full-instruction group ( P < .01 ) . In full-instruction and self-help participants with elevated blood pressure at baseline , systolic blood pressure decreased by 7 to 11 mm Hg and diastolic blood pressure decreased by 4 to 7 mm Hg ( P < .01 ) . Outcomes did not differ by literacy scores but were positively related to the reported initial frequency of using CARDES material s. APPLICATIONS/ CONCLUSIONS These results suggest that periodic nutrition counseling based on CARDES material s used for home study can enhance management of lipid levels and blood pressure in African-American out patients Abstract OBJECTIVE : To study the effects of three approaches to increasing utilization of screening mammography in a public hospital setting in Northwest Louisiana . DESIGN : R and omized intervention study . POPULATION : Four hundred forty-five women aged 40 years and over , predominantly low-income and with low literacy skills , who had not had a mammogram in the preceding year . INTERVENTION : All interventions were chosen to motivate women to get a mammogram . Group 1 received a personal recommendation from one of the investigators . Group 2 received the recommendation plus an easy-to-read National Cancer Institute ( NCI ) brochure . Group 3 received the recommendation , the brochure , and a 12-minute interactive educational and motivational program , including a soap-operastyle video , developed in collaboration with women from the target population . MEASUREMENTS AND MAIN RESULTS : Mammography utilization was determined at 6 months and 2 years after intervention . A significant increase ( p=.05 ) in mammography utilization was observed after the intervention design ed in collaboration with patients ( 29 % ) as compared with recommendation alone ( 21 % ) or recommendation with brochure ( 18 % ) at 6 months . However , at 2 years the difference favoring the custom-made intervention was no longer significant . CONCLUSIONS : At 6 months there was at least a 30 % increase in the mammography utilization rate in the group receiving the intervention design ed in collaboration with patients as compared with those receiving the recommendation alone or recommendation with brochure . Giving patients an easy-to-read NCI brochure and a personal recommendation was no more effective than giving them a recommendation alone , suggesting that simply providing women in a public hospital with a low-literacy-level , culturally appropriate brochure is not sufficient to increase screening mammography rates . In a multivariate analysis , the only significant predictor of mammography use at 6 months was the custom-made intervention

Subgroup analyses by parity ( primiparae versus multiparae ) and by surgical method ( midline versus mediolateral episiotomy ) did not identify any modifying effects . One trial examined selective episiotomy compared with routine episiotomy in women where an operative vaginal delivery was intended in 175 women , and did not show clear difference on severe perineal trauma between the restrictive and routine use of episiotomy , but the analysis was underpowered . Authors ' conclusions In women where no instrumental delivery is intended , selective episiotomy policies result in fewer women with severe perineal/vaginal trauma . Other findings , both in the short or long term , provide no clear evidence that selective episiotomy policies results in harm to mother or baby . The review thus demonstrates that believing that routine episiotomy reduces perineal/vaginal trauma is not justified by current evidence .

Background Some clinicians believe that routine episiotomy , a surgical cut of the vagina and perineum , will prevent serious tears during childbirth . On the other h and , an episiotomy guarantees perineal trauma and sutures . Objectives To assess the effects on mother and baby of a policy of selective episiotomy ( ' only if needed ' ) compared with a policy of routine episiotomy ( ' part of routine management ' ) for vaginal births .

OBJECTIVE : To compare the outcomes of the current practice of liberally or routinely employing episiotomy to prevent perineal tears and pelvic floor relaxation ( control group ) to a policy of restricting episiotomy use to specific fetal and maternal indications ( experimental group ) . DESIGN : A r and omized controlled trial ( RCT ) . SETTING : Three university hospitals in Montreal . SUBJECTS : Seven hundred three low-risk women enrolled at 30 to 34 weeks of gestation were r and omized late in labor to the design ated trial arm , by parity , and followed up to 3 months postpartum . MAIN OUTCOME MEASURES : Antepartum and postpartum information on perineal trauma and pain , pelvic floor symptoms ( urinary incontinence ) , and sexual activity was collected through the use of st and ard question naires ; pelvic floor function was measured by electromyographic ( EMG ) perineometry . RESULTS : Restricting episiotomy use in primiparous women was associated with similar sutured perineal trauma to the liberal or routine approach . Multiparous women in the restricted episiotomy group more often gave birth with an intact perineum ( 31 % compared with 19 % , odds ratio ( OR ) = 1.85 , 95 % confidence interval ( CI ) = 1.09 to 3.16 ) . All but one 3rd/4th-degree perineal tear was associated with median episiotomy ( 46 of 47 in primiparous women and 6 of 6 among multiparous women ) . No difference between trial groups was found in postpartum perineal pain , antepartum and 3-month postpartum EMG perineometry , and urinary and pelvic floor symptoms . CONCLUSIONS : We found no evidence that liberal or routine use of episiotomy prevents perineal trauma or pelvic floor relaxation . Virtually all severe perineal trauma was associated with median episiotomy . Restriction of episiotomy use among multiparous women result ed in significantly more intact perineums and less perineal suturing Background Despite all the evidence corroborating the selective use of episiotomy and although routine use of the procedure is contraindicated , there are no evidence s corroborating if episiotomy is necessary in any circumstance . The present clinical r and omized trial was performed to compare maternal and perinatal outcomes in women su bmi tted to a non-episiotomy protocol versus one of selective episiotomy . Methods An open-labelled , r and omized clinical trial was carried out in a tertiary teaching hospital in Recife , Northeastern Brazil . Women in labor with a full-term live foetus , dilatation of 6 to 8 cm and cephalic presentation ( vertex position ) were included . Exclusion criteria consisted of bleeding disorders and an indication for a caesarean section . After signing the consent form , 241 women were r and omized to a non-episiotomy protocol ( the experimental group ) or to a selective episiotomy group ( the control group ) . No episiotomies were to be performed in the experimental group except under exceptional circumstances . In the control group , selective episiotomies were to be performed in accordance with the healthcare professionals ’ clinical judgement . Maternal and perinatal outcomes were evaluated . Ratio Risk ( RR ) and the 95 % confidence interval ( 95 % CI ) were calculated for our outcomes . Results The analysis include 115 women assigned to a non-episiotomy protocol and 122 to selective episiotomy . There was no difference between the two groups with respect to maternal or perinatal outcomes . The episiotomy rate was similar ( two cases in each group , about 1.7 % ) , as was the duration of the second stage of labor , the frequency of perineal tears , severe perineal trauma , need for perineal suturing and blood loss at delivery . Conclusions A non-episiotomy protocol appears to be safe for mother and child , and highlights the need to investigate whether there is , in fact , any indication for this procedure . Trial registration This trial was registered at Clinical Trials.gov under reference number ( NCT02178111 ) OBJECTIVE To evaluate the prevalence of obstetrical anal sphincter injuries ( OASIS ) , which include third and fourth degree perineal tears in primigravida in routine versus selective mediolateral episiotomy . Secondly , to determine the rate of episiotomy in local setting s. METHODS This r and omized control trial was carried out in the labor ward of a tertiary hospital of the Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia between May and October 2009 . The trial included 171 primigravida beyond 38 weeks gestation who achieved vaginal delivery , and r and omly assigned to selective and routine episiotomy groups . The type of perineal injuries following childbirth among 171 women were evaluated . RESULTS The overall episiotomy rate from both groups was 76.6 % . The prevalence of third degree perineal tears was 3.7 % in the routine compared with selective mediolateral episiotomy at 1.1 % . There was no occurrence of fourth degree tears in both groups . However , selective mediolateral episiotomy was associated with an increased risk of periurethral and labial injury compared with the routine group ( 4.5 % versus 0 % ) . CONCLUSION Routine mediolateral episiotomy in primigravida is associated with a higher prevalence of obstetrical anal sphincter injuries . As anal sphincter injuries are known to have morbidities , selective mediolateral episiotomy in primigravida is therefore recommended in the implementation of new delivery practice , and in an attempt to reduce our high episiotomy rate OBJECTIVE To evaluate short-term perineal pain among primiparous women after mediolateral episiotomy ( MLE ) and lateral episiotomy ( LE ) . METHODS The prospect i ve r and omized study was conducted in the Czech Republic during 2010 - 2012 . Consecutive primiparous women who gave birth at or after 37 weeks of pregnancy and had indications for an episiotomy were enrolled and r and omly assigned to undergo MLE or LE . Patients were unaware of the episiotomy type performed . The primary outcomes were pain at 24 hours , 72 hours , and 10 days post partum , measured by a visual analog scale , verbal rating scale , interference with activities of daily living , and amount of analgesic use . RESULTS The analysis included 266 women who underwent MLE and 297 women who underwent LE . Complete relief of pain was observed in 6 ( 2.3 % ) of 266 women after 24 hours , 21 ( 8.0 % ) of 264 after 72 hours , and 77 ( 29.1 % ) of 265 after 10 days in the MLE group , and in 11 ( 3.9 % ) of 285 , 23 ( 7.7 % ) of 297 , and 78 ( 26.4 % ) of 295 in the LE group , respectively ( P=0.36 ) . There were no significant differences in overall pain scores from any rating system or in the amount of analgesics used . CONCLUSION Incidence and extent of pain in the first 10 days after LE correspond to those after adequately performed MLE Background . The influence of the restrictive use of episiotomy at perineal tears judged to be imminent on the urethral pressure profile , analmanometric , and other pelvic floor findings is unknown Introduction Episiotomy angle is a crucial factor in causation of obstetric anal sphincter injuries ( OASIS ) , which are the major cause of female bowel incontinence . Sutured episiotomies angled too close to the midline ( < 30 degree ) or too far away from the midline ( > 60 degree ) fail to unload the perineum sufficiently and predispose to OASIS . A 25-degree post-delivery episiotomy suture angle has a 10 % risk of OASIS while 45-degree episiotomy is associated with 0.5 % risk . To account for perineal distension at crowning , a 60-degree episiotomy incision is required to achieve 43–50 degree suture angles . We compared episiotomy suture angles with commonly used Braun-Stadler episiotomy scissors with the new fixed angle EPISCISSORS-60 ® . Methods Ethical approval was obtained . A prospect i ve cluster r and omization design was chosen . Thirty-one patients were required in each group for a 12-degree difference with power at 90 % and 5 % significance . Sutured episiotomy angles and post-delivery linear distance from caudal end of the sutured episiotomy to the anus were measured with protractors and rulers . Two-tailed t-tests were used to compare the two groups . Results Thirty-one nulliparae had episiotomies with EPISCISSORS-60 ® , 32 with Braun-Stadler . Mean age ( 25 versus 24.8 years ) was similar . EPISCISSORS-60 ® episiotomies were angled 12 degrees more laterally away from the anus compared to Braun-Stadler ( 40.6 degrees , 95 % confidence interval [ CI ] ±2 , interquartile range [ IQR ] 35–45 versus 28.3 degrees , 95 % CI ±2 , IQR 25–30 , P<0.0001 ) . The post-delivery linear distance from caudal end of the sutured episiotomy to the anus was 15 mm more with the EPISCISSORS-60 ® compared to Braun-Stadler ( 35 mm , 95 % CI ±2.2 , IQR = 30–39 versus 19.5 ; 95 % CI ±1.3 , IQR = 14.75–22.25 P<0.0001 ) . EPISCISSORS-60 ® episiotomies measured longer ( 47 mm versus 40 mm , P<0.0001 ) . There were no OASIS cases in the EPISCISSORS-60 ® group versus one in the Braun-Stadler group . Conclusion The EPISCISSORS-60 ® sutured episiotomies are much further away from the midline in angular and distance measures , hence at lower OASIS risk OBJECTIVE To evaluate the incidence and extent of vaginal and perineal trauma among primiparous women after mediolateral and lateral episiotomy . METHODS In a prospect i ve r and omized study at University Hospital Pilsen , Czech Republic , 790 consecutive primiparous women were enrolled between April 2010 and April 2012 . Mediolateral episiotomy ( MLE ) followed an angle of at least 60 ° from the midline . Lateral episiotomy ( LE ) started 1 - 2 cm laterally from the midline and was directed toward the ischial tuberosity . A rectal examination was performed before episiotomy repair . RESULTS MLE was performed for 390 women , and LE for 400 . The groups did not differ in maternal or neonatal characteristics . No difference was found in incidence or extent of vaginal and perineal trauma ; or in additional perineal ( 1.8 % vs 1.5 % , P=0.6 ) or vaginal ( 8.5 % vs 10.6 % , P=0.2 ) trauma continuing along the episiotomy incision . The incidence of anal sphincter injury did not differ between MLE and LE ( 1.5 % vs 1.3 % , P=0.7 ) . MLE was associated with shorter repair times ( P<0.05 ) , less suturing material ( P<0.05 ) , and shorter distances from the anus ( P<0.001 ) . CONCLUSION Risk of additional vaginal and perineal trauma , and anal sphincter injury after adequately performed mediolateral episiotomy is relatively low and corresponds to that of lateral episiotomy OBJECTIVE To evaluate whether physicians ' beliefs concerning episiotomy are related to their use of procedures and to differential outcomes in childbirth . DESIGN Post-hoc cohort analysis of physicians and patients involved in a r and omized controlled trial of episiotomy . SETTING Two tertiary care hospitals and one community hospital in Montreal . PARTICIPANTS Of the 703 women at low risk of medical or obstetric problems enrolled in the trial we studied 447 women ( 226 primiparous and 221 multiparous ) attended by 43 physicians . Subjects attended by residents or nurses were excluded . MAIN OUTCOME MEASURES PATIENTS intact perineum v. perineal trauma , length of labour , procedures used ( instrumental delivery , oxytocin augmentation of labour , cesarean section and episiotomy ) , position for birth , rate of and reasons for not assigning women to a study arm , postpartum perineal pain and satisfaction with the birth experience , physicians : beliefs concerning episiotomy . RESULTS Women attended by physicians who viewed episiotomy very unfavorably were more likely than women attended by the other physicians to have an intact perineum ( 23 % v. 11 % to 13 % , p < 0.05 ) and to experience less perineal trauma . The first stage of labour was 2.3 to 3.5 hours shorter for women attended by physicians who viewed episiotomy favourably than for women attended by physicians who viewed episiotomy very unfavorably ( p < 0.05 to < 0.01 ) , and the former physicians were more likely to use oxytocin augmentation of labour . Physicians who viewed episiotomy more favourably failed more often than those who viewed the procedure very unfavourably to assign patients to a study arm late in labour ( odds ratio [ OR ] 1.88 , p < 0.05 ) , both overall and because they felt that " fetal distress " or cesarean section necessitated exclusion of the subject . They used the lithotomy position for birth more often ( OR 3.94 to 4.55 , p < 0.001 ) , had difficulty limiting episiotomy in the restricted-use arm of the trial and diagnosed fetal distress and perineal inadequacy more often than the comparison groups . The patients of physicians who viewed episiotomy very favourably experienced more perineal pain ( p < 0.01 ) , and of those who viewed episiotomy favourably and very favourably experienced less satisfaction with the birth experience ( p < 0.01 ) than the patients of physicians who viewed the procedure very unfavourably . CONCLUSIONS Physicians with favourably views of episiotomy were more likely to use techniques to expedite labour , and their patients were more likely to have perineal trauma and to be less satisfied with the birth experience . This evidence that physician beliefs can influence patient outcomes has both clinical and research implication One hundred and eighty one primigravid women delivering vaginally in July and August 1982 in the Rotunda Hospital , Dublin , were r and omly allocated to one of two groups . Patients in one group were to undergo episiotomy . Those in the other group were not to undergo episiotomy unless it was considered to be essential . The outcome was compared with that of the clinical practice over the previous six months at the hospital . Of the 92 patients allocated not to undergo episiotomy , seven ( 8 % ) had one done for medical reasons compared with 507 ( 89 % ) in the previous six months . First degree tears occurred in 23 ( 25 % ) and second degree tears in 43 ( 47 % ) . Nineteen ( 21 % ) , however , retained an intact perineum compared with only 35 ( 6 % ) of the women who had delivered in the preceding six months . Assessment s of perineal pain , bruising , swelling , and healing and records of ingestion of analgesics were made for the first four days after delivery , and again at a check up six weeks after delivery , in patients who had had spontaneous vertex deliveries . Forty patients who underwent episiotomy and 37 who sustained a second degree tear formed two comparable groups . There was no difference in outcome between them . Data were also evaluated for 19 women who retained an intact perineum , 22 who sustained a first degree tear , and 11 who underwent episiotomy and epidural anaesthesia ; all 52 of these women had spontaneous vertex deliveries . Despite severe soft tissue injury in two patients those who fared best were those who retained an intact perineum . First degree tears were associated with symptoms similar to those associated with second degree tears . Those who fared worst were women who underwent episiotomy after epidural anaesthesia . The value of routine episiotomy in primigravid patients is question ed , but the final decision can be made only by the accoucheur at the time of imminent delivery OBJECTIVE To assess the morbidity from episiotomy . METHODS The prospect i ve r and omised control study was conducted at the Military Hospital Rawalpindi 's Gynaecology & Obstetrics Department from January 2006 to April 2008 . It comprised 100 patients who were given a mediolateral episiotomy at the crowning of the foetal head ( group 1 ) . Another group of 100 patients were delivered without an episiotomy ( group 2 ) . Postpartum morbidity was compared in the two groups . Morbidity included perineal damage by tears , subjective assessment of pain at perineum , dyspareunia after puerperium , feeling of pressure puerperium , incontinence and objective assessment of prolapse after puerperium . RESULTS Morbidity including perineal damage by tears , pain at perineum and dyspareunia , was much more in group I as compared to the group II . There was no significant difference in feeling of pressure perineum , subjective feeling of urinary and flatus incontinence or objective assessment of prolapse of vagina and uterus . CONCLUSION There are no significant advantages of episiotomy . In fact , it leads to morbidity which is otherwise avoidable in deliveries that are episiotomy-free OBJECTIVE The purpose of this study was to determine whether selective midline episiotomy contributes to the prevention of third- or fourth-degree perineal lacerations . STUDY DESIGN A r and omized controlled clinical trial was performed with 446 nulliparous women with deliveries after 28 weeks of pregnancy . Patients were r and omized to undergo either routine episiotomy or selective episiotomy . In the selective episiotomy group , episiotomies were performed only in cases of imminent lacerations , fetal distress , or forceps delivery . RESULTS In the group of 223 patients who underwent routine episiotomy , 32 ( 14.3 % ) had third- or fourth-degree perineal lacerations , as compared to 15 ( 6.8 % ) in the group of 222 patients undergoing selective episiotomy ( relative risk , 2.12 ; 95 % confidence interval , 1.18 - 3.81 ) . Only reduction in third-degree lacerations was significant when analyzed separately . Moreover , periurethral , labia minora , and superficial vaginal lacerations were significantly more frequent in the selective episiotomy group . CONCLUSION The policy of performing selective midline episiotomy in nulliparous patients results in a reduction in the risk of third-degree perineal lacerations OBJECTIVE Our purpose was to compare consequences for women of receiving versus not receiving median episiotomy early and 3 months post partum on the outcomes perineal pain , urinary and pelvic floor functioning by electromyography , and sexual functioning and to analyze the relationship between episiotomy and third- and fourth-degree tears . STUDY DESIGN A secondary cohort analysis was performed of participants within a r and omized clinical trial , analyzed by type of perineal trauma and pain , pelvic floor , and sexual consequences of such trauma , while controlling for trial arm . The study was conducted in three university or community hospitals ; 356 primiparous and 341 multiparous women were studied . RESULTS Early and 3-month-postpartum perineal pain was least for women who gave birth with an intact perineum . Spontaneous perineal tears were less painful than episiotomy . Sexual functioning was best for women with an intact perineum or perineal tears . Postpartum urinary and pelvic floor symptoms were similar in all perineal groups . At 3 months post partum those delivered with an intact perineum had the strongest pelvic floor musculature , those with episiotomy the weakest . Among primiparous women third- and fourth-degree tears were associated with median episiotomy ( 46/47 ) . After forceps births were removed and 21 other variables potentially associated within such tears were controlled for , episiotomy was strongly associated with third- and fourth-degree tears ( odds ratio + 22.08 , 95 % confidence interval 2.84 to 171.53 ) . Physicians using episiotomy at high rates also used other procedures , including cesarean section , more frequently . CONCLUSION Perineal and pelvic floor morbidity was greatest among women receiving median episiotomy versus those remaining intact or sustaining spontaneous perineal tears . Median episiotomy was causally related to third- and fourth-degree tears . Those using episiotomy at the highest rates were more likely use other interventions as well . Episiotomy use should be restricted to specified fetal-maternal indications Women who had participated in a r and omised controlled trial of policies of restricted ( 10 % ) versus liberal ( 51 % ) episiotomy during spontaneous vaginal delivery were recontacted by postal question naire three years after delivery . Altogether 674 out of 1000 responded , and there was no evidence of a differential response rate between the two trial groups . Similar numbers of women in the two groups reported further deliveries , almost all of which had been vaginal and spontaneous . Fewer women allocated to restrictive use of episiotomy required perineal suturing after subsequent delivery , but this difference was not significant . Pain during sexual intercourse and incontinence of urine were equally reported in the two groups . The similarity in incontinence rates persisted when severity , type of incontinence , and subsequent deliveries were taken into account . Liberal use of episiotomy does not seem to prevent urinary incontinence or increase long term dyspareunia One thous and women were allocated at r and om to one of two perineal management policies , both intended to minimise trauma during spontaneous vaginal delivery . In one the aim was to restrict episiotomy to fetal indications ; in the other the operation was to be used more liberally to prevent perineal tears . The result ant episiotomy rates were 10 % and 51 % respectively . An intact perineum was more common among those allocated to the restrictive policy . This group experienced more perineal and labial tears , however , and included four of the five cases of severe trauma . There were no significant differences between the two groups either in neonatal state or in maternal pain and urinary symptoms 10 days and three months post partum . Women allocated to the restrictive policy were more likely to have resumed sexual intercourse within a month after delivery . These findings provide little support either for liberal use of episiotomy or for cl aims that reduced use of the operation decreases postpartum morbidity The purpose of the study was to evaluate the influence of mediolateral episiotomy on the perineal state after spontaneous , singleton vaginal deliveries with the foetus in the occiput anterior position . The design was that of a population based , observational study . Two approaches were used in the analyses : Initially , we considered the parturients as quasi-r and omised to one of three equally sized groups of midwives with different attitudes towards episiotomy . Secondly , we studied the effect of episiotomy on the state of the anal sphincter , controlling for birth weight , parity , and duration of second stage of labour . The subjects were 2188 pregnant women delivering consecutively , and the main outcome measures were perineal lacerations and tearing of the anal sphincter . Women allocated to the group of midwives with the lowest rate of episiotomy were more likely to have an intact perineum after delivery ( OR = 1.8 ( 1.4 - 2.2 ) ) , had a slight tendency towards more perineal lacerations ( OR = 1.3 ( 1.0 - 1.5 ) ) , but no increased risk of tearing of the anal sphincter , compared with the women allocated to the two groups of midwives with higher frequencies of episiotomy . The second approach showed that episiotomy was related to an increased risk of tearing of the anal sphincter ( OR = 2.3 ( 1.2 - 4.6 ) ) . However , this relation was not found among the group of parturients delivered by the midwives with the lowest rate of episiotomy ( 22 % ) . Our results encourage a conservative approach to the use of mediolateral episiotomy , and in the light of previous findings , it seems reasonable to suggest that episiotomy should ideally be used in about one in five spontaneous vaginal deliveries AIM To compare two incision angles ( 60 ° vs 40 ° ) of mediolateral episiotomy in primiparous Egyptian women , regarding the incidence of anal sphincter injury as well as episiotomy-related pain and dyspareunia . METHODS The current prospect i ve r and omized controlled trial ( Clinical Trials.gov , NCT01930721 ) was conducted at Ain Shams University Maternity Hospital . Eligible women were r and omized into two groups : group 1 included women who had the episiotomy incision made at an angle of 60 ° to the midline ; and group 2 included women who had the episiotomy incision made at an angle of 40 ° to the midline . Primary outcome measures were differences in short-term related pain and rate of third/fourth degree perineal tears . RESULTS A total of 330 primiparous women were recruited . The shortest distance to the outer edge of the anal epithelium was significantly shorter in women of group 2 when compared to that in women of group 1 . Out of the included 330 women , 13 ( 4 % ) had third/fourth-degree perineal tears ( 4 [ 2.4 % ] in group 1 in contrast to nine [ 5.5 % ] in group 2 ) . This difference was not significant A 60 ° -angled mediolateral episiotomy was associated with significantly higher rates of moderate/severe episiotomy-related pain post-partum . The rates of moderate/severe episiotomy-related pain and dyspareunia assessed 6 months post-partum were also higher among women of group 1 , when compared to group 2 ; the latter two differences did not reach statistical significance , however . CONCLUSION When compared to the 40 ° -angled mediolateral episiotomies , 60 ° -angled ones were associated with significantly higher short-term-related pain . Although they were also associated with lower rate of third/fourth-degree perineal tears and higher rate of long-term related pain and dyspareunia , these differences did not reach a statistically significant level OBJECTIVES Comparison of the effects of two episiotomy types on sexual activity , dyspareunia and overall satisfaction after childbirth . STUDY DESIGN A prospect i ve follow-up study of a r and omized comparative trial evaluating peripartum outcome of a vaginal delivery after mediolateral ( MLE ) or lateral ( LE ) episiotomy . MAIN OUTCOME MEASURES The participants completed question naires regarding sexual activity , dyspareunia , perineal pain , aesthetic appearance and overall satisfaction 3 ( 3 M ) and 6 months ( 6 M ) postpartum . RESULTS A total of 648 women were available for the analyses ( 306 MLE , 342 LE ) . The groups showed no difference regarding resumption and regularity of sex , timing of resumption , frequency and intensity of dyspareunia , perineal pain , aesthetic appearance or overall satisfaction 3 M or 6 M postpartum . 98.0 % of women after MLE and 97.7 % after LE resumed sexual intercourse within 6 M after delivery ( p = 0.74 ) . In the same period 15.6 % of women after MLE and 16.1 % after LE suffered from considerable dyspareunia ( p = 0.86 ) . CONCLUSIONS Quality of sexual life and perception of perineal pain after MLE is equivalent to LE BACKGROUND Severe perineal tears sustained during childbirth cause significant distress and morbidity amongst women . The objective of this study was to compare the use of straight scissors for cutting an episiotomy with the use of curved scissors , which are design ed to curve away from the anal sphincter . METHODS We used a single-centre , r and omised feasibility trial . The intervention was the use of curved scissors . Women were recruited during a prenatal visit and r and omised in the delivery suite , when it became clear that an episiotomy was required . The feasibility outcomes were the proportion of women able to be recruited , r and omised and followed up . We also calculated the incidence of obstetric anal sphincter injury when either straight or curved scissors were used to cut an episiotomy . Other outcomes assessed were pain , length of hospital stay , perineal infection and perineal dehiscence . RESULTS Of the 155 patients recruited in the prenatal period , only 20 ( 12.9 % ) were eventually r and omised at birth . The main reasons for the high loss were that women either did not have a vaginal delivery ( 38 , 24.5 % ) , or they did not need an episiotomy ( 72 , 46.5 % ) . Rates of obstetric anal sphincter injury and other outcomes were similar between groups . DISCUSSION Anal sphincter injury during childbirth remains an important problem . Although the use of curved scissors provides a theoretical solution , we found that the high attrition rate made feasibility of conducting a suitably powered , r and omised trial using the current design untenable . Alternative strategies have been suggested to make any future study more viable

Blood lactate was significantly reduced in the levosimendan group while there was no difference in MAP , CI , norepinephrine dose and length of ICU stay . Conclusions Findings from this meta- analysis demonstrated that levosimendan treatment may not reduce mortality in patients with septic shock .

Object Several studies have investigated a survival benefit for levosimendan treatment in patients with septic shock . However , data are conflicting . We conducted a meta- analysis to evaluate the effect of levosimendan treatment on mortality in patients with septic shock .

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis . METHODS We conducted a double-blind , r and omized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis . Patients were r and omly assigned to receive a blinded infusion of levosimendan ( at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute ) for 24 hours or placebo in addition to st and ard care . The primary outcome was the mean daily Sequential Organ Failure Assessment ( SOFA ) score in the intensive care unit up to day 28 ( scores for each of five systems range from 0 to 4 , with higher scores indicating more severe dysfunction ; maximum score , 20 ) . Secondary outcomes included 28-day mortality , time to weaning from mechanical ventilation , and adverse events . RESULTS The trial recruited 516 patients ; 259 were assigned to receive levosimendan and 257 to receive placebo . There was no significant difference in the mean ( ±SD ) SOFA score between the levosimendan group and the placebo group ( 6.68±3.96 vs. 6.06±3.89 ; mean difference , 0.61 ; 95 % confidence interval [ CI ] , -0.07 to 1.29 ; P=0.053 ) . Mortality at 28 days was 34.5 % in the levosimendan group and 30.9 % in the placebo group ( absolute difference , 3.6 percentage points ; 95 % CI , -4.5 to 11.7 ; P=0.43 ) . Among patients requiring ventilation at baseline , those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days ( hazard ratio , 0.77 ; 95 % CI , 0.60 to 0.97 ; P=0.03 ) . More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia ( 3.1 % vs. 0.4 % ; absolute difference , 2.7 percentage points ; 95 % CI , 0.1 to 5.3 ; P=0.04 ) . CONCLUSIONS The addition of levosimendan to st and ard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality . Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia . ( Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others ; LeoPARDS Current Controlled Trials number , IS RCT N12776039 . ) Background — We determined the effects of levosimendan , a calcium sensitizer , on left ventricular ( LV ) diastolic function in patients with LV hypertrophy . Methods and Results — In this prospect i ve , r and omized , blinded study , 23 patients received either levosimendan ( 0.1 and 0.2 & mgr;g · kg−1 · min−1 ; n=12 ) or placebo ( n=11 ) after aortic valve replacement for aortic stenosis . The effects on LV performance , dimensions , filling patterns , and isovolumic relaxation time , as well as systemic hemodynamics , were assessed by pulmonary artery thermodilution catheterization and transesophageal 2-dimensional Doppler echocardiography . To circumvent the confounding effects of the levosimendan-induced hemodynamic changes on Doppler echocardiographic indexes of LV early relaxation , heart rate and mean arterial and central venous pressures were kept constant during levosimendan/placebo infusion by atrial pacing , vasopressor , and colloid infusions . In the levosimendan group , dose-dependent increases in cardiac output ( 28 % ; P<0.001 ) and stroke volume ( 26 % ; P<0.001 ) and a decrease in systemic vascular resistance ( −22 % ; P<0.001 ) were observed . There was a trend for an increase in LV ejection fraction ( 12 % ; P=0.058 ) with levosimendan . There were no significant differences in systolic , diastolic arterial , or LV filling pressures or LV end-diastolic area between the 2 groups . Isovolumic relaxation time decreased ( −23 % ; P<0.001 ) , as did the deceleration slope of early diastolic filling ( −45 % ; P<0.01 ) , whereas peak early diastolic filling velocity ( 16 % , P<0.01 ) and peak late diastolic filling velocity ( 15 % ; P<0.001 ) increased after levosimendan compared with placebo . Conclusion — Levosimendan , in addition to its inotropic effects , exerts a direct positive lusitropic effect in patients with LV hypertrophy as it shortens isovolumic relaxation time and improves LV filling Introduction The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug ( i.e. dobutamine ) . The primary end point was a difference of ≥ 20 % in the microvascular flow index of small vessels ( MFIs ) among groups . Methods The study was design ed as a prospect i ve , r and omized , double-blind clinical trial and performed in a multidisciplinary intensive care unit . After achieving normovolemia and a mean arterial pressure of at least 65 mmHg , 40 septic shock patients were r and omized to receive either levosimendan 0.2 μg·kg-1·min-1 ( n = 20 ) or an active comparator ( dobutamine 5 μg·kg-1·min-1 ; control ; n = 20 ) for 24 hours . Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging . Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after r and omization . Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test , as appropriate . Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test . Results Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group ( 24 hrs : MFIm 3.0 ( 3.0 ; 3.0 ) vs. 2.9 ( 2.8 ; 3.0 ) ; P = .02 ; MFIs 2.9 ( 2.9 ; 3.0 ) vs. 2.7 ( 2.3 ; 2.8 ) ; P < .001 ) . The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group ( dMFIm 10 ( 3 ; 23)% vs. 0 ( -1 ; 9)% ; P = .007 ; dMFIs 47 ( 26 ; 83)% vs. 10 ( -3 ; 27 ) ; P < .001 ) . In addition , the heterogeneity index decreased only in the levosimendan group ( dHI -93 ( -100 ; -84)% vs. 0 ( -78 ; 57)% ; P < .001 ) . There was no statistically significant correlation between systemic and microcirculatory flow variables within each group ( each P > .05 ) . Conclusions Compared to a st and ard dose of 5 μg·kg-1·min-1 of dobutamine , levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock , as reflected by changes in microcirculatory flow indices of small and medium vessels . Trial registration NCT00800306 Background We aim ed to investigate the effect of levosimendan on biomarkers of myocardial injury and systemic hemodynamics in patients with septic shock . Material / Methods After achieving normovolemia and a mean arterial pressure of at least 65 mmHg , 38 septic shock patients with low cardiac output ( left ventricular ejective fraction ) , LEVF ≤45 % ) were r and omly divided into two groups : levosimendan dobutamine . Patients in the levosimendan and dobutamine groups were maintained with intravenous infusion of levosimendan ( 0.2 μg/kg/minute ) and dobutamine ( 5 μg/kg/minute ) for 24 hours respectively . During treatment we monitored hemodynamics and LVEF , and measured levels of heart-type fatty acid binding protein ( HFABP ) , troponin I ( TNI ) , and brain natriuretic peptide(BNP ) . In addition , the length of mechanical ventilation , intensive care unit ( ICU ) stay , hospital stay , and 28-day mortality were compared between the two groups . Results The levosimendan group and the dobutamine group were well matched with respect to age ( years , 55.4±1 7.5 versus 50.2±13.6 ) and gender ( males , 68.4 % versus 57.9 % ) . Levosimendan-treated patients had higher stroke volume index ( SVI ) , cardiac index ( CI ) , LVEF , and left ventricular stroke work index ( LVSWI ) , and lower extravascular lung water index ( EVLWI ) compared to dobutamine-treated patients ( p<0.05 ) . HFABP , TNI , and BNP in the levosimendan group were less than in the dobutamine group ( p<0.05 ) . There was no difference in the mechanical ventilation time , length of stay in ICU and hospital , and 28-day mortality between the two groups . Conclusions Compared with dobutamine , levosimendan reduces biomarkers of myocardial injury and improves systemic hemodynamics in patients with septic shock . However , it does not reduce the days on mechanical ventilation , length of stay in ICU and hospital , or 28-day mortality OBJECTIVE To evaluate the effects of levosimendan on hemodynamics and cardiac function in patients with septic shock . METHODS A prospect i ve single-center r and omized controlled trial was conducted . The patients with septic shock admitted to the Department of Critical Care Medicine of the Third Hospital of Hebei Medical University from June 2011 to October 2013 were enrolled . The patients with septic shock received the conventional treatment according to international guidelines for management of severe sepsis and septic shock . Thirty-six patients received the examination of echocardiography and left ventricular ejection fraction (LVEF)≤ 0.45 after fluid resuscitation were enrolled the study , who were divided into two groups according to r and om number table , with 18 cases in each group . After the conventional treatment , the patients in dobutamine group received intravenous injection of 5 μg × kg⁻¹ min⁻¹ dobutamine for 48 hours immediately after fluid resuscitation , and those in levosimendan group received a 24-hour infusion of 5 μg × kg⁻¹ min⁻¹ dobutamine followed by a 24-hour infusion of 0.2 μg × kg⁻¹ × min⁻¹ levosimendan . The hemodynamics and cardiac function were evaluated by pulse indicator continuous cardiac output ( PiCCO ) and ultrasound during treatment . RESULTS Compared with dobutamine group , after the treatment in the levosimendan group , stroke volume index ( SVI ) , cardiac index ( CI ) and left ventricular stroke work index ( LVSWI ) were significantly increased [ SVI ( mL/m² ) : 39.8 ± 5.4 vs. 37.5 ± 4.5 , t=-2.762 , P=0.020 ; CI ( L × min⁻¹ × m⁻² ) : 4.6 ± 0.7 vs. 3.6 ± 0.7 , t=-9.829 , P=0.000 ; LVSWI ( kg ×min⁻ ¹ m⁻² ) : 33.7 ± 2.4 vs. 28.2 ± 1.2 , t=-6.307 , P=0.000 ] , and central venous pressure ( CVP ) , intrathoracic blood volume index ( ITBVI ) and extravascular lung water index ( EVLWI ) were significantly decreased [ CVP ( mmHg , 1 mmHg=0.133 kPa ) : 8.2 ± 0.9 vs. 12.1 ± 0.8 , t=3.928 , P=0.002 ; ITBVI ( mL/m² ) : 820 ± 42 vs. 978 ± 69 , t=9.472 , P=0.000 ; EVLWI ( mL/kg ) : 6.1 ± 1.6 vs. 8.9 ± 1.7 , t=4.467 , P=0.001 ] . Cardiac ultrasound showed that compared with dobutamine group , in the levosimendan group , left ventricular end-systolic volume ( LVESI ) and end-diastolic volume ( LVEDI ) were significantly lowered [ LVESI ( mL/m² ) : 32.7 ± 9.2 vs. 48.2 ± 13.4 , t=0.882 , P=0.000 ; LVEDI ( mL/m² ) : 61.7 ± 11.4 vs. 78.6 ± 13.6 , t=2.453 , P=0.032 ] , and the LVEF was significantly increased ( 0.463 ± 0.068 vs. 0.383 ± .085 , t=-2.439 , P=0.035 ) . Levosimendan also could decrease the lactic acid ( mmol/L : 3.4 ± 1.1 vs. 5.2 ± 1.2 , t=3.346 , P=0.007 ) , and increase the lactate clearance rate ( mL/min : 73.2 ± 13.5 vs. 47.6 ± 11.8 , t=-4.079 , P=0.002 ) , 24-hour urinary output ( mL : 2 213.4 ± 354.0 vs. 1 533.8 ± 402.0 , t=6.342 , P=0.000 ) and 24-hour cumulative intake ( mL : 5 746.6 ± 420.0 vs. 4 156.7 ± 215.0 , t=7.126 , P=0.000 ) . There were no significant differences in total volume of norepinephrine , mortality in intensive care unit ( ICU ) and 28-day mortality between two groups . CONCLUSIONS Levosimendan can increase cardiac ejection function , reduce the heart blood and vascular preload , intrathoracic lung water , improve heart function and systemic hemodynamic indexes of patients with septic shock This r and omized , placebo-controlled trial showed that levosimendan administration causes a significant reduction of circulating proinflammatory cytokine interleukin-6 and soluble apoptosis mediators , such as soluble Fas and Fas lig and in patients with decompensated heart failure . These immunomodulatory effects may lead to improvement of symptoms and echocardiographic markers of cardiac contractile performance in these patients Dynamic positron emission tomography ( PET ) with [11C]acetate allows noninvasive assessment of myocardial oxygen consumption . In combination with echocardiography , PET enables determination of cardiac efficiency ( defined as useful cardiac work per unit of oxygen consumption ) . We used this approach to compare the effects of levosimendan , a Ca2+‐dependent calcium sensitizer , with dobutamine and sodium nitroprusside in healthy male volunteers . The effects of levosimendan on kmono , an index of oxygen consumption , and cardiac efficiency were neutral , whereas the hemodynamic profile was consistent with balanced inotropism and vasodilatation . Dobutamine enhanced cardiac efficiency at the expense of increased oxygen requirement , but the effects of nitroprusside on kmono and cardiac efficiency were neutral . This study shows the feasibility of PET in phase 1 pharmacodynamic studies and suggests potential energetical advantages of calcium sensitization with levosimendan BACKGROUND Septic shock is the leading causes of death in intensive care units . In addition to generous fluid administration , inotropic agents are commonly used to improve cardiac output . The effects of inotropic agents on regional blood flow remains unknown . OBJECTIVE The aim of this study was to assess the effects of levosimendan vs dobutamine added to dopamine on liver functions assessed using noninvasive liver function monitoring ( LiMON ) in patients with septic shock . DESIGN Prospect i ve analysis . MEASUREMENTS AND RESULTS We analyzed 30 patients with septic shock who were treated in an intensive care unit . Indocyanine green plasma disappearance rate ( ICG-PDR ) was conducted concurrently using the LiMON system . A dose of 0.3 mg/kg ICG was given through a cubital fossa vein as a bolus . RESULTS Statistical analysis showed that the variation of hemodynamic variables was different between groups . In our results , the increase in systolic blood pressure , diastolic blood pressure , and mean arterial pressure was significantly higher in levosimendan group than in dobutamine group ( P < .05 ) . There was a decrease in before- and after-infusion ICG-PDR values in dobutamine group ( 20.38 ± 4.83 vs 20.34 ± 5.30 ) , and no statistical difference was detected ( P = .649 ) . There was an increase in before- and after-infusion ICG-PDR values in levosimendan group ( 18.70 ± 2.59 vs 21.65 ± 3.20 ) , and a statistical difference was detected ( P = .001 ) . There was statistical difference between groups ( P = .000 ) . CONCLUSION These results suggest that levosimendan added to dopamine improves systemic hemodynamics and increases splanchnic perfusion assessed using the user-friendly noninvasive bedside system LiMON in patients with septic shock compared with dobutamine Purpose The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a beneficial effect on tissue perfusion . Our objective was to determine the potential benefits of dobutamine on hemodynamic , metabolic , peripheral , hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation . Methods We design ed a r and omized , controlled , double-blind , crossover study comparing the effects of 2.5-h infusion of dobutamine ( 5 mcg/kg/min fixed-dose ) or placebo in 20 septic shock patients with cardiac index ≥2.5 l/min/m2 and hyperlactatemia . Primary outcome was sublingual perfused microvascular density . Results Despite an increasing cardiac index , heart rate and left ventricular ejection fraction , dobutamine had no effect on sublingual perfused vessel density [ 9.0 ( 7.9–10.1 ) vs. 9.1 n/mm ( 7.9–9.9 ) ; p = 0.24 ] or microvascular flow index [ 2.1 ( 1.8–2.5 ) vs. 2.1 ( 1.9–2.5 ) ; p = 0.73 ] compared to placebo . No differences between dobutamine and placebo were found for the lactate levels , mixed venous-arterial pCO2 gradient , thenar muscle oxygen saturation , capillary refill time or gastric-to-arterial pCO2 gradient . The indocyanine green plasma disappearance rate [ 14.4 ( 9.5–25.6 ) vs. 18.8 % /min ( 11.7–24.6 ) ; p = 0.03 ] and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test [ 2.1 ( 1.1–3.1 ) vs. 2.5 % /s ( 1.2–3.4 ) ; p = 0.01 ] were worse with dobutamine compared to placebo . Conclusions Dobutamine failed to improve sublingual microcirculatory , metabolic , hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion IMPORTANCE Norepinephrine is currently recommended as the first-line vasopressor in septic shock ; however , early vasopressin use has been proposed as an alternative . OBJECTIVE To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock . DESIGN , SETTING , AND PARTICIPANTS A factorial ( 2 × 2 ) , double-blind , r and omized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015 , enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock . INTERVENTIONS Patients were r and omly allocated to vasopressin ( titrated up to 0.06 U/min ) and hydrocortisone ( n = 101 ) , vasopressin and placebo ( n = 104 ) , norepinephrine and hydrocortisone ( n = 101 ) , or norepinephrine and placebo ( n = 103 ) . MAIN OUTCOMES AND MEASURES The primary outcome was kidney failure-free days during the 28-day period after r and omization , measured as ( 1 ) the proportion of patients who never developed kidney failure and ( 2 ) median number of days alive and free of kidney failure for patients who did not survive , who experienced kidney failure , or both . Rates of renal replacement therapy , mortality , and serious adverse events were secondary outcomes . RESULTS A total of 409 patients ( median age , 66 years ; men , 58.2 % ) were included in the study , with a median time to study drug administration of 3.5 hours after diagnosis of shock . The number of survivors who never developed kidney failure was 94 of 165 patients ( 57.0 % ) in the vasopressin group and 93 of 157 patients ( 59.2 % ) in the norepinephrine group ( difference , -2.3 % [ 95 % CI , -13.0 % to 8.5 % ] ) . The median number of kidney failure-free days for patients who did not survive , who experienced kidney failure , or both was 9 days ( interquartile range [ IQR ] , 1 to -24 ) in the vasopressin group and 13 days ( IQR , 1 to -25 ) in the norepinephrine group ( difference , -4 days [ 95 % CI , -11 to 5 ] ) . There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group ( 25.4 % for vasopressin vs 35.3 % for norepinephrine ; difference , -9.9 % [ 95 % CI , -19.3 % to -0.6 % ] ) . There was no significant difference in mortality rates between groups . In total , 22 of 205 patients ( 10.7 % ) had a serious adverse event in the vasopressin group vs 17 of 204 patients ( 8.3 % ) in the norepinephrine group ( difference , 2.5 % [ 95 % CI , -3.3 % to 8.2 % ] ) . CONCLUSIONS AND RELEVANCE Among adults with septic shock , the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days . Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation , the confidence interval included a potential clinical ly important benefit for vasopressin , and larger trials may be warranted to assess this further . TRIAL REGISTRATION clinical trials.gov Identifier : IS RCT N 20769191

No effects of mHealth app interventions were found on blood pressure , serum lipids , or weight . Smartphone apps offered moderate benefits for T2DM self-management .

BACKGROUND Mobile health interventions ( mHealth ) based on smartphone applications ( apps ) are promising tools to help improve diabetes care and self-management ; however , more evidence on the efficacy of mHealth in diabetes care is needed . The objective of this study was to conduct a systematic review and meta- analysis of r and omized controlled trials ( RCTs ) assessing the effect of mHealth apps on changes in hemoglobin A1c ( HbA1c ) , blood glucose , blood pressure , serum lipids , and body weight in type 2 diabetes mellitus ( T2DM ) patients .

OBJECTIVE This study was design ed to evaluate the impact of a teleassistance system on the metabolic control of type 2 diabetes patients . RESEARCH DESIGN AND METHODS We conducted a 1-year controlled parallel-group trial comparing patients r and omized ( 1 ) to an intervention group , assigned to a teleassistance system using real-time transmission of blood glucose results , with immediate reply when necessary , and telephone consultations , or ( 2 ) to a control group , being regularly followed-up at their healthcare center . Study subjects were type 2 diabetes patients > 30 years of age followed in the primary care setting . RESULTS A total of 328 type 2 diabetes patients were recruited from 35 family practice s in the province of Málaga , Spain . There was a reduction in hemoglobin A1c after 12 months from 7.62 + /- 1.60 % to 7.40 + /- 1.43 % ( P = 0.027 ) in the intervention group and from 7.44 + /- 1.31 % to 7.35 + /- 1.38 % ( P = 0.303 ) in the control group . The difference in the change between groups was not statistically significant . There was also a significant decrease in systolic and diastolic blood pressure , total cholesterol , low-density lipoprotein cholesterol , and body mass index in the intervention group . In the control group , the only significant decline was in low-density lipoprotein cholesterol . CONCLUSIONS A teleassistance system using real-time transmission of blood glucose results with an option to make telephone consultations is feasible in the primary care setting as a support tool for family physicians in their follow-up of type 2 diabetes patients OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with st and ard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS A cluster-r and omized clinical trial , the Mobile Diabetes Intervention Study , r and omly assigned 26 primary care practice s to one of three stepped treatment groups or a control group ( usual care ) . A total of 163 patients were enrolled and included in analysis . The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period . Secondary outcomes were changes in patient-reported diabetes symptoms , diabetes distress , depression , and other clinical ( blood pressure ) and laboratory ( lipid ) values . Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support . Patients received automated , real-time educational and behavioral messaging in response to individually analyzed blood glucose values , diabetes medications , and lifestyle behaviors communicated by mobile phone . Providers received quarterly reports summarizing patient ’s glycemic control , diabetes medication management , lifestyle behaviors , and evidence -based treatment options . RESULTS The mean declines in glycated hemoglobin were 1.9 % in the maximal treatment group and 0.7 % in the usual care group , a difference of 1.2 % ( P = 0.001 ) over 12 months . Appreciable differences were not observed between groups for patient-reported diabetes distress , depression , diabetes symptoms , or blood pressure and lipid levels ( all P > 0.05 ) . CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data , lifestyle behaviors , and patient self-management data individually analyzed and presented with evidence -based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year Background There is a strong will and need to find alternative models of health care delivery driven by the ever-increasing burden of chronic diseases . Objective The purpose of this 1-year trial was to study whether a structured mobile phone-based health coaching program , which was supported by a remote monitoring system , could be used to improve the health-related quality of life ( HRQL ) and /or the clinical measures of type 2 diabetes and heart disease patients . Methods A r and omized controlled trial was conducted among type 2 diabetes patients and heart disease patients of the South Karelia Social and Health Care District . Patients were recruited by sending invitations to r and omly selected patients using the electronic health records system . Health coaches called patients every 4 to 6 weeks and patients were encouraged to self-monitor their weight , blood pressure , blood glucose ( diabetics ) , and steps ( heart disease patients ) once per week . The primary outcome was HRQL measured by the Short Form ( 36 ) Health Survey ( SF-36 ) and glycosylated hemoglobin ( HbA1c ) among diabetic patients . The clinical measures assessed were blood pressure , weight , waist circumference , and lipid levels . Results A total of 267 heart patients and 250 diabetes patients started in the trial , of which 246 and 225 patients concluded the end-point assessment s , respectively . Withdrawal from the study was associated with the patients ’ unfamiliarity with mobile phones — of the 41 dropouts , 85 % ( 11/13 ) of the heart disease patients and 88 % ( 14/16 ) of the diabetes patients were familiar with mobile phones , whereas the corresponding percentages were 97.1 % ( 231/238 ) and 98.6 % ( 208/211 ) , respectively , among the rest of the patients ( P=.02 and P=.004 ) . Withdrawal was also associated with heart disease patients ’ comorbidities—40 % ( 8/20 ) of the dropouts had at least one comorbidity , whereas the corresponding percentage was 18.9 % ( 47/249 ) among the rest of the patients ( P=.02 ) . The intervention showed no statistically significant benefits over the current practice with regard to health-related quality of life — heart disease patients : beta=0.730 ( P=.36 ) for the physical component score and beta=-0.608 ( P=.62 ) for the mental component score ; diabetes patients : beta=0.875 ( P=.85 ) for the physical component score and beta=-0.770 ( P=.52 ) for the mental component score . There was a significant difference in waist circumference in the type 2 diabetes group ( beta=-1.711 , P=.01 ) . There were no differences in any other outcome variables . Conclusions A health coaching program supported with telemonitoring did not improve heart disease patients ' or diabetes patients ' quality of life or their clinical condition . There were indications that the intervention had a differential effect on heart patients and diabetes patients . Diabetes patients may be more prone to benefit from this kind of intervention . This should not be neglected when developing new ways for self-management of chronic diseases . Trial Registration Clinical Trials.gov NCT01310491 ; http:// clinical trials.gov/ct2/show/NCT01310491 ( Archived by WebCite at http://www.webcitation.org/6Z8l5FwAM ) BACKGROUND Drawing on previous web-based diabetes management programs based on the Chronic Care Model , we exp and ed an intervention to include care management through mobile phones and a game console web browser . METHODS The pilot intervention enrolled eight diabetes patients from the University of Washington in Seattle into a collaborative care program : connecting them to a care provider specializing in diabetes , providing access to their full electronic medical record , allowing wireless glucose uploads and e-mail with providers , and connecting them to the program 's web services through a game system . To evaluate the study , we conducted qualitative thematic analysis of semistructured interviews . RESULTS Participants expressed frustrations with using the cell phones and the game system in their everyday lives , but liked the wireless system for collaborating with a provider on uploaded glucoses and receiving automatic feedback on their blood sugar trends . A majority of participants also expressed that their participation in the trial increased their health awareness . DISCUSSION Mobile communication technologies showed promise within a web-based collaborative care program for type 2 diabetes . Future intervention design should focus on integrating easy-to-use applications within mobile technologies already familiar to patients and ensure the system allows for sufficient collaboration with a care provider Objective Few interventions have combined life-style and psychosocial approaches in the context of Type 2 diabetes management . The purpose of this study was to determine the effect of a multicomponent behavioral intervention on weight , glycemic control , renal function , and depressive symptoms in a sample of overweight/obese adults with Type 2 diabetes and marked depressive symptoms . Methods A sample of 111 adults with Type 2 diabetes were r and omly assigned to a 1-year intervention ( n = 57 ) or usual care ( n = 54 ) in a parallel groups design . Primary outcomes included weight , glycosylated hemoglobin , and Beck Depression Inventory II score . Estimated glomerular filtration rate served as a secondary outcome . All measures were assessed at baseline and 6 and 12 months after r and omization by assessors blind to r and omization . Latent growth modeling was used to examine intervention effects on each outcome . Results The intervention result ed in decreased weight ( mean [ M ] = 0.322 kg , st and ard error [ SE ] = 0.124 kg , p = .010 ) and glycosylated hemoglobin ( M = 0.066 % , SE = 0.028 % , p = .017 ) , and Beck Depression Inventory II scores ( M = 1.009 , SE = 0.226 , p < .001 ) , and improved estimated glomerular filtration rate ( M = 0.742 ml·min−1·1.73 m−2 , SE = 0.318 ml·min−1·1.73 m−2 , p = .020 ) each month during the first 6 months relative to usual care . Conclusions Multicomponent behavioral interventions targeting weight loss and depressive symptoms as well as diet and physical activity are efficacious in the management of Type 2 diabetes . Trial Registration : This study is registered at Clinical trials.gov ID : NCT01739205 Aim To explain the subadditive efficacy typically observed with initial combination treatments for type 2 diabetes . Methods Individual subject data from 1186 patients with type 2 diabetes [ mean glycated haemoglobin ( HbA1c ) = 8.8 % ] treated with metformin , canagliflozin or canagliflozin + metformin were used . The baseline HbA1c versus ΔHbA1c relationships for monotherapy arms were determined using analysis of covariance and then used to predict efficacy in the combination arms by modelling how applying one treatment lowers the ‘ effective baseline HbA1c ’ for a second treatment . The model was further tested using data from several published combination studies . Results The mean ΔHbA1c levels were −1.25 , −1.33 , −1.37 , −1.77 and −1.81 % with metformin , canagliflozin 100 mg , canagliflozin 300 mg , canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin , respectively . Using the monotherapy results , the predicted efficacy for the canagliflozin/metformin arms was within 10 % of the observed values using the new model , whereas assuming simple additivity overpredicted efficacy in the combination arms by nearly 50 % . For 10 other published initial combination studies , predictions from the new model [ mean ( st and ard error ) predicted ΔHbA1c = 1.67 % ( 0.14 ) ] were much more consistent with observed values [ ΔHbA1c = 1.72 % ( 0.12 ) ] than predictions based on assuming additivity [ predicted ΔHbA1c = 2.19 % ( 0.21 ) ] . Conclusions The less‐than‐additive efficacy commonly seen with initial combination treatments for type 2 diabetes can be largely explained by the impact of baseline HbA1c on the efficacy of individual treatments . Novel formulas have been developed for predicting the efficacy of combination treatments based on the efficacy of individual treatments and the baseline HbA1c of the target patients Abstract Background : Overseeing proper insulin initiation and titration remains a challenging task in diabetes care . Recent advances in mobile technology have enabled new models of collaborative care between patients and healthcare providers ( HCPs ) . We hypothesized that the adoption of such technology could help individuals starting basal insulin achieve better glycemic control compared with st and ard clinical practice . Material s and Methods : This was a 12 ± 2-week r and omized controlled study with 40 individuals with type 2 diabetes who were starting basal insulin due to poor glycemic control . The control group ( n = 20 ) received st and ard face-to-face care and phone follow-up as needed in a tertiary center , whereas the intervention group ( n = 20 ) received care through the cloud-based diabetes management program where regular communications about glycemic control and insulin doses were conducted via patient self-tracking tools , shared decision-making interfaces , secure text messages , and virtual visits ( audio , video , and shared screen control ) instead of office visits . Results : By intention-to-treat analysis , the intervention group achieved a greater hemoglobin A1c decline compared with the control group ( 3.2 ± 1.5 % vs. 2.0 % ± 2.0 % ; P = 0.048 ) . The Diabetes Treatment Satisfaction Question naire showed a significant improvement in the intervention group compared with the control group ( an increase of 10.1 ± 11.7 vs. 2.1 ± 6.5 points ; P = 0.01 ) . HCPs spent less time with patients in the intervention group compared with those in the control group ( 65.9 min per subject vs. 81.6 min per subject ) . However , the intervention group required additional training time to use the mobile device . Conclusions : Mobile health technology could be an effective tool in sharing data , enhancing communication , and improving glycemic control while enabling collaborative decision making in diabetes care Background Physical inactivity is a major public health problem . The It ’s LiFe ! monitoring and feedback tool embedded in the Self-Management Support Program ( SSP ) is an attempt to stimulate physical activity in people with chronic obstructive pulmonary disease or type 2 diabetes treated in primary care . Objective Our aim was to evaluate whether the SSP combined with the use of the monitoring and feedback tool leads to more physical activity compared to usual care and to evaluate the additional effect of using this tool on top of the SSP . Methods This was a three-armed cluster r and omised controlled trial . Twenty four family practice s were r and omly assigned to one of three groups in which participants received the tool + SSP ( group 1 ) , the SSP ( group 2 ) , or care as usual ( group 3 ) . The primary outcome measure was minutes of physical activity per day . The secondary outcomes were general and exercise self-efficacy and quality of life . Outcomes were measured at baseline after the intervention ( 4 - 6 months ) , and 3 months thereafter . Results The group that received the entire intervention ( tool + SSP ) showed more physical activity directly after the intervention than Group 3 ( mean difference 11.73 , 95 % CI 6.21 - 17.25 ; P<.001 ) , and Group 2 ( mean difference 7.86 , 95 % CI 2.18 - 13.54 ; P=.003 ) . Three months after the intervention , this effect was still present and significant ( compared to Group 3 : mean difference 10.59 , 95 % CI 4.94 - 16.25 ; P<.001 ; compared to Group 2 : mean difference 9.41 , 95 % CI 3.70 - 15.11 ; P<.001 ) . There was no significant difference in effect between Groups 2 and 3 on both time points . There was no interaction effect for disease type . Conclusions The combination of counseling with the tool proved an effective way to stimulate physical activity . Counseling without the tool was not effective . Future research about the cost-effectiveness and application under more tailored conditions and in other target groups is recommended . Trial Registration Clinical Trials.gov : NCT01867970 , https:// clinical trials.gov/ct2/show/NCT01867970 ( archived by WebCite at http://www.webcitation.org/6a2qR5BSr ) Background Self-management is crucial in the daily management of type 2 diabetes . It has been suggested that mHealth may be an important method for enhancing self-management when delivered in combination with health counseling . Objective The objective of this study was to test whether the use of a mobile phone – based self-management system used for 1 year , with or without telephone health counseling by a diabetes specialist nurse for the first 4 months , could improve glycated hemoglobin A1c ( HbA1c ) level , self-management , and health-related quality of life compared with usual care . Methods We conducted a 3-arm prospect i ve r and omized controlled trial involving 2 intervention groups and 1 control group . Eligible participants were persons with type 2 diabetes with an HbA1c level ≥7.1 % ( ≥54.1 mmol/mol ) and aged ≥18 years . Both intervention groups received the mobile phone – based self-management system Few Touch Application ( FTA ) . The FTA consisted of a blood glucose – measuring system with automatic wireless data transfer , diet manual , physical activity registration , and management of personal goals , all recorded and operated using a diabetes diary app on the mobile phone . In addition , one intervention group received health counseling based on behavior change theory and delivered by a diabetes specialist nurse for the first 4 months after r and omization . All groups received usual care by their general practitioner . The primary outcome was HbA1c level . Secondary outcomes were self-management ( heiQ ) , health-related quality of life ( SF-36 ) , depressive symptoms ( CES-D ) , and lifestyle changes ( dietary habits and physical activity ) . Data were analyzed using univariate methods ( t test , ANOVA ) and multivariate linear and logistic regression . Results A total of 151 participants were r and omized : 51 to the FTA group , 50 to the FTA-health counseling ( FTA-HC ) group , and 50 to the control group . Follow-up data after 1 year were available for 120 participants ( 79 % ) . HbA1c level decreased in all groups , but did not differ between groups after 1 year . The mean change in the heiQ domain skills and technique acquisition was significantly greater in the FTA-HC group after adjusting for age , gender , and education ( P=.04 ) . Other secondary outcomes did not differ between groups after 1 year . In the FTA group , 39 % were substantial users of the app ; 34 % of the FTA-HC group were substantial users . Those aged ≥63 years used the app more than their younger counterparts did ( OR 2.7 ; 95 % CI 1.02 - 7.12 ; P=.045 ) . Conclusions The change in HbA1c level did not differ between groups after the 1-year intervention . Secondary outcomes did not differ between groups except for an increase in the self-management domain of skill and technique acquisition in the FTA-HC group . Older participants used the app more than the younger participants did Introduction We investigated the experience of individuals diagnosed with type 2 diabetes mellitus ( T2DM ) who participated in an intervention in which the key elements were the provision of a smartphone and self-monitoring software . The interviews focused on use of a smartphone and the effects on motivation for health behavior change . Methods This was a qualitative evaluation of participants in a larger T2DM self-management r and omized controlled trial ( RCT ) conducted at the Black Creek Community Health Centre ( BCCHC ) in Toronto , Canada ( Clinical Trials.gov Identifier : NCT02036892 ) . The study is based on semi-structured interviews ( n = 11 ) that were audio taped and analyzed with a thematic analytic approach . The RCT compared the effectiveness of six months of smartphone-based self-monitoring and health coaching with a control group who received health coaching without internet or smartphone-based assistance . Results Qualitative data analyses result ed in derivation of four major themes that describe participant experience : ( a ) ‘ smartphone and software ’ , describes smartphone use in relation to health behavior change ; ( b ) ‘ health coach ’ describes how client/health coach relationships were assisted by smartphone use ; ( c ) ‘ overall experience ’ describes perceptions of the overall intervention ; and ( d ) ‘ frustrations in managing chronic conditions ’ describes difficulties with the complexities of T2DM management from a patient perspective . Discussion Findings suggest that interventions with T2DM assisted by smartphone software and health coaches actively engage individuals in improved hemoglobin A1c ( HbA1c ) control BACKGROUND Type 2 diabetes is an individual health challenge requiring ongoing self-management . Remote patient reporting of relevant health parameters and linked automated feedback via mobile telephone have potential to strengthen self-management and improve outcomes . This research involved development and evaluation of a mobile telephone-based remote patient reporting and automated telephone feedback system , guided by health behavior change theory , aim ed at improving self-management and health status in individuals with type 2 diabetes . SUBJECTS AND METHODS This research comprised a r and omized controlled trial . Inclusion criteria were diagnosis of type 2 diabetes , elevated glycosylated hemoglobin ( HbA1c ) levels ( range , 6.5 - 11 % ) or use of oral diabetes medication , and 30 - 70 years of age . Intervention subjects ( n=24 ) participated in remote patient reporting of health status parameters and linked health behavior change feedback . Control participants ( n=24 ) received st and ard of care including diabetes education and healthcare provider counseling . Patients were followed for approximately 10 months . RESULTS Intervention participants achieved , compared with controls and controlling for baseline , a significantly greater mean reduction in HbA1c of -0.40 % ( 95 % confidence interval [ CI ] -0.67 % to -0.14 % ) versus 0.036 % ( 95 % CI -0.23 % to 0.30 % ) ( P<0.03 ) and significantly greater weight reduction of -2.1 kg ( 95 % CI -3.6 to -0.6 kg ) versus 0.4 kg ( 95 % CI -1.1 to 1.9 kg ) . Nonsignificant trends for greater intervention compared with control improvement in systolic and diastolic blood pressure were observed . CONCLUSIONS Sophisticated information technology platforms for remote patient reporting linked with theory-based health behavior change automated feedback have potential to improve patient outcomes in type 2 diabetes and merit scaled-up research efforts A mobile phone with a glucometer integrated into the battery pack ( the ‘ Diabetes Phone ’ ) was launched in Korea in 2003 . We compared its effect on management of type 2 diabetes to the Internet-based glucose monitoring system ( IBGMS ) , which had been studied previously . We conducted a r and omized trial involving 69 patients for three months . Participants were assigned to an Internet group or a phone group . The phone group communicated with medical staff through the mobile phone only . Their glucose-monitoring data were automatically transferred to individual , web-based charts and they received medical recommendations by short message service . The Internet group used the IBGMS . There were no significant differences between the groups at baseline . After three months ' intervention , HbA1c levels of both groups had decreased significantly , from 7.6 % to 6.9 % for the Internet group and from 8.3 % to 7.1 % for the phone group ( P < 0.01 ) . Levels of patient satisfaction and adherence to medical advice were similar . Mobile , bidirectional communication between doctors and patients using the diabetes phone was as effective for glucose control as the previously-studied Internet-based monitoring system and it was good for patient satisfaction and adherence AIMS The rapidly increasing prevalence of chronic diseases is an important challenge to healthcare systems worldwide . To improve the quality and efficiency of chronic disease care , we investigated the effectiveness and applicability of the Ubiquitous Chronic Disease Care ( UCDC ) system using cellular phones and the internet for overweight patients with both Type 2 diabetes and hypertension . METHODS We conducted a r and omized , controlled clinical trial over 3 months that included 123 patients at a university hospital and a community public health centre . RESULTS After 12 weeks , there were significant improvements in HbA(1c ) in the intervention group ( 7.6 + /- 0.9 % to 7.1 + /- 0.8 % , P < 0.001 ) compared with the control group ( 7.4 + /- 0.9 % to 7.6 + /- 1.0 % , P = 0.03 ) . Furthermore , we observed a significant reduction in systolic and diastolic blood pressure , as well as improvements in total cholesterol , low-density lipoprotein-cholesterol and triglyceride levels in the intervention group . Furthermore , there was a significant increase in adiponectin levels in the intervention group compared with the control group , although high-sensitivity C-reactive protein and interleukin-6 levels did not change in either group . CONCLUSIONS The novel UCDC system presented in this paper improved multiple metabolic parameters simultaneously in overweight patients with both Type 2 diabetes and hypertension BACKGROUND Less than 63 % of individuals with diabetes meet professional guidelines target of hemoglobin A1c < 7.0 % , and only 7 % meet combined glycemic , lipid , and blood pressure goals . The primary study aim was to assess the impact on A1c of a cell phone-based diabetes management software system used with web-based data analytics and therapy optimization tools . Secondary aims examined health care provider ( HCP ) adherence to prescribing guidelines and assessed HCPs ' adoption of the technology . METHODS Thirty patients with type 2 diabetes were recruited from three community physician practice s for a 3-month study and evenly r and omized . The intervention group received cell phone-based software design ed by endocrinologists and CDEs ( WellDoc Communications , Inc. , Baltimore , MD ) . The software provided real-time feedback on patients ' blood glucose levels , displayed patients ' medication regimens , incorporated hypo- and hyperglycemia treatment algorithms , and requested additional data needed to evaluate diabetes management . Patient data captured and transferred to secure servers were analyzed by proprietary statistical algorithms . The system sent computer-generated logbooks ( with suggested treatment plans ) to intervention patients ' HCPs . RESULTS The average decrease in A1c for intervention patients was 2.03 % , compared to 0.68 % ( P < 0.02 , one-tailed ) for control patients . Of the intervention patients , 84 % had medications titrated or changed by their HCP compared to controls ( 23 % , P = 0.002 ) . Intervention patients ' HCPs reported the system facilitated treatment decisions , provided organized data , and reduced logbook review time . CONCLUSIONS Adults with type 2 diabetes using WellDoc 's software achieved statistically significant improvements in A1c . HCP and patient satisfaction with the system was clinical ly and statistically significant Background : Of adults with type 2 diabetes , 84 % take antihyperglycemic medication . Successful treatment requires active monitoring and medication dose adjustment by health providers . The objective of this study was to determine how a mobile-phone-based coaching system for diabetes management influences physician prescribing behavior . Method : This secondary data analysis is based on a cluster r and omized clinical trial that reported patients provided with mobile self-management had reduction in glycated hemoglobin ( HbA1c ) of 1.9 % over 1 year , compared to 0.7 % in control patients ( P < .001 ) . Participants were primary care patients with type 2 diabetes r and omized at physician practice level into a control group ( n = 55 ) and intervention group ( n = 62 ) . Main study measures were patients ’ medication records ( medication , dose , frequency , start and end date ) abstract ed at baseline and study end . Antihyperglycemic medications , including sulfonylureas or thiazolidinediones , and antihypertensive and antilipemic medications were analyzed . Results : A higher percentage of patients in the intervention group had modification and intensification of incretin mimetics during the 1-year study period ( 9.7 % vs 0.0 % and 8.1 % vs 0.0 % , both P = .008 ) . A higher percentage of patients in the intervention group had modification and intensification of metformin ( 24.2 % vs 7.3 % , P = .033 ) . The overall difference in physician prescribing of oral antihyperglycemic medications was not statistically significant . Conclusions : Our results suggest mobile diabetes interventions can encourage physicians to modify and intensify antihyperglycemic medications in patients with type 2 diabetes . Differences in physician prescribing behavior were modest , and do not appear to be large enough to explain a 1.2 % decrease in HbA1c RATIONALE , AIMS AND OBJECTIVES Self-management of type 2 diabetes through diet , exercise and for many medications , are vital in achieving and maintaining glycaemic control in type 2 diabetes . A number of interventions have been design ed to improve self-management , but the outcomes of these are rarely explored from a qualitative angle and even fewer through a process evaluation . METHOD A process evaluation was conducted using a qualitative design with participants r and omized to an intervention . Seventy-three people living with type 2 diabetes and hyperglycaemia for a minimum of 1 year , r and omized to one of two interventions ( n = 34 to an education intervention and n = 39 to an education and acceptance and commitment therapy intervention ) completed stage one of the process evaluation , immediately following the intervention through written feedback guided by open-ended questions . A purposive sample of 27 participants completed semi-structured interviews at 3 and 6 months post intervention . Interview data were transcribed and data analysed using a thematic analysis . RESULTS The majority of participants described an increase in knowledge around diabetes self-management and an increased sense of personal responsibility . Participants also described changes in self-management activities and reflected on the challenges in instigating and maintaining change to improve diabetes management . CONCLUSION The complexities of implementing change in daily life to improve glycaemic control indicate the need for ongoing support post intervention , which may increase and maintain the effectiveness of the intervention We conducted a r and omized controlled trial using mobile health technology in an ethnically diverse sample of 137 patients with complicated diabetes . Patients in the intervention group ( n = 72 ) were trained to measure their blood glucose with a sensor which transmitted the readings to a mobile phone via a Bluetooth wireless link . Clinicians were then able to examine and respond to the readings which were viewed with a web-based application . Patients in the control arm of the study ( n = 65 ) did not transmit their readings and received care with their usual doctor in the outpatient and /or primary care setting . The mean follow-up period was 9 months in each group . The default rate was higher in the patients in the intervention arm due to technical problems . In an intention-to-treat analysis there were no differences in HbA1c between the intervention and control groups . In a sub-group analysis of the patients who completed the study , the telemonitoring group had a lower HbA1c than those in the control group : 7.76 % and 8.40 % , respectively ( P = 0.06 )

A significantly higher 30-day and 1-year mortality was revealed in nonoperatively treated hip fracture patients . No data were found examining (HR)QOL and costs .

Introduction : Increasing numbers of patients with hip fractures also have advanced comorbidities . A majority are treated surgically . However , a significantly increasing percentage of medically unfit patients with unacceptably high risk of perioperative death are treated nonoperatively . Important questions about patients ’ prefracture quality of life ( QOL ) and future perspectives should be asked before considering different treatment options to assess what kind of treatment is advisable in frail elderly high-risk patients with a hip fracture . Objective : The aim of this review was to provide an overview of differences in mortality , health-related QOL [ (HR)QOL ] , functional outcome , and costs between nonoperative management ( NOM ) and operative management ( OM ) of hip fractures in patients above 65 years .

Background Research ers are increasingly investigating the potential for ordinal tasks such as ranking and discrete choice experiments to estimate QALY health state values . However , the assumptions of r and om utility theory , which underpin the statistical models used to provide these estimates , have received insufficient attention . In particular , the assumptions made about the decisions between living states and the death state are not satisfied , at least for some people . Estimated values are likely to be incorrectly anchored with respect to death ( zero ) in such circumstances . Methods Data from the Investigating Choice Experiments for the preferences of older people CAPability instrument ( ICECAP ) valuation exercise were analysed . The values ( previously anchored to the worst possible state ) were rescaled using an ordinal model proposed previously to estimate QALY-like values . Bootstrapping was conducted to vary artificially the proportion of people who conformed to the conventional r and om utility model underpinning the analyses . Results Only 26 % of respondents conformed unequivocally to the assumptions of conventional r and om utility theory . At least 14 % of respondents unequivocally violated the assumptions . Varying the relative proportions of conforming respondents in sensitivity analyses led to large changes in the estimated QALY values , particularly for lower-valued states . As a result these values could be either positive ( considered to be better than death ) or negative ( considered to be worse than death ) . Conclusion Use of a statistical model such as conditional ( multinomial ) regression to anchor quality of life values from ordinal data to death is inappropriate in the presence of respondents who do not conform to the assumptions of conventional r and om utility theory . This is clearest when estimating values for that group of respondents observed in valuation sample s who refuse to consider any living state to be worse than death : in such circumstances the model can not be estimated . Only a valuation task requiring respondents to make choices in which both length and quality of life vary can produce estimates that properly reflect the preferences of all respondents BACKGROUND Selecting elderly persons who need geriatric interventions and making accurate treatment decisions are recurring challenges in geriatrics . Chronological age , although often used , does not seem to be the best selection criterion . Instead , the concept of frailty , which indicates several concurrent losses in re sources , can be used . METHODS The predictive values of chronological age and frailty were investigated in a large community sample of persons aged 65 years and older , r and omly drawn from the register of six municipalities in the northern regions of the Netherl and s ( 45 % of the original addressees ) . The participants ' generative capacity to sustain well-being ( i.e. , self-management abilities ) was used as the main outcome measure . RESULTS When using chronological age instead of frailty , both too many and too few persons were selected . Furthermore , frailty related more strongly ( with beta values ranging from -.25 to -.39 ) to a decline in the participants ' self-management abilities than did chronological age ( with beta values ranging from -.06 to -.14 ) . Chronological age added very little to the explained variances of all outcomes once frailty was included . CONCLUSIONS Using frailty as the criterion to select older persons at risk for interventions may be better than selecting persons based only on their chronological age Proximal femoral fractures in elderly patients are a serious problem in the aging society . Recently , surgical indications have changed due to advancements in medical technology . The purpose of this study was to investigate the outcome of elderly patients with displaced proximal hip fractures according to our positive criteria for surgical treatment . Exclusion criteria included ( 1 ) terminal-stage malignancy ; ( 2 ) a combination of an inability to walk , a severe mental disorder , and caregiver refusal of surgery ; and ( 3 ) nonapproval of the anesthesiologist for surgery . The study group comprised 666 elderly patients . They were categorized into surgically and nonsurgically treated groups , and their treatment outcomes were retrospectively analyzed . The majority of patients were treated surgically ( 97.0 % vs 3.0 % ) . One-year survival rate was higher among surgically treated patients ( 82.2%-91.8 % ) than non-surgically treated patients ( 55 % ) . The major cause of death in nonsurgically treated patients was deterioration of comorbidities ( 66.7 % ) , whereas this was the cause of death in 18.9 % of surgically treated patients . One-year survival rates were worse in both groups with a lower American Society of Anesthesiologists grade . The 1-year survival rate of our patients suggests that our surgical criteria offer a reasonable outcome in surgically and nonsurgically treated patients . American Society of Anesthesiologists grade and preexisting comorbidities were strongly correlated with patient outcome We report a prospect i ve clinical trial of 150 cases for the treatment of unstable intertrochanteric fracture of the neck of the femur . Three methods were tested in our series -- skeletal traction with a tibial pin , medial displacement osteotomy and valgus osteotomy -- with 50 patients in each group . Our results showed no significant difference between those treated with the Dimon and Hughston osteotomy and those treated by the Sarmiento osteotomy . Conservative treatment of skeletal traction for unstable fracture was found to be well tolerated by the Chinese patient . A low mortality and morbidity rate was found in this series with an overall infection rate of 4 per cent Background : Because of specific method ological difficulties in conducting r and omized trials , surgical research remains dependent predominantly on observational or non‐r and omized studies . Few vali date d instruments are available to determine the method ological quality of such studies either from the reader 's perspective or for the purpose of meta‐ analysis . The aim of the present study was to develop and vali date such an instrument All elderly patients with extracapsular hip fractures seen in hospitals in Newcastle upon Tyne over a 12-month period were studied and followed up for six months . At one of the hospitals , patients were r and omised to treatment by AO dynamic hip-screw or by traction . Complications specific to the two treatments were low , and general complications , six-month mortality and prevalence of pain , leg swelling and unhealed sores , showed no difference between the two modes of treatment . Operative treatment gave better anatomical results and a shorter hospital stay , but significantly more of the patients treated by traction showed loss of independence six months after injury INTRODUCTION Mortality after hip fracture remains high in spite of the progress of medicine . Due to the trend toward longer life , the problem of hip fracture is getting more significant . The aim of this study is to determine the effects of surgical treatment in patients with high risk of hip fracture on mortality reduction . METHODS In the retrospective- prospect i ve study , 66 patients aged 65 - 92 with a hip fracture and a high cardiac risk have been analyzed . The risk estimation was based on the Lee index . The patients with three or more risk factors were considered high-risk . The first group consisted of surgically treated patients with a hip fracture and at high cardiac risk , and in the second group were conservatively treated patients with a hip fracture and high cardiac risk . RESULTS In the group of conservatively treated patients , 75 % were women and in operatively treated group 67.6 % . Patient in both group are similar in relation to the participation of risk factor . A difference has been noticed in terms of renal insufficiency ( RI ) . There was 18.8 % conservatively treated patient with RI and 2.9 % in operatively treated group . CONCLUSION Patients with hip fracture and at high cardiac risk have lower mortality when treated surgically The outcome of patients with a displaced intracapsular femoral neck fracture treated non-operatively was assessed at 1 year and compared with patients managed operatively over the same time period . Data were collected prospect ively for 102 consecutive patients . 80 patients underwent hemiarthroplasty and 22 were managed non-operatively . Patients were managed non-operatively if they were felt to have an unacceptably high risk of death within the perioperative period despite medical optimisation . Non-operative management entailed active early mobilisation without bed rest or traction . Patients managed non-operatively had a greater 30-day mortality compared with operatively managed patients . Deaths were due to pre-existing medical conditions or events , which had occurred at the time of hip fracture . No patient in the non-operative treatment group developed pneumonia , pressure sores or thrombo-embolic events . Patients treated non-operatively , who survived 30 days after fracture , had a mortality rate over the following year comparable with those who had undergone surgery . At 1 year , all non-operatively managed patients were able to transfer without pain and 6 of the 11 surviving patients were able to mobilise with walking aids . At 1 year , the majority of surviving non-operatively managed patients were living in their own homes . Surgical intervention is the treatment of choice for the majority of elderly patients with a displaced intracapsular femoral neck fracture . However , in patients with life-threatening medical co-morbidity , non-operative treatment with early mobilisation can yield acceptable results

Ziprasidone exposure was increased when the medication was administered with food , irrespective of fat content . The findings from this meta- analysis and review suggest that ziprasidone 120 - 160 mg/d is a less effective treatment for psychotic disorders compared with olanzapine and risperidone , but that the low levels of hyperprolactinemia and weight gain/metabolic adverse events associated with ziprasidone may make it a useful option in patients in whom antipsychotics are poorly tolerated for these reasons

BACKGROUND Among atypical antipsychotics , ziprasidone exhibits a unique clinical profile . However , prescription rates for this medication remain among the lowest of all atypical antipsychotics . OBJECTIVE The present meta- analysis examined premature study discontinuation ( PSD ) and dose-response associated with ziprasidone . Furthermore , a systematic review of the clinical pharmacokinetic and pharmacodynamic properties and tolerability of ziprasidone was conducted to explain the meta-analytic findings .

STUDY OBJECTIVE To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic drug ziprasidone . DESIGN Open , r and omized , three-way crossover study . SETTING University-based research facility . SUBJECTS Eight healthy male volunteers . INTERVENTIONS Ziprasidone 20 mg was administered under fasting conditions ( treatment A ) , and directly after ( treatment B ) and 2 hours after ( treatment C ) a st and ard high-fat breakfast . MEASUREMENTS AND MAIN RESULTS Serial blood sample s were obtained over 36 hours . Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose . Ziprasidone had a significant effect on area under the curve ( AUC0-infinity ) , maximum serum concentration , and half-life ( analysis of variance all p<0.05 ) , with the mean AUC0-infinity being significantly greater ( 627.2 + /- 206.4 vs 371.0 + /- 126.5 ng x hr/ml , ANOVA with Bonferroni 's criteria p<0.016 ) and half-life significantly shorter ( 4.7 + /- 0.8 vs 6.6 + /- 1.3 hrs , ANOVA with Bonferroni 's criteria p<0.016 ) after treatment B compared with treatment A. Although similar trends were observed after treatment C compared with treatment A , the differences did not reach statistical significance when Bonferroni 's correction criteria were applied ( p>0.016 ) . CONCLUSION These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods , possibly due to improved drug dissolution and solubilization . The drug 's longer half-life under fasting conditions may reflect dissolution-limited absorption , although this could not be directly assessed . Despite postpr and ial increases in ziprasidone AUC0-infinity and maximum concentration , daytime vigilance was not affected OBJECTIVE This prospect i ve , naturalistic study investigated the factors influencing physicians ' choice of antipsychotic drug therapy in the treatment of patients with schizophrenia . METHOD 108 in- and out patients treated at the Department of Psychiatry of the Medical University Innsbruck who started treatment with a new generation antipsychotic ( except clozapine ) were included . The following factors were investigated : sociodemographic and illness-related variables , pretreatment , the reasons for change of treatment ( lack of efficacy , side effects , non-compliance ) , side effects of pretreatment and body-mass-index ( BMI ) . RESULTS Sociodemographic and most illness-related variables did not have an influence on the physicians ' choice of medication . Risperidone was more frequently prescribed in patients with severe positive symptoms than amisulpride or quetiapine . Rigidity , orthostatic dizziness and gynecomastia during pretreatment were frequently associated with starting patients on ziprasidone . In patients with diminished sexual desire ziprasidone was preferred over olanzapine . Amisulpride was used more commonly than olanzapine if patients had experienced weight gain during pretreatment . Moreover , patients who were prescribed amisulpride had a significantly higher BMI in comparison to patients who were prescribed olanzapine . The reasons for current change of treatment , as well as the drug history ( total number of antipsychotic drugs prescribed during the course of the illness ) did not have an influence on the physicians ' choice of antipsychotic . CONCLUSION In summary , the data suggest that side effects have a larger influence on the choice of antipsychotic than demographic or illness-related variables , except the severity of positive symptoms There is limited information on the pharmacokinetics of ziprasidone ( ZIP ) in naturalistic clinical setting s. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone ( SMDZ ) , and the dose-normalized concentrations , using routine therapeutic drug monitoring ( TDM ) data . A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping , Sweden . This analytical service was available to all physicians in Sweden . Between January 2001 and December 2004 , 545 analyses , representing sample s from 370 patients , were performed . The median daily ZIP dose was 120 mg ( range 20 -320 mg ) . In all , 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation . The median ( 25th to 75th percentile ) serum concentration of ZIP was 125 nmol/L ( 82 - 188 nmol/L ) . The SMDZ : ZIP ratio decreased with increasing serum concentration of ZIP . The median ( 25th to 75th percentile ) dose-normalized concentrations ( nmol L−1 mg−1 d−1 ) for ZIP and SMDZ were 1.13 ( 0.74 - 1.77 ) and 0.62 ( 0.45 - 0.86 ) , respectively , with SMDZ : ZIP ratio of 0.57 ( 0.42 - 0.79 ) . The overall coefficients of variation for dose-normalized serum concentrations of ZIP , SMDZ , and SMDZ : ZIP ratio were 62 % , 56 % , and 57 % , respectively ( n = 121 ) . Smoking women had lower normalized ZIP concentrations than nonsmoking women . Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time . In summary , great interindividual and intraindividual differences in ZIP concentrations were observed . TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence Abstract A double-blind , placebo-controlled , multicenter study , was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder . Patients were r and omized to receive ziprasidone 40 mg/day , 120 mg/day or placebo for 28 days . Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total , CGI-S , BPRS depression cluster and BPRS anergia cluster scores ( all P < 0.05 ) . Similarly , the percentages of patients classified as responders on the BPRS ( ≥30 % reduction ) and the CGI improvement ( score ≤2 ) were significantly greater with ziprasidone 120 mg/day compared with placebo ( P < 0.05 ) . The number of patients who experienced an adverse event was similar in all three treatment groups , and discontinuation due to adverse events was rare ( five of 91 ziprasidone-treated patients ) . The most frequently reported adverse events , that were more common in either ziprasidone group than in the placebo group , were dyspepsia , constipation , nausea and abdominal pain . There was a notably low incidence extrapyramidal side-effects ( including akathisia ) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain . Ziprasidone-treated patients were not clinical ly different from placebo-treated patients on the Simpson-Angus Rating scale , Barnes Akathisia scale and AIMS assessment s. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive , negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia ; however , their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated . We aim ed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol , in first-episode schizophrenia . METHODS We did an open r and omised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites , in 14 countries . Eligible patients were aged 18 - 40 years , and met diagnostic criteria for schizophrenia , schizophreniform disorder , or schizoaffective disorder . 498 patients were r and omly assigned by a web-based online system to haloperidol ( 1 - 4 mg per day ; n=103 ) , amisulpride ( 200 - 800 mg per day ; n=104 ) , olanzapine ( 5 - 20 mg per day ; n=105 ) , quetiapine ( 200 - 750 mg per day ; n=104 ) , or ziprasidone ( 40 - 160 mg per day ; n=82 ) ; follow-up was at 1 year . The primary outcome measure was all-cause treatment discontinuation . Patients and their treating physicians were not blinded to the assigned treatment . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N68736636 . FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 ( Kaplan-Meier estimate 72 % ) for haloperidol , 32 ( 40 % ) for amisulpride , 30 ( 33 % ) for olanzapine , 51 ( 53 % ) for quetiapine , and 31 ( 45 % ) for ziprasidone . Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride ( hazard ratio [ HR ] 0.37 , [ 95 % CI 0.24 - 0.57 ] ) , olanzapine ( HR 0.28 [ 0.18 - 0.43 ] ) , quetiapine ( HR 0.52 [ 0.35 - 0.76 ] ) , and ziprasidone ( HR 0.51 [ 0.32 - 0.81 ] ) . However , symptom reductions were virtually the same in all the groups , at around 60 % . INTERPRETATION This pragmatic trial suggests that clinical ly meaningful antipsychotic treatment of first-episode of schizophrenia is achievable , for at least 1 year . However , we can not conclude that second-generation drugs are more efficacious than is haloperidol , since discontinuation rates are not necessarily consistent with symptomatic improvement INTRODUCTION Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions . The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia . METHODS The study was an 8-week , double-blind , parallel-group , r and omized , controlled multicenter trial ( NCT00145444 ) . Seventy-six patients with schizophreniform disorder , schizophrenia or schizoaffective disorder ( diagnosis < 5 y ) , and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study . Efficacy of ziprasidone ( 80 - 160 mg/d ) and olanzapine 10 - 20 mg was measured using the Positive and Negative Syndrome Scale ( PANSS ) , the Clinical Global Impression ( CGI ) Scale , the Calgary Depression Scale for Schizophrenia ( CDSS ) , and the Heinrich Quality of Life Scale ( HQLS ) ; tolerability assessment s included laboratory assessment s , body weight , and electroencephalogram . RESULTS Olanzapine ( n = 34 ) and ziprasidone ( n = 39 ) showed equal efficacy as measured by the PANSS , CDSS , CGI , and HQLS . However , mean weight gain was significantly higher in the olanzapine group ( 6.8 vs 0.1 kg , P < .001 ) . Ziprasidone was associated with decreasing levels of triglycerides , cholesterol , and transaminases , while these parameters increased in the olanzapine group ( all P values < .05 ) . There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects . Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently ( P < .05 ) . DISCUSSION The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile . However , there is a risk of a type II error with this sample size . Clinical ly significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine , while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms BACKGROUND In the treatment of schizophrenia , changing antipsychotics is common when one treatment is suboptimally effective , but the relative effectiveness of drugs used in this strategy is unknown . This r and omized , double-blind study compared olanzapine , quetiapine , risperidone , and ziprasidone in patients who had just discontinued a different atypical antipsychotic . METHOD Subjects with schizophrenia ( N=444 ) who had discontinued the atypical antipsychotic r and omly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness ( CATIE ) investigation were r and omly reassigned to double-blind treatment with a different antipsychotic ( olanzapine , 7.5 - 30 mg/day [ N=66 ] ; quetiapine , 200 - 800 mg/day [ N=63 ] ; risperidone , 1.5 - 6.0 mg/day [ N=69 ] ; or ziprasidone , 40 - 160 mg/day [ N=135 ] ) . The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason . RESULTS The time to treatment discontinuation was longer for patients treated with risperidone ( median : 7.0 months ) and olanzapine ( 6.3 months ) than with quetiapine ( 4.0 months ) and ziprasidone ( 2.8 months ) . Among patients who discontinued their previous antipsychotic because of inefficacy ( N=184 ) , olanzapine was more effective than quetiapine and ziprasidone , and risperidone was more effective than quetiapine . There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability ( N=168 ) . CONCLUSIONS Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic , risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason To eluci date the " atypicality " of ziprasidone , its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions . These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls . [18F]fallypride positron emission tomography ( PET ) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose . Binding potentials were calculated for striatal and extrastriatal regions . D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients . In a parallel [11C]raclopride-PET study , striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol . Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests . Occupancy in extrastriatal regions was approximately 10 % higher than in striatal regions . Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions ( temporal cortex : 39 ng/mL ; putamen : 64 ng/mL ) , irrespective of the time between last dosing and scan . Single ziprasidone doses result ed in higher occupancies exceeding the 95 % prediction limits of the occupancy versus plasma concentrations for chronic dosing . Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals . D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels , suggesting relatively high intraday variations of D2/D3-receptor binding . The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics . Single-dose studies may not be totally relied on for final dose selection In this double-blind study , patients with an acute exacerbation of schizophrenia or schizoaffective disorder were r and omized to receive either ziprasidone 80 mg/day ( n = 106 ) or 160 mg/day ( n = 104 ) or placebo ( n = 92 ) , for 6 weeks . Both doses of ziprasidone were statistically significantly more effective than placebo in improving the PANSS total , BPRS total , BPRS core items , CGI-S , and PANSS negative subscale scores ( p < .05 ) . Ziprasidone 160 mg/day significantly improved depressive symptoms in patients with clinical ly significant depression at baseline ( MADRS ≥ 14 , over-all mean 23.5 ) ( p < .05 ) as compared with placebo . The percentage of patients experiencing adverse events was similar in each treatment group , and result ant discontinuation was rare . The most frequent adverse events associated with ziprasidone were generally mild dyspepsia , nausea , dizziness , and transient somnolence . Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain . The results indicate that ziprasidone is effective and well tolerated in the treatment of the positive , negative , and depressive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder Positron emission tomography ( PET ) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic , CP-88,059 - 1 . In a double blind dose escalation study , seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059 - 1 , 5 h before PET scanning . One additional subject was assigned to placebo predose . Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied . Binding of11C-raclopride decreased in a dose dependent manner , and 85 % dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059 - 1 . The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059 - 1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg . The study highlights the potential of positron emission tomography in the pre clinical evaluation of new drugs STUDY OBJECTIVE To characterize the effect of oral ziprasidone and haloperidol on the corrected QT ( QTc ) interval under steady-state conditions . Design . Prospect i ve , r and omized , open-label , parallel-group study . SETTING Inpatient clinical research facility . Patients Fifty-nine adults ( age range 25 - 59 yrs ) with schizophrenia or schizoaffective disorder who had no clinical ly significant abnormality on electrocardiogram ( ECG ) at screening . Intervention . During period 1 ( days -10 to -4 ) , antipsychotic and anticholinergic drugs were tapered . On the first day ( day -3 ) of period 2 , the drugs were discontinued , and placebo was given for the next 3 days ( days -2 to 0 ) . On the last day ( day 0 ) of period 2 , serial baseline ECGs were collected . During period 3 ( days 1 - 16 ) , patients received escalating oral doses of ziprasidone and haloperidol to reach steady state . Period 4 ( days 17 - 19 ) allowed for study drug washout and initiation of outpatient antipsychotic therapy ; safety assessment s were also performed during this period . MEASUREMENTS AND RESULTS At each steady-state dose level , three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug . Point estimates and 95 % confidence intervals ( CIs ) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level . Mean changes from baseline in the QTc interval ( msec ) for ziprasidone were 4.5 ( 95 % CI 1.9 - 7.1 ) , 19.5 ( 95 % CI 15.5 - 23.4 ) , and 22.5 ( 95 % CI 15.7- 29.4 ) for steady-state doses of 40 , 160 , and 320 mg/day , respectively ; for haloperidol , -1.2 ( 95 % CI -4.1 - 1.7 ) , 6.6 ( 95 % CI 1.6 - 11.7 ) , and 7.2 ( 95 % CI 1.4 - 13.1 ) for steady-state doses of 2.5 , 15 , and 30 mg/day . Although no patient in either treatment group experienced a QTc interval of 450 msec or greater , the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day , respectively , and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day , respectively . Most treatment-emergent adverse drug reactions were mild in intensity , and none were severe . CONCLUSION The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose . Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater BACKGROUND More head-to-head comparisons of antipsychotics are needed to discern the relative efficacy and safety profiles of these compounds . Thus , we compared ziprasidone and risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder . METHOD Patients with DSM-III-R acute exacerbation of schizophrenia or schizoaffective disorder were r and omly assigned to double-blind ziprasidone 40 to 80 mg b.i.d . ( N = 149 ) or risperidone 3 to 5 mg b.i.d ( N = 147 ) for 8 weeks . Primary efficacy measures included Positive and Negative Syndrome Scale ( PANSS ) total score and Clinical Global Impressions-Severity of Illness scale ( CGI-S ) score ; secondary measures included scores on the PANSS negative sub-scale , CGI-Improvement scale ( CGI-I ) , and PANSS-derived Brief Psychiatric Rating Scale ( BPRSd ) total and core items . Safety assessment s included movement disorder evaluations , laboratory tests , electrocardiography , vital signs , and body weight . Efficacy analyses employed a prospect ively defined Evaluable Patients cohort . Treatment equivalence was conferred if the lower limit of the 95 % confidence interval of the ziprasidone/risperidone ratio of least-squares mean change from baseline was > 0.60 . Data were gathered from August 1995 to January 1997 . RESULTS Equivalence was demonstrated in PANSS total scores , CGI-S scores , PANSS negative subscale scores , BPRSd total and core item scores , and PANSS total and CGI-I responder rates . Both agents were well tolerated . Risperidone exhibited a significantly higher Movement Disorder Burden ( MDB ) score ( p < .05 ) and higher incidences of prolactin elevation and clinical ly relevant weight gain . However , compared with current recommendations , study dosing may have been high for some risperidone-treated patients ( mean dose = 7.4 mg/day ) and low for some ziprasidone-treated patients ( mean dose = 114.2 mg/day ) . CONCLUSION Both agents equally improved psychotic symptoms , and both were generally well tolerated , with ziprasidone demonstrating a lower MDB score and less effect on prolactin and weight than risperidone The efficacy , safety and tolerability of ziprasidone versus the comparators olanzapine , risperidone or quetiapine were investigated in adult patients with chronic schizophrenia , schizoaffective and schizophreniform disorders , with lack of efficacy or intolerance to their previous antipsychotic treatment based on clinical judgement of the investigator . A total of 293 patients were r and omized to 12 weeks treatment with either ziprasidone 80–160 mg/day ( n=147 ) or with one of the comparator drugs ( n=146 ) . In the latter group the investigator could choose between olanzapine 10–20 mg/day ( n=24 ) , risperidone 4–8 mg/day ( n=22 ) or quetiapine 300–750 mg/day ( n=97 ) . The study comprised four visits including a baseline examination prior to r and omization and further examinations at the end of weeks 1 , 4 and 12 . Ziprasidone was non-inferior ( defined as a difference of = 7 units or less on the PANSS scale to the disadvantage of ziprasidone . ) to the composite group ( olanzapine , risperidone or quetiapine ) on the total PANSS score as well as on all subscores ( P<0.0001 ) ; there were no significant between-group differences in the CGI-S and I and UKU scores . Ziprasidone-treated patients lost an average of 2.1 kg in the 12 weeks of the study , the mean weight for risperidone and quetiapine remained unchanged , and patients receiving olanzapine gained 3.1 kg on average BACKGROUND The relative effectiveness of second-generation ( atypical ) antipsychotic drugs as compared with that of older agents has been incompletely addressed , though newer agents are currently used far more commonly . We compared a first-generation antipsychotic , perphenazine , with several newer drugs in a double-blind study . METHODS A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and r and omly assigned to receive olanzapine ( 7.5 to 30 mg per day ) , perphenazine ( 8 to 32 mg per day ) , quetiapine ( 200 to 800 mg per day ) , or risperidone ( 1.5 to 6.0 mg per day ) for up to 18 months . Ziprasidone ( 40 to 160 mg per day ) was included after its approval by the Food and Drug Administration . The primary aim was to delineate differences in the overall effectiveness of these five treatments . RESULTS Overall , 74 percent of patients discontinued the study medication before 18 months ( 1061 of the 1432 patients who received at least one dose ) : 64 percent of those assigned to olanzapine , 75 percent of those assigned to perphenazine , 82 percent of those assigned to quetiapine , 74 percent of those assigned to risperidone , and 79 percent of those assigned to ziprasidone . The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine ( P<0.001 ) or risperidone ( P=0.002 ) group , but not in the perphenazine ( P=0.021 ) or ziprasidone ( P=0.028 ) group . The times to discontinuation because of intolerable side effects were similar among the groups , but the rates differed ( P=0.04 ) ; olanzapine was associated with more discontinuation for weight gain or metabolic effects , and perphenazine was associated with more discontinuation for extrapyramidal effects . CONCLUSIONS The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons . Olanzapine was the most effective in terms of the rates of discontinuation , and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine , risperidone , and ziprasidone . Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism Objective : The objective of this study is to compare olanzapine with ziprasidone therapy in patients with schizophrenia or schizoaffective disorder and experiencing depressive symptoms . Methods : This r and omized , double-blind , 24-week , fixed-dose study compared olanzapine ( n = 202 ) and ziprasidone ( n = 192 ) for patients with schizophrenia or schizoaffective disorder and experiencing prominent depressive symptoms . Outcome measures included change in Calgary Depression Scale for Schizophrenia ( CDSS ) score from baseline to 8 weeks ( primary outcome ) and changes in CDSS , Montgomery-Åsberg Depression Rating Scales , Positive and Negative Syndrome Scale , and Global Assessment of Functioning ( GAF ) scores for 24 weeks . Statistical analyses included mixed-effects model repeated measures ( primary analysis ) and change from baseline to last observation carried forward ( LOCF ) . Results : At baseline , patients had moderate depressive symptoms ( mean Montgomery-Åsberg Depression Rating Scales total score , 27.3 ) . For 8 weeks , patients treated with olanzapine or ziprasidone had significant improvements on CDSS . Treatment group differences were not statistically significant ( P = 0.493 , mixed-effects model repeated measures ; P = 0.497 , LOCF ) . For 24 weeks , olanzapine-treated patients showed significantly greater improvements in depressive symptoms ( results varied by depression measure and statistical approach ) and GAF ( P < 0.017 , LOCF ) . A significantly higher proportion of olanzapine-treated patients completed the study ( 44.6 % vs 29.7 % ; P = 0.003 ) and remained longer on medication ( median , 163 vs 73 days , P < 0.001 ) , compared with ziprasidone-treated patients . Olanzapine-treated patients experienced significantly ( P < 0.05 ) greater increases in triglycerides , HgbA1c , and weight . Conclusions : For 24 weeks , olanzapine-treated patients had greater and more sustained participation in treatment , during which time significantly greater improvements were observed in depressive symptoms and GAF scores , along with increases in weight and certain metabolic parameters as compared with ziprasidone-treated patients OBJECTIVE Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia . The purpose of this study was to investigate olanzapine 's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinical ly relevant doses . METHOD Twelve patients with schizophrenia were r and omly assigned to 5 , 10 , 15 , or 20 mg/day of olanzapine in a prospect i ve fashion . Three other subjects taking 30 - 40 mg/day were also included . Once steady-state plasma levels were achieved , dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging , respectively . Ratings of clinical status , extrapyramidal side effects , and prolactin levels were also obtained . RESULTS Olanzapine induced near saturation of the 5-HT2 receptors , even at 5 mg/day . Its D2 occupancy increased with dose : patients taking 5 - 20 mg/day showed 43%-80 % D2 occupancy , while patients taking 30 - 40 mg/day showed 83%-88 % . CONCLUSIONS Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses . However , its D2 occupancy is higher than that of clozapine and similar to that of risperidone . In the usual clinical dose range of 10 - 20 mg/day , its occupancy varies from 71 % to 80 % , and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation . However , doses of 30 mg/day and higher are associated with more than 80 % D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects Positron emission tomography ( PET ) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone . In a third party blind study , six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose . One additional subject was assigned to placebo predose and was scanned at 4 h post-dose . Binding potential ( BP ) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers . Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP , indicative of extensive D2 receptor binding by ziprasidone . With increasing time between dosing and PET scanning there was a curvilinear increase in BP , so that all studies performed at or after 18 h post-dose gave BPs in the normal range ( mean±2 SD ) . Elevated prolactin levels returned to within the normal range by 18 h post-dose . PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time Oral ziprasidone bioavailability is increased when taken with food . Here we describe two pharmacokinetic studies to quantify the impact of food on ziprasidone absorption in healthy volunteers . The first , an open-label , six-way crossover study , investigated ziprasidone absorption in eight healthy men . Subjects received oral ziprasidone ( 20 , 40 , and 80 mg ) after an 8-hour fast or immediately following a US Food and Drug Administration st and ard meal ( 50 % fat ) . In this study , area under the serum concentration- time curve ( AUC ) was greater in fed than in fasting states at each dose ( 20 mg , + 48 % ; 40 mg , + 87 % ; 80 mg , + 101 % ) . Under fasting conditions , increases in AUC and maximum drug concentration ( Cmax ) were less than dose-proportional ; under fed conditions , they were dose-proportional . The second , an open-label , r and omized , three-way crossover study , explored the impact of dietary fat on ziprasidone absorption in 14 healthy subjects . Subjects received ziprasidone ( 40 mg ) under three conditions : fasting , with a high-fat meal ( 60 % fat ) , and with a moderate-fat ( 30 % fat ) meal . AUC and Cmax under fed conditions increased by 104 % and 84 % ( 60%-fat meal ) and 79 % and 98 % ( 30%-fat meal ) , respectively , relative to the fasting state . There was no clear difference in ziprasidone bioavailability between the fed groups , suggesting that meal fat content is not a major determinant of bioavailability . Less pharmacokinetic variability was observed in the fed state , suggesting more consistent absorption of ziprasidone . These results demonstrate that administration of ziprasidone with food is crucial to ensure optimal , reliable dose-dependent bioavailability and thus predictable symptom control and tolerability Olanzapine is a new antipsychotic drug with affinity for 5-HT2 , D2 , D1 , and muscarinic receptors . Positron emission tomography and the radiolig and s [11C]raclopride and [11C]NMSP were used to measure D2 and 5-HT2 receptor occupancy in three healthy subjects after 10 mg olanzapine orally . After seven hours D2 receptor occupancy was 63 % , 62 % and 59 % , respectively . After 9.5 hours 5-HT2 receptor occupancy was 74 % , 86 % and 92 % . D2 and 5-HT2 receptor occupancy was comparable to that found in patients continuously treated with clozapine . Clinical efficacy has been demonstrated for olanzapine in the dose range 5 to 15 mg per day . Extrapolation from our present observations after a 10 mg single-dose suggest , that at the lower end of the clinical ly examined dose range the D2 and 5-HT2 receptor occupancy should be similar to that induced by st and ard doses of clozapine . Detailed evaluation of the dose-response characteristics of olanzapine and direct clinical comparison to clozapine will thus provide valuable leads to the clarification of atypical antipsychotic action OBJECTIVE Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2 ) receptors compared with dopamine D(2 ) receptors in vitro . The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography ( PET ) study . METHOD The authors conducted a PET study to evaluate D(2 ) occupancy ( using [(11)C]raclopride ) and 5-HT(2 ) occupancy ( using [(18)F]setoperone ) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder r and omly assigned to receive 40 , 80 , 120 , or 160 mg/day of ziprasidone , which reflected the recommended dose range . PET scanning was done after 3 weeks of administration and at trough plasma levels , i.e. , 12 - 16 hours after the last dose . RESULTS The mean 5-HT(2 ) receptor occupancy was significantly higher than the mean D(2 ) receptor occupancy ( mean=76 % , SD=15 % , and mean=56 % , SD=18 % , respectively ) . The estimated plasma ziprasidone concentration associated with 50 % maximal 5-HT(2 ) receptor occupancy was almost four times lower than that for D(2 ) receptor occupancy . CONCLUSIONS These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2 ) than D(2 ) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies . The relatively high D(2 ) receptor occupancy , even at trough plasma levels , suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine . Since ziprasidone plasma levels show significant ( more than twofold ) variation within a single dose cycle , studies that are aim ed at peak plasma levels ( 6 hours after the last dose ) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone OBJECTIVE To better underst and the efficacy and tolerability of atypical antipsychotics among racial groups , we review ed data from four short-term ( 4 - 6 weeks ) , fixed-dose , placebo-controlled trials of ziprasidone for black , white , and overall population s of patients with schizophrenia . METHODS Efficacy of ziprasidone in the black , white , and overall schizophrenic population s was compared to placebo using st and ard efficacy measures ( Positive and Negative Syndrome Scale [ PANSS ] total , PANSS negative , Brief Psychiatric Rating Scale [ BPRS ] , Clinical Global Impression-Severity [ CGI-S ] , CGI-Improvement [ CGI-I ] ) . RESULTS Black patients receiving ziprasidone demonstrated statistically significant improvements from baseline in PANSS total , PANSS negative , and BPRS , and improvements in CGI-S and CGI-I ( n=99 - 149 ) compared with placebo ( n=41 - 66 ) ; improvements were comparable to those observed in the overall population ( n=451 - 639 ) and the white population ( n=310 - 430 ) . Interaction effect ( treatment by race ) was not significant for any efficacy variables . Ziprasidone was well-tolerated among black patients ( n=175 ) . Adjusted mean ( least squares mean ) overall weight gain in black patients receiving ziprasidone ( n=124 ) was 1.8 kg . There were no increases in total cholesterol , triglycerides , or r and om glucose in the black population . CONCLUSION Ziprasidone has similar efficacy and safety in black patients with schizophrenia compared with patients in the white and overall population OBJECTIVE Limited r and omized , controlled trial data exist on possible differences between atypical antipsychotics in efficacy , overall tolerability , and important indices of health status . The authors compared the efficacy and tolerability of ziprasidone and olanzapine in the treatment of acutely ill in patients with schizophrenia or schizoaffective disorder . METHOD In this 6-week , multicenter , double-blind , parallel- design , flexible-dose trial , patients were r and omly assigned to receive ziprasidone ( N=136 ) or olanzapine ( N=133 ) . Primary efficacy measures were improvement in Brief Psychiatric Rating Scale and Clinical Global Impression ( CGI ) severity scale scores ; secondary measures were scores on the CGI improvement scale , Positive and Negative Syndrome Scale , and Calgary Depression Scale for Schizophrenia . Tolerability assessment s included fasting lipid profiles , fasting glucose and insulin measurements , electrocardiography , and monitoring of vital signs and body weight . RESULTS The overall mean daily doses were 129.9 mg ( SD=27.3 ) for ziprasidone and 11.3 mg ( SD=2.8 ) for olanzapine . Both antipsychotics were efficacious in improving symptoms and global illness severity . The two treatment groups did not differ significantly in primary or secondary efficacy measures at endpoint or in by-visit analysis . Both agents were well tolerated . Body weight , total cholesterol , triglycerides , and low-density lipoprotein cholesterol significantly increased with olanzapine but not with ziprasidone ; all between-group comparisons of these variables were significant and favored ziprasidone . Olanzapine , but not ziprasidone , was associated with significant increases in fasting insulin level . No patient in either group exhibited a corrected QT interval > /=500 msec . CONCLUSIONS During 6 weeks ' treatment , ziprasidone and olanzapine demonstrated comparable antipsychotic efficacy . Differences favoring ziprasidone were observed in metabolic parameters Rationale Conventional intramuscular ( IM ) antipsychotics used in managing acute exacerbation of schizophrenia are associated with side effects such as acute dystonia . Objectives To compare the efficacy and tolerability of sequential IM/oral ziprasidone with haloperidol in acute exacerbation of schizophrenia or schizoaffective disorder . Methods In a 6-week , multicenter , parallel-group , flexibly dosed study , patients were r and omized to ziprasidone ( IM up to 3 days , then oral 40–80 mg , b.i.d . ) or haloperidol ( IM up to 3 days , then oral 5–20 mg/day ) . Assessment s were rater-blinded . Results At the end of IM treatment , patients receiving ziprasidone ( n=427 ) showed significantly improved Brief Psychiatric Rating Scale Total ( BPRS total ) scores compared with those receiving haloperidol ( n=138 ) [ least-squares ( LS ) mean change −6.14 for ziprasidone versus −4.13 for haloperidol , P<0.0018 ] . At endpoint , there were no significant between-group differences in BPRS total scores . There was a significantly greater improvement in BPRS negative subscale scores in ziprasidone-treated patients , both at the end of IM treatment ( LS mean change −1.15 for ziprasidone and −0.28 for haloperidol , P<0.0001 ) and at study endpoint ( LS mean change −2.94 for ziprasidone and −2.24 for haloperidol , P<0.0001 ) . Haloperidol-treated patients exhibited significantly greater increases in Extrapyramidal Symptom Rating Scale at end of IM treatment and at endpoint ( P<0.0001 ) . They also had significantly higher ratings on the Barnes Akathisia Scale ( P<0.0001 ) and the Movement Disorder Burden Score ( P<0.005 ) , as well as higher incidences of movement disorder-related adverse events . Conclusions Sequential IM and oral ziprasidone offers important efficacy and tolerability advantages over haloperidol in acute schizophrenia BACKGROUND Higher dose ziprasidone has been associated with improved treatment outcomes in patients with schizophrenia or schizoaffective disorder . This study examines the relationship of ziprasidone dose and all-cause discontinuation in r and omized clinical trials in patients with an acute exacerbation of schizophrenia or schizoaffective disorder . METHOD Data were analyzed for the first 28 days from 4 pivotal , r and omized , double-blind , fixed-dose ziprasidone trials . Patients in these trials had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder where ziprasidone was administered twice daily with food . Data were analyzed to examine the association between ziprasidone dose and all-cause discontinuation due to lack of efficacy , adverse events , or because of other reasons , relative to placebo . Differences in discontinuation were evaluated using Cox proportional hazard models and number needed to treat ( NNT ) . RESULTS All-cause discontinuation for ziprasidone ranged from a low of 26.9 % for the 160 mg/d dose group , to 40.9 % for the 40 mg/d and 45.5 % for the 80 mg/d groups , compared with 49.5 % for placebo . The NNTs for avoiding 1 additional all-cause discontinuation compared with placebo were 12 ( 40 mg/d ; n=186 ) , 25 ( 80 mg/d ; n=154 ) , 9 ( 120 mg/d ; n=125 ) , and 4 ( 160 mg/d ; n=104 ) . The 120 mg/d and 160 mg/d groups were the only ziprasidone regimens associated with significantly lower all-cause discontinuation rates versus placebo in both the survival analysis ( p=0.031 and < 0.0001 , respectively ) and in examination of the NNT . The 160 mg/d group was associated with lower all-cause discontinuation rates versus lower-dose ziprasidone regimens ( p=0.0158 for versus 40 mg/d , p=0.002 for versus 80 mg/d ) . Efficacy accounted for 51 % of all medication discontinuations across ziprasidone groups , compared with 62 % for placebo . Findings for overall discontinuation due to lack of efficacy are consistent with results for all-cause discontinuation . CONCLUSIONS Consistent with previous reports , higher doses of ziprasidone ( 120 - 160 mg/d , dosed twice daily with meals ) are associated with significantly lower all-cause discontinuation rates and more favorable NNTs versus placebo . This was primarily driven by lower rates of discontinuation due to lack of efficacy BACKGROUND Ziprasidone is a novel antipsychotic with a unique pharmacologic profile . This study compared ziprasidone with the conventional antipsychotic haloperidol in out patients with stable schizophrenia . METHOD Three hundred one out patients with stable chronic or subchronic schizophrenia ( DSM-III-R ) were r and omized and participated in this double-blind , multicenter , parallel-group clinical study comparing flexible-dose oral ziprasidone , 80 - 160 mg/day ( N = 148 ) , with haloperidol , 5 - 15 mg/day ( N = 153 ) , over 28 weeks . Patients were assessed using the Positive and Negative Syndrome Scale ( PANSS ) , the Clinical Global Impressions-Severity of Illness scale , the Montgomery-Asberg Depression Rating Scale , the Simpson-Angus Scale , the Barnes Akathisia Scale , and the Abnormal Involuntary Movement Scale . RESULTS Modal doses at endpoint were 80 mg/day for ziprasidone and 5 mg/day for haloperidol . Improvements in all mean efficacy variables with both ziprasidone and haloperidol were observed . Significantly more patients were categorized as negative symptom responders ( > or = 20 % reduction in PANSS negative subscale score ) in the ziprasidone group ( 48 % ) compared with the haloperidol group ( 33 % ) ( p < .05 ) . Ziprasidone had clear advantages over haloperidol in all evaluations of movement disorders . Changes in body weight were negligible with both treatments . No pattern of laboratory or cardiovascular changes was observed . CONCLUSION Ziprasidone and haloperidol were both effective in reducing overall psychopathology ; ziprasidone demonstrated effective treatment of negative symptoms and was better tolerated than haloperidol . Ziprasidone appears to offer an effective alternative to haloperidol in the long-term treatment of stable out patients with schizophrenia Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind , exploratory , dose-ranging trial . After a single-blind washout period of 4 to 7 days , patients were r and omly assigned to receive one of four fixed doses of the new antipsychotic , ziprasidone 4 ( N = 19 ) , 10 ( N = 17 ) , 40 ( N = 17 ) , or 160 ( N = 20 ) mg/day or haloperidol 15 mg/day ( N = 17 ) for 4 weeks . A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity ( CGI-S ) score ( p = 0.002 ) but not in Brief Psychiatric Rating Scale ( BPRS ) total score ( p = 0.08 ) . The intent-to-treat analysis of mean changes from baseline in the BPRS total , BPRS Psychosis core , and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day . Despite the small sample size and short duration of the trial , the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day ( p = 0.001 and p = 0.005 , respectively ) . The percentage of patients classified as responders on both the BPRS total ( > or = 30 % improvement ) and CGI-Improvement ( score of 1 or 2 ) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group . On all assessment s of clinical efficacy , the improvements associated with ziprasidone 4 mg/day , 10 mg/day , and 40 mg/day were similar . Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day ( 15 % ) than with haloperidol ( 53 % ) . Haloperidol was associated with a sustained hyperprolactinemia , unlike ziprasidone , where only transient elevations in prolactin that returned to normal within the dosing interval were observed . Ziprasidone was well tolerated , and the incidence of adverse events was similar in all groups . The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms We evaluated relapse in patients with stable , chronic schizophrenia over a 1-year period ; in patients were r and omized to ziprasidone 40 mg/day ( n = 72 ) , 80 mg/day ( n = 68 ) , 160 mg/day ( n = 67 ) or placebo ( n = 71 ) . The probability of relapse ( Kaplan – Meier ) at 1 year was significantly lower in the ziprasidone 40 , 80 , and 160 mg/day groups ( 43 % , 35 % and 36 % , respectively ) compared to placebo ( 77%;P = 0.002 , P < 0.001 and P < 0.001 , respectively ) . In those patients who remained on treatment for at least 6 months , only 9 % subsequently relapsed on ziprasidone compared to 42 % on placebo ( P = 0.001 ) . All three doses of ziprasidone were significantly superior to placebo on Positive and Negative Syndrome Scale ( PANSS ) efficacy variables ( all P < 0.05 ) . Ziprasidone was associated with a significantly greater mean improvement in the PANSS negative symptom subscale compared to placebo ( P < 0.05 ) . Discontinuation due to adverse events was similar with ziprasidone and placebo . Ziprasidone treatment was indistinguishable from placebo in assessment s of movement disorders and was not associated with weight gain or cardiovascular abnormalities . These results demonstrate that ziprasidone was effective in reducing the frequency of relapse and was associated with long-term improvement in negative symptoms . Ziprasidone was well tolerated in this population of patients with chronic , stable schizophrenia AIMS To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers , and to determine the influence of ziprasidone on serum prolactin levels . METHODS Single and multiple doses of ziprasidone were given orally ( as two divided daily doses ) , at fixed dosages of 10 and 40 mg day(-1 ) , and using titrated regimens of 40 - 80 and 40 - 120 mg day(-1 ) , for 14 days . All dosages were taken immediately after food . The study adopted a r and omized , double-blind , placebo-controlled design . Prolactin response , sedative properties , tolerability , and extrapyramidal symptoms were also investigated . RESULTS Steady-state exposure to ziprasidone was attained after 1 day of dosing . Mean Cmax and AUC(0,12 h ) increased with increasing dose , with apparent dose-proportionality between the 20 and 60 mg dose levels . Trough-to-peak ratios at steady state ranged from 2 to 5 . Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels , respectively . Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state . There was a marginal , transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day(-1 ) doses , and which was noted to attenuate with chronic dosing . Ziprasidone was generally well tolerated . The most frequent side-effect was mild or moderate headache . A minority of patients suffered first-dose postural hypotension . Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued . There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance . CONCLUSIONS Ziprasidone is characterized by a predictable pharmacokinetic profile result ing in symptoms that reflect its pharmacological action BACKGROUND Food is known to increase the bioavailability of ziprasidone . Therefore , we evaluated the effects of meals of differing caloric and fat content on steady-state ziprasidone exposure in a stable , treated group of subjects with DSM-IV diagnoses of schizophrenia , schizoaffective disorder , bipolar disorder , or psychotic disorder ( not otherwise specified ) who were already receiving oral ziprasidone as their st and ard therapy . METHOD Patients took ziprasidone under 6 meal conditions in r and omized sequences ( fasted , low calorie/low fat , low calorie/high fat , medium calorie/high fat , high calorie/low fat , and high calorie/high fat ) ; each crossover period was separated by at least 3 days for washout of the previous meal condition . Serial blood sample s were obtained over the 12 hours postdose . The study was conducted from July 27 to September 28 of 2006 . RESULTS Maximum ziprasidone exposures in this study were observed with high-calorie meals ( 1000 kcal ) , which were nearly twice those observed under fasting conditions . The medium-calorie meal ( 500 kcal ) was associated with exposures similar to the high-calorie meals . Low-calorie meals ( 250 kcal ) were associated with exposures that were approximately 60 % to 90 % lower than those of medium- and high-calorie meals , and approached exposures seen under fasting conditions . Fat content of the meal had no significant effect on ziprasidone absorption . The ziprasidone exposures observed with medium- and high-calorie meals had less variability than those with low-calorie meals and under fasting conditions . CONCLUSIONS These results confirm that ziprasidone should be taken with food and that a meal equal to or greater than 500 kcal , irrespective of fat content , is required for optimal and reproducible bioavailability of the administered dose OBJECTIVE The efficacy and safety of olanzapine were compared with those of ziprasidone . METHOD This was a multicenter r and omized , double-blind , parallel-group , 28-week study of patients with schizophrenia . Patients were r and omly assigned to treatment with 10 - 20 mg/day of olanzapine or 80 - 160 mg/day of ziprasidone . The primary efficacy measure was the Positive and Negative Syndrome Scale total score . Secondary efficacy and safety measures included Positive and Negative Syndrome Scale subscales as well as mood , quality of life , and extrapyramidal symptom scales . Safety was evaluated by recording treatment-emergent adverse events and measuring vital signs and weight . RESULTS The study was completed by significantly more olanzapine-treated patients ( 165 of 277 , 59.6 % ) than ziprasidone-treated patients ( 115 of 271 , 42.4 % ) . At 28 weeks , the olanzapine-treated patients showed significantly more improvement than the ziprasidone-treated patients on the Positive and Negative Syndrome Scale overall scale and all subscales and on the Clinical Global Impression ratings of severity of illness and improvement . The responder rate was higher for olanzapine than for ziprasidone . Extrapyramidal symptoms were not significantly different between groups in change-to-endpoint analyses , but results favored olanzapine on baseline-to-maximum changes . Weight change was significantly greater with olanzapine ( mean=3.06 kg , SD=6.87 ) than with ziprasidone ( mean=-1.12 kg , SD=4.70 ) . Fasting lipid profiles were significantly superior in the ziprasidone group ; there was no significant difference in fasting glucose level . CONCLUSIONS Olanzapine treatment result ed in significantly greater psychopathology improvement and higher response and completion rates than ziprasidone treatment , while ziprasidone was superior for weight change and lipid profile

MRI has equivalent sensitivity and specificity to ultrasound for diagnosis of DVT , but has been evaluated in many fewer studies , using a variety of different techniques

Magnetic resonance imaging ( MRI ) may be used to diagnose deep vein thrombosis ( DVT ) in patients for whom ultrasound examination is inappropriate or unfeasible . We undertook a systematic review of the literature and meta- analysis to estimate the diagnostic accuracy of MRI for DVT .

We performed a prospect i ve , blinded study to assess and compare the values of preoperative contrast venography and magnetic resonance venography in the detection of deep venous thrombosis in the thigh and pelvis of forty-five consecutive patients who had a displaced acetabular fracture . The magnetic resonance venography and contrast venography were performed an average of seven days ( range , one to twenty-nine days ) after the injury . Twenty-four asymptomatic thrombi were identified with magnetic resonance venography in fifteen ( 33 percent ) of the patients . Four of the thrombi were in the superficial femoral vein , nine were in the common femoral vein , one was in the external iliac vein , seven were in the internal iliac vein , and three were in the common iliac vein . Ten ( 42 percent ) of the twenty-four thrombi were confirmed with contrast venography ; nine of them were located in the thigh . The remaining fourteen thrombi ( 58 percent ) that had been noted on magnetic resonance venography could not be seen with contrast venography because they were located either in the deep pelvic veins or in the uninjured extremity . The thrombi in the internal iliac vein were identified only with magnetic resonance venography . Twelve of the fifteen patients who had thrombi had a filter placed in the inferior vena cava preoperatively . In eight of these patients , the filter was placed because of the findings of magnetic resonance venography alone . Magnetic resonance venography result ed in a change in the therapeutic management of ten ( 22 per cent ) of the forty-five patients . There were no pulmonary emboli . We concluded that magnetic resonance venography is superior to contrast venography for the preoperative evaluation of proximal deep venous thrombosis in patients who have an acetabular fracture . Magnetic resonance venography is non-invasive , does not require the use of contrast medium , images the proximal aspects of both lower extremities simultaneously , and , most importantly , allows for the identification of deep venous thrombosis in the pelvis Magnetic resonance venography is a recently developed , noninvasive means of visualizing the proximal veins of the lower extremity and pelvis . Magnetic resonance venography is compared with st and ard contrast venography in the diagnosis of proximal deep vein thrombosis after total joint arthroplasty . Two hundred seven extremities were evaluated in a blinded study 5 to 7 days after surgery . St and ard contrast venography identified 11 proximal deep vein thromboses . Initial interpretations of the magnetic resonance venographies by staff radiologists identified 5 of the proximal vein thromboses ( sensitivity 45 % ) . Two patients with negative st and ard contrast venographies were identified as positive ( specificity 99 % ) . A retrospective review of all magnetic resonance venographies by a dedicated magnetic resonance angiographer identified 10 of 11 deep vein thromboses seen on st and ard contrast venography ( sensitivity 91 % ) . Both false negatives were identified as positives . St and ard contrast venography remains the gold st and ard for identifying proximal vein thromboses . Emerging magnetic resonance imaging techniques have created a potential alternative modality by which to identify deep vein thrombosis . The present study suggests that st and ard contrast venography continues to be the most accurate modality currently available . Although magnetic resonance venography seems to be accurate , its interpretation requires experience . As costs diminish and experience increases , magnetic resonance venography will have increased importance in the clinical recognition of deep vein thrombosis This is a prospect i ve comparative study of magnetic resonance imaging ( MRI ) of the deep veins versus contrast venography in consecutive patients treated for various injuries to their lower extremities , showing no clinical symptoms of deep vein thrombosis . The majority of examinations referred to in this study were performed according to the following methodology : First , the patient was subjected to MRI . Subsequently , within a 24-h interval , he/she was subjected to contrast venography . The acquired results were compared in a blinded manner . The diagnostic indices for MRI were calculated on the assumption that the results of contrast venography were sure to give an accurate indication of either presence or absence of thrombosis . Thirty-six patients were included in the study , of which 27 ( 15 males ) completed it . The overall incidence of distal deep venous thrombosis ( DVT ) was 22 % ( 6/27 ) . One patient showed extension of a crural thrombus into the popliteal vein . MRI did not detect any of the thrombi . This lack of result was ascribed to failure to fully demonstrate all segments of the crural veins . However , MRI did show three proximal thrombi in the superficial femoral vein , which were not shown by the venograms . Thus , both the sensitivity and specificity of MRI were 0 % , so MRI proved to be of no value in the diagnosis of asymptomatic deep venous thrombosis in this study RATIONALE AND OBJECTIVES The authors performed this study to compare magnetic resonance ( MR ) venography and conventional venography in the diagnosis of deep venous thrombosis ( DVT ) in the calf after sonography . MATERIAL S AND METHODS Sonography was performed in 595 patients who were suspected of having lower-extremity DVT . Patients with positive above-knee duplex sonograms , allergy to iodinated contrast material , renal insufficiency , or cardiac pacemakers and patients who were obese were excluded . The remaining 73 patients were asked to undergo MR venography and conventional venography . All studies were to be performed within 48 hours of the clinical diagnosis and according to st and ard clinical practice . Images were interpreted by radiologists who were blinded to the results of other modalities . Two separate analyses were performed : one in which conventional venography was used as the st and ard of reference , and one in which the presence of at least two positive studies for thrombus was considered diagnostic . RESULTS Although 36 patients agreed to participate in the study , only 14 underwent MR venography and conventional venography within 48 hours of the clinical diagnosis . With use of any two positive studies for confirmation , acute DVT was diagnosed in three patients . Conventional venography depicted two of the three cases , whereas sonography and MR venography each depicted all three . The findings were concordant in only five of the 14 patients . CONCLUSION Moderate discrepancy among modalities was demonstrated . This suggests radiologists should undertake comparisons among these three modalities for the detection of calf DVT . In patients with a high clinical suspicion , a second modality may be useful if the initial study is negative The aims of this study were to optimize image quality for indirect CT venography ( sequential versus spiral ) , and to evaluate different image reconstruction parameters for patients with suspected deep venous thrombosis ( DVT ) . Fifty-one patients ( 26/25 with/without DVT ) were prospect ively evaluated for pulmonary embolism ( PE ) with st and ard multidetector-row computed tomography ( MDCT ) protocol s. Retrospective image reconstruction was done with different slice thicknesses and reconstruction increments in sequential and spiral modes . All reconstructions were read for depiction of DVT and to evaluate best reconstruction parameters in comparison with the thinnest reconstruction ( “ gold st and ard ” ) . Image noise and venous enhancement were measured as objective criteria for image quality . Subjective image quality was rated on a four-point scale . Effective dose was estimated for all reconstructions . In sequential 10/50 reconstruction DVT was completely detected in 13/26 cases , partially in 10/26 cases and was not detected at all in 3/26 cases , and 15/26 , 9/26 and 2/26 cases for the 10/20 reconstruction , respectively . DVT was completely detected in all spiral reconstructions . Image noise ranged between 14.8 - 29.1 HU . Median image quality was 2 . Estimated effective dose ranged between 2.3 mSv and 11.8 mSv . Gaps in sequential protocol s may lead to false negative results . Therefore , spiral scanning protocol s for complete depiction of DVT are m and atory Despite considerable recent advances in diagnostic techniques for lower-limb deep venous thrombosis ( DVT ) , current methods have disadvantages . Ultrasonography , the most accurate noninvasive test , is widely available and cheap . As such , it has largely replaced venography as the test of first choice for symptomatic DVT . In a recent meta- analysis , the sensitivity of ultrasonography was 89 % overall for symptomatic DVT and 97 % for above-knee thrombosis ( 1 ) . Large outcome studies have shown that patients may be safely left untreated after a negative result on ultrasonography if they have a low clinical risk score , a low d-dimer level , or a negative result on repeated ultrasonography at 1 week ( 2 - 4 ) . However , these strategies may be complex and still require 3 % to 34 % of out patients and most in patients to undergo repeated ultrasonography at 1 week ( 2 - 4 ) . In practice , retesting after 1 week is inconvenient , and physicians often rely on a single test or request immediate venography ( 5 ) . Other problems with ultrasonography include poor sensitivity for asymptomatic disease , difficulties in diagnosing DVT recurrence , and limited visualization in the pelvis ( 1 , 6 , 7 ) . Impedance plethysmography is also commonly used ; however , it has a lower diagnostic accuracy than ultrasonography and has similar weaknesses in the setting of recurrent thrombosis , asymptomatic DVT , and DVT below the knee or in the pelvis ( 1 , 4 , 6 ) . Computed tomography and magnetic resonance imaging techniques can visualize DVT above the knee and in the pelvis but in general are unsuccessful below the knee ( 8 - 10 ) . The ability of these techniques to diagnose DVT recurrence and asymptomatic disease has not been tested . Venography is the reference st and ard diagnostic test , but it has in large part been replaced by noninvasive tests . In clinical practice , it is the most reliable test for the diagnosis of asymptomatic thrombosis and thrombosis isolated within the calf or pelvis . However , imaging in the pelvis is inadequate in up to 24 % of normal studies , and the proximal extent of thrombosis is frequently not delineated in patients with above-knee DVT ( 11 ) . Underfilling of vessels and vessels overlying one another also create problems with venography below the knee . Studies have shown that interobserver variability for venography is high ( 10 % to 16 % ) , especially below the knee ( = 0.46 to 0.73 below the knee and 0.46 to 0.84 above the knee ) ( 12 , 13 ) . In addition , a high proportion of studies are nondiagnostic for possible DVT recurrence ( 1 , 6 ) . A noninvasive test is needed that accurately diagnoses above-knee DVT and thrombus below the knee , in the pelvis , and in asymptomatic limbs . Unlike most imaging techniques , which identify thrombus as filling defects , magnetic resonance direct thrombus imaging ( MRDTI ) visualizes thrombus against a suppressed background ( 14 ) . In an unblinded comparison with venography , we previously showed that MRDTI precisely visualizes acute deep venous thrombus ( 14 , 15 ) . In the current study , we sought to assess prospect ively whether MRDTI is a reliable diagnostic test for suspected acute symptomatic DVT . Methods The ethics committee at our institution granted approval for the study , and all participants gave written informed consent . With the exceptions of pregnant women , patients with known contrast allergy , and those with renal failure , all patients with DVT suspected on the basis of lower limb symptoms are investigated by using venography at our institution . Participants were recruited after routine venography was done between May 1998 and September 1999 . During this time , 338 consecutive patients underwent routine contrast venography . Consecutive patients with positive venograms were selected , along with one quarter of those with negative venograms , according to a predetermined r and om sequence . This protocol was chosen to equalize the numbers of positive and negative cases and was based on a 6-month audit of venograms in our institution that found that 22 % of venograms were positive . Clinical diagnostic criteria were not used , and the decision to request investigation for suspected DVT had been made by the attending clinician ; however , patients who did not have leg symptoms were not recruited . Other exclusion criteria were failed or inconclusive venography , failed or inconclusive MRDTI , contraindications to MRI , and claustrophobia ( Figure 1 ) . Individual venous segments that were nondiagnostic at venography were also excluded from analysis . Figure 1 . Outline of the study . Magnetic resonance direct thrombus imaging was performed on all patients recruited within 48 hours of venography . The scans were interpreted by an experienced radiologist ( review er A ) and by a nonradiologist ( review er B ) trained to read MRDTI scans . For venograms and MRDTI scans , the review ers noted the presence or absence of DVT ; the diagnostic classification of DVT , divided into isolated calf DVT , femoropopliteal DVT , and ileofemoral DVT ; and the presence of thrombus in the calf , femoropopliteal , and iliac venous segments . Venograms were obtained and initially reported by the radiologists on duty . This initial report was used to make recruitment decisions ; if the results were discordant with those of MRDTI , ultrasonography was also performed . However , ultrasonography was not used in the calculations of the accuracy of MRDTI . After completion of the study , venograms were interpreted by an independent radiologist , and these results were used as the gold st and ard against which MRDTI was compared . Results of MRDTI and venography were reported without knowledge of the results of other tests and the other readings . The d-dimer level was measured in all patients at the time of the MRDTI scan by using the Nycocard ( Nycomed Pharma AS , Asker , Norway ) technique ( normal level < 0.3 mg/L ) . Venography Venography was performed by cannulating a dorsal pedal vein with a 21-gauge needle and rapidly injecting 50 to 100 mL of iodinated contrast medium ( I2 , 300 mg/mL ) , with the patient supine and tilted 30 degrees with his or her feet downward . A tourniquet was applied above the ankle . Anteroposterior and two oblique views of the deep calf and popliteal veins were obtained . Views of the femoral and iliac veins were then obtained . The study result was considered positive if intraluminal filling defects were seen or persistent nonfilling of veins with a sharp cut-off was detected . Magnetic Resonance Imaging Magnetic resonance imaging was performed by using a 1.5-Tesla unit ( Siemens Vision , Erlangen , Germany ) with a T1-weighted magnetization-prepared three-dimensional gradient-echo sequence . The sequence included a water-only excitation radiofrequency pulse to abolish the fat signal , and the effective inversion time was chosen to nullify the blood signal . Imaging was performed from the ankle to the inferior vena cava in two imaging blocks with a total acquisition time of 12 minutes by using a 55-cm body coil . Both legs were imaged simultaneously . Scanning was performed by radiographers in all cases . Image assessment involved reading of coronal source data and st and ard image reconstruction techniques . Acute thrombus was diagnosed on the basis of its high signal against the suppressed background ( Figure 2 ) . Figure 2 . Magnetic resonance direct thrombus imaging in three patients . A. arrows B. arrows C. single arrows double arrow Ultrasonography Color flow and compression ultrasonographic images of the symptomatic limb from the common femoral vein distally were obtained by using a 5-MHz linear array transducer . As much of the superficial femoral vein as possible was imaged , together with the popliteal vein and the calf veins . Augmentation of flow was used to verify patency . Examinations were performed by senior radiologists , and DVT was confirmed in all cases by noncompressibility on gray-scale images . The sonographer was unaware of the other test results , but in cases of possible isolated calf thrombosis , he or she was told to concentrate the examination below the knee to maximize accuracy in this region . Statistical Analysis Sensitivity and specificity were calculated for the overall diagnosis of DVT ; diagnosis of isolated calf DVT , femoropopliteal DVT , and ileofemoral DVT ; and presence of thrombus in the calf , femoropopliteal vein , and iliac vein . Exact CIs were calculated . Interobserver error was calculated for these observations by using the weighted statistic with equally spaced weights for positive , nondiagnostic , and negative studies . Confidence intervals for the statistic were calculated from asymptotic estimations of the st and ard error . Calculations were performed by using SPSS software ( SPSS , Inc. , Chicago , Illinois ) . Results One hundred four patients were recruited according to our protocol ( Figure 1 ) . The time between venography and MRDTI was less than 8 hours in 28 patients , 8 to 24 hours in 44 patients , and 24 to 48 hours in 32 patients . Age ranged from 20 to 95 years , and symptom onset varied from 1 to 35 days . Ninety-five patients were referred from medical specialties and 9 from surgical specialties ; 47 were in patients and 57 were out patients . Both review ers reported that 3 of 5 patients with ipsilateral total hip replacements had nondiagnostic MRDTI scans . Venography diagnosed femoropopliteal DVT in 1 of these patients and was negative in 2 patients . These 3 patients were excluded from further analysis , leaving 101 patients in the study . One patient could tolerate only the first scanning block from ankle to thigh level owing to claustrophobia ; however , femoropopliteal DVT could still be diagnosed . All other patients tolerated MRI . Eighteen of 148 patients ( 12 % ) were excluded from the study . Fifteen patients could not undergo MRI because of contraindications ( 9 patients ) or claustrophobia ( 6 patients ) , and 3 patients had inconclusive results on MRDTI . Venography failed ( 29 patients ) or was inconclusive ( 11 patients ) in 12 % of patients ( 40 of 338 ) . Venography was Current noninvasive imaging techniques for diagnosis of deep venous thrombosis ( DVT ) of extremities are limited in their ability to demonstrate central vein involvement and to distinguish acute from chronic changes . The utility of spin-echo magnetic resonance ( MR ) imaging for DVT was evaluated in 100 patients suspected of having either upper- ( n = 25 ) or lower-extremity ( n = 75 ) DVT . Ninety-seven patients were imaged successfully . In a subset of 36 patients , prospect i ve comparison of MR imaging with contrast venography revealed a sensitivity of 90 % , specificity of 100 % , and Kappa level of agreement of .752 ( P less than .0001 ) . MR imaging showed more central extent of thrombus than did venography in all five patients with upper-extremity DVT and in 13 of 25 patients ( 52 % ) with lower-extremity DVT . Although all patients in the study were evaluated for acute symptoms , 13 of 59 ( 22 % ) MR imaging studies positive for DVT demonstrated chronic disease . MR images demonstrated ancillary abnormalities in 18 of 41 ( 44 % ) patients who did not have DVT . Thus , MR imaging has a role as the definitive examination when the results of initial screening studies are unsatisfactory , or as a first-line examination if ( a ) there is suspicion of upper-extremity or pelvic vein thrombosis , ( b ) there is a history of prior DVT that necessitates distinction of acute from chronic changes , or ( c ) other tests are unavailable OBJECTIVE To determine the accuracy of gradient recalled echo magnetic resonance imaging in assessing deep venous thrombosis . DESIGN This is a retrospective review of a prospect i ve clinical experience in 216 consecutive patients studied using gradient recalled echo magnetic resonance imaging . Sixteen patients were unavailable for follow-up and 1 study was technically suboptimal , leaving 199 studies as the basis of this report . RESULTS In 79 cases with confirmatory venography ( n = 54 ) , ultrasound ( n = 16 , thigh veins only ) , or computed tomography ( n = 9 , pelvic veins only ) , magnetic resonance imaging was 97 percent sensitive , 95 percent specific , and 96 percent accurate . Including cases that were normal by magnetic resonance imaging , not anticoagulated , and with uneventful follow-up as true normal cases , the corresponding sensitivity , specificity , and accuracy of magnetic resonance imaging were as follows : 97 percent , 98 percent , and 97 percent . CONCLUSION Magnetic resonance imaging , using gradient recalled echo acquisitions , is capable of accurately diagnosing acute deep venous thrombosis Seventy-five patients ( 41 women and 34 men , 20 - 85 years old ) with clinical ly suspected deep venous thrombosis ( DVT ) were examined with MR imaging and sonography . In 26 patients , the final diagnosis was acute femoropopliteal DVT . The sensitivity of MR imaging for detecting this disease was 100 % with a 95 % confidence interval ( CI ) of 87 - 100 % ; the specificity was 100 % with a CI of 92 - 100 % ; and the accuracy was 96 % with a CI of 89 - 99 % . The correspond-ing sensitivity of sonography was 77 % with a CI of 53 - 92 % ; the specificity was 98 % with a CI of 89 - 100 % ; and the accuracy was 83 % with a CI of 72 - 90 % . In four of the 75 patients , MR images revealed thrombus of the pelvis ( n = 1 ) or calf ( n = 3 ) without femoropopliteal involvement . The estimated prevalence of isolated calf and /or pelvic DVT was 5 % with a CI of 1 - 13 % . MR imaging is significantly more sensitive ( P = .02 ) and accurate ( P < .01 ) than sonography in the detection of lower extremity DVT , but there was no difference in the specificity of MR imaging and that of sonography ( P = .31 ) Sixteen patients ( 17 lower extremities ) were prospect ively examined with venography and limited-flip-angle , gradient-refocused magnetic resonance ( MR ) imaging for the presence or absence of deep venous thrombosis . Thrombosed vessels showed decreased-to-absent signal intensity , while patent vessels had high signal intensity . In 16 of 17 extremities , MR images allowed accurate detection and localization of the thrombi found with venography . In the remaining extremity , MR imaging allowed correct identification of thrombus in the iliac and femoral veins but incorrectly demonstrated clot in the calf and popliteal veins . MR imaging with limited-flip-angle , gradient-refocused pulse sequences appears to be a sensitive , noninvasive means of detecting deep venous thrombosis OBJECTIVE This study was design ed to compare the diagnostic value of MR venography and color Doppler sonography in the assessment of deep venous thrombosis . SUBJECTS AND METHODS MR venograms and color Doppler examinations were obtained in 37 patients either with suspected deep venous thrombosis of the lower limbs or pelvis or with pulmonary embolism . Two-dimensional time-of-flight venography was used for all studies . MR and color Doppler data were collected prospect ively and analyzed in a blinded manner . In a subset of 21 patients , MR venography and color Doppler sonography were prospect ively compared with contrast-enhanced venography . RESULTS When compared with contrast-enhanced venography , MR venography was 100 % sensitive and 100 % specific in the diagnosis of deep venous thrombosis above the knee . Color Doppler imaging depicted 13 of 15 cases of deep venous thrombosis and 5 of 6 venous examinations that had normal results , yielding a sensitivity and a specificity of 87 % and 83 % , respectively . The differences in sensitivity and specificity between MR venography and color Doppler sonography were not statistically significant . MR venography was 95 % sensitive and 99 % specific in detecting the extension of deep venous thrombosis , compared with the 46 % sensitivity and 100 % specificity of color Doppler sonography ( differences in sensitivity , p < .01 ) . MR images showed 29 collateral vessels , whereas only 21 were detected by contrast-enhanced venography ( p < .04 ) . CONCLUSION MR venography seems to be more accurate than color Doppler sonography in detecting the extension of deep venous thrombosis . The positive diagnosis and extent of deep venous thrombosis can be easily detected and monitored by a noninvasive technique such as MR venography OBJECTIVE Preliminary reports have described the use of MR imaging for the detection of deep venous thrombosis . However , no prospect i ve study comparing MR imaging with contrast venography ( the gold st and ard ) has been reported . Accordingly , we performed a prospect i ve , blinded study of the efficacy of MR imaging in 61 consecutive patients with clinical ly suspected deep venous thrombosis . In cases of disagreement , additional testing was performed to determine the diagnosis . SUBJECTS AND METHODS From June 1991 to February 1992 , 61 patients with clinical ly suspected deep venous thrombosis were examined with venography and MR imaging . The average time between studies was 3 hr . In 21 of the 61 patients , the final diagnosis was deep venous thrombosis . RESULTS For detection of deep venous thrombosis in the pelvis , the sensitivity of MR imaging was 100 % ( 9/9 ) with a 95 % confidence interval of 72 - 100 % and the specificity was 95 % ( 52/55 ) with a 95 % confidence interval of 85 - 99 % . In the thigh , the sensitivity ( 16/16 ) and specificity ( 43/43 ) were both 100 % with 95 % confidence intervals of 83 - 100 % and 93 - 100 % , respectively . In the calf , the sensitivity was 87 % ( 13/15 ) with a 95 % confidence interval of 60 - 98 % and the specificity was 97 % ( 36/37 ) with a 95 % confidence interval of 86 - 100 % . CONCLUSION We found no statistically significant difference between MR imaging and contrast venography in the detection of deep venous thrombosis . This result suggests that MR imaging is at least as sensitive and specific as contrast venography in the detection of deep venous thrombosis

Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research , result ing in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered .

Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery . R and omized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987 , and systematic review s were conducted in 1992 and 1997 .

Background —Extracorporeal circulation induces a systemic inflammatory response , which may adversely affect organ function . One manifestation of this response is increased fibrinolysis . Antifibrinolytic drugs such as aprotinin and & egr;-aminocaproic acid have been effective in reducing fibrinolysis and blood loss after extracorporeal circulation ; however , the effects of antifibrinolytic drugs on proinflammatory and anti-inflammatory mediators are not known . This study examined the effects of aprotinin and & egr;-aminocaproic acid on plasma levels of proinflammatory [ interleukin-6 ( IL-6 ) ] and anti-inflammatory [ interleukin-10 ( IL-10 ) ] cytokines during and after extracorporeal circulation . Methods and Results —Seventy-two patients undergoing coronary artery bypass grafting with extracorporeal circulation were r and omly assigned in a double-blind study to receive high-dose aprotinin , & egr;-aminocaproic acid , or saline placebo . Plasma levels of IL-6 and IL-10 were measured at 5 time points before , during , and after extracorporeal circulation . In all 3 groups , both IL-6 and IL-10 rose significantly after institution of extracorporeal circulation and remained elevated through the first postoperative day . Compared with saline , aprotinin significantly reduced IL-10 ( P = 0.02 ) and peak IL-6 ( P = 0.02 ) after extracorporeal circulation . In contrast , none of the reductions in IL-6 and IL-10 by & egr;-aminocaproic acid achieved statistical significance . Both aprotinin and & egr;-aminocaproic acid decreased blood loss compared with saline , but there was no significant difference in the number of patients receiving blood products among the treatment groups . Conclusions —These data suggest that aprotinin and & egr;-aminocaproic acid differ in their effects on the inflammatory response to extracorporeal circulation . Aprotinin but not & egr;-aminocaproic acid appears to attenuate the rise in the proinflammatory and anti-inflammatory cytokines IL-6 and IL-10 . Further studies will be required to determine if these cytokine alterations translate to changes in clinical outcomes OBJECTIVES To examine pump-prime aprotinin action on coagulation and fibrinolysis in patients undergoing primary coronary revascularization . DESIGN A prospect i ve r and omized study . SETTING A university hospital . PARTICIPANTS Forty-three patients were r and omly assigned to either group A , 21 patients treated with 2 x 10(6 ) kallikrein inhibitor units ( KIU ) of aprotinin in the cardiopulmonary bypass ( CPB ) prime , or group B , 22 patients , untreated . INTERVENTIONS Patients , scheduled for elective coronary surgery , were treated with 2 x 10(6 ) KIU of aprotinin in the CPB prime . Markers of coagulation and fibrinolysis were evaluated . MEASUREMENTS AND MAIN RESULTS Surgical times , number of reopenings , and allogeneic blood requirements were collected for each patient . Blood sample s were obtained before and after surgery for assessing coagulation ( prothrombin time [ PT ] , activated partial thromboplastin time [ aPTT ] , ethanol test , factor VII , antithrombin III [ AT III ] , thrombin-antithrombin III complex [ TAT ] , fragment 1.2 of prothrombin [ F1.2 ] ) and fibrinolysis ( fibrin degradation products [ FOP ] , plasmin-antiplasmin complexes [ PAP ] , D-dimers ) markers variations . In group A surgical times were faster , there were fewer reopenings ( 0 v 3 ) , and fewer blood transfusions ( 1 patient v 4 patients ) . The two groups did not differ for PT , aPTT , and fibrinogen measurements . Postoperative FDP ( measurable in more patients of group B at the end of the operation ) , PAP , and D-dimers postoperatory levels ( less increased in aprotinin group ) show the antifibrinolytic properties of the drug . Regarding the coagulation markers , factor VII decreased , whereas TAT and F1.2 increased , all to a lesser extent in the aprotinin group compared with the untreated patients , at the end of operation . CONCLUSION Pump-prime aprotinin minimized , even if not completely inhibited , the activation of coagulation and fibrinolysis during CPB , possibly ensuring a less complicated and safer postoperative recovery . It seemed to allow the maintenance of a correct balance of hemostatic systems , avoiding the risk of thrombotic phenomena The serine proteinase inhibitor aprotinin significantly reduces postoperative blood loss in patients requiring cardiac surgery using cardiopulmonary bypass . This study compared two low‐dose regimens with administration of high‐dose aprotinin and a control protocol to determine whether the dose of aprotinin could be greatly decreased but still maintain efficacy after primary cardiac surgery . Some 100 patients were r and omly assigned to one of four groups : control group ( 0·9 per cent saline placebo , n = 25 ) ; high‐dose group ( aprotinin 2 × 106 kallikrein inactivator ( KI ) units intravenous patient bolus and 0·5 × 106 KI units h−1 plus 2 × 106 KI units into pump prime , n = 25 ) ; prime group ( aprotinin 2 × 106 KI units added to the pump prime , n = 24 ) ; and patient group ( aprotinin 106 KI units intravenous patient bolus plus 106 KI units added to the pump prime , n = 26 ) . Only patients from the high‐dose and patient groups had reduced intraoperative blood loss , but patients from all three aprotinin‐treated groups demonstrated a significant decrease in median postoperative blood loss compared with the control group ( high‐dose 350 ml , prime 420 ml , patient 340 ml versus control 780 ml ; P < 0·001 ) . There was an even greater reduction in measured median postoperative haemoglobin loss within the chest drains in the treated compared with the control patients ( high‐dose 15 g , prime 24 g , patient 14 g versus control 47 g ; P < 0·001 ) . These decreases were statistically the same for all the treated groups ; it is possible to lower the dose of aprotinin to approximately one‐third of the currently recommended dosage and still obtain significantly reduced postoperative blood loss in primary cardiac surgery To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrolment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results Background Patients on cardiopulmonary bypass ( CPB ) have an increased susceptibility to postoperative bleeding . Previous reports using desmopressin acetate ( DDAVP ) for the prevention of postoperative bleeding have given contradictory results , whereas the protease inhibitor aprotinin has been shown to reduce blood loss after this type of surgery . This r and omized study was performed to assess the efficacy of DDAVP versus aprotinin in the prevention of bleeding after CPB . Methods and Results One hundred nine of 122 eligible patients were r and omized to four different groups : Group A ( n=28 ) received aprotinin starting with a bolus of 2 × 106 KIU followed by a continuous infusion of 0.5 × 106 KIU/h until the end of surgery ; group B ( n=25 ) received of DDAVP 0.3 μ/kg IV on completion of CPB ; group C ( n=28 ) received two doses of DDAVP , the first as in group B and an additional dose 6 hours after surgery ; group D ( n=28 ) received no treatment . There was a marked reduction of postoperative blood loss either at 12 hours ( P<.01 ) or 72 hours ( P<.02 ) in the aprotinin group compared with all other groups , whereas no significant effect was observed in either of the two DDAVP regimens . A significant reduction in the amount of blood used was observed only in the aprotinin group ( P<.01 ) . Of the plasma fibrinolytic components assayed , there was a significant reduction of the fibrin degradation product generation in the aprotinin group ( P<.001 ) , whereas a significant systemic hyperfibrinolysis was observed in both DDAVP-treated groups and the control group . No side effects related to the study drugs were observed in any patient . Conclusions Aprotinin inhibited fibrinolysis ; this correlated with a significant reduction of postoperative blood loss and need for blood replacement after CPB . Neither one nor two doses of DDAVP had a beneficial effect . Aprotinin offers better alternative than DDAVP in the prevention of bleeding after CPB BACKGROUND Aprotinin therapy is now widely used during cardiac surgery . This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo . METHODS In a double blind , r and omized study , three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient ( AUS$ = Australian dollars ) , low-dose aprotinin costing AUS$220 per patient or placebo . Re source use influenced by aprotinin therapy was measured . RESULTS Both doses were effective in reducing chest drainage and postoperative transfusion requirements , high-dose being more effective than low-dose . Both doses reduced the rate of reoperations for hemostasis . A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient , respectively . If the demonstrated less significant reductions in operating room and ward stay are included , these savings become AUS$463 and AUS$715 , respectively . Alternately , if cross-matches are replaced by group- and -hold and cell savers are not used , the savings per patient would be AUS$196 and AUS$467 , respectively . CONCLUSIONS While high-dose aprotinin is clinical ly more effective than low-dose aprotinin , low-dose therapy demonstrates greater cost savings The effectiveness and mechanism of aprotinin reduced bleeding after cardiopulmonary bypass surgery was studied in a double blind r and omised study of 106 patients undergoing valve replacement surgery . Aprotinin therapy was associated with significant reduction in perioperative bleeding and postoperative blood transfusion requirements . Although initially tissue plasminogen activator ( t-PA ) activity was lower in the aprotinin than placebo group , as surgery proceeded this difference was reversed due to less plasminogen activator inhibitor-1 release in the aprotinin group . This indicates that aprotinin-mediated suppression of fibrinolysis as demonstrated by reduced D-dimer concentration was not related to t-PA . Furthermore , similar perioperative reduction of plasminogen levels in aprotinin and placebo groups indicated a similar degree of conversion of plasminogen to plasmin . However , less plasmin bound with alpha 2-antiplasmin in the plasma in the aprotinin group as it was already complexed with aprotinin where it remained protected from the natural inhibitor on the intact fibrin surface . The reduced fibrinolytic activity of the aprotinin group was thus brought about by the complexing of aprotinin with the plasmin which was bound to the fibrin surface Sixty consecutive patients undergoing elective open-heart surgery were prospect ively enrolled in a study to compare the efficacy of 3 different antifibrinolytic drugs to reduce postoperative bleeding and to reduce homologous blood requirements in combination with blood-saving techniques and restrictive indications for blood transfusion . The patients were r and omized to 1 of 4 intraoperative treatment regimens : 1 ) control ( no antifibrinolytic therapy ) ; 2 ) epsilon-aminocaproic acid ( 10 g IV at induction of anesthesia , followed by infusion of 2 g/h for 5 hours ) ; 3 ) tranexamic acid ( 10 mg/kg IV within 30 minutes after induction of anesthesia , followed by infusion of 1 mg/kg per hour for 10 hours ) ; or 4 ) high-dose aprotinin ( 2 million KIU IV at induction of anesthesia and 2 million KIU added to the extracorporeal circuit , followed by infusion of 500 thous and KIU/h during surgery ) . Hemoconcentration and reinfusion of blood drained from the operative field and the extracorporeal circuit after operation were used in all patients . Indications for blood transfusion were hypotension , tachycardia , or both , with hemoglobin values < 8.5 g/dL ; or severe anemia with hemoglobin values < 7 g/dL. Compared with the blood loss in the control group , patients receiving aprotinin and epsilon-aminocaproic acid showed significantly less postoperative blood loss at 1 hour ( control , 128 + /- 94 mL ; aprotinin , 54 + /- 47 mL , p = 0.01 ; and epsilon-aminocaproic acid , 69 + /- 35 mL , p = 0.03 ) ; this trend continued at 24 hours after operation ( control , 724 + /- 280 mL ; aprotinin , 344 + /- 106 mL , p < 0.0001 ; and epsilon-aminocaproic acid , 509 + /- 148 mL , p = 0.01 ) . Aprotinin was significantly more efficient than epsilon-aminocaproic acid ( p=0.002 ) . Tranexamic acid did not have a statistically significant effect on blood loss . Homologous blood requirements were not significantly different among the groups ; postoperative hematologic values and coagulation times were also comparable . Despite the efficacy of aprotinin and epsilon-aminocaproic acid shown in the present study , the blood requirements were not significantly different from those that are found when transfusions are restricted , autotransfusions are used , and blood from the operative field and extracorporeal circuit is concentrated and reinfused . Therefore , intraoperative antifibrinolysis may not be indicated in routine cardiac surgery when other blood-saving techniques are adopted One hundred patients due to undergo primary cardiac surgery were prospect ively r and omized to receive aprotinin or placebo . In the aprotinin group , 250,000 kallikrein inhibitory units ( KIU ) of aprotinin were added to the cardiopulmonary bypass prime solution . A further 250,000 KIU of aprotinin were infused intravenously over 30 minutes immediately before the start of cardiopulmonary bypass . The control group received 0.9 % saline in equal volumes at identical times . The study was design ed to have a 90 % chance of demonstrating a 30 % reduction in blood loss . No significant differences were found between the two groups . The median blood loss in the aprotinin group was 750 mL ( interquartile range 556 to 1025 mL , 95 % confidence interval 600 to 800 mL ) . In the control group , the median blood loss was also 750 mL ( interquartile range 500 to 988 mL , 95 % confidence interval 625 to 925 mL ) . In the aprotinin group , 12 patients received postoperative autotransfusion of shed mediastinal blood of median volume of 665 mL ( interquartile range 500 to 925 mL , 95 % confidence interval 450 to 1000 mL ) . In the control group , 14 patients received postoperative autotransfusion of mediastinal blood of median volume of 663 mL ( interquartile range 600 to 800 mL , 95 % confidence interval 600 to 700 mL ) . Five patients in the aprotinin group and seven patients in the control group required postoperative homologous blood transfusion . Re assessment of inclusion criteria showed a 19 % reduction in blood loss in patients undergoing only aortocoronary bypass receiving aprotinin compared with controls . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To evaluate the effects of minimal-dose aprotinin in patients undergoing coronary artery bypass grafting , we conducted a prospect i ve r and omized study . METHODS A total of 167 patients were r and omized to receive no aprotinin treatment ( control , n = 57 ) , minimal-dose aprotinin ( 1.0 x 10(6 ) KIU ; n = 55 ) , or low-dose aprotinin ( 2.7 + /- 0.5 x 10(6 ) KIU ; n = 55 ) . Blood loss and transfusion requirements , parameters of clotting and fibrinolysis , renal function , and early graft patency rates were assessed . RESULTS Postoperative blood loss and transfusion requirements were significantly ( p = 0.01 ) lower in both the minimal-dose and low-dose groups than in the control group . The increase in D-dimer level after cardiopulmonary bypass was significantly ( p < 0.05 ) less marked in the low-dose group than in the control group . The alpha 2-plasmin inhibitor and plasminogen activator inhibitor-1 levels were significantly ( p < 0.05 ) greater in the minimal-dose and low-dose groups than in the control group after bypass , suggesting the prevention of fibrinolysis by both aprotinin doses . No statistically significant differences in postoperative renal function and early vein graft patency rates were noted ( control group , 93.8 % ; minimal-dose group , 95.5 % ; low-dose group , 92.3 % ; p = 0.25 ) . CONCLUSIONS Aprotinin was not associated with a significant increase in the prevalence of renal dysfunction or early vein graft occlusion . Minimal-dose aprotinin inhibited enhanced fibrinolytic activity and reduced blood loss and transfusion requirements after bypass equivalently to low-dose aprotinin . The dose of 1 x 10(6 ) KIU added to the pump prime may be acceptably effective in reducing blood loss in patients undergoing primary coronary operations High-dose aprotinin reduces bleeding after cardiac surgery , but has also evoked concern with regard to potential side effects and hospital costs . To evaluate the effects of reduced-dose aprotinin on blood loss and need for blood transfusion , 40 patients undergoing myocardial revascularization were studied ( double-blind , placebo-controlled ) . Postoperative bleeding was reduced by 40 % and erythrocyte infusion by 85 % in the group given 3 x 10(6 ) KIU aprotinin ( 1 x 10(6 ) as a loading dose before cardiopulmonary bypass , 1 x 10(6 ) in the priming volume and 2.5 x 10(5)/hour intraoperatively ) Aprotinin concentrations during the operation were monitored and maintained above the required level . There were no adverse effects of the drug . Hospital expenditure on blood products was reduced by 51 % when aprotinin was used . Our study suggests that aprotinin in reduced dosage diminishes bleeding and requirements for blood products , and that it should be given before , during and after cardiopulmonary bypass Background Aprotinin causes a prolongation of the celite-activated clotting time ( CACT ) , but not of the kaolin-activated clotting time ( KACT ) . Therefore , concern has been raised regarding the reliability of CACT to monitor anticoagulation in the presence of aprotinin . The current study was design ed to test the efficacy of aprotinin to improve anticoagulation , and to investigate whether the prolongation of CACT reflects true anticoagulation or is an in vitro artifact . To eluci date this antithrombotic effect of aprotinin , this study was done in patients prone to reduced intraoperative heparin sensitivity BACKGROUND Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin , it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation . METHODS Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin ( 150 mg/d ) until the day before the operation were enrolled in a prospect i ve , r and omized , double-blind trial to receive a single dose of either placebo ( n = 29 ) or 2 x 10(6 ) kallikrein inhibiting units of aprotinin ( n = 26 ) at the time of sternal skin closure . RESULTS Patients in the aprotinin group had a lower rate ( 28 + /- 18 vs 43 + /- 21 mL/h [ mean + /- st and ard deviation ] , P < .005 ) and total volume of mediastinal drainage ( 955 + /- 615 vs 1570 + /- 955 mL , P < .007 ) , as well as a shorter duration of mediastinal drain tube insertion ( 24.4 + /- 13.8 vs 31.3 + /- 16.5 hours , P < .05 ) . In addition , a smaller proportion of patients receiving aprotinin required a blood product ( 31 % vs 62 % , P = .03 ) , result ing in a reduction in the use of packed cells by 47 % ( P = .05 ) , platelets by 77 % ( P = .01 ) , fresh frozen plasma by 88 % ( P = .03 ) , and total blood products by 68 % ( P = .01 ) in this group . CONCLUSIONS These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use BACKGROUND AND AIM OF THE STUDY High-dose aprotinin is an effective but costly method to reduce transfusions after cardiopulmonary bypass ( CPB ) . Very low doses of aprotinin have been shown to be effective in primary cardiac surgery , but not in patients undergoing procedures associated with the greatest usage of allogeneic blood products after CPB . We evaluated the efficacy of ultra-low-dose aprotinin in this patient population . METHODS Aprotinin 1 million KIU or placebo was added to the priming solution of the CPB circuit of 52 patients undergoing a reoperation and /or a complex surgical procedure . Dryness of operative field , hemoglobin concentrations , coagulation parameters , chest drainage , and transfusion requirements were compared . RESULTS Total chest drainage was not different between groups , but fewer patients in the aprotinin group required additional protamine postoperatively ( 35 % vs 69 % for controls , p = 0.03 ) and fewer received fresh frozen plasma ( FFP ; 19 % vs 46 % for controls , p = 0.04 ) . Red cell transfusion was smaller in the aprotinin group compared to placebo ( median 4 and 2 units , respectively , p = 0.04 ) . Transfusion of FFP , platelets , cryoprecipitates was not different between groups . Total number of units transfused tended to be reduced in the aprotinin group compared to control ( median 2 and 7 units , respectively , p = 0.06 ) . CONCLUSIONS Prophylactic administration of ultra-low-dose aprotinin reduced transfusions in patients undergoing repeat operations or complex procedures . Aprotinin could be used in a more economical manner , even in this patient population at high-risk of receiving allogeneic blood products Background Administration of aprotinin during extracorporeal circulation reduces blood loss and improves platelet function . Methods and Results To evaluate the protective effect of aprotinin on platelets , 50 patients undergoing cardiopulmonary bypass were r and omized before surgery to one of three groups . Seventeen patients ( group A ) received continuous high-dose aprotinin ( 7X106 KIU ) during cardiopulmonary bypass , 17 ( group B ) received a single bolus of aprotinin in the pump prime ( 2x106 KIU ) , and 16 ( group C ) received placebo . Scanning electron microscopy was used to evaluate platelet aggregation on extracellular matrix . The platelet function was grade d from 1 to 4 , with grade 4 being normal aggregation . Immediately after cardiopulmonary bypass , 16 patients in group A ( 94 % ) reached preoperative aggregation grade ( mean grade , 3.4±0.7 ) compared with nine of 17 in group B ( 52 % ) ( mean grade , 2.9±1.2 ) , and none in group C ( 0 % ) ( mean grade , 1.4±0.5 ; p<0.001 ) . Postoperative platelet count did not differ significantly among the three groups . After surgery , group A bled less than groups B and C ( 395±120 versus 488±135 and 780±408 ml , respectively ; p<0.01 ) . Patients in the aprotinin groups received fewer red blood cell units ( 0.9±1.2 and 1.9±1.2 versus 3.4±1.9 , respectively ; p<0.01 ) and were exposed to less homologous blood products ( 1.3±1.7 and 2.1±1.1 versus 6.1±5 , respectively ; p<0.001 ) . Conclusions By preserving platelet function , aprotinin improves postoperative hemostasis in all patients who receive high dose and in most who receive low dose OBJECTIVES Due to the discovery in the 1980s that blood transfusion can transmit HIV , there has been increased interest in technologies that reduce the amount of allogeneic blood used during and after surgery . These technologies include drugs ( aprotinin , tranexamic acid , epsilon-aminocaproic acid , erythropoietin ) , devices ( cell salvage ) , and techniques ( acute hemodilution , predeposited autologous donation ) . The purpose of this study was to ascertain the degree of practice variation , if any , that exists for eight technologies in nine countries in orthopedic and cardiac surgery . METHODS In each country , either all hospitals or a r and om sample of hospitals with medical/surgical beds were surveyed between 1995 and 1997 . Two instruments were used . The first instrument was a postcard that asked recipients whether the technologies were currently being used in their hospital for orthopedic and /or cardiac surgery to reduce perioperative allogeneic transfusion . The second question naire elicited information regarding the degree of use both in qualitative and quantitative terms . Data were collected , entered , and analyzed in each country , with summary results su bmi tted to the Canadian coordinating center on a st and ardized data collection form . RESULTS Pharmaceuticals were generally used in a much smaller proportion of hospitals in orthopedic than in cardiac surgery . Aprotinin and tranexamic acid were the drugs most frequently used in cardiac surgery . Nonpharmacological technologies were used to a greater degree than drugs in orthopedic surgery , although there was wide variation among technologies and countries . Acute hemodilution and cell salvage were used in a greater proportion of hospitals for cardiac surgery than orthopedic surgery . CONCLUSIONS The results of this survey indicate that there is considerable practice variation in the use of technologies to minimize exposure to perioperative allogeneic transfusion within and between countries Aprotinin reduces blood loss after cardiopulmonary bypass , but may sensitize recipients and is expensive . Tranexamic acid , a synthetic antifibrinolytic , has less disadvantages , but opinions differ regarding its efficacy . We studied three groups of patients undergoing cardiopulmonary bypass for coronary disease : recipients of aprotinin ( total dose 4.2 x 10(6 ) kallikrein inhibiting units , n = 14 ) , recipients of tranexamic acid ( total dose 20 mg/kg body weight , n = 15 ) , and nonmedicated controls ( n = 14 ) during 24 hours after cardiopulmonary bypass . Compared with controls , aprotinin reduced blood loss , the number of patients requiring transfusions , and the mean number of transfused red cell units ( all with p < 0.05 ) , whereas the recipients of tranexamic acid did not differ either from aprotinin recipients or from controls . Aprotinin and tranexamic acid both mitigated the early postoperative reduction of adenosine diphosphate-induced platelet aggregation seen in the controls ( p < 0.05 ) . Postoperative increases of plasma concentrations of the prothrombin activation fragment F1 + 2 and the thrombin-antithrombin III complex showed an activation of intravascular coagulation , without any intergroup differences . The balance between concentrations of tissue plasminogen activator and the type 1 plasminogen activator inhibitor disclosed an activation of fibrinolysis , without differences between the groups . The concentrations of D-dimer , a breakdown product of cross-linked fibrin , remained at baseline in the recipients of aprotinin and tranexamic acid but tripled in the controls ( p < 0.05 ) . By contrast , the plasma antiplasmin activity was equally depressed in the tranexamic acid and the control groups but decreased less in the recipients of aprotinin ( p < 0.05 ) . This discrepancy may reflect the different modes of action of the two agents , which may make aprotinin more efficacious than tranexamic acid in the " nonfibrinolytic " act of protecting platelet function against attack by plasmin during cardiopulmonary bypass Nowadays in many European heart centers the activation of the fibrinolytic system , always occurring during cardiopulmonary bypass , is routinely reduced by high-dose application of the proteinase inhibitor aprotinin ( total of > 4 million KIU ) . In this study parameters of myocardial ischemic injury were investigated with the aim of identifying further benefits of aprotinin , particularly the protection of the myocardium during the ischemic period of aortic crossclamping . Forty patients with coronary artery disease who underwent aorta-coronary bypass grafting were r and omly and in a double-blind fashion divided into two groups , one that received high-dose aprotinin therapy and one that received only saline solution . Markers such as troponin T , with high specificity for detection of myocardial ischemia and infa rct ion , and markers with more general specificity such as creatine kinase , its isoenzyme , and lactate dehydrogenase showed significantly increased values after ischemia in both groups . In patients who received high-dose aprotinin therapy 3 days after cardiopulmonary bypass all parameters measured showed significantly lower levels compared with those in the control group . Therefore we can presume that the application of high-dose aprotinin provides myocardial protection from perioperative ischemic injury OBJECTIVES To assess the relative efficacy of a " low-dose " aprotinin regimen and tranexamic acid on blood loss and homologous blood usage in patients undergoing primary cardiac surgery . DESIGN The trial was prospect i ve , r and omized , and controlled . SETTING A single center study in a regional cardiothoracic unit in the UK . PARTICIPANTS 75 Patients , age 18 years or over , who were scheduled for routine primary cardiac surgery . INTERVENTIONS The patients were r and omly allocated to receive neither drug nor placebo , a total of 5 g of tranexamic acid , or a total of 2 x 10(6 ) kallikrein inhibitory units of aprotinin in the perioperative period . MEASUREMENTS AND MAIN RESULTS The volume of blood loss and blood replacement were measured in the operative and postoperative periods . Hemoglobin concentration , platelet count , and white cell counts were determined preoperatively and at 24 hours postoperatively . Patients receiving tranexamic acid or aprotinin showed a significant reduction in postoperative blood loss ( median[interquartile range ] 375 mL [ 252 to 542 ] and 230 mL [ 137 to 547 ] ) , respectively , compared with the control group ( 615 mL [ 430 to 861 ] ) . Blood usage was also reduced in patients in both the tranexamic acid group ( 600 mL [ 415 to 800 ] ) and the aprotinin-treated group ( 420 mL [ 350 to 887 ] ) compared with the control group ( 1,050 mL [ 0 to 1,337 ] ) . There was no significant difference in blood loss or homologous blood use between patients treated with tranexamic acid or aprotinin . CONCLUSIONS Tranexamic acid is as effective as low-dose aprotinin in the reduction of postoperative blood loss and homologous blood transfusion in patients undergoing primary cardiac surgery Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin ( 2 million units loading dose , 2 million units added to the CPB prime , and 500,000 units/hr maintenance infusion ) or placebo . Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group ( 95 % confidence interval ( CI ) for difference = 95 to 189 ml ) . Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood . This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery OBJECTIVE To rule out the effect of high-dose aprotinin in respect to the balance of proinflammatory and anti-inflammatory mediators induced by cardiopulmonary bypass ( CPB ) . DESIGN R and omized , double-blind , placebo-controlled study . SETTING University-affiliated cardiac center . PARTICIPANTS Twenty patients scheduled for coronary artery bypass graft surgery . INTERVENTIONS In group A patients ( n = 10 ) , high-dose aprotinin was administered ( 2 x 106 KIU pre-CPB , 2 x 10(6 ) KIU in prime , 500,000 KIU/hr during CPB ) . In group C patients ( n = 10 ) , placebo was used instead . Proinflammatory interleukin (IL)-6 , anti-inflammatory IL-1-receptor antagonist , and clinical parameters were measured 8 times perioperatively . The values are presented as mean + /- SEM . MEASUREMENTS AND MAIN RESULTS Four hours after CPB , IL-6 concentration reached the maximum value , being significantly lower in group A patients as compared with group C patients ( 615 + /- 62 pg/mL v 1,409 + /- 253 pg/mL ; p = 0.019 ) . On the first postoperative day , the concentration of IL-6 in group A patients remained lower ( 219 + /- 24 pg/mL v 526 + /- 123 pg/mL ; p = 0.015 ) . In contrast , IL-1-receptor antagonist concentration was higher in group A patients as compared with group C patients after CPB ( 13,857 + /- 4,264 pg/mL v 5,675 + /- 1,832 pg/mL ; p = 0.03 ) . Total postoperative blood loss was lower in group A patients as compared with group C patients ( 648 + /- 64 mL v 1,284 + /- 183 mL ; p = 0.002 ) . CONCLUSIONS High-dose aprotinin treatment reduced the inflammatory reaction and postoperative blood loss . The anti-inflammatory reaction was significantly enhanced in these patients , which suggests that the physiologic reaction of the organism to reduce the deleterious effects from CPB is more pronounced by using high-dose aprotinin OBJECTIVE We examined the effects of aprotinin on graft patency , prevalence of myocardial infa rct ion , and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass . METHODS Patients from 13 international sites were r and omized to receive intraoperative aprotinin ( n = 436 ) or placebo ( n = 434 ) . Graft angiography was obtained a mean of 10.8 days after the operation . Electrocardiograms , cardiac enzymes , and blood loss and replacement were evaluated . RESULTS In 796 assessable patients , aprotinin reduced thoracic drainage volume by 43 % ( P < .0001 ) and requirement for red blood cell administration by 49 % ( P < .0001 ) . Among 703 patients with assessable saphenous vein grafts , occlusions occurred in 15.4 % of aprotinin-treated patients and 10.9 % of patients receiving placebo ( P = .03 ) . After we had adjusted for risk factors associated with vein graft occlusion , the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 ( 90 % confidence interval , 0.6 to 1.8 ) . These factors included female gender , lack of prior aspirin therapy , small and poor distal vessel quality , and possibly use of aprotinin-treated blood as excised vein perfusate . At United States sites , patients had characteristics more favorable for graft patency , and occlusions occurred in 9.4 % of the aprotinin group and 9.5 % of the placebo group ( P = .72 ) . At Danish and Israeli sites , where patients had more adverse characteristics , occlusions occurred in 23.0 % of aprotinin- and 12.4 % of placebo-treated patients ( P = .01 ) . Aprotinin did not affect the occurrence of myocardial infa rct ion ( aprotinin : 2.9 % ; placebo : 3.8 % ) or mortality ( aprotinin : 1.4 % ; placebo : 1.6 % ) . CONCLUSIONS In this study , the probability of early vein graft occlusion was increased by aprotinin , but this outcome was promoted by multiple risk factors for graft occlusion Various clinical trials have shown that hemostasis is improved by the administration of aprotinin during cardiopulmonary bypass . However , this effect has not been proved for those patients treated preoperatively with aspirin . Therefore , a double-blind , placebo-controlled study was conducted to test the efficacy of low-dose aprotinin ( 2 x 10(6 ) KIU in the pump prime solution ) in preserving hemostasis in 40 aspirin-treated ( 325 mg ) patients undergoing coronary artery bypass grafting . Aprotinin brought about a decrease in the postoperative blood loss ( p < 0.05 ) . The in vitro bleeding test ( Thrombostat ) demonstrated that aprotinin preserved the platelet hemostatic function in aspirin-treated patients during cardiopulmonary bypass ( p < 0.05 ) . The inhibitory effects of aspirin on collagen-induced platelet aggregation and thromboxane production were not influenced by aprotinin treatment . The findings from the present study indicate that aprotinin preserves hemostasis in aspirin-treated patients during cardiopulmonary bypass , but aspirin 's effect on platelets is maintained . Therefore , aprotinin seems to be a useful adjunct treatment in aspirin-treated patients undergoing coronary artery bypass grafting BACKGROUND Aprotinin reduces blood loss in operations done with cardiopulmonary bypass , whereas the use of desmopressin remains controversial . We compared aprotinin , desmopressin , and placebo in a double-blind , r and omized trial to evaluate bleeding and transfusion requirements . METHODS AND RESULTS One hundred forty-nine patients ( 48 received aprotinin , 50 desmopressin , 51 placebo ) were included . Blood loss and transfusion requirements were recorded and levels of Factor VIII coagulant activity , von Willebr and 's factor , thrombin-antithrombin complexes , and D-dimer were measured . Overall blood loss was 195 + /- 146 ml/m2 in the aprotinin group , 400 + /- 192 ml/m2 in the desmopressin group , and 489 + /- 361 ml/m2 in the placebo group ( 95 % confidence intervals : difference between desmopressin and aprotinin 98 to 312 ml/m2 , p < 0.001 ; difference between placebo and aprotinin 190 to 398 ml/m2 , p < 0.001 ) . Twenty-six percent of patients treated with aprotinin , 66 % of those treated with desmopressin , and 56 % of those treated with placebo were given transfusion ( 95 % confidence intervals : difference between aprotinin versus placebo plus desmopressin 51 % to 71 % , p < 0.001 ) . Fibrinolytic activation throughout cardiopulmonary bypass was markedly higher with placebo or desmopressin administration . D-dimer level correlated with overall blood loss in patients receiving desmopressin or placebo , but not in those receiving aprotinin . CONCLUSION Aprotinin administration reduces blood loss and transfusion requirements in cardiopulmonary bypass . This benefit may be explained by a lower activation of fibrinolysis OBJECTIVE To determine whether two low-dose regimens of aprotinin influence platelet function . DESIGN Prospect i ve , r and omized , single-blinded trial . SETTING University teaching hospital performing 600 cardiac operations per year . PARTICIPANTS Fifty-nine patients scheduled for cardiac surgery undergoing cardiopulmonary bypass ( CPB ) of expected duration of 60 minutes or more . INTERVENTIONS Patients were r and omized into three groups . Group C ( control ) included 21 patients who did not receive aprotinin . In group A2 , 17 patients received 14,286 kallikrein inhibitor units (KIU)/kg ( 2 mg/kg ) of aprotinin before surgery , followed by a continuous infusion of 7,143 KIU/kg/h ( 1 mg/kg/h ) until the end of surgery . In group A4 , 19 patients received 28,572 KIU/kg ( 4 mg/kg ) of aprotinin before surgery , followed by the same infusion . MEASUREMENTS AND MAIN RESULTS Postoperative bleeding and transfusion requirements were significantly less in group A4 . Changes in platelet number and function were similar in the three groups . Platelet aggregation was assessed in four periods : before CPB ( T1 ) , post-CPB ( T2 ) , and 2 hours ( T3 ) and 4 hours ( T4 ) after CPB . Platelet aggregation induced by adenosine diphosphate , 1 and 2 micromol/L ; ristocetin , 1 mg/mL ; and arachadonic acid ( AA ) , 1.4 mmol/L , decreased at T2 ( p < 0.001 ) in all groups , and for the ristocetin and AA groups , remained at less than baseline values at T3 and T4 . In five patients from each group , platelet receptors for glycoprotein IIb-IIIa ( GPIIb-IIIa ) and expression of platelet activation markers , guanosine monophosphate 140 ( GMP-140 ) and lysosomal protein , were measured by flow cytometry before and after CPB . Modifications in the expression of GPIIb-IIIa were always modest and without statistical significance . Platelet activation markers , GMP-140 or lysosomal protein , nearly doubled from baseline to post-CPB only in the A4 group , whereas they remained stable in both other groups ( statistically not significant ) . CONCLUSION The two regimens of aprotinin , both considered low dosage , did not exert a protective effect on platelet function . Neither dose produced changes in platelet GPIIb-IIIa or platelet activation markers . However , bleeding and transfusion needs were decreased BACKGROUND Patients having cardiac operations often require blood transfusions . Aprotinin reduces the need for blood transfusions during coronary artery bypass graft operations . To determine the safety and effectiveness of aprotinin in reducing the use of allogeneic blood and postoperative mediastinal chest tube drainage , we studied 212 patients undergoing primary sternotomy for valve replacement or repair . METHODS This study was multicenter , r and omized , prospect i ve , double-blind , and placebo-controlled . Patients received high-dose aprotinin ( n = 71 ) , low-dose aprotinin ( n = 70 ) , or placebo ( n = 71 ) . The study medication was given as a loading dose followed by a continuous infusion and pump prime dose . Heparin administration was st and ardized . Transfusions , postoperative mediastinal shed blood , and adverse events were tracked . RESULTS Demographic profiles were similar among the treatment groups . Aprotinin did not decrease the percentage of patients receiving transfusions when compared with placebo ( high-dose aprotinin , 63 % , p = 0.092 ; low-dose aprotinin , 52 % , p = 0.592 ; placebo , 48 % ) . Aprotinin was associated with a reduction in the volume of mediastinal shed blood ( high-dose aprotinin vs placebo , p = 0.002 ; low-dose aprotinin vs placebo , p = 0.017 ) . Adverse events were equally distributed among the treatment groups except for postoperative renal dysfunction ( high-dose aprotinin , 11 % ; low-dose aprotinin , 7 % ; placebo , 0 % ; p = 0.01 ) . A disproportionate number of patients in the high-dose aprotinin group with postoperative renal dysfunction also had diabetes mellitus . CONCLUSIONS Aprotinin treatment in this population did not reduce allogeneic blood use , although there were significant reductions in the volume of mediastinal shed blood BACKGROUND Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients . To examine the safety and dose-related efficacy of aprotinin , a prospect i ve , multicenter , placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft ( CABG ) surgery . METHODS AND RESULTS Two hundred eighty-seven patients were r and omly assigned to receive either high-dose aprotinin , low-dose aprotinin , pump-prime-only aprotinin , or placebo . Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume . The percentage of patients requiring donor-red-blood-cell ( RBC ) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups ( high-dose aprotinin , 54 % ; low-dose aprotinin , 46 % ; pump-prime only , 72 % ; and placebo , 75 % ; overall P = .001 ) . The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo ( high-dose aprotinin , 1.6 + /- 0.2 U ; low-dose aprotinin , 1.6 + /- 0.3 U ; pump-prime-only , 2.5 + /- 0.3 U ; and placebo , 3.4 + /- 0.5 U ; P = .0001 ) . There was also a significant difference in total blood-product exposures among treatment groups ( high-dose aprotinin , 2.2 + /- 0.4 U ; low-dose aprotinin , 3.4 + /- 0.9 U ; pump-prime-only , 5.1 + /- 0.9 U ; placebo , 10.3 + /- 1.4 U ) . There were no differences among treatment groups for the incidence of perioperative myocardial infa rct ion ( MI ) . CONCLUSIONS This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI Background : Aprotinin and tranexamic acid are routinely used to reduce bleeding in cardiac surgery . There is a large difference in agent price and perhaps in efficacy . Methods : In a prospect i ve , r and omized , partially blinded study , 168 cardiac surgery patients at high risk for bleeding received either a full-dose aprotinin infusion , tranexamic acid ( 10-mg/kg load , 1-mg · kg−1 · h−1 infusion ) , tranexamic acid with pre – cardiopulmonary bypass autologous whole-blood collection ( 12.5 % blood volume ) and reinfusion after cardiopulmonary bypass ( combined therapy ) , or saline infusion ( placebo group ) . Results : There were complete data in 160 patients . The aprotinin ( n = 40 ) and combined therapy ( n = 32 ) groups ( data are median [ range ] ) had similar reductions in blood loss in the first 4 h in the intensive care unit ( 225 [ 40–761 ] and 163 [ 25–760 ] ml , respectively;P = 0.014 ) , erythrocyte transfusion requirements in the first 24 h in the intensive care unit ( 0 [ 0–3 ] and 0 [ 0–3 ] U , respectively;P = 0.004 ) , and duration s of time from end of cardiopulmonary bypass to discharge from the operating room ( 92 [ 57–215 ] and 94 [ 37 , 186 ] min , respectively;P = 0.01 ) compared with the placebo group ( n = 43 ) . Ten patients in the combined therapy group ( 30.3 % ) required transfusion of the autologous blood during cardiopulmonary bypass for anemia . Conclusions : The combination therapy of tranexamic acid and intraoperative autologous blood collection provided similar reduction in blood loss and transfusion requirements as aprotinin . Cost analyses revealed that combined therapy and tranexamic acid therapy were the least costly therapies Cardiopulmonary bypass ( CPB ) increases risk of postoperative bleeding and need for transfusion . The aim of this study was to evaluate the effects of aprotinin , epsilon aminocaproic acid and tranexamic acid on coagulation patterns and need for banked blood transfusion . Ninety-six consecutive patients who underwent coronary artery bypass surgery were r and omly assigned to 4 groups ( 24 patients each ) . The following parameters were monitored before , during and after CPB : activated lotting time , hemoglobin , prothrombin time , activated prothromboplastin time , fibrinogen , antithrombin III , xDP , Factor VIII , Thrombin-Antithrombin Complex and plasminogen . Analysis of postoperative bleeding and need for transfusion showed that the aprotinin group had significantly lower mediastinal bleeding . Transfused patients were 2 , 4 , 12 and 18 respectively in the aprotinin , epsilon aminocaproic acid , tranexamic acid and placebo treated group . In conclusion the use of protease inhibitors significantly reduces postoperative bleeding and transfusion . The aprotinin-treated group had the lower need for transfusion To assess the efficacy and safety of the use of a high-dose regimen of aprotinin in routine cardiac operations , a placebo-controlled r and omized double- blind study was conducted in 93 adult patients undergoing cardiopulmonary bypass . Aprotinin-treated patients ( group A , n = 46 ) received 2 × 106 Kallikrein Inactivating Units ( KIU ) of aprotinin before incision , 2 × 106 KIU in the priming solution and 5 x 105 KIU/h during CPB . Control patients ( group B , n = 47 ) received the same volume of normal saline . Mean postoperative blood loss in ml after six hours and in total until removal of thoracic drains decreased significantly from 752 and 1933 in controls , to 358 and 1051 in treated patients ( p < 0.001 ) . Mean total transfusion needs were 2.6 ( A ) and 4.8 ( B ) units per patient . Adverse events were evenly distributed between both groups and could not be attributed to aprotinin use . We , therefore , recommend the use of a high-dose regimen of aprotinin for routine cardiac operations despite its cost One hundred sixty-five patients undergoing primary myocardial revascularization were prospect ively entered into a r and omized , double-blind , placebo-controlled study , in a single institution , in order to determine the influence of high- and low-dose aprotinin application on early coronary artery bypass graft patency . All patients were operated on by the same team and the three treatment groups were comparable in all demographic data and surgical variables . Postoperative chest tube drainage and transfusion requirements were significantly reduced in patients receiving high or low doses of aprotinin . In all patients vein and internal mammary artery graft patency was assessed by control coronary angiograms 4 to 15 days ( median 8.2 days ) postoperatively . In the high-dose aprotinin group , 140 of 142 vein grafts and in the low-dose aprotinin group all of the 128 vein grafts were patent compared with 138 of 139 in the placebo group . The difference was not statistically significant ( P > 0.05 ) . All pedicled internal mammary artery grafts were patent in the three treatment groups . The prevalence of perioperative myocardial infa rct ion was evaluated by serial creatine kinase-myocardial b and ( CK-MB ) isoenzyme measurements and by electrocardiographic recordings . No additional changes that could be attributed to aprotinin were observed . In conclusion , these results suggest that perioperative myocardial infraction secondary to aprotinin-induced native coronary artery or conduit thrombosis is not increased by aprotinin in patients undergoing primary myocardial revascularization CONTEXT Several journals have adopted the Consoli date d St and ards of Reporting Trials ( CONSORT ) recommendations to make assessment of the quality of r and omized controlled trials ( RCTs ) easier . One of these recommendations is that the trial 's results be discussed in light of the totality of the available evidence . OBJECTIVE To assess the extent to which reports of RCTs published in 5 general medical journals have discussed new results in light of all available evidence . DESIGN Assessment of the discussion sections in all 26 reports of RCTs published during May 1997 in Annals of Internal Medicine , BMJ , JAMA , The Lancet , and The New Engl and Journal of Medicine . MAIN OUTCOME MEASURE The inclusion or mention of a systematic review in the discussion section of each article . RESULTS In only 2 articles were the RCT 's results discussed in the context of an up date d systematic review of earlier trials . In a further 4 articles , references were made to relevant systematic review s , but no attempts were made to integrate the results of the new trials in up date d versions of these review s. One article was probably the first published trial to address the question studied . The remaining 19 articles included no evidence that any systematic attempt had been made to set the reported trial 's results in the context of previous trials . CONCLUSION There is little evidence that journals have adequately implemented the CONSORT recommendation that results of an RCT be discussed in light of the totality of the available evidence THE R AND OMIZED controlled trial ( RCT ) , more than any other methodology , can have a powerful and immediate impact on patient care . Ideally , the report of such an evaluation needs to convey to the reader relevant information concerning the design , conduct , analysis , and generalizability of the trial . This information should provide the reader with the ability to make informed judgments regarding the internal and external validity of the trial . Accurate and complete reporting also benefits editors and review ers in their deliberations regarding su bmi tted manuscripts . For RCTs to ultimately benefit patients , the published report should be of the highest possible st and ard BACKGROUND The recommended dose of aprotinin has been shown to reduce blood loss and need for blood transfusions , but the cost precludes its routine use . This study was design ed to determine whether a less expensive , ultra-low dose of aprotinin is effective when used in coronary artery bypass grafting with left internal mammary artery . METHODS Patients ( n = 202 ) were r and omized to receive either placebo or aprotinin , 0.5 million KIU before incision and 0.5 million KIU during initiation of cardiopulmonary bypass . Differences in quantity of blood transfused were analyzed . Further groups were analyzed to account for the effect of aspirin . Multivariable analysis was performed to determine risk factors for transfusion . Direct costs of blood products and aprotinin were tabulated for each group . RESULTS There was an important reduction in the proportion of patients transfused , and number of blood units transfused when aprotinin was given before coronary artery bypass grafting . These differences were even more important in patients on aspirin preoperatively . Independent predictors for increased number of transfusions were aspirin continued before operation , smaller body surface area , and the use of placebo instead of ultra-low dose aprotinin . There was no difference in morbidity between treatment groups . There was a reduction in direct costs associated with the use of aprotinin . CONCLUSIONS These data support the routine use of aprotinin 1 million KIU in coronary artery bypass grafting with left internal mammary artery to reduce cost and transfusion requirements CONTEXT Reliable interpretation of the results of a controlled trial entails setting its results in the context of similar research . A previous study showed that most reports of controlled trials published in 5 general medical journals in May 1997 were deficient in this respect . We assessed the extent to which reports of controlled trials published in the same 5 journals discussed new results in light of the totality of evidence from other controlled trials . METHODS Assessment of the discussion sections in all 33 reports of r and omized trials published during May 2001 in Annals of Internal Medicine , BMJ , JAMA , The Lancet , and The New Engl and Journal of Medicine . RESULTS Three reports appeared to have been the first published trials to address the questions studied . In none of the remaining 30 reports were the results of the new trial discussed in the context of an up date d systematic review of other trials . Although reference was made to relevant systematic review s in 3 of these 30 reports , there was no integration , quantitative or qualitative , of the results of the new trials in an up date of these review s. In the remaining 27 reports , there was no evidence that any systematic attempt had been made to set the new results in the context of previous trials . CONCLUSIONS Between 1997 and 2001 , there was no evidence of progress in the proportion of reports of trials published in general medical journals that discussed the new results within the context of , or with reference to , up-to- date systematic review s of relevant evidence from other controlled trials BACKGROUND High-dose aprotinin reduces transfusion requirements in patients undergoing coronary artery bypass grafting , but the safety and effectiveness of smaller doses is unclear . Furthermore , patient selection criteria for optimal use of the drug are not well defined . METHODS Seven hundred and four first-time coronary artery bypass grafting patients were r and omized to receive one of three doses of aprotinin ( high , low , and pump-prime-only ) or placebo . The patients were stratified as to risk of excessive bleeding . RESULTS All three aprotinin doses were highly effective in reducing bleeding and transfusion requirements . Consistent efficacy was not , however , demonstrated in the subgroup of patients at low risk for bleeding . There were no differences in mortality or the incidences of renal failure , strokes , or definite myocardial infa rct ions between the groups , although the pump-prime-only dose was associated with a small increase in definite , probable , or possible myocardial infa rct ions ( p = 0.045 ) . CONCLUSIONS Low-dose and pump-prime-only aprotinin regimens provide reductions in bleeding and transfusion requirements that are similar to those of high-dose regimens . Although safe , aprotinin is not routinely indicated for the first-time coronary artery bypass grafting patient who is at low risk for postoperative bleeding . The pump-prime-only dose is not currently recommended because of a possible association with more frequent myocardial infa rct ions BACKGROUND Cardiopulmonary bypass induces a systemic inflammatory response . Aprotinin , a nonspecific proteinase inhibitor is known to improve postoperative hemostasis and may modify the inflammatory reaction . This study evaluates the effects of low-dose aprotinin on inflammatory markers in patients scheduled for elective coronary artery bypass grafting . METHODS Patients were prospect ively r and omized into two groups : the control group ( C ) ( n = 14 ) and the low-dose aprotinin group ( A ) ( n = 15 ) with ( 2 x 10(6 ) KIU = 280 mg ) aprotinin added to the pump prime . Cytokine response ( interleukin-6 , soluble TNF II receptor ) , terminal complement production ( SC5b-9 ) , and neutrophil activation ( lactoferrin ) were assessed up to 6 hours postoperatively . Clinical data and hemostatic factors including fibrinopeptide A , thrombin-antithrombin complex , D-dimer , and plasmin/alpha2-antiplasmin were investigated . RESULTS In both study groups , a significant increase of all inflammatory markers was seen ( IL-6 , sTNF-IIR , SC5b-9 , lactoferrin ) , p less than 0.001 . Peak levels of complement production occurred after protamine administration , whereas cytokine increases were more pronounced postoperatively with marked elevation up to 6 hours . The markers did not differ significantly between groups throughout the study period ( p > 0.05 at each time of determination ) . However , after protamine administration reduced fibrinolysis ( D-dimer , plasmin/alpha2-antiplasmin ) was detected in group A. Measurements for coagulation ( fibrinopeptide A , thrombin-antithrombin complex ) were not significantly influenced by aprotinin . The total amount of blood loss during the first 24 hours was significantly reduced in group A ( p < 0.02 ) . CONCLUSIONS Low-dose aprotinin added to the pump prime does not inhibit the inflammatory response caused by cardiopulmonary bypass , but improves postoperative hemostasis . A potential effect of high-dose aprotinin on inflammatory markers remains to be eluci date BACKGROUND Aprotinin has been used increasingly to reduce postoperative blood loss in open heart operations . Although it was reported as safe in earlier studies , the overall safety of prophylactic use has been question ed recently . Because of the potential for complications and the high cost , it will be reasonable to use aprotinin more selectively in the postoperative period . METHODS We prospect ively studied the effect of postoperative low-dose aprotinin ( 2 million kallikrein inactivator units [ 280 mg ] ) on blood loss and transfusion requirements in patients undergoing cardiopulmonary bypass . Seventy-five patients were r and omly assigned to three groups : prophylactic high-dose aprotinin ( group 1 ) , postoperative aprotinin ( group 2 ) , or a nonmedicated control group ( group 3 ) . RESULTS The three groups were comparable in all demographic and operative variables . Postoperative chest tube drainage was significantly decreased in both aprotinin groups compared with that in the control group ( 295 mL in group 1 and 325 mL in group 2 versus 411 mL in group 3 ; p < 0.05 ) . No significant difference was seen between the two aprotinin groups . The use of homologous blood products was significantly less in group 1 and group 2 than in group 3 ( 1.15 + /- 1.13 U and 1.35 + /- 1.30 U versus 2.55 + /- 1.09 U ; p < 0.05 ) . CONCLUSIONS Our results suggest that postoperative aprotinin reduces blood loss and transfusion requirements comparably with prophylactic high-dose aprotinin . Thus , one can restrict its use to patients with excessive postoperative bleeding The proteinase inhibitor aprotinin is used in open heart surgery to reduce intraoperative and postoperative blood loss and transfusion requirements . To investigate a possible influence on graft patency , a r and omized double-blind group comparison study was carried out in male patients elected for primary bypass surgery . One hundred ten ( 55/55 ) patients received either placebo treatment or aprotinin according to the Hammersmith scheme ( 2 Mio KIU as loading dose before sternotomy , followed by an infusion of 0.5 Mio KIU/h until the end of surgery ; 2 Mio KIU added to the priming volume additionally ) . Graft patency was evaluated by angiography in 44 aprotinin and 35 placebo patients between the 18th and 35th days postoperatively . There was no difference in the overall graft occlusion : in the aprotinin group 89.5 % ( 111/124 ) grafts were found patent compared to 87.2 % ( 89/102 ) in the placebo group . Of the aprotinin patients 72.7 % ( 32/44 ) and 71.4 % ( 25/35 ) of the placebo patients had all grafts patent . Venous grafts were occluded in 16 % ( 7/44 ) of aprotinin patients and in 29 % ( 10/35 ) of placebo patients . On the other h and 5/27 patients in the aprotinin group vs 0/27 in the placebo group had occluded internal mammary artery ( IMA ) grafts ( P = 0.0511 % ) . Graft occlusions were not accompanied by signs of myocardial infa rct ion in any case . Fifty-one patients in the aprotinin group and 47 patients in the placebo group were valid for parameters of clinical efficacy : blood loss within 6 h postoperatively was reduced by 58.5 % in the aprotinin group ( P < 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Prophylactic aprotinin therapy has become a popular method to reduce bleeding associated with cardiac operations . Today essentially two dose regimens are used , a high-dose regimen with administration throughout the complete operative procedure and a low-dose regimen with administration only during bypass . In unblinded studies both regimens were found to be equally effective . This double-blind placebo-controlled study in 115 patients undergoing elective coronary artery bypass grafting was done to confirm these results without potential investigator bias . Intraoperative hemoglobin loss was significantly reduced ( p < 0.01 ) by 42 % in the high-dose group and by 17 % in the low-dose group compared with loss in control subjects . Blood loss 6 hours after operation was 377 ml in the low-dose and 266 ml in the high-dose group compared with 630 ml in the placebo group ( p < 0.05 and p < 0.001 , respectively ) . The average number of transfusions with packed red blood cells was reduced 31 % in the low-dose group and 45 % in the high-dose group , but the reductions were not significant . In a subgroup of patients , markers for coagulation and fibrinolysis were studied to investigate whether a different extent of activation existed . Fibrinolysis as measured by D-dimer levels was completely inhibited by the high-dose regimen , but was only partly suppressed in the low-dose group as compared with findings in the placebo group . Thrombin generation during cardiopulmonary bypass as reflected by F1 + 2 levels was lower in patients treated with aprotinin , but the difference was not significant . Concentrations of thrombin inactivated by antithrombin III were not different between the groups . The observation that low-dose aprotinin significantly improved hemostasis but did not inhibit hyperfibrinolysis supports our previous finding that low-dose aprotinin mainly protects platelet adhesive function . The better result obtained with high-dose aprotinin may indicate the contribution of hyperfibrinolysis to bleeding after cardiopulmonary bypass . Because high-dose aprotinin is administered outside the period of full heparinization and might therefore increase the risk of thromboembolic complications , we propose a modification of the low-dose schedule to increase aprotinin levels sufficient for plasmin inhibition before release of the aortic crossclamp We tested the efficacy and safety of aprotinin in 169 patients undergoing isolated reoperative myocardial revascularization . Patients were r and omly assigned to high-dose aprotinin , low-dose aprotinin , or placebo treatment groups in a double-blind , placebo-controlled study . Treatment groups did not differ significantly with respect to age , sex , red cell mass , number of grafts , use of internal thoracic artery , or incidence of preoperative aspirin therapy . Patients treated with aprotinin had a significant reduction in postoperative chest tube drainage ( 720 + /- 753 , 866 + /- 1,636 , and 1,121 + /- 683 mL , respectively , for high-dose aprotinin , low-dose aprotinin , and placebo ; p < 0.001 ) . Transfusion requirements were reduced in aprotinin-treated patients ( 2.1 + /- 4.2 , 4.8 + /- 11.8 , and 4.1 + /- 6.2 units for high-dose , low-dose , and placebo , respectively ; p < 0.001 ) . A similar reduction in chest tube drainage and transfusion requirements was seen in patients using aspirin preoperatively . Q-wave myocardial infa rct ions were increased in the aprotinin subgroups ( 17.5 % , 14.3 % , and 8.9 % for high-dose , low-dose , and placebo groups ; not significant ) . Acute vein graft thrombosis was found in six of 12 vein grafts studied at postmortem examination in patients receiving aprotinin but not in any of five grafts in patients receiving placebo . We conclude that aprotinin is extremely effective in reducing bleeding and transfusion requirements and may increase the risk of graft thrombosis Sixty patients ( four groups of 15 patients ) were entered in a r and omized , controlled study to compare the efficacy of prophylactic treatment with dipyridamole , tranexamic acid , and aprotinin to reduce bleeding after elective coronary artery bypass grafting . Only patients with a preoperative platelet count of less than 246 x 10(9)/L were selected because a previous study showed that these individuals are at risk for increased postoperative bleeding . Compared to control subjects , postoperative blood loss 6 hours after operation was significantly reduced by tranexamic acid ( 674 + /- 411 versus 352 + /- 150 mL ; p < 0.05 ) and by aprotinin ( 270 + /- 174 mL ; p < 0.01 ) . Dipyridamole did not reduce postoperative blood loss and was associated with complications in 3 patients . We conclude that hemostasis after cardiac operations can be improved with tranexamic acid and aprotinin . Dipyridamole appeared to be ineffective BACKGROUND Cytokines are implicated in the pathogenesis of the " whole-body inflammatory response " that may complicate the period after cardiopulmonary bypass ( CPB ) . Low-Dose aprotinin in the pump during CPB has been shown to improve postoperative hemostasis and platelet preservation . We tested the hypothesis that low-dose aprotinin influences the inflammatory reaction ( in terms of cytokine release ) after CPB . METHODS In a prospect i ve , r and omized study , 36 patients undergoing elective coronary artery bypass grafting were investigated . Nineteen patients received low-dose aprotinin ( 2 x 10(6 ) KIU ( 280 mg ] in the pump ) , and a control group of 19 did not . Complement activation , cytokine production , leukocyte elastase release . D-dimer level , full blood count , postoperative blood loss , and transfusion requirements were analyzed before , during , and after after CPB . RESULTS Interleukin-1 beta was not detected in either group , whereas traces of tumor necrosis factor-alpha were infrequently observed . Plasma elastase , interleukin-6 , interleukin-8 , and neutrophil count increased ( p < 0.001 ) during and after CPB compared with the baseline levels , reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours . Proinflammatory cytokine markers did not differ significantly ( p > 0.1 ) between the groups throughout the study period . The C5b-9 level increased ( p < 0.001 ) in both groups perioperatively , reaching its peak 15 minutes after protamine . Twenty-four-hour postoperative blood loss was significantly ( p < 0.001 ) reduced in the aprotinin group in association with markedly reduced D-dimer levels ( p < 0.001 ) . Patients in the aprotinin group also received significantly less banked blood postoperatively than the control group ( p < 0.01 ) . CONCLUSIONS Low-dose aprotinin fails to modify proinflammatory cytokine release , yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting OBJECTIVE As Aspirin ( ASA ) has proven efficacy in preventing patients with CAD from complications related to cardiovascular diseases , most patients scheduled for CABG are treated with ASA therapy . Consequently , impaired hemostasis is a problem in the management of CABG patients . Clinical studies have shown that Aprotinin can reduce bleeding and the use of blood products by 50 % in patients both with and without pre-operative ASA therapy . Concerning the combined effect of peri-operative low-dose ASA therapy and intra-operative high-dose Aprotinin therapy , the gathering of additional and prospect i ve data seemed to be necessary . METHODS We conducted a double-blind two-centre r and omised three-arm study in patients with elective primary CABG surgery . Three groups have been tested , comprising 119 patients in total ( group A : ASA + Aprotinin , group B : placebo + Aprotinin , group C : placebo + placebo ) to investigate a possible reduction of bleeding in Aprotinin treated patients . For all patients , thromboxane levels were used to identify ASA or placebo treatment . RESULTS The post-operative blood loss is significantly reduced by 21 % after Trasylol administration ( B vs. C ; P = 0.009 ) . The unexpected result of this study has been that the pre-treatment with ASA led to a further reduction of 18 % ( A vs. C ; P < 0.0001 ) . The difference between the two Aprotinin groups ( A and B ) is significant ( P = 0 . 01 ) in favour of ASA pre-treatment . Myocardial infa rct ion ( MI ) had been diagnosed at levels of 1.8 % in total ( 2/113 ) , 2.6 % ( 1/38 ) in group B and 3.2 % ( 1/31 ) in group C. An additional blinded evaluation of ECG , enzyme levels and clinical status revealed ' definite , probable and possible ' MIs of 5 % in group A , compared to 16 % in group B and 13 % in group C , thus providing no evidence for a higher risk of infa rct ion by Aprotinin treatment . When comparing the ASA group to non-ASA pre-treatment , a strong trend towards a reduction in MI rate becomes obvious , from 15 % to 5 % in favour of the ASA pre-treatment ( P = 0.08 ) . Concerning other peri-operative complications , no statistical difference between the groups could be detected . CONCLUSIONS A reduction in post-operative blood loss in primary elective CABG surgery with intra-operative Aprotinin treatment could be confirmed . A low-dose ASA treatment combined with a high-dose aprotinin administration during surgery not only neutralized a potentially higher risk of bleeding , but did in fact reduce the post-operative blood loss . The protective effect of ASA on peri-operative MI has been evident through a reduction of MI rate in ASA treated patients

The published data suggest that nonanthracycline alternatives are less toxic than anthracycline-containing regimens and equally , if not more , efficacious .

Anthracycline regimens have been the mainstay of adjuvant care in breast cancer for > 20 years . A growing body of clinical experience has uncovered an unacceptable rate of significant cardiac and leukomogenic toxicities .

PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitaxel was generally modest . CONCLUSION The addition of four cycles of paclitaxel after the completion of a st and ard course of CA improves the disease-free and overall survival of patients with early breast cancer BACKGROUND The purpose was to compare disease-free survival ( DFS ) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive ( N1 - 3 ) , estrogen-receptor-positive ( ER+ ) , postmenopausal early breast cancer ( EBC ) patients . PATIENTS AND METHODS We analyzed , retrospectively , 457 patients r and omized in FASG 02 and 07 trials who received : tamoxifen alone ( 30 mg/day , 3 years ) ; or FEC50 ( fluorouracil 500 mg/m2 , epirubicin 50 mg/m2 , cyclophosphamide 500 mg/m2 , six cycles every 21 days ) plus tamoxifen started concurrently . Radiotherapy was delivered after the third cycle in FASG 02 trial , and after the sixth in FASG 07 trial . RESULTS The 9-year DFS rates were 72 % with tamoxifen and 84 % with FEC50-tamoxifen ( P = 0.008 ) . The multivariate analysis showed that pathological tumor size > 2 cm was an independent prognostic factor ( P = 0.002 ) , and treatment effects remained significantly in favor of chemoendocrine therapy ( P = 0.0008 ) . The 9-year overall survival rates were 78 % and 86 % , respectively ( P = 0.11 ) . In the multivariate model , there was a trend in favor of chemoendocrine therapy ( P = 0.07 ) . CONCLUSION The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1 - 3 , ER+ and postmenopausal women . Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival BACKGROUND Amplification of the human epidermal growth factor receptor type 2 ( HER2 , also called HER2/neu ) gene and overexpression of its product in breast-cancer cells may be associated with responsiveness to anthracycline-containing chemotherapy regimens . METHODS In the r and omized , controlled Mammary.5 trial , we studied 639 formalin-fixed paraffin-embedded specimens obtained from 710 premenopausal women with node-positive breast cancer who had received either cyclophosphamide , epirubicin , and fluorouracil ( CEF ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) as adjuvant chemotherapy . HER2 amplification or overexpression was evaluated with the use of fluorescence in situ hybridization , immunohistochemical analysis , and polymerase-chain-reaction analysis . RESULTS Amplification of HER2 was associated with a poor prognosis regardless of the type of treatment . In patients whose tumors showed amplification of HER2 , CEF was superior to CMF when assessed on the basis of relapse-free survival ( hazard ratio , 0.52 ; 95 percent confidence interval , 0.34 to 0.80 ; P=0.003 ) and overall survival ( hazard ratio , 0.65 ; 95 percent confidence interval , 0.42 to 1.02 ; P=0.06 ) . For women whose tumors lacked amplification of HER2 , CEF did not improve relapse-free survival ( hazard ratio for relapse , 0.91 ; 95 percent confidence interval , 0.71 to 1.18 ; P=0.49 ) or overall survival ( hazard ratio for death , 1.06 ; 95 percent confidence interval , 0.83 to 1.44 ; P=0.68 ) . The adjusted hazard ratio for the interaction between treatment and HER2 amplification was 1.96 for relapse-free survival ( 95 percent confidence interval , 1.15 to 3.36 ; P=0.01 ) and 2.04 for overall survival ( 95 percent confidence interval , 1.14 to 3.65 ; P=0.02 ) . CONCLUSIONS Amplification of HER2 in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy . ( cancer.gov number , NCI-V90 - 0027 . ) PURPOSE To determine the influence of the epirubicin dose in operable node-positive breast cancer patients with factors of poor prognosis . PATIENTS AND METHODS Between April 1990 and July 1993 , 565 operable breast cancer patients with either more than three positive nodes or between one and three positive nodes with Scarff Bloom Richardson grade > or = 2 and hormone receptor negativity were r and omized after surgery to receive either fluorouracil 500 mg/m(2 ) , epirubicin 50 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) every 21 days for six cycles ( FEC 50 ) or the same regimen except with epirubicin dose of 100 mg/m(2 ) ( FEC 100 ) . Postmenopausal patients received tamoxifen 30 mg/d for 3 years at the beginning of chemotherapy . Radiotherapy was delivered at the end of chemotherapy in both groups . RESULTS The median follow-up was 67 months . The 5-year disease-free survival ( DFS ) was 54.8 % with FEC 50 and 66.3 % with FEC 100 ( P = .03 ) . The 5-year overall survival ( OS ) was 65.3 % and 77.4 % , respectively ( P = .007 ) . The mean relative dose-intensity was similar in the two groups ( 90.3 % and 86.1 % , respectively ) . Neutropenia and anemia were significantly more frequent in FEC 100 ( P < 10(-3 ) ) , as were nausea-vomiting ( P = .008 ) and stomatitis and alopecia ( P < 10(-3 ) ) . Nine cases of grade 3 infection occurred only with FEC 100 , and no toxic deaths occurred . Three cases of acute cardiac toxicity were observed ( FEC50 = 1 , FEC100 = 2 ) and 10 patients ( FEC50 = 6 , FEC100 = 4 ) presented delayed cardiac dysfunctions . Two cases of secondary leukemia were observed ( acute lymphatic leukemia with FEC 50 and acute myelogenous leukemia with FEC 100 ) . CONCLUSION After 5 years of follow-up , the increased epirubicin dose led to a significant benefit in terms of DFS and OS , with a high survival rate among patients with poor-prognosis breast cancer No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients . We retrospectively evaluated this role in patients enrolled in a phase III study comparing st and ard FEC21 ( 5-fluorouracil , epirubicin , and cyclophosphamide , administered every 3 weeks ) vs dose-dense FEC14 ( the same regimen repeated every 2 weeks ) . HER2 status was determined for 731 of 1214 patients . Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival ( EFS ) and overall survival ( OS ) ; EFS and OS were compared within each HER2 subgroup and within each treatment arm . Median follow-up was 6.7 years . Among FEC21-treated patients , both EFS ( HR=2.07 ; 95 % CI 1.27–3.38 ) and OS ( HR=2.47 ; 95 % CI 1.34–4.57 ) were significantly worse in HER2 + patients than in HER2 − patients . Among FEC14-treated patients , differences in either EFS ( HR=1.21 ; 95 % CI 0.65–2.24 ) or OS ( HR=1.85 ; 95 % CI 0.88–3.89 ) between HER2 + and HER2 − patients were not statistically significant . Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS . Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospect i ve studies BACKGROUND Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin . A retrospective study was design ed to test this hypothesis . METHODS In National Surgical Adjuvant Breast and Bowel Project protocol B-11 , patients with axillary lymph node-positive , hormone receptor-negative breast cancer were r and omly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil ( PF ) or a combination of L-phenylalanine mustard , 5-fluorouracil , and doxorubicin ( PAF ) . Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients . Statistical analyses were performed to test for interaction between treatment and erbB-2 status ( positive versus negative ) with respect to disease-free survival ( DFS ) , survival , recurrence-free survival ( RFS ) , and distant disease-free survival ( DDFS ) . Reported P values are two-sided . RESULTS Overexpression of erbB-2 ( i.e. , positive immunohistochemical staining ) was observed in 239 ( 37.5 % ) of the 638 tumors studied . Overexpression was associated with tumor size ( P=.02 ) , lack of estrogen receptors ( P=.008 ) , and the number of positive lymph nodes ( P=.0001 ) . After a mean time on study of 13.5 years , the clinical benefit from doxorubicin ( PAF versus PF ) was statistically significant for patients with erbB-2-positive tumors -- DFS : relative risk of failure (RR)=0.60 ( 95 % confidence interval [CI]=0.44 - 0.83 ) , P=.001 ; survival : RR=0.66 ( 95 % CI=0.47 - 0.92 ) , P = .01 ; RFS : RR=0.58 ( 95 % CI=0.42 - 0.82 ) , P=.002 ; DDFS : RR=0.61 ( 95 % CI=0.44 - 0.85 ) , P=.003 . However , it was not significant for patients with erbB-2-negative tumors-DFS : RR=0.96 ( 95 % CI=0.75 - 1.23 ) , P=.74 ; survival : RR = 0.90 ( 95 % CI=0.69 - 1.19 ) , P=.47 ; RFS : RR=0.88 ( 95 % CI=0.67 - 1.16 ) , P=.37 ; DDFS : RR=1.03 ( 95 % CI=0.79 - 1.35 ) , P=.84 . Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS ( P=.02 ) and DDFS ( P=.02 ) but not for survival ( P= .15 ) or RFS ( P=.06 ) . CONCLUSIONS These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer PURPOSE Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival ( RFS ) and overall survival ( OS ) compared with the classic regimen of cyclophosphamide , methotrexate , and fluorouracil in women with early-stage breast cancer . PATIENTS AND METHODS Between 1989 and 1993 , 710 pre- and perimenopausal women with axillary node-positive breast cancer were r and omly assigned to either cyclophosphamide 75 mg/m(2 ) orally days 1 through 14 , epirubicin 60 mg/m(2 ) intravenously days 1 and 8 , and fluorouracil 500 mg/m(2 ) intravenously days 1 and 8 ( CEF ) or CMF ( cyclophosphamide 100 mg/m(2 ) orally days 1 through 14 , methotrexate 40 mg/m(2 ) intravenously days 1 and 8 , and fluorouracil 600 mg/m(2 ) intravenously days 1 and 8) . On the basis of follow-up to May 1997 ( median follow-up time , 59 months ) , there was a statistically significant improvement in RFS and OS for CEF compared with CMF . RESULTS The trial results are now up date d , with a median follow-up of 10 years for live patients . The 10-year RFS is 52 % for patients who received CEF compared with 45 % for CMF patients ( hazard ratio [ HR ] for CMF v CEF = 1.31 ; stratified log-rank , P = .007 ) . The 10-year OS for patients who received CEF and CMF are 62 % and 58 % , respectively ( HR for CMF v CEF = 1.18 ; stratified log-rank , P = .085 ) . The rates of acute leukemia have not changed since the original report , whereas the rates of congestive heart failure are slightly higher but acceptable ( four patients [ 1.1 % ] in the CEF group v one patient [ 0.3 % ] in the CMF group ) . CONCLUSION The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . PURPOSE To determine whether a combination chemotherapy regimen that contains epirubicin ( fluorouracil , epirubicin , and cyclophosphamide [ FEC ] ) is superior to the st and ard cyclophosphamide , methotrexate , and fluorouracil ( CMF ) combination in premenopausal women with axillary node-positive operable breast cancer . PATIENTS AND METHODS The International Collaborative Cancer Group ( ICCG ) conducted a large r and omized trial in which two alternative schedules were used according to participating center : CMF1 versus FEC1 and CMF2 versus FEC2 . RESULTS Seven hundred fifty-nine patients were entered onto the trial . At a median follow-up time of 4.5 years , no significant benefit for the anthracycline-containing regimen was observed in terms of relapse-free ( P = .61 ) or overall survival ( P = .13 ) . FEC1 and CMF1 appear to be of similar efficacy , but there is a suggestion that FEC2 may be superior to CMF2 , since patients who received FEC2 had improved overall ( P = .02 ) and relapse-free survival ( P = .03 ) rates . Nausea and vomiting and alopecia were more common in the epirubicin-containing regimen ( P = .001 ) . CONCLUSION We conclude that the FEC2 regimen , in which epirubicin replaced the methotrexate in CMF , is the preferable adjuvant chemotherapy regimen for premenopausal patients with operable axillary node-positive breast cancer PURPOSE Using a 2 x 2 factorial design , we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin ( A ) , paclitaxel ( T ) , and cyclophosphamide ( C ) with concurrent doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel ( T ) for disease-free ( DFS ) and overall survival ( OS ) ; to determine whether the dose density of the agents improves DFS and OS ; and to compare toxicities . PATIENTS AND METHODS A total of 2,005 female patients were r and omly assigned to receive one of the following regimens : ( I ) sequential A x 4 ( doses ) -- > T x 4 -- > C x 4 with doses every 3 weeks , ( II ) sequential A x 4 -- > T x 4 -- > C x 4 every 2 weeks with filgrastim , ( III ) concurrent AC x 4 -- > T x 4 every 3 weeks , or ( IV ) concurrent AC x 4 -- > T x 4 every 2 weeks with filgrastim . RESULTS A protocol -specified analysis was performed at a median follow-up of 36 months : 315 patients had experienced relapse or died , compared with 515 expected treatment failures . Dose-dense treatment improved the primary end point , DFS ( risk ratio [ RR ] = 0.74 ; P = .010 ) , and OS ( RR = 0.69 ; P = .013 ) . Four-year DFS was 82 % for the dose-dense regimens and 75 % for the others . There was no difference in either DFS or OS between the concurrent and sequential schedules . There was no interaction between density and sequence . Severe neutropenia was less frequent in patients who received the dose-dense regimens . CONCLUSION Dose density improves clinical outcomes significantly , despite the lower than expected number of events at this time . Sequential chemotherapy is as effective as concurrent chemotherapy PURPOSE The purpose of this study is to evaluate HER-2 and topoisomerase IIalpha ( topo IIalpha ) as c and i date s for predicting the activity of anthracyclines in the adjuvant treatment of breast cancer patients . EXPERIMENTAL DESIGN In this study , we evaluated HER-2 and topo IIalpha gene aberrations by fluorescence in situ hybridization in a series of 430 primary breast cancer sample s. Sample s came from node-positive breast cancer patients r and omly treated either with one of two anthracycline-based regimens [ full-dose epirubicin-cyclophosphamide ( HEC ) and moderate-dose epirubicin-cyclophosphamide ( EC ) ] or with cyclophosphamide , methotrexate , and 5-fluorouracil ( CMF ) in the context of a Phase III adjuvant therapy trial . Event-free survival comparisons were performed between the three study arms in the subgroups of HER-2-amplified and nonamplified tumors . An explorative analysis was also performed to evaluate the predictive value of topo IIalpha in the cohort of HER-2-amplified patients . RESULTS HER-2 amplification was observed in 73 of the 354 evaluable sample s ( 21 % ) , whereas topo IIalpha amplification was found in 23 of the 61 evaluable HER-2-amplified tumors ( 38 % ) . The three event-free survival comparisons were CMF versus HEC , CMF versus EC , and EC versus HEC . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) were as follows : ( a ) CMF versus HEC , HR = 1.42 for HER-2-amplified tumors ( 95 % CI , 0.54 - 3.76 ; P = 0.48 ) and 0.84 for HER-2-nonamplified tumors ( 95 % CI , 0.49 - 1.44 ; P = 0.53 ) ; ( b ) CMF versus EC , HR = 1.65 for HER-2-amplified tumors ( 95 % CI , 0.66 - 4.13 ; P = 0.29 ) and 0.66 for HER-2-nonamplified tumors ( 95 % CI , 0.39 - 1.10 ; P = 0.11 ) ; and ( c ) EC versus HEC , HR = 0.93 for HER-2-amplified tumors ( 95 % CI , 0.31 - 2.77 , P = 0.90 ) and 1.33 for HER-2-nonamplified tumors ( 95 % CI , 0.82 - 2.14 ; P = 0.25 ) . Observed HRs suggest that the anthracycline-based therapy could be more effective than CMF in the subgroup of HER-2-amplified patients , whereas treatments could be equally active in the HER-2-nonamplified cohort . topo IIalpha evaluation suggests that the superiority of anthracyclines over CMF in HER-2-amplified patients could be confined to the subgroup of topo IIalpha-amplified tumors . CONCLUSIONS HER-2 could have a predictive value for the activity of anthracycline-based regimens in the adjuvant therapy of breast cancer patients . The predictive value of HER-2 would most likely be related to the concomitant amplification of the topo IIalpha gene PURPOSE Human epidermal growth factor receptor 2 ( HER2 ) overexpression was found to predict a good response in breast carcinoma patients treated with doxorubicin ( Adriamycin [ ADM ] ) . Evidence from our recent study indicates that node-positive patients respond to cyclophosphamide , methotrexate , and fluorouracil ( CMF ) regardless of HER2 status . We address the issue of whether therapy regimens including CMF and ADM versus CMF alone have the same therapeutic effect in patients with HER2 + and HER2- tumors in terms of relapse-free survival ( RFS ) and overall survival ( OS ) . METHODS Archival specimens of the primary tumors from 506 patients in a prospect i ve clinical trial were stained with the anti-HER2 monoclonal antibody CB11 . Originally , patients were r and omly allocated to receive either 12 courses of intravenous CMF or eight courses of the same regimen followed by four cycles of ADM . RFS and OS were analyzed by a Cox model taking into account treatment , HER2 status , and the interaction between treatment and HER2 status , adjusting for the effect of other known clinical and biopathologic factors . RESULTS Analysis of survival rates indicates a possible differential effect of treatment in the patients grouped according to HER2 status . Improved RFS and OS were observed in the HER2 + subgroup after treatment with CMF plus ADM versus CMF alone . With a median follow-up of 15 years , the hazard ratio ( HR ) for RFS was 0.83 in HER2 + tumors and 1.22 in HER2- tumors . The effect of treatment was more evident on OS in HER2 + patients ( HR = 0.61 ; CI , 0.32 to 1.16 ) than in HER2- patients ( HR = 1.26 ) . CONCLUSION Our data indicate that adding ADM to CMF might be beneficial for patients with HER2 + tumors PURPOSE The aim of the study was to evaluate the predictive value of HER2 and topoisomerase IIalpha gene ( TOP2A ) for the efficacy of epirubicin in the adjuvant setting of breast cancer patients . PATIENTS AND METHODS In the Danish Breast Cancer Cooperative Group trial 89D , 980 pre- and postmenopausal primary patients were r and omly allocated to either CMF ( cyclophosphamide , methotrexate , and fluorouracil ; n = 500 ) or CEF ( cyclophosphamide , epirubicin , and fluorouracil ; n = 480 ) times 9 , between January 1990 and November 1999 . Tumor tissue was retrospectively identified from 805 patients and was analyzed for HER2-positivity and for TOP2A-amplifications and deletions . RESULTS HER2-positivity was found in 33 % of the 805 investigated tumors and was not a predictive marker for epirubicin sensitivity . TOP2A changes were identified in 23 % of the 773 investigated tumors : 12 % had TOP2A amplifications and 11 % had TOP2A deletions . We found that patients with TOP2A amplification had an increased recurrence-free ( RFS ; hazard ratio [ HR ] , 0.43 ; 95 % CI , 0.24 to 0.78 ) and overall survival ( OS ; HR , 0.57 ; 95 % CI , 0.29 to 1.13 ) , respectively if treated with CEF compared with CMF , and that patients with TOP2A deletions had an almost identical hazard ratio ( RFS : HR , 0.63 ; 95 % CI , 0.36 to 1.11 ; OS : HR , 0.56 ; 95 % CI , 0.30 to 1.04 ) . This is in contrast to patients with a normal TOP2A genotype for whom similar outcome was observed in both treatment arms ( RFS : HR , 0.90 ; 95 % CI , 0.70 to 1.17 ; OS : HR , 0.88 ; 95 % CI , 0.66 to 1.17 ) . CONCLUSION TOP2A amplification- and possibly deletion-seems to be predictive markers for the effect of adjuvant epirubicin containing therapy in primary breast cancer , but a final conclusion has to await a confirmative study or a meta- analysis OBJECTIVE To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes . DESIGN A prospect i ve r and omized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) ( sequential regimen ) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses ( alternating regimen ) . All drug courses were recycled every 3 weeks . The median duration of follow-up at the time of current analysis was 9 years . SETTING The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan , Italy . Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology . PATIENTS A total of 405 women were entered into the study , 403 of whom met the protocol criteria . Patient characteristics were fairly well balanced between the two treatment groups , with the exception of extent of nodal involvement : 38 % with more than 10 positive nodes were r and omized to the alternating regimen compared with 29 % in the sequential regimen ( P = .08 ) . MAIN OUTCOME MEASURE Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method . RESULTS Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy . The relapse-free survival was 42 % vs 28 % ( P = .002 ) and total survival was 58 % vs 44 % ( P = .002 ) , respectively . The benefit of the sequential regimen was evident in all patient subsets . Treatment was fairly well tolerated , but we documented four cases of congestive heart failure , which was fatal in two patients . CONCLUSIONS Current findings indicate that in women with extensive nodal involvement , sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) conducted a r and omized clinical trial to determine whether tamoxifen ( TAM ) plus chemotherapy is more effective than TAM alone in improving disease-free survival ( DFS ) , distant disease-free survival ( DDFS ) , and survival ( S ) of positive-node , TAM-responsive patients aged greater than or equal to 50 years . Women were r and omized among three treatment groups : ( 1 ) TAM alone , ( 2 ) Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) , cyclophosphamide , and TAM ( ACT ) , or ( 3 ) melphalan ( L-PAM ) , fluorouracil ( 5-FU ) , and TAM ( PFT ) . The PFT arm was later modified so that new patients also received Adriamycin ( PAFT ) . Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone ( 84 % v 67 % ; P = .0004 ) . An advantage in DDFS and S was also observed after ACT therapy ( 83 % v 73 % [ P = .04 in the former ] and 93 % v 85 % [ P = .04 in the latter ] ) . Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone ( 83 % v 66 % , P = .0002 and 85 % v 73 % , P = .003 ) . PFT patients also fared better in DFS and DDFS than TAM patients ( 81 % v 72 % , P = .07 and 85 % v 74 % , P = .02 ) . Odds ratios consistently favored the three TAM-plus-chemotherapy groups . No significant S advantage is as yet evident in favor of the PAFT or PFT groups . Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM , which was administered simultaneously . The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer . The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy ( completed in 63 days ) than from prolonged TAM therapy alone PURPOSE We review ed follow-up of patients treated in 19 r and omized trials of adjuvant epirubicin in early breast cancer to determine incidence , risk , and risk factors for subsequent acute myeloid leukemia ( AML ) and myelodysplastic syndrome ( MDS ) . PATIENTS AND METHODS The patients ( N = 9,796 ) were observed from the start of adjuvant treatment ( 53,080 patient-years ) . Cases of AML or MDS ( AML/MDS ) were reported , with disease characteristics . Incidence and cumulative risk were compared for possible risk factors , for assigned regimens , and for administered cumulative doses of epirubicin and cyclophosphamide . RESULTS In 7,110 patients treated with epirubicin-containing regimens ( 92 % of whom also received cyclophosphamide ) , 8-year cumulative probability of AML/MDS was 0.55 % ( 95 % CI , 0.33 % to 0.78 % ) . The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle , planned epirubicin dose-intensity , and administered cumulative doses of epirubicin and cyclophosphamide . Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in st and ard regimens ( < /= 720 mg/m(2 ) and < /= 6,300 mg/m(2 ) , respectively ) had an 8-year cumulative probability of developing AML/MDS of 0.37 % ( 95 % CI , 0.13 % to 0.61 % ) compared with 4.97 % ( 95 % CI , 2.06 % to 7.87 % ) for patients administered higher cumulative doses of both epirubicin and cyclophosphamide . CONCLUSION Patients treated with st and ard cumulative doses of adjuvant epirubicin ( < /= 720 mg/m(2 ) ) and cyclophosphamide ( < /= 6,300 mg/m(2 ) ) for early breast cancer have a lower probability of secondary leukemia than patients treated with higher cumulative doses . Increased risk of secondary leukemia must be considered when assessing the potential benefit to risk ratio of higher than st and ard doses BACKGROUND Trastuzumab , a recombinant monoclonal antibody against HER2 , has clinical activity in advanced breast cancer that overexpresses HER2 . We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy . METHODS This international , multicenter , r and omized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy . RESULTS Data were available for 1694 women r and omly assigned to two years of treatment with trastuzumab , 1694 women assigned to one year of trastuzumab , and 1693 women assigned to observation . We report here the results only of treatment with trastuzumab for one year or observation . At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , contralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group . The unadjusted hazard ratio for an event in the trastuzumab group , as compared with the observation group , was 0.54 ( 95 percent confidence interval , 0.43 to 0.67 ; P<0.0001 by the log-rank test , crossing the interim analysis boundary ) , representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points . Overall survival in the two groups was not significantly different ( 29 deaths with trastuzumab vs. 37 with observation ) . Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab . CONCLUSIONS One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer . ( Clinical Trials.gov number , NCT00045032 . PURPOSE To assess whether the addition of epirubicin ( EPI ) therapy to prolonged treatment with tamoxifen ( TAM ) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer . PATIENTS AND METHODS Six hundred four patients entered onto a r and omized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m(2 ) intravenously on days 1 and 8 every 4 weeks for six cycles . Analysis was performed according to allocated treatment , with all r and omized patients included ( intention to treat ) , irrespective of eligibility status . RESULTS After a median follow-up period of 5.7 years , an improvement in relapse-free survival ( RFS ) was observed for the TAM and EPI-treated patients , compared with those who received TAM alone . The unadjusted hazard ratio was 0.72 ( 95 % confidence interval , 0.54 to 0.96 ) , with a corresponding reduction in the odds of recurrence of 27.9 % ( SD , 12 . 3 ) , which was statistically significant ( P = .023 ) . Adjustment for prognostic and /or predictive factors did not material ly affect the hazard ratio . No difference was observed in terms of overall survival ( reduction in odds of death , 11.9 % [ SD , 16.3 ] ; P = .46 ) . Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity . Twelve nonbreast second malignancies , including five hematologic malignancies ( two of which were cases of acute myelogenous leukemia ) , were observed . CONCLUSION The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer . No evidence was found , however , for an improvement in overall survival . The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists ' Collaborative Group overview . The trial presented here , however , provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM PURPOSE To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer . PATIENTS AND METHODS All 1,000 patients from three prospect i ve trials of adjuvant chemotherapy containing doxorubicin ( n = 637 , median total dose of 294 mg/m(2 ) ) or not containing the anthracycline ( cyclophosphamide , methotrexate , and fluorouracil [ CMF ] regimen alone , n = 363 ) were analyzed for the relative incidence of congestive heart failure ( CHF ) and myocardial infa rct ion ( MI ) during 14 years of follow-up . The 462 women continuously free of disease as of February 1996 were recalled , and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction ( LVEF ) to assess the relative incidence of abnormalities in long-term survivors . RESULTS Among the 1,000 patients , there were six cases of CHF and three cases of MI . Cumulative cardiac mortality accounted for 0.4 % ( doxorubicin-treated = 0.6 % ; CMF-treated = 0 ) . Eighteen ( 5 % ) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic ( < 50 % , n = 8) or borderline ( 50 % to 55 % , n = 10 ) LVEF . Systolic dysfunction was higher in doxorubicin-treated ( 15 of 192 ; 8 % ) than in CMF-treated patients ( three of 150 ; 2 % ) . Breast irradiation had a significant impact on the occurrence of early CHF ( four of 116 ; 3 % ) , but not on systolic dysfunctions . CONCLUSION At longer than 10 years of follow-up , the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease PURPOSE The 21-gene recurrence score ( RS ) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive , lymph node-negative breast cancer treated with adjuvant tamoxifen . The relationship between the RS and chemotherapy benefit is not known . METHODS The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B20 trial . Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS . RESULTS A total of 651 patients were assessable ( 227 r and omly assigned to tamoxifen and 424 r and omly assigned to tamoxifen plus chemotherapy ) . The test for interaction between chemotherapy treatment and RS was statistically significant ( P = .038 ) . Patients with high-RS ( > or = 31 ) tumors ( ie , high risk of recurrence ) had a large benefit from chemotherapy ( relative risk , 0.26 ; 95 % CI , 0.13 to 0.53 ; absolute decrease in 10-year distant recurrence rate : mean , 27.6 % ; SE , 8.0 % ) . Patients with low-RS ( < 18 ) tumors derived minimal , if any , benefit from chemotherapy treatment ( relative risk , 1.31 ; 95 % CI , 0.46 to 3.78 ; absolute decrease in distant recurrence rate at 10 years : mean , -1.1 % ; SE , 2.2 % ) . Patients with intermediate-RS tumors did not appear to have a large benefit , but the uncertainty in the estimate can not exclude a clinical ly important benefit . CONCLUSION The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative , estrogen receptor-positive breast cancer , but also predicts the magnitude of chemotherapy benefit BACKGROUND Adjuvant chemotherapy is widely used for breast cancer and is known to extend survival . Some clinicians seek a greater survival benefit by increasing the intensity of the dose , whereas others lower it to diminish toxicity . METHODS The Cancer and Leukemia Group B ( CALGB ) conducted a r and omized trial of different levels of doses and dose intensity ( dose per unit of time ) of adjuvant chemotherapy in 1572 women with node-positive , stage II breast cancer who were assigned to three treatment groups . One group received 400 mg of cyclophosphamide per square meter of body-surface area and 40 mg of doxorubicin per square meter once every 28 days and 400 mg of fluorouracil per square meter twice every 28 days , for six cycles . Another group received 50 percent higher doses of the three drugs ( 600 mg , 60 mg , and 600 mg , respectively ) but for only four cycles , so that the total dose was identical in these two groups but the dose intensity was higher in the first . The third group of women received half the total dose used in the other two groups and at half the dose intensity used in the second group . RESULTS After a median of 3.4 years of follow-up , the women treated with a high or moderate dose intensity had significantly longer disease-free survival ( P < 0.001 ) and overall survival ( P = 0.004 ) than those treated with a low dose intensity , in three-way log-rank comparisons . However , the difference in survival between the two groups treated with a moderate or high dose intensity was not significant . These results are consistent with either a dose-response effect or a threshold level of the dose or dose intensity . CONCLUSIONS The doses of chemotherapy used to treat breast cancer , especially early breast cancer , should not be reduced if the maximal benefit is to be achieved BACKGROUND The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined . The Cancer and Leukemia Group B ( CALGB ) conducted a r and omized adjuvant-chemotherapy trial ( CALGB 8541 ) comparing three doses ( high , moderate , and low ) of cyclophosphamide , doxorubicin , and fluorouracil in 1572 women with node-positive breast cancer . This study ( CALGB 8869 ) was design ed to determine whether the DNA index , the S-phase fraction , c-erbB-2 expression , or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy . METHODS Tissue blocks were obtained from 442 patients r and omly selected from the larger CALGB trial . Paraffin sections from the primary lesions were analyzed for DNA content , S-phase fraction , c-erbB-2 expression , and p53 accumulation . RESULTS Patients r and omly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression . No further information was gained by adding the data on S-phase fraction or p53 accumulation to the analysis . There was no clear evidence of a dose-response effect in patients with minimal or no c-erbB-2 expression . CONCLUSIONS There is a significant dose-response effect of adjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil in patients with overexpression of c-erbB-2 but not in patients with no c-erbB-2 expression or minimal c-erbB-2 expression . Overexpression of c-erbB-2 may be a useful marker to identify the patients who are most likely to benefit from high doses of adjuvant chemotherapy AIM To assess the frequency and type of cardiac effects in women treated with adjuvant chemotherapy with or without breast irradiation for operable breast cancer . PATIENTS AND METHODS Retrospective analysis of a series of 825 women taking part in prospect ively r and omized trials on adjuvant chemotherapy with or without adriamycin ( doxorubicin ; Farmitalia-Carlo Erba , Milan , Italy ) for operable breast cancer at high risk of new disease manifestations . A total of 360 patients ( 44 % ) also received breast irradiation because of conservative surgery . Median follow-up in first clinical complete remission from end of all adjuvant treatments was 80 months . According to the protocol requirements , electrocardiograms were obtained before breast cancer surgery , before starting therapy with adriamycin and at the end of all adjuvant treatments . During the follow-up observation , electrocardiograms were systematic ally obtained at least once a year . In the presence of suspicious findings as well as of clinical symptoms and signs of cardiovascular disease , additional cardiac investigations were undertaken . However , percutaneous endomyocardial biopsies were never performed . RESULTS Congestive heart failure occurred in a total of 4 women ( 0.5 % of all patients ; 0.8 % following adriamycin-containing chemotherapy ; 2.6 % after both adriamycin and irradiation to the left breast ) , in two of whom it was fatal . ST-segment and T-wave abnormalities in the absence of other symptoms and signs were detected in 3.4 % of the case series . Other cardiac events were documented in 6.8 % of all patients Overall , cardiac effects were more frequently detected in women who received irradiation to the left breast . In addition , age greater than 55 years at surgery and history of risk factors were important risk modifiers in the occurrence of cardiac events . CONCLUSIONS The addition of full-dose adriamycin to alkylating-containing adjuvant chemotherapy , as given in our studies , failed per se to increase the frequency of cardiac effects . Thus anthracyclines , which have the potential to improve current treatment results , deserve a proper place in the design of future adjuvant studies PURPOSE The combination of doxorubicin and cyclophosphamide ( AC ) is a st and ard adjuvant chemotherapy regimen . Studies of docetaxel and cyclophosphamide ( TC ) in metastatic breast cancer ( MBC ) showed promise in MBC . In 1997 , we initiated a r and omized adjuvant trial of TC compared with st and ard-dose AC with a primary end point of disease-free survival ( DFS ) . PATIENTS AND METHODS Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor . Between June 1997 and December 1999 , 1,016 patients were r and omly assigned to four cycles of either st and ard-dose AC ( 60 and 600 mg/m2 , respectively ; n = 510 ) or TC ( 75 and 600 mg/m2 , respectively ; n = 506 ) , administered intravenously every 3 weeks as adjuvant chemotherapy . Radiation therapy ( as indicated ) and tamoxifen , for patients with hormone receptor-positive disease , were administered after completion of chemotherapy . RESULTS Both treatment groups ( TC and AC ) were well balanced with respect to major prognostic factors . Patients were observed through 2005 for a median of 5.5 years . At 5 years , DFS rate was significantly superior for TC compared with AC ( 86 % v 80 % , respectively ; hazard ratio [ HR ] = 0.67 ; 95 % CI , 0.50 to 0.94 ; P = .015 ) . Overall survival rates for TC and AC were 90 % and 87 % , respectively ( HR = 0.76 ; 95 % CI , 0.52 to 1.1 ; P = .13 ) . More myalgia , arthralgia , edema , and febrile neutropenia occurred on the TC arm ; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure . CONCLUSION At 5 years , TC was associated with a superior DFS and a different toxicity profile compared with AC BACKGROUND The status of human epidermal growth factor receptor type 2 ( HER2 ) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy . We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above st and ard levels , from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide , or from both . METHODS We r and omly selected 1500 women from 3121 women with node-positive breast cancer who had been r and omly assigned to receive doxorubicin ( 60 , 75 , or 90 mg per square meter of body-surface area ) plus cyclophosphamide ( 600 mg per square meter ) for four cycles , followed by four cycles of paclitaxel ( 175 mg per square meter ) or observation . Tissue blocks from 1322 of these 1500 women were available . Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed . RESULTS No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter . HER2 positivity was , however , associated with a significant benefit from paclitaxel . The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 ( P=0.01 ) . Patients with a HER2-positive breast cancer benefited from paclitaxel , regardless of estrogen-receptor status , but paclitaxel did not benefit patients with HER2-negative , estrogen-receptor-positive cancers . CONCLUSIONS The expression or amplification , or both , of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin ( < 60 mg per square meter ) plus cyclophosphamide in node-positive breast cancer , regardless of estrogen-receptor status . Patients with HER2-negative , estrogen-receptor-positive , node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide PURPOSE To determine the long-term impact on disease-free survival ( DFS ) and overall survival ( OS ) of adjuvant anthracycline-based chemotherapy , when prospect ively compared by r and om allocation with st and ard cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in node-positive ( N+ ) breast cancer patients . PATIENTS AND METHODS Two hundred forty-nine patients with N+ breast cancer , recruited from eight French cancer centers , were r and omized to receive 12 monthly cycles of adjuvant chemotherapy , either CMF ( n = 112 ) or doxorubicin , vincristine , cyclophosphamide , and fluorouracil ( AVCF ) ( n = 136 ) . All had a negative metastatic work-up before inclusion , which was stratified by accrual center , tumor stage ( International Union Against Cancer [ UICC ] ) , and menopausal status . RESULTS No severe adverse effect related to grade 4 ( World Health Organization [ WHO ] ) toxicity was observed . There was no difference in second primary tumor incidence between the two arms . The treatment given was 88 % of planned for AVCF and 75 % for CMF in both premenopausal and menopausal patients . With a median follow-up time of 16 years ( range , 13 to 17 ) , the OS and DFS rates are significantly longer in the AVCF arm ( 56 % v 41 % [ P = .01 ] for OS , and 53 % v 36 % [ P = .006 ] for DFS ) . These differences are significant , irrespective of tumor stage ( T1 to T2 v T3 to T4 ) , and remain positive in patients with or without postoperative locoregional radiotherapy ( 55 % of cohort ) . When analyzed according to menopausal status , the differences remain significant only for premenopausal patients . CONCLUSION This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF , with both regimens given for 1 year

The effects of IFNs-beta and GA in the treatment of people with RRMS , including clinical ( e.g. people with relapse , risk to progression ) and MRI ( Gd-enhancing lesions ) measures , seem to be similar or to show only small differences . When MRI lesion load accrual is considered , the effect of the two treatments differs , in that IFNs-beta were found to limit the increase in lesion burden as compared with GA . Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes , such as quality -of-life measures

BACKGROUND Interferons-beta ( IFNs-beta ) and glatiramer acetate ( GA ) were the first two disease-modifying therapies ( DMTs ) approved 20 years ago for the treatment of multiple sclerosis ( MS ) . DMTs ' prescription rates as first or switching therapies and their costs have both increased substantially over the past decade . As more DMTs become available , the choice of a specific DMT should reflect the risk/benefit profile , as well as the impact on quality of life . As MS cohorts enrolled in different studies can vary significantly , head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared . The purpose of this systematic review is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through the analysis of head-to-head trials . This is an up date of the Cochrane review ' Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis ' ( first published in the Cochrane Library 2014 , Issue 7 ) . OBJECTIVES To assess whether IFNs-beta and GA differ in terms of safety and efficacy in the treatment of people with relapsing-remitting ( RR ) MS .

We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter , r and omized , double-blind , placebo-controlled trial of interferon beta-1b ( IFNB ) . Clinical results are presented in the preceding companion paper . Baseline MRI characteristics were the same in all treatment groups . Fifty-two patients at one center formed a cohort for frequent MRIs ( one every 6 weeks ) for analysis of disease activity . The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans ( median 80 % reduction , p = 0.0082 ) and appearance of new lesions . In addition , there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups ( mean group difference of 23 % , p = 0.001 ) . These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients BACKGROUND Interleukin 12 ( IL-12 ) , a cytokine that promotes generation of helper T cells subtype 1 , is increased in multiple sclerosis . Albuterol sulfate , a β2-adrenergic agonist , reduces IL-12 expression , so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy . OBJECTIVES To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment . DESIGN Single-center double-masked clinical trial . SETTING Academic research . Patients Subjects with relapsing-remitting multiple sclerosis . MAIN OUTCOME MEASURES In this single-center double-masked clinical trial , subjects with relapsing-remitting multiple sclerosis were r and omized to receive a subcutaneous injection of glatiramer acetate ( 20 mg ) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate ( 20 mg ) plus an oral dose of albuterol daily for 2 years . The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years , and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point . The classification level of evidence from this trial is C for each question , as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol . RESULTS Forty-four subjects were r and omized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo , and 39 subjects contributed to the analysis . Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month ( P = .005 ) and 12-month ( P = .04 ) time points but not at the 24-month time point . A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group ( P = .03 ) . Immunologically , IL-13 and interferon-γ production decreased in both treatment groups , and a treatment effect on IL-13 production was observed at the 12-month time point ( P < .05 ) . Adverse events were generally mild , and only 3 moderate or severe events were considered related to the treatment . CONCLUSION Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00039988 A double‐blind , r and omized , controlled study was undertaken to determine whether combined use of interferon β‐1a ( IFN ) 30μg intramuscularly weekly and glatiramer acetate ( GA ) 20 mg daily is more efficacious than either agent alone in relapsing – remitting multiple sclerosis OBJECTIVE To study changes in brain volume measured monthly in patients treated for relapsing multiple sclerosis due to loss of tissue and the appearance of inflammation . DESIGN AND PATIENTS The results from T2/fluid-attenuated inversion recovery axial images from 13 consecutive monthly 3-T brain magnetic resonance imaging tests conducted on 74 patients diagnosed with relapsing multiple sclerosis in the BECOME study were used to calculate whole brain volumes using automated software analysis tools . The patients had been r and omized to receive treatment with interferon beta-1b or glatiramer acetate . Ongoing inflammation was studied by counting the number of combined active lesions and measuring the volume of gadolinium enhancement . A mixed-effects model was used to analyze brain volumes over time . RESULTS There was a significant decrease in brain volume over time but there was no difference in its rate of change by age , sex , frequency of ongoing inflammation , multiple sclerosis type , or r and omized treatment assignment . The mean rate of brain volume change per month from multivariable models was -1.1 cm(3 ) ( 95 % CI , -1.5 to -0.6 ) and during times of magnetic resonance imaging activity , it increased transiently by an average of 1.2 cm(3)/lesion ( 95 % CI , 0.7 to 1.7 ) and 7.1 cm(3)/1 cm(3 ) of gadolinium volume . In a model with both measures , combined active lesions were independent predictors of brain volume but gadolinium volume was not . CONCLUSION Two major changes in brain volume occur in patients with relapsing multiple sclerosis , a steady decrease likely due to tissue loss with overlapping transient increases due to the appearance of inflammation Objective : To measure the effects of disease-modifying drugs ( DMDs ) on the development of cortical lesions ( CL ) and cortical atrophy in patients with relapsing – remitting multiple sclerosis ( RRMS ) . Methods : RRMS patients ( n = 165 ) were r and omized to subcutaneous ( sc ) interferon ( IFN ) beta-1a ( 44 mcg three times weekly ) , intramuscular ( i m ) IFN beta-1a ( 30 mcg weekly ) or glatiramer acetate ( GA ; 20 mg daily ) . The reference population comprised 50 untreated patients . Clinical and MRI examinations were performed at baseline , 12 months and 24 months . Results : One hundred and forty-one treated patients completed the study . After 12 months , 37/50 ( 74 % ) of untreated patients developed ≥1 new CL ( mean 1.6 ) , compared with 30/47 ( 64 % ) of i m IFN beta-1a-treated patients ( mean 1.2 , p = 0.021 ) , 24/48 ( 50 % ) of GA-treated patients ( mean 0.8 , p = 0.001 ) and 12/46 ( 26 % ) of sc IFN beta-1a-treated patients ( mean 0.4 , p < 0.001 ) . After 24 months , ≥1 new CL was observed in 41/50 ( 82 % ) of untreated ( mean 3.0 ) , 34/47 ( 72 % ) of i m IFN beta-1a-treated ( mean 1.6 , p < 0.001 ) , 30/48 ( 62 % ) of GA-treated ( mean 1.3 , p < 0.001 ) and 24/46 ( 52 % ) of sc IFN beta-1a-treated patients ( mean 0.8 , p < 0.001 ) . Mean grey matter fraction decrease in DMD-treated patients at 24 months ranged from 0.7 to 0.8 versus 1.0 in untreated patients ( p = 0.023 ) . Conclusions : Disease-modifying drugs significantly decreased new CL development and cortical atrophy progression compared with untreated patients , with faster and more pronounced effects seen with sc IFN beta-1a than with i m IFN beta-1a or GA Evidence of a significant improvement of IFNB-1b in clinical severity in the older population with RRMS has not been established so far . The aim of this exploratory post hoc analysis of the 250 mcg IFNB-1b group of the BEYOND study is to compare the efficacy and safety of older versus younger patients using a cut-off at the age of 50 and at the age of 40 , respectively . There was no difference between age groups in adjusted relapse risk ( age 50 cut-off : P = 0.482 , age 40 cut-off : P = 0.073 ) nor in adjusted time to confirmed EDSS progression ( age 50 cut-off : P = 0.096 , age 40 cut-off : P = 0.189 ) . There were no significant differences between patients < 50 and ≥50 years in the adjusted annualized relapse rate ( P = 0.285 ) , whereas relapse rate was higher in the < 40 as compared to the ≥40 group ( P = 0.024 ) . The proportion of patients with confirmed disability progression was not significantly different for the 50 cutoff ( P = 0.148 ) , whereas significantly fewer < 40 than ≥40 patients had disability progression ( P = 0.047 ) . Only minor differences in adverse event frequencies between the age groups for the two cut-offs were seen . These results indicate that IFNB-1b is as efficacious and safe in patients ≥50 years as < 50 years of age To evaluate the safety , tolerability , and efficacy of glatiramer acetate ( GA ) 40 mg compared to a 20 mg dose Switching treatment may be beneficial in patients with relapsing – remitting multiple sclerosis ( RRMS ) who respond inadequately to first‐line immunomodulatory therapy . The objective of this study was to evaluate clinical outcomes after switching treatment in such patients . This prospect i ve longitudinal observational study included 114 patients with RRMS who failed first‐line monotherapy and were switched treatments after 3 years . Every 3 months , patients underwent a full neurological examination . Outcome was compared between the 3‐year Before Switch and After Switch treatment periods . The primary outcome measure was the annualized relapse rate ; secondary outcome measures were the proportion of relapse‐free patients and the median change in Exp and ed Disability Status Scale ( EDSS ) . Patients were switched either from low‐dose to high‐dose interferon‐β ( IFNβ ; n = 31 ) , from IFNβ to glatiramer acetate ( GA ; n = 52 ) or mitoxantrone ( n = 13 ) , or from GA to IFNβ ( n = 16 ) . In 3 years after switching , annualized relapse rates fell by 57–78 % according to the group . The proportion of relapse‐free patients varied from 56 % to 81 % . Least improved was observed in patients switching between INFβ preparations . Median EDSS scores remained stable in all groups except the GA to IFNβ switchers . In conclusion , patients who fail first‐line immunomodulatory therapy generally benefit from switching to another class of immunomodulatory therapy BACKGROUND Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis ( RRMS ) , but no published r and omised trials have directly compared these two drugs . Our aim in the REGARD ( REbif vs Glatiramer Acetate in Relapsing MS Disease ) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS . METHODS In this multicentre , r and omised , comparative , parallel-group , open-label study , patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were r and omised to receive 44 mug subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse . A sub population of 460 patients ( 230 from each group ) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume . Treatments were assigned by a computer-generated r and omisation list that was stratified by centre . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00078338 . FINDINGS Between February and December , 2004 , 764 patients were r and omly assigned : 386 to interferon beta-1a and 378 to glatiramer acetate . After 96 weeks , there was no significant difference between groups in time to first relapse ( hazard ratio 0.94 , 95 % CI 0.74 to 1.21 ; p=0.64 ) . Relapse rates were lower than expected : 258 patients ( 126 in the interferon beta-1a group and 132 in the glatiramer acetate group ) had one or more relapses ( the expected number was 460 ) . For secondary outcomes , there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions , although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions ( 0.24 vs 0.41 lesions per patient per scan , 95 % CI -0.4 to 0.1 ; p=0.0002 ) . Safety and tolerability profiles were consistent with the known profiles for both compounds . The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks . INTERPRETATION There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome . The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity , which is an important consideration for ongoing and future trials in patients with RRMS The accepted st and ard treatment of relapsing multiple sclerosis consists of medications for disease symptoms , including treatment for acute exacerbations . However , currently there is no therapy that alters the progression of physical disability associated with this disease . The purpose of this study was to determine whether interferon beta‐1a could slow the progressive , irreversible , neurological disability of relapsing multiple sclerosis . Three hundred one patients with relapsing multiple sclerosis were r and omized into a double‐blinded , placebo‐controlled , multicenter phase I11 trial of interferon beta‐la . Interferon beta‐la , 6.0 million units ( 30 μg ) , was administered by intramuscular injection weekly . The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Exp and ed Disability Status Scale ( EDSS ) . Interferon beta‐la treatment produced a significant delay in time to sustained EDSS progression ( p equals ; 0.02 ) . The Kaplan‐Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9 % in the placebo group and 21.9 % in the interferon beta‐la‐treated group . Patients treated with interferon beta‐la also had significantly fewer exacerbations ( p = 0.03 ) and a significantly lower number and volume of gadolinium‐enhanced brain lesions on magnetic resonance images ( pvalues ranging between 0.02 and 0.05 ) . Over 2 years , the annual exacerbation rate was 0.90 in placebo‐treated patients versus 0.61 in interferon beta‐la‐treated patients . There were no major adverse events related to treatment . Interferon beta‐ la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability , exacerbation frequency , and disease activity measured by gadolinium‐enhanced lesions on brain magnetic resonance images . This treatment may alter the hndamen‐ tal course of relapsing multiple sclerosis Objective : To compare interferon β-1b ( IFNβ-1b ) and glatiramer acetate ( GA ) on new lesion ( NL ) ( gadolinium-enhancing , new T2 ) evolution into permanent black holes (PBH)—a marker of irreversible tissue damage — in patients with relapsing-remitting multiple sclerosis ( RRMS ) . Methods : BEYOND was a large , phase III , clinical trial comparing IFNβ-1b 250 μg , IFNβ-1b 500 μg , and GA ( 2:2:1 ) . Patient scans were reexamined post hoc for PBH in a rater-blinded manner . Two predefined co primary endpoints compared IFNβ-1b 250 μg with GA : first , number of PBH per patient at year 2 evolving from year 1 NL , then proportion of year 1 NL evolving into PBH at year 2 . IFNβ-1b 500 μg and GA were compared in an exploratory fashion . Results : Approximately 90 % ( 1,957/2,244 ) of patients had NL at year 1 with follow-up at year 2 . Mean numbers of PBH per patient at year 2 evolving from year 1 NL were lower for IFNβ-1b 250 μg than GA ( 0.30 vs 0.43 ; p = 0.0451 ) . The proportion of NL evolving into PBH was similar ( IFNβ-1b 250 μg vs GA : 21.6 % vs 23.5 % ; p > 0.20 ) . For IFNβ-1b 500 μg , both the mean PBH number per patient at year 2 evolving from year 1 NL ( 0.26 vs 0.43 ; p = 0.0037 ) and proportion of NL evolving into PBH ( 16.3 % vs 23.5 % ; p = 0.0409 ) were lower relative to GA . Conclusion : IFNβ-1b affected PBH development to a similar or better extent than GA . IFNβ-1b favorably influences an MRI outcome indicative of permanent tissue destruction in the brains of patients with multiple sclerosis . Classification of evidence : This study provides Class III evidence that IFNβ-1b is associated with a reduction in MRI PBH formation and evolution compared with GA between years 1 and 2 of treatment Background : The frequency and impact of neutralizing antibodies ( NAbs ) to interferon beta-1b ( IFNβ-1b ) on clinical and radiographic outcomes is controversial . Objective : To assess NAb impact in the BEYOND study . Methods : 2244 patients were r and omized ( 2:2:1 ) to receive IFNβ-1b , either 250 or 500 µg , or glatiramer acetate , 20 mg , and observed for 2–3.5 years . NAb titers were determined every 6 months . A titer ≥20 NU/ml was considered NAb positive . Efficacy was compared between NAb-positive and NAb-negative patients , using comprehensive statistical analyses , taking into account the delayed appearance of NAbs , the time-dependent changes in the relapse rate , spontaneous reversions to NAb-negative status , NAb-titer level , and also adjusting for baseline factors . Results : In the IFNβ-1b 250 µg group , NAb-positive titers were detected ( ≥ once ) in 319 patients ( 37.0 % ) ; of these , 112 ( 35.1 % ) reverted to NAb-negative status . In the IFNβ-1b 500 µg group , 340 patients ( 40.7 % ) became NAb-positive and 119 ( 35.0 % ) reverted to NAb-negative status . In both IFNβ groups , especially the 250 µg arm , NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis . By contrast , in both IFNβ groups , NAbs were associated with a very consistent deleterious impact on most MRI outcomes . Conclusion : There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes . On MRI measures , the impact was consistent and convincing , whereas on clinical measures a negative impact of NAbs was not found . The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex We previously reported results of a 12 month prospect i ve , non-r and omized , open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis ( RRMS ) . We now report the results after 18 months of follow-up . Our primary objective was to compare the effect of INFβ-1a ( Avonex ® ) , IFNβ-1b ( Betaseron ® ) , and Glatiramer Acetate ( GA , Copaxone ® ) to no treatment on the relapse rate in patients with RRMS . One hundred and fifty-six consecutive patients with clinical ly definite RRMS with a Kurtzke scale ( EDSS ) score of 4 or less were followed for 18 months . Prior 2-year relapse history and available chart information was carefully review ed at the time of enrollment . Thirty-three of 156 elected no treatment at enrollment ; 40 elected IFNβ-1a , 41 IFNβ-1b , and 42 chose GA . There were no statistically significant differences among the four groups at enrollment . After 18 months of treatment , 122 patients remained in their original treatment group . Compared to the untreated group ( 1.02 ) , mean annualized number of relapses was significantly reduced only in the GA ( 0.49 , P40.0001 ) and IFNβ-1b groups ( 0.55 , P=0.001 ) in contrast to the IFNβ-1a treated patients ( 0.81 , P=0.106 ) who did not show a significant reduction . Despite limitations of the study design , the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naïve RRMS patients we studied copolymer 1 ( Copaxone ) in a multicenter ( 11-university ) phase III trial of patients with relapsing-remitting multiple sclerosis ( MS ) . Two hundred fifty-one patients were r and omized to receive copolymer 1 ( n = 125 ) or placebo ( n = 126 ) at a dosage of 20 mg by daily subcutaneous injection for 2 years . The primary end point was a difference in the MS relapse rate . The final 2-year relapse rate was 1.19 ± 0.13 for patients receiving copolymer 1 and 1.68 ± 0.13 for those receiving placebo , a 29 % reduction in favor of copolymer 1 ( p = 0.007 ) ( annualized rates = 0.59 for copolymer 1 and 0.84 for placebo ) . Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1 . Disability was measured by the Exp and ed Disability Status Scale ( EDSS ) , using a two-neurologist ( examining and treating ) protocol . When the proportion of patients who improved , were unchanged , or worsened by ≥1 EDSS step from baseline to conclusion ( 2 years ) was evaluated , significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened ( p = 0.037 ) . Patient withdrawals were 19 ( 15.2 % ) from the copolymer 1 group and 17 ( 13.5 % ) from the placebo group at approximately the same intervals . The treatment was well tolerated . The most common adverse experience was an injection-site reaction . Rarely , a transient self-limited systemic reaction followed the injection in 15.2 % of those receiving copolymer 1 and 3.2 % of those receiving placebo . This reaction was characterized by flushing or chest tightness with palpitations , anxiety , or dyspnea and commonly lasted for 30 seconds to 30 minutes . This rigorous study confirmed the findings of a previous pilot trial and demonstrated that copolymer 1 treatment can significantly and beneficially alter the course of relapsing-remitting MS in a well-tolerated fashion BACKGROUND Glatiramer acetate , approved for the treatment of relapsing-remitting multiple sclerosis , reduces relapses and disease activity and burden monitored by MRI . We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinical ly definite multiple sclerosis . METHODS In this r and omised , double-blind trial , undertaken in 80 sites in 16 countries , 481 patients presenting with a clinical ly isolated syndrome with unifocal manifestation , and two or more T2-weighted brain lesions measuring 6 mm or more , were r and omly assigned to receive either subcutaneous glatiramer acetate 20 mg per day ( n=243 ) or placebo ( n=238 ) for up to 36 months , unless they converted to clinical ly definite multiple sclerosis . The r and omisation scheme used SAS-based blocks stratified by centre , and patients and all personnel were masked to treatment assignment . The primary endpoint was time to clinical ly definite multiple sclerosis , based on a second clinical attack . Analysis was by intention to treat . A preplanned interim analysis was done for data accumulated from 81 % of the 3-year study exposure . This study was registered with Clinical Trials.gov , number NCT00666224 . FINDINGS All r and omly assigned participants were analysed for the primary outcome . Glatiramer acetate reduced the risk of developing clinical ly definite multiple sclerosis by 45 % compared with placebo ( hazard ratio 0.55 , 95 % CI 0.40 - 0.77 ; p=0.0005 ) . The time for 25 % of patients to convert to clinical ly definite disease was prolonged by 115 % , from 336 days for placebo to 722 days for glatiramer acetate . The most common adverse events in the glatiramer acetate group were injection-site reactions ( 135 [ 56 % ] glatiramer acetate vs 56 [ 24 % ] placebo ) and immediate post-injection reactions ( 47 [ 19 % ] vs 12 [ 5 % ] ) . INTERPRETATION Early treatment with glatiramer acetate is efficacious in delaying conversion to clinical ly definite multiple sclerosis in patients presenting with clinical ly isolated syndrome and brain lesions detected by MRI . FUNDING Teva Pharmaceutical Industries , Israel BACKGROUND The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose ( BEYOND ) trial was to compare the efficacy , safety , and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis . METHODS Between November , 2003 , and June , 2005 , 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospect i ve , multicentre , r and omised trial . Patients were r and omly assigned 2:2:1 by block r and omisation with regional stratification to receive one of two doses of interferon beta-1b ( 250 microg or 500 microg ) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day . The primary outcome was relapse risk , defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the exp and ed disability status scale ( EDSS ) and change in T1-hypointense lesion volume . Clinical outcomes were assessed quarterly for 2.0 - 3.5 years ; MRI was done at screening and annually thereafter . Analysis was by per protocol . This study is registered , number NCT00099502 . FINDINGS We found no differences in relapse risk , EDSS progression , T1-hypointense lesion volume , or normalised brain volume among treatment groups . Flu-like symptoms were more common in patients treated with interferon beta-1b ( p<0.0001 ) , whereas injection-site reactions were more common in patients treated with glatiramer acetate ( p=0.0005 ) . Patient attrition rates were 17 % ( 153 of 888 ) on 250 microg interferon beta-1b , 26 % ( 227 of 887 ) on 500 microg interferon beta-1b , and 21 % ( 93 of 445 ) for glatiramer acetate . INTERPRETATION 500 microg interferon beta-1b was not more effective than the st and ard 250 microg dose , and both doses had similar clinical effects to glatiramer acetate . Although interferon beta-1b and glatiramer acetate had different adverse event profiles , the overall tolerability to both drugs was similar . FUNDING Bayer HealthCare Pharmaceuticals Two prior double‐blind , placebo‐controlled , r and omized trials demonstrated that glatiramer acetate ( GA ) reduces relapse rates in patients with relapsing remitting multiple sclerosis ( RRMS ) . This study was design ed to determine the effect , onset , and durability of any effect of GA on disease activity monitored with magnetic resonance imaging ( MRI ) in patients with RRMS . Two hundred thirty‐nine eligible patients were r and omized to receive either 20 mg GA ( n = 119 ) or placebo ( n = 120 ) by daily subcutaneous injection . Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI . The study was a r and omized , double‐blind , placebo‐controlled phase during which all patients studied underwent monthly MRI scans and clinical assessment s over 9 months . The primary outcome measure was the total number of enhancing lesions on T1‐weighted images . Secondary outcome measures included the proportion of patients with enhancing lesions , the number of new enhancing lesions and change in their volume ; the number of new lesions detected on T2‐weighted images and change in their volume , and the change in volume of hypointense lesions seen on unenhanced T1‐weighted images . Clinical measures of disease activity were also evaluated . The active treatment and placebo groups were comparable at entry for all demographic , clinical , and MRI variables . Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo ( −10.8 , 95 % confidence interval −18.0 to −3.7 ; p = 0.003 ) . Consistent differences favoring treatment with GA were seen for almost all secondary end points examined : number of new enhancing lesions ( p < 0.003 ) , monthly change in the volume of enhancing lesions ( p = 0.01 ) , and change in volume ( p = 0.006 ) and number of new lesions seen on T2‐weighted images ( p < 0.003 ) . The relapse rate was also significantly reduced by 33 % for GA‐treated patients ( p = 0.012 ) . All effects increased over time . Glatiramer acetate significantly reduced MRI‐measured disease activity and burden . Ann Neurol Objective : Immunomodulatory drugs ( IDs ) ( interferon beta ( IFNβ ) and glatiramer acetate ( GA ) ) reduce relapse rate and disease progression in relapsing-remitting multiple sclerosis ( RRMS ) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence . The aim of this study was to evaluate the impact of IFNβ and GA in MS patients treated before 16 years of age . Methods : A research group ( Immunomodulatory Treatment of Early onset MS ( ITEMS ) ) was promoted in Italy to collect a large series of patients affected by clinical ly definite and RRMS and treated with IDs before 16 years of age . Fifteen centres recognized subjects suitable for inclusion : 76 patients ( 52 females ) were collected with a mean age at onset of 12.4 ( SD 2.5 ) years , a mean disease duration of 18.6 ( SD 14.7 ) and a relapse rate of 3.1 ( SD 2.9 ) . Results : Results were evaluated in 65 ( 45 females ) subjects with a pretreatment and a treatment duration > 3 months : 38 were treated with IFNβ-1a once weekly ( Avonex ) , 18 with IFNβ three times weekly ( 16 with Rebif , 2 with Betaferon ) and nine with GA ( Copaxone ) . The mean pretreatment period was respectively 20 , 18 and 9.2 months . The treatment duration lasted respectively 23.3 , 40.7 and 33.3 months . The mean annualized relapse rate decreased dramatically during the treatment : from 2.4 to 0.4 in the Avonex group , from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group . The mean final EDSS scores were respectively ( in brackets the initial scores ) : 1.3 ( 1.4 ) , 1.6 ( 1.8 ) and 0.6 ( 1.1 ) . In the whole group , the final score was unchanged or reduced in all subjects except eight . Clinical side effects were recorded in 41/65 subjects ( mainly in subjects treated with IFNβ ) , abnormal laboratory findings were observed in 13/65 subjects : they were transient in most cases . IFNβ was stopped in six cases : in four because of inefficacy and in two cases because of side effects . Conclusions : Sixty-five clinical ly definite MS subjects were treated during childhood or adolescence with IDs . The treatment reduced the relapse rate and the progression of the disease in most cases . Side effects were common in subjects treated with IFNβ , but were well tolerated in most cases OBJECTIVE To investigate the value of Exp and ed Disability Status Scale ( EDSS ) worsening sustained for at least 6 months and other parameters as predictors for disability status . DESIGN Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data . SETTING The intramuscular interferon beta-1a pivotal trial was a double-blind , placebo-controlled phase 3 study . PARTICIPANTS Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postr and omization . INTERVENTION Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial . MAIN OUTCOME MEASURES Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years . A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up . RESULTS Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not . Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit , 8 years after r and omization . Other independent predictors were treatment arm assignment and baseline EDSS score . CONCLUSION In this phase 3 clinical trial of intramuscular interferon beta-1a , compared with effects of treatment , baseline EDSS score , and number of relapses during the study , worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinical ly significant disability 8 years after r and omization into the clinical trial To assess the efficacy and safety of glatiramer acetate ( GA ) 40 mg administered 3 × weekly ( tiw ) compared with placebo in patients with relapsing – remitting multiple sclerosis ( RRMS ) Over the last decade and a half , several disease-modifying therapies ( DMTs ) have been approved for the treatment of multiple sclerosis ( MS ) including glatiramer actetate ( GA ; Copaxone ) , interferon beta (IFNB)-1a ( Avonex , Rebif ) , IFNB-1b ( Betaferon/Betaseron ) , mitoxantrone ( Novantrone ) , and natalizumab ( Tysabri ) . R and omized controlled trials ( RCTs ) of each of these DMTs have demonstrated that treatment has a favourable impact on at least one ( often several ) of the short-term outcome measures typically used to assess efficacy in MS clinical trials . These outcomes include clinical measures of disease activity such as the number or frequency of relapses , the time to first relapse , etc . They also include clinical measures of disease severity such as disease progression on the Exp and ed Disability Status Scale ( EDSS ) or the MS Functional Composite score ( MSFC ) , determined either as a confirmed change over a 3 to 6 month interval or as a total change over the entire duration of the trial , in addition to various magnetic resonance imaging ( MRI ) measures such as the number and volume of T2 lesions , the number and volume of new or gadolinium (Gd)-enhancing lesions , or the number and volume of T1 dark lesions Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews Background : Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis ( MS ) but its clinical consequences remain controversial . Objective : Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents . Methods : Seventy-five treatment-naïve subjects with relapsing – remitting MS ( N = 61 ) or clinical ly isolated syndromes at risk of MS ( N = 14 ) from the BECOME study that had been r and omized to interferon beta-1b ( N = 39 ) or glatiramer acetate ( N = 36 ) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission . Results : MRI remission occurred in 46.4 % of participants transiently and in 23.2 % completely while it was never achieved in 30.4 % . There was no difference by treatment in MRI remission , progression of physical disability , or cognitive function . The percentage of relapse-free subjects was 87.5 % for the group in complete MRI remission , 47.6 % in the group never in remission and 59.4 % in the group in transient remission ( p = 0.017 ) . Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk ( p = 0.026 ) and by Exp and ed Disability Status Scale ( EDSS ) ( p = 0.10 ) . Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment ; this group improved the least upon repeated cognitive testing during the two years of treatment ( p < 0.001 ) . Conclusions : Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function Background : Hypointense lesions on T1 weighted MRI , referred to as black holes ( BH ) , are a marker of demyelination/axonal loss in multiple sclerosis ( MS ) . There is some evidence that glatiramer acetate ( GA ) may decrease the conversion of new brain lesions to BH . Methods : Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS r and omised to GA or Interferon β-1b ( IFNβ1b ) in the BECOME study . Findings : Of 1224 newly enhancing lesions ( NEL ) appearing at baseline through 24 months in 61 patients , 767 ( 62.7 % ) showed an acute BH ( ABH ) . The majority of ABH were transient and of similar duration by treatment group . Of 571 ABH in which MRI follow-up scans were available for ⩾1 year , 103 ( 18.8 % ) were still visible ⩾12 months after onset and were considered chronic BH ( CBH ) . Only 12.1 % of the 849 NEL with MRI follow-up ⩾1 year converted to CBH , 9.8 % with IFNβ1b and 15.2 % with GA ( p = 0.02 ) . The conversion from ABH to CBH was also lower with IFNβ1b ( 15.2 % ) than with GA ( 21.4 % ) , of borderline significance ( p = 0.06 ) . The majority of patients who developed NEL did not develop CBH ; however , about a quarter had conversion rates from ABH to CBH greater than 20 % . Interpretation : Only a minority of new brain lesions in patients with MS treated with GA or IFNβ1b convert to CBH BACKGROUND Interferon-β1a ( IFNB ) and glatiramer acetate ( GA ) are distinct therapies which are both partially effective for relapsing MS . It is not known if combining the two treatments would be more effective . OBJECTIVE To review the rationale , design , and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA . METHODS The key inclusion criteria included a diagnosis of relapsing MS , at least 2 episodes of MS activity in the previous 3 years , exp and ed disability status scale of 0 - 5.5 , and no prior treatment with either IFNB or GA . Subjects were r and omized to IFNB+GA , IFNB monotherapy , or GA monotherapy in a 2:1:1 ratio . RESULTS From 2005 to 2009 , we enrolled 1008 subjects . The participants were 72.4 % female and 87.6 % Caucasian with a mean age of 37.7 years . The median duration of symptoms was 2 years at entry into the study , and the mean EDSS was 2.1 . On the baseline MRI , the mean total lesion load was 12.2ml , and 40 % of the participants had enhancing lesions . CONCLUSION We have recruited a population of patients with clinical and MRI characteristics typical for early MS . The study results will aid in deciding on the optimum early treatment . This trial should serve as a model for future studies of combination therapy Background : There are no published MRI studies comparing interferon beta 1b ( IFNβ-1b ) and glatiramer acetate ( GA ) for treatment of relapsing multiple sclerosis ( MS ) . Objective : To compare the efficacy of IFNβ-1b and GA for suppression of MS disease activity as evidence d on frequent brain MRI . Methods : A total of 75 patients with relapsing-remitting MS or clinical ly isolated syndromes were r and omized to st and ard doses of IFNβ-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement . The primary outcome was the number of combined active lesions ( CAL ) per patient per scan during the first year , which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery ( FLAIR ) lesions . Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years . Results : Baseline characteristics were similar between the groups . The primary outcome showed similar median ( 75th percentile ) CAL per patient per scan for months 1–12 , 0.63 ( 2.76 ) for IFNβ-1b , and 0.58 ( 2.45 ) for GA ( p = 0.58 ) . There were no differences in new lesion or clinical relapses for 2 years . Only 4.4 % of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions . Conclusion : Patients with relapsing multiple sclerosis r and omized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity

Although we were able to calculate one estimation of DTA in , especially , the prediction of progression from MCI to ADD at four years follow-up , the small number of participants implies imprecision of sensitivity and specificity estimates .

BACKGROUND 18F-florbetaben uptake by brain tissue , measured by positron emission tomography ( PET ) , is accepted by regulatory agencies like the Food and Drug Administration ( FDA ) and the European Medicine Agencies ( EMA ) for assessing amyloid load in people with dementia . Its added value is mainly demonstrated by excluding Alzheimer 's pathology in an established dementia diagnosis . However , the National Institute on Aging and Alzheimer 's Association ( NIA-AA ) revised the diagnostic criteria for Alzheimer 's disease and confidence in the diagnosis of mild cognitive impairment ( MCI ) due to Alzheimer 's disease may be increased when using some amyloid biomarkers tests like 18F-florbetaben . These tests , added to the MCI core clinical criteria , might increase the diagnostic test accuracy ( DTA ) of a testing strategy . However , the DTA of 18F-florbetaben to predict the progression from MCI to Alzheimer 's disease dementia ( ADD ) or other dementias has not yet been systematic ally evaluated . OBJECTIVES To determine the DTA of the 18F-florbetaben PET scan for detecting people with MCI at time of performing the test who will clinical ly progress to ADD , other forms of dementia ( non-ADD ) , or any form of dementia at follow-up .

Of 57 individuals diagnosed with Alzheimer 's disease ( AD ) in a phase III study , 13 ( 23 % ) had amyloid-β ( Aβ ) levels on postmortem histopathology that did not explain the dementia . Based on postmortem histopathology , a wide range of different non-AD conditions was identified , including frontotemporal dementia , hippocampal sclerosis , and dementia with Lewy bodies . Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite st and ardized uptake value ratios . Thus , florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology BACKGROUND Subjects with a mild cognitive impairment ( MCI ) have a memory impairment beyond that expected for age and education yet are not demented . These subjects are becoming the focus of many prediction studies and early intervention trials . OBJECTIVE To characterize clinical ly subjects with MCI cross-sectionally and longitudinally . DESIGN A prospect i ve , longitudinal inception cohort . SETTING General community clinic . PARTICIPANTS A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease ( AD ) , all from a community setting as part of the Mayo Clinic Alzheimer 's Disease Center/Alzheimer 's Disease Patient Registry , Rochester , Minn. MAIN OUTCOME MEASURES The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination , Wechsler Adult Intelligence Scale-Revised , Wechsler Memory Scale-Revised , Dementia Rating Scale , Free and Cued Selective Reminding Test , and Auditory Verbal Learning Test . Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer 's Disease and Related Disorders Association criteria , respectively . RESULTS The primary distinction between control subjects and subjects with MCI was in the area of memory , while other cognitive functions were comparable . However , when the subjects with MCI were compared with the patients with very mild AD , memory performance was similar , but patients with AD were more impaired in other cognitive domains as well . Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD . CONCLUSIONS Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD . They appear to constitute a clinical entity that can be characterized for treatment interventions Evaluation of brain β‐amyloid by positron emission tomography ( PET ) imaging can assist in the diagnosis of Alzheimer disease ( AD ) and other dementias Objective : To investigate the 10-year risk of dementia in subjects with mild cognitive impairment ( MCI ) ages 40 to 85 years . Methods : We selected subjects from a memory clinic if they met one of the following definitions of MCI : cognitive complaints ( n = 181 ) , aging-associated cognitive decline ( AACD ) ( n = 163 ) , mild functional impairment ( n = 86 ) , or amnestic MCI ( n = 64 ) . Subjects were reassessed after 2 , 5 , and 10 years . The risk of dementia was calculated with Kaplan-Meier statistics . Analyses were conducted in the entire sample and in subgroups of subjects aged 40 to 54 years , 55 to 69 years , and 70 to 85 years . Results : The 10-year risk of dementia was 0.27 ( 95 % CI 0.20 to 0.34 ) in subjects with cognitive complaints , 0.28 ( 95 % CI 0.21 to 0.35 ) in subjects with AACD , 0.44 ( 95 % CI 0.32 to 0.56 ) in subjects with mild functional impairment , and 0.48 ( 95 % CI 0.35 to 0.61 ) in subjects with amnestic MCI . Ninety-one percent of the demented subjects had probable AD . The risk of dementia increased with increasing age for all MCI definitions ( p < 0.001 ) . Depending on the MCI definition used , the risk for dementia ranged from 0 to 0.06 in subjects aged 40 to 54 years , from 0.37 to 0.52 in subjects aged 55 to 69 years , and from 0.77 to 1.0 in subjects aged 70 to 85 years . Conclusions : The majority of subjects with MCI do not progress to dementia at the long term . Age strongly influences the dementia risk . MCI often represents the predementia stage of a neurodegenerative disorder in elderly subjects but rarely in younger subjects CONTEXT Small single-center studies have shown that cerebrospinal fluid ( CSF ) biomarkers may be useful to identify incipient Alzheimer disease ( AD ) in patients with mild cognitive impairment ( MCI ) , but large-scale multicenter studies have not been conducted . OBJECTIVE To determine the diagnostic accuracy of CSF beta-amyloid(1 - 42 ) ( Abeta42 ) , total tau protein ( T-tau ) , and tau phosphorylated at position threonine 181 ( P-tau ) for predicting incipient AD in patients with MCI . DESIGN , SETTING , AND PARTICIPANTS The study had 2 parts : a cross-sectional study involving patients with AD and controls to identify cut points , followed by a prospect i ve cohort study involving patients with MCI , conducted 1990 - 2007 . A total of 750 individuals with MCI , 529 with AD , and 304 controls were recruited by 12 centers in Europe and the United States . Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia . MAIN OUTCOME MEASURES Sensitivity , specificity , positive and negative likelihood ratios ( LRs ) of CSF Abeta42 , T-tau , and P-tau for identifying incipient AD . RESULTS During follow-up , 271 participants with MCI were diagnosed with AD and 59 with other dementias . The Abeta42 assay in particular had considerable intersite variability . Patients who developed AD had lower median Abeta42 ( 356 ; range , 96 - 1075 ng/L ) and higher P-tau ( 81 ; range , 15 - 183 ng/L ) and T-tau ( 582 ; range , 83 - 2174 ng/L ) levels than MCI patients who did not develop AD during follow-up ( 579 ; range , 121 - 1420 ng/L for Abeta42 ; 53 ; range , 15 - 163 ng/L for P-tau ; and 294 ; range , 31 - 2483 ng/L for T-tau , P < .001 ) . The area under the receiver operating characteristic curve was 0.78 ( 95 % confidence interval [ CI ] , 0.75 - 0.82 ) for Abeta42 , 0.76 ( 95 % CI , 0.72 - 0.80 ) for P-tau , and 0.79 ( 95 % CI , 0.76 - 0.83 ) for T-tau . Cut-offs with sensitivity set to 85 % were defined in the AD and control groups and tested in the MCI group , where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83 % ( 95 % CI , 78%-88 % ) , specificity 72 % ( 95 % CI , 68%-76 % ) , positive LR , 3.0 ( 95 % CI , 2.5 - 3.4 ) , and negative LR , 0.24 ( 95 % CI , 0.21 - 0.28 ) . The positive predictive value was 62 % and the negative predictive value was 88 % . CONCLUSIONS This multicenter study found that CSF Abeta42 , T-tau , and P-tau identify incipient AD with good accuracy , but less accurately than reported from single-center studies . Intersite assay variability highlights a need for st and ardization of analytical techniques and clinical procedures Background We assessed the clinical utility of β-amyloid ( Aβ ) imaging with 18F-florbetaben ( FBB ) in mild cognitive impairment ( MCI ) by evaluating its prognostic accuracy for progression to Alzheimer 's disease ( AD ) , comparing semiquantitative with visual scan assessment , and exploring the relationships among Aβ , hippocampal volume ( HV ) and memory over time . Methods 45 MCI underwent FBB positron emission tomography , MRI and neuropsychological assessment at baseline and 2 years and clinical follow-up at 4 years . Positive FBB ( FBB+ ) , defined by a cortical to cerebellar cortex st and ardised uptake value ratio ( SUVR ) ≥1.45 , was compared with visual assessment by five readers . Amnestic MCI ( aMCI ) was defined by a composite episodic memory ( EM ) Z-score of < −1.5 . Results At baseline , 24 ( 53 % ) MCI were FBB+ . Majority reads agreed with SUVR classification ( κ 0.96 ) . In 2 years , 18 ( 75 % ) FBB+ progressed to AD compared with 2 ( 9.5 % ) FBB− , yielding a predictive accuracy of 83 % ( 95 % CI 61 % to 94 % ) . Four FBB− developed non-AD dementia . Predictive accuracies of HV ( 58 % ( 95 % CI 42 % to 73 % ) ) and aMCI status ( 73 % ( 95 % CI 58 % to 81 % ) ) were lower . Combinations did not improve accuracy . By 4 years , 21 ( 87.5 % ) FBB+ had AD whereas 5 ( 24 % ) FBB− had non-AD dementia yielding a predictive accuracy of 94 % ( 95 % CI 74 % to 99 % ) . While the strong baseline association between FBB SUVR and EM declined over 2 years , the association between EM and HV became stronger . FBB SUVR increased 2.2%/year in FBB+ with no change in FBB−. Conclusions 18F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD . As neurodegeneration progresses , and in contrast with the early stages of the disease , hippocampal atrophy and not Aβ , seems to drive memory decline . Trial registration number NCT01138111 Assessment of disease biomarkers , particularly the in vivo assessment of amyloid-β ( Aβ ) burden with positron emission tomography ( PET ) , is gradually becoming central to the diagnosis of mild cognitive impairment ( MCI ) due to Alzheimer 's disease ( AD ) . However , the incorporation of biomarker evidence to the diagnostic process is currently restricted mainly to research setting s. The identification of memory measures that are associated with Aβ is of clinical relevance as this may enhance the confidence in making a diagnosis of MCI due to AD in clinical setting s. Forty one persons with amnestic MCI underwent Aβ imaging with (18)F-Florbetaben PET , magnetic resonance imaging , and a comprehensive neuropsychological assessment . All measures of episodic memory were significantly correlated with Aβ burden , but regression analyses revealed a strong and selective association between story recall and Aβ over and beyond the effects of age , education , global cognition , hippocampal volume , or other memory tests . Analyses of sensitivity and specificity of memory measures to detect high versus low Aβ scans suggested that word-list recall performed better when high sensitivity was preferred , whereas story recall performed better when high specificity was preferred . In conclusion , a measure of story recall may increase the confidence in making a diagnosis of MCI due to AD in clinical setting A retrospective clinico-pathological study of a consecutive autopsy series of 1050 elderly demented individuals ( mean age 83.4 + /- 6.0 years ; MMSE < 20 ) was performed . Clinical diagnoses were probable or possible Alzheimer disease ( 62.9 % ) , nonspecific degenerative dementia ( 10.4 % ) , vascular dementia ( 10 % ) , Parkinson disease with dementia ( 9.5 % ) , 1.5 % mixed dementia , and 5.7 % other disorders . At autopsy , 86 % revealed Alzheimer-related pathology , but only 42.8 % showed " pure " Alzheimer disease , with additional cerebrovascular lesions in 22.6 % and Lewy body pathology in 10.8 % , while among 660 cases of clinical ly suspected Alzheimer disease , Alzheimer pathology was seen in 93 % , only 44.7 % in " pure " form , and additional vascular lesions and Lewy bodies in 27.7 and 10 % , respectively . The non-Alzheimer cases included Huntington and Creutzfeldt-Jakob disease , frontotemporal dementias , and others . These and other recent data indicate that in patients with the clinical diagnosis of Alzheimer disease its combination with cerebrovascular lesions and Lewy body pathologies is rather frequent . Comparison of clinical and postmortem diagnoses revealed postmortem confirmation of Alzheimer disease in 93 % , of mixed and vascular dementia in 60 and 52.3 % , respectively . 78 % of clinical ly suspected degenerative dementias were pathologically definite Alzheimer disease , while in the clinical Parkinson + dementia group dementia with Lewy bodies accounted for 35 % , Parkinson+Alzheimer disease , and " pure " Alzheimer disease for 29 % , each . A sample of 207 prospect ively studied elderly showed significant negative correlation between the preterminal psychostatus assessed by MMSE and the neuritic Braak stages , with a broad " gray " zone of Alzheimer lesions in mildly to moderately demented subjects . Similar relations between CDR and Braak stages were seen in very old subjects . The present study and the results of other recent series indicate increasing agreement between clinical and autopsy diagnoses in demented aged individuals with variable accuracy rates for different forms of dementia disorders OBJECTIVES To determine the 2-year outcome from 16 different current classifications of mild cognitive impairment ( MCI ) in a population -based sample . DESIGN Prospect i ve cohort study : baseline and 2-year follow-up phases . SETTING Large-scale multicenter study , United Kingdom . PARTICIPANTS : Thirteen thous and four individuals aged 65 and older from the Medical Research Council Cognitive Function and Ageing Study . From this , a sub sample of 2,640 individuals was selected and completed a more-detailed cognitive assessment . Individuals who underwent further assessment were asked to complete annual or 2-year follow-ups . MEASUREMENTS Information on sociodemographic status , general health , cognitive impairment and functional ability were collected using a structured interview . Individuals were classified according to 16 different definitions of MCI . These were applied retrospectively . RESULTS The dominant outcome across definitions was an impairment that was not classifiable or reversion to normality . Progression to dementia was variable and generally poor . Overall progression was highest in classifications in which impairment extended to memory and nonmemory domains . Predictability was age dependent in some but not all classifications . CONCLUSION Current classifications of MCI have variable outcomes in population -based sample s. Progression to dementia is relatively rare and is dependent on age and definition . Selection criteria developed for the clinic are based on a " high risk " approach that leads to exclusion of a large percentage of the impaired population who are neither normal nor demented and for whom no intervention options are currently available . A refined definition of this construct is urgently needed if MCI is to be used to predict dementia in population -based studies BACKGROUND Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer 's disease . Florbetaben ( ¹⁸F ) is a promising ¹⁸F-labelled amyloid-β-targeted PET tracer in clinical development . We aim ed to assess the sensitivity and specificity of florbetaben ( ¹⁸F ) PET in discriminating between patients with probable Alzheimer 's disease and elderly healthy controls . METHODS We did a multicentre , open-label , non-r and omised phase 2 study in 18 centres in Australia , Germany , Switzerl and , and the USA . Imaging with florbetaben ( ¹⁸F ) PET was done on patients with probable Alzheimer 's disease ( age 55 years or older , mini-mental state examination [ MMSE ] score=18 - 26 , clinical dementia rating [CDR]=0·5 - 2·0 ) and age-matched healthy controls ( MMSE ≥ 28 , CDR=0 ) . Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched healthy controls on the basis of neocortical tracer uptake pattern 90 - 110 min post-injection . PET images were assessed visually by three readers masked to the clinical diagnosis and all other clinical findings , and quantitatively by use of pre-established brain volumes of interest to obtain st and ard uptake value ratios ( SUVRs ) , taking the cerebellar cortex as the reference region . This study is registered with Clinical Trials.gov , number NCT00750282 . FINDINGS 81 participants with probable Alzheimer 's disease and 69 healthy controls were assessed . Independent visual assessment of the PET scans showed a sensitivity of 80 % ( 95 % CI 71 - 89 ) and a specificity of 91 % ( 84 - 98 ) for discriminating participants with Alzheimer 's disease from healthy controls . The SUVRs in all neocortical grey-matter regions in participants with Alzheimer 's disease were significantly higher ( p < 0·0001 ) compared with the healthy controls , with the posterior cingulate being the best discriminator . Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85 % and a specificity of 91 % . Regional SUVRs also correlated well with scores of cognitive impairment such as the MMSE and the word-list memory and word-list recall scores ( r -0·27 to -0·33 , p ≤ 0·021 ) . APOE ɛ4 was more common in participants with positive PET images compared with those with negative scans ( 65%vs 22 % [ p=0·027 ] in patients with Alzheimer 's disease ; 50%vs 16 % [ p = 0·074 ] in healthy controls ) . No safety concerns were noted . INTERPRETATION We provide verification of the efficacy , safety , and biological relevance of florbetaben ( ¹⁸F ) amyloid-β PET and suggest its potential as a visual adjunct in the diagnostic algorithm of dementia . FUNDING Bayer Schering Pharma AG

Since exercise training confers substantial physiologic and clinical benefits and activity levels are inversely proportional to cardiovascular mortality ( 9 ) , it is not surprising that trials of exercise programs found positive effects on survival .

Cardiovascular disease remains the most common cause of office visits , hospitalizations , and death in the United States : More than 13 million Americans have documented coronary artery disease ( CAD ) , and costs for CAD are expected to exceed $ 393 billion in 2005 ( 1 ) . Control of the CAD epidemic requires a multifaceted strategy targeting the currently recognized modifiable risk factors for CAD that account for more than 90 % of risk , regardless of sex , age , or region ( 2 ) . This strategy should include primary prevention maneuvers ( for the general population and high-risk individuals ) and secondary prevention programs ( for patients with established CAD ) . Despite the abundant evidence base for CAD prevention ( 3 ) , health outcomes studies consistently demonstrate gaps in applying this evidence to clinical practice ; these gaps contribute to suboptimal patient outcomes ( 4 ) . Secondary prevention programs are often proposed as a way to improve management and outcomes . We demonstrated improvements in risk factor profiles and processes of care ( particularly the prescription of proven efficacious therapies ) but indeterminate effect on rates of death or recurrent MIs ( 10 ) . Because current guidelines recommend that secondary prevention programs should not be restricted to supervised exercise programs but should address the full range of modifiable risk factors ( 11 ) , we conducted a systematic review to up date earlier work and to determine the effects of different types of secondary prevention programs ( particularly those with a structured exercise component versus those without ) .

Of 22 r and omized trials of rehabilitation with exercise after myocardial infa rct ion ( MI ) , one trial had results that achieved conventional statistical significance . To determine whether or not these studies , in the aggregate , show a significant benefit of rehabilitation after myocardial infa rct ion , we performed an overview of all r and omized trials , involving 4,554 patients ; we evaluated total and cardiovascular mortality , sudden death , and fatal and nonfatal reinfa rct ion . For each endpoint , we calculated an odds ratio ( OR ) and 95 % confidence interval ( 95 % CI ) for the trials combined . After an average of 3 years of follow-up , the ORs were significantly lower in the rehabilitation than in the comparison group : specifically , total mortality ( OR = 0.80 [ 0.66 , 0.96 ] ) , cardiovascular mortality ( OR = 0.78 [ 0.63 , 0.96 ] ) , and fatal reinfa rct ion ( OR = 0.75 [ 0.59 , 0.95 ] ) . The OR for sudden death was significantly lower in the rehabilitation than in the comparison group at 1 year ( OR = 0.63 [ 0.41 , 0.97 ] ) . The data were compatible with a benefit at 2 ( OR = 0.76 [ 0.54 , 1.06 ] ) and 3 years ( OR = 0.92 [ 0.69 , 1.23 ] ) , but these findings were not statistically significant . For nonfatal reinfa rct ion , there were no significant differences between the two groups after 1 ( OR = 1.09 [ 0.76 , 1.57 ] ) , 2 ( OR = 1.10 [ 0.82 , 1.47 ] ) , or 3 years ( OR = 1.09 [ 0.88 , 1.34 ] ) of follow-up . The observed 20 % reduction in overall mortality reflects a decreased risk of cardiovascular mortality and fatal reinfa rct ion throughout at least 3 years and a reduction in sudden death during the 1st year after infa rct ion and possibly for 2 - 3 years . With respect to the independent effects of the physical exercise component of cardiac rehabilitation , the relatively small number of " exercise only " trials , combined with the possibility that they may have had a formal or informal nonexercise component precludes the possibility of reaching any definitive conclusion . To do so would require a r and omized trial of sufficient size to distinguish between no effect and the most plausible effect based on the results of this overview BACKGROUND Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis , but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications . This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects r and omly assigned to the usual care of their physician . METHODS AND RESULTS Three hundred men ( n = 259 ) and women ( n = 41 ) ( mean age , 56 + /- 7.4 years ) with angiographically defined coronary atherosclerosis were r and omly assigned to usual care ( n = 155 ) or multifactor risk reduction ( n = 145 ) . Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet , exercise , weight loss , smoking cessation , and medications to favorably alter lipoprotein profiles . Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years . The main angiographic outcome was the rate of change in the minimal diameter of diseased segments . All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years , and reasons for all hospitalizations and deaths were documented . Of the 300 subjects r and omized , 274 ( 91.3 % ) completed a follow-up arteriogram , and 246 ( 82 % ) had comparative measurements of segments with visible disease at baseline and follow-up . Intensive risk reduction result ed in highly significant improvements in various risk factors , including low-density lipoprotein cholesterol and apolipoprotein B ( both , 22 % ) , high-density lipoprotein cholesterol ( + 12 % ) , plasma triglycerides ( -20 % ) , body weight ( -4 % ) , exercise capacity ( + 20 % ) , and intake of dietary fat ( -24 % ) and cholesterol ( -40 % ) compared with relatively small changes in the usual-care group . No change was observed in lipoprotein(a ) in either group . The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47 % less than that for subjects in the usual-care group ( change in minimal diameter , -0.024 + /- 0.066 mm/y versus -0.045 + /- 0.073 mm/y ; P < .02 , two-tailed ) . Three deaths occurred in each group . There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group ( rate ratio , 0.61 ; P = .05 ; 95 % confidence interval , 0.4 to 0.9 ) . CONCLUSIONS Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events Background Significant regression of coronary and femoral atherosclerotic lesions has been documented by angiographic studies using aggressive lipid-lowering treatment . This study tested the applicability and effects of intensive physical exercise and low-fat diet on coronary morphology and myocardial perfusion in nonselected patients with stable angina pectoris . Methods and Results Patients were recruited after routine coronary angiography for stable angina pectoris ; they were r and omized to an intervention group ( n = 56 ) and a control group on “ usual care ” ( n = 57 ) . Treatment comprised intensive physical exercise in group training sessions ( minimum , 2 hr/wk ) , daily home exercise periods ( 20 min/d ) , and low-fat , low-cholesterol diet ( American Heart Association recommendation , phase 3 ) . No lipid-lowering agents were prescribed . After 12 months of participation , repeat coronary angiography was performed ; relative and minimal diameter reductions of coronary lesions were measured by digital image processing . Change in myocardial perfusion was assessed by 201TI scintigraphy . In patients participating in the intervention group , body weight decreased by 5 % ( p<0.001 ) , total cholesterol by 10 % ( p<0.001 ) , and triglycerides by 24 % ( p<0.001 ) ; high density lipoproteins increased by 3 % ( p = NS ) . Physical work capacity improved by 23 % ( p<0.0001 ) , and myocardial oxygen consumption , as estimated from maximal rate-pressure product , by 10 % , ( p<0.05 ) . Stress-induced myocardial ischemia decreased concurrently , indicating improvement of myocardial perfusion . Based on minimal lesion diameter , progression of coronary lesions was noted in nine patients ( 23 % ) , no change in 18 patients ( 45 % ) , and regression in 13 patients ( 32 % ) . In the control group , metabolic and hemodynamic variables remained essentially unchanged , whereas progression of coronary lesions was noted in 25 patients ( 48 % ) , no change in 18 patients ( 35 % ) , and regression in nine patients ( 17 % ) . These changes were significantly different from the intervention group ( p<0.05 ) . Conclusions In patients participating in regular physical exercise and low-fat diet , coronary artery disease progresses at a slower pace compared with a control group on usual care Background —Whether cardiac rehabilitation ( CR ) is effective in patients older than 75 years , who have been excluded from most trials , remains unclear . We enrolled patients 46 to 86 years old in a r and omized trial and assessed the effects of 2 months of post-myocardial infa rct ion ( MI ) CR on total work capacity ( TWC , in kilograms per meter ) and health-related quality of life ( HRQL ) . Methods and Results —Of 773 screened patients , 270 without cardiac failure , dementia , disability , or contraindications to exercise were r and omized to outpatient , hospital-based CR ( Hosp-CR ) , home-based CR ( Home-CR ) , or no CR within 3 predefined age groups ( middle-aged , 45 to 65 years ; old , 66 to 75 years ; and very old , > 75 years ) of 90 patients each . TWC and HRQL were determined with cycle ergometry and Sickness Impact Profile at baseline , after CR , and 6 and 12 months later . Within each age group , TWC improved with Hosp-CR and Home-CR and was unchanged with no CR . The improvement was similar in middle-aged and old persons but smaller , although still significant , in very old patients . TWC reverted toward baseline by 12 months with Hosp-CR but not with Home-CR . HRQL improved in middle-aged and old CR and control patients but only with CR in very old patients . Complications were similar across treatment and age groups . Costs were lower for Home-CR than for Hosp-CR . Conclusions —Post-MI Hosp-CR and Home-CR are similarly effective in the short term and improve TWC and HRQL in each age group . However , with lower costs and more prolonged positive effects , Home-CR may be the treatment of choice in low-risk older patients BACKGROUND Increases in life stress have been linked to poor prognosis , after myocardial infa rct ion ( MI ) . Previous research suggested that a programme of monthly screening for psychological distress , combined with supportive and educational home nursing interventions for distressed patients , may improve post-MI survival among men . Our study assessed this approach for both men and women . We aim ed to find out whether the programme would reduce 1-year cardiac mortality for women and men . METHODS We carried out a r and omised , controlled trial of 1376 post-MI patients ( 903 men , 473 women ) assigned to the intervention programme ( n = 692 ) or usual care ( n = 684 ) for 1 year . All patients completed a baseline interview that included assessment of depression and anxiety . Survivors were also interviewed at 1 year . FINDINGS The programme had no overall survival impact . Preplanned analyses showed higher cardiac ( 9.4 vs 5.0 % , p = 0.064 ) and all-cause mortality ( 10.3 vs 5.4 % , p = 0.051 ) among women in the intervention group . There was no evidence of either benefit or harm among men ( cardiac mortality 2.4 vs 2.5 % , p = 0.94 ; all-cause mortality 3.1 vs 3.1 % , p = 0.93 ) . The programme 's impact on depression and anxiety among survivors was small . INTERPRETATION Our results do not warrant the routine implementation of programmes that involve psychological-distress screening and home nursing intervention for patients recovering from MI . The poorer overall outcome for women , and the possible harmful impact of the intervention on women , underline the need for further research and the inclusion of adequate numbers of women in future post-MI trials Abstract Objective : To evaluate the effects of secondary prevention clinics run by nurses in general practice on the health of patients with coronary heart disease . Design : R and omised controlled trial of clinics over one year with assessment by self completed postal question naires and audit of medical records at the start and end of the trial . Setting : R and om sample of 19 general practice s in northeast Scotl and . Subjects : 1173 patients ( 685 men and 488 women ) under 80 years with working diagnoses of coronary heart disease who did not have terminal illness or dementia and were not housebound . Intervention : Clinic staff promoted medical and lifestyle aspects of secondary prevention and offered regular follow up . Main outcome measures : Health status measured by the SF-36 question naire , chest pain by the angina type specification , and anxiety and depression by the hospital anxiety and depression scale . Use of health services before and during the study . Results : There were significant improvements in six of eight health status domains ( all functioning scales , pain , and general health ) among patients attending the clinic . Role limitations attributed to physical problems improved most ( adjusted difference 8.52 , 95 % confidence interval 4.16 to 12.9 ) . Fewer patients reported worsening chest pain ( odds ratio 0.59 , 95 % confidence interval 0.37 to 0.94 ) . There were no significant effects on anxiety or depression . Fewer intervention group patients required hospital admissions ( 0.64 , 0.48 to 0.86 ) , but general practitioner consultation rates did not alter . Conclusions : Within their first year secondary prevention clinics improved patients ' health and reduced hospital admissions . Key messages Nurse led clinics in general practice were used to promote secondary prevention to patients with coronary heart disease Within the first year the health of patients invited to the clinics improved Most benefit was in functional status , but chest pain improved too There was no effects on anxiety or depression There were significant reductions in hospital admissions in the first The Women ’s Lifestyle Heart Trial was a small ( N=28 ) r and omized controlled trial to evaluate the effects of a comprehensive lifestyle self-management program ( very low-fat vegetarian diet , stress-management training , exercise , group support , and smoking cessation ) on reduction of cardiovascular risk factors in postmenopausal women with coronary heart disease ( CHD ) . Women assigned to the treatment condition ( Prime Time ) participated in a week-long retreat followed by twice-weekly 4-hour meetings . Endpoints were program adherence ; changes in lipid profiles , body mass , blood pressure , hypolipidemic and antihypertensive medications ; and quality of life . Risk factor and psychosocial evaluations were conducted at baseline and at 4 , 12 , and 24 months . Repeated measures analyses of covariance revealed that the dietary , stress management , and physical activity changes made by intervention women were dramatic and lasting . There were significantly greater improvements in the Prime Time condition compared to the usual care control group on body mass , angina symptoms , and quality of life , and a tendency for a greater reduction in blood pressure-lowering medications . Similar patterns were seen in lipids , blood pressure , and lipid-lowering medications , but did not reach significance . These results demonstrate that postmenopausal CHD women can make lasting lifestyle changes , and that these changes may reduce the need for cardiac medications and improve CHD risk factors and quality of life In a prospect i ve , r and omised , controlled trial to determine whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year , 28 patients were assigned to an experimental group ( low-fat vegetarian diet , stopping smoking , stress management training , and moderate exercise ) and 20 to a usual-care control group . 195 coronary artery lesions were analysed by quantitative coronary angiography . The average percentage diameter stenosis regressed from 40.0 ( SD 16.9)% to 37.8 (16.5)% in the experimental group yet progressed from 42.7 (15.5)% to 46.1 (18.5)% in the control group . When only lesions greater than 50 % stenosed were analysed , the average percentage diameter stenosis regressed from 61.1 (8.8)% to 55.8 (11.0)% in the experimental group and progressed from 61.7 (9.5)% to 64.4 (16.3)% in the control group . Overall , 82 % of experimental-group patients had an average change towards regression . Comprehensive lifestyle changes may be able to bring about regression of even severe coronary atherosclerosis after only 1 year , without use of lipid-lowering drugs Objective To evaluate whether nurse run clinics in general practice improve secondary prevention in patients with coronary heart disease . Design R and omised controlled trial . Setting A r and om sample of 19 general practice s in northeast Scotl and . Patients 1173 patients ( 685 men and 488 women ) under 80 years with working diagnoses of coronary heart disease , but without terminal illness or dementia and not housebound . Intervention Nurse run clinics promoted medical and lifestyle aspects of secondary prevention and offered regular follow up . Main outcome measures Components of secondary prevention assessed at baseline and one year were : aspirin use ; blood pressure management ; lipid management ; physical activity ; dietary fat ; and smoking status . A cumulative score was generated by counting the number of appropriate components of secondary prevention for each patient . Results There were significant improvements in aspirin management ( odds ratio 3.22 , 95 % confidence interval 2.15 to 4.80 ) , blood pressure management ( 5.32 , 3.01 to 9.41 ) , lipid management ( 3.19 , 2.39 to 4.26 ) , physical activity ( 1.67 , 1.23 to 2.26 ) and diet ( 1.47 , 1.10 to 1.96 ) . There was no effect on smoking cessation ( 0.78 , 0.47 to 1.28 ) . Of six possible components of secondary prevention , the baseline mean was 3.27 . The adjusted mean improvement attributable to intervention was 0.55 of a component ( 0.44 to 0.67 ) . Improvement was found regardless of practice baseline performance . Conclusions Nurse run clinics proved practical to implement in general practice and effectively increased secondary prevention in coronary heart disease . Most patients gained at least one effective component of secondary prevention and , for them , future cardiovascular events and mortality could be reduced by up to a third The effects of an exercise program started early after myocardial infraction and the added effects of an outpatient teaching-counseling program were studied . At r and om , 84 patients were allocated to a control group ( A ) , 88 patients to an exercise group ( B1 ) and 86 patients to an exercise and teaching-counseling group ( B2 ) . The same exercise program was prescribed for patients in groups B1 and B2 and was started about 4.5 days after myocardial infa rct ion and continued for 3 months . The outpatient teaching-counseling program consisted of eight group sessions pertaining to risk factor reduction and psychosocial adjustment to myocardial infraction . A low-level treadmill test and an exercise test were performed at 3 months and the exercise test was repeated at 6 months . The clinical , hemodynamic and electrocardiographic responses to these tests were not different among the three groups . However , by the end of 3 months , patients in group B1 and B2 reported walking greater distances than patients in group A. The incidence of morbidity and mortality was not different between the groups . No deleterious or beneficial physiologic effects of an exercise program either by itself or combined with a teaching-counseling program were demonstrated . Routine medical care and our interventions were equally effective in permitting the spontaneous hemodynamics improvements after myocardial infraction . More than 3 months after myocardial infa rct ion , the group as a whole manifested spontaneous recovery in the form of a significant decrease in resting heart rate ( p less than 0.001 ) and a significant increase in systolic and diastolic blood pressure at rest and with submaximal exercise ( p less than 0.001 ) . No further improvements were observed between 3 and 6 months BACKGROUND It was the aim of this study to assess the long-term effects of physical exercise and low-fat diet on the progression of coronary artery disease . At the beginning of the study , 113 male patients with coronary artery disease were r and omized to an intervention group ( n=56 ) or a control group ( n=57 ) ; 90 patients ( 80 % ) could be reevaluated after 6 years . METHODS AND RESULTS Patients in the intervention group ( n=40 ) showed a reduction in total serum cholesterol ( 6.03+/-1.03 versus 5.67+/-1.01 mmol/L ; P<.03 ) and triglyceride levels ( 1.94+/-0.8 versus 1.6+/-0.89 mmol/L ; P<.005 ) and maintained their initial body mass index ( 26+/-2 versus 27+/-2 kg/m2 ; P = NS ) , but results were not statistically different from the control group ( n=50 ) ( total serum cholesterol , 6.05+/-1.02 versus 5.79+/-0.88 mmol/L ; triglycerides , 2.25+/-1.28 versus 1.85+/-0.96 mmol/L [ both P = NS ] ; body mass index , 26+/-2 versus 28+/-3 kg/m2 [ P<.0001 ] ) . In the intervention group , there was a significant 28 % increase in physical work capacity ( 166+/-59 versus 212+/-89 W ; P<.001 ) , whereas values remained essentially unchanged in the control group ( 165+/-51 versus 170+/-60 W ; P = NS ; between groups , P<.05 ) . In the intervention group , coronary stenoses progressed at a significantly slower rate than in the control group ( P<.0001 ) . Energy expenditure during exercise was assessed in a subgroup ; patients with regression of coronary stenoses spent an average of 1784+/-384 kcal/wk ( approximately 4 hours of moderate aerobic exercise per week ) . Multivariate regression analysis identified only physical work capacity as independently contributing to angiographic changes . CONCLUSIONS After 6 years of multifactorial risk intervention , there is significant and persistent improvement in lipoprotein levels and physical work capacity , which results in a significant retardation of disease progression . These beneficial effects appear to be largely due to chronic physical exercise Twenty-eight male cardiac patients who had either experienced myocardial infa rct ion or undergone coronary bypass surgery were assigned to a treatment condition and participated in a 3-month , exercise-based Cardiac Rehabilitation Program , whereas 20 other cardiac patients were assigned to a routine-care condition and did not participate in the rehabilitation program . Cardiovascular , psychological , and psychosocial functioning were assessed before treatment or routine care was begun , after 3 months of treatment or routine care , and 4 months later . Results indicated that patients in the treatment condition evidence d reliably more efficient cardiovascular functioning ( resting heart rate , resting diastolic blood pressure , treadmill exercise performance , exercise heart rate , exercise systolic blood pressure ) , better underst and ing of heart disease , better underst and ing of and reported compliance with treatment recommendations , more positive self-perceptions ( health , body concept , self-concept , progress toward goals ) , and better psychosocial functioning ( e.g. , decreased employmentrelated stress , more active use and enjoyment of leisure time , more physical and sexual activity ) . Chronic patients benefited as much from the treatment as did acute patients , and the beneficial effects for all treated patients were evident not only just after rehabilitation , but also 4 months later . This investigation appears to be the first such test of effects of this type of treatment , and the results have wide generalizability and applicability Coronary artery diseases ( CAD ) are main causes of morbidity and hospitalisation in western countries and CAD patients are at considerable risk of suffering further cardiac events . The development and evaluation of secondary prevention programmes therefore an important task . This thesis includes investigations on CAD patients admitted to a secondary prevention programme at Malmö University Hospital , Malmö , Sweden . Four weeks after discharge from the hospital , consecutive male and female patients aged 50 - 70 years with acute myocardial infa rct ion ( AMI ) or treated with coronary artery bypass grafting ( CABG ) surgery were r and omised to a hospital organised preventive intervention or to usual follow-up at their general practitioners . In the three studies using this r and omised design , 87 ( study II ) , 90 ( study IV ) , and 106 ( study V ) intervention patients were available for evaluation . In addition , without r and omisation , lipid levels at four weeks after the event was compared with levels estimated within 24 hours after onset of symptoms in 141 AMI patients ( study I ) , and quality of life ( QL ) were estimated by question naire at one month and at one year after the event in 266 AMI , 94 CABG , and 16 percutaneous transluminal coronary angioplasty ( PTCA ) patients ( study III ) . The prevention programme was effective in improving food habits but showed no impact on smoking habits or physical exercise in AMI patients ( study II ) . The intervention also did not show any significant improvement in working capacity in AMI and CABG patients . However , working capacity improved in both intervention and reference CABG patients , most probably due to improved coronary circulation from the surgery ( study IV ) . Cholesterol levels decreased significantly in AMI and CABG intervention patients as compared to the corresponding reference patients . This difference most likely was due to a higher frequency of lipid lowering drugs used in the intervention patients ( study V ) . The prevention programme also decreased body mass index significantly in AMI but not in CABG patients ( study V ) . In AMI patients receiving thrombolysis , cholesterol levels estimated within 24 hours after onset of symptoms and at four weeks after the event were virtually equal . In AMI patients not receiving thrombolysis , the lipid estimates from four weeks after the event were slightly , but significantly , above the within 24 hours from onset of symptoms estimates ( study I ) . One month after the event , both somatic and psychological aspects of QL were negatively affected in AMI and CABG patients compared to population controls . One year after the event , patients differed from controls mainly in somatic symptoms ( study III ) . Thus , the intervention programme was most successful in affecting lipid levels and food habits in AMI patients . QL was considerably affected in patients following an cardiac event , especially during the initial recovery phase . In addition , in patients receiving thrombolysis , cholesterol levels estimated four weeks after an AMI are reasonably valid estimates of baseline values and may be used to decide about lipid lowering interventions BACKGROUND Disease management programs ( DMPs ) that use multidisciplinary teams and specialized clinics reduce hospital admissions and improve quality of life and functional status . Evaluations of cardiac DMPs delivered by home health nurses are required . METHODS Between August 1999 and August 2000 we identified consecutive patients admitted to hospital with elevated cardiac enzymes . Patients who agreed were r and omly assigned to participate in a DMP or to receive usual care . The DMP included 6 home visits by a cardiac-trained nurse , a st and ardized nurses ' checklist , referral criteria for specialty care , communication with the family physician and patient education . We measured readmission days per 1000 follow-up days for angina , congestive heart failure ( CHF ) and chronic obstructive pulmonary disease ( COPD ) ; all-cause readmission days ; and provincial cl aims for emergency department visits , physician visits , diagnostic or therapeutic services and laboratory services . RESULTS We screened 715 consecutive patients admitted with elevated cardiac markers between August 1999 and August 2000 . Of those screened 71 DMP and 75 usual care patients met the diagnostic criteria for myocardial infa rct ion , were eligible for visits from a home health nurse and consented to participate in the study . Readmission days for angina , CHF and COPD per 1000 follow-up days were significantly higher for usual care patients than for DMP patients ( incidence density ratio [ IDR ] = 1.59 , 95 % confidence interval [ CI ] 1.27 - 2.00 , p < 0.001 ) . All-cause readmission days per 1000 follow-up days were significantly higher for usual care patients than for DMP patients ( IDR = 1.53 , 95 % CI 1.37 - 1.71 , p < 0.001 ) . The difference in emergency department encounters per 1000 follow-up days was significant ( IDR = 2.08 , 95 % CI 1.56 - 2.77 , p < 0.001 ) . During the first 25 days after discharge , there were significantly fewer provincial cl aims su bmi tted for DMP patients than for usual care patients for emergency department visits ( p = 0.007 ) , diagnostic or therapeutic services ( p = 0.012 ) and laboratory services ( p = 0.007 ) . INTERPRETATION The results provide evidence that an appropriately developed and implemented community-based inner-city DMP delivered by home health nurses has a positive impact on patient outcomes OBJECTIVES The goal of this study was to determine the effects of exercise training ( ET ) on functional capacity and quality of life ( QOL ) in patients who received percutaneous transluminal coronary angioplasty ( PTCA ) or coronary stenting ( CS ) , the effects on the restenosis rate and the outcome . BACKGROUND It is unknown whether ET induces beneficial effects after coronary angioplasty . METHODS We studied 118 consecutive patients with coronary artery disease ( mean age 57+/-10 years ) who underwent PTCA or CS on one ( 69 % ) or two ( 31 % ) native epicardial coronary arteries . Patients were r and omized into two matched groups . Group T ( n = 59 ) was exercised three times a week for six months at 60 % of peak VO2 . Group C ( n = 59 ) was the control group . RESULTS Only trained patients had significant improvements in peak VO2 ( 26 % , p < 0.001 ) and quality of life ( 26.8 % , p = 0.001 vs. C ) . The angiographic restenosis rate was unaffected by ET ( T : 29 % ; C : 33 % , P = NS ) and was not significantly different after PTCA or CS . However , residual diameter stenosis was lower in trained patients ( -29.7 % , p = 0.045 ) . In patients with angiographic restenosis , thallium uptake improved only in group T ( 19 % ; p < 0.001 ) . During the follow-up ( 33+/-7 months ) trained patients had a significantly lower event rate than controls ( 11.9 vs. 32.2 % , RR : 0.71 , 95 % confidence interval [ CI ] : 0.60 to 0.91 , p = 0.008 ) and a lower rate of hospital readmission ( 18.6 vs. 46 % , RR : 0.69 , 95 % CI : 0.55 to 0.93 , p < 0.001 ) . CONCLUSIONS Moderate ET improves functional capacity and QOL after PTCA or CS . During the follow-up , trained patients had fewer events and a lower hospital readmission rate than controls , despite an unchanged restenosis rate Abstract Objective To establish the cost effectiveness of nurse led secondary prevention clinics for coronary heart disease based on four years ' follow up of a r and omised controlled trial . Design Cost effectiveness analysis . Setting 19 general practice s in north east Scotl and . Participants 1343 patients ( 673 in intervention group and 670 in control group , as originally r and omised ) aged under 80 years with a diagnosis of coronary heart disease but without terminal illness or dementia and not housebound . Intervention Nurse led clinics to promote medical and lifestyle components of secondary prevention . Main outcome measures Costs of clinics ; overall costs to health service ; and cost per life year and per quality adjusted life year ( QALY ) gained , expressed as incremental gain in intervention group compared with control group . Results The cost of the intervention ( clinics and drugs ) was £ 136 ( $ 254 ; € 195 ) per patient higher ( 1998 - 9 prices ) in the intervention group , but the difference in other NHS costs , although lower for the intervention group , was not statistically significant . Overall , 28 fewer deaths occurred in the intervention group leading to a gain in mean life years per patient of 0.110 and of 0.124 QALYs . The incremental cost per life year saved was £ 1236 and that per QALY was £ 1097 . Conclusion Nurse led clinics for the secondary prevention of coronary heart disease in primary care seem to be cost effective compared with most interventions in health care , with the main gains in life years saved A prospect i ve , r and omized , controlled clinical trial in patients with coronary artery disease ( CAD ) and a concurrent physical disability evaluated the effects of a home exercise training program on cardiovascular function and blood lipids . Eighty-eight men between the ages of 42 and 72 years ( mean 62 ) with documented CAD and a physical disability with functional use of > or = 2 extremities including 1 arm were r and omized to either a 6-month home exercise training program using wheelchair ergometry or to a control group that received usual and customary care . Both groups received dietary instructions and were requested to follow a fat-controlled diet . Exercise test variables with echocardiography and blood lipids were measured at baseline and at 6 months . The home exercise training group significantly improved both peak exercise left ventricular ejection fraction ( p = 0.007 ) and fractional shortening ( p = 0.01 ) between baseline to 6 months , whereas the control group showed no significant changes . Exercise training effects of decreased resting heart rate ( p = 0.03 ) and decreased peak rate pressure product ( p = 0.03 ) were also found in the treatment group . No exercise-related cardiac complications occurred . Both groups significantly ( p < or = 0.01 ) increased high-density lipoprotein cholesterol levels . These results indicate that physically disabled men with CAD can safely participate in a home exercise training program which may result in intrinsic cardiac benefits . The metabolic cost of activities of daily living imposed on this disabled population may also have a positive effect on high-density lipoprotein cholesterol levels Prognosis during 5 years of follow-up after first myocardial infa rct ion ( MI ) in a group of men ( aged 40 to 55 years ) was related to risk factors determined at the time of MI . Progression of coronary artery disease ( CAD ) was measured by the occurrence of severe angina pectoris , recurrent myocardial infa rct ion , and cardiac death . Only smoking and serum cholesterol level influenced prognosis . It was possible to identify a subgroup ( patients smoking less than 20 cigarettes/day and having a cholesterol level of less than 7.0 mmoles/L ) with low risk for progression of CAD . A r and omly applied 6-week rehabilitation program shortly after MI was associated with a 50 % decrease in progressive CAD when compared to the control group . Since only a slight decrease in cholesterol levels was found in the rehabilitation group , a direct effect of the rehabilitation program could thus not be excluded because the second important risk factor , smoking , did not show differences between the two groups . The smoking habits at the time of MI determined the continuation of cigarette smoking and rehabilitation did not influence smoking habits This prospect i ve study evaluated the effect of an individualized , comprehensive , home-based cardiac rehabilitation program combining exercise training with risk factor modification and psychosocial counseling on risk factors , psychological well-being , functional capacity , and work resumption in 99 post-percutaneous coronary interventions ( PCI ) patients r and omized to control ( st and ard care plus telephone follow-up , n=49 ) or intervention ( individualized , comprehensive , home-based cardiac rehabilitation , n=50 ) groups . Data were collected at time 1 ( T(1 ) ) during hospital admission , time 2 ( T(2 ) ) approximately 2 months post-PCI , and time 3 ( T(3 ) ) approximately 12 months post-PCI . Results suggest that the allocation to an individualized , comprehensive , home-based cardiac rehabilitation program provided more advantageous outcomes . At both follow-ups , the intervention group showed within-group improvement in serum cholesterol levels ( P<0.02 ; P<0.01 ) and exercise participation ( P<0.001 ; P<0.001 ) with differences in exercise participation favoring the intervention group ( P<0.01 ) at T(2 ) . Repeated measures ANOVA showed significant improvements over time in body mass index ( BMI ) ( P<0.01 ) , psychological well-being ( P<0.001 ) , and functional capacity ( P<0.001 ) for both groups . More patients in the intervention group had returned to work at T(2 ) ( P<0.001 ) and did so more quickly ( P<0.01 ) . These findings suggest that an individualized , comprehensive , home-based cardiac rehabilitation program improves risk factor profiles and work resumption patterns for patients following PCI OBJECTIVES This study evaluated the effectiveness of cardiac counseling and rehabilitation programs led by a nurse counselor , compared with normal care on outcomes for myocardial infa rct ion ( MI ) patients and their partners . METHODS A r and omized controlled trial with follow-up to 1 year was conducted with 100 patients recruited within 72 hours of a first MI and their partners : a Control group received normal care ; an Inpatient group received cardiac rehabilitation from a nurse counselor while in hospital ; and an Extended group received the same cardiac rehabilitation as the Inpatient group , but with additional sessions continuing up to 6 weeks after discharge from hospital . The scales for main outcome measures were 1 ) knowledge of heart disease and treatment ( correct , misconceptions , and uncertainty ) ; 2 ) mood ( Hospital Anxiety and Depression Scale ) ; 3 ) satisfaction ; 4 ) disability ( Functional Limitations Profile ) . RESULTS Inpatient cardiac counseling and rehabilitation result ed in more knowledge , less anxiety , less depression , and greater satisfaction with care in both patients and partners and in less disability in patients , with effects enduring to 1 year . There was some evidence of additional benefit from the Extended program . Both nurse counselors achieved benefits on all outcome variables . CONCLUSIONS This Inpatient cardiac counseling and rehabilitation program result ed in significant and enduring benefits of clinical value . It is likely that it would be acceptable to most post-MI patients , many of whom are not offered or are unable to accept outpatient cardiac rehabilitation This study was a secondary analysis of data collected on 202 patients hospitalized with common medical or surgical cardiac conditions who completed a 24-week postdischarge follow-up program as part of a large-scale r and omized clinical trial . Subjects were age 65 years or older , admitted from their homes with one of the following diagnosis-related groups : heart failure , angina , myocardial infa rct ion , coronary artery bypass graft surgery , or cardiac valve replacement . The intervention consisted of comprehensive discharge planning and home follow-up by an advanced practice nurse ( APN ) for 4 weeks after discharge . Control subjects received usual care . Findings indicated that medical patients in the intervention group had fewer multiple readmissions during the 24 weeks of follow-up and a reduced total number of days of rehospitalization . There were fewer hospital readmissions in the surgical group when measured from discharge to 6 weeks . There were no differences in functional status between intervention and control groups for either population . The findings of this study suggest that high-risk elders with significant cardiac problems may benefit from a care program that emphasizes collaborative , coordinated discharge planning and home follow-up that includes telephone and home visits by APNs Abstract Objective : To assess the effectiveness of three different methods of promoting secondary prevention of coronary heart disease in primary care . Design : Pragmatic , unblinded , cluster r and omised controlled trial . Setting : Warwickshire . Subjects : 21 general practice s received intervention ; outcome measured in 1906 patients aged 55 - 75 years with established coronary heart disease . Interventions : Audit of notes with summary feedback to primary health care team ( audit group ) ; assistance with setting up a disease register and systematic recall of patients to general practitioner ( GP recall group ) ; assistance with setting up a disease register and systematic recall of patients to a nurse led clinic ( nurse recall group ) . Main outcome measures : At 18 months ' follow up : adequate assessment ( defined ) of 3 risk factors ( blood pressure , cholesterol , and smoking status ) ; prescribing of hypotensive agents , lipid lowering drugs , and antiplatelet drugs ; blood pressure , serum cholesterol level , and plasma cotinine levels . Results : Adequate assessment of all 3 risk factors was much more common in the nurse and GP recall groups ( 85 % , 76 % ) than the audit group ( 52 % ) . The advantage in the nurse recall compared with the audit group was 33 % ( 95 % confidence interval 19 % to 46 % ) ; in the GP recall group compared with the audit group 23 % ( 10 % to 36 % ) , and in the nurse recall group compared with the GP recall group 9 % ( −3 % to 22 % ) . However , these differences in assessment were not reflected in clinical outcomes . Mean blood pressure ( 148/80 , 147/81 , 148/81 mm Hg ) , total cholesterol ( 5.4 , 5.5 , 5.5 mmol/l ) , and cotinine levels ( % probable smokers 17 % , 16 % , 19 % ) varied little between the nurse recall , GP recall , and audit groups respectively , as did prescribing of hypotensive and lipid lowering agents . Prescribing of antiplatelet drugs was higher in the nurse recall group ( 85 % ) than the GP recall or audit groups ( 80 % , 74 % ) . After adjustment for baseline levels , the advantage in the nurse recall group compared with the audit group was 10 % ( 3 % to 17 % ) , in the nurse recall group compared with the GP recall group 8 % ( 1 % to 15 % ) and in the GP recall group compared with the audit group 2 % ( −6 % to 10 % ) . Conclusions : Setting up a register and recall system improved patient assessment at 18 months ' follow up but was not consistently better than audit alone in improving treatment or risk factor levels . Underst and ing the reasons for this is the key next step in improving the quality of care of patients with coronary heart disease . What is already known on this topic Effective preventive care of patients with any chronic disease requires planned and quality assured follow up on the basis of an up to date register Strategies for changing clinical practice in primary care have been of limited effectiveness What this study adds Setting up a coronary heart disease register for a practice substantially increases follow up and adequate assessment of patients at risk Improved assessment and follow up does not necessarily improve clinical outcome Follow up by nurses is as effective as , and may be more effective than , follow up by doctors Patients are being followed up and adequately assessed without the recommended preventive drugs being To evaluate the efficacy of exercise training for increasing functional capacity in the 6 months after clinical ly uncomplicated myocardial infa rct ion , 198 men 52 + /- 9 years of age participated in a training study . They were r and omly assigned to one of four exercise protocol s : 8 to 26 weeks of training at home ( group 1 , n = 66 ) or in a group program ( group 2 , n = 61 ) following treadmill testing performed 3 weeks after infa rct ion , treadmill testing at 3 weeks without subsequent training ( group 3 , n = 34 ) , and treadmill testing for the first time at 26 weeks ( control , n = 37 ) . At 26 weeks functional capacity was significantly higher in patients training at home or in a group program than that in patients without training or in control patients : 8.1 + /- 1.5 , 8.5 + /- 1.3 , 7.5 + /- 1.8 , and 7.0 + /- 1.7 METs , respectively ( p less than .05 and p less than .001 ) . No significant differences in functional capacity were noted between patients training at home and those in a group program . No training-related complications occurred . Home and group training are equally effective in increasing functional capacity of low-risk patients after myocardial infa rct ion The aim of this study was to compare the effects of residential multifactorial cardiac rehabilitation , outpatient multifactorial rehabilitation , stress management , and st and ard coronary rehabilitation , on cardiac risk reduction . Out of 144 eligible male patients recently treated with percantaneous transluminal coronary angiography ( PTCA ) , coronary artery bypass graft ( CABG ) , or acute myocardial infa rct ion ( AMI ) , 132 were r and omized into this study . All interventions covered a 12-month active intervention , intense during the first months and subsequently leveled out . Main assessment s were performed before r and omization and after the intervention . Patients offered behavioral rehabilitation showed improved selfreported healthy diet habits and exercise frequency , and higher internal locus of control . Although blood lipids , exercise capacity , body mass , anxiety , depression , and Type A scores were changed in the expected direction , no significant difference emerged between active intervention and the st and ard care condition . St and ard care of today appears to have great potential in particular if supplemented with some kind of stress management Abstract Objective : To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities . Design : R and omised controlled trial of personal health education given every four months . Setting : 18 general practice s in the greater Belfast area . Subjects : 688 patients aged less than 75 years and known to have had angina for at least six months ; 342 r and omised to receive education and 346 to no education . Main outcome measures : Restriction of everyday activities , dietary habit , smoking habit , frequency of physical exercise ; blood pressure , body mass index , and serum total cholesterol concentration at entry to trial and after two years . Results : 317 in the intervention group and 300 in the control group completed the trial . At the two year review more of the intervention group ( 140 , 44 % ) reported taking daily physical exercise than the control group ( 70 , 24 % ) . The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity . No significant differences were found between the groups in smoking habit , systolic or diastolic blood pressure , cholesterol concentration , or body mass index . Conclusion : Despite having no significant effect on objective cardiovascular risk factors , personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities CONTEXT The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year . OBJECTIVES To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes ( without lipid-lowering drugs ) on coronary heart disease . DESIGN R and omized controlled trial conducted from 1986 to 1992 using a r and omized invitational design . PATIENTS Forty-eight patients with moderate to severe coronary heart disease were r and omized to an intensive lifestyle change group or to a usual-care control group , and 35 completed the 5-year follow-up quantitative coronary arteriography . SETTING Two tertiary care university medical centers . INTERVENTION Intensive lifestyle changes ( 10 % fat whole foods vegetarian diet , aerobic exercise , stress management training , smoking cessation , group psychosocial support ) for 5 years . MAIN OUTCOME MEASURES Adherence to intensive lifestyle changes , changes in coronary artery percent diameter stenosis , and cardiac events . RESULTS Experimental group patients ( 20 [ 71 % ] of 28 patients completed 5-year follow-up ) made and maintained comprehensive lifestyle changes for 5 years , whereas control group patients ( 15 [ 75 % ] of 20 patients completed 5-year follow-up ) made more moderate changes . In the experimental group , the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year ( a 4.5 % relative improvement ) and by 3.1 absolute percentage points after 5 years ( a 7.9 % relative improvement ) . In contrast , the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year ( a 5.4 % relative worsening ) and by 11.8 percentage points after 5 years ( a 27.7 % relative worsening ) ( P=.001 between groups . Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up ( risk ratio for any event for the control group , 2.47 [ 95 % confidence interval , 1.48 - 4.20 ] ) . CONCLUSIONS More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group . In contrast , in the control group , coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred The British Heart Foundation and the Chest , Heart and Stroke Association have allocated funds to develop cardiac rehabilitation programmes . We have recently completed and now evaluate an exercise-based rehabilitation course reinforced with advice about return to normal activity for 110 patients who had suffered acute myocardial infa rct ion . Patients admitted to the Plymouth cardiac care unit were r and omised into groups : a control group to receive st and ard hospital care , and a rehabilitation group who , in addition , received an exercise programme reinforced with advice . Patients were assessed at entry to the study and at intervals thereafter . Assessment was by question naire and objective tests consisting of a 12-minute walking test and weekly outpatient pedometry . In the rehabilitation group patients were able to walk further and faster , return to work earlier , undertake more housework , and resume normal sexual activity ; they were less short of breath and did not experience more angina . However , the rehabilitation course brought little benefit to the patients ' perception of well-being and their anxiety about health or their outlook on life . Exercise and advice are important components of a rehabilitation programme , but more attention needs to be given to the psychological aspects of recovery from a heart attack The merits or otherwise of publishing hospital specific death rates are much debated . This article compares the relative sensitivity of measures of process and outcome to differences in quality of care for the hospital treatment of myocardial infa rct ion . Aspects of hospital care that have a proved impact on mortality from myocardial infa rct ion are identified , and the results from meta- analysis and large r and omised controlled trials are used to estimate the impact that optimal use of these interventions would have on mortality in a typical district general hospital . Sample size calculations are then performed to determine how many years of data would be needed to detect significant differences between hospitals . A comparison is then made with the amount of data that would be needed to detect significant differences if information about process of care was being collected . Process measures based on the results of r and omised controlled trials were found to be able to detect relevant differences between hospitals that would not be identified by comparing hospital specific mortality , which is an insensitive indicator of the quality of care Abstract Objective : To evaluate rehabilitation after myocardial infa rct ion . Design : R and omised controlled trial of rehabilitation in unselected myocardial infa rct ion patients in six centres , baseline data being collected on admission and by structured interview ( of patients and spouses ) shortly after discharge and outcome being assessed by structured interview at six months and clinical examination at 12 months . Setting : Six district general hospitals . Subjects : All 2328 eligible patients admitted over two years with confirmed myocardial infa rct ion and discharged home within 28 days . Interventions : Rehabilitation programmes comprising psychological therapy , counselling , relaxation training , and stress management training over seven weekly group outpatient sessions for patients and spouses . Main outcome measures : Anxiety , depression , quality of life , morbidity , use of medication , and mortality . Results : At six months there were no significant differences between rehabilitation patients and controls in reported anxiety ( prevalence 33 % ) or depression ( 19 % ) . Rehabilitation patients reported a lower frequency of angina ( median three versus four episodes a week ) , medication , and physical activity . At 12 months there were no differences in clinical complications , clinical sequelae , or mortality . Conclusions : Rehabilitation programmes based on psychological therapy , counselling , relaxation training , and stress management seem to offer little objective benefit to patients who have experienced myocardial infa rct ion compared with previous reports of smaller trials . Key messages In this series there were no important differences by age , sex , hospital , or baseline anxiety or depression At six months the prevalence rates of clinical anxiety and depression remained high ( 33 % and 19 % respectively ) Patients and spouses rated programmes highly , which suggests a “ quality of care ” role for Community studies have demonstrated suboptimal achievement of lipid targets in the management of patients with coronary heart disease ( CHD ) . An effective strategy is required for the application of evidence -based prevention therapy for CHD . The objective of this study was to test coaching as a technique to assist patients in achieving the target cholesterol level of < 4.5 mmol/L. Patients with established CHD ( n = 245 ) underwent a stratified r and omization by cardiac procedure ( coronary artery bypass graft surgery or percutaneous coronary intervention ) to receive either the coaching intervention ( n = 121 ) or usual medical care ( n = 124 ) . The primary outcome measure was fasting serum total cholesterol ( TC ) , serum triglyceride ( TG ) , high-density lipoprotein cholesterol ( HDL-C ) , and calculated low-density lipoprotein cholesterol ( LDL-C ) level , measured at 6 months post-r and omization . At 6 months , the serum TC and LDL-C levels were significantly lower in the coaching intervention group ( n = 107 ) than the usual care group ( n = 112 ) : mean TC ( 95%CI ) 5.00 ( 4.82 - 5.17 ) mmol/L versus 5.54 ( 5.36 - 5.72 ) mmol/L ( P < .0001 ) ; mean LDL-C ( 95%CI ) 3.11 ( 2.94 - 3.29 ) mmol/L versus 3.57 ( 3.39 - 3.75 ) mmol/L ( P < .0004 ) , respectively . Coaching had no impact on TG or on HDL-C levels . Multivariate analysis showed that being coached ( P < .001 ) had an effect of equal magnitude to being prescribed lipid-lowering drug therapy ( P < .001 ) . The effectiveness of the coaching intervention is best explained by both adherence to drug therapy and to dietary advice given . Coaching may be an appropriate method to reduce the treatment gap in applying evidence -based medicine to the " real world . OBJECTIVE To study the effects of a comprehensive discharge planning protocol , design ed specifically for the elderly and implemented by nurse specialists , on patient and caregiver outcomes and cost of care . DESIGN R and omized clinical trial . SETTING Hospital of the University of Pennsylvania . PATIENTS 276 patients and 125 caregivers . Patients were 70 years and older and were placed in selected medical and surgical cardiac diagnostic-related groups . MEASUREMENTS Group differences in patient outcomes ( length of initial hospital stay , length of time between initial hospital discharge and readmission , and rehospitalization rates ) and charges for care ( charges for initial hospitalization , rehospitalizations , health services after discharge , and nurse specialist services ) were measured 2 , 6 , and 12 weeks after discharge . RESULTS From the initial hospital discharge to 6 weeks after discharge , patients in the medical intervention group had fewer readmissions , fewer total days rehospitalized , lower readmission charges , and lower charges for health care services after discharge . No differences in these outcomes were found between the surgical intervention and control groups during this period . CONCLUSIONS Study findings support the need for comprehensive discharge planning design ed for the elderly and implemented by nurse specialists to improve their outcomes after hospital discharge and to achieve cost savings . The findings also suggest that this intervention had its greatest effect in delaying or preventing rehospitalization of patients in the medical intervention group during the first 6 weeks after discharge A group of 93 coronary patients recently treated with percutaneous transluminal coronary angioplasty ( PTCA ) were r and omly assigned to either an intervention or a control group . Subjects in the intervention group participated in a comprehensive behaviorally oriented program aim ed at achieving significant long-term changes in risk factor-related lifestyle behavior . Assessment s of lifestyle behaviors , psychological factors , biological risk factors , and rehabilitation as well as secondary prevention endpoints were carried out , at inclusion and after 12 months . Results showed that the intervention patients , as compared with controls , improved significantly on measures assessing smoking , exercise , and diet habits . These self-rated changes were confirmed by weight reductions and improved exercise capacity , as well as by between-group differences in sub clinical chest pain during an exercise test . However , few effects were found on the different psychological variables , as well as on morbidity or return to work OBJECTIVE : To examine the ability of a secondary prevention programme to improve the lifestyle in myocardial infa rct ion patients aged 50 - 70 years . DESIGN : Habitual physical activity , food habits , and smoking habits were assessed from question naires at admission to hospital and at the one year follow up . Initially , all patients were invited to join an exercise programme and were informed about cardiovascular risk factors . Four weeks after discharge from the hospital , 87 patients were r and omised to follow up at the coronary prevention unit by a special trained nurse ( the intervention group ) , and 81 to follow up by their general practitioners ( the usual care group ) . After r and omisation , the intervention group was educated about the effects of smoking cessation , dietary management , and regular physical activity . The intervention group also participated in a physical training programme two to three times weekly for 10 - 12 weeks . MAIN RESULTS : 89 % of the patients referred to the intervention group improved their food habits compared with 62 % of the patients referred to the usual care group ( P = 0.008 ) . Furthermore , 50 % of the smokers referred to the intervention group stopped smoking compared to 29 % in the usual care group ( P = 0.09 ) . Changes in physical activity did not differ between the groups . CONCLUSIONS : This secondary prevention programme based on a nurse rehabilitator was successful in improving food habits in patients with acute myocardial infa rct ion . Initiating the smoking cessation programme during the hospital stay followed by repeated counselling during follow up might have improved the results . The exercise programme had no advantage in supporting physical activity compared to usual care BACKGROUND This study examined the effects of a nurse-case-managed , multifactorial , risk-reduction program on psychological distress among patients after myocardial infa rct ion ( MI ) . METHODS Five hundred eighty-five men and women aged 70 years or younger , who were hospitalized for acute MI in one of five San Francisco Bay Area hospitals , were r and omized to receive a nurse-managed , home-based , multifactorial risk-reduction program ( n = 293 ) or usual care ( n = 292 ) . The program , which began in the hospital , included a brief screen for five areas of psychological distress with further evaluation if indicated , monitoring during the follow-up phone calls , and referral for mental health treatment if needed . Patients were assessed with single-item scales at baseline , and at 6 and 12 months . Separate analyses were performed for patients with moderate-to-severe levels on the psychological distress domains and for those with low levels . RESULTS There was a significant reduction in the psychological distress variables for all patient groups between baseline and 12 months . The program had a significant effect on reducing anxiety in the patient group with low levels of anxiety and reducing anger in the patient group with frequent episodes of anger but , overall , the treatment and control groups showed equal levels of improvement . CONCLUSION Among patients post-MI without complications , psychological distress decreases significantly during the 12 months after MI We have followed physical working capacity and the plasma lipoprotein pattern in 37 males who underwent coronary artery surgery for severe disabling angina pectoris . In order to evaluate the effect of exercise training , 18 patients were r and omized to a supervised bicycle training programme three times a week for 12 weeks starting 6 weeks after surgery . Before surgery , working capacity was severely reduced in all subjects . The mean HDL cholesterol level was low ( 0.8 + /- 0.2 mmol l-1 ) and the mean plasma LDL concentration moderately elevated ( 4.6 + /- 0.9 mmol l-1 ) . In the non-training group , physical working capacity increased significantly , and 18 weeks after surgery reached a plateau about 45 % above the preoperative values . In the training group , a further improvement to about 60 % above preoperative levels was registered at the end of the training program . In the non-training group , HDL cholesterol concentrations rose rapidly to levels between 10 and 15 % above the preoperative values . One year after surgery , HDL cholesterol levels were 20 % higher than before surgery . There was a parallel rise in apolipoprotein A1 concentrations by about 10 % which indicates that the increase in HDL occurred mainly in the lipid rich HDL2 subfraction . There were no changes in plasma lipids or in LDL cholesterol concentrations . In the training group , the increase in HDL was about 20 % during the first 26 weeks . One year after surgery , HDL levels were 23 % above preoperative values . In this group , we also registered a significant decrease in plasma triglyceride levels by about 25 % after two months of exercise . ( ABSTRACT TRUNCATED AT 250 WORDS This study evaluated long-term effects of 12 weeks of supervised training , of at least 45 minutes duration with two sessions per week , on physical performance and psychological well-being after myocardial infa rct ion ( MI ) . Sixty-nine patients were r and omized to either an exercise or a nonexercise group . Maximum exercise capacity 6 weeks post-MI was inversely related to the acute peak aspartate aminotransferase values in serum , as an index of infa rct size . One year post-MI , the increase in level of fitness ( 10 % ) in the training group did not significantly exceed ( p = .10 ) that of the controls ( 2 % ) . No intergroup differences were registered in self-rated psychological well-being and physical scores or in the return to work rate . In the training group , but not in the controls , the change in perceived dyspnoea at leisure-time activities was positively related to the objective ly measured peak exercise capacity . We conclude that after MI only marginal improvements in physical performance are achieved 6 months after training is finished , with no long-term psychological benefits apparent versus a usual care program . The adaptive implication s of supervised conventional exercise programs post-MI are therefore question ed The aim of this study was to identify and describe the factors of importance for elderly ( > or = 65 years ) patients in being physically active one year after acute myocardial infa rct ion . Forty-three consecutive elderly patients with a recent myocardial infa rct ion were r and omized either to a supervised outpatient-group training programme , 50 min three times a week for 3 months , or to a control group . An independent observer interviewed the patients 12 months after r and omization in order to eluci date the factors that motivated the patients into being physically active . Both groups were identical at the start . The patients in the training group stated that the programme had made them more self-confident regarding physical activities and this seems to be an important factor for continuing to be physically active . Body mass index , age , gender and support from a physically active partner were of minor importance compared to the training programme or earlier experience of regular physical activity OBJECTIVE To assess the effectiveness of a programme to coordinate and support follow up care in general practice after a hospital diagnosis of myocardial infa rct ion or angina . DESIGN R and omised controlled trial ; stratified r and om allocation of practice s to intervention and control groups . SETTING All 67 practice s in Southampton and south west Hampshire , Engl and . SUBJECTS 597 adult patients ( 422 with myocardial infa rct ion and 175 with a new diagnosis of angina ) who were recruited during hospital admission or attendance at a chest pain clinic between April 1995 and September 1996 . INTERVENTION Programme to coordinate preventive care led by specialist liaison nurses which sought to improve communication between hospital and general practice and to encourage general practice nurses to provide structured follow up . MAIN OUTCOME MEASURES Serum total cholesterol concentration , blood pressure , distance walked in 6 minutes , confirmed smoking cessation , and body mass index measured at 1 year follow up . RESULTS Of 559 surviving patients at 1 year , 502 ( 90 % ) were followed up . There was no significant difference between the intervention and control groups in smoking ( cotinine vali date d quit rate 19 % v 20 % ) , lipid concentrations ( serum total cholesterol 5.80 v 5.93 mmol/l ) , blood pressure ( diastolic pressure 84 v 85 mm Hg ) , or fitness ( distance walked in 6 minutes 443 v 433 m ) . Body mass index was slightly lower in the intervention group ( 27.4 v 28.2 ; P=0.08 ) . CONCLUSIONS Although the programme was effective in promoting follow up in general practice , it did not improve health outcome . Simply coordinating and supporting existing NHS care is insufficient . Ischaemic heart disease is a chronic condition which requires the same systematic approach to secondary prevention applied in other chronic conditions such as diabetes mellitus The purpose of this prospect i ve r and omized controlled trial was to assess the impact of phase III comprehensive cardiac rehabilitation ( CR ) on health-related quality of life ( HRQOL ) in elderly patients with coronary artery disease ( CAD ) . Thirty-eight elderly males ( mean age , 70 years ) with CAD were stratified as the intervention group ( n=20 ) and the control group ( n=18 ) . In the intervention group , patients participated in CR for 6 months , whereas in the control group , they received st and ard care . Vali date d question naires were obtained to evaluate HRQOL using the Medical Outcome Study Short-Form 36 Health Status Survey ( SF-36 ) , State-trait anxiety inventory question naire ( STAI ) and Self-rating Depression Scale ( SDS ) at baseline and after 6 months . At baseline , scores of SF-36 except for general health , STAI and SDS were not different in either group . After 6 months , in the intervention group , scores of bodily pain , general health , vitality and mental health of SF-36 improved significantly compared with baseline . State anxiety scores also improved significantly ( p<0.01 ) , but SDS depression scores were not improved . In the control group , none of the parameters significantly changed . These results indicate that elderly patients with CAD should be vigorously encouraged to pursue CR even in chronic phase III Six weeks after acute myocardial infa rct ion , 303 men were r and omly divided into exercise and control groups . The exercise group attended the hospital gymnasium twice weekly for a three-month supervised exercise course . Both groups were exercise tested before and after the course and at subsequent follow-up . The exercise group increased their physical fitness greatly compared with the control group . Eight per cent of the exercise group died during the period of follow-up , compared with 14 per cent of the control group ; this difference is not significant . There was an apparent improvement in mortality in those with inferior MI who completed the exercise course , which was not seen in those with MI in other sites . For many patients after MI progressive exercise is safe , improves physical fitness and may reduce mortality for those after inferior MI BACKGROUND The long-term effects of disease management programmes for coronary heart disease on health status are unknown . In a r and omized trial of nurse-led secondary prevention clinics , we found significantly improved health status at 1 year . Participants were followed-up again at 4 years to determine if improvements had been sustained . OBJECTIVE Our aim was to evaluate the effects on health of nurse-led clinics for the secondary prevention of coronary heart disease in primary care . METHODS A total of 1343 patients with coronary heart disease were r and omized to nurse-led secondary prevention clinics or usual care , with follow-up at 1 and 4 years by review of medical case notes and national data sets , and postal question naires . The study involved a stratified , r and om sample of 19 general practice s in north-east Scotl and . Health status was measured by the SF-36 question naire , chest pain by the angina TyPE specification and anxiety and depression by the hospital anxiety and depression scale . RESULTS At 1 year , there were significant improvements in five of eight SF-36 domains ( all functioning scales , pain and general health ) in patients r and omized to clinics . Role limitations attributed to physical problems improved the most [ adjusted difference 8.52 , 95 % confidence interval ( CI ) 4.16 - 12.9 ] . At 4 years , the intervention group scored higher than control in all domains , but differences were no longer significant . At 1 year , fewer patients in the intervention group reported worsening chest pain ( odds ratio 0.59 , 95 % C1 0.37 - 0.94 ) . At 4 years , there were no significant differences between the proportion of intervention or control group patients who reported chest pain in the last week or who reported worsening chest pain . No significant effects were observed on anxiety or depression at 1 or 4 years . CONCLUSION We have demonstrated previously a significantly greater survival in attendees at nurse-led secondary prevention clinics . Despite this , improvements in health status achieved in the first year of the study were reduced at 4 years . The case for nurse-led clinics remains strong , but further research is required on ways to optimize current health status This study examined whether nurses could manage coronary risk factors in patients with unstable angina more effectively than physicians practicing usual care . Three hundred twenty-six patients were r and omized in the emergency room to a 6-month program of risk factor management by a registered nurse versus participation in usual care . The nurse intervention consisted of a 30-minute counseling visit at 6 to 10 days after the chest pain episode and a second 30-minute session 1 month later . Multiple risk factors were assessed and addressed : smoking , blood lipids , blood pressure , blood glucose , physical inactivity , weight , psychological stress , and social isolation . Compared with usual care , nurse intervention patients significantly reduced both triglycerides ( -29 + /- 8 vs 5 + /- 6 mg/dl ; p < 0.0004 ) and weight ( -0.9 + /- 3.3 vs + 0.1 + /- 2.1 kg ; p = 0.0071 ) , and had corresponding improvements in self-reported diet compliance and exercise ( + 34 + /- 106 vs + 9 + /- 98 minutes , p = 0.0491 ) . No significant differences between groups were observed in terms of 6-month changes in total , high-density lipoprotein , or low-density lipoprotein cholesterol , blood pressure , fasting blood glucose , percent body fat or waist-hip ratio , or psychological distress scores . The 6-month rate of recurrent events ( cardiac death , out-of-hospital cardiac arrest , myocardial infa rct ion ) and /or revascularizations ( coronary artery bypass surgery or coronary angioplasty ) was lower in the nurse intervention group ( 1 % vs 9 % ; p = 0.002 ) . We conclude that a nurse-delivered risk factor intervention program for patients with chest pain is feasible and more effective than usual care in terms of fostering lifestyle changes that may lower coronary risk One hundred six postmyocardial infa rct ion subjects who either achieved a mean work load of less than seven mets on treadmill testing , who were rated as anxious and /or depressed , or who met both criteria , participated in a controlled study comparing the rehabilitation effectiveness of exercise therapy and group counseling . Each intervention lasted 12 weeks . Follow-up evaluations were scheduled at three months , six months and one year . Exercise substantially increased mean work capacity , decreased fatigue , lessened anxiety and depression , and promoted independence and sociability . Counseling substantially reduced depression and promoted a sense of friendliness , and decreased interpersonal friction as well as greater independence and sociability . The control group reported no substantial change on any measured factor . Neither counseling nor exercise had an effect on mortality though subjects in the exercise group reported fewer major cardiovascular sequelae Two hundred patients who had suffered an acute myocardial infa rct ion 4 - 6 weeks before entered a r and omised controlled trial of exercise treatment at a community sports centre supervised by a general practitioner . Eighty one per cent of the treatment group continued to exercise until they returned to work and 73 % completed three months ' exercise . There were no serious complications of the exercise course . The prevalence of angina pectoris fell by 10 % in the treatment group but rose by 60 % in the control group . The perceived energy level rose by significantly more in the treatment group than in the controls . The rise in predicted maximum oxygen uptake was significantly greater in the treatment group than in the control group as was the reduction in the double product ( a reflection of myocardial workload ) at peak exercise . Coronary rehabilitation in the community can be both safe and effective The effects of a rehabilitation programme one year after myocardial infa rct ion ( MI ) were investigated in 171 patients under 65 years of age . These patients were allocated at r and om to rehabilitation and control groups before discharge from hospital . The groups were comparable with regard to age , sex and clinical data . The programme included physical exercise , counselling of patients and relatives , and social measures over a 3-month period during the convalescent stage . One year after MI patients in the rehabilitation group showed lower systolic blood pressure at rest and lower diastolic pressure on submaximal exercise than controls . No differences were found with regard to mean work capacity , days off work , return to work , psychological status , and underst and ing of the illness . At 12 months all patients were less physically and socially active than before MI , they were more dependent on their relatives than before , and they had poor underst and ing of their illness The study was set up to evaluate the long-term effects on mortality of a comprehensive rehabilitation and secondary prevention programme lasting 3 years after acute myocardial infa rct ion . The study group consisted of 375 consecutive , non-selected patients under 65 years of age r and omly allocated to an intervention group ( 188 patients ) or a control group ( 187 patients ) . After 15 years follow-up significantly lower incidence of sudden death ( 16.5 % vs 28.9 % , P = 0.006 ) and coronary mortality ( 47.9 % vs 58.5 % , P = 0.04 ) were seen in the intervention group compared with controls . Total mortality was 64.4 % and 66.8 % , respectively ( ns ) . The incidence of cancer death was 16 in the intervention group and three in the controls . Cardiac failure , enlarged heart , New York Heart Association functional class II or more and membership in the control group were significantly associated with coronary mortality during the first 3 years , and after 3 years enlarged heart , diabetes and reinfa rct ion were associated with late coronary death . Thus , comprehensive multifactorial intervention after acute myocardial infa rct ion had favourable long-term effects on coronary mortality and sudden death but no effect on total mortality R and omized clinical trials of cardiac rehabilitation following myocardial infa rct ion have typically demonstrated a lower mortality in treated patients , but with a statistically significant reduction in only one trial . To overcome the problem of not being able to detect small but clinical ly important benefits in mortality in r and omized clinical trials of exercise and risk factor rehabilitation after myocardial infa rct ion with small numbers of patients , we carried out a meta- analysis on the combined results of ten r and omized clinical trials that included 4347 patients ( control , 2145 patients ; rehabilitation , 2202 patients ) . The pooled odds ratios of 0.76 ( 95 % confidence intervals , 0.63 to 0.92 ) for all-cause death and of 0.75 ( 95 % confidence intervals , 0.62 to 0.93 ) for cardiovascular death were significantly lower in the rehabilitation group than in the control group , with no significant difference for nonfatal recurrent myocardial infa rct ion . These results suggest that , for appropriately selected patients , comprehensive cardiac rehabilitation has a beneficial effect on mortality but not on nonfatal recurrent myocardial infa rct ion Background The study was design ed to determine whether a 1-year hospital-based secondary prevention programme would have any long-term effects on serum lipid levels and the use of lipid-lowering drugs in patients with coronary artery disease 4 years after referral to primary care facilities for follow-up . Design / methods After acute myocardial infa rct ion or coronary bypass surgery , 241 consecutive patients were r and omly assigned to conventional care ( CC ) by the primary health care facilities or to a 1-year hospital-based secondary prevention programme ( SPP ) with target levels for serum cholesterol ( < 5.2 mmol/l ) and triglycerides ( < 1.5 mmol/l ) . After 1 year all patients were referred to the primary care sector for a further 4-year follow-up . Results At the 1-year follow-up there was a significant decrease in serum cholesterol , LDL-cholesterol and triglyceride levels in the SPP group but no change in the CC group , and lipid-lowering drugs were used more frequently in the SPP group . These changes were maintained after 5 years . The proportion of patients achieving target serum cholesterol and triglyceride levels were larger in the SPP group . Conclusions Initiatives regarding cholesterol lowering and drug treatment taken by specialists within a structured hospital-based SPP have long-term impact . Accordingly , drug treatment should be initiated and adjusted to adequate doses before patients are referred to primary care for follow-up BACKGROUND Acute hospitalizations represent substantial financial liability to closed health care systems . Among hospitalized patients , those with repeated admissions are high-cost users . Most managed care plans employ case management to control hospital use . This technique attempts to detect and fulfill unmet medical and social needs , intensify postdischarge care , identify and mobilize effective community services , and enhance primary care access . Despite the popularity of case management to control hospital use , few trials have examined its efficacy . METHODS We conducted a r and omized controlled trial of an intervention of case managers at a university-affiliated Veterans Affairs medical center . Six hundred sixty-eight patients aged 45 years or older who were discharged from the general medicine inpatient service , who had access to a telephone , and who received primary care at the hospital 's clinics were r and omized to the intervention ( N = 333 ) and control ( N = 335 ) groups . Within 24 hours of discharge , case managers mailed educational material s and access information to intervention patients , and within 5 days they called to review and resolve unmet needs , early warning signs , barriers to keeping appointments , and any readmissions . Case managers contacted intervention patients if they made no visits for 30 days . This result ed in a total of 6260 patient-case manager contacts . Control and intervention patients were followed up for 12 months . RESULTS Intervention patients had more frequent visits per patient per month to the general medicine clinic ( 0.30 + /- 0.23 vs 0.26 + /- 0.22 , P = .008 ) , but we detected no significant differences between groups in nonelective readmissions , readmission days , or total readmissions . CONCLUSIONS Frequent contacts for education , care , and accessibility by case managers using protocol s were ineffective in reducing nonelective readmissions Health promotion programmes for patients with coronary heart disease are valuable,1 2 but there is little evidence on their lasting effect.3 A r and omised controlled trial in which patients who received personalised health promotion for two years showed significant benefits in lifestyle and quality of life.2 4 We investigated whether the differences in lifestyle , quality of life , and risk factors persisted between the two groups five years after enrolment . Patients aged under 75 who had had angina ( all grade s included ) for at least six months and no other concurrent serious illness were identified by 18 general practice s in Belfast . Their diagnosis was confirmed at interview , and they were r and omly allocated to receive either usual NHS care and personal health promotion from a trained nurse every four months for two years or usual NHS care alone . Sealed envelopes opened at interview showed group allocations . Both groups were review ed This study enrolled 651 men with myocardial infa rct ion in five participating centers in a r and omized 3 year clinical trial of the effects of prescribed supervised exercise . The subjects , aged to 30 to 64 years , were screened for eligibility 2 to 36 months after their qualifying myocardial infa rct ion . The men in the exercise group pursued intensive exercise in the laboratory for 8 weeks and then in a gymnasium for 34 months . The experience of the exercise group was more favorable than that of the control group in most of the comparisons made . The cumulative 3 year total mortality rate was 7.3 percent for the control group and 4.6 percent for the exercise group ; the 3 year rate for recurrent myocardial infa rct ion was 7.0 and 5.3 percent , respectively . Mortality rates in the two groups did not differ significantly , but the data were consistent with an assumption of substantial benefit from exercise . Adjustment for small differences in baseline variables by multivariate methods did not material ly alter the estimate of effect of exercise . Certain subgroups showed a greater benefit from exercise The aim of the study was to evaluate a multifactorial rehabilitation programme based on interdisciplinary caring efforts for myocardial infa rct ion ( MI ) patients . R and omly chosen MI- patients participated , either in a six-month rehabilitation programme ( intervention group = 53 ) or in routine cardiac follow-ups ( control group = 63 ) . Subjective and objective instruments were used for measuring their health recovery . Biophysical improvements were showed as an increased physical capacity ( p less than 0.001 ) using a submaximal exercise test six months after MI , and less reinfa rct ions ( p less than 0.024 ) twelve months after MI , to the intervention patients ' advantage . Psychological improvements were demonstrated in a higher life satisfaction ( p less than 0.001 ) six months and ( 0.1 greater than p greater than 0.05 ) twelve months after MI to the intervention patients ' advantage . Social improvements were indicated as a better leisure situation ( p less than 0.004 ) six months after MI , and as a better partner situation ( p less than 0.010 ) , including a less influenced sex life ( p less than 0.017 ) , twelve months after MI to the intervention patients ' advantage . As to the overall view , the caring rehabilitation programme appeared to be required for the MI- patients ' health recovery . In order to be able to reach an optimal state of human health , an even more individualised programme seems to be necessary OBJECTIVE To evaluate the effectiveness of a nurse led shared care programme to improve coronary heart disease risk factor levels and general health status and to reduce anxiety and depression in patients awaiting coronary artery bypass grafting ( CABG ) . DESIGN R and omised controlled trial . SETTING Community , January 1997 to March 1998 . STUDY GROUPS 98 ( 75 male ) consecutive patients were recruited to the study within one month of joining the waiting list for elective CABG at Glasgow Royal Infirmary University NHS Trust . Patients were r and omly assigned to usual care ( control ; n = 49 ) or a nurse led intervention programme ( n = 49 ) . INTERVENTION A shared care programme consisting of health education and motivational interviews , according to individual need , was carried out monthly . Care was provided in the patients ' own homes by the community based cardiac liaison nurse alternating with the general practice nurse at the practice clinic . OUTCOME MEASURES Smoking status , obesity , physical activity , anxiety and depression , general health status , and proportion of patients exceeding target values for blood pressure , plasma cholesterol , and alcohol intake . RESULTS Compared with patients who received usual care , those participating in the nurse led programme were more likely to stop smoking ( 25 % v 2 % , p = 0.001 ) and to reduce obesity ( body mass index > 30 kg/m2 ) ( 16.3 % v 8.1 % , p = 0.01 ) . Target systolic blood pressure improved by 19.8 % compared with a 10.7 % decrease in the control group ( p = 0.001 ) and target diastolic blood pressure improved by 21.5 % compared with 10.2 % in the control group ( p = 0.000 ) . However , there was no significant difference between groups in the proportion of patients with cholesterol concentrations exceeding target values . There was a significant improvement in general health status scores across all eight domains of the 36 item short form health survey with changes in difference in mean scores between the groups ranging from 8.1 ( p = 0.005 ) to 36.1 ( p < 0.000 ) . Levels of anxiety and depression improved ( p < 0.000 ) and there was improvement in time spent being physically active ( p < 0.000 ) . CONCLUSIONS This nurse led shared care intervention was shown to be effective for improving care for patients on the waiting list for CABG BACKGROUND Despite the large body of evidence confirming the effectiveness of lipid lowering for the secondary prevention of coronary heart disease ( CHD ) events , undertreatment of hyperlipidemia is common . This study tested the effectiveness of a nurse case management program to lower blood lipids in patients with CHD . METHODS A total of 228 consecutive , eligible adults with hypercholesterolemia and CHD were recruited during hospitalization after coronary revascularization . Patients were r and omized to receive lipid management , including individualized lifestyle modification and pharmacologic intervention , from a nurse practitioner for 1 year after discharge in addition to their usual care ( NURS ) , or to usual care enhanced with feedback on lipids to their primary provider and /or cardiologist ( EUC ) . RESULTS Significantly more patients in the NURS group than in the EUC group achieved low-density lipoprotein cholesterol ( LDL-C ) levels < 2.59 mmol/dL ( 100 mg/dL , 65 % vs 35 % , P = .0001 ) . Favorable changes in lipids and lipoproteins were accompanied by significant improvements in dietary and exercise patterns in the NURS group . In a multivariate analysis adjusting for other covariates , being assigned to the NURS group ( P = .0001 ) and being on a lipid-lowering medication ( P = .001 ) were significant independent predictors of LDL-C level . CONCLUSIONS Control of hypercholesterolemia in patients who have undergone coronary revascularization can be improved by a nurse case-management program . Because the National Cholesterol Education Program Adult Treatment Panel III guidelines have broadened the definition of high-risk population s that warrant aggressive treatment , nurse case-management programs may offer key opportunities to enhance appropriate application of new treatment paradigms AIM Previous studies have reported lifestyle and risk factor deterioration following completion of a cardiac rehabilitation program ( CRP ) . We report the results of a one-year Extensive Lifestyle Management Intervention ( ELMI ) aim ed at preventing these adverse changes . METHODS AND RESULTS A total of 302 men and women with ischaemic heart disease were recruited following completion of a CRP and r and omized to either the ELMI ( consisting of exercise sessions , telephone follow-ups and risk factor and lifestyle counselling ) or usual care . The primary outcome was global cardiovascular risk using the Framingham and Procam risk scores . Secondary outcomes included risk factors and lifestyle behaviours . Baseline characteristics were similar between the two groups . Adherence to the ELMI was high . There was a non-significant trend in favour of the ELMI between for both the Framingham ( 6.6+/-3.1 to 6.2+/-2.9 vs 6.6+/-3.2 to 6.7+/-3.2 , P=0.138 ) and Procam ( 20.0+/-20.0 to 20.6+/-19.5 vs 19.1+/-18.7 to 21.8+/-19.1 , P=0.089 ) scores . There were no differences in secondary outcomes . CONCLUSIONS A one-year multi-factorial post-CRP intervention results in modest , non-significant benefits to global risk compared to usual care . The absence of deterioration in the usual care group may be due to improved practice s in usual care The effect of regular , moderate exercise on the lipoprotein subfractions of male survivors of myocardial infa rct ion was studied . Nineteen men were r and omly allocated to an incremental exercise program and 23 to a control group . Both groups were studied for 6 months . No change occurred in any lipoprotein class in the control group . In the trained group , total triglyceride and low-density lipoprotein ( LDL ) cholesterol concentrations decreased significantly ( 0.01 > p > 0.001 and 0.05 > p > 0.01 , respectively ) and high-density lipoprotein ( HDL ) cholesterol and apolipoprotein A-i rose ( both p < 0.001 ) . The concentration of the HDL2 subfraction increased with training ( 0.01 > p > 0.001 ) and HDL , did not change . No relationship was found between changes in lipoproteins and treadmill exercise test performance . Thus , in survivors of myocardial infa rct ion , exercise may alter plasma lipoprotein values beneficially BACKGROUND Rehabilitation is an important part of the treatment of patients with ischemic heart disease . Therefore , many patients undergoing coronary artery bypass surgery ( CABS ) also participate in cardiac rehabilitation programs . This study was conducted to investigate whether rehabilitation influences quality of life and work status after CABS . METHODS Consecutive patients undergoing elective CABS were r and omly assigned to a rehabilitation group ( R , N = 119 ) and a hospital-treatment group ( H N = 109 ) . All patients received usual medical care . Group R participated in a rehabilitation program based on exercise and counseling . The follow-up time was 5 years . The measured domains of health-related quality of life were heart symptoms , functional class , exercise capacity , use of medication , depression , the patients ' perception of health , and overall life situation . The Nottingham Health Profile as a measure of perceived distress was used . RESULTS Symptoms , use of medication , exercise capacity , and depression scores did not differ between groups R and H. Five years after the CABS , the patients in group R reported less restriction in physical mobility on the Nottingham Health Profile than patients in group H ( P = 0.005 ) , and more patients in group R than in group H perceived their health ( P = 0.03 ) and overall life situation ( P = 0.02 ) as good . The increase in the proportion of subjects working was higher in group R than group H at 3 years after the CABS ( P = 0.02 ) , but not at other follow-up times . CONCLUSION A cardiac rehabilitation program in conjunction with usual medical care after CABS may induce a perception of improved health . The influence on return to work is limited Background Lifestyle measures of coronary heart disease ( CHD ) prevention have been overshadowed by the efficacy of drug treatments . This is particularly the case in the setting of secondary prevention where the benefits of lipid lowering , anti-platelet and anti-hypertensive drugs have been emphasised in numerous trials . Lifestyle measures address several CHD risk factors at once and are generally free of serious side effects . Objectives The objective of the present study was to determine whether a comprehensive programme of lifestyle modification could favourably influence dietary and exercise habits in addition to smoking cessation over two years . In addition , an attempt was made to evaluate if this programme could favourably influence the five-year CHD-risk in the male population included in the study . Design A total of 197 patients with proven coronary heart disease were included and r and omised to a lifestyle intervention programme or to usual care . Follow-up was after a period of two years . Methods Intervention comprised a low fat diet , regular exercise , smoking cessation , psychosocial support and education , delivered by nurses on the rationale for pharmacological and lifestyle measures . Usual care comprised follow-up in the routine outpatient clinic . Both groups were given the same comprehensive medication according to recent guidelines . Results Patients in the lifestyle intervention group reduced the intake of saturated fat , sugar and cholesterol ( P<0.001 ) , increased their exercise level ( P<0.01 ) and stopped smoking ( P<0.05 ) when compared with the usual care group . A sub analysis of the influence of five-year CHD calculated risk in males result ed in a relative risk reduction of 22 % ( 95 % confidence intervals 9 - 35 ) . Although significant , this result must be interpreted with caution due to poor statistical power and reproducibility of the method . Conclusions In the presence of modern drug treatments for secondary cardiovascular disease prevention it remains possible through a favourable diet , exercise and smoking cessation to show an additional reduction in the five-year risk for CHD in males The effect of a three-phase multifactorial institution-based rehabilitation programme on coronary heart disease ( CHD ) risk factors was studied in an open r and omised trial comprising 228 patients undergoing coronary artery bypass surgery allocated into a rehabilitation ( R ) group ( n = 119 ) and a hospital ( H = control ) group ( n = 109 ) . Follow-up examinations were performed at 6 and 12 months . Serum total cholesterol and triglyceride levels decreased significantly in both groups during follow-up . These decreases were not significantly different between the R and H groups . Serum high density lipoprotein ( HDL ) cholesterol level increased significantly at 6 and 12 months in the R group , but not in the H group . The differences in the changes between the groups were not significant . The ratio of serum HDL cholesterol to total cholesterol increased significantly in the R group from the preoperative value of 0.154 to 0.179 ( P less than 0.001 ) at 6 months and to 0.180 ( P less than 0.001 ) at 12 months . In the H group these values were 0.152 , 0.166 ( P less than 0.001 ) and 0.168 ( P less than 0.001 ) , respectively . The significance of the differences in the changes between the groups were P = 0.01 at 6 months and 0.06 at 12 months . These differences were more obvious in patients aged 55 years or under . There was a significant decrease ( P = 0.005 ) in the proportion of smokers in the R group and a significant increase in the proportion of patients taking regular exercise in both groups as assessed by question naire . ( ABSTRACT TRUNCATED AT 250 WORDS Abstract Objectives : To evaluate the effects of nurse led clinics in primary care on secondary prevention , total mortality , and coronary event rates after four years . Design : Follow up of a r and omised controlled trial by postal question naires and review of case notes and national data sets . Setting : Stratified , r and om sample of 19 general practice s in north east Scotl and . Participants : 1343 patients ( 673 intervention and 670 control ) under 80 years with a working diagnosis of coronary heart disease but without terminal illness or dementia and not housebound . Intervention : Nurse led secondary prevention clinics promoted medical and lifestyle components of secondary prevention and offered regular follow up for one year . Main outcome measures : Components of secondary prevention ( aspirin , blood pressure management , lipid management , healthy diet , exercise , non-smoking ) , total mortality , and coronary events ( non-fatal myocardial infa rct ions and coronary deaths ) . Results : Mean follow up was at 4.7 years . Significant improvements were shown in the intervention group in all components of secondary prevention except smoking at one year , and these were sustained after four years except for exercise . The control group , most of whom attended clinics after the initial year , caught up before final follow up , and differences between groups were no longer significant . At 4.7 years , 100 patients in the intervention group and 128 in the control group had died : cumulative death rates were 14.5 % and 18.9 % , respectively ( P=0.038 ) . 100 coronary events occurred in the intervention group and 125 in the control group : cumulative event rates were 14.2 % and 18.2 % , respectively ( P=0.052 ) . Adjusting for age , sex , general practice , and baseline secondary prevention , proportional hazard ratios were 0.75 for all deaths ( 95 % confidence intervals 0.58 to 0.98 ; P=0.036 ) and 0.76 for coronary events ( 0.58 to 1.00 ; P=0.049 ) Conclusions : Nurse led secondary prevention improved medical and lifestyle components of secondary prevention and this seemed to lead to significantly fewer total deaths and probably fewer coronary events . Secondary prevention clinics should be started sooner rather than later . What is already known on this topic Several effective interventions exist for the secondary prevention of coronary heart disease , but implementing them in practice has proved difficult Secondary prevention programmes for coronary heart disease have improved short term outcomes such as processes of care and quality of life What this study adds Short term improvements in uptake of secondary prevention produced by nurse led clinics are maintained in the longer term Improved medical and lifestyle components of secondary prevention produced by nurse led clinics seem to lead to fewer total deaths and coronary BACKGROUND We evaluated the effectiveness of a low-cost group visit intervention for changing the dietary intake and lipid levels of patients with known coronary artery disease ( CAD ) . METHODS We performed a controlled r and om group assignment trial in 4 community outpatient clinics . The Dietary Intervention and Evaluation Trial r and omized 97 patients with CAD to either a control group that followed the National Cholesterol Education Program 's Step II-III diet plan ( n=48 ) or an experimental group that received meal plans , recipes , and nutritional information during monthly group office sessions ( n=49 ) . Both groups received lipid-lowering medications and were followed-up over 12 months . We assessed dietary intake , fasting lipid profiles , hemoglobin A1C levels , and per member per month ( PMPM ) expense data . RESULTS Food frequency data showed that eating fruits and vegetables and cooking with monounsaturated fat increased significantly in the experimental group compared with the control group at 1 year ( P=.0072 ; P=.0001 ; P=.0004 ) . The total PMPM expenses decreased for both groups ( 38 % for the experimental group and 10 % for the control group ) , but the cost difference was statistically nonsignificant ( P=.2975 ) . Both groups noted low-density lipoprotein reductions , significant only in the experimental group ( P=.0035 ) . CONCLUSIONS Our study suggests that using group office visits for patients with CAD was an effective method for helping subjects make dietary changes and for improving lipid levels . Patients with known CAD and elevated lipid levels were willing to make significant lifestyle changes when offered a program that emphasizes healthy foods in a group visit format OBJECTIVE To determine how frequently the National Cholesterol Education Program ( NCEP ) goal of a low-density lipoprotein ( LDL ) cholesterol level of 100 mg/dL or less is achieved in clinical practice in patients with coronary artery disease and what fraction of patients can achieve this goal without drug therapy . DESIGN We examined the results of lipid management in 152 consecutive patients who had completed cardiac rehabilitation after an acute coronary event . Patients were r and omized to follow-up by specially trained nurses or by preventive cardiologists , and they were not receiving lipid-lowering drugs at the start of the study . MATERIAL AND METHODS Patients were given aggressive diet and exercise recommendations and lipid-lowering drugs in accordance with NCEP guidelines . Follow-up was continued for a mean of 526 days after the first lipid assessment subsequent to the coronary event . Multiple logistic regression analysis was used to identify independent predictors of a final LDL cholesterol level of 100 mg/dL or less . RESULTS Of the study group , 39 % achieved the NCEP goal LDL cholesterol level of 100 mg/dL or less . Characteristics of the patients with LDL cholesterol levels of 100 mg/dL or less in comparison with those with LDL cholesterol levels of more than 100 mg/dL included a greater frequency of drug therapy ( 65 % versus 38 % ) , more rigorous dietary compliance , longer follow-up ( 586 + /- 317 days versus 493 + /- 264 days ) , more favorable weight change ( -0.3 + /- 4.9 kg versus + 1.7 + /- 5.0 kg ) , and more extensive weekly exercise ( 183 + /- 118 minutes versus 127 + /- 107 minutes ) . CONCLUSION The registered nurses managed the lipids of these patients as effectively as did the preventive cardiologists . Appropriate drug therapy was the most important factor in achieving an LDL cholesterol level of 100 mg/dL or less , but 35 % of patients attaining this NCEP goal were not receiving drug therapy . Exercise , dietary compliance , and weight loss were also important factors To evaluate the short-term effects of an intervention that consists of stress management training and dietary changes in patients with ischemic heart disease ( IHD ) , we compared the cardiovascular status of 23 patients who received this intervention with a r and omized control group of 23 patient who did not . After 24 days , patients in the experimental group demonstrated a 44 % mean increase in duration of exercise , a 55 % mean increase in total work performed , somewhat improved left ventricular regional wall motion during peak exercise , and a net change in the left ventricular ejection fraction from rest to maximum exercise of + 6.4 % . Also , we measured a 20.5 % mean decrease in plasma cholesterol levels and a 91.0 % mean reduction in frequency of anginal episodes . In this selected sample , short-term improvements in cardiovascular status seem to result from these adjuncts to conventional treatments of IHD In this study we assessed the short- and long-term effects of 4-weeks of exercise training ( MI ) soon after myocardial infa rct ion in patients on beta-blocker treatment . Thirty-seven male patients < or = 65 years of age were included in the study , 19 of them r and omized to exercise training ( ET ) and 18 to a control group ( Ctr ) . Cumulated work ( CW ) , calculated in kiloJoules ( kJ ) , was recorded before immediately after the intervention period and again six months after the MI . In the short term the mean ( SD ) CW increased by 22 % ( from 65(20 ) to 79(25 ) kJ ) in the ET group , compared with no change in the Ctr patients ( 65(24 ) vs 65(21 ) kJ ) ( p = 0.009 ) . At late follow-up CW was 14 % above baseline in the ET patients ( 65(20 ) vs 74(20 ) kJ ) p = 0.036 , compared with only 6 % in the 15 Ctr patients who were still available for follow-up ( 68(24 ) vs 72(29 ) kJ ) , but without a significant between-group difference . In post-MI patients on beta-blocker treatment , and with a high baseline exercise capacity , physical training improved exercise capacity in the short term , but there was no significant between-group difference at long-term follow-up BACKGROUND Coronary artery surgery improves symptoms and prognosis in patients with angina . Aerobic exercise rehabilitation improves exercise capacity and prognosis in cardiac patients . Strength exercise training has not been extensively studied . DESIGN We studied the effects of 6 months aerobic and strength exercise training after coronary artery surgery in 81 men , mean age 57 years . RESULTS Treadmill time(s ) increased by 130.3 ( 95 % confidence interval 46.4 to 214.2 ) in the aerobic group ; by 83.1 ( 0.9 to 165.3 ) in the strength group , and by 34.3 ( -1 to 69.6 ) in the control group ( P = 0.04 , control versus aerobic ) after 3 months ; and by 196.4 ( 112.2 to 280.7 ) in the aerobic group , by 122.7 ( 37.7 to 207.6 ) in the strength group and by 27 ( -40.4 to 94.4 ) in the control group ( P = 0.002 , control versus aerobic , and P = 0.03 control versus strength ) after 6 months . The level of fitness improved more in the strength-trained group , and there was a minor reduction in body weight and degree of fatness . There were no changes in lipoprotein levels . Aerobic exercise training causes early and sustained benefit in treadmill exercise capacity , while the effects of strength exercise training are later in onset . Exercise training alone did not influence lipid levels . CONCLUSION Cardiac rehabilitation programmes should be comprehensive , including advice on diet and other risk factor modifications in addition to exercise sessions involving aerobic and strength training elements Abstract The purpose of the trial was to analyze whether supervised physical training could reduce death and nonfatal reinfa rct ion in a nonselected series of postinfa rct patients . All patients born in 1913 and later , who were hospitalized for a myocardial infa rct ion during 1968–1970 in Goteborg Sweden , were r and omized to a training group ( 158 patients ) and a control group ( 157 patients ) . Other treatment was exactly the same and st and ardized for the two groups . Twenty-seven percent were excluded from training . Training started 3 months after the infa rct and was scheduled for three times a week . The training group had higher physical working capacity after 1 yr than the control group . Blood pressure was lower , but there was no differences in blood lipids . During 4 yr of follow-up , 28 patients died in the training group and 35 in the control group . The numbers of nonfatal reinfa rcts were 25 and 28 , respectively . Within the training group patients adhering to the program had lower mortality than those who did not , but the former also had lower initially predicted risk of dying . A special analysis of patients who attended the training program in comparison to matched controls also showed a lower mortality . No differences in mortality between the training group and the control group were statistically significant , however 375 consecutive patients below 65 years who had an acute myocardial infa rct ion ( AMI ) took part in a r and omised rehabilitation and secondary prevention trial ( part of a W.H.O.-coordinated project ) design ed to study the effects of a multifactorial intervention programme on morbidity , mortality , return to work , & c. After three years ' follow-up the cumulative coronary mortality was significantly smaller in the intervention group than in the controls ( 18.6 % versus 29.4 % , p = 0.02 ) . This difference was mainly due to a reduction of sudden deaths in the intervention group ( 5.8 % versus 14.4 % , p less than 0.01 ) . The reduction was greatest during the first six months after AMI . 18.1 % in the intervention group and 11.2 % in the controls ( p less than 0.10 ) presented with non-fatal reinfa rct ions . The number of patients with new Q-QS findings at the end of the three years was , however , almost the same in both groups . The results suggest that organised aftercare during the first six months after AMI with special emphasis on optimum medical control and health education contributes significantly to a reduction in the number of sudden deaths

Most review s including children and adolescents with compromised bone mass showed an improvement of BMD at lower limbs , lumbar spine , and whole body . In conclusion , WBV interventions seem to help children and adolescents with compromised bone mass to increase their BMD , but these improvements are limited in postmenopausal women and there is insufficient evidence for young adults .

Whole-body vibration ( WBV ) intervention studies and review s have been increasing lately . However , the results regarding its effects on bone tissue in different population s are still inconclusive . The goal of this overview was to summarize systematic review s assessing the effects of WBV training on bone parameters .

BACKGROUND Although data from studies in animals demonstrated beneficial effects of whole-body vibration ( WBV ) therapy on bone , clinical trials in postmenopausal women showed conflicting results . OBJECTIVE To determine whether WBV improves bone density and structure . DESIGN A 12-month , single-center , superiority , r and omized , controlled trial with 3 parallel groups . ( Clinical Trials.gov registration number : NCT00420940 ) SETTING Toronto General Hospital , Ontario , Canada . PARTICIPANTS 202 healthy postmenopausal women with bone mineral density ( BMD ) T-scores between -1.0 and -2.5 who were not receiving prescription bone medications . INTERVENTION Participants were r and omly assigned to 1 of 3 groups ( 1:1:1 ratio ) by using a block-r and omization scheme and sealed envelopes . They were asked to st and on a low-magnitude ( 0.3 g ) 90-Hz or 30-Hz WBV platform for 20 minutes daily or to serve as control participants ; all participants received calcium and vitamin D. MEASUREMENTS Bone outcome assessors , who were blinded to group assignment , determined trabecular volumetric BMD and other measurements of the distal tibia and distal radius with high-resolution peripheral quantitative computed tomography and areal BMD with dual-energy x-ray absorptiometry at baseline and at 12 months . RESULTS 12 months of WBV therapy had no significant effect on any bone outcomes compared with no WBV therapy . For the primary outcome of tibial trabecular volumetric BMD , mean change from baseline was 0.4 mg/cm(3 ) ( 95 % CI , -0.4 to 1.2 mg/cm(3 ) ) in the 90-Hz WBV group , -0.1 mg/cm(3 ) ( CI , -1.0 to 0.8 mg/cm(3 ) ) in the 30-Hz WBV group , and -0.2 mg/cm(3 ) ( CI , -1.1 to 0.6 mg/cm(3 ) ) in the control group ( P = 0.55 ) . Changes in areal BMD at the femoral neck , total hip , and lumbar spine were also similar among the groups . Overall , low-magnitude WBV at both 90 and 30 Hz was well-tolerated . LIMITATIONS Adherence to WBV ranged from 65 % to 79 % . Double-blinding was not possible . CONCLUSION Whole-body vibration therapy at 0.3 g and 90 or 30 Hz for 12 months did not alter BMD or bone structure in postmenopausal women who received calcium and vitamin D supplementation BACKGROUND whole-body vibration training may improve neuromuscular function , falls risk and bone density , but previous studies have had conflicting findings . OBJECTIVE this study aim ed to evaluate the influence of vertical vibration ( VV ) and side-alternating vibration ( SV ) on musculoskeletal health in older people at risk of falls . DESIGN single-blind , r and omised , controlled trial comparing vibration training to sham vibration ( Sham ) in addition to usual care . PARTICIPANTS participants were 61 older people ( 37 women and 24 men ) , aged 80.2 + 6.5 years , referred to an outpatient falls prevention service . METHODS participants were r and omly assigned to VV , SV or Sham in addition to the usual falls prevention programme . Participants were requested to attend three vibration sessions per week for 12 weeks , with sessions increasing to six , 1 min bouts of vibration . Falls risk factors and neuromuscular tests were assessed , and blood sample s collected for determination of bone turnover , at baseline and following the intervention . RESULTS chair st and time , timed-up- and -go time , fear of falling , NEADL index and postural sway with eyes open improved in the Sham group . There were significantly greater gains in leg power in the VV than in the Sham group and in bone formation in SV and VV compared with the Sham group . Conversely , body sway improved less in the VV than in the Sham group . Changes in falls risk factors did not differ between the groups . CONCLUSIONS whole-body vibration increased leg power and bone formation , but it did not provide any additional benefits to balance or fall risk factors beyond a falls prevention programme in older people at risk of falls OBJECTIVE To test whether training on a high-frequency ( 28Hz ) vibrating platform improves muscle power and bone characteristics in postmenopausal women . DESIGN R and omized controlled trial with 6-month follow-up . SETTING Outpatient clinic in a general hospital in Italy . PARTICIPANTS Twenty-nine postmenopausal women ( intervention group , n=14 ; matched controls , n=15 ) . INTERVENTION Participants stood on a ground-based oscillating platform for three 2-minute sessions for a total of 6 minutes per training session , twice weekly for 6 months . The controls did not receive any training . Both groups were evaluated at baseline and after 6 months . MAIN OUTCOME MEASURES Muscle power , calculated from ground reaction forces produced by l and ing after jumping as high as possible on a forceplate , cortical bone density , and biomarkers of bone turnover . RESULTS Over 6 months , muscle power improved by about 5 % in women who received the intervention , and it remained unchanged in controls ( P=.004 ) . Muscle force remained stable in both the intervention and control groups . No significant changes were observed in bone characteristics . CONCLUSION Reflex muscular contractions induced by vibration training improve muscle power in postmenopausal women Background Whole-body vibration ( WBV ) is a new type of exercise that has been increasingly tested for the ability to prevent bone fractures and osteoporosis in frail people . There are two currently marketed vibrating plates : a ) the whole plate oscillates up and down ; b ) reciprocating vertical displacements on the left and right side of a fulcrum , increasing the lateral accelerations . A few studies have shown recently the effectiveness of the up- and -down plate for increasing Bone Mineral Density ( BMD ) and balance ; but the effectiveness of the reciprocating plate technique remains mainly unknown . The aim was to compare the effects of WBV using a reciprocating platform at frequencies lower than 20 Hz and a walking-based exercise programme on BMD and balance in post-menopausal women . Methods Twenty-eight physically untrained post-menopausal women were assigned at r and om to a WBV group or a Walking group . Both experimental programmes consisted of 3 sessions per week for 8 months . Each vibratory session included 6 bouts of 1 min ( 12.6 Hz in frequency and 3 cm in amplitude with 60 ° of knee flexion ) with 1 min rest between bouts . Each walking session was 55 minutes of walking and 5 minutes of stretching . Hip and lumbar BMD ( g·cm-2 ) were measured using dual-energy X-ray absorptiometry and balance was assessed by the blind flamingo test . ANOVA for repeated measurements was adjusted by baseline data , weight and age . Results After 8 months , BMD at the femoral neck in the WBV group was increased by 4.3 % ( P = 0.011 ) compared to the Walking group . In contrast , the BMD at the lumbar spine was unaltered in both groups . Balance was improved in the WBV group ( 29 % ) but not in the Walking group . Conclusion The 8-month course of vibratory exercise using a reciprocating plate is feasible and is more effective than walking to improve two major determinants of bone fractures : hip BMD and balance Purpose . To examine the effects of two doses of low-frequency ( 12 Hz ) , low-magnitude ( 0.3 g ) , whole body vibration on markers of bone formation and resorption in postmenopausal women . Methods . Women were recruited and r and omized into a sham vibration control group , one time per week vibration group ( 1 × /week ) , or three times per week vibration group ( 3 × /week ) . Vibration exposure consisted of 20 minutes of intermittent vibration for the 1 × /week and 3 × /week groups , and sham vibration ( < 0.1 g ) for the control group for eight weeks . Double-blinded primary outcome measures were urine markers of bone resorption : N-telopeptide X normalised to creatinine ( NTx/Cr ) and bone formation : bone-specific alkaline phosphatase ( ALP ) . Results . Forty-six women ( 59.8 ± 6.2 years , median 7.3 years since menopause ) were enrolled . NTx/Cr was significantly reduced ( 34.6 % ) in the 3 × /wk vibration group but not in the 1 × /wk vibration group compared with sham control ( P < .01 ) group . No effect of time or group allocation was observed on the bone formation marker ALP ( P = .27 ) . Conclusion . We have shown for the first time that low-frequency , low-magnitude vibration 3 × /week for eight weeks in postmenopausal women results in a significant reduction in NTx/Cr , a marker of bone resorption , when compared with sham vibration exposure OBJECTIVES We aim ed to clarify whether a short-term whole body vibration training has a beneficial effect on bone mass and structure in elderly men and women . DESIGN R and omised controlled trial . METHODS A total of 49 non-institutionalised elderly ( 20 men and 29 women ) volunteered to participate in the study . Participants who met the inclusion criteria were r and omly assigned to one of the study groups ( whole body vibration or control ) . A total of 24 elderly trained squat positioned on a vibration platform 3 times per week for 11 weeks . Bone-related variables were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography . Two-way repeated measures one-way analysis of variance ( group by time ) was used to determine the effects of the intervention on the bone-related variables and also to determinate the changes within group throughout the intervention period . Analysis of covariance was used to test the differences between groups for bone-related variables in pre- and post-training assessment s and in the percentage of change between groups . All analysis were carried out including age , height , subtotal lean mass and daily calcium intake as covariates . RESULTS 11 weeks of whole body vibration training led to no changes in none of the bone mineral content and bone mineral density parameters measured by dual-energy X-ray absorptiometry through the skeleton . At the tibia , total , trabecular and cortical volumetric bone mineral density decreased significantly in the whole body vibration group ( all P<0.05 ) . CONCLUSIONS A short-term whole body vibration therapy is not enough to cause any changes on bone mineral content or bone mineral density and it only produces a slight variation on bone structure among elderly people Background and aims : Exercise may enhance the effect of alendronate on bone mineral density ( BMD ) and reduce chronic back pain in elderly women with osteoporosis . The aim of this study was to determine whether whole-body vibration exercise would enhance the effect of alendronate on lumbar BMD and bone turnover , and reduce chronic back pain in post-menopausal women with osteoporosis . Methods : Fifty post-menopausal women with osteoporosis , 55–88 years of age , were r and omly divided into two groups of 25 patients each : one taking alendronate ( 5 mg daily , ALN ) and one taking alendronate plus exercise ( ALN+EX ) . Exercise consisted of whole-body vibration using a Galileo machine ( Novotec , Pforzheim , Germany ) , at an intensity of 20 Hz , frequency once a week , and duration of exercise 4 minutes . The study lasted 12 months . Lumbar BMD was measured by dual energy X-ray absorptiometry ( Hologic QDR 1500W ) . Urinary cross-linked N-terminal telopeptides of type I collagen ( NTX ) and serum alkaline phos-phatase ( ALP ) levels were measured by enzyme-linked immunosorbent assay and st and ard laboratory techniques , respectively . Chronic back pain was evaluated by face scale score at baseline and every 6 months . Results : There were no significant differences in baseline characteristics , including age , body mass index , years since menopause , lumbar BMD , urinary NTX and serum ALP levels , or face scale score between the two groups . The increase in lumbar BMD and the reduction in urinary NTX and serum ALP levels were similar in the ALN and ALN+EX groups . However , the reduction in chronic back pain was greater in the ALN+EX group than in the ALN group . Conclusions : The results of this study suggest that whole-body vibration exercise using a Galileo machine appears to be useful in reducing chronic back pain , probably by relaxing the back muscles in post-menopausal osteoporotic women treated with alendronate Nonpharmacologic approaches to preserve or increase bone mineral density ( BMD ) include whole-body vibration ( WBV ) , but its efficacy in elderly persons is not clear . Therefore , we conducted the Vibration to Improve Bone in Elderly Subjects ( VIBES ) trial , a r and omized , placebo-controlled trial of 10 minutes of daily WBV ( 0.3 g at 37 Hz ) in seniors recruited from 16 independent living communities . The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography ( QCT ) and biochemical markers of bone turnover . We r and omized 174 men and women ( 89 active , 85 placebo ) with T-scores -1 to -2.5 who were not taking bone active drugs and had no diseases affecting the skeleton ( mean age 82 ± 7 years , range 65 to 102 ) . Participants received daily calcium ( 1000 mg ) and vitamin D ( 800 IU ) . Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring ; placebo platforms resembled the active platforms . In total , 61 % of participants in the active arm and 73 % in the placebo arm completed 24 months . The primary outcomes , median percent changes ( interquartile range [ IQR ] ) in total volumetric femoral trabecular BMD ( active group ( 2.2 % [ -0.8 % , 5.2 % ] ) versus placebo 0.4 % [ -4.8 % , 5.0 % ] ) and in mid-vertebral trabecular BMD of L1 and L2 ( active group ( 5.3 % [ -6.9 % , 13.3 % ] ) versus placebo ( 2.4 % [ -4.4 % , 11.1 % ] ) , did not differ between groups ( all p values > 0.1 ) . Changes in biochemical markers of bone turnover ( P1NP and sCTX ) also were not different between groups ( p = 0.19 and p = 0.97 , respectively ) . In conclusion , this placebo-controlled r and omized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers ; however , the high variability in vBMD changes limited our power to detect small treatment effects . The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals BACKGROUND Mortality increases after hip fractures in women and more so in men . Little is known , however , about mortality after other fractures . We investigated the mortality associated with all fracture types in elderly women and men . METHODS We did a 5-year prospect i ve cohort study in the semi-urban city of Dubbo , Australia , of all residents aged 60 years and older ( 2413 women and 1898 men ) . Low-trauma osteoporotic fractures that occurred between 1989 and 1994 , confirmed by radiography and personal interview , were classified as proximal femur , vertebral , and groupings of other major and minor fractures . We calculated st and ardised mortality rates from death certificates for people with fractures compared with the Dubbo population . FINDINGS 356 women and 137 men had low-trauma fractures . In women and men , mortality was increased in the first year after all major fractures . In women , age-st and ardised mortality ratios were 2.18 ( 95 % CI 2.03 - 2.32 ) for proximal femur , 1.66 ( 1.51 - 1.80 ) for vertebral , 1.92 ( 1.70 - 2.14 ) for other major , and 0.75 ( 0.66 - 0.84 ) for minor fractures . In men , these ratios were 3.17 ( 2.90 - 3.44 ) for proximal femur , 2.38 ( 2.17 - 2.59 ) for vertebral , 2.22 ( 1.91 - 2.52 ) for other major , and 1.45 ( 1.25 - 1.65 ) for minor fractures . There were excess deaths ( excluding minor fractures in women ) in all age-groups . INTERPRETATION All major fractures were associated with increased mortality , especially in men . The loss of potential years of life in the younger age-group shows that preventative strategies for fracture should not focus on older patients at the expense of younger women and of men Beck BR , Norling TL : The effect of 8 mos of twice-weekly low- or higher intensity whole body vibration on risk factors for postmenopausal hip fracture . Objective : Whole body vibration is a potential therapy for age-related loss of musculoskeletal competence . Vibration has improved bone in animal models , but evidence in humans is limited . Relative efficacy of low- vs. high-intensity whole body vibration is also unknown . Our goal was to observe the effect of brief low- and higher intensity whole body vibration on risk factors for hip fracture in postmenopausal women . Design : We used an 8-mo r and omized controlled trial design to examine the influence of twice-weekly low-intensity whole body vibration ( 15 mins , 30 Hz , 0.3 g ) or higher intensity whole body vibration ( 2 × 3 mins , 12.5 Hz , 1 g ) on anthropometrics , bone ( whole body , hip , spine , forearm , and heel ) , muscle ( wall squat and chair rise ) , and balance ( t and em walk and single leg stance ) . Physical activity , daily calcium , and compliance were recorded . Effects were examined by repeated- measures analysis of covariance , controlling for age , height , weight , calcium , physical activity , compliance , and baseline values . Results : Forty-seven women ( 71.5 ± 9.0 yrs ) completed the trial . There were no between-group differences in any measure at 8 mos , but within-group effects were evident . Controls lost bone at the trochanter ( −6 % , P = 0.03 ) and lumbar spine ( −6.6 % , P = 0.02 ) , whereas whole body vibration groups did not . Whole body vibration subjects improved wall squat ( up to 120 % , P = 0.004 ) and chair rise performance ( up to 10.5 % , P = 0.05 ) . Conclusions : Eight mos of twice-weekly whole body vibration may reduce bone loss at the hip and spine and improve lower limb muscle function . These changes may translate to a decreased risk of falls and hip fracture The purpose of this study was to examine the effect of whole-body vibration ( WBV ) on calcaneal quantitative ultrasound ( QUS ) measurements ; which has rarely been examined . We conducted a single-centre , 12-month , r and omized controlled trial . 202 postmenopausal women with BMD T score between −1.0 and −2.5 , not receiving bone medications , were asked to st and on a 0.3 g WBV platform oscillating at either 90- or 30-Hz for 20 consecutive minutes daily , or to serve as controls . Calcium and vitamin D was provided to all participants . Calcaneal broadb and attenuation ( BUA ) , speed of sound , and QUS index were obtained as pre-specified secondary endpoints at baseline and 12 months by using a Hologic Sahara Clinical Bone Sonometer . 12-months of WBV did not improve QUS parameters in any of our analyses . While most of our analyses showed no statistical differences between the WBV groups and the control group , mean calcaneal BUA decreased in the 90-Hz ( −0.4 [ 95 % CI −1.9 to 1.2 ] dB MHz−1 ) and 30-Hz ( −0.7 [ 95 % CI −2.3 to 0.8 ] dB MHz−1 ) WBV groups and increased in the control group ( 1.3 [ 95 % CI 0.0–2.6 ] dB MHz−1 ) . Decreases in BUA in the 90- , 30-Hz or combined WBV groups were statistically different from the control group in a few of the analyses including all r and omized participants , as well as in analyses excluding participants who had missing QUS measurement and those who initiated hormone therapy or were < 80 % adherent . Although there are consistent trends , not all analyses reached statistical significance . 0.3 g WBV at 90 or 30 Hz prescribed for 20 min daily for 12 months did not improve any QUS parameters , but instead result ed in a statistically significant , yet small , decrease in calcaneal BUA in postmenopausal women in several analyses . These unexpected findings require further investigation UNLABELLED The osteogenic potential of short duration s of low-level mechanical stimuli was examined in children with disabling conditions . The mean change in tibia vTBMD was + 6.3 % in the intervention group compared with -11.9 % in the control group . This pilot r and omized controlled trial provides preliminary evidence that low-level mechanical stimuli represent a noninvasive , non-pharmacological treatment of low BMD in children with disabling conditions . INTRODUCTION Recent animal studies have demonstrated the anabolic potential of low-magnitude , high-frequency mechanical stimuli to the trabecular bone of weight-bearing regions of the skeleton . The main aim of this prospect i ve , double-blind , r and omized placebo-controlled pilot trial ( RCT ) was to examine whether these signals could effectively increase tibial and spinal volumetric trabecular BMD ( vTBMD ; mg/ml ) in children with disabling conditions . MATERIAL S AND METHODS Twenty pre-or postpubertal disabled , ambulant , children ( 14 males , 6 females ; mean age , 9.1 + /- 4.3 years ; range , 4 - 19 years ) were r and omized to st and ing on active ( n = 10 ; 0.3 g , 90 Hz ) or placebo ( n = 10 ) devices for 10 minutes/day , 5 days/week for 6 months . The primary outcomes of the trial were proximal tibial and spinal ( L2 ) vTBMD ( mg/ml ) , measured using 3-D QCT . Posthoc analyses were performed to determine whether the treatment had an effect on diaphyseal cortical bone and muscle parameters . RESULTS AND CONCLUSIONS Compliance was 44 % ( 4.4 minutes per day ) , as determined by mean time on treatment ( 567.9 minutes ) compared with expected time on treatment over the 6 months ( 1300 minutes ) . After 6 months , the mean change in proximal tibial vTBMD in children who stood on active devices was 6.27 mg/ml ( + 6.3 % ) ; in children who stood on placebo devices , vTBMD decreased by -9.45 mg/ml ( -11.9 % ) . Thus , the net benefit of treatment was + 15.72 mg/ml ( 17.7 % ; p = 0.0033 ) . In the spine , the net benefit of treatment , compared with placebo , was + 6.72 mg/ml , ( p = 0.14 ) . Diaphyseal bone and muscle parameters did not show a response to treatment . The results of this pilot RCT have shown for the first time that low-magnitude , high-frequency mechanical stimuli are anabolic to trabecular bone in children , possibly by providing a surrogate for suppressed muscular activity in the disabled . Over the course of a longer treatment period , harnessing bone 's sensitivity to these stimuli may provide a non-pharmacological treatment for bone fragility in children Summary Adolescents with Down syndrome ( DS ) have poorer bone health than their peers without DS . Twenty-five adolescents with DS were r and omly assigned to whole-body vibration training ( WBV ) or control groups . The results indicate that a 20-week WBV might be useful to improve subtotal bone mineral content and density in adolescents with DS . Introduction This study aims to determine the effects of 20 weeks of whole body vibration training ( WBV ) on bone mineral content ( BMC ) , density ( BMD ) , and structure variables in adolescents with Down syndrome ( DS ) . Methods This r and omized controlled trial of 25 adolescents ( 12–18 years ) with DS ( 8 females ) generated 2 non-equal groups , WBV group ( n = 11 ) and CON group ( n = 14 ) . Using an efficacy analysis , the primary outcomes were BMC and BMD by dual-energy X-ray absorptiometry and the secondary were bone structure variables by peripheral quantitative computed tomography . A synchronous vibration platform ( PowerPlate ® ) was used ( 3/week , 10 repetitions ( 30–60 s ) 1-min rest , frequency of 25–30 Hz , and peak-to-peak displacement of 2 mm ( peak acceleration 2.5–3.6 g ) ) . Results WBV group improved whole body BMC 2.8 % , 95 % CI [ 3.5 , 2.1 ] , subtotal area , BMC , and BMD by 2.8 , 4.8 , and 2 % , respectively , 95 % confidence intervals ( CIs ) [ 3.4 , 2.1 ] , [ 6.5 , 3.1 ] , and [ 2.8 , 1.1 ] , respectively ( all , p < 0.05 ) , showing group by time interactions in BMC and BMD ( both p < 0.05 ) . Lumbar spine BMC and BMD also increased in the WBV group by 6.6 and 3.3 % both p < 0.05 , 95 % CIs [ 8.6 , 4.7 ] , and [ 4.9 , 1.7 ] , respectively . Regarding bone structure , WBV group showed improvements in tibial BMC at 4 % ( 2.9 % , 95 % CI [ 3.0 , 2.8 ] ) and in volumetric BMD ( vBMD ) , cortical vBMD , and cortical thickness at 66 % of the radius ( by 7.0 , 2.4 , and 10.9 % ; 95 % CIs [ 7.4 , 6.7 ] , [ 2.6 , 2.3 ] , and [ 12.4 , 9.3 ] , respectively ) ( all , p < 0.05 ) . Conclusions A 20-week WBV , with this protocol , might be useful to improve subtotal BMC and BMD in adolescents with DS In this study , we compared the efficacy of 8 months of low-frequency vibration and a walk-based program in health-related fitness . Twenty-seven postmenopausal women were r and omly assigned into two groups : whole-body vibration ( WBV ) group ( n = 18 ) performed three times/week a static exercise on a vibration platform ( 6 sets of 1-min with 1 min of rest , with a 12.6 Hz of frequency and an amplitude of 3 mm ) ; walk-based program ( WP ) group ( n = 18 ) performed three times/week a 60-min of walk activity at 70–75 % of maximal heart rate . A health-related battery of tests was applied . Maximal unilateral concentric and eccentric isokinetic torque of the knee extensors was recorded by an isokinetic dynamometer . Physical fitness was measured using the following tests : vertical jump test , chair rise test and maximal walking speed test over 4 m. Maximal unilateral isokinetic strength was measured in the knee extensors in concentric actions at 60 and 300 ° /s , and eccentric action at 60 ° /s . After 8 months , the WP improved the time spent to walk 4 m ( 20 % ) and to perform the chair rise test ( 12 % ) compared to the WBV group ( P = 0.006 , 0.002 , respectively ) . In contrast , the comparison of the changes in vertical jump showed the higher effectiveness of the vibratory exercise in 7 % ( P = 0.025 ) . None of exercise programs showed change on isokinetic measurements . These results indicate that both programs differed in the main achievements and could be complementary to prevent lower limbs muscle strength decrease as we age [ IS RCT N76235671 ] The amount of bone that is gained during adolescence is the main contributor to peak bone mass , which , in turn , is a major determinant of osteoporosis and fracture risk in the elderly . We examined whether computed tomography measurements for the density and the volume of bone in the axial and the appendicular skeletons could be tracked through puberty in 40 healthy white children ( 20 girls and 20 boys ) . Longitudinal measurements of the cross-sectional area and cancellous bone density of the vertebral bodies and the cross-sectional and cortical bone areas of the femurs at the beginning of puberty accounted for 62 - 92 % of the variations seen at sexual maturity ; on average , 3 yr later . When baseline values for these bone traits were divided into quartiles , a linear relation across Tanner stages of sexual development was observed for each quartile in both girls and boys . The regression lines differed among quartiles for each trait , paralleled each other , and did not overlap . Thus , we are now in a position to identify those children who are genetically prone to develop low values for peak bone mass and toward whom osteoporosis prevention trials should be geared Recent animal studies have given evidence that vibration loading may be an efficient and safe way to improve mass and mechanical competence of bone , thus providing great potential for preventing and treating osteoporosis . R and omized controlled trials on the safety and efficacy of the vibration on human skeleton are , however , lacking . This r and omized controlled intervention trial was design ed to assess the effects of an 8-month whole body vibration intervention on bone , muscular performance , and body balance in young and healthy adults . Fifty-six volunteers ( 21 men and 35 women ; age , 19 - 38 years ) were r and omly assigned to the vibration group or control group . The vibration intervention consisted of an 8-month whole body vibration ( 4 min/day , 3 - 5 times per week ) . During the 4-minute vibration program , the platform oscillated in an ascending order from 25 to 45 Hz , corresponding to estimated maximum vertical accelerations from 2 g to 8 g. Mass , structure , and estimated strength of bone at the distal tibia and tibial shaft were assessed by peripheral quantitative computed tomography ( pQCT ) at baseline and at 8 months . Bone mineral content was measured at the lumbar spine , femoral neck , trochanter , calcaneus , and distal radius using DXA at baseline and after the 8-month intervention . Serum markers of bone turnover were determined at baseline and 3 , 6 , and 8 months . Five performance tests ( vertical jump , isometric extension strength of the lower extremities , grip strength , shuttle run , and postural sway ) were performed at baseline and after the 8-month intervention . The 8-month vibration intervention succeeded well and was safe to perform but had no effect on mass , structure , or estimated strength of bone at any skeletal site . Serum markers of bone turnover did not change during the vibration intervention . However , at 8 months , a 7.8 % net benefit in the vertical jump height was observed in the vibration group ( 95 % CI , 2.8 - 13.1 % ; p = 0.003 ) . On the other performance and balance tests , the vibration intervention had no effect . In conclusion , the studied whole body vibration program had no effect on bones of young , healthy adults , but instead , increased vertical jump height . Future human studies are needed before clinical recommendations for vibration exercise UNLABELLED Age-related changes in body composition are well-documented with a decrease in lean body mass and a redistribution of body fat generally observed . Resistance training alone has been shown to have positive effects on body composition , however , these benefits may be enhanced by the addition of a vibration stimulus . OBJECTIVE The purpose of this study was to determine the effects of 8 months of resistance training with and without whole-body vibration ( WBV ) on body composition in sedentary postmenopausal women . METHODS Fifty-five women were assigned to resistance only ( RG , n=22 ) , vibration plus resistance ( VR , n=21 ) or non-exercising control ( CG , n=12 ) groups . Resistance training ( 3 sets 10 repetitions 80 % strength ) was performed using isotonic weight training equipment and whole-body vibration was done with the use of the power plate ( Northbrooke , IL ) vibration platform for three times per week for 8 months . Total and regional body composition was assessed from the total body DXA scans at baseline ( pre ) and after 8 months ( post ) of training . RESULTS In the VR group , total % body fat decreased from pre- to post-time points ( p<0.05 ) , whereas , the CG group had a significant increase in total % body fat ( p<0.05 ) . Both training groups exhibited significant increases in bone free lean tissue mass for the total body , arm and trunk regions from pre to post ( p<0.05 ) . CG did not show any changes in lean tissue . CONCLUSION In older women , resistance training alone and with whole-body vibration result ed in positive body composition changes by increasing lean tissue . However , only the combination of resistance training and whole-body vibration was effective for decreasing percent body fat Summary We determined whether the effect of exercise on bone mineral density ( BMD ) and falls can be enhanced by whole body vibration ( WBV ) . In summary , the multi- purpose exercise training was effective to increase lumbar BMD but added WBV did not enhance this effect . However , falls were lowest in the exercise program combined with WBV . Introduction WBV is a new approach to reduce the risk of osteoporotic fractures . In the “ Erlangen Longitudinal Vibration Study ” ( ELVIS ) , we investigated whether WBV enhances the effect of multifunctional exercise on BMD and falls . Methods One hundred fifty-one postmenopausal women ( 68.5 ± 3.1 years ) were r and omly assigned to a : ( 1 ) conventional training group ( TG ) ; ( 2 ) conventional training group including vibration ( TGV ) ; and ( 3 ) wellness control group ( CG ) . TG conducted an exercise program consisting of 20 min dancing aerobics , 5 min balance training , 20 min functional gymnastics , and 15 min dynamic leg-strength training on vibration plates ( without vibration ) twice a week . TGV performed an identical exercise regimen with vibration ( 25–35 Hz ) during the leg-strengthening sequence . CG performed a low-intensity wellness program . BMD was measured at the hip and lumbar spine at baseline and follow-up using the DXA method . Falls were recorded daily via the calendar method . Results After 18 months , an increase in BMD at the lumbar spine was observed in both training groups ( TGV : + 1.5 % vs. TG : + 2.1 % ) . The difference between the TG and the CG ( 1.7 % ) was significant . At the hip no changes were determined in either group . The fall frequency was significantly lower in TGV ( 0.7 falls/person ) compared with CG ( 1.5 ) , whereas the difference between TG ( 0.96 ) and CG was not significant . Conclusions A multifunctional training program had a positive impact on lumbar BMD . The application of vibration did not enhance these effects . However , only the training including WBV affected the number of falls significantly UNLABELLED The potential for brief periods of low-magnitude , high-frequency mechanical signals to enhance the musculoskeletal system was evaluated in young women with low BMD . Twelve months of this noninvasive signal , induced as whole body vibration for at least 2 minutes each day , increased bone and muscle mass in the axial skeleton and lower extremities compared with controls . INTRODUCTION The incidence of osteoporosis , a disease that manifests in the elderly , may be reduced by increasing peak bone mass in the young . Preliminary data indicate that extremely low-level mechanical signals are anabolic to bone tissue , and their ability to enhance bone and muscle mass in young women was investigated in this study . MATERIAL S AND METHODS A 12-month trial was conducted in 48 young women ( 15 - 20 years ) with low BMD and a history of at least one skeletal fracture . One half of the subjects underwent brief ( 10 minutes requested ) , daily , low-level whole body vibration ( 30 Hz , 0.3 g ) ; the remaining women served as controls . Quantitative CT performed at baseline and at the end of study was used to establish changes in muscle and bone mass in the weight-bearing skeleton . RESULTS Using an intention-to-treat ( ITT ) analysis , cancellous bone in the lumbar vertebrae and cortical bone in the femoral midshaft of the experimental group increased by 2.1 % ( p = 0.025 ) and 3.4 % ( p < 0.001 ) , respectively , compared with 0.1 % ( p = 0.74 ) and 1.1 % ( p = 0.14 ) , in controls . Increases in cancellous and cortical bone were 2.0 % ( p = 0.06 ) and 2.3 % ( p = 0.04 ) greater , respectively , in the experimental group compared with controls . Cross-sectional area of paraspinous musculature was 4.9 % greater ( p = 0.002 ) in the experimental group versus controls . When a per protocol analysis was considered , gains in both muscle and bone were strongly correlated to a threshold in compliance , where the benefit of the mechanical intervention compared with controls was realized once subjects used the device for at least 2 minute/day ( n = 18 ) , as reflected by a 3.9 % increase in cancellous bone of the spine ( p = 0.007 ) , 2.9 % increase in cortical bone of the femur ( p = 0.009 ) , and 7.2 % increase in musculature of the spine ( p = 0.001 ) compared with controls and low compliers ( n = 30 ) . CONCLUSIONS Short bouts of extremely low-level mechanical signals , several orders of magnitude below that associated with vigorous exercise , increased bone and muscle mass in the weight-bearing skeleton of young adult females with low BMD . Should these musculoskeletal enhancements be preserved through adulthood , this intervention may prove to be a deterrent to osteoporosis in the elderly

Conclusion : Lymphodepletion regimen may play a crucial role in predicting the prognosis of patients with hematological malignancies . Lymphodepletion patients had better progression-free survival than those who did not

Purpose : Chimeric Antigen Receptor T(CAR-T ) cell therapy is an immunotherapy approach used in treating cancer which has seen rapid development over the decades . It becomes the preferred treatment choice after patients have failed conventional chemotherapy .

We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor ( CAR ) . Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2 . Six of the 8 patients treated on our protocol obtained remissions of their advanced , progressive B-cell malignancies . Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+ ) B-lineage cells . Cells containing the anti-CD19 CAR gene were detected in the blood of all patients . Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF . The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels . The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions . Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+ ) cells in vivo ; however , reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions BACKGROUND Chimeric antigen receptor ( CAR ) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas , but feasibility , toxicity , and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported . We aim ed to define feasibility , toxicity , maximum tolerated dose , response rate , and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells . METHODS This phase 1 , dose-escalation trial consecutively enrolled children and young adults ( aged 1 - 30 years ) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma . Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains . All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells . Using a st and ard 3 + 3 design to establish the maximum tolerated dose , patients received either 1 × 10(6 ) CAR-transduced T cells per kg ( dose 1 ) , 3 × 10(6 ) CAR-transduced T cells per kg ( dose 2 ) , or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated . After the dose-escalation phase , an expansion cohort was treated at the maximum tolerated dose . The trial is registered with Clinical Trials.gov , number NCT01593696 . FINDINGS Between July 2 , 2012 , and June 20 , 2014 , 21 patients ( including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation ) were enrolled and infused with CD19-CAR T cells . 19 received the prescribed dose of CD19-CAR T cells , whereas the assigned dose concentration could not be generated for two patients ( 90 % feasible ) . All patients enrolled were assessed for response . The maximum tolerated dose was defined as 1 × 10(6 ) CD19-CAR T cells per kg . All toxicities were fully reversible , with the most severe being grade 4 cytokine release syndrome that occurred in three ( 14 % ) of 21 patients ( 95 % CI 3·0 - 36·3 ) . The most common non-haematological grade 3 adverse events were fever ( nine [ 43 % ] of 21 patients ) , hypokalaemia ( nine [ 43 % ] of 21 patients ) , fever and neutropenia ( eight [ 38 % ] of 21 patients ) , and cytokine release syndrome ( three [ 14 % ) of 21 patients ) . INTERPRETATION CD19-CAR T cell therapy is feasible , safe , and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia . All toxicities were reversible and prolonged B-cell aplasia did not occur . FUNDING National Institutes of Health Intramural funds and St Baldrick 's Foundation BACKGROUND Relapsed acute lymphoblastic leukemia ( ALL ) is difficult to treat despite the availability of aggressive therapies . Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease . METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor ( CTL019 ) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76 × 10(6 ) to 20.6 × 10(6 ) CTL019 cells per kilogram of body weight . Patients were monitored for a response , toxic effects , and the expansion and persistence of circulating CTL019 T cells . RESULTS A total of 30 children and adults received CTL019 . Complete remission was achieved in 27 patients ( 90 % ) , including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation . CTL019 cells proliferated in vivo and were detectable in the blood , bone marrow , and cerebrospinal fluid of patients who had a response . Sustained remission was achieved with a 6-month event-free survival rate of 67 % ( 95 % confidence interval [ CI ] , 51 to 88 ) and an overall survival rate of 78 % ( 95 % CI , 65 to 95 ) . At 6 months , the probability that a patient would have persistence of CTL019 was 68 % ( 95 % CI , 50 to 92 ) and the probability that a patient would have relapse-free B-cell aplasia was 73 % ( 95 % CI , 57 to 94 ) . All the patients had the cytokine-release syndrome . Severe cytokine-release syndrome , which developed in 27 % of the patients , was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab . CONCLUSIONS Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL . CTL019 was associated with a high remission rate , even among patients for whom stem-cell transplantation had failed , and durable remissions up to 24 months were observed . ( Funded by Novartis and others ; CART19 Clinical Trials.gov numbers , NCT01626495 and NCT01029366 . ) Adoptively transferred gene-modified T cells exp and in vivo , eliminate leukemic cells , and form functional memory cells in patients . Go CAR-Ts in the Fast Lane As members of the body ’s police force , cells of the immune system vigilantly pursue bad actors that harm healthy tissues , such as infection or cancer , and then try to deter dangerous activity . Research ers have long sought to harness the power of the immune system to fight cancers such as leukemia ; however , targeting functional immune T cells to the tumor and maintaining these cells in patients remains challenging . Now , Kalos et al. have genetically modified T cells to express a chimeric antigen receptor ( CAR ) to yield so-called CAR T cells that specifically target chronic lymphocytic leukemia ( CLL ) ( a B cell cancer ) . The design er T cells not only exp and ed , persisted , and attacked tumor cells after transfer into patients ; they also mediated cancer remission . Innocent byst and ers were also targeted , as reflected by decreased numbers of B cells and plasma cells and the development of hypogammaglobulinemia . The CAR T cells used in this study expressed an antigen receptor that consists of antibody binding domains that bind in a restricted manner to the CD19 protein ( which is found solely on normal B cells and plasma cells ) attached to both a T cell – specific costimulatory domain and a T cell – specific intracellular signaling domain . The result ing chimeric receptor could activate T cells in response to CD19 in the absence of major histocompatibility complex restriction , allowing for much broader cellular targeting than is obtained with normal T cells . After transfer into three CLL patients , these CAR T cells exp and ed > 1000-fold , persisted for more than 6 months , and eradicated CLL cells . Some of these CAR T cells persisted with a memory phenotype , which would allow them to respond more quickly and on a larger scale with a second exposure to CLL cells . Indeed , two of the three CLL patients who underwent the CAR T cell treatment had complete remission of their leukemia . Although this is early in the clinical study , these results highlight the potential for CAR-modified T cells to bring cancer therapy up to speed . Tumor immunotherapy with T lymphocytes , which can recognize and destroy malignant cells , has been limited by the ability to isolate and exp and T cells restricted to tumor-associated antigens . Chimeric antigen receptors ( CARs ) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens ; however , to date , lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials . We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non – cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia ( CLL ) . The engineered T cells exp and ed > 1000-fold in vivo , trafficked to bone marrow , and continued to express functional CARs at high levels for at least 6 months . Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia . On average , each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells . Furthermore , a CD19-specific immune response was demonstrated in the blood and bone marrow , accompanied by complete remission , in two of three patients . Moreover , a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality , indicating the potential of this major histocompatibility complex – independent approach for the effective treatment of B cell malignancies Five adults with chemotherapy-refractory B-ALL were induced into molecular remissions after treatment with CD19 CAR-targeted T cells . CARving a Niche for Cancer Immunotherapy Acute lymphoblastic leukemia ( ALL ) is a cancer of the white blood cells that fend off infection . It ’s most common in children but — as with many diseases that primarily affect children — has a much worse prognosis when it affects adults . Adults with relapsed disease have a very low chance of survival , and new therapies are desperately needed . Now , Brentjens et al. test T cells engineered to target CD19 , which is expressed on both healthy B lymphocytes and B-ALL cells , in five chemotherapy-refractory adult B-ALL patients . Here , the authors treat patients with the patients ’ own T cells altered to express not only CD19 but also a fusion of the costimulatory molecule CD28 with CD3ζ chain — so-called “ second-generation chimeric antigen receptor ( CAR ) T cells . ” All patients treated with these cells achieved tumor eradication and complete remission . These CAR T cells were well tolerated , although there was substantial cytokine release in some patients that correlated to tumor burden . These patients were treated with steroid therapy . Long-term follow-up in four of these patients was not possible because the CAR T cell therapy allowed these patients to be eligible for subsequent hematopoietic stem cell transplant ( HSCT ) , which result ed in restored hematopoiesis . The remaining patient experienced a relapse of CD19 + cells that coincided with the lack of persistence of the CAR T cells from circulation . These data suggest that subsequent transfusions should be considered for patients unable to undergo HSCT . Adults with relapsed B cell acute lymphoblastic leukemia ( B-ALL ) have a dismal prognosis . Only those patients able to achieve a second remission with no minimal residual disease ( MRD ) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) . We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor ( CAR ) termed 19 - 28z . All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD− complete remissions as assessed by deep sequencing polymerase chain reaction . Therapy was well tolerated , although significant cytokine elevations , specifically observed in those patients with morphologic evidence of disease at the time of treatment , required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities . Indeed , cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions . Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy , who was ineligible for additional allo-HSCT or T cell therapy , exhibited persistent expression of CD19 and sensitivity to autologous 19 - 28z T cell – mediated cytotoxicity , which suggests potential clinical benefit of additional CAR-modified T cell infusions . These results demonstrate the marked antitumor efficacy of 19 - 28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions , forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT Autologous T cells expressing a CD19-specific chimeric antigen receptor ( CD19.CAR ) are active against B-cell malignancies , but it is unknown whether allogeneic CD19.CAR T cells are safe or effective . After allogeneic hematopoietic stem cell transplantation ( HSCT ) , infused donor-derived virus-specific T cells ( VSTs ) exp and in vivo , persist long term , and display antiviral activity without inducing graft-vs-host disease ; therefore , we determined whether donor VSTs , engineered to express CD19.CAR , retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity . We treated 8 patients with allogeneic ( donor-derived ) CD19.CAR-VSTs 3 months to 13 years after HSCT . There were no infusion-related toxicities . VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites . Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence , whereas 2 patients who received cells while in remission remain disease free . In 2 of 3 patients with viral reactivation , donor CD19.CAR-VSTs exp and ed concomitantly with VSTs . Hence CD19.CAR-VSTs display antitumor activity and , because their number may be increased in the presence of viral stimuli , earlier treatment post-HSCT ( when lymphodepletion is greater and the incidence of viral infection is higher ) or planned vaccination with viral antigens may enhance disease control PURPOSE T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor ( CAR ) . We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+ ) B-cell malignancies . PATIENTS AND METHODS We treated 15 patients with advanced B-cell malignancies . Nine patients had diffuse large B-cell lymphoma ( DLBCL ) , two had indolent lymphomas , and four had chronic lymphocytic leukemia . Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells . RESULTS Of 15 patients , eight achieved complete remissions ( CRs ) , four achieved partial remissions , one had stable lymphoma , and two were not evaluable for response . CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL ; three of these four CRs are ongoing , with duration s ranging from 9 to 22 months . Acute toxicities including fever , hypotension , delirium , and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells ; these toxicities resolved within 3 weeks after cell infusion . One patient died suddenly as a result of an unknown cause 16 days after cell infusion . CAR T cells were detected in the blood of patients at peak levels , ranging from nine to 777 CAR-positive T cells/μL. CONCLUSION This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells . These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells . The numerous remissions obtained provide strong support for further development of this approach

Findings demonstrated a benefit of behavioural support in addition to pharmacotherapy . There is high-certainty evidence that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates . Subgroup analysis suggests that the incremental benefit from more support is similar over a range of levels of baseline support .

BACKGROUND Pharmacotherapies for smoking cessation increase the likelihood of achieving abstinence in a quit attempt . It is plausible that providing support , or , if support is offered , offering more intensive support or support including particular components may increase abstinence further . OBJECTIVES To evaluate the effect of adding or increasing the intensity of behavioural support for people using smoking cessation medications , and to assess whether there are different effects depending on the type of pharmacotherapy , or the amount of support in each condition . We also looked at studies which directly compare behavioural interventions matched for contact time , where pharmacotherapy is provided to both groups ( e.g. tests of different components or approaches to behavioural support as an adjunct to pharmacotherapy ) .

Tobacco use is the single most important preventable cause of death in military personnel . The purpose of this r and omized clinical trial was to evaluate the effectiveness of two behavioral interventions when added to nicotine-replacement therapy on smoking cessation . The sample of 512 included 52 % active duty military , 29 % family , 11 % retirees , and 8 % Department of Defense civilians . There was a main effect of compliance at the end of the program ( EOP ) ; 69 % of those who attended 75 % of the classes were abstinent from tobacco ; regression analysis found the more intensive program to be twice as effective at EOP and at 3 months , an outcome not continued at 6 months . The longer , more intensive V and erbilt University Medical Center program was significantly more effective at helping the civilian portion of the population ( 85 % versus 60 % in the American Cancer Society program ) but not the active duty participants Residential treatment for substance use disorders ( SUD ) provides opportunity for smoking intervention . A r and omized controlled trial compared : ( 1 ) motivational interviewing ( MI ) to brief advice ( BA ) , ( 2 ) in one session or with two booster sessions , for 165 alcoholics in SUD treatment . All received nicotine replacement ( NRT ) . MI and BA produced equivalent confirmed abstinence , averaging 10 % at 1 month , and 2 % at 3 , 6 and 12 months . However , patients with more drug use pretreatment ( > 22 days in 6 months ) given BA had more abstinence at 12 months ( 7 % ) than patients in MI or with less drug use ( all 0 % ) . Boosters produced 16 - 31 % fewer cigarettes per day after BA than MI . Substance use was unaffected by treatment condition or smoking cessation . Motivation to quit was higher after BA than MI . Thus , BA plus NRT may be a cost-effective way to reduce smoking for alcoholics with comorbid substance use who are not seeking smoking cessation Background There is no more effective intervention for secondary prevention of coronary heart disease than smoking cessation . Yet , evidence about the (cost-)effectiveness of smoking cessation treatment methods for cardiac in patients that also suit nursing practice is scarce . This protocol describes the design of a study on the (cost-)effectiveness of two intensive smoking cessation interventions for hospitalised cardiac patients as well as first results on the inclusion rates and the characteristics of the study population . Methods / design An experimental study design is used in eight cardiac wards of hospitals throughout the Netherl and s to assess the (cost-)effectiveness of two intensive smoking cessation counselling methods both combined with nicotine replacement therapy . R and omization is conducted at the ward level ( cross-over ) . Baseline and follow-up measurements after six and 12 months are obtained . Upon admission to the cardiac ward , nurses assess patients ’ smoking behaviour , ensure a quit advice and subsequently refer patients for either telephone counselling or face-to-face counselling . The counselling interventions have a comparable structure and content but differ in provider and delivery method , and in duration . Both counselling interventions are compared with a control group receiving no additional treatment beyond the usual care . Between December 2009 and June 2011 , 245 cardiac patients who smoked prior to hospitalisation were included in the usual care group , 223 in the telephone counselling group and 157 in the face-to-face counselling group . Patients are predominantly male and have a mean age of 57 years . Acute coronary syndrome is the most frequently reported admission diagnosis . The ultimate goal of the study is to assess the effects of the interventions on smoking abstinence and their cost-effectiveness . Telephone counselling is expected to be more (cost-)effective in highly motivated patients and patients with high SES , whereas face-to-face counselling is expected to be more (cost-)effective in less motivated patients and patients with low SES . Discussion This study examines two intensive smoking cessation interventions for cardiac patients using a multi-centre trial with eight cardiac wards . Although not all eligible patients could be included and the distribution of patients is skewed in the different groups , the results will be able to provide valuable insight into effects and costs of counselling interventions varying in delivery mode and intensity , also concerning subgroups . Trial registration Dutch Trial Register Subjects ( N = 139 ) were assigned to intensive behavioral or to low-contact smoking treatment and to 2-mg nicotine gum or to placebo gum in a 2 X 2 factorial design . The 2-mg gum produced higher abstinence rates than did the placebo . Subjects receiving the low-contact condition plus the 2-mg nicotine gum had excellent abstinence rates at both 26 weeks ( 56 % abstainers ) and 52 weeks ( 50 % abstainers ) . Smokers who scored at the median on a measure of physical dependence to nicotine were more likely to benefit by nicotine gum treatment than subjects who scored either higher or lower , but this relation was nonsignificant . The results of this study are compared with an earlier nonblind trial OBJECTIVE To compare the efficacy of Mindfulness-Based Addiction Treatment ( MBAT ) to a Cognitive Behavioral Treatment ( CBT ) that matched MBAT on treatment contact time , and a Usual Care ( UC ) condition that comprised brief individual counseling . METHOD Participants ( N = 412 ) were 48.2 % African American , 41.5 % non-Latino White , 5.4 % Latino , and 4.9 % other , and 57.6 % reported a total annual household income < $ 30,000 . The majority of participants were female ( 54.9 % ) . Mean cigarettes per day was 19.9 ( SD = 10.1 ) . Following the baseline visit , participants were r and omized to UC ( n = 103 ) , CBT ( n = 155 ) , or MBAT ( n = 154 ) . All participants were given self-help material s and nicotine patch therapy . CBT and MBAT groups received 8 2-hr in-person group counseling sessions . UC participants received 4 brief individual counseling sessions . Biochemically verified smoking abstinence was assessed 4 and 26 weeks after the quit date . RESULTS Logistic r and om effects model analyses over time indicated no overall significant treatment effects ( completers only : F(2 , 236 ) = 0.29 , p = .749 ; intent-to-treat : F(2 , 401 ) = 0.9 , p = .407 ) . Among participants classified as smoking at the last treatment session , analyses examining the recovery of abstinence revealed a significant overall treatment effect , F(2 , 103 ) = 4.41 , p = .015 ( MBAT vs. CBT : OR = 4.94 , 95 % CI : 1.47 to 16.59 , p = .010 , Effect Size = .88 ; MBAT vs. UC : OR = 4.18 , 95 % CI : 1.04 to 16.75 , p = .043 , Effect Size = .79 ) . CONCLUSION Although there were no overall significant effects of treatment on abstinence , MBAT may be more effective than CBT or UC in promoting recovery from lapses . ( PsycINFO Data base OBJECTIVES To investigate the effects on serum lipids , plasma fibrinogen , plasma insulin , plasma C-peptide and blood glucose , of smoking cessation after 4 months . To develop a group-based smoking intervention programme in primary health care . SETTING Twenty health centres in primary health care in southern Sweden . SUBJECTS Four hundred habitual smokers ( > 10 cigarettes per day-1 , > 10 years ) , recruited by advertisement in local papers . INTERVENTION The smokers were r and omized , after stratification for age and sex , to one intervention group ( n = 200 ) and one control group ( n = 200 ) . The intervention group was offered supportive group sessions and free nicotine supplementation ( patches , chewing gum ) . MAIN OUTCOME MEASURES All participants were investigated at the start and after 4 months ( medical history , physical examination , laboratory evaluation ) . Blood sample s were drawn for determination of glucose , insulin and C-peptide , both in the fasting state and during an oral glucose tolerance test ( OGTT ) , and for measurement of lipoproteins , fibrinogen , nicotine and cotinine . RESULTS In the intervention group 98 of the subjects ( 48 % ) had quit smoking after 4 months . They were compared with the 156 subjects in the control group ( 91 % ) who were still daily smokers during the whole period . There were no significant differences in any variable between the two ( total ) experimental groups at baseline . Plasma nicotine and cotinine decreased ( P < 0.001 ) in the intervention group following smoking cessation , and weight increased by 2.7 kg . In the intervention group HDL-cholesterol increased by 11 % ( P < 0.001 ) , whereas HbA1c increased by 2 % ( P < 0.05 ) only in the control group . No changes occurred in levels of glucose , insulin , C-peptide and fibrinogen . CONCLUSION The smoking cessation programme had a success rate of almost 50 % over 4 months . Smoking cessation was associated with a marked increase in HDL-cholesterol levels but did not affect glucose tolerance . A concomitant weight increase may have blunted any independent beneficial effect of smoking cessation on glucose metabolism ABSTRACT Background : Tobacco use is higher among homeless individuals than the general population . Homeless individuals are also more likely to have symptoms of depression . Depression symptoms may add to the burden of homelessness by increasing psychological distress and serve as a barrier to quitting smoking . Objectives : The primary goal of this study is to assess the impact of depression symptoms on psychological distress in homeless smokers . The effect of depression symptoms on abstinence and the effect of Motivational Interviewing ( MI ) on cessation among smokers is also explored . Methods : Homeless smokers ( N = 430 ) enrolled in a smoking cessation study were r and omized to Motivational Interviewing ( MI ) or st and ard care ( SC ) . Participants received nicotine replacement therapy and were followed for 26 weeks . Participants were categorized into a depression symptoms ( DS ) group or control group using the Patient Health Question naire-9 . Between group differences of perceived stress , hopelessness , confidence , craving and abstinence were assessed at weeks 8 and 26 . The interaction between depression symptoms ( levels : DS and control ) and the intervention ( levels : MI and SC ) was also assessed . Results : Homeless smokers in the DS group reported higher levels of hopelessness , perceived stress , and craving . There was no effect of DS status on abstinence at week 8 or week 26 . There was no significant interaction between depression symptoms ( DS vs. Control ) and the intervention ( MI vs. SC ) . Conclusion : Despite reporting greater psychological distress , homeless smokers with depression symptoms in this sample had abstinence levels similar to the control group . Future research should explore protective factors among depressed smokers INTRODUCTION Identifying successful smoking treatment interventions and methods of delivery is critical given the smoking rates among HIV-positive population s and the medical implication s of smoking in this population . This study compared the efficacy of 3 smoking cessation interventions provided in HIV clinical treatment setting s. METHODS Following a baseline assessment , 209 HIV-positive smokers were r and omly assigned to 1 of 3 conditions in a parallel group design . Treatment conditions were individual counseling plus nicotine replacement treatment ( NRT ) , a computer-based Internet smoking treatment plus NRT , and self-help plus NRT . Smoking status was determined at follow-up assessment s completed at 12 , 24 , 36 , and 52 weeks following treatment initiation . RESULTS Cessation rates ranged from 15 % to 29 % ; however , no statistically significant differences in abstinence were found among the treatment conditions over time . Those employed , those who reported a greater desire to quit , or those with lower mood disturbance scores were more likely to achieve abstinence ( p < .01 ) . The number of cigarettes participants reported smoking in the 24hr prior to each assessment significantly declined over time ( p < .001 ) . CONCLUSIONS Although we found no differences in abstinence rates across groups , the results indicate that integration of smoking cessation interventions is feasible in HIV clinical treatment setting s , and cessation results are promising . The overall abstinence rates we report are comparable to those found in similar treatment studies across multiple population s. Further research is warranted AIM The study aim ed to test simultaneously our underst and ing of the effects of bupropion sustained-release ( SR ) treatment on putative mediators and our underst and ing of determinants of post-quit abstinence , including withdrawal distress , cigarette craving , positive affect and subjective reactions to cigarettes smoked during a lapse . The specificity of bupropion SR effects was also tested in exploratory analyses . DESIGN Data from a r and omized , placebo-controlled clinical trial of bupropion SR were su bmi tted to mediation analyses . SETTING Center for Tobacco Research and Intervention , Madison , WI , USA . PARTICIPANTS A total of 403 adult , daily smokers without contraindications to bupropion SR use . INTERVENTION Participants were assigned r and omly to receive a 9-week course of bupropion SR or placebo pill and to receive eight brief individual counseling sessions or no counseling . MEASUREMENTS Ecological momentary assessment ratings of smoking behavior and putative mediators were collected pre- and post-quit . FINDINGS Results of structural equation and hierarchical linear models did not support the hypothesis that bupropion SR treatment improves short-term abstinence by reducing withdrawal distress or affecting the subjective effects of a lapse cigarette , but provided partial support for mediation by cigarette craving reduction and enhanced positive affect . Bupropion SR effects on point-prevalence abstinence at 1 month post-quit were also mediated partially by enhanced motivation to quit and self-efficacy . CONCLUSIONS Results provided some support for models of bupropion SR treatment and relapse and suggested that motivational processes may partially account for bupropion SR efficacy Quitlines are successful tools for smoking cessation , but no known study has examined whether type of phone service ( cell phone only ( CPO ) vs. l and line ( LL ) ) impacts quitline utilization , quit attempts , and sustained cessation . This report details an observational study examining the association between phone service and quitline utilization and cessation among Ohio Appalachian adults willing to quit smoking and enrolled in a cessation trial from 2010 to 2014 . A secondary analysis was conducted with data obtained from smokers enrolled in the Ohio Tobacco Quitline arm of a group r and omized trial ( n = 345 ) . The intermediate outcome variables included number of calls , cumulative total call length , average call length , verified shipments of NRT , and 24-hour quit attempt . The primary outcome measure was biologically confirmed 7-day point prevalence abstinence from tobacco at 3 , 6 , and 12 months post treatment . Participants with LL service , on average , made almost one more call to the quitline and spoke 17.2 min longer over the course of treatment than those with CPO service . Those with LL service were more likely to receive a second 4-week supply of NRT . Phone service status was not associated with average quitline call length , receiving at least one NRT shipment , having made one quit attempt at the end of treatment , or biochemically confirmed abstinence at 3 , 6 , or 12-month follow-up . Participants with LL services completed more counseling calls , accrued a longer cumulative length , and received more NRT when compared with CPO service participants . However , type of phone service did not deter abstinence outcomes Sustained-release bupropion and nortriptyline have been shown to be effcacious in treating cigarette smoking . Psychological intervention is also recognized as efficacious . The cost and cost-effectiveness of the 2 drug therapies have not been estimated . It was hypothesized that nortriptyline would be more cost-effective than bupropion . Hypotheses were not originally proposed concerning the cost-effectiveness of psychological versus drug treatment , but the 2 were compared using exploratory analyses . This was a 3 ( bupropion versus nortriptyline versus placebo ) by 2 ( medical management alone versus medical management plus psychological intervention ) r and omized trial . Participants were 220 cigarette smokers . Outcome measures were cost and cost-effectiveness computed at week 52 . Nortriptyline cost less than bupropion . Nortriptyline was more cost-effective than bupropion ; the difference was not statistically significant . Psychological intervention cost less than the 2 drug treatments , and was more cost-effective , but not significantly so . Prospect i ve investigations of the cost and cost-effectiveness of psychological and pharmacological intervention , using adequate sample sizes , are warranted BACKGROUND Sustained-release bupropion hydrochloride and nortriptyline hydrochloride have been shown to be efficacious in the treatment of cigarette smoking . It is not known whether psychological intervention increases the efficacy of these antidepressants . This study compared both drugs with placebo . It also examined the efficacy of these 2 drugs and placebo with and without psychological intervention . METHODS This was a 2 ( medical management vs psychological intervention ) x 3 ( bupropion vs nortriptyline vs placebo ) r and omized trial . Participants were 220 cigarette smokers . Outcome measures were biologically verified abstinence from cigarettes at weeks 12 , 24 , 36 , and 52 . RESULTS Psychological intervention produced higher 7-day point-prevalence rates of biochemically verified abstinence than did medical management alone . With the use of point-prevalence abstinence , both nortriptyline and bupropion were more efficacious than placebo . On rates of 1-year continuous abstinence , the 2 drugs did not differ from each other or from placebo . Psychological intervention did not differ from medical management alone on rates of 1-year continuous abstinence . CONCLUSIONS Both nortriptyline and bupropion are efficacious in producing abstinence in cigarette smokers . Similarly , psychological intervention produces better abstinence rates than simple medical management . Both drugs , and psychological intervention , have limited efficacy in producing sustained abstinence . The data also suggest that combined psychological intervention and antidepressant drug treatment may not be more effective than antidepressant drug treatment alone Background Smoking cessation following hospitalization for Acute Coronary Syndrome ( ACS ) significantly reduces subsequent mortality . Depressed mood is a major barrier to cessation post-ACS . Although existing counseling treatments address smoking and depression independently in ACS patients , no integrated treatment addresses both . We developed an integrated treatment combining gold st and ard cessation counseling with behavioral activation-based mood management ; Behavioral Activation Treatment for Cardiac Smokers ( BAT-CS ) . The purpose of this pilot r and omized controlled trial was to test feasibility , acceptability , and preliminary efficacy of BAT-CS vs. St and ard of Care ( SC ) . Methods Participants were recruited during hospitalization for ACS and were r and omly assigned to BAT-CS or SC . The nicotine patch was offered in both conditions . Smoking , mood , and stress outcomes were collected at end-of-treatment and 24-week follow-up . Results Fifty-nine participants ( 28 BAT-CS , 31 SC ) were recruited over 42 weeks , and assessment completion was above 80 % in both conditions . Treatment acceptability and fidelity were high . At 24 week follow-up adjusted odds ratios favoring BAT-CS were 1.27 ( 95 % CI : 0.41–3.93 ) for 7-day point prevalence abstinence and 1.27 ( 95 % CI : 0.42–3.82 ) for continuous abstinence . Time to first smoking lapse was significantly longer in BAT-CS ( 62.4 vs. 31.8 days , p = 0.03 ) . At 24-weeks , effect sizes for mood and stress outcomes ranged from η2partial of.07–.11 , with significant between treatment effects for positive affect , negative affect , and stress . Conclusions The design of this study proved feasible and acceptable . Results provide preliminary evidence that combining behavioral activation with st and ard smoking cessation counseling could be efficacious for this high risk population . A larger trial with longer follow-up is warranted . Trial registration NCT01964898 . First received by clinical trials.gov October 15 , 2013 Background : More than half of the persons living with human immunodeficiency virus ( HIV ; PLWH ) in the US smoke cigarettes , and tobacco use is responsible for considerable morbidity and mortality in this group . Little is known about the efficacy of tobacco treatment strategies in PLWH . Design : R and omized controlled trial comparing Positively Smoke Free ( PSF ) , an intensive group-therapy intervention targeting HIV-infected smokers , to st and ard care . Methods : A cohort of 145 PLWH smokers , recruited from an HIV-care center in the Bronx , New York , were r and omized 1:1 into the PSF program or st and ard care . All were offered a 3-month supply of nicotine replacement therapy . PSF is an 8-session program tailored to address the needs and concerns of HIV-infected smokers . The sessions were cofacilitated by a graduate student and an HIV-infected peer . The primary outcome was biochemically confirmed , 7-day point-prevalence abstinence at 3 months . Results : In the intention-to-treat analysis , PSF condition subjects had nearly double the quit rate of controls ( 19.2 % vs. 9.7 % , P = 0.11 ) . In the complete case , as-treated analysis , assignment to PSF was associated with increased odds of quitting ( odds ratioadj 3.55 , 95 % confidence interval 1.04 to 12.0 ) . Latino ethnicity and lower loneliness score were predictive of abstinence . The subjects in the PSF condition exhibited significant decreases in daily cigarette consumption and significant increases in self-efficacy and in motivation to quit . Attendance of ≥7 sessions was associated with higher quit rates . Conclusions : These findings suggest a positive effect of PSF on cessation rates in PLWH smokers . Loneliness and self-efficacy are influential factors in the smoking behaviors of PLWH INTRODUCTION Varenicline , a first-line non-nicotine medication , has not been evaluated in Black smokers , and limited attention has been paid to pharmacotherapy adherence in smoking cessation trials . This pilot study estimated quit rates for Black smokers treated with varenicline and tested a behavioral intervention to aid varenicline adherence . METHODS Seventy-two Black smokers ( > 10 cigarettes per day ; cpd ) were r and omly assigned to adherence support ( AS ; n = 36 ) or st and ard care ( n = 36 ) . All participants received 3 months of varenicline and a single counseling session focused on making a quit plan . AS participants received 5 additional counseling sessions to encourage medication use . Outcome measures included salivary cotinine , and carbon monoxide confirmed smoking abstinence , reductions in self-reported cpd , and pill counts of varenicline adherence at Months 1 , 2 , and 3 . RESULTS Sixty-one participants ( 84.7 % ) completed follow-up at Month 3 . Participants were female ( 62.5 % ) , 46.8 years of age , and smoked 16.3 cpd . No treatment group differences were found on the smoking or adherence outcome measures ( p > .05 ) . Collapsing across treatment , varenicline adherence was adequate ( 86.1 % ) , yet despite a reduction of 12.2 ( 6.5 ) cpd from baseline to Month 3 ( p < 0.001 ) , only 23.6 % were confirmed quit at Month 3 . Participants who were quit at Month 3 had higher varenicline adherence rates ( 95.8 % ) than those who continued to smoke ( 80.8 % , p ≤ .05 ) . CONCLUSIONS Studies are needed to examine the efficacy of varenicline among Black smokers . Interventions to facilitate adherence to pharmacotherapy warrant further attention as adherence is linked to improved tobacco abstinence OBJECTIVE We conducted a pilot r and omized trial of telephone-delivered acceptance and commitment therapy ( ACT ) versus cognitive behavioral therapy ( CBT ) for smoking cessation . METHOD Participants were 121 uninsured South Carolina State Quitline callers who were adult smokers ( at least 10 cigarettes/day ) and who wanted to quit within the next 30 days . Participants were r and omized to 5 sessions of either ACT or CBT telephone counseling and were offered 2 weeks of nicotine replacement therapy ( NRT ) . RESULTS ACT participants completed more calls than CBT participants ( M = 3.25 in ACT vs. 2.23 in CBT ; p = .001 ) . Regarding satisfaction , 100 % of ACT participants reported their treatment was useful for quitting smoking ( vs. 87 % for CBT ; p = .03 ) , and 97 % of ACT participants would recommend their treatment to a friend ( vs. 83 % for CBT ; p = .06 ) . On the primary outcome of intent-to-treat 30-day point prevalence abstinence at 6 months postr and omization , the quit rates were 31 % in ACT versus 22 % in CBT ( odds ratio [ OR ] = 1.5 , 95 % confidence interval [ CI ] = 0.7 - 3.4 ) . Among participants depressed at baseline ( n = 47 ) , the quit rates were 33 % in ACT versus 13 % in CBT ( OR = 1.2 , 95 % CI = 1.0 - 1.6 ) . Consistent with ACT 's theory , among participants scoring low on acceptance of cravings at baseline ( n = 57 ) , the quit rates were 37 % in ACT versus 10 % in CBT ( OR = 5.3 , 95 % CI = 1.3 - 22.0 ) . CONCLUSIONS ACT is feasible to deliver by phone , is highly acceptable to quitline callers , and shows highly promising quit rates compared with st and ard CBT quitline counseling . As results were limited by the pilot design ( e.g. , small sample ) , a full-scale efficacy trial is now needed BACKGROUND This study tested the impact of free nicotine patches plus proactive telephone peer support to help low-income women stop smoking . METHODS A total of 214 Medicaid-eligible women smokers of childbearing age were r and omized to receive free nicotine patches through the mail or free nicotine patches through the mail plus the provision of proactive support by telephone from a woman ex-smoker for up to 3 months . Assessment s were conducted by telephone at baseline , 10 days , and 3 and 6 months after enrollment . RESULTS At the 3-month follow-up , significantly more women in the patch plus proactive telephone support condition were abstinent ( 42 % ) compared to the patch only condition ( 28 % ) ( P = 0.03 ) . Similarly , more women in the experimental condition were abstinent at both the 10-day and 3-month assessment s ( 32 v 19 % , P = 0.02 ) . However , differences were not found at the 6-month follow-up , suggesting that the addition of proactive telephone peer support enhanced short-term , but not long-term cessation . CONCLUSIONS This is the first study to demonstrate a beneficial effect for the addition of proactive telephone support as an adjunct to free nicotine replacement in a low-income population Background Telephone quit lines are accessible to many smokers and are used to engage motivated smokers to make quit attempts . Smoking cessation counselling provided via telephone can either be reactive ( i.e. primarily involving the provision of evidence -based information ) , or proactive ( i.e. primarily involving repeated , sequenced calls from and interaction with trained cessation counsellors ) . Some studies have found proactive telephone counselling more effective and this trial will investigate whether or not proactive telephone support for smoking cessation , delivered through the National Health Service ( NHS ) Smoking Helpline is more effective or cost-effective than reactive support . It will also investigate whether or not providing nicotine replacement therapy ( NRT ) , in addition to telephone counselling , has an adjunctive impact on smoking cessation rates and whether or not this is cost effective . Methods This will be a parallel group , factorial design RCT , conducted through the English national NHS Smoking Helpline which is run from headquarters in Glasgow . Participants will be smokers who call the helpline from any location in Engl and and who wish to stop smoking . If 644 participants are recruited to four equally-sized trial groups ( total sample size = 2576 ) , the trial will have 90 % power for detecting a treatment effect ( Odds Ratio ) of 1.5 for each of the two interventions : i ) proactive versus reactive support and ii ) the offer of NRT versus no offer . The primary outcome measure for the study is self-reported , prolonged abstinence from smoking for at least six months following an agreed quit date . A concurrent health economic evaluation will investigate the cost effectiveness of the two interventions when delivered via a telephone helpline . Discussion The PORTSSS trial will provide high quality evidence to determine the most appropriate kind of counselling which should be provided via the NHS Smoking Helpline and also whether or not an additional offer of cost-free NRT is effective and cost effective for smoking cessation . Trial Registration ( clinical trials.gov ) : Objective : People living with psychotic disorders ( schizophrenia spectrum and bipolar disorders ) have high rates of cardiovascular disease risk behaviours , including smoking , physical inactivity and poor diet . We report cardiovascular disease risk , smoking cessation and other risk behaviour outcomes over 36 months following recruitment into a two-arm r and omised controlled trial among smokers with psychotic disorders . Methods : Participants ( N = 235 ) drawn from three sites were r and omised to receive nicotine replacement therapy plus ( 1 ) a Healthy Lifestyles intervention delivered over approximately 9 months or ( 2 ) a largely telephone-delivered intervention ( design ed to control for nicotine replacement therapy provision , session frequency and other monitoring ) . The primary outcome variables were 10-year cardiovascular disease risk and smoking status , while the secondary outcomes included weekly physical activity , unhealthy eating , waist circumference , psychiatric symptomatology , depression and global functioning . Results : Significant reductions in cardiovascular disease risk and smoking were detected across the 36-month follow-up period in both intervention conditions , with no significant differences between conditions . One-quarter ( 25.5 % ) of participants reported reducing cigarettes per day by 50 % or more at multiple post-treatment assessment s ; however , few ( 8.9 % ) managed to sustain this across the majority of time points . Changes in other health behaviours or lifestyle factors were modest ; however , significant improvements in depression and global functioning were detected over time in both conditions . Participants experiencing worse ‘ social discomfort ’ at baseline ( e.g. anxiety , mania , poor self-esteem and social disability ) had on average significantly worse global functioning , lower scores on the 12-Item Short Form Health Survey physical scale and significantly greater waist circumference . Conclusion : Although the telephone-delivered intervention was design ed as a comparison condition , it achieved excellent retention and comparable outcomes . Telephone-delivered smoking cessation support may potentially help to reduce smoking rates among people with psychotic disorders . Discomfort in social situations may also be a useful target for future health interventions , addressing confidence and social skills , and promoting social networks that reduce inactivity Background : Previously , we have linked theoretically based cognitive and emotional variables to the ability of cancer patients to quit smoking . Purpose : In this study , we evaluated the impact of cognitive-behavioral therapy ( CBT ) , which addressed these theoretically derived cognitive and emotional variables linked to tobacco use in this population , for promoting smoking cessation in a sample of cancer patients and assessed longitudinal predictors of smoking cessation . Methods : Cancer patients ( N=109 ) were r and omized to either the theoretically based CBT intervention or to a general health education ( GHE ) condition , and all patients received nicotine replacement therapy . Results : Contrary to our expectation , no significant difference in 30-day point-prevalence abstinence between the CBT and GHE conditions was detected at either a 1-month ( 44.9 % vs. 47.3 % , respectively ) or 3-month ( 43.2 % vs. 39.2 % , respectively ) follow-up evaluation . Higher quit motivation and lower cons of quitting were related to smoking cessation . Conclusions : Implication s for the implementation of smoking cessation behavioral treatments in the oncologic context are discussed , as are directions for future research in this area Background Exercise has been proposed as a useful smoking cessation aid . Purpose The purpose of the present study is to determine the effect of an exercise-aided smoking cessation intervention program , with built-in maintenance components , on post-intervention 14- , 26- and 56-week cessation rates . Method Female cigarette smokers ( n = 413 ) participating in a supervised exercise and nicotine replacement therapy ( NRT ) smoking cessation program were r and omized to one of four conditions : exercise + smoking cessation maintenance , exercise maintenance + contact control , smoking cessation maintenance + contact control or contact control . The primary outcome was continuous smoking abstinence . Results Abstinence differences were found between the exercise and equal contact non-exercise maintenance groups at weeks 14 ( 57 vs 43 % ) , 26 ( 27 vs 21 % ) and 56 ( 26 vs 23.5 % ) , respectively . Only the week 14 difference approached significance , p = 0.08 . Conclusions An exercise-aided NRT smoking cessation program with built-in maintenance components enhances post-intervention cessation rates at week 14 but not at weeks 26 and 56 Introduction Varenicline reduces smoking satisfaction during the pre-cessation run-in period , which may contribute to extinction of cravings and smoking behavior . Research indicates that efficacy is enhanced when the run-in period is increased from 1 to 4 weeks , providing a longer extinction opportunity . We hypothesized that efficacy could be further enhanced by harnessing basic and applied research on extinction . We developed a pre-cessation extinction-facilitating intervention and tested its feasibility in a pilot trial . Methods The facilitated extinction ( FE ) intervention comprised brief counseling and workbook-recommending strategies to maximize extinction processes during the run-in , including instructions to smoke at a normal rate across context s and cues , and use of an extinction cue to enhance generalization . Participants were r and omly assigned to one of three varenicline interventions : st and ard ( 1-week run-in ) , extended ( 4-week run-in ) , and extended + FE . Interventions were delivered prior to the target quit date ( TQD ) . Assessment s were conducted in weeks 1 and 4 pre-TQD and 1 and 3 months post-TQD , with focus on feasibility indices . Results Recruitment and retention goals were met ( N = 58 ) . Treatment satisfaction was high across groups . The majority of FE participants adhered to instructions and maintained their usual smoking rate during the run-in period . Greater decreases in craving and smoking satisfaction were observed among participants in both extended groups versus the st and ard group ( p < .005 ) . Conclusions Feasibility was demonstrated . Participants adhered to the FE intervention , thereby optimizing the number and variety of extinction trials . Findings support testing the novel FE smoking cessation intervention in a fully powered trial . Implication s This study exp and s the research on the clinical benefits of extending the pre-cessation run-in period of varenicline . It introduces the hypothesis that further benefit might be achieved by translating basic behavioral research , as well as cue-exposure research and therapy for other disorders , to improve the extinction and generalization processes thought to underlie much of varenicline 's effect . A FE intervention was developed and found acceptable to smokers and feasible to implement in a research setting . The study sets the stage for a subsequent r and omized controlled trial Introduction This study tested the efficacy of group-based culturally specific cognitive behavioral therapy ( CBT ) for smoking cessation among low-income African Americans . Methods Participants ( N = 342 ; 63.8 % male ; M = 49.5 years old ; M cigarettes per day = 18 ) were r and omly assigned to eight sessions of group-based culturally specific or st and ard CBT , plus 8 weeks of transdermal nicotine patches . Biochemically verified 7-day point prevalence abstinence ( ppa ) was assessed at the end-of-therapy ( ie , CBT ) ( EOT ) , and 3- , 6- , and 12-month follow-ups . Primary outcomes were the longitudinal intervention effect over the 12-month follow-up period , and 7-day ppa at the 6-month follow-up . Secondary outcomes included 7-day ppa at the EOT and 12-month follow-up , and intervention ratings . Generalized linear mixed modeling tested the longitudinal effect and logistic regression tested effects at specific timepoints . Results Generalized linear mixed modeling demonstrated a longitudinal effect of intervention condition . Specifically , 7-day ppa was two times ( P = .02 ) greater following culturally specific CBT versus st and ard CBT when tested across all timepoints . Analyses by timepoint found no significant difference at 6 or 12 months , yet culturally specific CBT was efficacious at the EOT ( 62.5 % vs. 51.5 % abstinence , P = .05 ) and the 3-month follow-up ( 36.4 % vs. 22.9 % abstinence , P = .007 ) . Finally , intervention ratings in both conditions were high , with no significant differences . Conclusions Culturally specific CBT had a positive longitudinal effect on smoking cessation compared to a st and ard approach ; however , the effects were driven by short-term successes . We recommend the use of group-based culturally specific CBT in this population when possible , and future research on methods to prevent long-term relapse . Implication s Culturally specific interventions are one approach to address smoking-related health disparities ; however , evidence for their efficacy in African Americans is equivocal . Moreover , the method ological limitations of the existing literature preclude an answer to this fundamental question . We found a positive longitudinal effect of culturally specific CBT versus st and ard CBT for smoking cessation across the follow-up period . Analyses by assessment point revealed that the overall effect was driven by early successes . Best practice s for treating tobacco use in this population should attend to ethnocultural factors , but when this is not possible , st and ard CBT is an alternative approach for facilitating long-term abstinence Abstract Quitting smoking and aerobic exercise each improve health . Although smokers may be concerned that quitting smoking will reduce their quality of life ( QOL ) , recent research has shown that cessation is associated with QOL benefits . Elements of smoking cessation interventions , such as exercise , may contribute to changes in QOL . However , it is unknown whether initiating exercise in the context of smoking cessation is associated with greater or different effects on QOL than smoking cessation alone . The current study is a secondary analysis of data from a r and omized trial ( n = 61 ) of an exercise intervention for smoking cessation . We hypothesized that smoking abstinence and engagement in exercise would have positive , additive effects on QOL at end-of-treatment , 6- and , 12-month follow-ups . Sedentary adult smokers were r and omized to the exercise intervention or a health education control ( HEC ) group . Additionally , all participants received smoking cessation counseling and nicotine patches . Data were analyzed using actual engagement in exercise , rather than group assignment as a proxy for exercise engagement , because some HEC participants also began exercising . Abstinence was positively associated with higher total and physical health QOL at follow-up . Exercise was not associated with total QOL and only marginally associated with physical health QOL , but was positively related to overall sense of well-being . Emphasizing that smoking cessation is associated with higher QOL may help motivate smokers to initiate quit attempts Construction workers have the highest smoking rate among all occupations ( 39 % ) . Hispanic/Latino workers constitute a large and increasing group in the US construction industry ( over 2.6 million ; 23 % of all workers ) . These minority workers have lower cessation rates compared to other groups due to their limited access to cessation services , and lack of smoking cessation interventions adapted to their culture and work/life circumstances . Formative research was conducted to create an intervention targeting Hispanic/Latino construction workers . This paper describes the intervention development and the design , methods , and data analysis plans for an ongoing cluster pilot two-arm r and omized controlled trial comparing an Enhanced Care worksite cessation program to St and ard Care . Fourteen construction sites will be r and omized to either Enhanced Care or St and ard Care and 126 participants ( 63/arm ) will be recruited . In both arms , recruitment and intervention delivery occur around " food trucks " that regularly visit the construction sites . Participants at Enhanced Care sites will receive the developed intervention consisting of a single face-to-face group counseling session , 2 phone calls , and a fax referral to Florida tobacco quitline ( QL ) . Participants at St and ard Care sites will receive a fax referral to the QL . Both groups will receive eight weeks of nicotine replacement treatment and two follow-up assessment s at three and six months . Feasibility outcomes are estimated recruitment yield , barriers to delivering the intervention onsite , and rates of adherence/compliance to the intervention , follow-ups , and QL enrollment . Efficacy outcomes are point-prevalence and prolonged abstinence rates at six month follow-up confirmed by saliva cotinine < 15 ng/ml Smoking disproportionally affects minority and underserved population s but only a h and ful of interventions tailored to these population s have demonstrated effectiveness in real-life situations . We use community-based participatory research ( CBPR ) to test two interventions delivered by a community-based health care center . Methods . Participants r and omly assigned to individual or group-based intervention for smoking cessation ( N= 400 ) . Both included cessation counseling and health education , a contingency behavioral program , Nicotine Replacement Therapy , and health care for other comorbidities . Smoking cessation was verified by expired carbon monoxide at the end of the program . Results . No differences were observed between the two treatment modalities ( 8.9 % and 8.6 % , respectively ) . Those with greater attendance had 1.4 times better odds of cessation per additional session . Retention and follow up proved to be challenging with this population Racial/ethnic disparities in tobacco cessation are such that U.S. minorities have greater difficulty quitting compared to White non-Hispanics . Group differences in distress ( i.e. , perceived stress and depressive symptoms ) may contribute to cessation disparities . The allostasis model of health suggests that the toll of chronic stress experienced by racial/ethnic minorities may lead to dysregulation of the physiological stress system and drug use . Previous research suggests that group cognitive behavioral therapy ( CBT ) for tobacco cessation addresses distress as a modifiable mechanism and has the potential to reduce/eliminate disparities . The present study is a dualsite r and omized controlled trial aim ed at evaluating the efficacy of group CBT in eliminating racial/ethnic differences in smoking cessation and distress . The study utilizes a [ 2 ( intervention : group CBT or group general health education [ GHE ] ) × 3 ( race/ethnicity : African American/Black , Hispanic , White ) ] factorial design by r and omizing 225 adult smokers from the community . Both interventions provide eight counseling sessions and eight weeks of nicotine patch therapy . Assessment s occur at the end-of-therapy , and at 3- , 6- , and 12-months . Generalized longitudinal mixed modeling will be used to test our primary abstinence outcome , biochemically-confirmed 7-day point prevalence abstinence at 12-months . We hypothesize that group CBT will reduce or eliminate racial/ethnic differences in perceived stress , depressive symptoms , and smoking cessation compared to group GHE . We also hypothesize that reductions in physiological distress , assessed by salivary cortisol , will mediate racial/ethnic group differences in smoking cessation , particularly among racial/ethnic minorities . This study has implication s for eliminating disparities in psychosocial factors related to tobacco use and cessation . TRIAL REGISTRATION Clinical trials.govNCT02511236 . Registered on July 27 , 2015 Smoking cessation programs are efficacious and have been vali date d to assist the 10 % to 30 % of smokers who are ready to quit in the next 30 days . While the majority of smokers want to quit smoking in the future , only 69 % are planning to quit within the next year . Planning a Change Easily ( PACE ) is a nation-wide , telephone-based comparative effectiveness , r and omized controlled trial for smokers not ready to quit ( SNRTQ ) . This project , as well as its intervention components , outcomes , and hypotheses are discussed . This study will compare the effectiveness of four intervention conditions that could potentially help SNRTQ to quit smoking : Brief Advice , Motivational Interviewing , Rate Reduction , and Motivational Interviewing plus Rate Reduction combined . Rate Reduction conditions will include the provision of nicotine replacement therapy in the form of gum . Approximately 840 participants will be recruited and r and omized to the four intervention conditions . The main outcomes for this study include self-report prolonged and point prevalence abstinence with biochemical verification of cessation . Secondary outcomes include quit attempts , cost-per-quit , and cost-effectiveness analyses . Informed by evidence d-based interventions , strong clinical guidelines , and economic analysis , PACE has the potential for significant public health impact . Results could readily be disseminated and translated to tobacco quitlines , which are present in all 50 states and are offered free to the public Introduction Community health workers ( CHW ) may be effective in the delivery of tobacco dependence treatment with underserved groups . This study evaluated two evidence -based CHW models of treatment . It was hypothesized that smokers assigned to a CHW face-to-face condition would have higher abstinence at 12-month posttreatment than smokers enrolled in CHW referral to a state-sponsored quitline condition . Intrapersonal and treatment-related factors associated with abstinence at 12 months were determined . Methods A group-r and omized trial was conducted with residents of 12 Ohio Appalachian counties with counties ( n = 6 ) r and omized to either a CHW face-to-face ( F2F ) or CHW quitline ( QL ) condition . Both conditions included behavioral counseling and free nicotine replacement therapy for 8 weeks . Follow-up data were collected at 3- , 6- , and 12-month posttreatment . Biochemically vali date d abstinence at 12 months served as the primary outcome . Results Seven hundred and seven participants were enrolled ( n = 353 CHWF2F ; n = 354 CHWQL ) . Baseline sample characteristics did not differ by condition . Using an intent-to-treat analysis ( 85.4 % retention at 12 months ) , 13.3 % of CHWF2F participants were abstinent at 12 months , compared to 10.7 % of CHWQL members ( OR = 1.28 ; 95 % confidence interval [ CI ] = 0.810 , 2.014 ; p = .292 ) . No differences in abstinence were noted at 3 or 6 months by condition . Age , marital status , and baseline levels of cigarette consumption , depressive symptoms , and self-efficacy for quitting in positive setting s were associated with abstinence , as was counseling dose during treatment . Conclusions This research adds to the body of science evaluating the effectiveness of CHW models of tobacco dependence treatment . Both approaches may offer promise in low-re source setting s and underserved regions . Implication s This 12-county community-based group-r and omized trial in Ohio Appalachia adds to the body of science evaluating the effectiveness of CHW models of tobacco dependence treatment . Both CHW approaches may offer promise in low-re source setting s and underserved regions . These findings are useful to national , state , and local tobacco control agencies , as they exp and delivery of preventive health care services postadoption of the Affordable Care Act in the United States This study is a r and omized , double-blind , placebo-controlled clinical trial examining the effects of an intensive cognitive-behavioral mood management treatment ( CBTD ) and of bupropion , both singularly and in combination , on smoking cessation in adult smokers . As an extension of our previous work , we planned to examine the synergistic effects of CBTD and bupropion on smoking cessation outcomes in general and among smokers with depression vulnerability factors . Participants were 524 smokers ( 47.5 % female , M ( age ) = 44.27 years ) who were r and omized to one of four 12-week treatments : ( a ) st and ard , cognitive-behavioral smoking cessation treatment ( ST ) plus bupropion ( BUP ) , ( b ) ST plus placebo ( PLAC ) , ( c ) st and ard cessation treatment combined with cognitive-behavioral treatment for depression ( CBTD ) plus BUP , and ( d ) CBTD plus PLAC . Follow-up assessment s were conducted 2 , 6 , and 12 months after treatment , and self-reported abstinence was verified biochemically . Consistent with previous studies , bupropion , in comparison with placebo , result ed in better smoking outcomes in both intensive group treatments . Adding CBTD to st and ard intensive group treatment did not result in improved smoking cessation outcomes . In addition , neither CBTD nor bupropion , either alone or in combination , was differentially effective for smokers with single-past-episode major depressive disorder ( MDD ) , recurrent MDD , or elevated depressive symptoms . However , findings with regard to recurrent MDD and elevated depressive symptoms should be interpreted with caution given the low rate of recurrent MDD and the low level of depressive symptoms in our sample . An a priori test of treatment effects in smokers with these depression vulnerability factors is warranted in future clinical trials OBJECTIVES There remains a need to identify effective smoking cessation interventions in severely disadvantaged population s. This trial aim ed to examine the effectiveness of an intervention ( Call it Quits ) developed to promote smoking cessation and delivered by community social service case-workers . METHODS Call it Quits was a pragmatic , parallel r and omised trial of a case-worker delivered smoking cessation intervention conducted in a non-government community social service organisation in New South Wales ( NSW ) , Australia . Adult smokers requiring financial assistance were r and omly assigned to the five-session Call it Quits intervention or usual care control group . Of the 618 eligible individuals , 300 were r and omised to the intervention group , of whom 187 ( 62 % ) consented and 318 were r and omised to the control group , of whom 244 ( 77 % ) consented , result ing in 431 participants . The primary outcome measure was self-reported continuous abstinence up to 6-month follow-up with biochemical verification . Primary analysis was performed using all the available data from participants under the assumption the data is missing completely at r and om , followed by sensitivity analyses . RESULTS No statistically significant differences in the primary outcome were found ( 1.4 % in the control group versus 1.0 % in the intervention group , OR = 0.77 , p = 0.828 ) . CONCLUSIONS A multi-component smoking cessation intervention delivering motivational interviewing-based counselling and free NRT by a trained case-worker within a community social service setting was not effective at achieving abstinence in a highly disadvantaged sample of smokers but increased attempts to stop and led to a reduction in number of cigarettes smoked daily INTRODUCTION Individuals in the U.S. criminal justice system now represent over 12 % of all current U.S. smokers . With smoking banned in most U.S. jails and prisons , the cessation focus for this population has shifted to individuals who are under community correction supervision ( e.g. , probation , parole ) . The aim of this study was to examine predictors of successful smoking cessation among criminal justice individuals supervised in the community . METHODS Five hundred participants under community corrections supervision were r and omized to receive either four sessions of smoking cessation counseling or no counseling in conjunction with 12weeks of bupropion treatment plus brief physician advice to quit . Logistic regression analyses examined associations of smoking variables with medication adherence and successful abstinence . Mediation analysis evaluated the indirect effects of medication adherence on smoking abstinence . RESULTS The strongest associate of medication adherence was previous use of bupropion , while the strongest associate of smoking abstinence was medication adherence . Mediation analysis indicated that previous use of bupropion indirectly increased cessation rates through the pathway of increased medication adherence . CONCLUSIONS These results highlight the importance of medication adherence for smoking cessation among community corrections smokers . Providing exposure to medication may be a promising intervention to increase medication adherence and subsequent cessation rates in this population Background This study will test the uptake and effectiveness of a flexible package of smoking cessation support provided primarily by the practice nurse ( PN ) and tailored to meet the needs of a diversity of patients . Methods / Design This study is a cluster r and omised trial , with practice s allocated to one of three groups 1 ) Quit with Practice Nurse 2 ) Quitline referral 3 ) GP usual care . PNs from practice s r and omised to the intervention group will receive a training course in smoking cessation followed by access to mentoring . GPs from practice s r and omised to the Quitline referral group will receive information about the study and the process of written referral and GPs in the usual care group will receive information about the study . Eligible patients are those aged 18 and over presenting to their GP who are daily or weekly smokers and who are able to give informed consent . Patients on low incomes in all three groups will be able to access free nicotine patches . Primary outcomes are sustained abstinence and point prevalence abstinence at the three month and 12 month follow-up points ; and incremental cost effectiveness ratios at 12 months . Process evaluation on the reach and acceptability of the intervention approached will be collected through Computer Assisted Telephone Interviews ( CATI ) with patients and semi-structured interviews with PNs and GPs . The primary analysis will be by intention to treat . Cessation outcomes will be compared between the three arms at three months and 12 month follow-up using multiple logistic regression . The incremental cost effectiveness ratios will be estimated for the 12 month quit rate for the intervention groups compared to usual care and to each other . Analysis of qualitative data on process outcomes will be based on thematic analysis . Discussion High quality evidence on effectiveness of practice nurse interventions is needed to inform health policy on development of practice nurse roles . If effective , flexible support from the PN in partnership with the GP and the Quitline could become the preferred model for providing smoking cessation advice in Australian general practice .Trial Registration Background Tobacco use remains prevalent among Veterans of military service and those residing in rural areas . Smokers frequently experience tobacco-related issues including risky alcohol use , post-cessation weight gain , and depressive symptoms that may adversely impact their likelihood of quitting and maintaining abstinence . Telephone-based interventions that simultaneously address these issues may help to increase treatment access and improve outcomes . Methods This study was a two-group r and omized controlled pilot trial . Participants were r and omly assigned to an individually-tailored telephone tobacco intervention combining counseling for tobacco use and related issues including depressive symptoms , risky alcohol use , and weight concerns or to treatment provided through their state tobacco quitline . Selection of pharmacotherapy was based on medical history and a shared decision interview in both groups . Participants included 63 rural Veteran smokers ( mean age = 56.8 years ; 87 % male ; mean number of cigarettes/day = 24.7 ) . The primary outcome was self-reported 7-day point prevalence abstinence at 12 weeks and 6 months . Results Twelve-week quit rates based on an intention-to-treat analysis did not differ significantly by group ( Tailored = 39 % ; Quitline Referral = 25 % ; odds ratio [ OR ] ; 95 % confidence interval [ CI ] = 1.90 ; 0.56 , 5.57 ) . Six-month quit rates for the Tailored and Quitline Referral conditions were 29 and 28 % , respectively ( OR ; 95 % CI = 1.05 ; 0.35 , 3.12 ) . Satisfaction with the Tailored tobacco intervention was high . Conclusions Telephone-based treatment that concomitantly addresses other health-related factors that may adversely affect quitting appears to be a promising strategy . Larger studies are needed to determine whether this approach improves cessation outcomes .Trial registration Clinical Trials.gov identifier number NCT01592695 registered 11 April 2012 Nearly , one-fifth of childhood cancer survivors ( CCSs ) smoke cigarettes . Because CCSs are already at greater medical smoking-related risks , targeting them for smoking cessation efforts is a high priority . One of the major challenges with smoking cessation in CCSs is how to reach such a geographically dispersed population . This study aims to demonstrate that these challenges can be overcome through the use of telephone-based tobacco quit lines ( QLs ) . This report describes the design of the St. Jude Cancer Survivor Tobacco QL study , which is a r and omized controlled clinical trial that will examine the long-term ( 1-year ) efficacy of a counselor initiated vs. participant initiated tobacco QL with adjunctive nicotine replacement therapy ( NRT ) in both groups . Participants ( N=950 ) will be recruited nationally and r and omly assigned to one of the two interventions . The counselor initiated intervention includes six scheduled telephone sessions of a behavioral intervention and provision of 8 weeks of NRT . The participant initiated intervention allows the participant to call the QL at their convenience , but includes the same six telephone sessions and provision of 2 weeks of NRT . Both groups will receive two follow-up phone calls at 8 weeks and 1 year after enrollment to assess their smoking status . The primary outcome measure is cotinine-vali date d self-reported smoking abstinence at 1-year follow-up . Results from this study will provide the first evidence about the efficacy of intensive QL cessation intervention in this high-risk population . Such evidence can lead as well to the dissemination of this intervention to other medically compromised population OBJECTIVE This study evaluated changes in smoking-related beliefs and behavior following a brief , culturally adapted smoking cessation intervention for Chinese and Korean smokers . METHOD From May 2002 to March 2003 , 66 smokers residing in or around southeastern Pennsylvania were r and omly assigned to a theory-based smoking cessation intervention or general health counseling . Participants completed assessment s of perceived risks of smoking , pros and cons of quitting , quitting self-efficacy , and distress at baseline and follow-up time points . Sessions were conducted in the participant 's native language ( Korean , Cantonese , or M and arin ) . Both groups received nicotine replacement therapy . RESULTS Overall , 38 % of participants reported quitting smoking at 3-month follow-up . Quit rates were higher ( 52.6 % among Chinese , 60.0 % among Korean ) in the intervention condition compared to the control condition ( 23.5 % among Chinese , 40.0 % among Korean ) at 1-month , but not 3-month , follow-up . There was a main effect of treatment condition for self-efficacy with intervention participants reporting significantly higher levels of self-efficacy compared to control participants . Further , a treatment x time interaction was observed for cons of quitting , reflecting fewer cons in the intervention group than the control group at 1-month and 3-month follow-up . CONCLUSION A culturally adapted intervention for Chinese and Korean Americans can be effective in changing specific smoking-related cognitions and behavior . This study represents a promising first step toward advancing our underst and ing of the associations between smoking-related cognitions and behavior among Asian American smokers This article describes the test of the hypothesis that a cognitive-behavioral mood management intervention would be effective for smokers with a history of major depressive disorder ( MDD ) . The method was r and omized trial ; the assessment s occurred at Weeks 0 , 8 , 12 , 26 , and 52 . Ss were 149 smokers ; 31 % had a history of MDD . All received 2 mg of nicotine gum . Mood management was provided in 10 group sessions over 8 weeks . St and ard treatment was provided in 5 group sessions over 8 weeks . Outcome was continuous abstinence . History-positive Ss were more likely to be abstinent when treated with mood management . Treatment condition differences were not significant for history-negative Ss . For history-positive Ss , less anger at baseline predicted abstinence . For history-negative Ss , more years smoked and higher baseline carbon monoxide ( CO ) predicted abstinence . Cognitive-behavioral therapy did not affect mood after quitting . Abstinence predictors differed as a function of baseline diagnosis We conducted a r and omized , controlled study to evaluate whether pharmacists ' advice on smoking cessation would result in a higher smoking cessation rate using Nicorette ( nicotine gum preparation ) . Fourteen pharmacies in Tokyo , Kanagawa , and Nagano participated . Smokers who visited pharmacies to buy Nicorette from March 1 , 2002 , through August 31 , 2002 , were recruited and r and omly assigned to two groups . For the intervention group ( A ) , pharmacists provided both regular instructions on Nicorette use and smoking cessation advice at the first sale and then gave follow-up advice just before starting a cessation and 1 , 3 , and 8 weeks and 3 months thereafter . For the control group ( B ) , pharmacists provided regular instructions alone . The primary outcome measure was the self-reported smoking cessation rate and the secondary outcome measure was the relationship between the smoker 's egogram and effectiveness of intervention . Twenty-eight smokers were enrolled and r and omized into group A ( n=11 ) or group B ( n=17 ) . The absolute abstinence rate in groups A and B at 3 months was 45.5 % and 31.2 % , respectively . The odds ratio was 1.83 , which was not statistically significant . There was no difference in egogram score between absolute abstinence subjects and nonabstinence subjects in group A. The egogram scores in Adapted Child of absolute abstinence subjects in group B were significantly higher than in nonabstinence subjects . In conclusion , instructions and advice given by pharmacists may improve the smoking cessation rate in smokers receiving nicotine replacement therapy INTRODUCTION Approximately 60%-70 % of cigarette smokers who try to quit relapse by 2 weeks postcessation . We tested the efficacy of a front-loaded ( FL ) counseling intervention whose goal was to increase the likelihood of successful early abstinence and subsequent long-term abstinence . METHODS We r and omized 278 adult smokers to an FL or weekly behavioral smoking cessation counseling schedule . The total number of sessions across treatment was the same for both groups . However , those assigned to the FL schedule received 6 counseling sessions in the first 2 weeks postcessation , while those in the weekly condition received 2 sessions . Participants in both groups also received st and ard nicotine patch treatment . RESULTS At 1 year postcessation , FL participants were significantly less likely to have relapsed when continuous abstinence was used as the definition of abstinence/relapse ( 11.7 % abstinent vs. 6.3 % , hazard ratio [ HR ] = 0.69 , p = .007 ) ; and there were nonsignificant trends for FL subjects to have better outcomes when abstinence was defined as never smoking for 7 or more consecutive days nor for 7 or more consecutive episodes ( 18.4 % abstinent vs. 14.8 % , HR = 0.83 , p = .20 ) and as point prevalence abstinence ( 15.6 % abstinent vs. 12.9 % , p = .11 ) . The relationship between FL counseling treatment and continuous abstinence was partially mediated by higher postcessation levels of social support perceived from counseling and greater use of cessation-related coping strategies . CONCLUSIONS We conclude that FL counseling is a promising treatment model that should be evaluated further , perhaps using modifications of the FL schedule used in this study The A1 allele of the dopamine D2 receptor gene ( DRD2 ) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior . In a study of smokers enrolled in an open-label , r and omized effectiveness trial , we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling . Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months , respectively , following a target quit date . Compared to women who carry both A2 alleles , women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects ( odds ratio (OR)=1.91 , 95 % confidence interval (CI)=1.01–3.60 ; P<0.04 ) and at 12 months were somewhat more likely to report smoking ( OR=0.76 , 95 % CI=0.56–1.03 ; P<0.076 ) . Significant associations or trends were not observed in men . In women , individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function Despite considerable progress in reducing cigarette smoking prevalence and enhancing smoking cessation treatments , most smokers who attempt to quit relapse . The current r and omized clinical trial evaluated the efficacy of an adjunctive behavioral smoking cessation treatment based on learning theory . Adult daily smokers were r and omly assigned to st and ard treatment ( N = 47 ) with nicotine patch and individual counseling or to st and ard treatment plus a " practice quitting " program involving seven sessions of escalating prescribed abstinence periods ( N = 46 ) prior to a target stop smoking date . Practice quitting was design ed to extinguish smoking in response to withdrawal symptoms . Retention in treatment was excellent and the treatment manipulation increased the interval between cigarettes across practice quitting sessions on average by 400 % . The primary endpoint , seven-day point-prevalence abstinence four weeks post-quit , was not significantly affected by practice quitting ( 31.9 % in the st and ard treatment condition , 37.0 % in the practice quitting condition ) . Practice quitting increased latency to a first lapse among those who quit smoking for at least one day and prevented progression from a first lapse to relapse ( smoking daily for a week ) relative to st and ard treatment , however . Practice quitting is a promising adjunctive treatment in need of refinement to enhance adherence and efficacy Internet interventions for smoking cessation are ubiquitous . Yet , to date , there are few r and omized clinical trials that gauge their efficacy . This study is a r and omized clinical trial ( N= 284 , n= 140 in the treatment group , n= 144 in the control group ) of an Internet smoking cessation intervention . Smokers were r and omly assigned to receive either bupropion plus counseling alone , or bupropion and counseling in addition to 12 weeks of access to the Comprehensive Health Enhancement Support System for Smoking Cessation and Relapse Prevention ( CHESS SCRP ; a Web site which provided information on smoking cessation as well as support ) . We found that access to CHESS SCRP was not significantly related to abstinence at the end of the treatment period ( OR= 1.13 , 95 % CI 0.66 - 2.62 ) or at 6 months postquit ( OR= 1.48 , 95 % CI 0.66 - 2.62 ) . However , the number of times participants used CHESS SCRP per week was related to abstinence at both end of treatment ( OR= 1.79 , 95 % CI 1.25 - 2.56 ) and at the 6-month follow-up ( OR= 1.59 , 95 % CI 1.06 - 2.38 ) . Participants with access to CHESS SCRP logged in an average of 33.64 times ( SD=30.76 ) over the 90-day period of access . Rates of CHESS SCRP use did not differ by ethnicity , level of education or gender ( all p>.05 ) . In sum , results suggest that participants used CHESS SCRP frequently , CHESS SCRP use was related to success , but the effects in general did not yield intergroup effects ABSTRACT BACKGROUND Varenicline may be associated with greater mood disturbance and side-effects among smokers with psychiatric history , but empirical evidence is limited . Differential treatment effectiveness by psychiatric history may also exist . OBJECTIVE To compare mood , prevalence and intensity of treatment side-effects , and abstinence among people with a probable history of major depression ( DH+ ) or not ( DH− ) who took varenicline and received behavioral smoking cessation treatment . DESIGN Smokers participated in a r and omized behavioral intervention effectiveness trial . Treatment side-effects and outcomes were compared between DH+ and DH− participants ( n = 1,117 ) at 2 days and 3 months after the target quit date . PARTICIPANTS Smokers recruited from a large regional health plan . MEASUREMENTS Change in stress and depression scores , prevalence and intensity of treatment side-effects , and abstinence rates . RESULTS All side-effects averaged moderate intensity or less and were similar across DH groups , except DH+ ’s endorsed slightly worse confusion , nausea ( adjusted P = 0.04 ) and trouble sleeping ( adjusted P = 0.008 ) at 21 days . Depression and stress scores declined in both DH groups and an equal proportion of each evidence d new/worsening depressive symptoms . Despite few differences in symptom intensity , more DH+ participants reported recent tension/agitation , irritability/anger , confusion , and depression at 21 days ( adjusted P < 0.05 ) , and depression and anxiety ( adjusted P < 0.01 ) at three months . Nonsmoking rates did not differ by DH group at follow-up . CONCLUSION While some group differences were noted , DH+ smokers did not report qualitatively worse neuropsychiatric symptoms , more new/worsening mood disturbance , or differential abstinence rates compared to DH- smokers The benefits of smoking cessation on patients ' medical conditions are well documented . Cardiovascular patients who quit smoking significantly reduce their risk of a new event compared with those who continue smoking . Several studies have found that smoking is related to poor quality of life ( QoL ) . In cardiovascular patients , however , less attention has been given to the effect of smoking cessation on patients ' QoL. The present study examined the extent to which smoking cessation leads to changes in QoL in these patients within the first year of follow-up . Data were collected in the context of a r and omized clinical trial . Smoking out patients ( N = 346 ) with atherosclerotic disease were included and received medical treatment . They were r and omized to receive either nicotine replacement therapy ( NRT ) or NRT plus a behavioral intervention meant to promote smoking cessation . At baseline , sociodemographic and clinical characteristics were established . Generic and disease-specific QoL as well as smoking status were assessed at baseline and with three follow-up measurements . Multilevel modeling showed that generic and disease-specific QoL in atherosclerotic patients improved significantly within the first year of follow-up . No main differences were found between quitters and smokers in terms of improvement in QoL. In fact , some subgroups reported a poorer QoL after smoking cessation : More highly educated patients reported lower general QoL ( p < .05 ) , and patients suffering from coronary artery disease who had a low level of education ( p < .01 ) and patients suffering from peripheral arterial disease who had low nicotine dependency ( p < .01 ) reported lower disease-specific QoL. Atherosclerotic patients ' QoL improved significantly but was not enhanced by smoking cessation activities Efficacy of bupropion SR and individual counseling as smoking cessation treatments was assessed in a r and omized , placebo-controlled clinical trial among adult daily smokers . Bupropion SR treatment and counseling were fully crossed in this factorial design so that the efficacy of each treatment and the combination could be estimated , relative to a placebo medication and assessment control condition . Intent-to-treat analyses indicated that bupropion SR increased abstinence rates at the end of treatment , relative to the placebo medication conditions , for both biochemically confirmed 7-day point-prevalence abstinence ( OR = 1.97 , 95 % CI 1.04 - 3.72 ) and self-reported prolonged abstinence ( OR = 2.90 , 95 % CI 1.66 - 5.06 ) . Bupropion SR treatment also improved latency to lapse and relapse and improved the latency between lapse and relapse in survival analyses . Medication effects were more modest for both 12-month point-prevalence abstinence ( OR = 1.47 , 95 % CI 0.74 - 2.92 ) and prolonged abstinence ( OR = 1.34 , 95 % CI 0.66 - 2.72 ) . Counseling was not associated with increases in the likelihood of abstinence at any time point ( odds ratios ranged from 0.80 to 1.16 across abstinence outcomes in the full intent-to-treat sample ) . Counseling and medication did not significantly interact at any time point , and adding counseling did not improve end-of-treatment point-prevalence abstinence ( OR = 1.17 , 95 % CI 0.68 - 2.03 ) or prolonged abstinence ( OR = 1.26 , 95 % CI 0.75 - 2.12 ) substantially when offered in conjunction with active medication BACKGROUND Observational studies have shown that attentional bias for smoking-related cues is associated with increased craving and relapse . Laboratory experiments have shown that manipulating attentional bias may change craving . Interventions to reduce attentional bias could reduce relapse in smokers seeking to quit . We report a clinical trial of attentional retraining in treatment-seeking smokers . METHODS This was a double-blind r and omised controlled trial that took place in UK smoking cessation clinics . Smokers interested in quitting were r and omised to five weekly sessions of attentional retraining ( N=60 ) or placebo training ( N = 58 ) using a modified visual probe task from one week prior to quit day . Both groups received 21 mg nicotine patches ( from quit day onwards ) and behavioural support . Primary outcomes included change in attentional bias reaction times four weeks after quit day on the visual probe task and craving measured weekly using the Mood and Physical Symptoms Scale . Secondary outcomes were changes in withdrawal symptoms , time to first lapse and prolonged abstinence . RESULTS No attentional bias towards smoking cues was found in the sample at baseline ( mean difference = 3 ms , 95 % CI = -2 , 9 ) . Post-training bias was not significantly lower in the retraining group compared with the placebo group ( mean difference = -9 ms , 95 % CI = -20 , 2 ) . There was no difference between groups in change in craving ( p = 0.89 ) and prolonged abstinence at four weeks ( risk ratio = 1.00 , 95 % CI = 0.70 , 1.43 ) . CONCLUSIONS Taken with one other trial , there appears to be no effect from clinic-based attentional retraining using the visual probe task . Attentional retraining conducted out of clinic may prove more effective . CLINICAL TRIAL REGISTRATION UK Clinical Trials IS RCT N 54375405 Background Smoking is an important risk factor for recurrent events in cardiovascular patients . Evidence exists that nicotine replacement therapy ( NRT ) approximately doubles smoking cessation rates . The minimal intervention strategy ( MIS ) has been used successfully to assist patients to quit smoking in general practice , and was recently adapted for cardiology in patients ( C-MIS ) . It is hypothesized that in cardiovascular out patients the combination of C-MIS and NRT significantly increases the number of quitters compared to NRT alone . Methods A r and omized clinical trial in 385 smoking patients who attended the cardiovascular outpatient departments in the Academic Medical Centre , Amsterdam for the treatment of atherosclerotic disease . Patients were allocated to either NRT + C-MIS or NRT alone . Self-reported and biochemically vali date d abstinence rates were measured at 12 months ' follow-up . Results Including patients with incomplete follow-up as smokers , abstinence was reported by 19 % of the NRT + C-MIS group and 14 % of the NRT group [ absolute risk reduction ( ARR ) = 0.05 ; 95 % confidence interval ( CI ) = −0.02 ; 0.12 ] . According to biochemical markers , abstinence rates were 28 and 24 % , respectively ( ARR = 0.04 , 95 % CI = −0.06 ; 0.14 ) . Hence , no significant differences between groups were found . The number of cigarettes smoked a day decreased significantly at 12 months : from 21 to 15 a day in the experimental group , and from 21 to 14 in the control group ( P<0.001 ) , but did not differ between groups ( P=0.32 ) . Conclusions The effectiveness of a minimal contact intervention was investigated in order to reach as many cardiovascular patients as possible in the setting of outpatient departments . This intervention was not found to be effective This correlational study examined the adherence rates of transdermal nicotine ( TN ) use among a population of males and females 18 years of age and older ( N = 619 ) who received varying levels of behavioral intervention . Rates of patch adherence were assessed for demographic ( e.g. , gender , ethnicity , and age ) , income- , smoking- [ e.g. , baseline carbon monoxide ( CO ) , nicotine dependence , and follow-up quit status ] , and treatment-related ( e.g. , condition , and drop status ) variables . Loglinear and logistic regression analyses were performed to assess adherence rates . Results indicated that male gender [ chi2(2 , n = 485 ) = 20.39 , P = .038 ] , not dropping out of the study [ chi2(2 , n = 485 ) = 13.94 , P < .001 ] , and intensive treatment ( compared to the st and ard care ) [ chi2(4 , n = 485 ) = 14.96 , P = .005 ] were associated with greater adherence to TN . Furthermore , patch adherence was associated with quit status at 6 months ( OR = 2.47 , CI = 1.56 - 3.91 , P < .001 ) and 12 months ( OR = 2.12 , CI = 1.34 - 3.37 , P = .001 ) . Complete and partial patch adherence ( compared to minimal/no adherence ) were associated with a greater number of telephone intervention contacts completed ( OR = 2.621 , CI = 1.421 - 4.832 , P = .002 ) . Noteworthy however , was the lack of association between level of income and patch adherence . These findings suggest characteristics of those more and less likely to adhere to TN in research and clinical setting Background Although smoking prevalence remains strikingly high in homeless population s ( ~70 % and three times the US national average ) , smoking cessation studies usually exclude homeless persons . Novel evidence -based interventions are needed for this high-risk sub population of smokers . Purpose To describe the aims and design of a first-ever smoking cessation clinical trial in the homeless population . The study was a two-group r and omized community-based trial that enrolled participants ( n = 430 ) residing across eight homeless shelters and transitional housing units in Minnesota . The study objective was to test the efficacy of motivational interviewing ( MI ) for enhancing adherence to nicotine replacement therapy ( NRT ; nicotine patch ) and smoking cessation outcomes . Methods Participants were r and omized to one of the two groups : active ( 8 weeks of NRT + 6 sessions of MI ) or control ( NRT + st and ard care ) . Participants attended six in-person assessment sessions and eight retention visits at a location of their choice over 6 months . Nicotine patch in 2-week doses was administered at four visits over the first 8 weeks of the 26-week trial . The primary outcome was cotinine-verified 7-day point-prevalence abstinence at 6 months . Secondary outcomes included adherence to nicotine patch assessed through direct observation and patch counts . Other outcomes included the mediating and /or moderating effects of comorbid psychiatric and substance abuse disorders . Results Lessons learned from the community-based cessation r and omized trial for improving recruitment and retention in a mobile and vulnerable population included : ( 1 ) the importance of engaging the perspectives of shelter leadership by forming and convening a Community Advisory Board ; ( 2 ) locating the study at the shelters for more visibility and easier access for participants ; ( 3 ) minimizing exclusion criteria to allow enrollment of participants with stable psychiatric comorbid conditions ; ( 4 ) delaying the baseline visit from the eligibility visit by a week to protect against attrition ; and ( 5 ) regular and persistent calls to remind participants of upcoming appointments using cell phones and shelter-specific channels of communication . Limitations The study ’s limitations include generalizability due to the sample drawn from a single Midwestern city in the United States . Since inclusion criteria encompassed willingness to use NRT patch , all participants were motivated and were ready to quit smoking at the time of enrollment in the study . Findings from the self-select group will be generalizable only to those motivated and ready to quit smoking . High incentives may limit the degree to which the intervention is replicable . Conclusions Lessons learned reflect the need to engage communities in the design and implementation of community-based clinical trials with vulnerable population BACKGROUND AND OBJECTIVE GPs are an important source of smoking cessation advice . This research examined whether a model encouraging GP referral of patients who smoke to a specialist service would be acceptable and effective for increased smoking cessation when compared with a model of in- practice management . METHODS The study design was cluster r and omized controlled trial . Practice s were r and omized to one of two interventions , at a rate of 1:2 : ( i ) st and ard in- practice GP management or ( ii ) referral to a quitline service . The main outcome measures were sustained abstinence of > or=1 month duration at 3-month follow-up and > or=10 months duration at 12 months , using intention to treat analysis . RESULTS At 3-month follow-up , patients in the referral condition were twice as likely to report sustained abstinence than those in the in- practice condition [ 12.3 % compared with 6.9 % ; odds ratio ( OR ) = 1.92 ( 95 % confidence interval ( CI ) 1.17 - 3.13 ] . At 12-month follow-up , patients in the referral condition had nearly three times the odds of sustained abstinence [ 6.5 % compared with 2.6 % ; OR = 2.86 ( 95 % CI 0.94 - 8.71 ) ] . The intervention effect was mediated by the amount of help received outside the practice . CONCLUSIONS This research provided evidence that GPs referring smokers to an evidence -based quitline service results in increased cessation . The benefit is largely due to patients in the referral condition receiving more external help than patients in the in- practice condition , as they received equivalent practice -based help . Where suitable services exist , we recommend that referral become the normative strategy for management of smoking cessation in general practice to complement any practice -based help provided Background Despite progress in reducing cigarette smoking in the general U.S. population , smoking rates , cancer morbidity and related heart disease remain strikingly high among the poor and underserved . Homeless individuals ’ cigarette smoking rate remains an alarming 70 % or greater , and this population is generally untreated with smoking cessation interventions . Furthermore , the majority of homeless smokers also abuse alcohol and other drugs , which makes quitting more difficult and magnifies the health consequences of tobacco use . Methods / Design Participants will be r and omized to one of three groups , including ( 1 ) an integrated intensive smoking plus alcohol intervention using cognitive behavioral therapy ( CBT ) , ( 2 ) intensive smoking intervention using CBT or ( 3 ) usual care ( i.e. , brief smoking cessation and brief alcohol counseling ) . All participants will receive 12-week treatment with a nicotine patch plus nicotine gum or lozenge . Counseling will include weekly individual sessions for 3 months , followed by monthly booster group sessions for 3 months . The primary smoking outcome is cotinine-verified 7-day smoking abstinence at follow-up week 52 , and the primary alcohol outcome will be breathalyzer-verified 90-day alcohol abstinence at week 52 . Discussion This study protocol describes the design of the first community-based controlled trial ( n = 645 ) design ed to examine the efficacy of integrating alcohol abuse treatment with smoking cessation among homeless smokers . To further address the gap in effectiveness of evidence -based smoking cessation interventions in the homeless population , we are conducting a renewed smoking cessation clinical trial called Power to Quit among smokers experiencing homelessness . Trial registration Clinical Trials.gov Identifier : NCT01932996 . Date of registration : 20 November 2014 Pharmacological interventions for smoking cessation are typically evaluated using volunteer sample s ( efficacy trials ) but should also be evaluated in population -based trials ( effectiveness trials ) . Nicotine replacement therapy ( NRT ) alone and in combination with behavioral interventions was evaluated on a population of smokers from a New Engl and Veterans Affairs Medical Center . Telephone interviews were completed with 3,239 smokers , and 2,054 agreed to participate ( 64 % ) . Participants were r and omly assigned to one of four conditions : stage-matched manuals ( MAN ) ; NRT plus manuals ( NRT + MAN ) ; expert system plus NRT and manuals ( EXP + NRT + MAN ) ; and automated counseling plus NRT , manuals , and expert system ( TEL + EXP + NRT + MAN ) . Assessment s were completed at baseline , 10 , 20 , and 30 months . The point prevalence cessation rates at final follow-up ( 30 months ) were MAN , 20.3 % ; NRT + MAN , 19.3 % ; EXP + NRT + MAN , 17.6 % ; and TEL + EXP + NRT + MAN , 19.9 % . Stage-matched manuals provided cessation rates comparable with previous studies . The addition of NRT , expert system interventions , and automated telephone counseling failed to produce a further increase in intervention effectiveness Background The use of spirometry for early detection of chronic obstructive pulmonary disease ( COPD ) is still an issue of debate , particularly because of a lack of convincing evidence that spirometry has an added positive effect on smoking cessation . We hypothesise that early detection of COPD and confrontation with spirometry for smoking cessation may be effective when applying an approach we have termed " confrontational counselling " ; a patient-centred approach which involves specific communication skills and elements of cognitive therapy . An important aspect is to confront the smoker with his/her airflow limitation during the counselling sessions . The primary objective of this study is to test the efficacy of confrontational counselling in comparison to regular health education and promotion for smoking cessation delivered by specialized respiratory nurses in current smokers with previously undiagnosed mild to moderate airflow limitation . Methods / Design The study design is a r and omized controlled trial comparing confrontational counselling delivered by a respiratory nurse combined with nortriptyline for smoking cessation ( experimental group ) , health education and promotion delivered by a respiratory nurse combined with nortriptyline for smoking cessation ( control group 1 ) , and " care as usual " delivered by the GP ( control group 2 ) . Early detection of smokers with mild to moderate airflow limitation is achieved by means of a telephone interview in combination with spirometry . Due to a comparable baseline risk of airflow limitation and motivation to quit smoking , and because of the st and ardization of number , duration , and scheduling of counselling sessions between the experimental group and control group 1 , the study enables to assess the " net " effect of confrontational counselling . The study has been ethically approved and registered . Discussion Ethical as well as method ological considerations of the study are discussed in this protocol . A significant and relevant effect of confrontational counselling would provide an argument in favour of early detection of current smokers with airflow limitation . Successful treatment of tobacco dependence in respiratory patients requires repeated intensive interventions . The results of this study may also show that respiratory nurses are able to deliver this treatment and that intensive smoking cessation counselling is more feasible . Trial registration : Netherl and s Trial Register ( IS RCT N 64481813 ) INTRODUCTION Combining behavioural support and pharmacotherapy is most effective for smoking cessation and recommended in clinical guidelines . Despite that smoking cessation assistance from the general practitioner can be effective , dissemination of clinical practice guidelines and efforts on upskilling has not lead to the routine provision of smoking cessation advice among general practitioners . Intensive counselling from the practice nurse could contribute to better smoking cessation rates in primary care . However , the effectiveness of intensive counselling from a practice nurse versus usual care from a general practitioner in combination with varenicline is still unknown . MATERIAL S AND METHODS A pragmatic r and omized controlled trial was conducted comparing : ( a ) intensive individual counselling delivered by a practice nurse and ( b ) brief advice delivered by a general practitioner ; both groups received 12-weeks of open-label varenicline . A minimum of 272 adult daily smoking participants were recruited and treated in their routine primary care setting . The primary outcome was defined as prolonged abstinence from weeks 9 to 26 , biochemically vali date d by exhaled carbon monoxide . Data was analysed blinded according to the intention-to-treat principle and participants with missing data on their smoking status at follow-up were counted as smokers . Secondary outcomes included : one-year prolonged abstinence , short-term incremental cost-effectiveness , medication adherence , and baseline predictors of successful smoking cessation . DISCUSSION This trial is the first to provide scientific evidence on the effectiveness , cost-effectiveness , and potential mechanisms of action of intensive practice nurse counselling combined with varenicline under real-life conditions . This paper explains the methodology of the trial and discusses the pragmatic and /or explanatory design aspects . TRIAL REGISTRATION Dutch Trial Register NTR3067 INTRODUCTION Tobacco use has emerged as a leading killer among persons living with HIV , with effective approaches to tobacco treatment still unknown . HIV infection is nearly 3 times as prevalent in Latinos than in non-Latino Whites . This study reports the results of a r and omized trial comparing a tailored intervention to brief counseling for smoking cessation among Latino smokers living with HIV ( LSLWH ) . METHODS LSLWH ( N = 302 ; 36 % female , 10 % employed full-time , 49 % born in United States ) were r and omized to 4 in-person sessions of a tailored intervention ( Aurora ) or 2 in-person sessions of brief advice ( enhanced st and ard care [ ESC ] ) . Both groups received 8 weeks of nicotine replacement therapy ( NRT ) patch . Biochemically vali date d 6- and 12-month 7-day point-prevalence abstinence ( PPA ) rates were compared , along with secondary outcomes ( e.g. , reduction to light smoking , NRT adherence ) . RESULTS Seven-day PPA rates reached 8 % versus 11 % at 6 months and 6 % versus 7 % at 12 months , for Aurora and ESC , respectively , with no between-group differences ( p values > .40 ) . Significant changes from baseline to 6 and 12 months among intervention targets were noted ( percentage reduction in heavy smoking and dependence ; increases in knowledge and self-efficacy ) . Baseline smoking frequency , older age , and higher intensity of patch use during the trial emerged as significant predictors of abstinence at 6 months . CONCLUSIONS There was no evidence that the tailored intervention improved cessation rates . Interventions that encourage use of , and adherence to , empirically vali date d cessation aids require further development to reduce tobacco-related death and disease in this vulnerable population Objective To examine the effects of five intervention components on smokers ’ adherence to combined nicotine patch and nicotine gum during a quit attempt and assess whether adherence is related to cessation . MethodS mokers interested in quitting ( N = 513 ; 59 % female ; 87 % White ) received nicotine patch plus nicotine gum and participated in a 2x2x2x2x2 r and omized factorial experiment ( i.e. , 32 treatment conditions ) evaluating five intervention components : ( 1 ) medication adherence counseling versus none ; ( 2 ) automated medication adherence calls versus none ; ( 3 ) electronic medication monitoring with feedback and counseling versus e-monitoring alone ; ( 4 ) 26 versus 8 weeks of nicotine patch plus nicotine gum ; and ( 5 ) maintenance counseling versus none . Adherence was assessed over the first 6 weeks post-target quit day via timeline follow-back ( nicotine patch ) and electronic medication dispenser ( gum ) . Results In the first 6 weeks post-quit day , 12 % of participants used no patches or gum , and 40 % used the patch every day . Only 1.4 % used both patch and gum adherently every day in the 6 weeks post-target quit day . E-monitoring counseling increased gum use ( from 1.9 to 2.6 pieces/day ; p < .001 ) but did not increase abstinence . More adherent patch and gum use in the first 6 weeks were each associated with higher point-prevalence abstinence rates through 1 year . Conclusions This large experiment with electronic monitoring of nicotine gum adherence showed that e-monitoring counseling increased gum use but not abstinence . Adherence to nicotine patch and to gum were each strongly related to abstinence , but it is unclear whether adherence increases abstinence , or relapse causes medication discontinuation . Clinical Trial Registration Clinical Trials.gov NCT01120704 Despite advances in behavioral and pharmacological treatment for tobacco use and dependence , quit rates remain suboptimal . Increasing physical activity has shown some promise as a strategy for improving cessation outcomes . However , initial efficacy studies focused on intensive , highly structured exercise programs that may not be applicable to the general population of smokers . We describe the rationale and study design and report baseline participant characteristics from the Lifestyle Enhancement Program ( LEAP ) , a two-group , r and omized controlled trial . Adult smokers who engaged in low levels of leisure time physical activity were r and omly assigned to treatment conditions consisting of an individualized physical activity intervention delivered by health fitness instructors in community-based exercise facilities or an equal contact wellness control . All participants received st and ard cognitive behavioral smoking cessation counseling combined with nicotine replacement therapy . The primary outcomes are seven-day point prevalence abstinence at seven weeks , six- and 12 months . Secondary outcomes include self-reported physical activity , dietary intake , body mass index , waist circumference , percent body fat , and nicotine withdrawal symptoms . Participants consist of 392 sedentary smokers ( mean [ st and ard deviation ] age = 44.6 [ 10.2 ] = years ; 62 % female ; 31 % African American ) . Results reported here provide information regarding experiences recruiting smokers willing to change multiple health behaviors including smoking and physical activity Objectives : State and national tobacco quitlines have exp and ed rapidly and offer a range of services . We examined the effectiveness and cost effectiveness of offering callers single session versus multisession counselling , with or without free nicotine patches . Methods : This 3 × 2 r and omised trial included 4614 Oregon tobacco quitline callers and compared brief ( one 15-minute call ) , moderate ( one 30-minute call and a follow-up call ) and intensive ( five proactive calls ) intervention protocol s , with or without offers of free nicotine patches ( nicotine replacement therapy , NRT ) . Blinded staff assessed tobacco use by phone at 12 months . Results : Abstinence odds ratios were significant for moderate ( OR = 1.22 , CI = 1.01 to 1.48 ) and intensive ( OR = 1.29 , CI = 1.07 to 1.56 ) intervention , and for NRT ( OR = 1.58 , CI = 1.35 to 1.85 ) . Intent to treat quit rates were as follows : brief no NRT ( 12 % ) ; brief NRT ( 17 % ) ; moderate no NRT ( 14 % ) ; moderate NRT ( 20 % ) ; intensive no NRT ( 14 % ) ; and intensive NRT ( 21 % ) . Relative to brief no NRT , the added costs for each additional quit was $ 2467 for brief NRT , $ 1912 for moderate no NRT , $ 2109 for moderate NRT , $ 2641 for intensive no NRT , and $ 2112 for intensive NRT . Conclusion : Offering free NRT and multisession telephone support within a state tobacco quitline led to higher quit rates , and similar costs per incremental quit , than less intensive protocol Background Hospitalized smokers often quit smoking , voluntarily or involuntarily ; most relapse soon after discharge . Extended follow-up counseling can help prevent relapse . However , it is difficult for hospitals to provide follow-up and smokers rarely leave the hospital with quitting aids ( for example , nicotine patches ) . This study aims to test a practical model in which hospitals work with a state cessation quitline . Hospital staff briefly intervene with smokers at bedside and refer them to the quitline . Depending on assigned condition , smokers may receive nicotine patches at discharge or extended quitline telephone counseling post-discharge . This project establishes a practical model that lends itself to broader dissemination , while testing the effectiveness of the interventions in a rigorous r and omized trial . Methods / design This r and omized clinical trial ( N = 1,640 ) tests the effect of two interventions on long-term quit rates of hospitalized smokers in a 2 x 2 factorial design . The interventions are ( 1 ) nicotine patches ( eight-week , step down program ) dispensed at discharge and ( 2 ) proactive telephone counseling provided by the state quitline after discharge . Subjects are r and omly assigned into : usual care , nicotine patches , telephone counseling , or both patches and counseling . It is hypothesized that patches and counseling have independent effects and their combined effect is greater than either alone . The primary outcome measure is thirty-day abstinence at six months ; a secondary outcome is biochemically vali date d smoking status . Cost-effectiveness analysis is conducted to compare each intervention condition ( patch alone , counseling alone , and combined interventions ) against the usual care condition . Further , this study examines whether smokers ’ medical diagnosis is a moderator of treatment effect . Generalized linear ( binomial ) mixed models will be used to study the effect of treatment on abstinence rates . Clustering is accounted for with hospital-specific r and om effects . Discussion If this model is effective , quitlines across the U.S. could work with interested hospitals to set up similar systems . Hospital accreditation st and ards related to tobacco cessation performance measures require follow-up after discharge and provide additional incentive for hospitals to work with quitlines . The ubiquity of quitlines , combined with the consistency of quitline counseling delivery as central ized state operations , make this partnership attractive . Trial registration Smoking cessation in hospitalized smokers NCT01289275 . Date of registration February 1 , 2011 ; date of first patient August 3 , 2011 Background Despite a significant decrease in smoking prevalence over the past ten years , cigarette smoking still represents the leading cause of preventable morbidity and mortality in the United States . Moreover , smoking prevalence is significantly higher among those with low levels of education and those living at , or below , the poverty level . These groups tend to be confronted with significant barriers to utilizing more traditional smoking cessation intervention approaches . The purpose of the study , Project ACTION ( Adult smoking Cessation Treatment through Innovative Outreach to Neighborhoods ) , is to utilize a mobile clinic model , a network of community sites ( i.e. , community centers and churches ) and an interactive mobile messaging system to reach and deliver smoking cessation treatment to underserved , low-income communities . Methods / Design We are using a group-r and omized design , with the community site as the sampling unit , to compare the efficacy of three smoking cessation interventions : 1 ) St and ard Care - brief advice to quit smoking , nicotine replacement therapy ( NRT ) , and self-help material s ; 2 ) Enhanced Care - st and ard care components plus a cell phone-delivered text/graphical messaging component ; and 3 ) Intensive Care - enhanced care components plus a series of 11 cell phone-delivered proactive counseling sessions . An economic evaluation will also be performed to evaluate the relative cost effectiveness of the three treatment approaches . We will recruit 756 participants ( 252 participants in each of the 3 intervention groups ) . At the time of r and omization , participants complete a baseline assessment , consisting of smoking history , socio-demographic , and psychosocial variables . Monthly cell phone assessment s are conducted for 6 months-post enrollment , and a final 12-month follow-up is conducted at the original neighborhood site of enrollment . We will perform mixed-model logistic regression to compare the efficacy of the three smoking cessation intervention treatment groups . Discussion It is hypothesized that the intensive care approach will most successfully address the needs of the target population and result in the highest smoking cessation rates . In addition to increasing cessation rates , the intervention offers several features ( including neighborhood outreach and use of mHealth technology ) that are likely to reduce treatment barriers while enhancing participant engagement and retention to treatment . Trial registration This r and omized controlled trial is registered with clinical trials.gov registration number NCT00948129 Background Smoking prevalence rates among the lesbian , gay , bisexual , and transgender ( LGBT ) population are significantly higher than the general population . However , there is limited research on smoking cessation treatments in this group , particularly on culturally targeted interventions . Moreover , there are few interventions that address culturally specific psychosocial variables ( e.g. , minority stress ) that may influence outcomes . This paper describes the protocol for a comparative effectiveness trial testing an evidence -based smoking cessation program , Courage to Quit , against a culturally tailored version for LGBT smokers , and examines the role of culturally specific psychosocial variables on cessation outcomes . Methods / Design To examine the effectiveness of a culturally targeted versus st and ard smoking cessation intervention , the study utilizes a 2-arm block , r and omized , control trial ( RCT ) design . Adult LGBT participants ( n = 400 ) are r and omized to one of the two programs each consisting of a six-session group program delivered in a community center and an eight week supply of the transdermal nicotine patch . Four individualized telephone counseling sessions occur at weeks 2 , 5 , 7 , and 9 , at times of greatest risk for relapse . Study outcome measures are collected at baseline , and 1 , 3 , 6 , and 12 months post quit date . Primary outcomes are expired air carbon monoxide verified 7-day point-prevalence quit rates at each measurement period . Secondary outcomes assess changes in cravings , withdrawal symptoms , smoking cessation self-efficacy , and treatment adherence . Additionally , study staff examines the role of culturally specific psychosocial variables on cessation outcomes using path analysis . Discussion Determining the efficacy of culturally specific versus st and ard evidence based approaches to smoking cessation is a critical issue facing the field today . This study provides a model for the development and implementation of a culturally tailored smoking cessation intervention for LGBT participants and addresses a gap in the field by examining the role of culturally psychosocial variables associated with cessation outcomes .Trial registration U.S. National Institutes of Health Clinical Trials NCT01633567 Registered 30 May 2012 Background Cigarette smoking is the number one cause of preventable death among American Indian and Alaska Natives , AI/ANs . Two out of every five AI/AN will die from tobacco-related diseases if the current smoking rates of AI/ANs ( 40.8 % ) persist . Currently , there is no proven , effective culturally-tailored smoking cessation program design ed specifically for a heterogeneous population of AI.The primary aim of this group r and omized clinical trial is to test the efficacy of " All Nations Breath of Life " ( ANBL ) program compared to a non-tailored " Current Best Practice s " smoking cessation program among AI smokers . Methods We will r and omize 56 groups ( 8 smokers per group ) to the tailored program or non-tailored program for a total sample size of 448 American Indian smokers . All participants in the proposed study will be offered pharmacotherapy , regardless of group assignment . This study is the first controlled trial to examine the efficacy of a culturally-tailored smoking cessation program for American Indians . If the intervention is successful , the potential health impact is significant because the prevalence of smoking is the highest in this population .Trial Registration Clinical Trials.gov : AIMS To screen promising intervention components design ed to reduce smoking and promote abstinence in smokers initially unwilling to quit . DESIGN A balanced , four-factor , r and omized factorial experiment . SETTING Eleven primary care clinics in southern Wisconsin , USA . PARTICIPANTS A total of 517 adult smokers ( 63.4 % women , 91.1 % white ) recruited during primary care visits who were willing to reduce their smoking but not quit . INTERVENTIONS Four factors contrasted intervention components design ed to reduce smoking and promote abstinence : ( 1 ) nicotine patch versus none ; ( 2 ) nicotine gum versus none ; ( 3 ) motivational interviewing ( MI ) versus none ; and ( 4 ) behavioral reduction counseling ( BR ) versus none . Participants could request cessation treatment at any point during the study . MEASUREMENTS The primary outcome was percentage change in cigarettes smoked per day at 26 weeks post- study enrollment ; the secondary outcomes were percentage change at 12 weeks and point-prevalence abstinence at 12 and 26 weeks post- study enrollment . FINDINGS There were few main effects , but a significant four-way interaction at 26 weeks post- study enrollment ( P = 0.01 , β = 0.12 ) revealed relatively large smoking reductions by two component combinations : nicotine gum combined with BR and BR combined with MI . Further , BR improved 12-week abstinence rates ( P = 0.04 ) , and nicotine gum , when used without MI , increased 26-week abstinence after a subsequent aided quit attempt ( P = 0.01 ) . CONCLUSIONS Motivation-phase nicotine gum and behavioral reduction counseling are promising intervention components for smokers who are initially unwilling to quit OBJECTIVES To investigate the effectiveness of telephone counselling as an adjunct to nicotine replacement therapy ( NRT ) by transdermal patch in smoking cessation . DESIGN R and omised controlled trial . PARTICIPANTS AND SETTING 854 smokers from New South Wales , aged 18 years and older , who had smoked at least 10 cigarettes per day for the past year and responded to newspaper advertisements between October 2001 and January 2002 ; the trial was conducted between October 2001 and August 2002 . INTERVENTIONS R and om allocation to either NRT alone or NRT plus telephone counselling ( 5 sessions spaced according to a relapse-sensitive call schedule ) . MAIN OUTCOME MEASURES Self-reported abstinence assessed by telephone question naires at 1 , 2 , 3 and 6 months : 28-day continuous abstinence at 3 and 6 months , and 90-day continuous abstinence at 6 months . RESULTS 28-day continuous abstinence rates among participants receiving telephone counselling were significantly greater than among those not receiving telephone counselling at both 3 and 6 months ( 31.6 % v 25.1 % ; P = 0.04 at 3 months ; and 30.1 % v 22.4 % ; P = 0.01 at 6 months ) . Similarly , 90-day continuous abstinence rates at 6 months were significantly greater for participants receiving counselling ( 26.7 % v 18.6 % ; P = 0.004 ) . CONCLUSION Telephone counselling as an adjunct to NRT increases abstinence rates beyond the use of NRT alone Background Smoking is an important risk factor for cardiovascular disease ( CVD ) , and quitting is highly beneficial . Yet , less than 30 % of CVD patients stop smoking . Relapse-prevention strategies seem most effective when initiated during the exacerbation of the disease . Objective A nurse-delivered inpatient smoking cessation program based on the Transtheoretical Model with telephone follow-up tailored to levels of readiness to quit smoking was evaluated on smoking abstinence and progress to ulterior stages of change . Method Participants ( N = 168 ) were r and omly assigned by cohorts to inpatient counseling with telephone follow-up , inpatient counseling , and usual care . The inpatient intervention consisted of a 1-hr counseling session , and the telephone follow-up included 6 calls during the first 2 months after discharge . The nursing intervention was tailored to the individual 's stage of change . End points at 2 and 6 months included actual and continuous smoking cessation rates ( biochemical markers ) and increased motivation ( progress to ulterior stages of change ) . Results Assuming that surviving patients lost to follow-up were smokers , the 6-month smoking abstinence rate was 41.5 % in the inpatient counseling with telephone follow-up group , compared with 30.2 % and 20 % in the inpatient counseling and usual care groups , respectively ( p = .05 ) . Progress to ulterior stages of change was 43.3 % , 32.1 % , and 18.2 % , respectively ( p = .02 ) . Stage of change at baseline and intervention predicted smoking status at 6 months . Discussion This tailored smoking cessation program with telephone follow-up significantly increased smoking cessation at 6 months , and progression to ulterior stages of change . The telephone follow-up was an important adjunct . It is , therefore , recommended to include such comprehensive smoking cessation programs within hospital setting s for individuals with CVD Background Smoking among cancer survivors increases the risk of late effects and second cancers . This article reports on Partnership for Health-2 (PFH-2)—an effort to develop an effective and scalable version of Partnership for Health ( PFH ) , which was a previously tested peer-delivered telephone counseling program that doubled smoking cessation rates among childhood cancer survivors who smoke . Objective This paper presents results from a r and omized controlled trial evaluating the effectiveness of PFH-2 in targeted and tailored Web-based versus print formats . The overall goal was to determine whether the intervention outcomes in these self-guided scalable formats approximate what was found in a more intensive telephone counseling program . Methods This study was a r and omized controlled trial with a 15-month follow-up that included 374 smokers who were survivors of childhood or young adult cancers , recruited from five survivorship clinics . Participants were r and omly assigned to a Web-based or print format of the PFH intervention ; all had access to free pharmacotherapy . The website was design ed to provide new content at each log-on , and a peer counselor moderated a forum/chat feature . The primary outcome was smoking status at 15 months post r and omization . Results In total , 58.3 % ( 77/132 ) of Web participants logged on at least once ( mean visits 3.25 ) . Using multiple imputation methods for missing data , there were similar rates of cessation in the two arms ( print : 20/128 , 15.6 % ; Web : 33/201 , 6.4 % ) , and no differences in quit attempts or readiness to quit . The quit rates were equivalent to those found in our previous telephone counseling intervention . There were high rates of satisfaction with both of the PFH-2 interventions . Conclusions The print and Web formats yielded equivalent levels of success to those found with our telephone-delivered intervention and are comparable to other Internet treatment studies . This study provides important options for survivorship programs that may not have re sources for interpersonal forms of cessation counseling . Efforts to increase patient use of the interventions may result in higher cessation rates . Trial Registration Clinical trials.gov NCT00588107 ; http:// clinical trials.gov/ct2/show/NCT00588107 ( Archived by WebCite at http://www.webcitation.org/6K1gJtFEC ) AIMS To identify promising intervention components that help smokers attain and maintain abstinence during a quit attempt . DESIGN A 2 × 2 × 2 × 2 × 2 r and omized factorial experiment . SETTING Eleven primary care clinics in Wisconsin , USA . PARTICIPANTS A total of 544 smokers ( 59 % women , 86 % white ) recruited during primary care visits and motivated to quit . INTERVENTIONS Five intervention components design ed to help smokers attain and maintain abstinence : ( 1 ) extended medication ( 26 versus 8 weeks of nicotine patch + nicotine gum ) ; ( 2 ) maintenance ( phone ) counseling versus none ; ( 3 ) medication adherence counseling versus none ; ( 4 ) automated ( medication ) adherence calls versus none ; and ( 5 ) electronic medication monitoring with feedback and counseling versus electronic medication monitoring alone . MEASUREMENTS The primary outcome was 7-day self-reported point-prevalence abstinence 1 year after the target quit day . FINDINGS Only extended medication produced a main effect . Twenty-six versus 8 weeks of medication improved point-prevalence abstinence rates ( 43 versus 34 % at 6 months ; 34 versus 27 % at 1 year ; P = 0.01 for both ) . There were four interaction effects at 1 year , showing that an intervention component 's effectiveness depended upon the components with which it was combined . CONCLUSIONS Twenty-six weeks of nicotine patch + nicotine gum ( versus 8 weeks ) and maintenance counseling provided by phone are promising intervention components for the cessation and maintenance phases of smoking treatment No studies to date have examined the effect of counselor techniques on smoking cessation over the course of treatment . To address this gap , we examined the degree to which the use of specific Acceptance and Commitment Therapy ( ACT ) counseling techniques in a given session predicted smoking cessation reported at the next session . The data came from the ACT arm of a r and omized controlled trial of a telephone-delivered smoking cessation intervention . Trained raters coded 139 counseling sessions across 44 participants . The openness , awareness and activation components of the ACT model were rated for each telephone counseling session . Multilevel logistic regression models were used to estimate the predictive relationship between each component during any given telephone session and smoking cessation at the following telephone session . For every 1-unit increase in counselors ' use of openness and awareness techniques there were 42 % and 52 % decreases in the odds of smoking at the next counseling session , respectively . However , there was no significant predictive relationship between counselors ' use of activation techniques and smoking cessation . Overall , results highlight the theoretical and clinical value of examining therapists ' techniques as predictors of outcome during the course of treatment BACKGROUND St and ard , generic self-help material s have been largely ineffective as behavioral treatments for smoking cessation . In contrast , self-help programs tailored to the needs of specific smokers have shown promise in facilitating quitting . OBJECTIVE To evaluate the incremental efficacy of the Committed Quitters Program ( CQP ) , a set of computer-tailored material s offered to purchasers of nicotine polacrilex gum , compared with a briefuntailored user 's guide and audiotape , both as supplements to nicotine replacement therapy . METHODS We conducted a r and omized , open-label trial with 3 parallel arms . Subjects were smokers who purchased 2- or 4-mg nicotine polacrilex gum and called the CQP toll-free enrollment line . Three thous and six hundred twenty-seven subjects consented to participate in 1 of 3 study arms : ( 1 ) those receiving the CQP material s ( CQP group , n= 1,217 ) , ( 2 ) those receiving CQP material s and an outbound telephone call ( CQP + C group , n= 1,207 ) ; and ( 3 ) those receiving no supplemental intervention beyond the user 's guide and audiotape that were prepackaged with the nicotine polacrilex gum ( UG group , n= 1,203 ) . Twenty-eight-day continuous abstinence rates were assessed by telephone interviews at 6 weeks and 10-week continuous rates at 12 weeks into treatment . RESULTS Abstinence rates among respondents at the 6- and 12-week assessment s were significantly higher for the CQP ( 36.2 % and 27.6 % ) and CQP + C ( 35.5 % and 27.3 % ) groups compared with the UG group ( 24.7 % and 17.7 % ) at both intervals . The quit rates for the CQP and CQP + C groups were almost identical . CONCLUSIONS The CQP proved to be an effective behavioral treatment , enhancing quit rates over and above nicotine replacement therapy and a brief untailored written guide and audiotape OBJECTIVES To examine the impact of knowing quitters on cessation among homeless smokers . METHODS Secondary analysis of data derived from a community-based r and omized controlled trial of 430 homeless smokers . We conducted multivariable logistic regression analysis to determine whether knowing quitters impacted the likelihood of cessation ( salivary cotinine ≤ 20 ng/ml ) at 26-week follow-up . RESULTS Multivariable logistic regression showed cessation was more likely for smokers who knew ≥ 5 quitters compared with those who knew no quitters ( Odds Ratio = 3.79 , CI = 1.17 , 12.27 , p = .008 ) , adjusting for age , education , income , and time to first cigarette in morning . CONCLUSIONS Knowing former smokers was associated with increased likelihood of achieving smoking abstinence among homeless smokers We assessed the efficacy of a comprehensive programme for stopping smoking in 210 smokers scheduled for surgery , before admission and 3 months after attending a pre‐operative clinic . Participants were r and omly allocated to receive an intervention incorporating nicotine replacement therapy for patients smoking more than 10 cigarettes per day ( ‘ dependent smokers ’ ) , or to a control group to receive usual care . Dependent smokers allocated to the intervention group were more likely to report abstinence before surgery than those allocated to receive usual‐care ( 63 ( 73 % ) vs. 29 ( 56 % ) , respectively ; OR 2.2 ( 95 % CI 1.0–4.8 ) ) , and 3 months after attendance ( 16 ( 18 % ) vs. 3 ( 5 % ) , respectively ; OR = 3.9 ( 95 % CI 1.0–21.7 ) Background : There is insufficient and conflicting evidence about whether more intensive behavioural support is more effective than basic behavioural support for smoking cessation and whether primary care nurses can deliver effective behavioural support . Methods : A r and omised controlled trial was performed in 26 UK general practice s. 925 smokers of ⩾10 cigarettes per day were r and omly allocated to basic or weekly support . All participants were seen before quitting , telephoned around quit day , and seen 1 and 4 weeks after the initial appointment ( basic support ) . Participants receiving weekly support had an additional telephone call at 10 days and 3 weeks after the initial appointment and an additional visit at 2 weeks to motivate adherence to nicotine replacement and renew quit attempts . 15 mg/16 h nicotine patches were given to all participants . The outcome was assessed by intention to treat analyses of the percentage confirmed sustained abstinence at 4 , 12 , 26 and 52 weeks after quit day . Results : Of the 469 and 456 participants in the basic and weekly arms , the numbers ( % ) who quit and the percentage difference were 105 ( 22.4 % ) vs 102 ( 22.4 % ) , 0.1 % ( 95 % CI −5.3 % to 5.5 % ) at 4 weeks , 66 ( 14.1 % ) vs 52 ( 11.4 % ) , −2.6 % ( 95 % CI −6.9 % to 1.7 % ) at 12 weeks , 50 ( 10.7 % ) vs 40 ( 8.8 % ) , −1.9 % ( 95 % CI −5.7 % to 2.0 % ) at 26 weeks and 36 ( 7.7 % ) vs 30 ( 6.6 % ) , −1.1 % ( 95 % CI −4.4 % to 2.3 % ) at 52 weeks . Conclusions : The absolute quit rates achieved are those expected from nicotine replacement alone , implying that neither basic nor weekly support were effective . Primary care smoking cessation treatment should provide pharmacotherapy with sufficient support only to ensure it is used appropriately , and those in need of support should be referred to specialists AIM To assess the efficacy of World Wide Web-based tailored behavioral smoking cessation material s among nicotine patch users . DESIGN Two-group r and omized controlled trial . SETTING World Wide Web in Engl and and Republic of Irel and . PARTICIPANTS A total of 3971 subjects who purchased a particular br and of nicotine patch and logged-on to use a free web-based behavioral support program . INTERVENTION Web-based tailored behavioral smoking cessation material s or web-based non-tailored material s. MEASUREMENTS Twenty-eight-day continuous abstinence rates were assessed by internet-based survey at 6-week follow-up and 10-week continuous rates at 12-week follow-up . FINDINGS Using three approaches to the analyses of 6- and 12-week outcomes , participants in the tailored condition reported clinical ly and statistically significantly higher continuous abstinence rates than participants in the non-tailored condition . In our primary analyses using as a denominator all subjects who logged-on to the treatment site at least once , continuous abstinence rates at 6 weeks were 29.0 % in the tailored condition versus 23.9 % in the non-tailored condition ( OR = 1.30 ; P = 0.0006 ) ; at 12 weeks continuous abstinence rates were 22.8 % versus 18.1 % , respectively ( OR = 1.34 ; P = 0.0006 ) . Moreover , satisfaction with the program was significantly higher in the tailored than in the non-tailored condition . CONCLUSIONS The results of this study demonstrate a benefit of the web-based tailored behavioral support material s used in conjunction with nicotine replacement therapy . A web-based program that collects relevant information from users and tailors the intervention to their specific needs had significant advantages over a web-based non-tailored cessation program The aim of this study was to examine moderating and mediating factors of the efficacy of World Wide Web-based tailored behavioral smoking cessation material s. The design was a two-group r and omized controlled trial in Engl and and the Republic of Irel and . Participants were 3971 subjects who purchased a particular br and of nicotine patch and logged on to use a free Web-based behavioral support program . The intervention was Web-based tailored behavioral smoking cessation material s or Web-based nontailored material s. The 10-week continuous abstinence rate was assessed by Internet-based survey at 12-week follow-up . Potential treatment moderators were examined using subgroups of established or possible predictors of smoking cessation . Treatment mediators examined included 6-week follow-up measures of program relevance and amount of the Web-based material s read . Within all subgroups examined , subjects in the Web-based tailored intervention were more likely to report 10-week continuous abstinence at 12-week follow-up . Significant moderators , indicating a significant difference in program efficacy between subgroups , included presence of a tobacco-related illness ( larger treatment-control differences among subjects with a tobacco-related illness ) , presence of nonsmoking children in the household ( larger treatment-control differences among subjects with nonsmoking children in the household ) , and frequent alcohol consumption ( larger treatment-control differences among subjects with higher alcohol consumption ) . Perceived program relevance at 6-week follow-up was a mediator of cessation at 12-week follow-up . Robust results of the tailored program may be explained by the tailoring strategies utilized in the treatment conditions . Moderating variables may be particularly useful to address in tailored messaging . The mediating factor of perceived message relevance may provide a partial mechanism of effective program tailoring BACKGROUND We previously documented that cognitive behavioral therapy for smoking-related weight concerns ( CONCERNS ) improves cessation rates . However , the efficacy of combining CONCERNS with cessation medication is unknown . We sought to determine if the combination of CONCERNS and bupropion therapy would enhance abstinence for weight-concerned women smokers . METHODS In a r and omized , double-blind , placebo-controlled trial , weight-concerned women ( n = 349 ; 86 % white ) received smoking cessation counseling and were r and omized to 1 of 2 adjunctive counseling components : CONCERNS or ST AND ARD ( st and ard cessation treatment with added discussion of smoking topics but no specific weight focus ) , and 1 of 2 medication conditions : bupropion hydrochloride sustained release ( B ) or placebo ( P ) for 6 months . Rates and duration of biochemically verified prolonged abstinence were the primary outcomes . Point-prevalent abstinence , postcessation weight gain , and changes in nicotine withdrawal , depressive symptoms , and weight concerns were evaluated . RESULTS Women in the CONCERNS + B group had higher rates of abstinence ( 34.0 % ) and longer time to relapse than did those in the ST AND ARD + B ( 21 % ; P = .05 ) or CONCERNS + P ( 11.5 % ; P = .005 ) groups at 6 months , although rates of prolonged abstinence in the CONCERNS + B and ST AND ARD + B groups did not differ significantly at 12 months . Abstinence rates and duration did not differ in the ST AND ARD + B group ( 21 % and 19 % ) compared with the ST AND ARD + P group ( 10 % and 7 % ) at 6 and 12 months , respectively . There were no differences among abstinent women in postcessation weight gain or weight concerns , although ST AND ARD + B produced greater decreases in nicotine withdrawal and depressive symptoms than did ST AND ARD + P. CONCLUSIONS Weight-concerned women smokers receiving the combination of CONCERNS + B were most likely to sustain abstinence . This effect was not related to differences in postcessation weight gain or changes in weight concerns . Trial Registration clinical trials.gov Identifier : NCT00006170 This study examines the efficacy of targeted versus st and ard care smoking cessation material s among urban African American smokers . Five hundred smokers ( 250 to each group ) are r and omized to receive a culturally targeted or st and ard care videotape and print guide . Both groups receive 8 weeks of nicotine patches and reminder telephone calls at Weeks 1 and 3 . Process outcomes include material use and salience at 1 and 4 weeks postbaseline . Smoking outcomes include 7-day abstinence , smoking reduction , and readiness to quit at 4 weeks and 6 months postbaseline . Despite greater use of the targeted guide ( 68.8 % vs. 59.6 % , p < .05 ) , intervention participants do not perceive the targeted material s as more salient , and no significant differences are found between groups on the smoking outcomes . Findings point to the importance of greater audience segmentation and individual tailoring to better match intervention material s to the needs of the priority population AIMS To determine whether African American light smokers who smoked menthol cigarettes had lower cessation when treated with nicotine replacement therapy and counseling . DESIGN Data were derived from a clinical trial that assessed the efficacy of 2 mg nicotine gum ( versus placebo ) and counseling ( motivational interviewing counseling versus Health Education ) for smoking cessation among African American light smokers ( smoked < or = 10 cigarettes per day ) . PARTICIPANTS The sample consisted of 755 African American light smokers . MEASUREMENTS The primary outcome variable was verified 7-day point-prevalence smoking cessation at 26 weeks follow-up . Verification was by salivary cotinine . FINDINGS Compared to non-menthol smokers , menthol smokers were younger and less confident to quit smoking ( P = 0.023 ) . At 26 weeks post-r and omization , 7-day verified abstinence rate was significantly lower for menthol smokers ( 11.2 % versus 18.8 % for non-menthol , P = 0.015 ) . CONCLUSIONS Among African American light smokers , use of menthol cigarettes is associated with lower smoking cessation rates . Because the majority of African American smokers use menthol cigarettes , a better underst and ing of the mechanism for this lower quit rate is needed We assessed the impact of three conditions on one-year smoking cessation rates . Physicians in 70 community general practice s were r and omly allocated by practice to one of three groups : In the usual care group , smoking patients were to receive the care they normally would receive . In the gum only group , physicians were asked to speak to patients about smoking cessation and offer nicotine gum . In the gum plus group , physicians were trained in the experimental intervention . This intervention involved advice to stop smoking , the setting of a quit date , the offer of nicotine gum , and four follow-up visits . Smoking cessation was measured by self-report after one year and vali date d using saliva cotinine measures . Using a criterion of at least three months of abstinence , 8.8 % of the patients of the trained physicians had stopped smoking at the one-year follow-up compared with 4.4 % and 6.1 % of the patients in the usual care and gum only groups , respectively This article examines reported symptoms , nonsmoking rates , and medication use among 1,018 smokers using varenicline in a r and omized trial comparing three forms of behavioral support for smoking cessation ( phone , Web , or phone + Web ) . One month after beginning varenicline , 168 people ( 17 % ) had discontinued the medication . Most ( 53 % ) quit due to side effects and other symptoms . The most common side effect among all users was nausea ( reported by 57 % of users ) . At 1 month post medication initiation , those not taking varenicline were more likely to report smoking than those who continued the medication ( 57 % vs. 16 % , p < .001 ) . Women reported more symptoms but did not discontinue medication at higher rates . Participants who received any telephone counseling ( n = 681 ) were less likely to discontinue their medication than those with Web support only ( 15 % vs. 21 % , p < .01 ) . Counseling may improve tolerance of this medication and reduce the rate of discontinuation due to side effects OBJECTIVE Depressive symptoms are associated with poor smoking cessation outcomes , and there remains continued interest in behavioral interventions that simultaneously target smoking and depressive symptomatology . In this pilot study , we examined whether a behavioral activation treatment for smoking ( BATS ) can enhance cessation outcomes . METHOD A sample of 68 adult smokers with mildly elevated depressive symptoms ( M = 43.8 years of age ; 48.5 % were women ; 72.7 % were African American ) seeking smoking cessation treatment were r and omized to receive either BATS paired with st and ard treatment ( ST ) smoking cessation strategies including nicotine replacement therapy ( n = 35 ) or ST alone including nicotine replacement therapy ( n = 33 ) . BATS and ST were matched for contact time and included 8 sessions of group-based treatment . Quit date was assigned to occur at Session 4 for each treatment condition . Participants completed a baseline assessment ; furthermore , measures of smoking cessation outcomes ( 7-day verified point-prevalence abstinence ) , depressive symptoms ( Beck Depression Inventory-II ; Beck , Steer , & Brown , 1996 ) , and enjoyment from daily activities ( Environmental Reward Observation Scale ; Armento & Hopko , 2007 ) were obtained at 1 , 4 , 16 , and 26 weeks post assigned quit date . RESULTS Across the follow-ups over 26 weeks , participants in BATS reported greater smoking abstinence ( adjusted odds ratio = 3.59 , 95 % CI [ 1.22 , 10.53 ] , p = .02 ) than did those in ST . Participants in BATS also reported a greater reduction in depressive symptoms ( B = -1.99 , SE = 0.86 , p = .02 ) than did those in ST . CONCLUSIONS Results suggest BATS is a promising intervention that may promote smoking cessation and improve depressive symptoms among underserved smokers of diverse background AIMS Tobacco dependence treatments achieve abstinence rates of 25 - 30 % at 1 year . Low rates may reflect failure to conceptualize tobacco dependence as a chronic disorder . The aims of the present study were to determine the efficacy of extended cognitive behavioral and pharmacological interventions in smokers > or = 50 years of age , and to determine if gender differences in efficacy existed . DESIGN Open r and omized clinical trial . SETTING A free-st and ing , smoking treatment research clinic . PARTICIPANTS A total of 402 smokers of > or = 10 cigarettes per day , all 50 years of age or older . INTERVENTION Participants completed a 12-week treatment that included group counseling , nicotine replacement therapy ( NRT ) and bupropion . Participants , independent of smoking status , were then assigned r and omly to follow-up conditions : ( i ) st and ard treatment ( ST ; no further treatment ) ; ( ii ) extended NRT ( E-NRT ; 40 weeks of nicotine gum availability ) ; ( iii ) extended cognitive behavioral therapy ( E-CBT ; 11 cognitive behavioral sessions over a 40-week period ) ; or ( iv ) E-CBT plus E-NRT ( E-combined ; 11 cognitive behavioral sessions plus 40 weeks nicotine gum availability ) . MEASUREMENTS Primary outcome variable was 7-day point prevalence cigarette abstinence verified biochemically at weeks 24 , 52 , 64 and 104 . FINDINGS The most clinical ly important findings were significant main effects for treatment condition , time and the treatment x time interaction . The E-CBT condition produced high cigarette abstinence rates that were maintained throughout the 2-year study period [ ( week 24 ( 58 % ) , 52 ( 55 % ) , 64 ( 55 % ) and 104 ( 55 % ) ] , and was significantly more effective than E-NRT and ST across that period . No other treatment condition was significantly different to ST . No effects for gender were found . CONCLUSIONS Extended cognitive behavioral treatments can produce high and stable cigarette abstinence rates for both men and women . NRT does not add to the efficacy of extended CBT , and may hamper its efficacy . Research is needed to determine if these results can be replicated in a sample with a greater range of ages , and improved upon with the addition of medications other than NRT Objective : To assess the relative impacts of three physician-delivered smoking interventions in combination with follow-up contact from behavioral counselors . Design : R and omized controlled trial with pre-post measures of smoking rates . This paper reports six-month outcome data . Setting : Participants were recruited from among patients seen by 196 medical and family practice residents in five primary care clinics . Participants : Participants were 1,286 patients out of 1,946 eligible smokers approached . The patient group was 57 % female and 91 % white , had an average age of 35 years , and smoked , on average , slightly over one pack per day . Intervention : Physicians were trained to provide each of three interventions : advice only , brief patient-centered counseling , and counseling plus prescription of nicotine-containing gum ( Nicorette ™ ) . Half the patients received follow-up in the form of telephone counseling at three-monthly intervals from behavioral counselors . Measurements and main results : Changes in smoking behaviors were assessed by telephone interview six months after physician intervention . The differences in one-week point prevalence cessation rates among the physician interventions were significant ( p<0.01 ) : advice only , 9.1 % ; counseling , 11.9 % ; counseling plus gum , 17.4 % ; with no effect for telephone counseling . The time elapsed from physician encounter to initial quitting and the length of that period of abstinence also showed significant benefit of the counseling interventions . Patients receiving physician counseling were much more likely than those not receiving counseling to rate their physician as very helpful ( p<0.001 ) . Multiple regression analyses are also reported . Conclusion : Smoking intervention counseling provided by physicians is well received by patients and significantly increases the likelihood of cessation at six months , an effect that is augmented by the prescription of nicotine-containing gum , when compared with physician-delivered advice . Follow-up telephone counseling does not contribute significantly to smoking behavior changes INTRODUCTION People with severe mental disorders typically experience a range of health problems ; consequently , interventions addressing multiple health behaviors may provide an efficient way to tackle this major public health issue . This two-arm r and omized controlled trial among people with psychotic disorders examined the efficacy of nicotine replacement therapy ( NRT ) plus either a face-to-face or predominantly telephone delivered intervention for smoking cessation and cardiovascular disease ( CVD ) risk reduction . METHODS Following baseline assessment and completion of a common , individually delivered 90-minute face-to-face intervention , participants ( n = 235 ) were r and omized to receive NRT plus : ( 1 ) a " Healthy Lifestyles " intervention for smoking cessation and CVD risk behaviors or ( 2 ) a predominantly telephone-based intervention ( design ed to control for NRT provision , session frequency , and other monitoring activities ) . Research assistants blind to treatment allocation performed assessment s at 15 weeks ( mid-intervention ) and 12 months after baseline . RESULTS There were no significant differences between intervention conditions in CVD risk or smoking outcomes at 15 weeks or 12 months , with improvements in both conditions ( eg , 12 months : 6.4 % confirmed point prevalence abstinence rate ; 17 % experiencing a 50 % or greater smoking reduction ; mean reduction of 8.6 cigarettes per day ; mean improvement in functioning of 9.8 points ) . CONCLUSIONS The health disparity experienced by people with psychotic disorders is high . Face-to-face Healthy Lifestyle interventions appear to be feasible and somewhat effective . However , given the accessibility of telephone delivered interventions , potentially combined with lower cost , further studies are needed to evaluate telephone delivered smoking cessation and lifestyle interventions for people with psychotic disorders INTRODUCTION Smoking prevalence in homeless population s is strikingly high ( ∼70 % ) ; yet , little is known about effective smoking cessation interventions for this population . We conducted a community-based clinical trial , Power To Quit ( PTQ ) , to assess the effects of motivational interviewing ( MI ) and nicotine patch ( nicotine replacement therapy [ NRT ] ) on smoking cessation among homeless smokers . This paper describes the smoking characteristics and comorbidities of smokers in the study . METHODS Four hundred and thirty homeless adult smokers were r and omized to either the intervention arm ( NRT + MI ) or the control arm ( NRT + Brief Advice ) . Baseline assessment included demographic information , shelter status , smoking history , motivation to quit smoking , alcohol/other substance abuse , and psychiatric comorbidities . RESULTS Of the 849 individuals who completed the eligibility survey , 578 ( 68.1 % ) were eligible and 430 ( 74.4 % of eligibles ) were enrolled . Participants were predominantly Black , male , and had mean age of 44.4 years ( S D = 9.9 ) , and the majority were unemployed ( 90.5 % ) . Most participants reported sleeping in emergency shelters ; nearly half had been homeless for more than a year . Nearly all the participants were daily smokers who smoked an average of 20 cigarettes/day . Nearly 40 % had patient health question naire-9 depression scores in the moderate or worse range , and more than 80 % screened positive for lifetime history of drug abuse or dependence . CONCLUSIONS This study demonstrates the feasibility of enrolling a diverse sample of homeless smokers into a smoking cessation clinical trial . The uniqueness of the study sample enables investigators to examine the influence of nicotine dependence as well as psychiatric and substance abuse comorbidities on smoking cessation outcomes OBJECTIVES We evaluated smoking-cessation efficacy of an extended course of sustained-release bupropion ( bupropion SR ) and cognitive-behavioral treatment ( CBT ) . METHODS Participants who smoked at least 10 cigarettes per day and who smoked within 30 minutes of arising ( n = 406 ) completed a 12-week smoking-cessation treatment including group counseling , nicotine-replacement therapy , and bupropion SR . Participants were then r and omly assigned to 1 of 5 conditions : ( 1 ) no further treatment , ( 2 ) active bupropion SR for 40 weeks , ( 3 ) placebo for 40 weeks , ( 4 ) active bupropion SR and 11 sessions of CBT for 40 weeks ( A-CBT ) , or ( 5 ) placebo and 11 sessions of CBT for 40 weeks . Participants were assessed at baseline and at weeks 12 , 24 , 52 , 64 , and 104 . RESULTS A-CBT was not superior to the other 3 extended treatments . From weeks 12 through 104 , all extended treatment conditions were superior to st and ard treatment . At weeks 64 and 104 , the 2 CBT conditions produced significantly higher abstinence rates than did the other 3 conditions . CONCLUSIONS Brief contact with providers can increase abstinence during treatment . CBT may increase long-term abstinence after extended treatment is terminated The study was conducted to examine the relative effectiveness of cognitive behavior therapy with a cultural tailoring intervention compared to brief medication management . The study used a two-arm r and omized controlled trial in which participant assignment was stratified by gender . The intervention condition received eight weekly 40-min individualized counseling sessions of culturally tailored cognitive behavior therapy , while the control condition received eight weekly 10-min individualized counseling sessions of medication management . Both conditions received nicotine patches for 8 weeks . Data were collected at baseline and at four follow-up points ( one and 4 weeks , and three and 6 months post-quit ) . Treatment outcomes were presented as an intention-to-treat analysis . Thirty Korean immigrants participated in the study . At 6-month follow-up , 57.1 % of participants in the intervention and 18.8 % of participants in the control had 7-day point prevalence abstinence ( odds ratio = 5.8 , 95 % confidence interval = 1.12–26.04 , P = 0.04 ) . Participants ’ self-reported abstinence was biochemically verified with exhaled carbon monoxide and salivary cotinine levels . A combination of the culturally tailored cognitive behavior therapy and nicotine replacement therapy had a better treatment outcome compared to brief medication management . The promising result suggests a need to further test the intervention in larger sample s and longer follow-up assessment s before it can be adapted in clinical setting Alcohol dependent smokers ( N=118 ) enrolled in an intensive outpatient substance abuse treatment program were r and omized to a concurrent brief or intensive smoking cessation intervention . Brief treatment consisted of a 15-min counseling session with 5 min of follow-up . Intensive intervention consisted of three 1-hr counseling sessions plus 8 weeks of nicotine patch therapy . The cigarette abstinence rate , verified by breath carbon monoxide , was significantly higher for the intensive treatment group ( 27.5 % ) versus the rate for the brief treatment group ( 6.6 % ) at 1 month after the quit date but not at 6 months , when abstinence rates fell to 9.1 % for the intensive treatment group and 2.1 % for the brief treatment group . Smoking treatment assignment did not significantly impact alcohol outcomes . Although intensive smoking treatment was associated with higher rates of short-term tobacco abstinence , other , perhaps more intensive , smoking interventions are needed to produce lasting smoking cessation in alcohol dependent smokers Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid ( LCPUFA ) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age . Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome ( DOMInO ) r and omised controlled trial . Setting Adelaide , South Australia . Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial . Interventions The intervention group ( n=368 ) was r and omly allocated to receive fish oil capsules ( providing 900 mg of n-3 LCPUFA daily ) from 21 weeks ’ gestation until birth ; the control group ( n=338 ) received matched vegetable oil capsules without n-3 LCPUFA . Main outcome measure Immunoglobulin E associated allergic disease ( eczema or food allergy with sensitisation ) at 1 year of age . Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups ( 32/368 ( 9 % ) v 43/338 ( 13 % ) ; unadjusted relative risk 0.68 , 95 % confidence interval 0.43 to 1.05 , P=0.08 ; adjusted relative risk 0.70 , 0.45 to 1.09 , P=0.12 ) , although the percentage of infants diagnosed as having atopic eczema ( that is , eczema with associated sensitisation ) was lower in the n-3 LCPUFA group ( 26/368 ( 7 % ) v 39/338 ( 12 % ) ; unadjusted relative risk 0.61 , 0.38 to 0.98 , P=0.04 ; adjusted relative risk 0.64 , 0.40 to 1.02 , P=0.06 ) . Fewer infants were sensitised to egg in the n-3 LCPUFA group ( 34/368 ( 9 % ) v 52/338 ( 15 % ) ; unadjusted relative risk 0.61 , 0.40 to 0.91 , P=0.02 ; adjusted relative risk 0.62 , 0.41 to 0.93 , P=0.02 ) , but no difference between groups in immunoglobulin E associated food allergy was seen . Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life , although atopic eczema and egg sensitisation were lower . Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12610000735055 ( DOMInO trial : ACTRN12605000569606 ) Abstract OBJECTIVE : To examine the predictors of quitting among African American ( AA ) light smokers ( < 10 cigarettes per day ) enrolled in a smoking cessation trial . METHODS : Baseline variables were analyzed as potential predictors from a 2 × 2 cessation trial in which participants were r and omly assigned to 1 of 4 treatment groups : nicotine gum plus health education ( HE ) counseling , nicotine gum plus motivational interviewing ( MI ) counseling , placebo gum plus HE counseling , or placebo gum plus MI counseling . Chi-square tests , 2 sample t-tests , and multiple logistic regression analyses were used to identify predictors of cotinine ( COT ) verified abstinence at month 6 . RESULTS : In the final regression model , HE rather than MI counseling ( odds ratio [OR]=2.26 % , 95 % confidence interval [CI]=1.36 to 3.74 ) , older age ( OR=1.03 % , 95 % CI=1.01 to 1.06 ) , and higher body mass index ( OR=1.04 % , 95 % CI=1.01 to 1.07 ) significantly increased the likelihood of quitting , while female gender ( OR=0.46 % , 95 % CI=0.28 to 0.76 ) , ≤$1,800/month income ( OR=0.60 % , 95 % CI=0.37 to 0.97 ) , higher baseline COT ( OR=0.948 % , 95 % CI=0.946 to 0.950 ) , and not completing all counseling sessions ( OR=0.48 % , 95 % CI=0.27 to 0.84 ) reduced the odds of quitting . CONCLUSIONS : Individual characteristics may decrease the likelihood of quitting ; however , the provision of directive , advice-oriented counseling focused on the addictive nature of nicotine , health consequences of smoking , benefits of quitting , and development of a concrete quit plan may be an important and effective facilitator of quitting among AA light smokers OBJECTIVE To compare the efficacy and safety of 22-mg and 44-mg doses of transdermal nicotine therapy when it is paired with minimal , individual , or group counseling to improve smoking cessation rates . DESIGN An 8-week clinical trial ( 4 weeks double-blind followed by 4 weeks open label ) using r and om assignment of participants to both dose ( 22 or 44 mg ) and counseling ( minimal , individual , or group ) conditions . PARTICIPANTS Daily cigarette smokers ( > or = 15 cigarettes per day for at least 1 year ) who volunteered to participate in a study of smoking cessation treatment . A total of 504 participants were enrolled at two sites . INTERVENTION Four weeks of 22- or 44-mg transdermal nicotine therapy followed by 4 weeks of dosage reduction ( 2 weeks of 22 mg followed by 2 weeks of 11 mg ) . Counseling consisted of a self-help pamphlet ( minimal ) ; a self-help pamphlet , a brief physician motivational message , and three brief ( < 15 minutes ) follow-up visits with a nurse ( individual ) ; or the pamphlet , the motivational message , and eight weekly 1-hour group smoking cessation counseling visits ( group ) . All participants returned weekly to turn in question naires and for assessment of their smoking status . MAIN OUTCOME MEASURES Abstinence from smoking was based on self-report , confirmed by an expired carbon monoxide concentration lower than 10 ppm . Withdrawal severity was assessed by means of an eight-item self-report question naire completed daily . RESULTS Smoking cessation rates for the two nicotine patch doses and three levels of counseling did not differ significantly at either 8 weeks or 26 weeks following the quit date . Among those receiving minimal contact , the 44-mg dose produced greater abstinence at 4 weeks than did the 22-mg dose ( 68 % vs 45 % ; P < .01 ) . Participants receiving minimal-contact adjuvant treatment were less likely to be abstinent at the end of 4 weeks than those receiving individual or group counseling ( 56 % vs 67 % ; P < .05 ) . The 44-mg dose decreased desire to smoke more than the 22-mg dose , but this effect was not related to success in quitting smoking . Transdermal nicotine therapy at doses of 44 mg produced a significantly greater frequency of nausea ( 28 % ) , vomiting ( 10 % ) , and erythema with edema at the patch site ( 30 % ) than did a 22-mg dose ( 10 % , 2 % , and 13 % , respectively ; P < .01 for each adverse effect ) . Three serious adverse events occurred during use of the 44-mg patch dose . CONCLUSIONS There does not appear to be any general , sustained benefit of initiating transdermal nicotine therapy with a 44-mg patch dose or of providing intense adjuvant smoking cessation treatment . The two doses and all adjuvant treatments produced equivalent effects at the 26-week follow-up , and the higher patch dose produced more adverse effects . Higher-dose ( 44-mg ) nicotine replacement does not appear to be indicated for general clinical population s , although it may provide short-term benefit to some smokers attempting to quit with minimal adjuvant treatment Whereas telephone-based counseling has been found to be effective in supporting smokers interested in quitting smoking , it is not known whether proactive efforts to reach smokers receiving cessation medications will enhance their likelihood of successful quitting . We had an opportunity to test , in a health plan setting , an offer of telephone-based counseling with smokers identified from health plan records as recently filling a prescription for nicotine replacement therapy or bupropion . After we removed 31 members determined to be ineligible , 1,329 were r and omly allocated to receive an invitation either to telephone-based counseling ( n = 663 ) or to a control group ( n = 666 ) . On average , 7 days ( range = 3 - 15 days ) elapsed from the day of the prescription fill until the Center for Health Promotion began calling to invite members to participate in telephone counseling . The Center for Health Promotion was able to reach 49 % of those in the intervention group ( 323/663 ) . Of these members , 118 ( 37 % ) declined any participation . Therefore , in response to the proactive contact , 63 % ( 205/323 ) of those reached and 31 % ( 205/663 ) of those eligible participated in some smoking cessation counseling . At the 3-month follow-up , we observed an increased quit rate ( 33.1 % vs. 27.4 % ) among health plan members r and omized to telephone-based smoking cessation counseling . The results varied by gender and amount smoked . In addition , the variables associated with quitting in a multivariate logistic regression model included older age and using more than 30 days of medication Introduction : Few studies have evaluated exercise interventions for smokers with depression or other psychiatric comorbidities . This pilot study evaluated the potential role of supervised vigorous exercise as a smoking cessation intervention for depressed females . Methods : Thirty adult women with moderate – severe depressive symptoms were enrolled and r and omly assigned to 12 weeks of thrice weekly , in person sessions of vigorous intensity supervised exercise at a YMCA setting ( EX ; n = 15 ) or health education ( HE ; n = 15 ) . All participants received behavioral smoking cessation counseling and nicotine patch therapy . Assessment s were done in person at baseline , at the end of 12 weeks of treatment , and at 6 months post-target quit date . Primary end points were exercise adherence ( proportion of 36 sessions attended ) and biochemically confirmed 7-day point prevalence abstinence at Week 12 . Biomarkers of inflammation were explored for differences between treatment groups and between women who smoked and those abstinent at Week 12 . Results : Treatment adherence was high for both groups ( 72 % for EX and 66 % for HE ; p = .55 ) . The Week 12 smoking abstinence rate was higher for EX than HE ( 11/15 [ 73 % ] vs. 5/15 [ 33 % ] ; p = .028 ) , but no significant differences emerged at 6-month follow-up . Interleukin-6 levels increased more for those smoking than women abstinent at Week 12 ( p = .040 ) . Conclusions : Vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers . Innovative and cost-effective strategies to bolster long-term exercise adherence and smoking cessation need evaluation in this population . Inflammatory biomarkers could be examined in future research as mediators of treatment efficacy . Implication s : This preliminary study found that vigorous intensity supervised exercise is feasible and enhances short-term smoking cessation among depressed female smokers . This research addressed an important gap in the field . Despite decades of research examining exercise interventions for smoking cessation , few studies were done among depressed smokers or those with comorbid psychiatric disorders . A novel finding was increases in levels of a pro-inflammatory biomarker observed among women who smoked at the end of the intervention compared to those who did not Posttraumatic stress disorder ( PTSD ) is related to an increased risk of smoking cessation failure . In fact , the quit rate in smokers with PTSD ( 23.2 % ) is one of the lowest of all mental disorders . Features of PTSD that contribute to smokers ' progression to nicotine dependence and cessation relapse include negative affect , fear , increased arousal , irritability , anger , distress intolerance , and anxiety sensitivity . Anxiety sensitivity is higher in people with PTSD than in any other anxiety disorder except for panic disorder . High anxiety sensitivity is uniquely associated with greater odds of lapse and relapse during quit attempts . Distress intolerance , a perceived or behavioral tendency to not tolerate distress , is related to both the maintenance of PTSD and problems in quitting smoking . Prolonged exposure ( PE ) and interoceptive exposure ( IE ) reduce PTSD symptoms , distress intolerance , and anxiety sensitivity . Thus , they emerge as promising c and i date s to augment st and ard smoking cessation interventions for individuals with PTSD . The present study tests a 12-session specialized treatment for smokers with PTSD . This Integrated PTSD and Smoking Treatment ( IPST ) combines cognitive-behavioral therapy and nicotine replacement treatment for smoking cessation ( st and ard care ; SC ) with PE to target PTSD symptoms and IE to reduce anxiety sensitivity and distress intolerance . Adult smokers ( N=80 ) with PTSD will be r and omly assigned to either : ( 1 ) IPST or ( 2 ) SC . Primary outcomes are assessed at weeks 0 , 6 , 8 , 10 , 14 , 16 , 22 , and 30 OBJECTIVE Greater depressive symptoms and low positive affect ( PA ) are associated with poor smoking cessation outcomes . Smoking cessation approaches that incorporate a focus on PA may benefit smokers trying to quit . The purpose of this study was to conduct a pilot r and omized clinical trial to compare st and ard smoking cessation treatment ( ST ) with smoking cessation treatment that targets positive affect , termed positive psychotherapy for smoking cessation ( PPT-S ) . METHOD Smokers who were seeking smoking cessation treatment were assigned by urn r and omization to receive , along with 8 weeks of nicotine replacement therapy , either ST ( n = 31 ) or PPT-S ( n = 35 ) . Seven-day point prevalence smoking abstinence was biochemically confirmed at 8 , 16 , and 26 weeks . RESULTS Compared to ST , a greater percentage of participants in PPT-S were abstinent at 8 weeks , 16 weeks , and 26 weeks , but these differences were nonsignificant . In a more statistically powerful longitudinal model , participants in PPT-S had a significantly higher odds of abstinence ( adjusted odds ratio [ AOR ] = 2.75 ; 95 % CI = 1.02 , 7.42 ; p = .046 ) across follow-ups compared to those in ST . The positive effect of PPT-S was stronger for those higher in PA ( OR = 6.69 , 95 % CI = 1.16 , 38.47 , p = .03 ) . Greater use of PPT-S strategies during the initial 8 weeks of quitting was associated with a less steep decline in smoking abstinence rates over time ( OR = 2.64 , 95 % CI = 1.06 , 6.56 , p = .04 ) . CONCLUSION This trial suggests substantial promise for incorporating PPT into smoking cessation treatment BACKGROUND Smoking remains the primary preventable cause of death and illness in the U.S. Effective , convenient treatment programs are needed to reduce smoking prevalence . PURPOSE This study compared the effectiveness of three modalities of a behavioral smoking-cessation program in smokers using varenicline . METHODS Current treatment-seeking smokers ( n=1202 ) were recruited from a large healthcare organization between October 2006 and October 2007 . Eligible participants were r and omized to one of three smoking-cessation interventions : web-based counseling ( n=401 ) ; proactive telephone-based counseling ( PTC ; n=402 ) ; or combined PTC and web counseling ( n=399 ) . All participants received a st and ard 12-week FDA -approved course of varenicline . Self-report determined the primary outcomes ( 7-day point prevalent abstinence at 3- and 6-month follow-ups ) ; the number of days varenicline was taken ; and treatment-related symptoms . Behavioral measures determined utilization of both the web- and Phone-based counseling . RESULTS Intent-to-treat analyses revealed relatively high percentages of abstinence at 3 months ( 38.9 % , 48.5 % , 43.4 % ) and at 6 months ( 30.7 % , 34.3 % , 33.8 % ) for the web , PTC , and PTC-web groups , respectively . The PTC group had a significantly higher percentage of abstinence than the web group at 3 months ( OR=1.48 , 95 % CI=1.12 , 1.96 ) , but no between-group differences in abstinence outcomes were seen at 6 months . CONCLUSIONS Phone counseling had greater treatment advantage for early cessation and appeared to increase medication adherence , but the absence of differences at 6 months suggests that any of the interventions hold promise when used in conjunction with varenicline AIM Approximately 50 % of African American smokers are light smokers ( smoke < or = 10 cigarettes a day ) . The prevalence of light smoking in the United States is increasing , yet there has not been a single smoking cessation clinical trial targeting light smokers . The purpose of this 2 x 2 factorial , r and omized clinical trial was to evaluate the efficacy of nicotine gum ( 2 mg versus placebo ) and counseling ( motivational interviewing versus health education ) for African American light smokers . DESIGN Participants were assigned r and omly to one of four study arms : 2 mg nicotine gum plus health education ( HE ) ; 2 mg nicotine gum plus motivational interviewing ( MI ) ; placebo gum plus HE ; and placebo gum plus MI . PARTICIPANTS AND SETTING A total of 755 African American light smokers ( 66 % female , mean age = 45 ) were enrolled at a community health center over a 16-month period . INTERVENTION AND MEASUREMENTS Participants received an 8-week supply of nicotine gum and six counseling sessions during the course of the 26-week study . Biochemical measures included expired carbon monoxide ( CO ) and serum and salivary cotinine . FINDINGS Seven-day quit rates for nicotine gum were no better than for the placebo group ( 14.2 % versus 11.1 % , P = 0.232 ) at 6 months . However , a counseling effect emerged , with HE performing significantly better than MI ( 16.7 % versus 8.5 % , P < 0.001 ) . These results were consistent across outcome time-points ( weeks 1 , 8 , and 26 ) . CONCLUSIONS Results highlight the potential positive impact of directive information and advice-oriented counseling on smoking cessation . Studies are needed to assess other interventions that may further improve quit rates among African American light smokers who are motivated to quit Pharmacists may be effective health care practitioners to deliver smoking cessation interventions . This paper examines the short-term outcomes of smokers r and omized to one of two models of a pharmacist-led smoking cessation intervention . Methods : An open-label pragmatic r and omized trial compared two models of a pharmacist-led behavioral intervention [ Group A ( 3-sessions ) vs. Group B ( 1-session ) ] in conjunction with 5 weeks of nicotine replacement therapy ( NRT ) . Ninety-eight pharmacies in Ontario , Canada delivered the intervention . Baseline demographic and smoking behavior data were recorded , as were intervention characteristics . Self-reported , 7-day point prevalence quit rates were obtained 5-week postintervention start date . Results : 6,987 individuals participated ; 51.4 % ( n = 3588 ) r and omized to Group A ; 48.6 % ( n = 3399 ) to Group B. Approximately , 50 % of Group A participants completed all three sessions . Quit rates were significantly higher among Group A , 3-session completers ( 27.7 % ; n = 478 ) compared to Group B participants ( 18.0 % ; n = 604 ) . Multivariable results suggest that even when controlling for possible confounders and clustering across pharmacies , Group A participants who completed all three sessions were more likely to quit compared to Group B [ OR = 1.72 ( 95 % CI : 1.53 , 1.94 ) ] . Conclusions : Cessation outcomes are higher among participants completing three intervention sessions compared to one session ; however , many do not return for follow-up sessions OBJECTIVE The present study assessed the effectiveness of smoking cessation programs combining individual and telephone counselling , compared to individual or telephone counselling alone . METHOD A r and omized , multicentre , open-label trial was performed between January 2009 and July 2011 at six smoking cessation clinics in Spain . Of 772 smokers assessed for eligibility , 600 ( 77 % ) met inclusion criteria and were r and omized . Smokers were r and omized to receive individual counselling , combined telephone and individual counselling , or telephone counselling . The primary outcome was biochemically vali date d continuous abstinence at 52 weeks . RESULTS The 52-week abstinence rate was significantly lower in the telephone group compared to the combined group ( 20.1 % vs. 29.0 % ; OR , 1.32 ; 95 % CI , 1.1 - 2.7 ) and to the individual counselling group ( 20.1 % vs. 27.9 % ; OR , 1.37 ; 95 % CI , 1.0 - 2.8 ) . The 52-week abstinence rates were not significantly higher in the combined group than the individual group ( OR , 0.97 ; 95 % CI , 0.7 - 1.4 ) . CONCLUSION Individual counselling and combined individual and telephone counselling were associated with higher 52-week abstinence rates than telephone counselling alone . A combined approach may be highly useful in the clinical treatment of smokers , as it involves less clinic visits than individual counselling alone , thus reducing the program cost , and it increases patient compliance compared to telephone counselling alone OBJECTIVE Accepted treatments for cigarette smoking rarely achieve abstinence rates of > 35 % at 1 year . Low rates may reflect failure to provide extended and multifocal treatment for this complex and chronic addiction . Using a chronic disease model of smoking , the authors undertook a study to determine the effects of long-term antidepressant and psychological treatment . METHOD One hundred sixty smokers of > or = 10 cigarettes/day were r and omly assigned to one of four treatment conditions in a two-by-two ( nortriptyline versus placebo by brief versus extended treatment ) design . All subjects received 8 weeks of a transdermal nicotine patch , five group counseling sessions , and active or placebo treatment . Interventions for subjects in brief treatment ended at this point . Subjects in extended treatment continued taking drug or placebo to week 52 and received an additional 9 monthly counseling sessions , with checkup telephone calls midway through each session . Subjects were assessed at baseline and weeks 12 , 24 , 36 , and 52 . The principal outcome variables were repeated abstinence at each assessment after the first over a 1-year period and a point prevalence of 7 days of abstinence . RESULTS At week 52 , point-prevalence abstinence rates with missing subjects imputed as smokers were 30 % for placebo brief treatment , 42 % for placebo extended treatment , 18 % for active brief treatment , and 50 % for active extended treatment . With missing subjects omitted , these rates were 32 % , 57 % , 21 % , and 56 % , respectively . CONCLUSIONS Comprehensive extended treatments that combine drug and psychological interventions can produce consistent abstinence rates that are substantially higher than those in the literature This was the first r and omized , controlled smoking cessation trial assessing the efficacy of an exercise intervention as an adjunct to nicotine gum therapy in comparison with both equal contact control and st and ard care control conditions . Sedentary female smokers aged 18 - 55 years were provided with nicotine gum treatment along with brief behavioral counseling and were r and omized into one of these three behavioral adjunct conditions . In the " intent-to-treat " sample ( N = 182 ) , at end of treatment and at 1-year follow-up , there were clear , but nonsignificant , trends in univariate analyses in which the exercise and equal contact control conditions both had higher rates of abstinence than the st and ard care control . However , when adjusting for other predictors of relapse in a multiple logistic regression , both exercise and equal contact control showed an advantage over st and ard care control in avoiding early relapse ( i.e. , after 1 week ) . In a multivariate survival model adjusting for other predictors , the equal contact condition had a significantly lower likelihood of relapse compared with the st and ard care condition and there was a near significant trend in which exercise offered an advantage over st and ard care as well . While these findings suggest a slightly improved likelihood of abstinence with exercise compared with st and ard care , exercise did not differ from equal contact control in its efficacy . Potential explanations for these equivalent levels of efficacy and implication s for the findings are discussed Korean men and women have the highest current smoking rates across all Asian ethnic subgroups in the United States . This is a 2-arm r and omized controlled study of a culturally adapted smoking cessation intervention . The experimental condition received eight weekly 40-min individualized counseling sessions that incorporated Korean-specific cultural elements , whereas the control condition received eight weekly 10-min individualized counseling sessions that were not culturally adapted . All participants also received nicotine patches for 8 weeks . One-hundred nine Korean immigrants ( 91 men and 18 women ) participated in the study . The rate of biochemically verified 12-month prolonged abstinence was significantly higher for the experimental condition than the control condition ( 38.2 vs. 11.1 % , χ2 = 10.7 , p < 0.01 ) . Perceived family norm significantly mediated the effect of cessation intervention on abstinence . Smoking cessation intervention for Korean Americans should be culturally adapted and involve family members to produce a long-term treatment effect Behavioral couples therapy ( BCT ) has been found to improve long-term abstinence rates in alcohol- and substance-dependent population s but has not been tested for smoking cessation . This pilot study examined the feasibility and acceptability of BCT for smoking-discordant couples . Forty-nine smokers ( smoking > 10 cigarettes/day ) with nonsmoking partners were r and omized to receive a couples social support ( BCT-S ) intervention or an individually delivered , st and ard smoking cessation treatment ( ST ) . The couples were married or had been cohabiting for at least 1 year , with partners who had never smoked or had not used tobacco in 1 year . Both treatments included 7 weekly sessions and 8 weeks of nicotine replacement therapy . Participants were followed for 6 months posttreatment . The Partner Interaction Question naire was used to measure perceived smoking-specific partner support . Participants were 67 % male and 88 % White . Biochemically verified cessation rates were 40.9 % , 50 % , and 45 % in BCT-S and 59.1 % , 50 % , and 55 % in ST at end of treatment , after 3 month , and after 6 months , respectively , and did not differ significantly between treatment conditions at any time point . Perceived smoking-specific partner support at posttreatment did not significantly differ between treatment groups . Results of this pilot study do not provide support for the efficacy of BCT in smoking-discordant couples Abstract INTRODUCTION : Many smokers reduce their cigarette consumption during failed attempts to quit . We report the impact of changes in consumption on smoking-related respiratory symptom severity ( SRRSS ) . METHODS : Between February 2002 and May 2004 we recruited 383 smokers from 5 methadone maintenance programs for a r and omized trial of nicotine replacement plus behavioral treatment versus nicotine replacement alone for smoking cessation . Cigarette use in the 28 days prior to the interview , and severity of SRRSS using a 7-item respiratory index , were assessed at baseline and at 3-month follow-up . OUTCOME : Baseline minus 3-month assessment difference in SRRSS score . RESULTS : Follow-up of 319 participants ( 83.3 % ) , mean age 40.4 years , 51.4 % male , who smoked 26.4 cigarettes per day , demonstrated a mean reduction of 16.7 cigarettes per day . A reduction in cigarette use was positively and significantly ( b=0.29 , t=5.16 , P<.001 ) associated with a reduction in smoking-related symptom severity after adjusting for age , gender , race , years of regular smoking , baseline nicotine dependence , and history of treatment for asthma or emphysema . A 1 st and ard deviation reduction in average daily smoking ( about 14.1 cigarettes ) was associated with a 0.28 st and ard deviation decrease in smoking-related symptom severity . CONCLUSION : Reduction in symptom severity increases as absolute reduction in daily smoking increases . This is the first study to demonstrate an association between subjective short-term health changes and reduction in smoking UNLABELLED PRIMARY AIM : Examine the effectiveness of extended cognitive behavior therapy ( CBT ) in promoting longer-term smoking abstinence . DESIGN Open-label treatment phase followed by extended treatment phase . R and omization conducted prior to entry into open-label treatment phase ; analysis based on intention-to-treat to avoid threat of selection bias . SETTING Community smoking cessation clinic . PARTICIPANTS A total of 304 adult smokers ( > or = 18 years of age ; > or = 10 cigarettes/day ) . INTERVENTION Open-label ( 8 weeks ) : all participants received bupropion SR , nicotine patch , CBT . Extended treatment ( 12 weeks ) : participants received either CBT + voicemail monitoring and telephone counseling or telephone-based general support . MEASUREMENTS Seven-day point prevalence abstinence , expired-air carbon monoxide . RESULTS At week 20 follow-up , CBT produced a higher 7-day point prevalence abstinence rate : 45 % versus 29 % , P = 0.006 ; at 52 weeks the difference in abstinence rates ( 31 % versus 27 % ) was not significant . History of depression was a moderator of treatment . Those with a positive history had a better treatment response at 20 weeks when assigned to the less intensive telephone support therapy ( P < 0.05 ) . CONCLUSION The superiority of CBT to 20 weeks suggests that continued emphasis on the development of cognitive and behavioral strategies for maintaining non-smoking during an extended treatment phase may help smokers to maintain abstinence in the longer term . At present , the minimum duration of therapy is unknown AIM To test , in combination with the nicotine patch , the incremental efficacy of a maximal , tailored behavioral treatment over a minimal treatment for smoking cessation . DESIGN R and omized clinical trial with 6-month follow-up . SETTING Five methadone maintenance treatment centers in Rhode Isl and . PARTICIPANTS Three hundred and eighty-three methadone-maintained smokers . INTERVENTION Participants were assigned r and omly to nicotine patch ( 8 - 12 weeks ) plus either ( 1 ) a baseline tailored brief motivational intervention , a quit date behavioral skills counseling session and a relapse prevention follow-up session ( Max ) or ( 2 ) brief advice using the National Cancer Institute 's 4 As model ( Min ) . An intent-to-treat analysis with those lost to follow-up assumed to smoke was used . MEASUREMENTS Carbon monoxide (CO)-confirmed 7-day point smoking cessation prevalence at 3 and 6 months , and self-reported numbers of cigarettes smoked per day . FINDINGS Participants had a mean age of 40 years , were 53 % male , 78 % Caucasian , smoked 26.7 ( + /- 12.2 ) cigarettes/day and had a mean methadone dose of 95.5 mg . At 3 months , 317 ( 83 % ) were re-interviewed ; at 6 months , 312 ( 82 % ) were re-interviewed . The intent-to-treat , 7-day point prevalence estimate of cessation was 5.2 % in the Max group and 4.7 % in the Min group ( P=0.81 ) at 6 months . In logistic models with treatment condition , age , gender , race , Fagerström Test for Nicotine Dependence and cigarettes per day as covariates , males were more likely to be abstinent at 3 months ( OR 4.67 ; P=0.003 ) and 6 months ( OR 4.01 ; P=0.015 ) . CONCLUSION A tailored behavioral intervention did not increase quit rates over patch and minimal treatment . Smoking cessation rates in methadone-maintained smokers are low , with men having greater success Gender data for bupropion suggest that it may be a particularly effective smoking cessation medication for women . It is not known whether the efficacy of this pharmacotherapy differs as a function of the psychotherapy with which it is administered . This study used a two level factorial design to examine the independent and interactive effects of medication ( bupropion 300 mg/day vs. placebo ) and psychotherapy ( cognitive-behavioral therapy [ CBT ] vs. supportive therapy [ ST ] ) . In addition to testing the hypothesis that bupropion with CBT would be most effective of all the treatments , we examined medication compliance and its role in the efficacy of bupropion . Participants were 154 women , aged at least 30 years and smoking more than 10 cigarettes/day . Compliance with study medication was assessed using Medication Event Monitoring Systems ( MEMS ) over 7 weeks of treatment . Psychological interventions were delivered in 60-min weekly group sessions . Longitudinal analysis of abstinence outcomes from end of treatment ( EOT ) through 12 months after treatment revealed a significant interaction of medication and therapy . Higher abstinence rates at EOT and 3- , 6- , 9- , and 12-month follow-ups were observed when bupropion was delivered concurrently with CBT ( 44 % , 24 % , 30 % , 23 % , 17 % ) rather than with ST ( 18 % , 1 % , 8 % , 5 % , 2 % ) . The bupropion-CBT combination , however , was not clearly superior to placebo , regardless of therapy assignment . Higher rates of medication compliance were positively predictive of abstinence , and this effect was most evident in the placebo condition . Findings provide only modest support for CBT as the preferred type of intensive therapy in conjunction with bupropion in women We evaluated gender differences in demographic , smoking history , nicotine dependence , transtheoretical , and perceived stress variables as predictors of smoking cessation . Participants ( n = 381 ) smoked at least 15 cigarettes per day and were motivated to quit . The outcome variable was 7-day abstinence at 1-year follow-up . Predictor variables included : age , education level , number of years smoking , cigarettes per day , quit attempts , nicotine dependence , stage of change , decisional balance , processes of change , self-efficacy , and perceived stress . Logistic regression analysis was used to derive predictive models for women and men . In women , lower scores for pre- and mid-treatment perceived stress significantly increased the likelihood of being abstinent at follow-up . For men , a higher level of education or number of quit attempts lasting > 24 hours in the past year , along with less frequent use of behavioural processes of change at baseline increased the probability of being abstinent at follow-up INTRODUCTION Telephone tobacco quitlines are effective and are widely used , with more than 500,000 U.S. callers in 2010 . This study investigated the clinical effectiveness and cost-effectiveness of 3 different quitline enhancements : combination nicotine replacement therapy ( NRT ) , longer duration of NRT , and counseling to increase NRT adherence . METHODS In this study , 987 quitline callers were r and omized to a combination of quitline treatments in a 2 × 2 × 2 factorial design : NRT duration ( 2 vs. 6 weeks ) , NRT type ( nicotine patch only vs. patch plus nicotine gum ) , and st and ard 4-call counseling ( SC ) versus SC plus medication adherence counseling ( MAC ) . The primary outcome was 7-day point-prevalence abstinence ( PPA ) at 6 months postquit in intention-to-treat ( ITT ) analyses . RESULTS Combination NRT for 6 weeks yielded the highest 6-month PPA rate ( 51.6 % ) compared with 2 weeks of nicotine patch ( 38.4 % ) , odds ratios [ OR ] = 1.71 ( 95 % confidence interval [CI]:1.20 - 2.45 ) . A similar result was found for 2 weeks of combination NRT ( 48.2 % ) , OR = 1.49 ( 95 % CI : 1.04 - 2.14 ) but not for 6 weeks of nicotine patch alone ( 46.2 % ) , OR = 1.38 ( 95 % CI : 0.96 - 1.97 ) . The MAC intervention effect was nonsignificant . Cost analyses showed that the 2-week combination NRT group had the lowest cost per quit ( $ 442 vs. $ 464 for 2-week patch only , $ 505 for 6-week patch only , and $ 675 for 6-week combination NRT ) . CONCLUSIONS Combination NRT for 2 or 6 weeks increased 6-month abstinence rates by 10 % and 13 % , respectively , over rates produced by 2 weeks of nicotine patch when offered with quitline counseling . A 10 % improvement would potentially yield an additional 50,000 quitters annually , assuming 500,000 callers to U.S. quitlines per year Background Smokers have a higher risk of complicated tissue and wound healing after surgery than nonsmokers . We tested the hypothesis that short‐term pre‐operative cessation of smoking in colorectal surgery decreases the incidence of postoperative tissue and wound complications UNLABELLED There are different modalities for management of Nicotine dependence , but it is still inconclusive which is the best modality for the treatment of Nicotine dependence syndrome ( NDS ) . In this background the present study was carried out to assess the efficacy and to compare different modalities for the treatment of NDS . METHODS Patients diagnosed as NDS as per ICD-10 were taken up for study . These patients were administered proforma to elicit sociodemographic details , Fagerstrom test for Nicotine Dependence , Question naire of Smoking Urges-Brief and breath analysis was done using carbon monoxide meter . Assessment was done at base line and at weekly follow-ups for 12 weeks . Patients were divided into six groups r and omly . Group A received BUP at a dose of 150mg/day for 3 days ; subsequently increased to 300mg/day , Group B : for initial 6 weeks Nicotine gum of 4 mg every 1 - 2 hourly was used and next 6 weeks every 2 - 4 hourly was used , Group C : BI , Group D : BI+BUP , Group E : BI+NRT , Group F received BUP+NRT+BI . RESULTS The quit rates at end of the study were BUP-30 % , NRT-26.66 % , BI-23.33 % , BI+BUP-43.33 % , BI+NRT-33.33 % , and BI+BUP+NRT-50 % . BI+BUP+NRT had 2 - 3 times more quit rates than the individual modality treatment group . CONCLUSION There was no statistically significant difference between the study groups , but there was clinical difference in quit rates . Among the groups BI+BUP+NRT had higher quit rates compared to other groups . Combination modalities yield better quit rates than individual modalities BACKGROUND A history of major depressive disorder ( MDD ) predicts failure to quit smoking . We determined the effect of nortriptyline hydrochloride and cognitive-behavioral therapy on smoking treatment outcome in smokers with a history of MDD . The study also addressed the effects of diagnosis and treatment condition on dysphoria after quitting smoking and the effects of dysphoria on abstinence . METHODS This was a 2 ( nortriptyline vs placebo ) x 2 ( cognitive-behavioral therapy vs control ) x 2 ( history of MDD vs no history ) r and omized trial . The participants were 199 cigarette smokers . The outcome measures were biologically verified abstinence from cigarettes at weeks 12 , 24 , 38 , and 64 . Mood , withdrawal , and depression were measured at 3 , 5 , and 8 days after the smoking quit date . RESULTS Nortriptyline produced higher abstinence rates than placebo , independent of depression history . Cognitive-behavioral therapy was more effective for participants with a history of depression . Nortriptyline alleviated a negative affect occurring after smoking cessation . Increases in the level of negative affect from baseline to 3 days after the smoking quit date predicted abstinence at later assessment s for MDD history-negative smokers . There was also a sex-by-depression history interaction ; MDD history-positive women were less likely to be abstinent than MDD history-negative women , but depression history did not predict abstinence for men . CONCLUSIONS Nortriptyline is a promising adjunct for smoking cessation . Smokers with a history of depression are aided by more intensive psychosocial treatments . Mood and diagnosis interact to predict relapse . Increases in negative affect after quitting smoking are attenuated by nortriptyline Earlier research indicated that a 10-session mood management ( MM ) intervention was more effective than a 5-session st and ard intervention for smokers with a history of major depressive disorder ( MDD ) . In a 2 x 2 factorial design , the present study compared MM intervention to a contact-equivalent health education intervention ( HE ) and 2 mg to 0 mg of nicotine gum for smokers with a history of MDD . Participants were 201 smokers , 22 % with a history of MDD . Contrary to the earlier findings , the MM and HE interventions produced similar abstinence rates : 2 mg gum was no more effective than placebo . History-positive participants had a greater increase in mood disturbance after the quit attempt . Independent of depression diagnosis , increases in negative mood immediately after quitting predicted smoking . No treatment differences were found in trends over time for measures of mood , withdrawal symptoms , pleasant activities and events , self-efficacy , and optimism and pessimism . History-positive smokers may be best treated by interventions providing additional support and contact , independent of therapeutic content OBJECTIVES The aims of this study were to identify prospect i ve determinants of smoking cessation in COPD patients , and to assess whether prospect i ve determinants vary between two different cessation interventions . METHODS Two hundred and twenty-five moderate to severe COPD patients were r and omly allocated to two smoking cessation interventions . One-year cotinine-vali date d continuous abstinence rates were 9 % for the minimal intervention strategy for lung patients ( LMIS ) and 19 % for the SmokeStopTherapy ( SST ) . The baseline characteristics that showed a significant univariate relationship with 1-year continuous abstinence ( p<.20 ) were included in the logistic regression model . This procedure was performed for each intervention separately . Variables that did not remain independent predictors were removed . RESULTS For the SST separately , no independent significant predictor remained . For the LMIS , attitude towards smoking cessation ( OR : 11.8 ; 95 % CI : 1.7 - 81.5 ; p=.013 ) and cotinine level ( OR : 2.1 ; 95 % CI : 1.08 - 3.93 ; p=.028 ) remained significant predictors . Within the LMIS , 31 % of the variance in continuous abstinence was explained by these variables ( p=.003 ) . CONCLUSION This study suggests that a moderately intensive intervention ( LMIS ) is primarily suitable for COPD patients with a positive attitude regarding smoking cessation . The more intensive SST can be an alternative for patients without such baseline characteristic . PRACTICE IMPLICATION S This stepped-care approach in smoking cessation counseling may be useful in clinical practice and will enable health care providers to match interventions to individual needs and increase efficiency The objective of the present study was to test whether confronting smokers with previously undetected chronic obstructive pulmonary disease ( COPD ) increases the rate of smoking cessation . In total , 296 smokers with no prior diagnosis of COPD were detected with mild-to-moderate airflow limitation by means of spirometry and r and omly allocated to : confrontational counselling by a nurse with nortriptyline for smoking cessation ( experimental group ) ; regular counselling by a nurse with nortriptyline ( control group 1 ) ; or “ care as usual ” for smoking cessation by the general practitioner ( control group 2 ) . Only the experimental group was confronted with their abnormal spirometry ( mean forced expiratory volume in one second ( FEV1 ) post-bronchodilator 80.5 % predicted , mean FEV1/forced vital capacity post-bronchodilator 62.5 % ) . There was no difference in cotinine-vali date d prolonged abstinence rate between the experimental group ( 11.2 % ) and control group 1 ( 11.6 % ) from week 5–52 ( odds ratio ( OR ) 0.96 , 95 % confidence interval ( CI ) 0.43–2.18 ) . The abstinence rate was approximately twice as high in the experimental group compared with control group 2 ( 5.9 % ) , but this difference was not statistically significant ( OR 2.02 , 95 % CI 0.63–6.46 ) . The present study did not provide evidence that the confrontational approach increases the rate of long-term abstinence from smoking compared with an equally intensive treatment in which smokers were not confronted with spirometry . The high failure rates ( ≥88 % ) highlight the need for treating tobacco addiction as a chronic relapsing disorder The purpose of this study was to test two combination motivational plus pharmacological interventions for smoking cessation among HIV positive smokers . Participants were 40 adults receiving HIV care who smoked daily reporting interest in smoking reduction . Measures were administered at baseline , 1-month , and 3-month follow-ups . Participants were r and omly assigned to self-guided reading plus nicotine patch ( n = 18 ) or motivational interviewing plus nicotine patch ( n = 22 ) . Groups did not differ at 3 months on biochemically-verified abstinence . The sample reduced cigarettes per day by half a pack and the percent of smoking days by 41 % , and 22 % were abstinent at 3-month follow-up . Compliance with the nicotine patch was poor and declined over time , but patch use was unrelated to carbon monoxide level at 3-month follow-up . Smoking cessation interventions for people with HIV can be helpful and should include components that encourage some smoke-free days , increase self-efficacy , and attend to adherence to nicotine replacement treatment The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy ( NRT ) and weekly group cognitive behavioral therapy ( CBT ) for smoking reduction or cessation in schizophrenia . Fifty-one adult smokers with schizophrenia were r and omly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch , nicotine polacrilex gum , and CBT . The treatment goal was smoking cessation . The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50 % to 100 % smoking reduction at week 12 . Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide ( CO ) and psychiatric symptoms . Subjects on bupropion + NRT had a greater rate of 50 % to 100 % smoking reduction at weeks 12 ( 60 % vs. 31 % ; P = 0.036 ) and 24 , a lower expired air CO in the treatment and follow-up periods , ( F = 13.8 ; P < 0.001 ) and a greater continuous abstinence rate at week 8 , before NRT taper , ( 52 % vs. 19 % ; P = 0.014 ) . However , relapse rates in subjects on bupropion + dual NRT were 31 % during NRT taper ( weeks 8 - 12 ) and 77 % at the 12-month follow-up . Abstinence rates did not differ by treatment group at weeks 12 ( 36 % vs. 19 % ) , 24 ( 20 % vs. 8 % ) , or 52 ( 12 % vs. 8 % ) . Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment , study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention BACKGROUND Little is known about the effectiveness of bupropion SR for smoking cessation outside the context of clinical efficacy trials , where in-person screening and treatment occur at a higher level than provided in a typical health care system . This article describes the methods for recruitment , screening for exclusions , and result ing sample in a field trial of bupropion SR undertaken in a managed-care setting . METHODS A total of 2979 telephone interviews were conducted to screen and identify eligible volunteers using a detailed protocol that allowed for consultation with study physicians when necessary . The volunteers ' primary care physicians were given the option to override their eligibility , and pharmacy data bases were used to verify medication reporting . RESULTS A total of 1909 ( 64 % ) volunteers were considered eligible for the study . The most common reason for exclusion was use of contraindicated medications ( 32 % ) , followed by recent use of one of the behavioral cessation programs ( 14 % ) , brain injury that reduced seizure threshold ( 14 % ) , current depression ( 14 % ) , and high levels of alcohol use ( 13 % ) . CONCLUSIONS The methods used in this field trial show that it is possible to enroll subjects in an effectiveness trial that is successful from the st and point of the consumer , provider , and health care system INTRODUCTION Nearly 80 % of substance dependent individuals also use tobacco , and smoking cessation efforts during treatment for other substance use is associated with similar or even improved outcomes . However , smoking cessation is not routinely addressed during treatment for substance use disorders . The present study tested a computerized brief motivational intervention ( C- BMI ) for smoking cessation in an understudied population : a cohort recruited from a recovery community organization ( RCO ) center . METHODS Following baseline assessment , participants were r and omly assigned to either a 30-minute C- BMI plus access to free nicotine replacement therapy ( NRT ) , or an information-only control group plus NRT access . RESULTS Reductions in CO were observed for both groups . Quit rates in the C- BMI group ( 5%-7 % , vs. 0 % for the control group ) approximated those observed elsewhere for physician advice and minimal counseling . Participants in the C- BMI group were also more likely to express a desire to quit . CONCLUSIONS Computer-delivered smoking cessation interventions within RCOs appear feasible . These organizations treat a wide variety of individuals , and C- BMI s for smoking in this context have the potential to reduce smoking-related morbidity and mortality INTRODUCTION Relatively few well- design ed smoking cessation studies have been conducted with teen smokers . This study examined the efficacy of extended cognitive-behavioral treatment in promoting longer term smoking cessation among adolescents . METHODS Open-label smoking cessation treatment consisted of 10 weeks of school-based , cognitive-behavioral group counseling along with 9 weeks of nicotine replacement ( nicotine patch ) . A total of 141 adolescent smokers in continuation high schools in the San Francisco Bay Area were r and omized to either 9 additional group sessions over a 14-week period ( extended group ) or 4 monthly smoking status calls ( nonextended group ) . Intention-to-treat logistic regression analysis was used to assess the primary outcome of biologically confirmed ( carbon monoxide < 9 ppm ) point prevalence abstinence at Week 26 ( 6-month follow-up from baseline ) . RESULTS At Week 26 follow-up , the extended treatment group had a significantly higher abstinence rate ( 21 % ) than the nonextended treatment ( 7 % ; OR = 4.24 , 95 % CI : 1.20 - 15.02 ) . Females also were more likely to be abstinent at the follow-up than males ( OR = 4.15 , 95 % CI : 1.17 - 14.71 ) . CONCLUSIONS The significantly higher abstinence rate at follow-up for the extended treatment group provides strong support for continued development of longer term interventions for adolescent smoking cessation Compared to the general population , smokers with schizophrenia ( SCZ ) have reduced success in quitting smoking with usual approaches . This study tested two manualized behavioral counseling approaches-Treatment of Addiction to Nicotine in Schizophrenia ( TANS ) or Medication Management (MM)-for smokers who were motivated to quit . Individual counseling sessions were provided by mental health clinicians in mental health setting s , along with nicotine patch . The two treatments varied in intensity and frequency of sessions . Eighty-seven subjects were r and omized and attended at least one treatment session . Twenty-one percent ( n = 18 ) of participants had continuous abstinence at 12 weeks after the target quit date , which was not significantly different between conditions ( 15.6 % TANS vs. 26.2 % MM , chi(2 ) = 1.50 , p = .221 ) . Smokers in both groups significantly reduced smoking as measured by cigarettes per day and expired carbon monoxide . Findings support that mental health clinicians can be trained to effectively help smokers with SCZ maintain tobacco abstinence Objectives : This study evaluated the effectiveness of behavioral interventions ( brief counseling , nonspecific psychological support in groups — NSGS and cognitive behavioral group therapy — CBGT ) in combination with bupropion SR for smoking cessation in the field , through a smoking cessation clinic . Methods : Two-hundred- and -five smokers were enrolled in a 19-week course during 2007/ 2008 , and were r and omly assigned to : bupropion SR combined with brief counseling ( group A ) , bupropion SR combined with NSGS ( group B ) , bupropion SR combined with CBGT ( group C ) , or CBGT as the only approach ( group D ) . Results : Continuous abstinence rates at the end of therapy were 53.2 % for group A , 62.9 % for group B , 50.0 % for group C , and 22.2 % ( p < 0.05 ) for group D. Sustained abstinence rates in 12 months were 29.6 % , 28.1 % , 34.3 % and 19.4 % ( p > 0.05 ) , respectively . Conclusions : Bupropion SR is an effective aid for smoking cessation in clinical practice . NSGT increased the chances for success at the end of therapy when combined with bupropion SR , while CBGT as monotherapy was less effective compared with the approaches including pharmacotherapy . It is suggested that smoking cessation interventions in real-life healthcare setting s should be implemented through comprehensive programs using pharmacotherapy where applicable , combined with NSGT , and integrated by specialized healthcare professionals This study examines the efficacy of a smoking cessation intervention on abstinence rates and motivation to quit smoking . Participants were adult smokers ( N = 543 ) who presented to the emergency department with chest pain and who were admitted to an observation unit for 24-hour observation to rule out myocardial infa rct ion . Participants were r and omly assigned to either usual care or a tailored intervention employing motivational interviewing and telephone follow-up . All individuals choosing to quit were offered nicotine patch therapy . Follow-up assessment s were conducted at 1 , 3 and 6 months . Abstinence ( 7-day point prevalence ) rates were significantly greater among participants receiving the tailored intervention compared with those given usual care ( OR = 1.62 , 95 % CI [ 1.05 - 2.50 ] ) . The largest difference occurred at 1 month : 16.8 % of usual care and 27.3 % of the tailored intervention group were abstinent , with differences decreasing over time . One-third of participants who were quit at month 6 were late quitters whose initial abstinence began after the 1-month follow up . In addition to treatment assignment , psychosocial variables including motivation to quit , confidence , reduced temptation to smoke in response to negative affect , and the perception that their chest pain was related to their smoking , were significant predictors of cessation . Tailored interventions are effective in promoting initial quit attempts for emergency chest pain patients admitted to an observation unit . Additional intervention may be needed to assist late quitters and to prevent relapse INTRODUCTION Hospitalization provides an opportunity for smokers to quit , but tobacco interventions can require specialized services that are not available to many hospitals . This study tests the hypothesis that a brief intervention to facilitate the use of telephone quitline services for both initial and follow-up counseling is effective in helping patients achieve sustained abstinence . DESIGN This was a population -based RCT . SETTING Participants were Olmsted County , MN residents who reported current smoking and were admitted to Mayo Clinic hospitals in Rochester , MN between May 2012 and August 2014 . INTERVENTION A control group received brief ( ~5-minute ) cessation advice ; an intervention group received a brief ( ~5-minute ) quitline facilitation intervention , with either warm h and off or faxed referral to a national quitline provider . All were offered a 2-week supply of nicotine patches at discharge . MAIN OUTCOME MEASURES Outcomes included self-reported 7-day point prevalence abstinence at 6 months after hospitalization and quitline utilization . Data analysis was performed from September 2014 to March 2015 . RESULTS Of the 1,409 eligible patients who were approached , 600 ( 47 % ) were r and omized . The quitline intake call was completed by 195 subjects ( 65 % of the intervention group ) . Of these , 128 ( 66 % ) completed the first coaching call . Self-reported abstinence rates at 6 months after discharge were identical in both groups ( 24 % ) . CONCLUSIONS The quitline facilitation intervention did not improve self-reported abstinence rates compared with a st and ard brief stop-smoking intervention . These results do not support the effectiveness of quitlines in providing tobacco use interventions to a general population of hospitalized smokers Background . The aim was to study the effect of a multimodal smoking cessation intervention regimen on a number of pregnant smokers Two hundred smokers who were judged by their general practitioner to be motivated to stop smoking were allocated to one of two groups . All were offered an initial appointment at which they were advised to stop smoking and offered nicotine gum . One group then received no further appointments . The other was offered four further appointments over three months . Both groups were followed up at six and 12 months . At one year follow up 15.5 % overall had stopped smoking , 14 % in the low and 17 % in the high contact group . This is better than most results so far reported for nicotine chewing gum in general practice , suggesting that general practitioners can use it to good effect . We compare this result with others achieved in general practice INTRODUCTION Despite decades of tobacco use decline among the general population in the United States , tobacco use among low-income population s continues to be a major public health concern . Smoking rates are higher among individuals with less than a high school education , those with no health insurance , and among individuals living below the federal poverty level . Despite these disparities , smoking cessation treatments for low-income population s have not been extensively tested . In the current study , the efficacy of 2 adjunctive smoking cessation interventions was evaluated among low-income smokers who were seen in a primary care setting . METHODS A total of 846 participants were r and omly assigned either to motivational enhancement treatment plus brief physician advice and 8 weeks of nicotine replacement therapy ( NRT ) or to st and ard care , which consisted of brief physician advice and 8 weeks of NRT . Tobacco smoking abstinence was at 1 , 2 , 6 , and 12 months following baseline . RESULTS The use of the nicotine patch , telephone counseling , and positive decisional balance were predictive of increased abstinence rates , and elevated stress levels and temptation to smoke in both social/habit and negative affect situations decreased abstinence rates across time . Analyses showed intervention effects on smoking temptations , length of patch use , and number of telephone contacts . Direct intervention effects on abstinence rates were not significant , after adjusting for model predictors and selection bias due to perir and omization attrition . CONCLUSIONS Integrating therapeutic approaches that promote use of and adherence to medications for quitting smoking and that target stress management and reducing negative affect may enhance smoking cessation among low-income smokers INTRODUCTION Patient adherence to smoking cessation medications can impact their effectiveness . It is important to underst and the extent to which prescribed medications are actually taken by smokers , how this influences smoking cessation outcomes , and what factors may influence adherence . METHODS Smokers recruited from a large health plan were r and omized to receive different modes of cessation counseling in combination with varenicline ( Swan , G. E. , McClure , J. B. , Jack , L. M. , Zbikowski , S. M. , Javitz , H. S. , Catz , S. L. , et al. 2010.Behavioral counseling and varenicline treatment for smoking cessation . American Journal of Preventive Medicine , 38 , 482 - 490 ) . One thous and one hundred and sixty-one participants were mailed a 28-day varenicline supply when they set a quit date and were able to request up to two refills from the health plan pharmacy at no cost . Pharmacy fill records were obtained and telephone surveys completed at baseline , 21 days , 12 weeks , and 6 months post target quit date . RESULTS Good adherence to varenicline ( ≥80 % of days taken ) was associated with a twofold increase in 6-month quit rates compared with poor adherence ( 52 % vs. 25 % ) . Smokers were more likely than nonsmokers to stop varenicline early . Purpose ful nonadherence was associated with smoking at 12 weeks and was predicted in multivariate analyses by age , gender , adherence self-efficacy , and initial medication side effect severity . CONCLUSIONS Innovative methods for increasing adherence to smoking cessation medications are needed , particularly early in the quit process . Simple metrics of adherence such as number of days cessation medication is taken can and should be routinely incorporated in effectiveness trials and reported to advance future attempts to underst and and reduce nonadherence A. Batra , S.E. Collins , I. Torchalla , M. Schröter , and G. Buchkremer ( 2008 ) showed that smokers reporting higher levels of nicotine dependence , novelty seeking/hyperactivity , and depressivity ( i.e. , at-risk smokers ) evinced higher rates of posttreatment smoking than smokers reporting lower scores on self-report psychological symptom measures ( i.e. , lower risk smokers ) . This study aim ed to replicate the smoker subgroups and test the comparative effectiveness of st and ard pharmacobehavioral smoking cessation versus modified smoking cessation matched to at-risk smokers ' needs . On the basis of their self-report responses , adult regular smokers ( N = 268 ) were classified into smoker subgroups . At-risk smokers were r and omly assigned to receive the st and ard or modified treatments ; lower risk smokers received st and ard treatment . Modified treatment produced higher abstinence rates than the st and ard treatment for depressive smokers but not for other at-risk smokers . Overall , abstinence rates among at-risk smokers receiving modified treatment were not significantly different from those of lower risk smokers ; however , abstinence among higher dependence smokers receiving modified treatment decreased at higher rates than among lower risk smokers INTRODUCTION Relatively few treatment programs have been developed specifically for smokeless tobacco ( ST ) users who want to quit . Their results suggest that self-help material s , telephone counseling , and nicotine lozenges are efficacious . This study provides the first direct examination of the separate and combined effects of telephone counseling and lozenges . METHODS We recruited ST users online ( N = 1067 ) and r and omly assigned them to 1 of 3 conditions : ( a ) a lozenge group ( n = 356 ) , who were mailed 4-mg nicotine lozenges ; ( b ) a coach calls group ( n = 354 ) , who were offered 3 coaching phone calls ; or ( c ) a lozenge + coach calls group ( N = 357 ) , who received both lozenges and coaching calls . Additionally , all participants were mailed self-help material s. Self-reported tobacco abstinence was assessed at 3 and 6 months after r and omization . RESULTS Complete-case and intention-to-treat ( ITT ) analyses for all tobacco abstinence were performed at 3 months , 6 months , and both 3 and 6 months ( repeated point prevalence ) . ITT analyses revealed a highly similar result : the lozenge + coach calls condition was significantly more successful in encouraging tobacco abstinence than either the lozenge group or the coach calls group , which did not differ . CONCLUSIONS Combining nicotine lozenges and phone counseling significantly increased tobacco abstinence rates compared with either intervention alone , whereas coach calls and lozenges were equivalent . The study confirms the high tobacco abstinence rates for self-help ST cessation interventions and offers guidance to providing tobacco treatment to ST users The authors evaluated whether completing a multi-item assessment of smoking craving ( the Question naire of Smoking Urges [ QSU ] ) promoted increases in smoking craving . A sample of 39 regular smokers was r and omly assigned to 1 of 3 manipulations ( each of 3 min duration ): ( a ) complete the QSU-Brief ( 10 items ) , ( b ) complete a noncraving question naire that was structurally identical to the QSU-Brief ( scale-based control ) , and ( c ) a time-based control . Participants responded to an oral question assessing their degree of craving immediately before and after the manipulations . Results indicated that the QSU did not promote increases in craving compared to the 2 control conditions . Despite continuing debate over the most appropriate self-report measure of craving , investigators who use the QSU-Brief can be reasonably sure that the scores that result are not biased due to reactivity effects The authors compared 9- , 16- , 26- , and 52-week outcomes for two r and omly assigned groups of nicotine-dependent subjects : 1 ) nicotine patch plus four smoking cessation sessions with a nurse-practitioner giving advice and instruction ( n = 36 ; moderate-intensity condition , MI ) ; or 2 ) the foregoing treatments plus 16 weekly individual cognitive/ behavioral relapse-prevention therapy sessions ( n = 33 ; high-intensity condition , HI ) . Patch completion rates were 69.7 % in the HI group and 55.6 % in the MI group ( NS ) . Self-reported abstinence rates at the four follow-up points were comparable for the two treatment groups ; HI : 39 % , 36 % , 36 % , and 36 % ; MI : 44 % , 28 % , 25 % , and 28 % , respectively . There was some indication that MI patients with high nicotine dependence had lower abstinence rates than highly dependent HI patients To determine predictors of smoking cessation duration in a r and omized clinical trial , we assigned participants to nicotine patch ( 8 - 12 weeks ) plus either ( a ) a baseline tailored brief motivational intervention , a quit date behavioral skills counseling session , and a relapse prevention follow-up session , or ( b ) brief advice using the National Cancer Institute 's 4A 's model . A total of 383 smokers from five methadone maintenance treatment centers in Rhode Isl and were enrolled , of whom 312 ( 82 % ) completed 6-month follow-up assessment s. The primary outcome was longest period of self-reported abstinence during follow-up . Participants were on average 40.5 years of age ; 51.9 % were male , and 77.6 % were White . In multivariate analysis controlling for demographics , nicotine dependence , depressive symptoms , and smoking-related symptoms , we found longer periods of abstinence in persons reporting at least one 24-hr quit attempt in the year prior to baseline ( OR = 1.97 , p = .003 ) , in those anticipating success in cessation ( OR = 1.33 , p = .024 ) , and in those with a greater percentage of nicotine patch use days ( OR = 2.78 , p<.001 ) . Past quit attempts , self-efficacy , and constant nicotine replacement were associated with duration of abstinence among methadone-maintained smokers . Attention to these domains in future intervention studies may improve treatment success PURPOSE To determine whether an intensive cognitive-behavioral intervention begun during hospitalization when combined with transdermal nicotine replacement therapy is more effective than a minimal counseling intervention combined with transdermal nicotine replacement therapy in helping in patients to quit smoking . METHODS A total of 223 patients who smoked were enrolled in a hospital-based r and omized smoking cessation trial at the San Francisco Veterans Affairs Medical Center . One hundred and seven participants ( 48 % ) received intensive counseling and outpatient telephone follow-up ; 116 participants ( 52 % ) received minimal counseling . All study participants received 2 months of transdermal nicotine replacement therapy . We determined 6-month quit rates by self-report and measured saliva cotinine levels or obtained proxy reports to confirm self-reported smoking cessation at 12 months . Analyses adjusted for baseline differences in the distribution of coronary disease . RESULTS At 6 months , 35 % ( 36/103 ) of the intensive intervention group reported quitting , compared with 21 % ( 23/109 ) of the comparison group ( relative risk [ RR ] = 1.7 ; 95 % confidence interval [ CI ] : 1.1 to 2.7 ) . At 12 months , the self-reported quit rate was 33 % ( 33/99 ) in the intensive intervention group versus 20 % ( 21/103 ) in the comparison group ( RR = 1.7 ; 95 % CI : 1.1 to 2.7 ) . Based on biochemical or proxy confirmation , 29 % ( 30/102 ) in the intensive intervention group versus 20 % ( 21/107 ) in the comparison group quit smoking at 12 months ( RR = 1.6 ; 95 % CI : 0.96 to 2.5 ) . CONCLUSION Hospital-initiated smoking cessation interventions that include transdermal nicotine replacement therapy can improve long-term quit rates INTRODUCTION An inability to tolerate distress is a significant predictor of early smoking lapse following a cessation attempt . We conducted a preliminary r and omized controlled trial to compare a distress tolerance ( DT ) treatment that incorporated elements of exposure-based therapies and Acceptance and Commitment Therapy to st and ard smoking cessation treatment ( ST ) . METHODS Smokers with a history of early lapse in prior quit attempts received either DT ( N = 27 ; 9 2-hr group and 6 50-min individual sessions ) or ST ( N = 22 ; 6 90-min group and 1 20-min individual session ) , plus 8 weeks of transdermal nicotine patch . RESULTS At the end of behavioral treatment , odds of abstinence among participants receiving DT were 6.46 times greater than among participants receiving ST ( 66.7 % vs. 31.8 % ) , equivalent to a medium- to large-effect size . Odds of abstinence for DT were still 1.73 times greater at 8 weeks , corresponding to a small- to medium-effect size , although neither this difference nor those at 13 and 26 weeks were statistically significant . Furthermore , of those who lapsed to smoking during the first week postquit , DT participants had more than 4 times greater odds of abstinence than ST participants at the end of treatment . Relative to ST , DT participants also reported a larger decrease in experiential avoidance , a hypothesized DT treatment mediator , prior to quit day . The trajectory of negative mood and withdrawal symptoms in DT differed from ST and was largely consistent with hypotheses . CONCLUSIONS Reasons for the decrease in abstinence in DT after treatment discontinuation and suggestions for future research are discussed BACKGROUND The efficacy of pharmacotherapy for smoking cessation is well documented . However , due to relapse rates and side effects , hypnotherapy is gaining attention as an alternative treatment option . The aim of this one-center r and omized study was to compare the efficacy of hypnotherapy alone , as well as hypnotherapy with nicotine replacement therapy ( NRT ) , to conventional NRT in patients hospitalized with a cardiac or pulmonary illness . METHODS We evaluated self-reported and biochemically verified 7-day prevalence smoking abstinence rates at 12 and 26 weeks post-hospitalization . Patients ( n=164 ) were r and omized into one of three counseling-based treatment groups : NRT for 30 days ( NRT ; n=41 ) , a 90-min hypnotherapy session ( H ; n=39 ) , and NRT with hypnotherapy ( HNRT ; n=37 ) . Treatment groups were compared to a " self-quit " group of 35 patients who refused intervention . RESULTS Hypnotherapy patients were more likely than NRT patients to be nonsmokers at 12 weeks ( 43.9 % vs. 28.2 % ; p=0.14 ) and 26 weeks after hospitalization ( 36.6 % vs. 18.0 % ; p=0.06 ) . Smoking abstinence rates in the HNRT group were similar to the H group . There was no difference in smoking abstinence rates at 26 weeks between " self quit " and participants in any of the treatment groups . In multivariable regression analysis adjusting for diagnosis and demographic characteristics , H and HNRT were over three times more likely than NRT participants to abstain at 26-weeks post-discharge ( RR=3.6 ; p=0.03 and RR=3.2 ; p=0.04 , respectively ) . CONCLUSION Hypnotherapy is more effective than NRT in improving smoking abstinence in patients hospitalized for a smoking-related illness , and could be an asset to post-discharge smoking cessation programs OBJECTIVE To assess the feasibility and potential effectiveness of a modified version of the Ottawa Model for Smoking Cessation in an outpatient respirology clinic . METHODS Adult tobacco smokers attending the respirology clinic and willing to choose a quit date within one month of enrollment were r and omly assigned to receive st and ard care or the intervention . St and ard care participants received smoking cessation advice , a brochure and a prescription for smoking cessation medication if requested . Intervention participants received a $ 110 voucher to purchase smoking cessation pharmacotherapy and were registered to an automated calling system . Answers to automated calls determined which participants required nurse telephone counselling . Feasibility indicators included recruitment and retention rates , and intervention adherence . The effectiveness indicator was self-reported smoking status at 26 to 52 weeks . RESULTS Forty-nine ( 54.4 % ) of 90 eligible smokers were r and omly assigned to the intervention ( n=23 ) or control ( n=26 ) group . Self-reported smoking status at 26 to 52 weeks was available for 32 ( 65.3 % ) participants . The quit rate for intervention participants was 18.2 % compared with 7.7 % for controls ( OR2.36 [ 95 % CI 0.39 to 14.15 ] ) . CONCLUSION It would be feasible to evaluate this intervention in a larger trial . Alternatives to face-to-face follow-up at the clinic are recommended PURPOSE To conduct an exploratory study of two interventions to help smokers abstain over a period of 3 months . The specific aims were to describe the outcomes , test feasibility of the study design , and evaluate effect size . DESIGN AND METHODS A r and omized experimental design was used in a sample of 42 patients who received multicomponent treatment intervention ( MTI ) or st and ard care ( SC ) in a midwestern city in the United States . Variables were behavioral ( quit rate , self-efficacy , motivation ) , psychosocial ( depression , partner interaction ) , and symptom management ( use of nicotine replacement therapy [ NRT ] ) . Data analysis included descriptive statistics and repeated measures ANOVA . RESULTS The typical participant was Caucasian , middle aged , nicotine dependent , married or partnered , and employed , and had a high school education . Participants in the MTI group were more likely to use NRT and to have higher self-reported quit rates at follow-up . Statistically significant differences were found between groups over time for self-efficacy and positive to negative behavior ratio . Barriers to quitting were relapse , stress , weight gain , lack of support , and depression that were more frequent in the SC group . For effect size ( 0.25 ) , probability level ( .05 ) , and power ( .80 ) , a sample size of 140 patients was calculated . CONCLUSIONS The MTI group had higher quit rates , more NRT , higher self-efficacy , and more positive behavioral interactions . Limitations of the study included self-report of tobacco use , small sample , and attrition . The investigators suggest a future study with a larger sample to test whether multicomponent interventions with telephone calls after discharge are more effective than is st and ard care in helping patients to quit and continue to abstain from smoking INTRODUCTION Quit rates for smoking cessation attempts are maximized by using counseling with medication . Internet-based counseling might be a suitable replacement for in-person counseling . METHODS Patients in a military medical system in the active phase of quitting presented for study intake . They were r and omized to in-person counseling ( n = 44 ) or Internet counseling ( n = 173 ) . In-person counseling consisted of four 1.5 hour classes based on the American Cancer Society 's Freshstart program . Internet counseling consisted of daily e-mails with recommended activities through Pfizer 's GetQuit program . Both groups were concomitantly treated with st and ard dose varenicline . The primary outcome was the quit rate at 12 weeks , defined as abstinence and an exhaled carbon monoxide level < 10 ppm at the 12-week visit . All those lost to follow-up were considered persistent smokers . RESULTS 217 smokers were r and omized , of which 43 % returned for the 12-week follow-up visit . Quit rates between the two groups were similar ( Internet group : 21 % , n = 36/173 ; in-person group : 18 % , n = 8/44 , p = 0.7 ) . CONCLUSIONS Internet-based counseling might be equivalent to in-person counseling for smoking cessation in patients taking varenicline . Additional studies with more complete and longer-term ( ≥1 year ) follow-up are needed to confirm these findings Smokers ( N = 99 ) were r and omly assigned to one of three conditions : nicotine gum ( NG ) , nicotine gum plus psychological treatment ( NG-PT ) , and nicotine gum plus psychological treatment and partner support ( NG-PT-PS ) . Data were collected at Weeks 0 , 4 , 12 , 26 , and 52 from study start . Contrary to expectations , NG-PT-PS and NG-PT failed to increase abstinence rates . Subjects who were closer to their support partners had significantly lower abstinence rates with NG-PT-PS than with the other conditions , although not significantly at Weeks 26 and 52 . Treatments without partner participation ( NG-PT and NG ) were significantly more effective for subjects who had an extremely close support partner outside the treatment setting than for those who did not at all weeks . The role of social support in smoking treatment is discussed Purpose . When a patient is diagnosed with lung cancer , members of his/her social network may be more likely to engage in smoking cessation efforts . Proactive telephone counseling combined with a tailored self-directed intervention may be more effective at promoting smoking cessation than a tailored self-directed intervention alone . Design . R and omized controlled trial . Setting . Four clinical sites . Subjects . Current smokers who are family members and close friends of patients with lung cancer . Intervention . Six counselor-initiated counseling calls using motivational interviewing techniques and focusing on teaching adaptive coping skills based on the transactional model of stress and coping along with tailored self-directed material s ( including nicotine patches , if not contraindicated ) ( n = 245 ) vs. tailored self-directed material s ( including nicotine patches , if not contraindicated ) ( n = 251 ) . Measures . Participants were surveyed at baseline and at 2 weeks , 6 months , and 12 months postintervention . The outcome was 7-day point prevalent abstinence . Analysis . The objective of this study was to test for arm differences in smoking cessation rates at 2 weeks and 6 months postintervention ( primary ) and at 12 months postintervention ( secondary ) . Results . We found no overall effect of the proactive intervention on cessation rates . Among younger participants ( age < 50 ) , the cessation rate in the intervention group was higher than in the control group at 2 weeks postintervention ( 16 % vs. 4 % , p = .046 ) . For older participants ( age > 50 ) , there were no group differences . Conclusion . Proactive telephone counseling focusing on adaptive coping skills was difficult to implement among smokers in lung cancer patients ' social network . Although this study did not demonstrate any added benefit to cessation rates , this null finding may be a result of an intervention that was weaker than intended , owing to difficulties in completing the counseling phone calls . We discuss lessons learned and areas for future research in this special population The patch adherence behavior of 101 smokers receiving 8 weeks of the nicodermal patch was examined while undergoing one of three levels of adjunctive psychosocial treatment . Additionally , regression analyses were undertaken to : ( 1 ) identify subject variables predictive of patch adherence and ( 2 ) to determine the predictive validity of patch treatment dropout , smoking and patch adherence during patch treatment to smoking 9 and 26 weeks post-treatment entry . Fifty-five percent of the patients wore the patch as prescribed for at least 50 of 56 treatment days . A multiple regression model including the Fagerström severity of dependence score , psychosocial treatment group , and the URICA commitment score predicted 18 % of the variance in days of patch use . All treatment dropouts were found to be smoking at followup . Although both smoking and low patch compliance during treatment were significant predictors subjects of week 9 and 26 smoking for the remaining subjects , at the individual variable level of analysis , only smoking during treatment predicted week 9 and 26 outcomes in a two-variable predictor model INTRODUCTION Most smokers abstain from smoking during hospitalization but relapse upon discharge . This study tests the effectiveness of two proven treatments ( i.e. , nicotine patches and telephone counseling ) in helping these patients stay quit after discharge from the hospital , and assesses a model of hospital-quitline partnership . STUDY DESIGN This study had a 2 × 2 factorial design in which participants were stratified by recruitment site and smoking rate and r and omly assigned to usual care , nicotine patches only , counseling only , or patches plus counseling . They were evaluated at 2 and 6 months post-r and omization . SETTING / PARTICIPANTS A total of 1,270 hospitalized adult smokers were recruited from August 2011 to November 2013 from five hospitals within three healthcare systems . INTERVENTION Participants in the patch condition were provided 8 weeks of nicotine patches at discharge ( or were mailed them post-discharge ) . Quitline staff started proactively calling participants in the counseling condition 3 days post-discharge to provide st and ard quitline counseling . MAIN OUTCOME MEASURES The primary outcome measure was self-reported 30-day abstinence at 6 months using an intention-to-treat analysis . Data were analyzed from September 2015 to May 2016 . RESULTS The 30-day abstinence rate at 6 months was 22.8 % for the nicotine patch condition and 18.3 % for the no-patch condition ( p=0.051 ) . Nearly all participants ( 99 % ) in the patch condition were provided nicotine patches , although 36 % were sent post-discharge . The abstinence rates were 20.0 % and 21.1 % for counseling and no counseling conditions , respectively ( p=0.651 ) . Fewer than half of the participants in the counseling condition ( 47 % ) received counseling ( mean follow-up sessions , 3.6 ) . CONCLUSIONS Provision of nicotine patches proved feasible , although their effectiveness in helping discharged patients stay quit was not significant . Telephone counseling was not effective , in large part because of low rates of engagement . Future interventions will need to be more immediate to be effective . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT01289275 We tested whether a 3-month beneficial effect of telephone counseling as an adjunct to the use of medications for smoking cessation was maintained through 12 months . Health plan members filling a prescription for cessation medications were r and omized either to a no-contact control group or to proactive recruitment into telephone counseling . An increased point-prevalence quit rate at 3 months ( 33.1 % vs. 27.4 % , p<.05 ) among smokers r and omized to proactive recruitment for telephone counseling was not maintained . Although at 12 months smokers in the proactive recruitment arm were more likely to report a 24-hr quit attempt , compared with control group smokers ( 86.7 % vs. 80.8 % , p = .027 ) , we found no differences between the groups in repeated ( 3-month and 12-month ) 7-day point-prevalence quit rates . In an analysis of predictors of quitting , age , marital status , making a lifestyle change , and the presence of household smokers were associated with repeated 3-month and 12-month point-prevalence abstinence . Offering telephone counseling to insured smokers who have filled prescriptions for cessation medications did not increase long-term quit rates . Although other variations of this approach might be tested , we suspect that it might be more useful to test innovative ways to influence the factors we identified as being most strongly predictive of lack of successful quitting INTRODUCTION Bupropion and cognitive-behavioral treatment ( CBT ) for depression have been used as components of treatments design ed to alleviate affective disturbance during smoking cessation . Studies of treatment-related changes in precessation affect or urges to smoke are needed to evaluate the proposed mechanisms of these treatments . METHODS The present report examines affective trajectories and urges to smoke prior to , on quit day , and after quitting in a sample of 524 smokers r and omized to receive bupropion versus placebo and CBT versus st and ard smoking cessation CBT . RESULTS Bupropion and /or CBT did not affect the observed decreases in positive affect and increases in negative affect prior to cessation . However , on quit day , observed levels of negative affect and urges to smoke were diminished significantly among individuals receiving bupropion . Decreases in positive affect prior to quitting , lower levels of positive affect , and increased levels of negative affect and urges to smoke on quit day were each related to higher risk of smoking lapse . Depression proneness was an independent predictor of lower positive affect and higher negative affect but did not moderate the effects of bupropion on outcomes . In mediational analyses , the effect of bupropion was accounted for in part by lower negative affect and urges to smoke on quit day . DISCUSSION Results support the efficacy of bupropion in reducing relapse risk associated with urges to smoke and negative affect and suggest the need to better underst and the role of low positive affect as a risk factor for early lapse This study evaluated a treatment combining bupropion with a novel acceptance and relationship focused behavioral intervention based on the acceptance and relationship context ( ARC ) model . Three hundred and three smokers from a community sample were r and omly assigned to bupropion , a widely used smoking cessation medication , or bupropion plus functional analytic psychotherapy ( FAP ) and acceptance and commitment therapy ( ACT ) . Objective measures of smoking outcomes and self-report measures of acceptance and relationship processes were taken at pretreatment , posttreatment , 6-month , and 1-year follow-up . The combined treatment was significantly better than bupropion alone at 1-year follow-up with 7-day point prevalence quit rates of 31.6 % in the combined condition versus 17.5 % in the medication-alone condition . Acceptance and the therapeutic relationship at posttreatment statistically mediated 12-month outcomes . Bupropion outcomes were enhanced with an acceptance and relationship focused behavioral treatment OBJECTIVE To describe the design , implementation , baseline data , and feasibility of establishing a disease management program for smoking cessation in rural primary care . METHOD The study is a r and omized clinical trial evaluating a disease management program for smoking cessation . The intervention combined pharmacotherapy , telephone counseling , and physician feedback , and repeated intervention over two years . The program began in 2004 and was implemented in 50 primary care clinics across the State of Kansas . RESULTS Of eligible patients , 73 % were interested in study participation . 750 enrolled participants were predominantly Caucasian , female , employed , and averaged 47.2 years of age ( SD=13.1 ) . In addition to smoking , 427 ( 57 % ) had at least one additional major risk factor for cardiovascular disease ( diabetes , hypertension , high cholesterol , heart disease or stroke ) . Participants smoked on average 23.7 ( SD=10.4 ) cigarettes per day , were contemplating ( 61 % ) or preparing to quit ( 30 % ) , were highly motivated and confident of their ability to quit smoking , and reported seeing their physicians multiple times in the past twelve months ( Median=3.50 ; Mean=5.48 ; SD=6.58 ) . CONCLUSION Initial findings demonstrate the willingness of patients to enroll in a two-year disease management program to address nicotine dependence , even among patients not ready to make a quit attempt . These findings support the feasibility of identifying and enrolling rural smokers within the primary care setting This collaborative , community-engaged project developed and tested a Culturally Tailored Treatment ( CTT ) for American Indian/Alaska Native ( AI/AN ) smokers in the Menominee tribal community . One hundred three adult AI/AN smokers were r and omized to receive either St and ard Treatment ( ST ; n = 53 ) or CTT ( n = 50 ) for smoking cessation . Both treatment conditions included 12 weeks of varenicline and four individual counseling sessions but differed in terms of cultural tailoring of the counseling . The primary outcome was 7-day , biochemically confirmed point-prevalence abstinence ( PPA ) at the 6-month end-of- study visit . Both intention-to-treat ( ITT ) and responder-only analyses were conducted . There were no statistically significant group differences in 7-day PPA . The overall ITT abstinence rate at 6 months was 20 % ; the responder-only rate was 42 % . The current study represents the first r and omized smoking cessation clinical trial testing a culturally tailored smoking cessation intervention design ed for a specific AI/AN tribal community that combined Food and Drug Administration ( FDA ) -approved cessation medication ( varenicline ) and innovative cultural intervention components OBJECTIVE The purpose of the study ( conducted 2010 - 2013 ) was to determine the efficacy of two common types of tobacco quitlines in adult cancer survivors who regularly smoked cigarettes . METHOD Adult onset cancer survivors in Memphis , Tennessee ( n=427 , 67 % female , 60 % Caucasian ) were r and omized either to a Proactive ( i.e. , counselor-initiated calls ) or Reactive ( i.e. , participant-initiated calls ) quitline . Both conditions also received nicotine replacement therapy . The primary outcome was biochemically-verified ( i.e. , salivary cotinine ) smoking cessation . RESULTS While 12-month self-reported abstinence was consistent with other published studies of smoking cessation ( 22 % and 26 % point prevalence abstinence for Proactive and Reactive conditions , respectively ) , 48 % of participants who were tested for cotinine failed biochemical verification , indicating a considerable falsification of self-reported cessation . Adjusted cessation rates were less than 5 % in both intervention conditions . CONCLUSION Our results are consistent with other studies indicating that traditional smoking cessation interventions are ineffective among cancer survivors . Moreover , self-reports of cessation were unreliable in cancer survivors participating in a quitline intervention , indicating that future studies should include biochemical verification . Given the importance of smoking cessation among cancer survivors and low cessation rates in the current study , it may be necessary to design alternative interventions for this population . Clinical Trials.gov identifier : NCT00827866 Patterns of smoking cessation using 6- and 12-month follow-up data are reported for 1,261 primary care patients r and omized to 3 physician-delivered smoking interventions : advice only ( AO ) , counseling ( CI ) , and counseling plus availability of nicotine-containing gum ( CI + NCG ) . One-week-point-prevalence cessation rates at 12 months did not differ among the interventions : AO ( 15.2 % ) , CI ( 12.9 % ) and CI + NCG ( 16.7 % ) . However , maintained cessation rates ( abstinent at both 6 and 12 months ) increased with intervention intensity : AO ( 6.0 % ) , CI ( 7.8 % ) and CI + NCG ( 10.0 % ) : Test of trend chi 2 = 5.06 , p = .02 . CI + NCG was significantly higher than AO ( p = .02 ) . The findings support the following conclusions : Brief physician-delivered intervention with availability of nicotine-containing gum can have a beneficial long-term effect on smoking cessation , and cohort data as well as point-prevalence rates are important when assessing the long-term impact of lifestyle interventions This study , which tested two motivational interviewing treatment approaches , assessed the feasibility of conducting a community-based smoking cessation intervention among homeless smokers . Participants ( N = 46 ) were recruited from multiple facilities in the Kansas City area and were r and omized to two counseling conditions in which they received five individual motivational interviewing sessions , six group meetings , and their choice of 8 weeks of 21-mg nicotine patch or 4-mg nicotine lozenge . The two counseling conditions consisted of motivational interviewing targeted either to smoking behaviors exclusively ( smoking only ) or to smoking and other addictions or life events that could affect ability to quit ( smoking plus ) . Group meetings were design ed to provide educational information and social support . Measures of feasibility assessed included the proportion of participants who returned for r and omization among those eligible , adherence to prescribed nicotine replacement therapies , retention rates at the week 26 final study visit , and biochemically verified 7-day abstinence at week 26 . Most participants ( 69.6 % ) chose nicotine patches , and 32 % of those participants reported using at least four patches per week . Carbon monoxide verified 7-day abstinence rates in the smoking-only and smoking-plus groups were 13.04 % and 17.39 % ( ns ) , respectively , at week 8 and 8.70 % and 17.39 % ( ns ) , respectively , at week 26 . Participants who used at least four patches per week were more likely to have quit at 8 weeks than were those who used fewer patches ( 33.3 % vs. 10.5 % , p = .30 ) . Results support the feasibility of conducting a smoking cessation intervention among homeless smokers . Findings also show promising effects for nicotine replacement therapy and counseling in this population . Developing programs to improve smoking cessation outcomes in underserved population s is an essential step toward achieving national health objectives and for ultimately reducing tobacco-related health disparities OBJECTIVES Transdermal nicotine patches have shown considerable promise in improving smoking cessation outcomes . The present study assessed telephone support as an adjunct to a managed care-based , single-session group orientation smoking cessation program with nicotine patch therapy . METHODS The unit of r and omization was the orientation session ( n = 35 ) . Subjects ( n = 509 ) were r and omly assigned to a group session without telephone support , the session plus access to a toll-free help line , or the session with telephone help line plus active telephone outreach . RESULTS Contrary to hypothesis , there were no differences between treatment conditions . Overall abstinence rates were 22 % at 6 months and 21 % at 1 year . Fewer than 1 % of eligible subjects called the toll-free help line . An average of 3.8 of a possible 4 calls were completed in the telephone outreach condition . CONCLUSIONS Abstinence results obtained in this program were comparable to those obtained with more extensive counseling . However , there was no evidence of benefit from telephone support beyond the initial physician-led group orientation session Purpose : The purpose of this study was to investigate the effects of a cognitive behavioral therapy – oriented anger management and stress control program on smokers ' quit rates . Methods : Of 2348 smokers , 350 were r and omly allocated into study and control groups ( n = 175 each ) . An individualized therapy cessation technique was selected for each participant ( combination of behavioral counseling , nicotine replacement therapy , and /or pharmacotherapy ) . The participants in the control group attended a st and ard quit program , whereas the study group also received an additional 5-session ( 90 minutes each ) cognitive behavioral therapy – oriented program aim ed at improving their anger and stress coping skills . At the beginning of the study , both groups were asked to complete the Trait Anger Scale ( TAS ) of the State and Trait Anger Scale and the Self-Confident ( SCS ) and Hopeless ( HS ) subscales of the Stress Coping Styles Inventory ; pretest smoking status of both groups and their coping skills were compared with each other as soon as the program ended ( post-test results ) and after 3 and 6 months ( first and second follow-up tests ) . Results : Although there was no difference between pretest scores on the TAS ( P = .234 ) , SCS ( P = .130 ) , and HS ( P = .148 ) subscales , post-test results indicate that the study groups ' TAS and HS scores decreased and SCS scores increased ( P < .001 ) , whereas there was no change in the control group ( P > .05 ) . The study group had a better quit level after 6 months compared with the control group ( 44 % vs 27.4 % ; P < .001 ) . The anger management and stress control program was found to have a significant effect on cessation ( odds ratio , 2.09 ; 95 % confidence interval , 1.14–3.85 ) . Conclusion : The anger and stress coping skills program may increase the success of quitting smoking OBJECTIVES To determine the differential cost effectiveness of 2 dosing regimens of bupropion sustained release ( SR ) in combination with behavioral interventions of minimal intensity ( tailored mailings [ TM ] ) or moderate intensity ( proactive telephone calls [ PTC ] ) for smoking cessation in an actual practice setting . STUDY DESIGN Open-label , r and omized trial , with 1-year follow-up , conducted in a large health system based in Seattle , Washington . METHODS A total of 1524 adult smokers interested in quitting smoking were r and omly assigned to receive 150 mg bupropion SR daily and PTC ( n = 382 ) , 150 mg bupropion SR daily and TM ( n = 381 ) , 300 mg bupropion SR daily and PTC ( n = 383 ) , or 300 mg bupropion SR daily and TM ( n = 378 ) . Sufficient medication for 8 weeks of dosing was provided to patients . The primary outcome measure was self-reported point-prevalence 7-day nonsmoking status at 12 months after the target quit date . RESULTS Although the 300-mg dose was associated with a higher 12-month nonsmoking rate relative to the 150-mg dose with both PTC and TM , the additional cost result ed in lower cost effectiveness . The PTC behavioral intervention was more expensive than TM , but the additional effectiveness result ed in almost equivalent cost effectiveness at the 150-mg dose . Costs per additional 12-month nonsmoker ( above that expected for placebo ) for the 150-mg dose groups averaged 950 dollars and per additional lifetime quitter averaged 1508 dollars ; for the 300-mg groups these costs were 1342 dollars and 2129 dollars , respectively . Cost per life-year and quality -adjusted life-years ( QALYs ) saved varied substantially by age and treatment , but were no greater than 1100 dollars for all treatment groups when averaged across the age and sex distribution for the study population . CONCLUSIONS Although the cost per life-year and QALYs saved were sufficiently low for all doses to rate these smoking cessation interventions as among the most cost effective of life-saving medical treatments , within the regimens tested 150 mg bupropion combined with either PTC or TM was the most cost effective AIMS To examine heterogeneity in outcome following treatment for smoking cessation with combined bupropion SR and behavioral counseling in women and men . DESIGN , SETTING , PARTICIPANTS This study included 875 women and 649 men recruited from a large health-care system and r and omized to one of four combinations of treatment [ two dosage levels of bupropion SR ( Zyban , 150 mg and 300 mg ) were crossed with two counseling programs of lower and higher intensity to create a four-cell design ] . MEASUREMENTS AND FINDINGS A comprehensive set of relevant individual characteristics prior to treatment and treatment characteristics was included in the analysis . Smoking outcome at 12 months was defined as point-prevalence of any regular smoking within the 7 days prior to follow-up contact . Classification and regression tree analysis identified six subgroups in women that ranged in proportion of non-smokers from 9.8 % to 42.9 % and six subgroups in men that ranged in proportion of non-smokers from 17.3 % to 50.0 % . CONCLUSIONS These results indicate the presence of a substantial amount of variation in treatment outcome among women and men receiving combined bupropion SR and counseling . Variation in outcome could be reduced by providing treatments tailored to subgroups of individuals who are at exceptionally high risk for smoking following cessation OBJECTIVE Fear of jeopardizing drinking outcomes has result ed in a reluctance to treat tobacco dependence concurrently with alcohol dependence , in spite of the high prevalence of smoking among patients with alcohol dependence . The objective of this study was to compare the effects of smoking treatment and intensive treatment for alcohol dependence , delivered concurrently , with delayed smoking treatment on smoking and alcohol use . METHOD For the study , 1,943 patients in intensive treatment for alcohol dependence or abuse were screened for participation . Of these , 499 smokers were enrolled and r and omized to concurrent ( during alcohol treatment ) or delayed ( 6 months later ) smoking intervention . The smoking intervention included individual behavioral counseling and nicotine replacement . The main smoking outcome measure was 7-day point prevalent tobacco abstinence , and the main drinking outcome was 6-month prolonged abstinence from alcohol ; both measured 18 months after study enrollment . RESULTS Participants in the concurrent group were more likely to participate in smoking treatment than those in the delayed group ( 78.5 % vs 64.5 % , p = .005 ) , but there was no significant difference in cessation rates at 18 months ( 12.4 % vs 13.7 % ) . Prolonged , 6-month abstinence from alcohol was worse in the concurrent group than in the delayed group at 6 , 12 and 18 months ( 41 % vs 56 % , p = .001 ; 33 % vs 42%,p = .06 ; 41 % vs 48 % , p = .14 , respectively ) , and 30-day prolonged alcohol abstinence was also worse in the concurrent treatment group ( 51 % vs 64 % , p = .004 ; 46 % vs 53 % , p = .11 ; 48 % vs 60 % , p = .01 , respectively ) . CONCLUSIONS These data show that patients in alcohol treatment are interested in smoking cessation , participate in treatment and demonstrate success ; but there was no benefit of concurrent treatment . Drinking outcomes were worse with concurrent tobacco treatment . These findings suggest that smoking cessation intervention should be provided to patients after intensive alcohol treatment ; however , the data require confirmation because they are not consistent with the existing literature BACKGROUND Previous studies have found that offering additional callback counseling support to smokers calling a telephone quit line increases quit rates . However , what is less certain is the most cost-efficient protocol for offering such a service . OBJECTIVE This study compares the efficacy of offering 2 versus 4 counseling callbacks after an initial call from Medicaid/uninsured adult smokers contacting the New York State Smokers ' Quit Line ( NYSSQL ) . Outcomes compared are the 7- and 30-day nonsmoker prevalence rates measured at 3-month follow-up and the cost per quit . DESIGN A 2-group r and omized trial was conducted . SETTING AND PARTICIPANTS The study population included 1923 adult ( 18 + years ) Medicaid/uninsured current smokers ( 10 + cigarettes per day ) who called the NYSSQL between February and March 2009 seeking help to stop smoking . At the time of the study , the NYSSQL provided Medicaid/uninsured callers with up to 6 weeks of free nicotine medications and up to 4 counseling callbacks . Half the subjects were r and omized to st and ard care with up to 4 counseling callbacks with the remaining subjects offered only 2 counseling callbacks . All participants were sent a minimum of a 2-week supply of nicotine replacement therapy , with some receiving up to 6 weeks . Participants were recontacted 3 months after enrollment in the study to assess smoking status . MAIN OUTCOME MEASURES Quit rates , total counseling callbacks completed , reductions in cigarette consumption , and cost per quit measures . RESULTS There was not a significant difference between study groups in the number of callbacks completed . There was also no difference in 7- or 30-day nonsmoker prevalence rates measured after 3 months ' follow-up or reported use of the free nicotine replacement therapy between those assigned to either the 2- or 4-callback protocol s. The cost per quit was essentially the same in both groups ( 2 callbacks--$442 per quit vs 4 callbacks--$445 per quit ) . CONCLUSION There was no advantage in terms of quit success or cost to offering up to 4 callbacks instead of 2 callbacks INTRODUCTION Tobacco use is a serious public health problem among low-income Chinese Americans with limited English proficiency . Chinese men are at high risk for smoking-related morbidity and mortality . We tested the feasibility of a culturally and linguistically sensitive smoking intervention program with combined counseling and pharmacological components for Chinese smokers in New York City ; identified factors and techniques that enhance the administration and appropriateness of the intervention program ; and examined the overall impact of this program on quit attempts , quit rates , and overall smoking reduction . METHODS We were guided by the transtheoretical model and used an adapted motivational interviewing ( MI ) approach . The study involved a r and omized sample with pretreatment assessment and multiple follow-up measures . Eligible participants ( N = 122 ) were r and omly assigned to intervention ( 4 individualized counselor-led MI sessions and nicotine replacement therapy [ NRT ] ) or control groups ( 4 general health education sessions , self-help material s , and NRT ) . RESULTS Quit rate at 6 months in the intervention group was 67 % versus 32 % for the control group , indicating minimal relapse and a highly successful intervention program . Increase in self-efficacy and decease in pros of smoking from baseline to 6-month follow-up were positively associated with smoking cessation . The number of cigarette smoked at baseline was inversely related to smoking cessation . Results indicate that a combined intensive behavioral counseling and pharmacological intervention can reduce smoking substantially . CONCLUSION The results of this pilot will be used as a basis for a large-scale r and omized trial of an intervention with combined culturally and linguistically sensitive MI and NRT components for Chinese and other Asian ethnic groups OBJECTIVE A pilot study was conducted to determine the feasibility and potential efficacy of an interactive voice response ( IVR ) follow-up system for smokers recently hospitalized with coronary heart disease ( CHD ) . METHODS Ninety-nine smokers hospitalized with CHD completed a baseline question naire , were provided with bedside counseling , and offered nicotine replacement therapy . They were r and omly assigned to a usual care ( UC ) or an IVR group . The IVR group received automated telephone follow-up calls 3 , 14 and 30 days after discharge inquiring about their smoking status and confidence in remaining smoke-free . When deemed necessary , they were offered additional counseling . Smoking status was determined 52 weeks after hospital discharge . RESULTS The 52-week point prevalence abstinence rate in the IVR group was 46.0 % compared to 34.7 % in the UC group ( OR=1.60 , 95 % CI : 0.71 - 3.60 ; P=.25 ) . After adjustment for education , age , reason for hospitalization , length of hospitalization , and quit attempts in the past year , the odds of quitting in the IVR group compared to the UC group were 2.34 ( 95 % CI : 0.92 - 5.92 ; P=.07 ) . CONCLUSIONS IVR is a promising technology for following CHD patients attempting to quit smoking following discharge from hospital , however , a larger trial is required to confirm its efficacy . PRACTICE IMPLICATION S IVR may enhance the timely provision of follow-up counseling for smoking cessation in patients with CHD To date , only one study has been published on individual characteristics associated with outcome following st and ard treatment with bupropion SR for smoking cessation . To investigate treatment outcome beyond the 6-week end-of-treatment point , the present study examined characteristics associated with more clinical ly relevant smoking endpoints following treatment with bupropion SR in a large health care system . A total of 1,524 smokers ( 649 men and 875 women ) of average age 45.1 years were r and omized to receive one of four combinations of bupropion SR ( 150 or 300 mg ) and behavioral counseling ( tailored mailings or proactive telephone counseling ) and assessed for point-prevalent smoking status at 3 and 12 months . Multiple logistic regression analyses of potential risk factors for 12-month point-prevalent smoking and for persistent smoking ( point-prevalent smoking at both follow-ups ) following treatment were conducted for men and women combined and separately . Risk factors for smoking at both endpoints in the combined sample included treatment with tailored mailings , female gender , younger age , higher levels of tobacco dependence , shorter previous quit attempts , previous use of nicotine replacement therapy , and report of current depressive symptoms or lifetime depression . Risk factors for smoking following treatment identified in women only included treatment with the lower dose of bupropion SR , younger age , and higher perceived stress , whereas those that were unique to men included the presence of lifetime depression . The results are discussed in terms of their implication s for the need for more effective treatments in general , and the role of individual differences in the likelihood of returning to smoking following treatment for quitting BACKGROUND The authors evaluated the incremental efficacy of telephone counselling by a nurse in addition to physician advice and nicotine replacement therapy in helping patients to stop smoking . METHODS The trial was conducted at the University of Ottawa Heart Institute . A total of 396 volunteers who smoked 15 or more cigarettes daily were r and omly assigned to either of 2 groups : usual care ( control group ) and usual care plus telephone counselling ( intervention group ) ; the groups were stratified by sex and degree of nicotine dependence . Usual care involved the receipt of physician advice on 3 occasions , self-help material s and 12 weeks of nicotine replacement therapy . Telephone counselling was provided by a nurse at 2 , 6 and 13 weeks after the target quit date . Point-prevalent quit rates were determined at 52 weeks after the target quit date . RESULTS The point-prevalent quit rates at 52 weeks did not differ significantly between the control and intervention groups ( 24.1 % v. 23.4 % respectively ) . The quit rates did not differ significantly at the secondary measurement points of 4 , 12 and 26 weeks . INTERPRETATION Brief physician assistance , along with nicotine replacement therapy , can help well-motivated smokers to quit . Three additional sessions of telephone counselling by a nurse were ineffective in increasing quit rates . This form of assistance may be useful in the absence of physician advice or when self-selected by patients The study evaluated the efficacy of the Committed Quitters Program ( CQP ) , a computer-tailored set of printed behavioral support material s offered free to purchasers of NicoDerm CQ patches , as a supplement to the nicotine patch and the st and ard brief User 's Guide ( UG ) and audiotape . Callers to the CQP enrollment were r and omized to either CQP ( n=1854 ) or just the UG ( n=1829 ) . Abstinence and use of program material s were assessed by telephone interview at 6 and 12 weeks ( the latter falling 2 weeks after patch use was to be discontinued ) . Considering all respondents , abstinence rates did not differ significantly between the UG and CQP groups . As expected , among those who reported they used their assigned material s ( 80.1 % of the sample ) smokers who received CQP demonstrated higher quit rates at both 6 weeks ( 38.8 % v. 30.7 % ) and 12 weeks ( 18.2 % v. 11.1 % ) , compared to the UG group . Among those who used it , the Committed Quitters Program proved to be an effective behavioral treatment , improving quit rates over nicotine replacement therapy and a brief untailored written guide and audiotape Context Smoking cessation is difficult and may require repeated or intensive interventions . Contribution In this multicenter trial , 750 primary care patients who smoked at least 10 cigarettes per day were r and omly assigned to pharmacotherapy ( nicotine patch or bupropion ) , pharmacotherapy supplemented with up to 2 calls from trained counselors , or pharmacotherapy supplemented with up to 6 counseling calls . Utilization of the interventions , which were offered every 6 months for 2 years , declined over time . Smoking abstinence rates at 2 years were 23 % , 24 % , and 28 % in the 3 groups . Caution Pharmacotherapy was free . Smoking abstinence was self-reported . The Editors Cigarette smoking is a chronic illness characterized by repeated cycles of quit attempts and relapse . Most models for addressing smoking cessation are based on single , short-term interventions lasting only a few weeks or months ( 1 ) . Although most smokers will not quit after a single intervention , few studies have addressed the chronic nature of nicotine dependence by providing systematic , repetitive treatment opportunities ( 1 ) . Providing treatment only to smokers who are already prepared to quit further limits the reach of current smoking cessation interventions ( 2 ) . New models of chronic disease care might provide an alternative approach for exp and ing the reach and effectiveness of smoking cessation efforts ( 3 ) . Physicians are in direct contact with approximately 70 % of smokers each year ( 4 , 5 ) . Their potential role in promoting smoking cessation has been well delineated and incorporated into current clinical practice guidelines ( 1 ) . With the development of new , more effective prescription pharmacotherapy for smoking cessation , the role of primary care practice s in promoting smoking cessation is now more important than ever . Unfortunately , only half of the smokers who see their physicians are asked about their smoking ( 6 ) , and even fewer receive advice from their health care provider to quit or receive pharmacotherapy or follow-up ( 4 , 7 ) . Smoking cessation counseling competes with other pressing clinical tasks , and beyond brief advice , many physicians feel they are too busy to routinely and repeatedly counsel participants who smoke ( 810 ) . To assist primary care physicians in the treatment of rural smokers , we developed KanQuit , a smoking cessation program based on the chronic care model ( 4 ) , which integrates principles of disease management into the treatment of smokers seen in rural primary care . Our objective was to enroll smokers , regardless of their willingness to quit , into a disease registry and compare cessation rates among smokers who received pharmacotherapy alone or combined with either moderate-intensity or high-intensity disease management that includes counseling and provider feedback . Methods Design Overview We did a r and omized , single-blind trial of varying levels of disease management for smoking cessation . We recruited participants who smoked more than 10 cigarettes per day from rural primary care clinics across Kansas and r and omly assigned them to receive pharmacotherapy alone , pharmacotherapy supplemented by 1 to 2 counseling calls every 6 months ( moderate-intensity disease management ) , or pharmacotherapy supplemented by up to 6 counseling calls every 6 months ( high-intensity disease management ) . For recipients of moderate-intensity and high-intensity disease management , we faxed periodic progress reports to their physician . We offered all participants free pharmacotherapy ( either bupropion or transdermal nicotine patch ) every 6 months . We enrolled participants from June 2004 to October 2005 and followed them for 24 months , completing follow-up in December 2007 . All participants provided written informed consent . The University of Kansas Medical Center 's Human Subjects Committee approved the study . Setting and Participants We conducted our study in 50 rural primary care practice s in the Kansas Physicians Engaged in Prevention Research network ( 11 ) . As part of a rural primary care research experience , trained medical students systematic ally screened participants , identified smokers , and recruited them for this study , regardless of their interest in quitting ( 12 ) . We considered smokers eligible if they had a primary care physician who participated in this study ; were older than 18 years ; smoked more than 10 cigarettes per day for at least 1 year and for at least 25 of the past 30 days ; spoke English ; and had a telephone . We excluded smokers if they were pregnant or planned to become pregnant , planned to move out of the study area , had signs of dementia or mental illness that would preclude participation , or lived with a smoker already enrolled in the study . Of the 1827 smokers we screened , 61 % met criteria for study entry ( Figure 1 ) . Of these , we enrolled 67 % . Figure 1 . Study flow diagram . HDM = high-intensity disease management ; MDM = moderate-intensity disease management ; PM = pharmacotherapy management . R and omization and Interventions Participant R and omization R and omization occurred at the participant level . A computer-generated r and om-number table was used to generate allocation cards in blocks of 24 , with allocation equally distributed across treatment groups . To conceal allocation , we placed these cards in sequentially numbered , opaque , sealed envelopes . After research assistants verified participant eligibility and completed the baseline assessment , the project director opened the next sequential sealed envelope and determined the participant 's treatment allocation . One of 9 counselors trained in smoking cessation and motivational interviewing ( 12 ) conducted all interventions from a single central site . We assigned participants to counselors without regard to practice site . Pharmacotherapy At baseline , all smokers received a health education mailing that consisted of a welcome letter , information about the use of bupropion and the nicotine patch for smoking cessation , and copies of You Can Quit Smoking : Consumer Guide ( 13 ) and When Smokers QuitThe Health Benefits Over Time ( 14 ) . At baseline and at 6 , 12 , and 18 months , participants received a mailed offer for free pharmacotherapy that consisted of either a 6-week course of a nicotine patch ( 21 mg/d ) or a 7-week course of sustained-release bupropion ( 150 mg twice daily ) . Participants interested in using either medication could return a postage-paid postcard or call a toll-free number . We screened all participants who requested pharmacotherapy for potential contraindications ( 15 ) . Participants with absolute contraindications for a given drug were ineligible to receive that drug but were offered the option of receiving the other drug . Participants with contraindications to both drugs were not eligible to receive medication from the study but could participate in all other aspects of the intervention . For participants who requested bupropion and those with relative contraindications to the nicotine patch , research staff faxed a prescription request to their primary care physicians . This prescription request delineated any relative contraindications or potential drug interactions . For these participants , their physicians made the final assessment of the appropriateness of the bupropion or the patch . For participants without contraindications to the nicotine patch or on receipt of a faxed , signed prescription , the bupropion or patches were mailed to the participant along with instructions for use . Disease Management In addition to pharmacotherapy , the moderate-intensity and high-intensity disease management groups received educational support , telephone counseling , and periodic progress reports with counseling suggestions faxed to their physician . Every 6 months , they received a KanQuit newsletter that addressed tips on quitting smoking , talking with their physician about smoking , and using pharmacotherapy for cessation . The newsletters were personalized to include study up date s , counselor photographs , physician feature stories , and testimonials of participants who had quit smoking . We offered participants assigned to moderate-intensity disease management up to 2 telephone-based counseling sessions every 6 months ( 1 session to promote a quit attempt and 1 additional follow-up session for those who made a quit attempt ) . We offered participants assigned to high-intensity disease management up to 6 counseling calls every 6 months to either promote quitting or prevent relapse . We scheduled calls at the participant 's convenience , and they varied according to the participant 's quit plan but followed a rough schedule of calls at 1 , 3 , 6 , 9 , and 16 weeks after the onset of each 6-month treatment cycle . Counselors used motivational interviewing techniques and followed a semistructured protocol to promote a cessation attempt or , for abstinent smokers , to encourage relapse prevention . During counseling calls , case managers reminded participants about the availability of pharmacotherapy and , for interested participants , provided immediate support for acquiring either the nicotine patch or bupropion , as described previously . We faxed personalized progress reports with suggestions for interventions to the participant 's physician after the first counseling call ( both moderate-intensity and high-intensity disease management participants ) and after the last counseling call ( high-intensity disease management participants only ) during each 6-month cycle . We faxed additional progress reports to the participant 's physician whenever the moderate-intensity or high-intensity disease management participant set a quit date . Outcomes , Measurements , and Follow-up Research assistants who were blinded to treatment group assignment conducted assessment s by telephone at baseline and at 6 , 12 , 18 , and 24 months . Primary Outcome The primary outcome measure was self-reported 7-day abstinence at 24 months , defined as not having smoked a cigarette during the previous 7 days . Although self-reported abstinence has been AIMS This paper sets out to evaluate the possibility that smoking cessation interventions which make use of current psychological theories and constructs can be more successful than programmes based largely on nicotine replacement therapy and will be more satisfying to participants . RATIONALE Nicotine replacement therapy is currently the most widely used method for helping smokers give up the habit . Numerous studies have shown this to be a successful approach for many smokers , but the majority still fail to benefit . Typically three quarters of smokers given nicotine replacement are smoking again one year later . This study investigates whether nicotine replacement can be enhanced by the addition of psychological techniques . DESIGN Smokers recruited via publicity in the local media were r and omly assigned to one of two treatment conditions . The first condition consisted of a series of group sessions in which volunteers were instructed in nicotine replacement , and a number of psychological techniques , the most important being cognitive counter conditioning . The second condition was identical to the first but without the cognitive counter conditioning . Finally background quit rate was determined using waiting list controls . RESULTS Both interventions were successful in helping smokers quit the habit , based upon an analysis at 6 months , compared with waiting list controls . The experimental condition incorporating cognitive counter conditioning produced a much higher quit rate than the condition based largely upon nicotine replacement , although the difference was not significant . CONCLUSIONS This study is highly suggestive that nicotine replacement therapy can be enhanced by the inclusion of psychological techniques in group work , result ing in abstention rates higher than nicotine replacement alone and increasing participant satisfaction . Further work is needed with larger numbers to verify that this is indeed a significant gain and to investigate whether psychological techniques can give longer term benefits AIMS To study the effectiveness of intensive counselling by a practice nurse ( PN ) versus brief advice by a general practitioner ( GP ) , each combined with pharmacotherapy , for 6 months ' tobacco abstinence ( primary outcome ) . Secondary outcomes included 12-month abstinence , medication adherence and incremental costs per life-year gained . DESIGN A multi-site ( n = 10 ) , two-group , parallel , pragmatic r and omized controlled trial . SETTING A network of primary health-care centres in the Netherl and s. PARTICIPANTS A total of 295 adult daily smokers ( mean age = 48 years ; mean cigarettes/day = 19 ) . INTERVENTION AND COMPARATOR Patients were r and omized to receive individual counselling by a practice nurse ( PN ) ( n = 149 ) or brief advice by a general practitioner ( GP ) ( 146 ) . All patients received 12 weeks of open-label varenicline . MEASUREMENTS The primary outcome was prolonged biochemically vali date d abstinence from weeks 9 to 26 after treatment initiation . Secondary outcomes included abstinence from weeks 9 to 52 , good dosing adherence ( > 80 % days taken ) and incremental costs per life-year gained . FINDINGS Abstinence rates in the PN versus GP groups were 32.2 % ( n = 48 ) versus 39.0 % [ n = 57 ; odds ratio ( OR ) = 0.71 ; 95 % confidence interval ( CI ) = 0.44 - 1.16 ] from weeks 9 to 26 and 25.5 % ( n = 38 ) versus 28.8 % ( n = 42 ; OR = 0.84 , 95 % CI = 0.50 - 1.43 ) from weeks 9 to 52 , respectively . Values of the Bayes factor indicated that the PN and GP were equally effective . Good dosing adherence was significantly lower in the PN ( 45.5 % , n = 56/123 ) than in the GP group ( 62.0 % , n = 75/121 ; OR = 0.45 , 95 % CI = 0.26 - 0.77 ) , and the incremental costs per life-year gained were -€416.10 . CONCLUSIONS Among people seeking help to stop smoking from their general practice , one-off brief advice from a general practitioner appears to be as effective as several sessions of behavioural support from a practice nurse when smoking cessation medication is provided Abstract Tobacco dependence is prevalent among alcohol dependent patients , and causes increased morbidity and mortality . Concurrent treatment for these disorders may be advantageous , but there are concerns about adverse effects on alcohol treatment outcomes . The Timing of Alcohol and Smoking Cessation ( TASC ) Study is a r and omized controlled clinical trial to compare the effectiveness of smoking cessationtreatment offered concurrently or six months following intensive rehabilitation for alcohol dependence . This paper describes the study design and baseline characteristics of the study population . Participants were current smokers in intensive alcohol dependence treatment , with willingness to consider quitting smoking . Smoking intervention offered behavioral and pharmacological treatment . One thous and nine hundred forty — three patients were screened for enrollment ; 499 were eligible and participated ( 26 % ) . We describe demographic characteristics , smoking behavior and attitudes among participants and non participants toward smoking cessation and drinking . We conclude that there is considerable interest in smoking cessation in alcohol dependent treatment population s , and recruitment to research studies is feasible Introduction : The majority of people with schizophrenia have a diagnosis of tobacco dependence during their lifetime . A major obstacle to reducing the burden of cigarette smoking in this population is that these smokers have lower quit rates when undergoing st and ard treatment compared to smokers with no mental illness . We sought to determine if combination extended treatment ( COMB-EXT ) and home visits ( HV ) would lead to improved outcomes in smokers with schizophrenia . Methods : Thirty-four cigarette smokers with schizophrenia completed either COMB-EXT with HV , COMB-EXT without HV , or treatment as usual ( TAU ) ( r and om assignment ) . COMB-EXT consisted of group cognitive-behavioral therapy ( CBT ) , bupropion , nicotine patch , and nicotine lozenge , which were initiated within 2 weeks and continued for 26 weekly visits . HV consisted of biweekly visits to the home with assessment of secondh and smoke ( SHS ) exposure and brief behavioral therapy with participants and others in the home environment . TAU consisted of group CBT plus serial single or combination medication trials as per st and ard care . Results : Smokers with schizophrenia who received COMB-EXT ( with or without HV ) had greater reductions in cigarettes per day than those treated with TAU ( both ps < .01 ) . In addition , 7-day point prevalence abstinence rates for the three groups were 45 % , 20 % , and 8 % , respectively , which was significantly higher for COMB-EXT plus HV than TAU ( & khgr;2(1 ) = 4.8 , p = .03 ) . Groups did not differ significantly in the number of adverse events , and HV were easily scheduled . Conclusion : COMB-EXT improves outcomes for smokers with schizophrenia . HV appeared to provide additional benefit for smoking cessation in this treatment-resistant population . Implication s : The clear benefit found here of rapidly initiated , combination , extended treatment over TAU suggests that aggressive and extended treatment should be considered in clinical practice for smokers with schizophrenia . Furthermore , HV to address SHS exposure showed initial promise for assisting smokers with schizophrenia in maintaining abstinence , indicating that this intervention may be worthy of future research AIM To evaluate potential mediators of an extended cognitive behavioral smoking cessation intervention . DESIGN Analysis of data from a r and omized clinical trial of smoking cessation . SETTING The Habit Abatement Clinic , University of California , San Francisco . PARTICIPANTS Participants were older cigarette smokers ( > /=50 years old ) . Those receiving St and ard Treatment ( N=100 ) were compared to those receiving extended cognitive behavioral treatment ( N=99 ) . MEASUREMENTS Negative affect was measured with the Profile of Mood States ( POMS ) , the Medical Outcome Studies 36-item Short-Form Health Survey ( SF-36 ) , and the Perceived Stress Scale ( PSS ) . Abstinence-specific social support was measured with the Partner Interaction Question naire ( PIQ ) . Motivation to quit and abstinence self-efficacy were measured on 1 - 10 scales with the Thoughts about Abstinence Question naire . All were measured at the beginning of treatment and week 52 . RESULTS Analyses revealed that extended CBT increased abstinence self-efficacy over the first 52 weeks postcessation . This effect , in turn , was positively associated with 7-day point prevalence abstinence at week 64 while controlling for treatment condition , and eliminated the independent effect of treatment condition on abstinence . The test of mediation indicated a significant effect , and abstinence self-efficacy accounted for 61 % to 83 % of the total effect of treatment condition on smoking abstinence . Results failed to support a mediational role of negative affect , abstinence-specific social support , or motivation to quit . CONCLUSIONS The results of the present study are consistent with theories of relapse and studies of more time-limited interventions , and underscore the importance of abstinence self-efficacy in achieving long-term abstinence from cigarettes BACKGROUND Action aim ed at changing smoking behavior to prevent cardiovascular patients from further impairing their health is advisable . Cognitive behavioral interventions can be effective in this regard since they attempt to influence cognitive determinants that presumably lead to smoking cessation . The Minimal Intervention Strategy for Cardiology patients ( C-MIS ) is such an intervention , tailored to the patients ' readiness to change . Our aim is to investigate whether the C-MIS is successful in changing patients ' cognitions such as attitudes , social influence , self-efficacy and intention to quit during a 1-year period . METHODS Smoking out patients ( N = 315 ) with cardiovascular disease were included . They were r and omized and received either Nicotine Replacement Therapy ( NRT ) or NRT + C-MIS . At baseline ( T1 ) , sociodemographic and clinical characteristics were measured . Cognitions and quitting behavior were assessed at baseline and at four follow-up measurements . RESULTS Comparing treatments , the C-MIS did not affect pros of quitting , pros of smoking and social influence . We did find small effects of the C-MIS on intention to quit and self-efficacy , although only for higher-educated patients . CONCLUSION The C-MIS appears successful in affecting intention to quit and self-efficacy abilities , but only for patients with higher education levels . Initial positive changes in cognitions may also emerge in a medical intervention , such as the provision of NRT BACKGROUND Lack of interest has been cited as a reason not to offer cessation assistance to smokers , but research suggests that smokers accept treatments offered proactively . This study assessed acceptability , utilization , and effectiveness of free smoking cessation treatment among diverse primary care patients . METHOD Medical assistants invited 4174 adult smokers to participate . Enrollees ( 1869 ) self-selected or were assigned to receive free nicotine patch therapy alone or in combination with the Committed Quitters(R ) program , and for some , individual counseling . RESULTS In nearly 68 % of cases , patients accepted a treatment invitation ; 77 % of eligible smokers enrolled ; 85 % of these picked up free patches . Given a choice of treatments , 75 % of participants elected a psychosocial treatment in addition to patch therapy . Thirteen percent of treatment initiators achieved biochemically confirmed 7-day point-prevalence abstinence at 1 year , with no significant treatment effects . Minority patients showed greater initial interest but less utilization did than White patients . CONCLUSIONS Free , readily accessible smoking cessation treatment offered in primary care setting s was accepted and used by the majority of unselected smokers of diverse racial/ethnic origins . Psychosocial treatment components did not significantly increase abstinence rates . Barriers , rather than lack of interest , may keep minority smokers from using cessation treatments BACKGROUND There is a high prevalence of smoking among people who experience severe mental ill health ( SMI ) . Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health , increase longevity and also reduce health inequalities . Around half of people with SMI who smoke express an interest in cutting down or quitting smoking . There is limited evidence that smoking cessation can be achieved for people with SMI . Those with SMI rarely access routine NHS smoking cessation services . This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI . OBJECTIVE The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment , r and omisation and follow-up . We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness . The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation ( BSC ) intervention with usual general practitioner ( GP ) care for people with SMI . DESIGN A pilot pragmatic two-arm individually r and omised controlled trial ( RCT ) . Simple r and omisation was used following a computer-generated r and om number sequence . Participants and practitioners were not blinded to allocation . SETTING Primary care and secondary care mental health services in Engl and . PARTICIPANTS Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking . INTERVENTIONS A BSC intervention delivered by mental health specialists trained to deliver evidence -supported smoking cessation interventions compared with usual GP care . MAIN OUTCOME MEASURES The primary outcome was carbon monoxide-verified smoking cessation at 12 months . Smoking-related secondary outcomes were reduction of number of cigarettes smoked , Fagerstrom test of nicotine dependence and motivation to quit ( MTQ ) . Other secondary outcomes were Patient Health Question naire-9 items and Short Form Question naire-12 items to assess whether there were improvements or deterioration in mental health and quality of life . We also measured body mass index to assess whether or not smoking cessation was associated with weight gain . These were measured at 1 , 6 and 12 months post r and omisation . RESULTS The trial recruited 97 people aged 19 - 73 years who smoked between 5 and 60 cigarettes per day ( mean 25 cigarettes ) . Participants were recruited from four mental health trusts and 45 GP surgeries . Forty-six people were r and omised to the BSC intervention and 51 people were r and omised to usual GP care . The odds of quitting at 12 months was higher in the BSC intervention ( 36 % vs. 23 % ) but did not reach statistical significance ( odds ratio 2.9 ; 95 % confidence interval 0.8 % to 10.5 % ) . At 3 and 6 months there was no evidence of difference in self-reported smoking cessation . There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence . MTQ and number of quit attempts all increased in the BSC group compared with usual care . There was no difference in terms of quality of life at any time point , but there was evidence of an increase in depression scores at 12 months for the BSC group . There were no serious adverse events thought likely to be related to the trial interventions . The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis . CONCLUSIONS It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication . The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants . A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research ( NIHR ) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness . TRIAL REGISTRATION Current Controlled Trials IS RCT N79497236 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment , Vol . 19 , No. 25 . See the NIHR Journals Library website for further project information Objective : Among people living with HIV , cigarette smoking rates are higher than among the general population , and anxiety , depression , and their disorders are common and associated with smoking and poorer outcomes during cessation . This study evaluated the efficacy of an integrated smoking cessation intervention , developed to target anxiety , depression , and smoking cessation concurrently among people living with HIV . Method : Smokers living with HIV who reported at least moderate motivation to quit smoking were r and omized into a novel 9-week integrated intervention ( QUIT ) , consisting of 1 psychoeducation ( prer and omization ) session and 9 weekly 1-hour sessions of cognitive behavioral therapy for smoking cessation and anxiety/depression plus nicotine replacement therapy , or a 9-week enhanced st and ard smoking intervention ( ETAU ) , consisting of 1 psychoeducation session ( prer and omization ) and 4 brief weekly check-in sessions plus nicotine replacement therapy . All were instructed to make a quit attempt at week 6 . Results : Seventy-two participants were enrolled , and 53 were r and omized . 41/53 participants completed the active treatment phase of the study . 7-day point-prevalence abstinence , verified with expired carbon monoxide , was significantly higher among those in the integrated intervention than those in the enhanced st and ard intervention both end-of-treatment { [ MQUIT = 59 % , METAU = 9 % ; b = 5.60 , 95 % confidence interval : ( 2.64 to 8.56 ) , t(332 ) = 3.72 , P < 0.001 ] } and 6-months post-quit date { [ MQUIT = 46 % , METAU = 5 % ; b = 7.69 , 95 % confidence interval : ( 4.60 to 10.78 ) , t(332 ) = 4.90 , P < 0.001]}. Consideration of patterns of missingness did not alter the significance of these findings . Conclusions : The integrated intervention was associated with substantially higher short-term and long-term abstinence rates than the enhanced st and ard intervention . These data provide promising initial evidence supporting the benefits of an integrated anxiety – depression/smoking cessation program specifically tailored for people living with HIV AIMS To test the efficacy of two smoking cessation interventions in a HIV positive ( HIV+ ) sample : st and ard care ( SC ) treatment plus nicotine replacement therapy ( NRT ) versus more intensive motivationally enhanced ( ME ) treatment plus NRT . DESIGN R and omized controlled trial . SETTING HIV+ smoker referrals from eight immunology clinics in the northeastern United States . PARTICIPANTS A total of 444 participants enrolled in the study ( mean age = 42.07 years ; 63.28 % male ; 51.80 % European American ; mean cigarettes/day = 18.27 ) . INTERVENTIONS SC participants received two brief sessions with a health educator . Those setting a quit date received self-help quitting material s and NRT . ME participants received four sessions of motivational counseling and a quit-day counseling call . All ME intervention material s were tailored to the needs of HIV+ individuals . MEASUREMENTS Biochemically verified 7-day abstinence rates at 2-month , 4-month and 6-month follow-ups . FINDINGS Intent-to-treat ( ITT ) abstinence rates at 2-month , 4-month and 6-month follow-ups were 12 % , 9 % and 9 % , respectively , in the ME condition , and 13 % , 10 % and 10 % , respectively , in the SC condition , indicating no between-group differences . Among 412 participants with treatment utilization data , 6-month ITT abstinence rates were associated positively with low nicotine dependence ( P = 0.02 ) , high motivation to quit ( P = 0.04 ) and Hispanic American race/ethnicity ( P = 0.02 ) . Adjusting for these variables , each additional NRT contact improved the odds of smoking abstinence by a third ( odds ratio = 1.32 , 95 % confidence interval = 0.99 - 1.75 ) . CONCLUSIONS Motivationally enhanced treatment plus NRT did not improve cessation rates over and above st and ard care treatment plus NRT in this HIV+ sample of smokers . Providers offering brief support and encouraging use of nicotine replacement may be able to help HIV+ patients to quit smoking INTRODUCTION Phone counseling has become st and ard for behavioral smoking cessation treatment . Newer options include Web and integrated phone-Web treatment . No prior research , to our knowledge , has systematic ally compared the effectiveness of these three treatment modalities in a r and omized trial . Underst and ing how utilization varies by mode , the impact of utilization on outcomes , and predictors of utilization across each mode could lead to improved treatments . METHODS One thous and two hundred and two participants were r and omized to phone , Web , or combined phone-Web cessation treatment . Services varied by modality and were tracked using automated systems . All participants received 12 weeks of varenicline , printed guides , an orientation call , and access to a phone supportline . Self-report data were collected at baseline and 6-month follow-up . RESULTS Overall , participants utilized phone services more often than the Web-based services . Among treatment groups with Web access , a significant proportion logged in only once ( 37 % phone-Web , 41 % Web ) , and those in the phone-Web group logged in less often than those in the Web group ( mean = 2.4 vs. 3.7 , p = .0001 ) . Use of the phone also was correlated with increased use of the Web . In multivariate analyses , greater use of the phone- or Web-based services was associated with higher cessation rates . Finally , older age and the belief that certain treatments could improve success were consistent predictors of greater utilization across groups . Other predictors varied by treatment group . CONCLUSIONS Opportunities for enhancing treatment utilization exist , particularly for Web-based programs . Increasing utilization more broadly could result in better overall treatment effectiveness for all intervention modalities INTRODUCTION Although homeless individuals smoke at an alarmingly high rate , few smoking cessation clinical trials have focused on this vulnerable population . Little is known about recruitment efforts and suitable eligibility criteria for tobacco control research in homeless population s. METHODS The aim of this article is to describe the recruitment , eligibility , and enrollment of homeless smokers who participated in the Power to Quit smoking study , a r and omized smoking cessation clinical trial funded by the National Institutes of Health . The study compared motivational interviewing and st and ard counseling while participants received an 8-week treatment of the nicotine patch . RESULTS Working with local emergency shelters , a total of 839 adult smokers were screened for study eligibility , 580 of whom ( 69.1 % ) met eligibility criteria . Of those eligible , 430 ( 74.1 % ) returned for r and omization . Those who returned for r and omization were older and more likely to have a phone number compared with eligible participants not enrolled . The most common reasons for exclusion included exhaled carbon monoxide levels less than or equal to 5 parts per million ( indicating nonsmoking status ) , use of smoking cessation aid during the past 30 days , and not meeting the study definition of homelessness . CONCLUSION Knowledge of these factors may help research ers tailor criteria that accurately identify and include homeless smokers in future research OBJECTIVE To examine whether reimbursement for Provider Counseling , Pharmacotherapies , and a telephone Quitline increase smoking cessation relative to Usual Care . STUDY DESIGN R and omized comparison trial testing the effectiveness of four smoking cessation benefits . SETTING Seven states that best represented the national population in terms of the proportion of those > or = 65 years of age and smoking rate . PARTICIPANTS There were 7,354 seniors voluntarily enrolled in the Medicare Stop Smoking Program and they were followed-up for 12 months . INTERVENTION(S ) ( 1 ) Usual Care , ( 2 ) reimbursement for Provider Counseling , ( 3 ) reimbursement for Provider Counseling with Pharmacotherapy , and ( 4 ) telephone counseling Quitline with nicotine patch . MAIN OUTCOME MEASURE Seven-day self-reported cessation at 6- and 12-month follow-ups . PRINCIPAL FINDINGS Unadjusted quit rates assuming missing data = smoking were 10.2 percent ( 9.0 - 11.5 ) , 14.1 percent ( 11.7 - 16.5 ) , 15.8 percent ( 14.4 - 17.2 ) , and 19.3 percent ( 17.4 - 21.2 ) at 12 months for the Usual Care , Provider Counseling , Provider Counseling + Pharmacotherapy , and Quitline arms , respectively . Results were robust to sociodemographics , smoking history , motivation , health status , and survey nonresponse . The additional cost per quitter ( relative to Usual Care ) ranged from several hundred dollars to $ 6,450 . CONCLUSIONS A telephone Quitline in conjunction with low-cost Pharmacotherapy was the most effective means of reducing smoking in the elderly AIMS To assess the effects of adding motivational interviewing ( MI ) counseling to nicotine patch for smoking cessation among homeless smokers . DESIGN Two-group r and omized controlled trial with 26-week follow-up . PARTICIPANTS AND SETTING A total of 430 homeless smokers from emergency shelters and transitional housing units in Minneapolis/St Paul , Minnesota , USA . INTERVENTION AND MEASUREMENTS All participants received 8-week treatment of 21-mg nicotine patch . In addition , participants in the intervention group received six individual sessions of MI counseling which aim ed to increase adherence to nicotine patches and to motivate cessation . Participants in the st and ard care control group received one session of brief advice to quit smoking . Primary outcome was 7-day abstinence from cigarette smoking at 26 weeks , as vali date d by exhaled carbon monoxide and salivary cotinine . FINDINGS Using intention-to-treat analysis , verified 7-day abstinence rate at week 26 for the intervention group was non-significantly higher than for the control group ( 9.3 % versus 5.6 % , P = 0.15 ) . Among participants who did not quit smoking , reduction in number of cigarettes from baseline to week 26 was equally high in both study groups ( -13.7 ± 11.9 for MI versus -13.5 ± 16.2 for st and ard care ) . CONCLUSIONS Adding motivational interviewing counseling to nicotine patch did not increase smoking rate significantly at 26-week follow-up for homeless smokers Cigarette smoking is highly prevalent among people living with HIV/AIDS and poses unique health risks . Smoking cessation programs tailored to this population have documented improved smoking outcomes with nicotine replacement therapy ( NRT ) . The current study examined 6-month abstinence rates from a r and omized clinical trial targeting 412 HIV-positive adult current smokers ( 51 % European American , 19 % African American , and 17 % Hispanic American ) and tested whether psychosocial variables , such as self-efficacy and decisional balance , mediated the relationship between NRT and long-term abstinence . Meeting criteria for complete mediation , 6-month smoking abstinence rates improved significantly with increases in these mediators , and the association of NRT and smoking abstinence was no longer significant once changes in self-efficacy and decisional balance were taken into account . Failure to translate gains in self-efficacy among African Americans into improved abstinence rates accounted for racial/ethnic differences among participants . Specific psychosocial factors , such as self-efficacy , may be particularly amenable to change in cessation interventions and should be addressed with greater awareness of how cultural and social context ual factors impact treatment response among people living with HIV/AIDS

RESULTS The incorporation of nystatin ( in general , 500 000 units ) into tissue conditioners to prevent the onset of the disease and immersion in sodium hypochlorite for disinfection were the methods most often described in this systematic review , and both methods were able to prevent or inhibit C and ida colonization , depending on their concentrations . The 0.5 % sodium hypochlorite concentration can disinfect tissue conditioners and denture liners . Microwave irradiation has also been described an alternative method of disinfection . The literature suggests that the use of 0.5 % sodium hypochlorite can help disinfect denture liners and tissue conditioners . The incorporation of nystatin in those material s is also able to treat or prevent oral c and idiasis .

STATEMENT OF PROBLEM Denture liners are well known for their poor physical properties that favor the accumulation of plaque and colonization by C and ida species , which can irritate the oral tissues and lead to denture stomatitis . PURPOSE A systematic review was conducted to determine the feasibility of a prevention protocol for C and ida colonization in denture liners and an effective treatment after the fungi has colonized the material .

This study investigated the C. albicans adhesion to cold- and heat-polymerized soft lining material s that were initially incubated in two different artificial body fluids , namely saliva and nasal secretion , and examined the surface roughness the material s ( cold and heat polymerized soft liner ) tested in vitro . Cold ( Visco Gel ) and heat-polymerized ( Molloplast B ) soft liner specimens ( N=32 , n=8 per group ) ( 10x10x1.5 mm ) were r and omly produced to express the relationship between surface roughness and contamination , and influence of body fluids , and incubated in 1.5 ml contaminated solutions for 2 h. After fixation , all of material s were evaluated under optical microscope ( x400 ) and SEM . Surface roughness measurements were examined with profilometre for each material . Data were analyzed using two-way ANOVA , Tukey 's HSD and Dunnett T3 tests ( alpha=0.05 ) . Material type ( p<0.05 ) and contamination media ( p<0.05 ) showed a significant influence on the C. albicans adherence . The surface roughness of cold polymerized soft liner ( Visco Gel ) was significantly higher than heat-polymerized soft liner ( Molloplast B ) ( p<0.05 ) OBJECTIVE This study evaluated . the effect of mouthrinses and tissue conditioner on the clinical findings and microbial flora of 60 patients with Newton 's type II denture stomatitis ( N2DS ) BACKGROUND : Denture stomatitis is a common problem in complete denture wearers . MATERIAL S AND METHODS Sixty patients with N2DS were included in this study and divided into three groups . Two groups of patients were instructed to rinse their mouth with the design ated mouthrinses DioxiDent and Corsodyl twice daily for 1 min and to soak their dentures overnight in these solutions for 15 days . For the third group , tissue conditioner was placed in each of 20 patients ' existing maxillary dentures . Patients were evaluated both clinical ly and microbiologically at baseline and after 15 days . Palatal swabs and smears were taken from each patient before and after treatment and these sample s were examined mycologically . The difference between C and ida colonisation before and after treatment and the differences between pre-treatment and post-treatment clinical findings were assessed . RESULTS DioxiDent and Corsodyl showed an improvement in palatal inflammation and a decrease in C and ida colonisation compared to Visco-gel . CONCLUSIONS The effectiveness of topical chlorine dioxide and chlorhexidine gluconate in the management of N2DS was demonstrated As poor denture hygiene is related to C and ida colonisation , disinfectant solutions have been proposed as an effective method of preventing denture stomatitis . This study assessed the efficacy of denture cleansers on C and ida albicans and C and ida glabrata adherence on denture liners . Another aim was to correlate material s ’ surface roughness ( Ra ) to C and ida adherence . Specimens of three denture liners ( soft and hard polymethyl methacrylate (PMMA)-based and soft silicone-based ) were prepared and had their Ra measured . Specimens were r and omly divided to adherence assays with C. albicans or C. glabrata . After contamination with the fungi , specimens were treated with an enzymatic cleanser solution , a cleanser solution or a 0.5 % NaOCl solution by soaking for 3 , 15 or 10 min , respectively . Control group specimens were soaked in distilled water for 15 min . Number of remaining C and ida cells after treatment was determined by light microscopy ( ×400 ) . Analysis of variance ( α = 0.05 ) showed that Ra of the silicone-based liner was lower than that of the PMMA-based liners ( p < 0.05 ) . The overall results showed high C. glabrata adherence ( p < 0.001 ) , while the lowest levels of remaining C and ida cells were found for the treatment with 0.5 % NaOCl ( p = 0.0019 ) . No difference among denture cleansers and control was found ( p = 0.19 ) . There was no correlation between Ra and C. albicans or C. glabrata adherence in all material s tested . The only treatment able to reduce both C and ida species adherence on all material s tested was 0.5 % NaOCl solution Polymer-gel material s used as short-term denture soft linings are blended with plasticizers to lower the glass transition temperature ( Tg ) . A lower Tg allows for greater polymer chain mobility , thus producing a more flexible material . The present work evaluated the loss of plasticizers due to leaching both in vivo and in vitro . Two commercial denture soft-lining material s ( A and B ) were tested . These were both poly(ethyl methacrylate ) polymers , blended with alcohol and phthalate esters . A clinical study was conducted in which patients wore , sequentially , dentures bearing ( on separate occasions ) each of the two soft-polymer lining material s. The two material s A and B were r and omly assigned for each of ten patients and were worn for 14 and 30 days , respectively . With one exception , patients wore dentures with both lining material s , for a total of 19 clinical evaluations . The plasticizer loss occurring during the clinical trial was determined by GC analysis from the initial and terminal day sampling of plasticizer content of the soft polymer-gel material s. The results of this analysis were compared with results obtained from an in vitro leachability study by use of sink conditions in water at 37 ° C for the same two commercial soft polymers conducted over the same time periods of 14 and 30 days . The results indicated that a higher loss of plasticizer occurred in vivo , compared with the in vitro tests for 17 of the 19 clinical evaluations . The average plasticizer lost in vivo from material A at 14 days was 122 ± 58 mg/g , and for material B at 30 days it was 33 ± 27 mg/g . This can be compared with the in vitro loss that was 13.41 ± 1.11 mg/g for material A at 14 days , and 8.47 ± 0.73 mg/g for material B at 30 days . It is not known how much of the plasticizer lost from the denture soft lining in the in vivo trial was ingested by the patient . Patients were caution ed against soaking the denture in any liquid ; however , it is not known how much was lost due to cleaning of the denture by the patients BACKGROUND Soft denture lining- material s are more susceptible to microbial adhesion than hard denture base acrylic resin . Poor oral hygiene and C and ida albicans infection are common among elderly denture wearers as these patients usually have difficulty in keeping them clean . PURPOSE To evaluate the influence of the oral hygiene methods on the formation of a biofilm over a soft denture-lining material . MATERIAL AND METHODS Twenty volunteers were r and omly separated into two groups : G1 and G2 . Ten volunteers performed daily hygiene of the prostheses with a soft toothbrush and toothpaste . The G2 performed a treatment identical to G1 but also immersed the prostheses in sodium hypochlorite 0.5 % for 20 min , once a week . Quantification of the mean score values of biofilm formation at different times were statistically analysed using analysis of variance and Tukey 's test ( alpha = 0.05 ) . RESULTS G1 ( 0.65 + /- 0.52 ) showed the lowest mean score values of biofilm formation . There was statistical difference between G1 and G2 . The highest mean score values were found at 6 weeks ( 1.3 + /- 1.08 ) and were statistically different from other times . CONCLUSION The oral hygiene methods had a significant effect in the formation of the biofilm over a soft denture-lining material This study evaluated the long-term efficacy of denture cleansers against C and ida spp . biofilm recolonization on liner surface . Specimens were fabricated of a poly(methyl methacrylate)-based denture liner and had their surface roughness evaluated at baseline and after cleansing treatments . C. albicans or C. glabrata biofilms were formed on liner surface for 48 h , and then the specimens were r and omly assigned to one of cleaning treatments : two alkaline peroxides ( soaking for 3 or 15 min ) , 0.5 % sodium hypochlorite ( 10 min ) or distilled water ( control ; 15 min ) . After the treatments , the specimens were sonicated to disrupt the biofilm , and residual cells were counted ( cell/mL ) . Long-term effectiveness of the cleaning processes was determined by su bmi tting a set of cleaned specimens to biofilm growth conditions for 48 h followed by estimation of cell counts . The topography of specimens after cleaning treatments was analyzed by SEM . Data were analyzed by ANOVA and Tukey 's test ( α ; = 0.05 ) . Results of cell count estimation showed significant differences in cleanliness among the treatments ( p < 0.001 ) , and it could be observed by SEM . However , no significant difference ( p > 0.05 ) was observed among the C and ida species regarding the recolonization condition . Alkaline denture cleansers showed similar cleaning performance and both differed from the control ( p < 0.001 ) . Sodium hypochlorite was the only treatment that removed biofilm efficiently , since no viable cells were found after its use . In conclusion , alkaline peroxide denture cleansers were not effective in removing C and ida spp . biofilm from denture liner surfaces and preventing biofilm recolonization PURPOSE The aim of this study was to evaluate if the use of a varnish on a tissue conditioner would affect biofilm adhesion . BACKGROUND After the surgery has been performed , before the delivery of a complete denture , it is often necessary to use material s such as tissue conditioners on the surgical wound . However , these material s present deficient physico-mechanical properties , which allow biofilm development . METHODS Forty elderly volunteers wearing complete maxillary dentures were selected . They were r and omly allocated into two groups ( n = 20 ) , G1 and G2 . In both groups , a silicone-based tissue conditioner was placed in a recess created at the base of the denture , according to the manufacturer 's guidelines . In group G1 , a varnish was applied to the tissue conditioner , while in group G2 , no treatment was applied . All volunteers performed daily hygiene of the prosthesis with a soft toothbrush , and toothpaste . Quantification of the mean score values of biofilm formed at different time points ( baseline , 1 week and 3 weeks ) was statistically analysed using anova ( alpha = 0.05 ) . RESULTS Group G2 ( 1.6 + /- 1.2 ) showed the lowest mean score values of biofilm formation and there was a statistical difference between the groups ( p = 0.03 ) . The highest mean score values were found after 3 weeks ( 2.7 + /- 1.4 ) and were statistically different from the other time points studied ( baseline and 1 week ) . CONCLUSION The use of a varnish had a detrimental effect on the tissue conditioner studied , allowing higher biofilm formation

There is no evidence to support the use of low-dose aspirin or other NSAIDs of any class ( celecoxib , rofecoxib or naproxen ) for the prevention of dementia , but there was evidence of harm .

BACKGROUND Dementia is a worldwide concern . Its global prevalence is increasing . At present , there is no medication licensed to prevent or delay the onset of dementia . Inflammation has been suggested as a key factor in dementia pathogenesis . Therefore , medications with anti-inflammatory properties could be beneficial for dementia prevention . OBJECTIVES To evaluate the effectiveness and adverse effects of aspirin and other non-steroidal anti-inflammatory drugs ( NSAIDs ) for the primary or secondary prevention of dementia .

Objective To examine whether observed differences in dementia rates between black and white older people living in the community could be explained by measures of socioeconomic status ( income , financial adequacy , education , and literacy ) and health related factors . Design Prospect i ve cohort study . Setting General community from two clinic sites in the United States ( Pittsburgh , Pennsylvania and Memphis , Tennessee ) . Participants 2457 older people ( mean age 73.6 years ; 1019 ( 41.5 % ) black ; 1233 ( 50.2 % ) women ) , dementia-free at baseline , in the Health , Aging , and Body Composition study . Main outcome measure Dementia was determined over 12 years ( ending January 2011 ) by prescribed dementia drugs , hospital records , and decline in global cognitive scores . The influence of socioeconomic status and health related factors on dementia rates was examined in a series of Cox proportional hazard models in which these variables were added sequentially in covariate blocks . Results Over follow-up , 449 ( 18.3 % ) participants developed dementia . Black participants were more likely than white participants to develop dementia ( 211 ( 20.7 % ) v 238 ( 16.6 % ) , P<0.001 ; unadjusted hazard ratio 1.44 , 95 % confidence interval 1.20 to 1.74 ) . The hazard ratio lessened somewhat after adjustment for demographics , apolipoprotein E e4 , comorbidities , and lifestyle factors ( 1.37 , 1.12 to 1.67 ) but was greatly reduced and no longer statistically significant when socioeconomic status was added ( 1.09 , 0.87 to 1.37 ) . Conclusion These findings suggest that differences in the burden of risk factors , especially socioeconomic status , may contribute to the higher rates of dementia seen among black compared with white older people . Strategies aim ed at reducing these disparities may favorably affect the incidence of dementia Background and Purpose — Although aspirin is effective in prevention of stroke , fewer studies have examined the impact of aspirin on stroke morbidity . Methods — The Women ’s Health Study is a completed r and omized , placebo-controlled trial design ed to test the effect of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer , which enrolled 39 876 women . We used multinomial logistic regression to evaluate the relationship between r and omized aspirin assignment and functional outcomes from stroke . Possible functional outcomes were neither stroke nor transient ischemic attack ( TIA ) , modified Rankin scale ( mRS ) score 0 to 1 , 2 to 3 , and 4 to 6 . Results — After a mean of 9.9 years of follow-up , 460 confirmed strokes ( 366 ischemic , 90 hemorrhagic , and 4 unknown type ) and 405 confirmed TIAs occurred . With regard to total and ischemic stroke , women who were r and omized to aspirin had a nonsignificant decrease in risk of any outcome compared to women not r and omized to aspirin . This decrease in risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA ( odds ratio=0.77 ; 95 % confidence interval , 0.63–0.94 ) . For hemorrhagic stroke , a nonsignificant increase in the risk of achieving an mRS score 2 to 3 or 4 to 6 compared with no stroke or TIA was observed for the women r and omized to aspirin compared to those r and omized to placebo . Conclusions — Results from this large r and omized clinical trial provide evidence that 100 mg of aspirin every other day may reduce the risk of ischemic cerebral vascular events but does not have differential effects on functional outcomes from stroke Objective To determine whether low dose aspirin protects women aged 65 or more against cognitive decline . Design Cohort study within both arms of the women 's health study , a r and omised , double blind , placebo controlled trial of low dose aspirin for the primary prevention of cardiovascular disease and cancer , 1992 - 5 . Setting Women 's health study , 1998 - 2004 . Participants 6377 women aged 65 or more . Interventions Low dose aspirin ( 100 mg on alternate days ) or placebo for a mean of 9.6 years . Main outcome measures Women had three cognitive assessment s at two year intervals by telephone . The battery to assess cognition included five tests measuring general cognition , verbal memory , and category fluency . The primary prespecified outcome was a global score , averaging performance across all tests . The key secondary outcome was a verbal memory score , averaging performance on four measures of verbal memory . Results At the initial assessment ( mean 5.6 years after r and omisation ) cognitive performance in the aspirin group was similar to that of the placebo group ( mean difference in global score −0.01 , 95 % confidence interval −0.04 to 0.02 ) . Mean decline in the global score from the first to the final cognitive assessment was also similar in the aspirin compared with placebo groups ( mean difference 0.01 , −0.02 to 0.04 ) . The risk of substantial decline ( in the worst 10th centile of decline ) was also comparable between the groups ( relative risk 0.92 , 0.77 to 1.10 ) . Findings were similar for verbal memory ; however , a 20 % lower risk was observed for decline in category fluency with aspirin ( relative risk 0.80 , 0.67 to 0.97 ) . Conclusion Long term use of low dose aspirin does not provide overall benefits for cognition among generally healthy women aged 65 or more Background Amnestic mild cognitive impairment represents , in many cases , the earliest clinical phases of Alzheimer disease . Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease . In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system . Methods We conducted a r and omized , double-blind , placebo-controlled trial of Triflusal in patients with amnestic mild cognitive impairment . Subjects were r and omly assigned to receive 900 mg of Triflusal or placebo for 18 months . The primary outcome was a change in Cognitive subscale of the Alzheimer Disease Assessment Scale ; conversion to dementia was a secondary outcome . Results A slow rate of recruitment forced a premature cessation of the study . Two hundred and fifty-seven subjects were enrolled and followed-up for an average of 13 months . The significance level was not reached for the primary outcome even though a trend in favor of Triflusal was observed . However , there was a significant difference in the probability of progression to dementia of Alzheimer 's type with a lower risk in the Triflusal compared with the placebo group ( hazard ratio , 2.10 ; 95 % confidence interval , 1.10 - 4.01 ; P=0.024 ) . Conclusions In this study , Triflusal therapy was associated with a significant lower rate of conversion to dementia that is likely to be clinical ly relevant . Because the trial was prematurely halted , these results should be interpreted with caution and require further confirmation BACKGROUND Selective inhibition of cyclooxygenase-2 ( COX-2 ) may be associated with an increased risk of thrombotic events , but only limited long-term data have been available for analysis . We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term , multicenter , r and omized , placebo-controlled , double-blind trial design ed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas . METHODS A total of 2586 patients with a history of colorectal adenomas underwent r and omization : 1287 were assigned to receive 25 mg of rofecoxib daily , and 1299 to receive placebo . All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee . RESULTS A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up ( 1.50 events per 100 patient-years ) , as compared with 26 patients in the placebo group during 3327 patient-years of follow-up ( 0.78 event per 100 patient-years ) ; the corresponding relative risk was 1.92 ( 95 percent confidence interval , 1.19 to 3.11 ; P=0.008 ) . The increased relative risk became apparent after 18 months of treatment ; during the first 18 months , the event rates were similar in the two groups . The results primarily reflect a greater number of myocardial infa rct ions and ischemic cerebrovascular events in the rofecoxib group . There was earlier separation ( at approximately five months ) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure , pulmonary edema , or cardiac failure ( hazard ratio for the comparison of the rofecoxib group with the placebo group , 4.61 ; 95 percent confidence interval , 1.50 to 18.83 ) . Overall and cardiovascular mortality was similar in the two groups . CONCLUSIONS Among patients with a history of colorectal adenomas , the use of rofecoxib was associated with an increased cardiovascular risk Objective To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk . Design R and omised double blind placebo controlled trial . Setting Central Scotl and . Participants 3350 men and women aged over 50 participating in the aspirin for asymptomatic atherosclerosis trial . Intervention Low dose aspirin ( 100 mg daily ) or placebo for five years . Main outcome measures Tests of memory , executive function , non-verbal reasoning , mental flexibility , and information processing five years after r and omisation , with scores used to create a summary cognitive score ( general factor ) . Results At baseline , mean vocabulary scores ( an indicator of previous cognitive ability ) were similar in the aspirin ( 30.9 , SD 4.7 ) and placebo ( 31.1 , SD 4.7 ) groups . In the primary intention to treat analysis , there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score ( 32.7 % and 34.8 % respectively , odds ratio 0.91 , 95 % confidence interval 0.79 to 1.05 , P=0.20 ) or in mean scores on the individual cognitive tests . There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline . Conclusion Low dose aspirin does not affect cognitive function in middle aged to elderly people at increased cardiovascular risk . Trial registration IS RCT N 66587262 Inflammatory mechanisms have been implicated in Alzheimer 's disease ( AD ) and might be mediated via the COX-2 enzyme . Previous studies with the selective COX-2 inhibitors , rofecoxib and celecoxib , have shown that they do not alter the progression of AD . We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment ( MCI ) , a group with an expected annual AD diagnosis rate of 10–15 % . MCI patients ⩾65 years were r and omized to rofecoxib 25 mg ( N=725 ) or placebo ( N=732 ) daily for up to 4 years . The primary end point was the percentage of patients with a clinical diagnosis of AD . The estimated annual AD diagnosis rate was lower than the anticipated 10–15 % : 6.4 % in the rofecoxib group vs 4.5 % in the placebo group ( rofecoxib : placebo hazard ratio=1.46 ( 95 % CI : 1.09 , 1.94 ) , p=0.011 ) . Analyses of secondary end points , including measures of cognition ( eg the cognitive subscale of the AD Assessment Scale ( ADAS-Cog ) ) and global function ( eg the Clinical Dementia Rating ( CDR ) ) , did not demonstrate differences between treatment groups . There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24–26 in the present MCI study and in a previous AD treatment study with a similar design . The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD . In conjunction with the lack of effects observed in previous AD studies , the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD BACKGROUND Selective cyclooxygenase-2 ( COX-2 ) inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use . Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern . METHODS We review ed all potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib ( 200 mg or 400 mg twice daily ) with placebo for the prevention of colorectal adenomas . All deaths were categorized as cardiovascular or noncardiovascular , and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme . RESULTS For all patients except those who died , 2.8 to 3.1 years of follow-up data were available . A composite cardiovascular end point of death from cardiovascular causes , myocardial infa rct ion , stroke , or heart failure was reached in 7 of 679 patients in the placebo group ( 1.0 percent ) , as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily ( 2.3 percent ; hazard ratio , 2.3 ; 95 percent confidence interval , 0.9 to 5.5 ) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily ( 3.4 percent ; hazard ratio , 3.4 ; 95 percent confidence interval , 1.4 to 7.8 ) . Similar trends were observed for other composite end points . On the basis of these observations , the data and safety monitoring board recommended early discontinuation of the study drug . CONCLUSIONS Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes , myocardial infa rct ion , stroke , or heart failure . In light of recent reports of cardiovascular harm associated with treatment with other agents in this class , these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events Objective The aim of this study was to examine whether low-dose acetylsalicylic acid ( ASA ) influences the rate of cognitive change in elderly women . Design Prospect i ve , population -based cohort study . Setting The city of Gothenburg , Sweden , including those living in private households as well as in residential care . Participants The sample was derived from the Prospect i ve Population Study of Women and from the H70 Birth Cohort Study in Gothenburg , Sweden . Both sample s were obtained from the Swedish Population Register , based on birth date , and included 789 ( response rate 71 % ) women aged 70–92 years . After the exclusion of individuals with dementia and users of warfarin , clopidogrel or heparin at baseline , 681 women were examined . Among all participants , 95.4 % ( N=601 ) had a high cardiovascular risk ( CVD ) , defined as 10 % or higher 10-year risk of any CVD event according to the Framingham heart study and 129 used low-dose ASA ( 75–160 mg daily ) at baseline . After 5 years a follow-up was completed by 489 women . Primary outcome and secondary outcome measures Cognitive decline and dementia incidence in relation to the use of low-dose ASA and cardiovascular risk factors . Cognition was measured using the Mini Mental State Examination ( MMSE ) , word fluency , naming ability and memory word tests . Dementia was diagnosed according to the DSM-III-R criterion . As secondary outcome incidence of stroke and peptic ulcer in relation to low-dose ASA use was studied . Results Women on regular low-dose ASA declined less on MMSE at follow-up than those not on ASA . This difference was even more pronounced in those who had ASA at both examinations ( p=0.004 compared with never users ; n=66 vs n=338 ) . All other cognitive tests showed the same trends . There were no differences between the groups regarding short-term risk for dementia ( N=41 ) . Conclusion Low-dose ASA treatment may have a neuroprotective effect in elderly women at high cardiovascular risk In a geriatric evaluation and rehabilitation unit ( GERU ) , 258 elderly patients ( M : 71 , F : 187 ; mean age 77.4 + /- 7.5 ) scoring 22 or more at Mini-Mental State Examination ( MMSE ) consecutively admitted were assessed in order to evaluate the effects of non-steroidal anti-inflammatory drugs ( NSAID ) chronic treatment on cognitive status in non-demented elderly patients . Sixty-six patients ( 25.6 % ) were considered chronic NSAID users . Patients chronically assuming NSAADs showed a significantly higher MMSE score than non-users ( 26.9+/-2.1 vs 25.7+/-2.5 , P<0.0005 ) . After controlling for potential confounders in a multivariate model , chronic NSAID use remained independently associated with MMSE score . The results support a positive association between chronic NSAID use and cognitive function in non-demented elderly patients . R and omized controlled trials will be needed to definitively prove this beneficial effect Article abstract -In a longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging , we examined whether the risk of Alzheimer 's disease ( AD ) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs ( NSAIDs ) . In addition , we examined use of acetaminophen , a pain-relief medication with little or no anti-inflammatory activity , to assess the specificity of the association between AD risk and self-reported medications . Information on use of medications was collected during each biennial examination between 1980 and 1995 . The relative risk ( RR ) for AD decreased with increasing duration of NSAID use . Among those with 2 or more years of reported NSAID use , the RR was 0.40 ( 95 % confidence interval [ CI ] : 0.19 - 0.84 ) compared with 0.65 ( 95 % CI : 0.33 - 1.29 ) for those with less than 2 years of NSAID use . The overall RR for AD among aspirin users was 0.74 ( 95 % CI : 0.46 - 1.18 ) , and no trend of decreasing risk of AD was observed with increasing duration of aspirin use . No association was found between AD risk and use of acetaminophen ( RR = 1.35 ; 95 % CI : 0.79 - 2.30 ) , and there was no trend of decreasing risk with increasing duration of use . These findings are consistent with evidence from cross-sectional studies indicating protection against AD risk among NSAID users and with evidence suggesting that one stage of the pathophysiology leading to AD is characterized by an inflammatory process . NEUROLOGY 1997;48 : 626 - BACKGROUND Quality of Life ( QoL ) is a key outcome in dementia . AIM To compare care recipients ' ( CR ) and caregivers ' ( CG ) views on CRs ' QoL and identify determinants . METHODS CRs and CGs completed the Quality of Life - Alzheimer 's Disease ( QOL-AD ) scale . RESULTS One hundred and ninety-one CR/CG dyads were interviewed . There were differences between determinants of the CRs and CGs views about QoL. Family-CGs rated CRs ' QoL higher when CRs had fewer depressive symptoms , less irritability , less apathy , less daily living impairment and lived at home . Fewer depressive symptoms , living at home and taking acetylcholinesterase-inhibitors ( AChEI ) predicted higher CR rated QoL. CONCLUSION Proxy ratings in dementia do not replicate CRs ' views of QoL. This is the first study to employ a vali date d QoL measure for people with dementia taking AChEIs . R and omised controlled trials are needed before drawing conclusions about their effect on QoL. Interpretation of correlations between QoL and symptoms should be cautious as QoL is design ed to reflect the impact of psychological and physical symptoms OBJECTIVES To examine the association of cognitive impairment with platelet activation and reactive oxygen species and total homocysteine levels ; and to assess the biochemical efficacy of treatment with aspirin and vitamin supplements in people at high risk of dementia . SUBJECTS People with dementia or mild cognitive impairment . DESIGN AND INTERVENTION In a 2 x 2 x 2 factorial design trial , 149 people at high-risk of dementia were r and omized to receive either low-dose aspirin ( 81 mg ) or placebo ; and folic acid ( 2 mg ) plus vitamin B12 ( 1 mg ) or placebo ; and vitamins E ( 500 mg ) plus C ( 200 mg ) or placebo . Participants were seen twice before and once after 12 weeks of treatment . MAIN OUTCOME MEASURES At each visit , participants had their cognitive function assessed and had blood collected for homocysteine , folate and vitamin B12 determination and urine collected for markers of platelet activation ( 11-dehydro-thromboxane B2 ) and reactive oxygen species ( 8-epi-PGF2 alpha ) . RESULTS Prior to treatment , cognitive function was inversely related with homocysteine and with urinary thromboxane and isoprostane , and these associations were independent of age . Aspirin was associated with a median reduction in 11-dehydrothromboxane B2 of 73 % ( P < 0.001 ) . B-vitamins lowered plasma homocysteine concentration by 30 % ( P < 0.0001 ) and antioxidant vitamins lowered isoprostane excretion by 26 % ( P < 0.1 ) . No effect of treatment on cognitive function was detected . CONCLUSIONS Aspirin and B-vitamins were effective in reducing biochemical factors associated with cognitive impairment in people at risk of dementia . Large-scale trials are now required to assess the relevance of aspirin and B-vitamins for the maintenance of cognitive function in people at risk of dementia Objective : To evaluate the efficacy and safety of naproxen and celecoxib for the primary prevention of Alzheimer disease ( AD ) . Methods : R and omized , placebo-controlled , double-masked clinical trial conducted at six US dementia research clinics . Volunteers aged 70 + years , with cognitive screening scores above design ated cut-offs and a family history of AD , were r and omly assigned to celecoxib 200 mg BID , naproxen sodium 220 mg BID , or placebo . Enrollment began in early 2001 . The main outcome measure was diagnosis of AD after r and omization . Results : On December 17 , 2004 , treatments were suspended . Events while on treatment yielded hazard ratios vs placebo of 1.99 ( 95 % CI 0.80 to 4.97 ; p = 0.14 ) for celecoxib and 2.35 ( 0.95 to 5.77 ; p = 0.06 ) for naproxen . Imperfect screening measures led to enrollment of 7 individuals with dementia and 46 others with milder cognitive syndromes . Their ( prevalent ) illness was detected at enrollment and diagnosed within 6 months following r and omization . Secondary analyses that excluded the 7 cases of prevalent dementia showed increased hazard ratios for AD with both treatments . Neither treatment produced a notable effect on the incidence of milder cognitive syndromes . Conclusions : These results do not support the hypothesis that celecoxib or naproxen prevent Alzheimer dementia , at least within the early years after initiation of treatment . Masked long-term follow-up of these participants will be essential CONTEXT Anti-inflammatory medications have an inverse association with Alzheimer disease ( AD ) . OBJECTIVES To examine at what doses this anti-inflammatory drug effect occurs and whether other medications and /or International Classification of Diseases , Ninth Revision , Clinical Modification diagnoses affect the association . DESIGN Subjects 75 years and older from a r and om population sample were classified by consensus using International Classification of Diseases , Ninth Revision , Clinical Modification diagnoses . Drug associations with different types of dementia with and without the International Classification of Diseases , Ninth Revision , Clinical Modification diagnoses as well as dosage data were analyzed . SETTING The Centre for Education and Research on Aging , Concord Hospital , Concord , Australia . PATIENTS The Sydney Older Persons Study recruited 647 subjects ( average age , 81 years ) . A total of 163 patients were given diagnoses placing them in different dementia categories and were compared with 373 control subjects . Of the patients with dementia , 78 had AD without vascular dementia , 45 had vascular dementia ( permissive of other dementia diagnoses ) , and 40 had other dementia diagnoses ( without AD or vascular dementia ) . MAIN OUTCOME MEASURES Fifty drugs or drug groups were subjected to a 2 ( drug used vs drug not used ) x 4 ( dementia and control groups ) chi(2 ) analysis . Drugs with inverse associations were identified and potential confounders ( logistic regression ) and dosage data ( exact small sample 1-tailed tests ) analyzed . RESULTS As expected , there was an inverse association between nonsteroidal anti-inflammatory drugs and aspirin ( and unexpectedly angiotensin-converting enzyme inhibitors ) and AD . This association was not observed with vascular dementia or any other diagnoses . Analysis showed no evidence for a dosage effect , ie , responses were equivalent for low and high doses . CONCLUSIONS This study does not support a high-dose anti-inflammatory action of nonsteroidal anti-inflammatory drugs or aspirin in AD . Potential mechanisms for the beneficial effects of these medications are discussed A retrospective clinico-pathological study of a consecutive autopsy series of 1050 elderly demented individuals ( mean age 83.4 + /- 6.0 years ; MMSE < 20 ) was performed . Clinical diagnoses were probable or possible Alzheimer disease ( 62.9 % ) , nonspecific degenerative dementia ( 10.4 % ) , vascular dementia ( 10 % ) , Parkinson disease with dementia ( 9.5 % ) , 1.5 % mixed dementia , and 5.7 % other disorders . At autopsy , 86 % revealed Alzheimer-related pathology , but only 42.8 % showed " pure " Alzheimer disease , with additional cerebrovascular lesions in 22.6 % and Lewy body pathology in 10.8 % , while among 660 cases of clinical ly suspected Alzheimer disease , Alzheimer pathology was seen in 93 % , only 44.7 % in " pure " form , and additional vascular lesions and Lewy bodies in 27.7 and 10 % , respectively . The non-Alzheimer cases included Huntington and Creutzfeldt-Jakob disease , frontotemporal dementias , and others . These and other recent data indicate that in patients with the clinical diagnosis of Alzheimer disease its combination with cerebrovascular lesions and Lewy body pathologies is rather frequent . Comparison of clinical and postmortem diagnoses revealed postmortem confirmation of Alzheimer disease in 93 % , of mixed and vascular dementia in 60 and 52.3 % , respectively . 78 % of clinical ly suspected degenerative dementias were pathologically definite Alzheimer disease , while in the clinical Parkinson + dementia group dementia with Lewy bodies accounted for 35 % , Parkinson+Alzheimer disease , and " pure " Alzheimer disease for 29 % , each . A sample of 207 prospect ively studied elderly showed significant negative correlation between the preterminal psychostatus assessed by MMSE and the neuritic Braak stages , with a broad " gray " zone of Alzheimer lesions in mildly to moderately demented subjects . Similar relations between CDR and Braak stages were seen in very old subjects . The present study and the results of other recent series indicate increasing agreement between clinical and autopsy diagnoses in demented aged individuals with variable accuracy rates for different forms of dementia disorders The adverse effects of low‐dose aspirin ( 100 mg daily ) in the elderly were studied over a 12‐month period in a double‐blind , r and omized , placebo‐controlled trial of 400 subjects who were 70 years of age or older and had no preexisting major vascular diseases at the time of entry . Subjects were r and omized so that 200 subjects received low‐dose enteric‐coated aspirin ( 100 mg daily ) and 200 subjects received placebo . Compliance with medication , assessed by pill count , was 86 % . Gastrointestinal symptoms were reported by 18 % ( n = 36 ) of participants receiving aspirin and 13 % ( n = 26 ) of those receiving placebo . Clinical ly evident gastrointestinal bleeding occurred in 3 % ( n = 6 ) of subjects receiving aspirin and none receiving placebo . Aspirin‐treated subjects had a significant decrease in mean hemoglobin levels of 0.33 gm/dl during the 12‐month study period , which was significantly greater than the decrease in the placebo‐treated group ( 0.11 gm/dl ; p < 0.05 ) . These rates of unwanted symptoms are comparable with previous studies that used higher doses of aspirin . Until the risk‐benefit trade‐off from the use of low‐dose aspirin in the elderly is established with an appropriate clinical trial , caution should be exercised when this compound is used for primary prevention of cardiovascular disease in this age group 1 . Cognitive function was studied after single and multiple doses of indomethacin ( I ) and matched placebo ( P ) in 20 healthy elderly volunteers using a double-blind crossover design . 2 . Arousal , attention , integration , coordination , memory and mood were investigated using a battery of psychomotor tests and the Hospital Anxiety and Depression Scale . Assessment s were performed before and after the first and last doses of a 7 day course of medication . 3 . Critical flicker fusion threshold fell by a mean of 1.96 % on indomethacin compared with a 1.13 % rise on placebo 5 h after the first dose ( P = 0.029 ) . A beneficial effect on choice reaction time latency ( P = 0.012 ) was seen both after acute and continuing administration of indomethacin . Performance at the most discriminating level ( level 3 ) of the paired word association test was significantly better following 8 days of treatment with indomethacin in the younger ( 55 - 65 year-old ) age group ( P = 0.001 ) . 4 . There was no significant difference in performance on the symbol-digit substitution test and the continuous attention task . No change was seen in hospital anxiety and depression scale scores . 5 . These results suggest that performance on tests of sensorimotor coordination and short term memory may improve in healthy volunteers following indomethacin administration , whereas tests of attention and psychomotor speed remain unaffected . However , further controlled studies in rheumatic patients are needed to evaluate fully the psychomotor effects of indomethacin and other NSAIDs in clinical practice OBJECTIVE To investigate the protective effect of NSAIDs and aspirin separately on cognitive decline in elderly subjects , controlling for consistent use of these agents over a prolonged period of time . METHODS The study sample consisted of 1007 subjects , drawn from a population -based r and om sample of elderly individuals , 62 - 85 years old , who participated in a 3-year follow-up study . From this sample subjects were selected , who did use NSAIDs and completed all cognitive tests at both measurements ( n=137 ) , and subjects who did not use NSAIDs and completed all cognitive tests ( n=475 ) . Cognitive tests included the Mini-Mental State Examination ( MMSE ) , tests for episodic memory ( Auditory Verbal Learning Test ) and information processing speed ( coding task ) . Cognitive decline was computed using Edwards-Nunnally method . Multiple logistic regression analyses were performed to examine the association between NSAID ( with and without aspirin ) and decline in cognitive performance . Besides , the interaction of NSAIDs with age on cognitive decline was determined . RESULTS The relative risk estimates of decline in episodic memory ( immediate recall ) adjusted for age , gender , education , baseline MMSE , vascular diseases , diabetes mellitus and ( rheumatoid ) arthritis for aspirin users only was more than three times reduced ( OR : 0.30 , 95 % CI : 0.09 - 0.82 ) . The odds ratio for decline in memory of NSAID use without aspirin , adjusted for age , gender , education , baseline MMSE , vascular diseases , diabetes mellitus and ( rheumatoid ) arthritis was not significant ( OR : 1.00 , 95 % CI : 0.39 - 2.93 ) . The effect of aspirin was significant only in persons of 75 years and over ( OR : 0.10 , 95 % CI : 0.01 - 0.81 ) , not in subjects younger than 75 years ( OR : 0.52 , 95 % CI : 0.14 - 1.96 ) . NSAIDs did not have benefit on information processing speed . In 92 % of aspirin users a low dose of 100 mg daily or less was used . CONCLUSION Low-dose aspirin might be protective for decline in memory in individuals of 75 years and over . The benefit of a low-dose aspirin does not support an anti-inflammatory effect , but suggests an antiplatelet effect . Therefore , a possible protective effect of low-dose aspirin on cognitive decline is likely only in subjects with aspirin use over a prolonged period of time Background : Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs ( NSAIDs ) may be useful for the prevention of Alzheimer disease ( AD ) . By contrast , clinical trials have not supported NSAID use to delay or treat AD . Few studies have evaluated cognitive trajectories of NSAID users over time . Methods : Residents of Cache County , UT , aged 65 or older on January 1 , 1995 , were invited to participate in the study . At baseline , participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination ( 3MS ) . Participants ( n = 3,383 ) who were cognitively normal at baseline were re-examined after 3 and 8 years . The association between NSAID use and 3MS scores over time was estimated using r and om effects modeling . Results : Associations depended upon when NSAIDs were started and APOE genotype . In participants who started NSAID use prior to age 65 , those with no APOE ε4 alleles performed similarly to nonusers ( a difference of 0.10 points per year ; p = 0.19 ) , while those with one or more ε4 allele(s ) showed more protection ( 0.40 points per year ; p = 0.0005 ) . Among participants who first used NSAIDs at or after age 65 , those with one or more ε4 alleles had higher baseline scores ( 0.95 points ; p = 0.03 ) but did not show subsequent difference in change in score over time ( 0.06 points per year ; p = 0.56 ) . Those without an ε4 allele who started NSAID use after age 65 showed greater decline than nonusers ( −0.16 points per year ; p = 0.02 ) . Conclusions : Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life . This effect may be more notable in those who have one or more APOE ε4 alleles BACKGROUND Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs ( NSAIDs ) may help to prevent Alzheimer 's disease . The results , however , are inconsistent . METHODS We studied the association between the use of NSAIDs and Alzheimer 's disease and vascular dementia in a prospect i ve , population -based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line , in 1991 . To detect new cases of dementia , follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999 . The risk of Alzheimer 's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records . We defined four mutually exclusive categories of use : nonuse , short-term use ( 1 month or less of cumulative use ) , intermediate-term use ( more than 1 but less than 24 months of cumulative use ) , and long-term use ( 24 months or more of cumulative use ) . Adjustments were made by Cox regression analysis for age , sex , education , smoking status , and the use or nonuse of salicylates , histamine Hz-receptor antagonists , antihypertensive agents , and hypoglycemic agents . RESULTS During an average follow-up period of 6.8 years , dementia developed in 394 subjects , of whom 293 had Alzheimer 's disease , 56 vascular dementia , and 45 other types of dementia . The relative risk of Alzheimer 's disease was 0.95 ( 95 percent confidence interval , 0.70 to 1.29 ) in subjects with short-term use of NSAIDs , 0.83 ( 95 percent confidence interval , 0.62 to 1.11 ) in those with intermediate-term use , and 0.20 ( 95 percent confidence interval , 0.05 to 0.83 ) in those with long-term use . The risk did not vary according to age . The use of NSAIDs was not associated with a reduction in the risk of vascular dementia . CONCLUSIONS The long-term use of NSAIDs may protect against Alzheimer 's disease but not against vascular dementia BACKGROUND In the primary analysis of the Aspirin in Reducing Events in the Elderly ( ASPREE ) trial , now published in the Journal , we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability‐free survival among older adults . A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo . METHODS From 2010 through 2014 , we enrolled community‐dwelling persons in Australia and the United States who were 70 years of age or older ( or ≥65 years of age among blacks and Hispanics in the United States ) and did not have cardiovascular disease , dementia , or disability . Participants were r and omly assigned to receive 100 mg of enteric‐coated aspirin or placebo . Deaths were classified according to the underlying cause by adjudicators who were unaware of trial‐group assignments . Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group , and post hoc exploratory analyses of specific causes of death were performed . RESULTS Of the 19,114 persons who were enrolled , 9525 were assigned to receive aspirin and 9589 to receive placebo . A total of 1052 deaths occurred during a median of 4.7 years of follow‐up . The risk of death from any cause was 12.7 events per 1000 person‐years in the aspirin group and 11.1 events per 1000 person‐years in the placebo group ( hazard ratio , 1.14 ; 95 % confidence interval [ CI ] , 1.01 to 1.29 ) . Cancer was the major contributor to the higher mortality in the aspirin group , accounting for 1.6 excess deaths per 1000 person‐years . Cancer‐related death occurred in 3.1 % of the participants in the aspirin group and in 2.3 % of those in the placebo group ( hazard ratio , 1.31 ; 95 % CI , 1.10 to 1.56 ) . CONCLUSIONS Higher all‐cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer‐related death . In the context of previous studies , this result was unexpected and should be interpreted with caution . ( Funded by the National Institute on Aging and others ; ASPREE Clinical Trials.gov number , NCT01038583 .

The ALT-mortality association was inconsistent and seems particularly susceptible to age after synthesizing the previous prospect i ve studies . In terms of the age , ALT activity was more valuable in predicting mortality in the older population ; extremely low ALT levels indicated a higher all-cause , CV-related , and cancer-related mortality . ALT activity may therefore be a useful biomarker when predicting the long-term survival of elderly patients

OBJECTIVE Controversy exists in using alanine aminotransferase ( ALT ) activity for predicting long-term survival . Therefore , this research study investigated the association between ALT activity and mortality through a systematic review and meta- analysis of previous prospect i ve studies .

Serum biochemical liver tests ( LTs ) ( ALT , AST , GGT ) and platelet counts are often used to screen for chronic liver disease . Population ‐based data on abnormal LTs in Mediterranean areas are lacking . The prevalence and etiology of abnormal LTs were assessed from 2002 to 2003 in a 1 in 5 systematic r and om sample of the general population who were 12 years of age or older in Cittanova , a southern Italian town with 10,600 inhabitants . LTs , indices of metabolism , and markers of HBV and HCV infection were assayed and alcohol intake was recorded in the selected population . In virus‐free individuals with abnormal LTs , LTs were retested , and upper abdominal echography and tests for other causes of liver damage were undertaken . Among the 1,645 individuals screened , the prevalence of anti‐HCV was 6.5 % ; the prevalence was particularly high in individuals over 50 years of age . The corresponding prevalence for HBsAg was 0.8 % . The overall prevalence of individuals with abnormal LTs was 12.7 % ( 95 % CI : 11.1‐14.3 ) . The probable cause of abnormal LTs was excessive alcohol in 45.6 % , HCV in 18.6 % , HBV in 1 % , alcohol plus HCV and /or HBV in 8.8 % , and rare diseases in 2 % . In 24 % of individuals with abnormal LTs , the probable cause was nonalcoholic fatty liver disease ( NAFLD ) ; in this subgroup , increased body weight , hypercholesterolemia , and hyperglycemia were common , and 63.3 % of them had a bright liver at echography . In conclusion , in southern Italy , a Mediterranean area where dietary habits are different from those in industrialized areas , one eighth of the general population has abnormal LTs suggestive of possible liver damage ; NAFLD appears to be emerging as a potentially important etiology of this presumed liver injury . ( HEPATOLOGY 2005;41:1151–1159 . BACKGROUND & AIMS Elevated serum alanine aminotransferase ( ALT ) and gamma-glutamyltransferase ( GGT ) activities are markers of liver injury , but may also be associated with other diseases and death . In a prospect i ve , national , population -based sample , we examined whether elevated ALT and GGT were associated with increased risk of all-cause and disease-specific mortality . METHODS Death certificate-based 12-year mortality was analyzed among 14,950 adult participants in the third US National Health and Nutrition Examination Survey , 1988 - 1994 , who were negative for markers of viral hepatitis B and C. Abnormal ALT was defined as > 30 U/L in men or > 19 U/L in women , and abnormal GGT as > 51 U/L in men or > 33 U/L in women . RESULTS Cumulative mortality was 13.9 % from all causes , including 4.2 % from cardiovascular disease , 4.2 % from neoplasms , 0.44 % from diabetes , and 0.13 % from liver disease . In multivariate-adjusted analyses , elevated ALT was not associated with all-cause mortality ( hazard ratio [ HR ] , 1.2 ; 95 % confidence interval [ CI ] , 0.88 - 1.6 ) . ALT elevation was associated with deaths from liver disease ( HR , 8.2 ; 95 % CI , 2.1 - 31.9 ) , but not from cardiovascular disease ( HR , 0.90 ; 95 % CI , 0.56 - 1.4 ) , neoplasms ( HR , 1.0 ; 95 % CI , 0.65 - 1.5 ) , or diabetes ( HR , 2.4 ; 95 % CI , 0.65 - 9.1 ) . All-cause mortality increased with elevated GGT ( HR , 1.5 ; 95 % CI , 1.2 - 1.8 ) , as did mortality from liver disease ( HR , 13.0 ; 95 % CI , 2.4 - 71.5 ) , neoplasms ( HR , 1.5 ; 95 % CI , 1.01 - 2.2 ) , and diabetes ( HR , 3.3 ; 95 % CI , 1.4 - 7.6 ) , but not from cardiovascular disease ( HR , 1.3 ; 95 % CI , 0.80 - 2.0 ) . CONCLUSIONS In the US population , elevated GGT was associated with mortality from all causes , liver disease , cancer , and diabetes , while ALT was associated only with liver disease mortality Abstract Objective To examine the relation between the normal range of serum aminotransferase concentration and mortality from liver disease . Design Prospect i ve cohort study . Setting Korea Medical Insurance Corporation study with eight years ' follow up . Participants 94 533 men and 47 522 women aged 35 - 59 years . Main outcome measure Mortality from liver diseases according to death certificate . Results There was a positive association between the aminotransferase concentration , even within normal range ( 35 - 40 IU/l ) , and mortality from liver disease . Compared with the concentration < 20 IU/l , the adjusted relative risks for an aspartate aminotransferase concentration of 20 - 29 IU/l and 30 - 39 IU/l were 2.5 ( 95 % confidence interval 2.0 to 3.0 ) and 8.0 ( 6.6 to 9.8 ) in men and 3.3 ( 1.7 to 6.4 ) and 18.2 ( 8.1 to 40.4 ) in women , respectively , The corresponding risks for alanine aminotransferase were 2.9 ( 2.4 to 3.5 ) and 9.5 ( 7.9 to 11.5 ) in men and 3.8 ( 1.9 to 7.7 ) and 6.6 ( 1.5 to 25.6 ) in women , respectively . According to receiver operating characteristic curves the best cut-off values for the prediction of liver disease in men were 31 IU/l for aspartate aminotransferase and 30 IU/l for alanine aminotransferase . Conclusion People with slightly increased aminotransferase activity , but still within the normal range , should be closely observed and further investigated for liver diseases Background Although serum γ-glutamyltransferase ( GGT ) predicted cardiovascular diseases ( CVD ) in prospect i ve studies and may be useful in risk assessment , prediction in older adults was weaker in several studies . Methods We performed a nested case-control study with 5 - 12-year follow-up in 137 CVD deaths and 249 controls ( frequency-matched on age , sex , and examination year , age range 26 - 85 years ) . Results An age interaction of serum GGT and CVD mortality ( P value for interaction = 0.02 ) was observed . After adjusting for known CVD risk factors , compared with the lowest tertile , odds ratios ( 95 % confidence intervals ) in participants less than 70 years ( half the participants ) were : middle tertile : 2.17 ( 0.68 - 6.97 ) , top tertile up to GGT less than 50 U/I : 3.54 ( 1.07 - 11.7 ) , and GGT ≥ 50 U/l : 4.69 ( 1.16 - 18.9 ) . In participants aged more than or equal to 70 years , GGT was not related to CVD . Well-known demographic and health behavior associations with serum GGT were observed only in controls among participants aged less than 70 years . Conclusion Our findings suggest that serum GGT within its normal range can predict CVD mortality in those aged less than 70 years , but may have limited usefulness for risk assessment in older adults . Eur J Cardiovasc Prev Rehabil 16:16 - 20 © 2009 The European Society of Background — There is evidence from recent studies that γ-glutamyltransferase ( GGT ) is likely to be associated with cardiovascular disease ( CVD ) . However , few studies to date with sufficient sample size and follow-up investigated the association of GGT with CVD mortality . Methods and Results — The relation of GGT to the risk of death from CVD was examined in a cohort of 163 944 Austrian adults that was monitored for up to 17 years . To evaluate GGT as an independent predictor , Cox proportional hazards models were calculated , which adjusted for established risk factors . In both men and women , high GGT was significantly ( P<0.001 ) associated with total mortality from CVD , showing a clear dose-response relationship . Adjusted hazard ratios ( 95 % CI ) per log GGT increase were 1.66 ( 1.40 to 1.98 ) in men and 1.64 ( 1.36 to 1.97 ) in women . In men , subgroup analyses showed that high GGT was positively associated with incident fatal events of chronic forms of coronary heart disease ( P=0.009 ) , congestive heart failure ( P<0.001 ) , and hemorrhagic ( P=0.01 ) and ischemic stroke ( P<0.001 ) . No significant associations were observed for acute myocardial infa rct ion ( P=0.16 ) . In women , hazard ratios suggested associations in all subgroups ; however , for hemorrhagic and ischemic stroke they were not statistically significant ( P=0.09 and P=0.07 , respectively ) . In addition , subgroup analyses stratified by age revealed a stronger relationship of GGT in younger participants . Hazard ratios for total CVD were 2.03 ( 1.53 to 2.69 ) in men and 2.60 ( 1.53 to 4.42 ) in women younger than 60 years . Conclusions — This study demonstrates in a large , prospect ively observed cohort that GGT is independently associated with cardiovascular mortality Context Current upper limits ( 500 nkat/L [ 30 U/L ] for women , 667 nkat/L [ 40 U/L ] for men ) for serum alanine aminotransferase ( ALT ) level were defined in population s that included persons with nonalcoholic fatty liver disease ( NAFLD ) and persons with hepatitis C virus ( HCV ) infection . Contribution This study redefined ALT limits in blood donors at low risk for NAFLD and without hepatitis B or C ( 317 nkat/L [ 19 U/L ] in women , 500 nkat/L [ 30 U/L ] in men ) . When applied to 209 anti-HCV-positive donors , the new thresholds had 76.3 % sensitivity and 88.5 % specificity in identifying patients with hepatitis C viremia compared with 55 % and 97.4 % for old thresholds . Implication s Laboratories should consider revising the upper limits of normal for ALT to improve the sensitivity of this test in identifying sub clinical liver disease . The Editors Serum alanine aminotransferase ( ALT ) concentration is the most commonly used variable for assessment of liver disease ( 1 , 2 ) . However , particularly in the case of chronic hepatitis C virus ( HCV ) infection , ALT measurement often fails to identify patients with minimal to mild necroinflammatory activity ( 3 - 7 ) . Current upper limits of normal for ALT level were set , on average , at 667 nkat/L ( 40 U/L ) ( range , 500 to 833 nkat/L [ 30 to 50 U/L ] ) in studies conducted over the past 10 years ( 1 , 3 - 5 , 7 , 8) . Such thresholds , however , were mostly computed in the 1980s , when ALT testing was introduced as a surrogate marker for the screening of non-A , non-B hepatitis among blood donors and before anti-HCV testing and restrictive behavioral criteria for donor selection were implemented . Furthermore , so-called reference population s were likely to include many persons with nonalcoholic fatty liver disease , now recognized as the most prevalent cause of chronic liver disease in developed countries ( 8 - 10 ) . Current reference ranges for ALT level probably underestimate the frequency of chronic liver disease . Because dietary and behavioral risks for liver disease are widespread in many countries , a critical revision of ALT limits would require the definition of healthy ranges rather than a generic up date of normal ranges . Thus far , several factors have hampered this task . For example , to obtain solid data , many clinical , biochemical , and behavioral variables potentially related to liver disease must be investigated , requiring screening of large numbers of persons . Furthermore , repeated blood donors , who currently represent the vast majority of blood-donation c and i date s , can not be included in the sampling frame , because they have been selected on the basis of ALT activity during the past two decades . We report the results of a 4-year study of first-time blood-donation c and i date s. To up date the definitions of healthy ranges for serum ALT level , we identified a population at low risk for sub clinical liver disease by exploring factors related to enzyme activity in both healthy persons and those with mild abnormalities on liver tests . Next , we tested the sensitivity and specificity of the ranges obtained from these participants in the clinical evaluation of anti-HCVpositive persons with and without chronic liver damage . Methods Participants Figure 1 summarizes the selection of the study participants . Figure 1 . Procedures for selection of the study participants . * Donor c and i date s were not suitable for the following reasons : previous blood transfusion ( 2 % ) ; use of major illicit drugs ( 1.5 % ) ; at-risk sexual exposures ( 9 % ) ; history of hepatitis or other blood borne infections ( 4 % ) ; recent exposure in a malaria-endemic area ( 5 % ) ; low hemoglobin level ( 15 % ) ; use of medication not compatible with blood donation ( 4 % ) ; seizure or central nervous system disorders ( 12 % ) ; hypertension , arrhythmias , or cardiac disease ( 8 % ) ; hypotension ( 9 % ) ; recent surgery ( 2 % ) or other medical or behavioral risks ( 26 % ) ; serologic reactivity on screening assays ( antiHIV 1 , antiHIV 2 , hepatitis B surface antigen , antihepatitis C virus [ HCV ] , or syphilis ) on the sample collected at blood donation ( 2.5 % ) . St and ard upper limits were 667 nkat/L ( 40 U/L ) in men , and 500 nkat/L ( 30 U/L ) in women . Two trained hepatologists used a recently proposed algorithm ( 2 ) to re-evaluate medical history and physical examination . Participants also underwent additional blood testing , including measurement of the following values : aspartate aminotransferase , alanine aminotransferase ( ALT ) , alkaline phosphatase , -glutamyl transpeptidase , total proteins , bilirubin , iron , total iron-binding capacity , serum ferritin , serum protein electrophoresis , creatine kinase , ceruloplasmin , 1-antitrypsin , antibodies to cytomegalovirus and EpsteinBarr virus , and autoantibodies . Participants also underwent ultrasonography of the liver . Anti-HCVNegative First-Time Blood Donors From 1 September 1995 through 26 October 1999 , 9221 blood-donor c and i date s presenting for first-time donation underwent clinical and laboratory examinations as part of procedures for donor selection at Centro Transfusionale e di Immunologia dei Trapianti in Milan , Italy . A blood-bank physician 1 ) administered a psychosocial question naire [ 11 , 12 ] , which was aim ed at identifying and excluding from donation persons at high risk for blood-borne infections ; 2 ) took a medical history ; and 3 ) examined all potential participants and measured body weight and height . Donors c and i date s had blood drawn for laboratory testing . Clinical data and laboratory-test results were recorded in a relational data base management system , as described previously ( 11 ) . We included in the study donor c and i date s who had no medical or behavioral contraindication to blood donation ( 12 ) and who had negative results on tests for hepatitis B surface antigen ( HBsAg ) , anti-HCV , antiHIV 1 , antiHIV 2 , and hemagglutination ( to assess for presence of syphilis ) . In addition , we used a recently recommended diagnostic algorithm ( 2 ) to conduct a diagnostic work-up in donors who repeatedly had abnormal ALT measurements ( that is , they had increased values , according to current ALT ranges , in three subsequent measurements taken at 1-month intervals in the absence of HBsAg and anti-HCV reactivity ) ( 2 ) . Anti-HCVPositive Blood Donors We also studied 209 blood-donor c and i date s with confirmed anti-HCV reactivity between 1990 and 1999 who presented to our outpatient liver disease clinic for regular follow-up . Of these patients , 78 were HCV RNA negative at initial screening ( 59 patients ) or after antiviral treatment ( 19 patients ) , and 131 were HCV RNA positive . Serum ALT activity was determined at presentation and in at least two other serial serum sample s collected at 1- to 3-month intervals over at least 6 months . In patients with viremia who underwent treatment , the pattern of serum ALT levels was defined during the period of presumed viremia ( that is , not during or after therapy ) . Liver biopsy was performed in 133 anti-HCVpositive blood donors ( 103 of whom were HCV RNA positive and 30 of whom were HCV RNA negative ) for diagnostic reasons ( 32 patients ) or within clinical trials . These clinical trials were conducted between 1993 and 1998 to define the optimal management of anti-HCVpositive patients with normal or slightly altered ALT levels ( 101 patients ) ( 3 , 4 , 11 , 13 , 14 ) . Laboratory Methods A fasting blood sample was collected in the morning and was centrifuged within 30 minutes of collection . The Laboratory of Biochemistry and the Laboratory of Virology of the Centro Trasfusionale e di Immunologia dei Trapianti at IRCCS Ospedale MaggioreMilan , Italy , performed all analyses by using consistent methods throughout the study period . Complete blood counts were performed by using an NE 8000 automatic cell counter ( Sysmex , Kobe , Japan ) . Analyses of serum biochemistry were performed by using an Olympus AU510 analyzer ( EppendorfNetheler , Hamburg , Germany ) . Upper reference limits for serum biochemistry analyses were computed in 1983 on the basis of findings from 5093 women and 9849 men who were apparently healthy donors with negative results on hepatitis B surface antigen and syphilis tests ( 4 , 15 ) . These limits were as follows : for total cholesterol level , 5.70 mmol/L ( 220 mg/dL ) ; for triglyceride level , 2.26 mmol/L ( 200 mg/dL ) ; for blood glucose level , 5.83 mmol/L ( 105 mg/dL ) in men and 5.44 mmol/L ( 98 mg/dL ) in women ; for ALT level , 667 mmol/L ( 40 U/L ) in men and 500 nkat/L ( 30 U/L ) in women . Virologic tests included an hepatitis B surface antigen test ( Wellcozyme HBsAg , Abbott Laboratories , Chicago , Illinois ) , an anti-HIV test ( Ortho HIV1/HIV2 , Ortho Diagnostic Systems , Raritan , New Jersey ) , and an anti-HCV test ( Ortho HCV 3.0 , Ortho Diagnostic Systems ) . Anti-HCV reactivity was confirmed by third-generation recombinant immunoblot assay ( RIBA-3 , Ortho Diagnostic Systems ) . Qualitative analysis of serum HCV RNA was performed by using the Amplicor HCV kit ( Roche Molecular Systems , Basel , Switzerl and ) . Body mass index ( BMI ) was calculated by dividing the weight ( in kg ) by the squared height ( in m ) . On the basis of a recent recommendation ( 16 ) , we considered a BMI of 24.9 kg/m2 the upper limit for healthy weight . The laboratory and the blood donor center were certified according to International Organization for St and ardization 9002 st and ards . The laboratory intra-assay coefficient of variation ( CV ) for ALT was 1.1 % , and the interassay CV over a 2-week period was 2.4 % . Within-individual and between-individual variability were estimated on the basis of 20 donors who were r and omly chosen among those with two measurements taken at 3-month intervals . Within-individual variability , expressed as CV , was 21.4 % ( CI , 16.4 % to 31.0 % ) ; between-individual variability was 49.8 % ( CI , 37.9%- to 72.8 % ) . Statistical Analysis Statistical analyses were performed by using the SAS package version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . The 5th , 25th , 50th ( median ) , 75th , and 95th percentiles for ALT level were calculated on the basis of the empirical distribution of the data . OBJECTIVES To find possible association between liver enzymes and mortality in older people . DESIGN A prospect i ve cohort study . SETTING Jerusalem . PARTICIPANTS A systematic ally selected representative sample of 455 70-year-old ambulatory individuals was prospect ively followed for 12 years . MEASUREMENTS An extensive social and medical profile was developed at age 70 using a detailed interview and physical and ancillary examination . Information on mortality was obtained annually . Differences in survival between subjects stratified according to liver enzyme levels were assessed using the Kaplan-Meier method . Multivariable survival analyses using a Cox proportional hazards model were performed to determine the association between liver enzyme levels at age 70 and mortality over 12 years . RESULTS Median alanine aminotransferase ( ALT ) activity of the study population was 11.00 U/L for women and 13.00 U/L for men . Twelve-year survival rates for women with ALT below and above the median levels were similar ( 78 % ) . For men , these rates were 54 % and 65 % , respectively ( P < .001 ) . Proportional hazards models demonstrated that this greater mortality risk was independent of numerous common risk factors for mortality ( hazard ratio ( HR ) = 1.5 , 95 % confidence interval ( CI ) = 1.08 - 2.19 ) . Adding an interaction between sex and low ALT to the model demonstrated a higher risk of mortality for men with low ALT levels ( HR = 2.42 , 95 % CI = 1.15 - 5.08 ) . No such risk was demonstrated for the other liver enzymes . CONCLUSION ALT activity represents a strong and independent surrogate marker for mortality in community-dwelling elderly men BACKGROUND High serum alanine aminotransferase ( ALT ) levels have been associated with increased risk of diabetes and with increased mortality , but associations of variations of ALT in the normal range with outcomes have been less well studied . METHODS We studied the relationship between ALT , mortality and cardiovascular events in the West of Scotl and Coronary Prevention Study ( WOSCOPS ) and the Prospect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) trials that explicitly excluded subjects with clinical ly significant liver damage , plus the Leiden 85-plus , a study of survivors to age 85 years . The associations between ALT and morbidity and mortality outcomes were investigated using Cox proportional hazard models adjusting for a comprehensive panel of cardiovascular risk factors . RESULTS In all three study cohorts , ALT displayed an independent inverse relationship with all-cause mortality so that hazard ratios for fourth versus first quarter of ALT were all below 1.0 ; HRs 0.64 [ 95 % confidence interval ( CI ) 0.50 - 0.81 ] , 0.86 ( 0.73 - 1.01 ) , 0.66 ( 0.50 - 0.87 ) ; WOSCOPS , PROSPER , Leiden 85-plus , respectively . In WOSCOPS and PROSPER , ALT was also inversely associated with risk of fatal plus non-fatal cardiovascular events , including coronary heart disease ( CHD ) events and stroke . CONCLUSIONS In three independent population s , ALT in the normal range displayed an inverse relationship with total mortality , cardiovascular events and non-cardiovascular events in middle-to-older aged subjects without evidence of clinical ly significant liver damage , independent of traditional cardiovascular and other risk factors . These findings indicate that the relationship between ALT and clinical outcomes is more complex than generally appreciated

Conclusions and Relevance Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens . Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis

Importance If not promptly recognized , endocrine dysfunction can be life threatening . The incidence and risk of developing such adverse events ( AEs ) following the use of immune checkpoint inhibitor ( ICI ) regimens are unknown . Objective To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration – approved ICI regimens .

PURPOSE Programmed death-1 ( PD-1 ) , an inhibitory receptor expressed on activated T cells , may suppress antitumor immunity . This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity , pharmacodynamics , and immunologic correlates . PATIENTS AND METHODS Thirty-nine patients with advanced metastatic melanoma , colorectal cancer ( CRC ) , castrate-resistant prostate cancer , non-small-cell lung cancer ( NSCLC ) , or renal cell carcinoma ( RCC ) received a single intravenous infusion of anti-PD-1 ( MDX-1106 ) in dose-escalating six-patient cohorts at 0.3 , 1 , 3 , or 10 mg/kg , followed by a 15-patient expansion cohort at 10 mg/kg . Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy . RESULTS Anti-PD-1 was well tolerated : one serious adverse event , inflammatory colitis , was observed in a patient with melanoma who received five doses at 1 mg/kg . One durable complete response ( CRC ) and two partial responses ( PRs ; melanoma , RCC ) were seen . Two additional patients ( melanoma , NSCLC ) had significant lesional tumor regressions not meeting PR criteria . The serum half-life of anti-PD-1 was 12 to 20 days . However , pharmacodynamics indicated a sustained mean occupancy of > 70 % of PD-1 molecules on circulating T cells > or = 2 months following infusion , regardless of dose . In nine patients examined , tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment . CONCLUSION Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity . Exploration of alternative dosing regimens and combinatorial therapies with vaccines , targeted therapies , and /or other checkpoint inhibitors is warranted BACKGROUND Treatments for small-cell lung cancer ( SCLC ) after failure of platinum-based chemotherapy are limited . We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens . METHODS The SCLC cohort of this phase 1/2 multicentre , multi-arm , open-label trial was conducted at 23 sites ( academic centres and hospitals ) in six countries . Eligible patients were 18 years of age or older , had limited-stage or extensive-stage SCLC , and had disease progression after at least one previous platinum-containing regimen . Patients received nivolumab ( 3 mg/kg bodyweight intravenously ) every 2 weeks ( given until disease progression or unacceptable toxicity ) , or nivolumab plus ipilimumab ( 1 mg/kg plus 1 mg/kg , 1 mg/kg plus 3 mg/kg , or 3 mg/kg plus 1 mg/kg , intravenously ) every 3 weeks for four cycles , followed by nivolumab 3 mg/kg every 2 weeks . Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg . Depending on tolerability , patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg . The primary endpoint was objective response by investigator assessment . All analyses included patients who were enrolled at least 90 days before data base lock . This trial is ongoing ; here , we report an interim analysis of the SCLC cohort . This study is registered with Clinical Trials.gov , number NCT01928394 . FINDINGS Between Nov 18 , 2013 , and July 28 , 2015 , 216 patients were enrolled and treated ( 98 with nivolumab 3 mg/kg , three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg , 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg , and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg ) . At data base lock on Nov 6 , 2015 , median follow-up for patients continuing in the study ( including those who had died or discontinued treatment ) was 198·5 days ( IQR 163·0 - 464·0 ) for nivolumab 3 mg/kg , 302 days ( IQR not calculable ) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg , 361·0 days ( 273·0 - 470·0 ) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg , and 260·5 days ( 248·0 - 288·0 ) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg . An objective response was achieved in ten ( 10 % ) of 98 patients receiving nivolumab 3 mg/kg , one ( 33 % ) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg , 14 ( 23 % ) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg , and ten ( 19 % ) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg . Grade 3 or 4 treatment-related adverse events occurred in 13 ( 13 % ) patients in the nivolumab 3 mg/kg cohort , 18 ( 30 % ) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort , and ten ( 19 % ) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort ; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase ( none vs 5 [ 8 % ] vs none ) and diarrhoea ( none vs 3 [ 5 % ] vs 1 [ 2 % ] ) . No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event . Six ( 6 % ) patients in the nivolumab 3 mg/kg group , seven ( 11 % ) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group , and four ( 7 % ) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events . Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events ( myasthenia gravis and worsening of renal failure ) , and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis . INTERPRETATION Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC . These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 r and omised controlled trials in SCLC . FUNDING Bristol-Myers Squibb BACKGROUND Blockade of programmed death 1 ( PD-1 ) , an inhibitory receptor expressed by T cells , can overcome immune resistance . We assessed the antitumor activity and safety of BMS-936558 , an antibody that specifically blocks PD-1 . METHODS We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration-resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks . Response was assessed after each 8-week treatment cycle . Patients received up to 12 cycles until disease progression or a complete response occurred . RESULTS A total of 296 patients received treatment through February 24 , 2012 . Grade 3 or 4 drug-related adverse events occurred in 14 % of patients ; there were three deaths from pulmonary toxicity . No maximum tolerated dose was defined . Adverse events consistent with immune-related causes were observed . Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or renal-cell cancer . Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) . Responses were durable ; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up . To assess the role of intratumoral PD-1 lig and ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients . Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P=0.006 ) . CONCLUSIONS Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use . Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response . ( Funded by Bristol-Myers Squibb and others ; Clinical Trials.gov number , NCT00730639 . ) PURPOSE Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy . Several lines of evidence support the study of immunotherapy in triple-negative breast cancer ( TNBC ) . We assessed the safety and antitumor activity of the programmed cell death protein 1 ( PD-1 ) inhibitor pembrolizumab in patients with advanced TNBC . METHODS KEYNOTE-012 ( Clinical Trials.gov identifier : NCT01848834 ) was a multicenter , nonr and omized phase Ib trial of single-agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with advanced PD-L1-positive ( expression in stroma or ≥ 1 % of tumor cells by immunohistochemistry ) TNBC , gastric cancer , urothelial cancer , and head and neck cancer . This report focuses on the TNBC cohort . RESULTS Among 111 patients with TNBC whose tumor sample s were screened for PD-L1 expression , 58.6 % had PD-L1-positive tumors . Thirty-two women ( median age , 50.5 years ; range , 29 to 72 years ) were enrolled and assessed for safety and antitumor activity . The median number of doses administered was five ( range , 1 to 36 doses ) . Common toxicities were mild and similar to those observed in other tumor cohorts ( eg , arthralgia , fatigue , myalgia , and nausea ) , and included five ( 15.6 % ) patients with grade ≥ 3 toxicity and one treatment-related death . Among the 27 patients who were evaluable for antitumor activity , the overall response rate was 18.5 % , the median time to response was 17.9 weeks ( range , 7.3 to 32.4 weeks ) , and the median duration of response was not yet reached ( range , 15.0 to ≥ 47.3 weeks ) . CONCLUSION This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated , advanced TNBC . A single-agent phase II study examining a 200-mg dose given once every 3 weeks ( Clinical Trials.gov identifier : NCT02447003 ) is ongoing BACKGROUND Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer . As part of the phase 1b KEYNOTE-012 study , we aim ed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction . METHODS This study was a multicentre , open-label , phase 1b trial done at 13 cancer research centres in the USA , Israel , Japan , South Korea , and Taiwan . We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction . Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred . Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 . The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan . The study is registered with Clinical Trials.gov , number NCT01848834 , and is ongoing but no longer enrolling patients . FINDINGS From Oct 23 , 2013 , to May 5 , 2014 , 39 patients were enrolled . 36 were evaluable for response by central assessment . Eight ( 22 % , 95 % CI 10 - 39 ) patients were judged to have had an overall response at central review ; all responses were partial . All 39 patients were included in the safety analyses . Five ( 13 % ) patients had a total of six grade 3 or 4 treatment-related adverse events , consisting of two cases of grade 3 fatigue , one case each of grade 3 pemphigoid , grade 3 hypothyroidism , and grade 3 peripheral sensory neuropathy , and one case of grade 4 pneumonitis . No treatment-related deaths occurred . INTERPRETATION In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer , pembrolizumab had a manageable toxicity profile and promising antitumour activity , warranting further study in phase 2 and 3 trials . FUNDING Merck & BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel . The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) BACKGROUND Nivolumab , a fully human IgG4 PD-1 immune checkpoint inhibitor antibody , can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors . We assessed the efficacy and safety of nivolumab compared with investigator 's choice of chemotherapy ( ICC ) as a second-line or later-line treatment in patients with advanced melanoma . METHODS In this r and omised , controlled , open-label , phase 3 trial , we recruited patients at 90 sites in 14 countries . Eligible patients were 18 years or older , had unresectable or metastatic melanoma , and progressed after ipilimumab , or ipilimumab and a BRAF inhibitor if they were BRAF(V 600 ) mutation-positive . Participating investigators r and omly assigned ( with an interactive voice response system ) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC ( dacarbazine 1000 mg/m(2 ) every 3 weeks or paclitaxel 175 mg/m(2 ) combined with carboplatin area under the curve 6 every 3 weeks ) until progression or unacceptable toxic effects . We stratified r and omisation by BRAF mutation status , tumour expression of PD-L1 , and previous best overall response to ipilimumab . We used permuted blocks ( block size of six ) within each stratum . Primary endpoints were the proportion of patients who had an objective response and overall survival . Treatment was given open-label , but those doing tumour assessment s were masked to treatment assignment . We assessed objective responses per- protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks , and safety in all patients who had had at least one dose of treatment . The trial is closed and this is the first interim analysis , reporting the objective response primary endpoint . This study is registered with Clinical Trials.gov , number NCT01721746 . FINDINGS Between Dec 21 , 2012 , and Jan 10 , 2014 , we screened 631 patients , r and omly allocating 272 patients to nivolumab and 133 to ICC . Confirmed objective responses were reported in 38 ( 31·7 % , 95 % CI 23·5 - 40·8 ) of the first 120 patients in the nivolumab group versus five ( 10·6 % , 3·5 - 23·1 ) of 47 patients in the ICC group . Grade 3 - 4 adverse events related to nivolumab included increased lipase ( three [ 1 % ] of 268 patients ) , increased alanine aminotransferase , anaemia , and fatigue ( two [ 1 % ] each ) ; for ICC , these included neutropenia ( 14 [ 14 % ] of 102 ) , thrombocytopenia ( six [ 6 % ] ) , and anaemia ( five [ 5 % ] ) . We noted grade 3 - 4 drug-related serious adverse events in 12 ( 5 % ) nivolumab-treated patients and nine ( 9 % ) patients in the ICC group . No treatment-related deaths occurred . INTERPRETATION Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor . Nivolumab represents a new treatment option with clinical ly meaningful durable objective responses in a population of high unmet need . FUNDING Bristol-Myers Squibb BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer ( NSCLC ) who have disease progression during or after first-line chemotherapy have limited treatment options . This r and omized , open-label , international , phase 3 study evaluated the efficacy and safety of nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , as compared with docetaxel in this patient population . METHODS We r and omly assigned 272 patients to receive nivolumab , at a dose of 3 mg per kilogram of body weight every 2 weeks , or docetaxel , at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS The median overall survival was 9.2 months ( 95 % confidence interval [ CI ] , 7.3 to 13.3 ) with nivolumab versus 6.0 months ( 95 % CI , 5.1 to 7.3 ) with docetaxel . The risk of death was 41 % lower with nivolumab than with docetaxel ( hazard ratio , 0.59 ; 95 % CI , 0.44 to 0.79 ; P<0.001 ) . At 1 year , the overall survival rate was 42 % ( 95 % CI , 34 to 50 ) with nivolumab versus 24 % ( 95 % CI , 17 to 31 ) with docetaxel . The response rate was 20 % with nivolumab versus 9 % with docetaxel ( P=0.008 ) . The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel ( hazard ratio for death or disease progression , 0.62 ; 95 % CI , 0.47 to 0.81 ; P<0.001 ) . The expression of the PD-1 lig and ( PD-L1 ) was neither prognostic nor predictive of benefit . Treatment-related adverse events of grade 3 or 4 were reported in 7 % of the patients in the nivolumab group as compared with 55 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced , previously treated squamous-cell NSCLC , overall survival , response rate , and progression-free survival were significantly better with nivolumab than with docetaxel , regardless of PD-L1 expression level . ( Funded by Bristol-Myers Squibb ; CheckMate 017 Clinical Trials.gov number , NCT01642004 . ) BACKGROUND Outcomes are poor for patients with previously treated , advanced or metastatic non-small-cell lung cancer ( NSCLC ) . The anti-programmed death lig and 1 ( PD-L1 ) antibody atezolizumab is clinical ly active against cancer , including NSCLC , especially cancers expressing PD-L1 on tumour cells , tumour-infiltrating immune cells , or both . We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC , analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population . METHODS In this open-label , phase 2 r and omised controlled trial , patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practice s across 13 countries in Europe and North America . Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 , measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 ( RECIST v1.1 ) , and adequate haematological and end-organ function . Patients were stratified by PD-L1 tumour-infiltrating immune cell status , histology , and previous lines of therapy , and r and omly assigned ( 1:1 ) by permuted block r and omisation ( with a block size of four ) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2 ) once every 3 weeks . Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of PD-L1-expressing tumour cells TC3≥50 % , TC2≥5 % and < 50 % , TC1≥1 % and < 5 % , and TC0<1 % ) and tumour-infiltrating immune cells ( as percentage of tumour area : IC3≥10 % , IC2≥5 % and < 10 % , IC1≥1 % and < 5 % , and IC0<1 % ) . The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths . Biomarkers were assessed in an exploratory analysis . We assessed safety in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01903993 . FINDINGS Patients were enrolled between Aug 5 , 2013 , and March 31 , 2014 . 144 patients were r and omly allocated to the atezolizumab group , and 143 to the docetaxel group . 142 patients received at least one dose of atezolizumab and 135 received docetaxel . Overall survival in the intention-to-treat population was 12·6 months ( 95 % CI 9·7 - 16·4 ) for atezolizumab versus 9·7 months ( 8·6 - 12·0 ) for docetaxel ( hazard ratio [ HR ] 0·73 [ 95 % CI 0·53 - 0·99 ] ; p=0·04 ) . Increasing improvement in overall survival was associated with increasing PD-L1 expression ( TC3 or IC3 HR 0·49 [ 0·22 - 1·07 ; p=0·068 ] , TC2/3 or IC2/3 HR 0·54 [ 0·33 - 0·89 ; p=0·014 ] , TC1/2/3 or IC1/2/3 HR 0·59 [ 0·40 - 0·85 ; p=0·005 ] , TC0 and IC0 HR 1·04 [ 0·62 - 1·75 ; p=0·871 ] ) . In our exploratory analysis , patients with pre-existing immunity , defined by high T-effector-interferon-γ-associated gene expression , had improved overall survival with atezolizumab . 11 ( 8 % ) patients in the atezolizumab group discontinued because of adverse events versus 30 ( 22 % ) patients in the docetaxel group . 16 ( 11 % ) patients in the atezolizumab group versus 52 ( 39 % ) patients in the docetaxel group had treatment-related grade 3 - 4 adverse events , and one ( < 1 % ) patient in the atezolizumab group versus three ( 2 % ) patients in the docetaxel group died from a treatment-related adverse event . INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC . Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells , suggesting that PD-L1 expression is predictive for atezolizumab benefit . Atezolizumab was well tolerated , with a safety profile distinct from chemotherapy . FUNDING F Hoffmann-La Roche/Genentech BACKGROUND Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma . The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study . METHODS We r and omly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab ( at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks ) or dacarbazine ( at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks ) . The primary end point was overall survival . RESULTS At 1 year , the overall rate of survival was 72.9 % ( 95 % confidence interval [ CI ] , 65.5 to 78.9 ) in the nivolumab group , as compared with 42.1 % ( 95 % CI , 33.0 to 50.9 ) in the dacarbazine group ( hazard ratio for death , 0.42 ; 99.79 % CI , 0.25 to 0.73 ; P<0.001 ) . The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group ( hazard ratio for death or progression of disease , 0.43 ; 95 % CI , 0.34 to 0.56 ; P<0.001 ) . The objective response rate was 40.0 % ( 95 % CI , 33.3 to 47.0 ) in the nivolumab group versus 13.9 % ( 95 % CI , 9.5 to 19.4 ) in the dacarbazine group ( odds ratio , 4.06 ; P<0.001 ) . The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups , including subgroups defined by status regarding the programmed death lig and 1 ( PD-L1 ) . Common adverse events associated with nivolumab included fatigue , pruritus , and nausea . Drug-related adverse events of grade 3 or 4 occurred in 11.7 % of the patients treated with nivolumab and 17.6 % of those treated with dacarbazine . CONCLUSIONS Nivolumab was associated with significant improvements in overall survival and progression-free survival , as compared with dacarbazine , among previously untreated patients who had metastatic melanoma without a BRAF mutation . ( Funded by Bristol-Myers Squibb ; CheckMate 066 Clinical Trials.gov number , NCT01721772 . ) Purpose Ipilimumab is design ed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses . In studies of predominantly Caucasian patients with advanced melanoma , ipilimumab was associated with durable response , long-term survival benefit , and a manageable safety profile . This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma . Methods Patients received ipilimumab 3 mg/kg every 3 weeks for four doses . The data base lock for the original analysis was in August 2014 . Overall survival , progression-free survival , and data on deaths were based on an up date d , follow-up analysis ( data base lock April 2015 ) . Results Data are reported from 20 patients . Fifteen patients ( 75 % ) received all four doses of ipilimumab during induction . Twelve patients ( 60 % ) had at least one drug-related adverse event ( AE ) , and no patients discontinued due to a drug-related AE . There were no deaths related to study drug . The most common drug-related AEs were rash ( n = 7 ) , pyrexia ( n = 3 ) , increased aspartate aminotransferase ( AST ; n = 3 ) , and increased alanine aminotransferase ( ALT ; n = 3 ) . Twelve patients ( 60 % ) reported immune-related AEs ( irAEs ) ; most frequent were skin ( n = 9 ) and liver ( n = 3 ) disorders . Grade 3 irAEs were ALT and AST elevation ( n = 2 ) and diabetes mellitus ( n = 1 ) . Two patients had a partial response and two had stable disease , yielding a 20 % disease control rate . Median overall survival and progression-free survival were 8.71 and 2.74 months , respectively . Conclusion Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients . Clinical Trials.gov identifierNCT01990859 PURPOSE Nivolumab , a programmed death-1 ( PD-1 ) immune checkpoint inhibitor antibody , has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer ( NSCLC ) . First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I , multicohort , Checkmate 012 trial . METHODS Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity ; postprogression treatment was permitted per protocol . The primary objective was to assess safety ; secondary objectives included objective response rate ( ORR ) and 24-week progression-free survival ( PFS ) rate ; overall survival ( OS ) was an exploratory end point . RESULTS Any- grade treatment-related adverse events ( AEs ) occurred in 71 % of patients , most commonly : fatigue ( 29 % ) , rash ( 19 % ) , nausea ( 14 % ) , diarrhea ( 12 % ) , pruritus ( 12 % ) , and arthralgia ( 10 % ) . Ten patients ( 19 % ) reported grade 3 to 4 treatment-related AEs ; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient ( n = 2 ; 4 % ) . Six patients ( 12 % ) discontinued because of a treatment-related AE . The confirmed ORR was 23 % ( 12 of 52 ) , including four ongoing complete responses . Nine of 12 responses ( 75 % ) occurred by first tumor assessment ( week 11 ) ; eight ( 67 % ) were ongoing ( range , 5.3 + to 25.8 + months ) at the time of data lock . ORR was 28 % ( nine of 32 ) in patients with any degree of tumor PD-lig and 1 expression and 14 % ( two of 14 ) in patients with no PD-lig and 1 expression . Median PFS was 3.6 months , and the 24-week PFS rate was 41 % ( 95 % CI , 27 to 54 ) . Median OS was 19.4 months , and the 1-year and 18-month OS rates were 73 % ( 95 % CI , 59 to 83 ) and 57 % ( 95 % CI , 42 to 70 ) , respectively . CONCLUSION First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC Purpose : This phase I study evaluated the safety , maximum tolerated dose , antitumor activity , and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors . Experimental Design : In a 3 + 3 dose escalation study , 10 patients received pembrolizumab 1 , 3 , or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity . Seven additional patients received 10 mg/kg every 2 weeks . Thirteen patients participated in a 3-week intrapatient dose escalation ( dose range , 0.005–10 mg/kg ) followed by 2 or 10 mg/kg every 3 weeks . Tumor response was assessed by Response Evaluation Criteria in Solid Tumors ( RECIST ) version 1.1 . Results : No dose-limiting toxicities were observed . Maximum administered dose was 10 mg/kg every 2 weeks . One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56 + weeks ' duration , respectively . Three patients with melanoma experienced partial responses . Fifteen patients with various malignancies experienced stable disease . One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation , following prolonged corticosteroid use for grade 2 gastritis considered drug related . Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies . Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks . Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks . Conclusions : Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors . The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks . Clin Cancer Res ; 21(19 ) ; 4286–93 . © 2015 AACR . See related commentary by van Elsas et al. , p. PURPOSE Programmed death-1 ( PD-1 ) , a coinhibitory immune signal receptor expressed in T cells , binds to PD-1 lig and and regulates antitumor immunity . Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling . We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer . PATIENTS AND METHODS Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg ( constituting two 10-patient cohorts ) from October 21 , 2011 . This phase II trial defined the primary end point as the best overall response . Patients received up to six cycles ( four doses per cycle ) of nivolumab treatment or received doses until disease progression occurred . Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7 , 2014 . RESULTS Grade 3 or 4 treatment-related adverse events occurred in eight ( 40 % ) of 20 patients . Two patients had severe adverse events . In the 20 patients in whom responses could be evaluated , the best overall response was 15 % , which included two patients who had a durable complete response ( in the 3-mg/kg cohort ) . The disease control rate in all 20 patients was 45 % . The median progression-free survival time was 3.5 months ( 95 % CI , 1.7 to 3.9 months ) , and the median overall survival time was 20.0 months ( 95 % CI , 7.0 months to not reached ) at study termination . CONCLUSION This study , to our knowledge , is the first to explore the effects of nivolumab against ovarian cancer . The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations ( UMIN Clinical Trials Registry UMIN000005714 ) BACKGROUND Despite recent advances in the treatment of advanced non-small-cell lung cancer , there remains a need for effective treatments for progressive disease . We assessed the efficacy of pembrolizumab for patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . METHODS We did this r and omised , open-label , phase 2/3 study at 202 academic medical centres in 24 countries . Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1 % of tumour cells were r and omly assigned ( 1:1:1 ) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg , pembrolizumab 10 mg/kg , or docetaxel 75 mg/m(2 ) every 3 weeks . The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50 % of tumour cells . We used a threshold for significance of p<0.00825 ( one-sided ) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival . This trial is registered at Clinical Trials.gov , number NCT01905657 . FINDINGS Between Aug 28 , 2013 , and Feb 27 , 2015 , we enrolled 1034 patients : 345 allocated to pembrolizumab 2 mg/kg , 346 allocated to pembrolizumab 10 mg/kg , and 343 allocated to docetaxel . By Sept 30 , 2015 , 521 patients had died . In the total population , median overall survival was 10.4 months with pembrolizumab 2 mg/kg , 12.7 months with pembrolizumab 10 mg/kg , and 8.5 months with docetaxel . Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel ( hazard ratio [ HR ] 0.71 , 95 % CI 0.58 - 0.88 ; p=0.0008 ) and for pembrolizumab 10 mg/kg versus docetaxel ( 0.61 , 0.49 - 0.75 ; p<0.0001 ) . Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg , 4.0 months with pembrolizumab 10 mg/kg , and 4.0 months with docetaxel , with no significant difference for pembrolizumab 2 mg/kg versus docetaxel ( 0.88 , 0.74 - 1.05 ; p=0.07 ) or for pembrolizumab 10 mg/kg versus docetaxel ( HR 0.79 , 95 % CI 0.66 - 0.94 ; p=0.004 ) . Among patients with at least 50 % of tumour cells expressing PD-L1 , overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 14.9 months vs 8.2 months ; HR 0.54 , 95 % CI 0.38 - 0.77 ; p=0.0002 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 17.3 months vs 8.2 months ; 0.50 , 0.36 - 0.70 ; p<0.0001 ) . Likewise , for this patient population , progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 5.0 months vs 4.1 months ; HR 0.59 , 95 % CI 0.44 - 0.78 ; p=0.0001 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 5.2 months vs 4.1 months ; 0.59 , 0.45 - 0.78 ; p<0.0001 ) . Grade 3 - 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel ( 43 [ 13 % ] of 339 patients given 2 mg/kg , 55 [ 16 % ] of 343 given 10 mg/kg , and 109 [ 35 % ] of 309 given docetaxel ) . INTERPRETATION Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . These data establish pembrolizumab as a new treatment option for this population and vali date the use of PD-L1 selection . FUNDING Merck & Pre clinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors . In particular , cytotoxic T lymphocyte-associated antigen-4 ( CTLA-4 ) antibodies have been successfully combined with GM-CSF cell-based vaccines ( GVAX ) . Ipilimumab ( anti-CTLA-4 ) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma ( PDA ) result ing in a delayed response at a dose of 3 mg/kg . Our study evaluated ipilimumab 10 mg/kg ( arm 1 ) and ipilimumab 10 mg/kg+GVAX ( arm 2 ) . A total of 30 patients with previously treated advanced PDA were r and omized ( 1:1 ) . Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks . Two patients in arm 1 showed evidence of stable disease ( 7 and 22 wk ) but none demonstrated CA19 - 9 biochemical responses . In contrast , 3 patients in arm 2 had evidence of prolonged disease stabilization ( 31 , 71 , and 81 wk ) and 7 patients experienced CA19 - 9 declines . In 2 of these patients , disease stabilization occurred after an initial period of progression . The median overall survival ( OS ) ( 3.6 vs. 5.7 mo , hazards ratio : 0.51 , P=0.072 ) and 1 year OS ( 7 vs. 27 % ) favored arm 2 . Similar to prior ipilimumab studies , 20 % of patients in each arm had grade 3/4 immune-related adverse events . Among patients with OS>4.3 months , there was an increase in the peak mesothelin-specific T cells ( P=0.014 ) and enhancement of the T-cell repertoire ( P=0.031 ) . In conclusion , checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study BACKGROUND The anti-programmed-death-receptor-1 ( PD-1 ) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma . We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma . METHODS In an open-label , international , multicentre expansion cohort of a phase 1 trial , patients ( aged ≥18 years ) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were r and omly assigned with a computer-generated allocation schedule ( 1:1 final ratio ) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression , intolerable toxicity , or consent withdrawal . Primary endpoint was overall response rate ( ORR ) assessed with the Response Evaluation Criteria In Solid Tumors ( RECIST , version 1.1 ) by independent central review . Analysis was done on the full- analysis set ( all treated patients with measurable disease at baseline ) . This study is registered with Clinical Trials.gov , number NCT01295827 . FINDINGS 173 patients received pembrolizumab 2 mg/kg ( n=89 ) or 10 mg/kg ( n=84 ) . Median follow-up duration was 8 months . ORR was 26 % at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group ( difference 0 % , 95 % CI -14 to 13 ; p=0·96 ) . Treatment was well tolerated , with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths . The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue ( 29 [ 33 % ] vs 31 [ 37 % ] ) , pruritus ( 23 [ 26 % ] vs 16 [ 19 % ] ) , and rash ( 16 [ 18 % ] vs 15 [ 18 % ] ) . Grade 3 fatigue , reported in five ( 3 % ) patients in the 2 mg/kg pembrolizumab group , was the only drug-related grade 3 to 4 adverse event reported in more than one patient . INTERPRETATION The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options . FUNDING Merck Sharp and Dohme ABSTRACT Introduction : Immune checkpoint inhibitors targeting programmed death protein 1 ( PD-1 ) receptor and its lig and , PD-L1 , have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer . Areas covered : Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1 . In the phase I KEYNOTE-001 trial , the overall response rate ( ORR ) was 19.4 % , the median progression-free survival ( PFS ) and overall survival ( OS ) were 3.7 months and 12.0 months for 495 unselected NSCLC patients . Strong PD-L1 expression ( ≥ 50 % ) was associated with higher ORR , longer PFS , and longer OS . The phase II/III r and omized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC . Expert opinion : Pembrolizumab , demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1 , thereby suggests a new treatment paradigm . However , many issues remain to be explored , including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors . Along with the identification of predictive biomarkers , further underst and ing of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies BACKGROUND Patients with melanoma that progresses on ipilimumab and , if BRAF(V600 ) mutant-positive , a BRAF or MEK inhibitor or both , have few treatment options . We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma . METHODS We carried out a r and omised phase 2 trial of patients aged 18 years or older from 73 hospitals , clinics , and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and , if BRAF(V600 ) mutant-positive , previous treatment with a BRAF or MEK inhibitor or both . Patients had to have resolution of all ipilimumab-related adverse events to grade 0 - 1 and prednisone 10 mg/day or less for at least 2 weeks , an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 , and at least one measurable lesion to be eligible . Using a central ised interactive voice response system , we r and omly assigned ( 1:1:1 ) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy ( paclitaxel plus carboplatin , paclitaxel , carboplatin , dacarbazine , or oral temozolomide ) . R and omisation was stratified by ECOG performance status , lactate dehydrogenase concentration , and BRAF(V600 ) mutation status . Individual treatment assignment between pembrolizumab and chemotherapy was open label , but investigators and patients were masked to assignment of the dose of pembrolizumab . We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT01704287 . The study is closed to enrolment but continues to follow up and treat patients . FINDINGS Between Nov 30 , 2012 , and Nov 13 , 2013 , we enrolled 540 patients : 180 patients were r and omly assigned to receive pembrolizumab 2 mg/kg , 181 to receive pembrolizumab 10 mg/kg , and 179 to receive chemotherapy . Based on 410 progression-free survival events , progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg ( HR 0·57 , 95 % CI 0·45 - 0·73 ; p<0·0001 ) and those assigned to pembrolizumab 10 mg/kg ( 0·50 , 0·39 - 0·64 ; p<0·0001 ) compared with those assigned to chemotherapy . 6-month progression-free survival was 34 % ( 95 % CI 27 - 41 ) in the pembrolizumab 2 mg/kg group , 38 % ( 31 - 45 ) in the 10 mg/kg group , and 16 % ( 10 - 22 ) in the chemotherapy group . Treatment-related grade 3 - 4 adverse events occurred in 20 ( 11 % ) patients in the pembrolizumab 2 mg/kg group , 25 ( 14 % ) in the pembrolizumab 10 mg/kg group , and 45 ( 26 % ) in the chemotherapy group . The most common treatment-related grade 3 - 4 adverse event in the pembrolizumab groups was fatigue ( two [ 1 % ] of 178 patients in the 2 mg/kg group and one [ < 1 % ] of 179 patients in the 10 mg/kg group , compared with eight [ 5 % ] of 171 in the chemotherapy group ) . Other treatment-related grade 3 - 4 adverse events include generalised oedema and myalgia ( each in two [ 1 % ] patients ) in those given pembrolizumab 2 mg/kg ; hypopituitarism , colitis , diarrhoea , decreased appetite , hyponatremia , and pneumonitis ( each in two [ 1 % ] ) in those given pembrolizumab 10 mg/kg ; and anaemia ( nine [ 5 % ] ) , fatigue ( eight [ 5 % ] ) , neutropenia ( six [ 4 % ] ) , and leucopenia ( six [ 4 % ] ) in those assigned to chemotherapy . INTERPRETATION These findings establish pembrolizumab as a new st and ard of care for the treatment of ipilimumab-refractory melanoma . FUNDING Merck Sharp & Dohme BACKGROUND The immune checkpoint inhibitor ipilimumab is the st and ard-of-care treatment for patients with advanced melanoma . Pembrolizumab inhibits the programmed cell death 1 ( PD-1 ) immune checkpoint and has antitumor activity in patients with advanced melanoma . METHODS In this r and omized , controlled , phase 3 study , we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab ( at a dose of 10 mg per kilogram of body weight ) every 2 weeks or every 3 weeks or four doses of ipilimumab ( at 3 mg per kilogram ) every 3 weeks . Primary end points were progression-free and overall survival . RESULTS The estimated 6-month progression-free-survival rates were 47.3 % for pembrolizumab every 2 weeks , 46.4 % for pembrolizumab every 3 weeks , and 26.5 % for ipilimumab ( hazard ratio for disease progression , 0.58 ; P<0.001 for both pembrolizumab regimens versus ipilimumab ; 95 % confidence intervals [ CIs ] , 0.46 to 0.72 and 0.47 to 0.72 , respectively ) . Estimated 12-month survival rates were 74.1 % , 68.4 % , and 58.2 % , respectively ( hazard ratio for death for pembrolizumab every 2 weeks , 0.63 ; 95 % CI , 0.47 to 0.83 ; P=0.0005 ; hazard ratio for pembrolizumab every 3 weeks , 0.69 ; 95 % CI , 0.52 to 0.90 ; P=0.0036 ) . The response rate was improved with pembrolizumab administered every 2 weeks ( 33.7 % ) and every 3 weeks ( 32.9 % ) , as compared with ipilimumab ( 11.9 % ) ( P<0.001 for both comparisons ) . Responses were ongoing in 89.4 % , 96.7 % , and 87.9 % of patients , respectively , after a median follow-up of 7.9 months . Efficacy was similar in the two pembrolizumab groups . Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups ( 13.3 % and 10.1 % ) than in the ipilimumab group ( 19.9 % ) . CONCLUSIONS The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high- grade toxicity than did ipilimumab in patients with advanced melanoma . ( Funded by Merck Sharp & Dohme ; KEYNOTE-006 Clinical Trials.gov number , NCT01866319 . ) BACKGROUND In patients with melanoma , ipilimumab ( an antibody against cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] ) prolongs overall survival , and nivolumab ( an antibody against the programmed death 1 [ PD-1 ] receptor ) produced durable tumor regression in a phase 1 trial . On the basis of their distinct immunologic mechanisms of action and supportive pre clinical data , we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma . METHODS We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses , followed by nivolumab alone every 3 weeks for 4 doses ( concurrent regimen ) . The combined treatment was subsequently administered every 12 weeks for up to 8 doses . In a sequenced regimen , patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses . RESULTS A total of 53 patients received concurrent therapy with nivolumab and ipilimumab , and 33 received sequenced treatment . The objective -response rate ( according to modified World Health Organization criteria ) for all patients in the concurrent-regimen group was 40 % . Evidence of clinical activity ( conventional , unconfirmed , or immune-related response or stable disease for ≥24 weeks ) was observed in 65 % of patients . At the maximum doses that were associated with an acceptable level of adverse events ( nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram ) , 53 % of patients had an objective response , all with tumor reduction of 80 % or more . Grade 3 or 4 adverse events related to therapy occurred in 53 % of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible . Among patients in the sequenced-regimen group , 18 % had grade 3 or 4 adverse events related to therapy and the objective -response rate was 20 % . CONCLUSIONS Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy , with rapid and deep tumor regression in a substantial proportion of patients . ( Funded by Bristol-Myers Squibb and Ono Pharmaceutical ; Clinical Trials.gov number , NCT01024231 . ) BACKGROUND In a phase 1 dose-escalation study , combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response , including complete responses , among patients with advanced melanoma . METHODS In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment , we r and omly assigned patients in a 2:1 ratio to receive ipilimumab ( 3 mg per kilogram of body weight ) combined with either nivolumab ( 1 mg per kilogram ) or placebo once every 3 weeks for four doses , followed by nivolumab ( 3 mg per kilogram ) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects . The primary end point was the rate of investigator-assessed , confirmed objective response among patients with BRAF V600 wild-type tumors . RESULTS Among patients with BRAF wild-type tumors , the rate of confirmed objective response was 61 % ( 44 of 72 patients ) in the group that received both ipilimumab and nivolumab ( combination group ) versus 11 % ( 4 of 37 patients ) in the group that received ipilimumab and placebo ( ipilimumab-monotherapy group ) ( P<0.001 ) , with complete responses reported in 16 patients ( 22 % ) in the combination group and no patients in the ipilimumab-monotherapy group . The median duration of response was not reached in either group . The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy ( hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death , 0.40 ; 95 % confidence interval , 0.23 to 0.68 ; P<0.001 ) . Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors . Drug-related adverse events of grade 3 or 4 were reported in 54 % of the patients who received the combination therapy as compared with 24 % of the patients who received ipilimumab monotherapy . Select adverse events with potential immunologic causes were consistent with those in a phase 1 study , and most of these events resolved with immune-modulating medication . CONCLUSIONS The objective -response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy . Combination therapy had an acceptable safety profile . ( Funded by Bristol-Myers Squibb ; Clinical Trials.gov number , NCT01927419 . ) BACKGROUND Nivolumab , a programmed death 1 ( PD-1 ) checkpoint inhibitor , was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma . This r and omized , open-label , phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment . METHODS A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were r and omly assigned ( in a 1:1 ratio ) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily . The primary end point was overall survival . The secondary end points included the objective response rate and safety . RESULTS The median overall survival was 25.0 months ( 95 % confidence interval [ CI ] , 21.8 to not estimable ) with nivolumab and 19.6 months ( 95 % CI , 17.6 to 23.1 ) with everolimus . The hazard ratio for death with nivolumab versus everolimus was 0.73 ( 98.5 % CI , 0.57 to 0.93 ; P=0.002 ) , which met the prespecified criterion for superiority ( P≤0.0148 ) . The objective response rate was greater with nivolumab than with everolimus ( 25 % vs. 5 % ; odds ratio , 5.98 [ 95 % CI , 3.68 to 9.72 ] ; P<0.001 ) . The median progression-free survival was 4.6 months ( 95 % CI , 3.7 to 5.4 ) with nivolumab and 4.4 months ( 95 % CI , 3.7 to 5.5 ) with everolimus ( hazard ratio , 0.88 ; 95 % CI , 0.75 to 1.03 ; P=0.11 ) . Grade 3 or 4 treatment-related adverse events occurred in 19 % of the patients receiving nivolumab and in 37 % of the patients receiving everolimus ; the most common event with nivolumab was fatigue ( in 2 % of the patients ) , and the most common event with everolimus was anemia ( in 8 % ) . CONCLUSIONS Among patients with previously treated advanced renal-cell carcinoma , overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus . ( Funded by Bristol-Myers Squibb ; CheckMate 025 Clinical Trials.gov number , NCT01668784 . ) BACKGROUND Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus ( MCPyV ) . Advanced Merkel-cell carcinoma often responds to chemotherapy , but responses are transient . Blocking the programmed death 1 ( PD-1 ) immune inhibitory pathway is of interest , because these tumors often express PD-L1 , and MCPyV-specific T cells express PD-1 . METHODS In this multicenter , phase 2 , noncontrolled study , we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab ( anti-PD-1 ) at a dose of 2 mg per kilogram of body weight every 3 weeks . The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors , version 1.1 . Efficacy was correlated with tumor viral status , as assessed by serologic and immunohistochemical testing . RESULTS A total of 26 patients received at least one dose of pembrolizumab . The objective response rate among the 25 patients with at least one evaluation during treatment was 56 % ( 95 % confidence interval [ CI ] , 35 to 76 ) ; 4 patients had a complete response , and 10 had a partial response . With a median follow-up of 33 weeks ( range , 7 to 53 ) , relapses occurred in 2 of the 14 patients who had had a response ( 14 % ) . The response duration ranged from at least 2.2 months to at least 9.7 months . The rate of progression-free survival at 6 months was 67 % ( 95 % CI , 49 to 86 ) . A total of 17 of the 26 patients ( 65 % ) had virus-positive tumors . The response rate was 62 % among patients with MCPyV-positive tumors ( 10 of 16 patients ) and 44 % among those with virus-negative tumors ( 4 of 9 patients ) . Drug-related grade 3 or 4 adverse events occurred in 15 % of the patients . CONCLUSIONS In this study , first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56 % . Responses were observed in patients with virus-positive tumors and those with virus-negative tumors . ( Funded by the National Cancer Institute and Merck ; Clinical Trials.gov number , NCT02267603 . ) BACKGROUND Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes . We assessed the activity of nivolumab , a fully human IgG4 PD-1 immune checkpoint inhibitor antibody , for patients with advanced , refractory , squamous non-small-cell lung cancer . METHODS We did this phase 2 , single-arm trial at 27 sites ( academic , hospital , and private cancer centres ) in France , Germany , Italy , and USA . Patients who had received two or more previous treatments received intravenous nivolumab ( 3 mg/kg ) every 2 weeks until progression or unacceptable toxic effects . The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee . We included all treated patients in the analyses . This study is registered with Clinical Trials.gov , number NCT01721759 . FINDINGS Between Nov 16 , 2012 , and July 22 , 2013 , we enrolled and treated 117 patients . 17 ( 14·5 % , 95 % CI 8·7 - 22·2 ) of 117 patients had an objective response as assessed by an independent radiology review committee . Median time to response was 3·3 months ( IQR 2·2 - 4·8 ) , and median duration of response was not reached ( 95 % CI 8·31-not applicable ) ; 13 ( 77 % ) of 17 of responses were ongoing at the time of analysis . 30 ( 26 % ) of 117 patients had stable disease ( median duration 6·0 months , 95 % CI 4·7 - 10·9 ) . 20 ( 17 % ) of 117 patients reported grade 3 - 4 treatment-related adverse events , including : fatigue ( five [ 4 % ] of 117 patients ) , pneumonitis ( four [ 3 % ] ) , and diarrhoea ( three [ 3 % ] ) . There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease . INTERPRETATION Nivolumab has clinical ly meaningful activity and a manageable safety profile in previously treated patients with advanced , refractory , squamous non-small cell lung cancer . These data support the assessment of nivolumab in r and omised , controlled , phase 3 studies of first-line and second-line treatment . FUNDING Bristol-Myers Squibb

There was fairly consistent evidence for the cost-effectiveness/favorable cost-benefit of removing indoor lead to prevent lead poisoning and sequelae , and retrofitting insulation to prevent lung disease . But the value of assessing and improving home safety and providing smoke alarms to prevent injuries was more mixed and the economic evidence was inconclusive or insufficient for : home ventilation to prevent lung disease , installing heaters to prevent lung disease and regulating tap water temperatures to prevent scalding . Conclusions This systematic review provides up date d evidence that several housing improvement interventions ( such as removing indoor lead and retrofitting insulation ) and also the provision of insecticide-treated bednets are cost-effective interventions .

Background Housing improvements have considerable potential for improving health . So does the provision of insecticide-treated bednets for malaria prevention . Therefore we aim ed to conduct up date d systematic review s of health economic analyses in both these intervention domains .

BACKGROUND There has been little rigorous economic analysis of the relationship between asthma and improved housing . AIM To evaluate the cost-effectiveness of installing ventilation systems , and central heating if necessary , in homes of children with ' moderate ' or ' severe ' asthma . DESIGN AND SETTING An incremental cost-effectiveness analysis alongside a pragmatic r and omised controlled trial of a tailored package of housing modifications design ed to improve ventilation and household heating in homes within Wrexham County Borough , Wales , UK . METHOD A total of 177 children aged between 5 and 14 years , identified from general practice registers , were studied . Parents reported on the quality of life of their children over a 12-month period . General practice s reported on health-service re sources used by those children , and their asthma-related prescriptions , over the same period . RESULTS The tailored package shifted 17 % of children in the intervention group from ' severe ' to ' moderate ' asthma , compared with a 3 % shift in the control group . The mean cost of these modifications was £ 1718 per child treated or £ 12300 per child shifted from ' severe ' to ' moderate ' . Healthcare costs over 12 months following r and omisation did not differ significantly between intervention and control groups . Bootstrapping gave an incremental cost-effectiveness ratio ( ICER ) of £ 234 per point improvement on the 100-point PedsQL ™ asthma-specific scale , with 95 % confidence interval ( CI ) = £ 140 to £ 590 . The ICER fell to £ 165 ( 95 % CI = £ 84 to £ 424 ) for children with ' severe ' asthma . CONCLUSION This novel and pragmatic trial , with integrated economic evaluation , reported that tailored improvement of the housing of children with moderate to severe asthma is likely to be a cost-effective use of public re sources . This is a rare example of evidence for collaboration between local government and the NHS Evaluating cost effectiveness of interventions for aging in place is essential for adoption in service setting s. We present the cost effectiveness of Advancing Better Living for Elders ( ABLE ) , previously shown in a r and omized trial to reduce functional difficulties and mortality in 319 community-dwelling elders . ABLE involved occupational and physical therapy sessions and home modifications to address client-identified functional difficulties , performance goals , and home safety . Incremental cost-effectiveness ratio ( ICER ) , expressed as additional cost to bring about one additional year of life , was calculated . Two models were then developed to account for potential cost differences in implementing ABLE . Probabilistic sensitivity analyses were conducted to account for variations in model parameters . By two years , there were 30 deaths ( 9 : ABLE ; 21 : control ) . Additional costs for 1 additional year of life was $ 13,179 for Model 1 and $ 14,800 for Model 2 . Investment in ABLE may be worthwhile depending on society 's willingness to pay Aims To assess the cost-effectiveness of installing thermostatic mixer valves ( TMVs ) in reducing risks of bath water scalds and estimate the costs of avoiding bath water scalds . Methods The evaluation was undertaken from the perspective of the UK public sector , and conducted in conjunction with a r and omised control trial of TMVs installed in social housing in Glasgow . Installation costs were borne by the social housing organisation , while support material s were provided by the UK NHS . Effectiveness was represented by the number of families with at-risk bath water temperatures pre- and post-installation , and the number of bath scalds avoided as a result of installation . Differences in the number of families with at-risk temperatures between groups were derived from the RCT . Cost-effectiveness was assessed and a series of one-way sensitivity analyses were conducted . Results Unit costs associated with installation were calculated to be £ 13.68 , while costs associated with treating bath water scalds ranged from £ 25 226 to £ 71 902 . The cost of an avoided bath water scald ranged from net savings to public purse of £ 1887 to £ 75 520 and at baseline produced a net saving of £ 3 229 008 ; that is , £ 1.41 saved for every £ 1 spent . Conclusion It is very likely that installing TMVs as st and ard in social housing in new buildings and major refurbishments accompanied by educational information represents value for money . Trial registration number IS RCT N:21179067 BACKGROUND In 2001 , 486 deaths and 17,300 injuries occurred in domestic fires in the UK . Domestic fires represent a significant cost to the UK economy , with the value of property loss alone estimated at pounds 375 million in 1999 . In 2001 in the US , there were 383 500 home fires , result ing in 3110 deaths , 15,200 injuries and dollar 5.5 billion in direct property damage . METHODS A cluster RCT was conducted to determine whether a smoke alarm give-away program , directed to an inner-city UK population , is effective and cost-effective in reducing the risk of fire-related deaths/injuries . Forty areas were r and omized to the give-away or control group . The number of injuries/deaths and the number of fires in each ward were collected prospect ively . Cost-effectiveness analysis was undertaken to relate the number of deaths/injuries to re source use ( damage , fire service , healthcare and give-away costs ) . Analytical methods were used which reflected the characteristics of the trial data including the cluster design of the trial and a large number of zero costs and effects . RESULTS The mean cost for a household in a give-away ward , including the cost of the program , was pounds 12.76 , compared to pounds 10.74 for the control ward . The total mean number of deaths and injuries was greater in the intervention wards then the control wards , 6.45 and 5.17 . When an injury/death avoided is valued at pounds 1000 , a smoke alarm give-away has a probability of being cost effective of 0.15 . CONCLUSIONS A smoke alarm give-away program , as administered in the trial , is unlikely to represent a cost-effective use of re sources Background : Housing is an important environmental influence on population health , and there is growing evidence of health effects from indoor environment characteristics such as low indoor temperatures . However , there is relatively little research , and thus little firm guidance , on the cost-effectiveness of public policies to retrospectively improve the st and ards of houses . The purpose of this study was to value the health , energy and environmental benefits of retrofitting insulation , through assessing a number of forms of possible benefit : a reduced number of visits to GPs , hospitalisations , days off school , days off work , energy savings and CO2 savings . Methods : All these metrics are used in a cluster r and omised trial — the “ Housing , Insulation and Health Study ” —of retrofitting insulation in 1350 houses , in which at least one person had symptoms of respiratory disease , in predominantly low-income communities in New Zeal and . Results : Valuing the health gains , and energy and CO2 emissions savings , suggests that total benefits in “ present value ” ( discounted ) terms are one and a half to two times the magnitude of the cost of retrofitting insulation . Conclusion : This study points to the need to consider as wide a range of benefits as possible , including health and environmental benefits , when assessing the value for money of an intervention to improve housing quality . From an environmental , energy and health perspective , the value for money of improving housing quality by retrofitting insulation is compelling Background Despite much success in reducing the burden of malaria in Vietnam , pockets of malaria persist and eliminating them remains an important development goal . In central Vietnam , insecticide-treated hammocks have recently been introduced to help counter the disease in the highly forested , mountainous areas , where other measures have so far been unsuccessful . This study assesses the cost-effectiveness of using long-lasting insecticide-treated hammocks in this area . Methods and Findings This cost-effectiveness study was run alongside a r and omized control trial testing the efficacy of the long-lasting insecticide-treated hammocks . Data were collected through an exit survey , a household survey , expenditure records and key informant interviews . The study estimates that under normal ( non-trial ) conditions the total net societal cost per malaria episode averted in using long-lasting insecticide-treated hammocks in this area was 126 USD . Cost per hammock , including insecticidal netting , sewing , transport , and distribution was found to be approximately 11.76 USD per hammock . Average savings per episode averted were estimated to be $ 14.60 USD for the health system and 14.37 USD for households ( including both direct and indirect cost savings ) . The study estimates that the annual financial outlay required of government to implement this type of programme to be 3.40 USD per person covered per year . Conclusion The study finds that the use of a hammock intervention could represent good value for money to help prevent malaria in more remote areas , where traditional control measures such as insecticide-treated bednets and indoor residual spraying are insufficient or inappropriate to control malaria . However , the life span of the hammock – the number of years over which it effectively deters mosquitoes – has a significant impact on the cost-effectiveness of the intervention and study results should be interpreted in light of the evidence on effectiveness gathered in the years to come OBJECTIVES To model the incremental cost-utility of seven interventions reported as effective for preventing falls in older adults . DESIGN Mathematical epidemiological model populated by data based on direct clinical experience and a critical review of the literature . SETTING Model represents population level interventions . PARTICIPANTS No human subjects were involved in the study . MEASUREMENS : The last Cochrane data base review and meta-analyses of r and omized controlled trials categorized effective fall-prevention interventions into seven groups : medical management ( withdrawal ) of psychotropics , group tai chi , vitamin D supplementation , muscle and balance exercises , home modifications , multifactorial individualized programs for all elderly people , and multifactorial individualized treatments for high-risk frail elderly people . Fall-related hip fracture incidence was obtained from the literature . Salary figures for health professionals were based on Bureau of Labor Statistics data . Using an integrated healthcare system perspective , healthcare costs were estimated based on practice and studies on falls in older adults . Base case incremental cost utility ratios were calculated , and probabilistic sensitivity analyses were conducted . RESULTS Medical management of psychotropics and group tai chi were the least-costly , most-effective options , but they were also the least studied . Excluding these interventions , the least-expensive , most-effective options are vitamin D supplementation and home modifications . Vitamin D supplementation costs less than home modifications , but home modifications cost only $ 14,794/ quality -adjusted life year ( QALY ) gained more than vitamin D. In probabilistic sensitivity analyses excluding management of psychotropics and tai chi , home modification is most likely to have the highest economic benefit when QALYs are valued at $ 50,000 or $ 100,000 . CONCLUSION Of single interventions studied , management of psychotropics and tai chi reduces costs the most . Of more-studied interventions , home modifications provide the best value . These results must be interpreted in the context of the multifactorial nature of falls Objective To determine whether insulating existing houses increases indoor temperatures and improves occupants ' health and wellbeing . Design Community based , cluster , single blinded r and omised study . Setting Seven low income communities in New Zeal and . Participants 1350 households containing 4407 participants . Intervention Installation of a st and ard retrofit insulation package . Main outcome measures Indoor temperature and relative humidity , energy consumption , self reported health , wheezing , days off school and work , visits to general practitioners , and admissions to hospital . Results Insulation was associated with a small increase in bedroom temperatures during the winter ( 0.5 � C ) and decreased relative humidity ( −2.3 % ) , despite energy consumption in insulated houses being 81 % of that in uninsulated houses . Bedroom temperatures were below 10 � C for 1.7 fewer hours each day in insulated homes than in uninsulated ones . These changes were associated with reduced odds in the insulated homes of fair or poor self rated health ( adjusted odds ratio 0.50 , 95 % confidence interval 0.38 to 0.68 ) , self reports of wheezing in the past three months ( 0.57 , 0.47 to 0.70 ) , self reports of children taking a day off school ( 0.49 , 0.31 to 0.80 ) , and self reports of adults taking a day off work ( 0.62 , 0.46 to 0.83 ) . Visits to general practitioners were less often reported by occupants of insulated homes ( 0.73 , 0.62 to 0.87 ) . Hospital admissions for respiratory conditions were also reduced ( 0.53 , 0.22 to 1.29 ) , but this reduction was not statistically significant ( P=0.16 ) . Conclusion Insulating existing houses led to a significantly warmer , drier indoor environment and result ed in improved self rated health , self reported wheezing , days off school and work , and visits to general practitioners as well as a trend for fewer hospital admissions for respiratory conditions Background Insecticide-treated bed nets ( ITN ) reduce malaria morbidity and mortality consistently in Africa , but their benefits have been less consistent in Asia . This study ’s objective was to evaluate the malaria protective efficacy of village-wide usage of ITN in Western Myanmar and estimate the cost-effectiveness of ITN compared with extending early diagnosis and treatment services . Methods A cluster-r and omized controlled trial was conducted in Rakhine State to assess the efficacy of ITNs in preventing malaria and anaemia in children and their secondary effects on nutrition and development . The data were aggregated for each village to obtain cluster-level infection rates . In total 8,175 children under 10 years of age were followed up for 10 months , which included the main malaria transmission period . The incidence and prevalence of Plasmodium falciparum and Plasmodium vivax infections , and the biting behaviour of Anopheles mosquitoes in the area were studied concurrently . The trial data along with costs for current recommended treatment practice s were modelled to estimate the cost-effectiveness of ITNs compared with , or in addition to extending the coverage of early diagnosis and treatment services . Results In aggregate , malaria infections , spleen rates , haemoglobin concentrations , and weight for height , did not differ significantly during the study period between villages with and without ITNs , with a weighted mean difference of −2.6 P. falciparum episodes per 1,000 weeks at risk ( 95 % Confidence Interval −7 to 1.8 ) . In areas with a higher incidence of malaria there was some evidence ITN protective efficacy . The economic analysis indicated that , despite the uncertainty and variability in their protective efficacy in the different study sites , ITN could still be cost-effective , but not if they displaced funding for early diagnosis and effective treatment which is substantially more cost-effective . Conclusion In Western Myanmar deployment of ITNs did not provide consistent protection against malaria in children living in malaria endemic villages . Early diagnosis and effective treatment is a more cost effective malaria control strategy than deployment of ITNs in this area where the main vector bites early in the evening , often before people are protected by an ITN Objective : To assess the short term health effects of improving housing . Design : R and omised to waiting list . Setting : 119 council owned houses in south Devon , UK . Participants : About 480 residents of these houses . Intervention : Upgrading houses ( including central heating , ventilation , rewiring , insulation , and re-roofing ) in two phases a year apart . Main outcome measures : All residents completed an annual health question naire : SF36 and GHQ12 ( adults ) . Residents reporting respiratory illness or arthritis were interviewed using condition-specific question naires , the former also completing peak flow and symptom diaries ( children ) or spirometry ( adults ) . Data on health service use and time lost from school were collected . Results : Interventions improved energy efficiency . For those living in intervention houses , non-asthma-related chest problems ( Mann – Whitney test , p = 0.005 ) and the combined asthma symptom score for adults ( Mann – Whitney test , z = 2.7 , p = 0.007 ) diminished significantly compared with control houses . No difference between intervention and control houses was seen for SF36 or GHQ12 . Conclusions : Rigorous study design s for the evaluation of complex public health and community based interventions are possible . Quantitatively measured health benefits are small , but as health benefits were measured over a short time scale , there may have been insufficient time for measurable improvements in general and disease-specific health to become apparent BACKGROUND Despite the considerable injury burden attributable to falls at home among the general population , few effective safety interventions have been identified . We tested the safety benefits of home modifications , including h and rails for outside steps and internal stairs , grab rails for bathrooms , outside lighting , edging for outside steps , and slip-resistant surfacing for outside areas such as decks and porches . METHODS We did a single-blind , cluster-r and omised controlled trial of households from the Taranaki region of New Zeal and . To be eligible , participants had to live in an owner-occupied dwelling constructed before 1980 and at least one member of every household had to be in receipt of state benefits or subsidies . We r and omly assigned households by electronic coin toss to either immediate home modifications ( treatment group ) or a 3-year wait before modifications ( control group ) . Household members in the treatment group could not be masked to their assigned status because modifications were made to their homes . The primary outcome was the rate of falls at home per person per year that needed medical treatment , which we derived from administrative data for insurance cl aims . Coders who were unaware of the r and om allocation analysed text descriptions of injuries and coded injuries as all falls and injuries most likely to be affected by the home modifications tested . To account for clustering at the household level , we analysed all injuries from falls at home per person-year with a negative binomial generalised linear model with generalised estimating equations . Analysis was by intention to treat . This trial is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12609000779279 . FINDINGS Of 842 households recruited , 436 ( n=950 individual occupants ) were r and omly assigned to the treatment group and 406 ( n=898 occupants ) were allocated to the control group . After a median observation period of 1148 days ( IQR 1085 - 1263 ) , the crude rate of fall injuries per person per year was 0.061 in the treatment group and 0.072 in the control group ( relative rate 0.86 , 95 % CI 0.66 - 1.12 ) . The crude rate of injuries specific to the intervention per person per year was 0.018 in the treatment group and 0.028 in the control group ( 0.66 , 0.43 - 1.00 ) . A 26 % reduction in the rate of injuries caused by falls at home per year exposed to the intervention was estimated in people allocated to the treatment group compared with those assigned to the control group , after adjustment for age , previous falls , sex , and ethnic origin ( relative rate 0.74 , 95 % CI 0.58 - 0.94 ) . Injuries specific to the home-modification intervention were cut by 39 % per year exposed ( 0.61 , 0.41 - 0.91 ) . INTERPRETATION Our findings suggest that low-cost home modifications and repairs can be a means to reduce injury in the general population . Further research is needed to identify the effectiveness of particular modifications from the package tested . FUNDING Health Research Council of New Zeal and This study compares the effectiveness and cost-effectiveness of indoor residual house-spraying ( IRS ) and insecticide-treated bednets ( ITNs ) against infection with Plasmodium falciparum as part of malaria control in the highl and s of western Kenya . Homesteads operationally targeted for IRS and ITNs during a district-based emergency response undertaken by an international relief agency were selected at r and om for evaluation . Five hundred and ninety homesteads were selected ( 200 with no vector control , 200 with IRS and 190 with ITNs ) . In July 2000 , residents in these homesteads were r and omly sample d according to three age-groups : 6 months-4 years , 5 - 15 years , and > 15 years for the presence of P. falciparum antigen ( Pf HRP-2 ) using the rapid whole blood immunochromatographic test ( ICT ) . The prevalence of P. falciparum infection amongst household members not protected by either IRS or ITN was 13 % . Sleeping under a treated bednet reduced the risk of infection by 63 % ( 58 - 68 % ) and sleeping in a room sprayed with insecticide reduced the risk by 75 % ( 73 - 76 % ) . The economic cost per infection case prevented by IRS was US$ 9 compared to US$ 29 for ITNs . This study suggests that IRS may be both more effective and cheaper than ITNs in communities subjected to low , seasonal risks of infection and as such should be considered as part of the control armamentarium for malaria prevention This study compared the costs and effects of insecticide (permethrin)-treated bed net ( ITN ) use in children less than five years of age in an area of intense , perennial malaria transmission in western Kenya . The data were derived from a group-r and omized controlled trial of ITNs conducted between 1996 and 1999 . The annual net cost per life-year gained was 34 U.S. dollars and the net annual cost per all-cause sick child clinic visit averted was 49 U.S. dollars . After taking into account a community effect ( protection from malaria afforded to non-ITN users who lived within 300 meters from users ) these estimates decreased to 25 U.S. dollars and 38 U.S. dollars , respectively . This study provides further evidence that ITNs are a highly cost-effective use of scarce health care re sources Malaria is one of the leading causes of morbidity and mortality in the developing world and a major public health problem in India . Disillusioned by in-house residual spraying ( IRS ) , and increasingly aware that insecticide-treated nets ( ITNs ) have proved to be effective in reducing malaria mortality and morbidity in various epidemiological setting s , policy-makers in India are keen to identify which is the more cost-effective malaria control intervention . A community r and omised controlled trial was set up in Surat to compare the effectiveness and efficiency of IRS and ITNs . Both control strategies were shown to be effective in preventing malaria over the base-case scenario of early diagnosis and prompt treatment . The mean costs per case averted for ITNs was statistically significantly lower ( Rs . 1848 , 1567 - 2209 ; US$ 52 ) than IRS ( Rs . 3121 , 2386 - 4177 , US$ 87 ) . The incremental cost-effectiveness ratio for ITNs over IRS was Rs . 799 ( US$ 22 ) . The conclusions were robust to changes in assumptions . This study exp and s the scope of recent comparative economic evaluations of ITNs and IRS , since it was carried out in a low mortality malaria endemic area BACKGROUND : The effectiveness of individual components ( other than exercise ) of multifactorial intervention packages aim ed to reduce the incidence of falls in older people is uncertain . There have been no r and omised trials of home modifications alone for the prevention of falls

This pooled analysis confirms that continuing T beyond the first progression continues to be 1 of the effective and preferred choices in HER2 + MBC , failing a ( T-based ) first-line regimen

BACKGROUND In HER2 + MBC , continuing trastuzumab ( T ) after the progression during a first-line T-based regimen , represents 1 of the possible strategies , even if few data from r and omized trials exist in this setting .

Background : Recent UK clinical guidance advises against continuing trastuzumab ( T ) beyond disease progression ( PD ) in the absence of brain metastases in patients with HER-2 positive ( + ve ) advanced breast cancer .We have retrospectively evaluated the outcome of patients with HER-2+ve locally advanced ( LA ) or metastatic breast cancer ( MBC ) who continued T beyond PD , treated in our unit . Methods : All HER-2+ve patients on our prospect ively maintained data base with LA or MBC who received T beyond PD after adjuvant or one line of T for advanced disease were assessed for response and outcome . From the timepoint of T continuation beyond PD , we calculated the overall disease control rate , time to progression ( TTP ) , and overall survival ( OS ) . Results : One hundred and fourteen patients with HER-2+ve LA or MBC treated with T beyond PD were identified . The main site of disease was visceral_in 84 ( 74 % ) patients . Seventy-six ( 66 % ) had one line of chemotherapy before continuation of T beyond PD and 21 ( 19 % ) had two or more . Post-progression , 66 ( 58 % ) received T combined with chemotherapy . Of the 93 ( 82 % ) patients with documented clinical or radiological response evaluation , 67 ( 59 % ) were considered as having stable disease or better . The median TTP was 24 weeks ( 95 % CI : 21–28 ) and the median OS was 19 months ( 95 % CI : 12–24 ) . Conclusion : Our results from an unselected group of patients provide additional evidence that continuation of T beyond PD is of clinical benefit Background Combining trastuzumab and chemotherapy is st and ard in her2/neu overexpressing advanced breast cancer . It is not established however , whether trastuzumab treatment should continue after the failure of one earlier combination . In this trial , we report our experience with continued treatment beyond disease progression . Methods Fifty-four patients , median age 46 years , range 25–73 years , were included . We analysed for time to tumour progression ( TTP ) for first , second and beyond second line treatment , response rates and overall survival . Results Median time of observation was 24 months , range 7–51 . Response rates for first line treatment were 7.4 % complete remission ( CR ) , 35.2 % partial remissions ( PR ) , 42.6 % stable disease > 6 months ( SD ) and 14.8 % of patients experienced disease progression despite treatment ( PD ) . Corresponding numbers for second line were 3.7 % CR , 22.2 % PR , 42.6 % SD and 31.5 % PD ; numbers for treatment beyond second line ( 60 therapies , 33 pts 3rd line , 18 pts 4th line , 6 pts 5th line , 2 pts 6th line and 1 patient 7th line ) were 1.7 % CR , 28.3 % PR , 28.3 % SD and 41.6 % PD respectively . Median TTP was 6 months ( m ) in the first line setting , and also 6 m for second line and beyond second line . An asymptomatic drop of left ventricular ejection fraction below 50 % was observed in one patient . No case of symptomatic congestive heart failure was observed . Conclusion The data presented clearly strengthen evidence that patients do profit from continued trastuzumab treatment . The fact that TTP did not decrease significantly from first line to beyond second line treatment is especially noteworthy . Still , r and omized trials are warranted HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab . This novel agent , when administered until disease progression in combination with chemotherapy , extends the survival of women with HER2-positive metastatic breast cancer ( MBC ) . However , the optimal duration of trastuzumab therapy remains to be confirmed . We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression . Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach . One hundred five patients ( median age , 47 years ; range , 24 - 77 years ) were identified in 13 centers . Women had received < /=6 chemotherapy regimens ( median , 1 ) before trastuzumab therapy . Median survival from first trastuzumab dose was 29 months . The overall response rate to trastuzumab alone or with a taxane as the first regimen was 39 % ; a further 30 % of patients had stable disease as the best response . These rates were 36 % and 38 % after a second regimen of trastuzumab alone or with paclitaxel or vinorelbine was administered . Some patients responded to both the first and second regimens ; others responded to the second regimen after the first had failed . Twenty-two patients experienced cardiac events , of whom 18 received > /=1 more trastuzumab regimen . Trastuzumab treatment beyond progression appears to be of value , producing responses and clinical benefit , and is well tolerated without significant cardiac toxicity . The feasibility of this approach warrants examination in prospect i ve trials Purpose Lapatinib is a small molecule , dual tyrosine kinase inhibitor of epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor type 2 ( HER2 ) . Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab . Up date d efficacy and initial biomarker results from this trial are reported . Methods Women with HER2-positive , locally advanced or metastatic breast cancer previously treated with anthracycline- , taxane- , and trastuzumab-containing regimens were r and omized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m2 days 1–14 of a 21-day cycle or capecitabine 2,500 mg/m2 on the same schedule . The primary endpoint was time to progression ( TTP ) as determined by an independent review panel . Relationship between progression-free survival ( PFS ) and tumor HER2 expression and serum levels of HER2 extracellular domain ( ECD ) were assessed . Results 399 women were r and omized . The addition of lapatinib prolonged TTP with a hazard ratio ( HR ) of 0.57 ( 95 % CI , 0.43–0.77 ; P < 0.001 ) and provided a trend toward improved overall survival ( HR : 0.78 , 95 % CI : 0.55–1.12 , P = 0.177 ) , and fewer cases with CNS involvement at first progression ( 4 vs. 13 , P = 0.045 ) . Baseline serum HER2 ECD did not predict for benefit from lapatinib . Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive , advanced breast cancer progressing after treatment with anthracycline- , taxane- , and trastuzumab-based therapy . Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine BACKGROUND Patients with HER2-positive breast cancer whose disease has become resistant to the anti-HER2 monoclonal antibody trastuzumab can benefit from lapatinib , a dual epidermal growth factor receptor/HER2 tyrosine kinase ( TK ) inhibitor . Before the availability of this compound , trastuzumab was often continued beyond disease progression , usually in addition to further chemotherapy , an approach which was not based on r and omized studies . We sought to retrospectively compare the clinical outcomes of patients who , upon progression during an initial trastuzumab-based regimen , stopped or continued trastuzumab in addition to further chemotherapy . PATIENTS AND METHODS From the clinical records of 407 patients with HER2-positive advanced breast cancer , we identified 279 patients progressing during an initial trastuzumab-based treatment . Of these patients , 83 continued trastuzumab in addition to chemotherapy , and 112 received chemotherapy alone . RESULTS We found no difference in response rate ( 28 % vs. 30 % ; P = .5 ) , median time to second tumor progression ( 8.4 months vs. 7 months ; P = .24 ) , or median postprogression survival ( 20.6 months and 15.4 months ; P = .29 ) according to whether patients continued or stopped trastuzumab . At multivariate analysis , continuation of trastuzumab was associated with a statistically insignificant trend toward reduced risk of second progression ( hazard ratio , 0.753 ; P = .08 ) . CONCLUSION Patients with HER2-positive advanced breast cancer developing tumor progression during an initial trastuzumab-based regimen did not seem to benefit significantly from the continuation of trastuzumab in addition to chemotherapy . For these patients , there is evidence from a large r and omized trial that effective HER2 targeting can be accomplished by inhibiting the HER2 TK activity with lapatinib PURPOSE To evaluate the efficacy and safety of weekly paclitaxel and trastuzumab in patients with HER2-positive metastatic breast cancer , with trastuzumab administered beyond disease progression . PATIENTS AND METHODS Twenty-six women with metastatic breast cancer , that was HER2-positive as determined by immunohistochemistry , were treated with weekly paclitaxel 70 or 90 mg/m2 and trastuzumab ( 4 mg/kg initial dose followed by 2 mg/kg weekly ) . RESULTS The median duration of treatment was 28 ( 8 - 72 ) weeks for paclitaxel and 59 ( 14 - 150 ) weeks for trastuzumab . Two ( 8 % ) patients experienced complete and 14 ( 54 % ) partial responses , for an overall response rate of 62 % . The median time to disease progression was 11 ( 2.89 - 36 ) months and median survival 34 + months . Grade 3/4 adverse events were alopecia ( 46 % ) , neurotoxicity ( 15 % ) , leukopenia ( 12 % ) and neutropenia ( 12 % ) . Infusion-related reactions were mild to moderate . No symptomatic cardiac toxicity was observed . No patient discontinued trastuzumab due to toxicity . CONCLUSION Prolonged administration of weekly paclitaxel and trastuzumab is effective and well-tolerated in women with HER2-positive metastatic breast cancer BACKGROUND Continuation of trastuzumab plus capecitabine ( XH ) showed a significantly improved overall response rate and time to progression compared with capecitabine ( X ) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment . Here , we report the final analysis on overall survival . PATIENTS AND METHODS Patients with HER2-positive , advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospect ively r and omised to X ( 2500mg/m(2 ) on days 1 - 14 , q3w ) or XH ( 6 (8)mg/kg , q3w ) . Overall survival was a pre-specified secondary end-point . RESULTS Median follow-up at June 2010 was 20.7months . Fifty nine of 74 and 60 of 77 patients died in the X and XH arm , respectively . Median overall survival was 20.6 and 24.9months with X and XH , respectively ( HR=0.94 [ 0.65 - 1.35 ] ; p=0.73 ) . Performance status and metastatic site were independent prognosticators for overall survival . No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit , respectively . Patients who continued/restarted anti-HER2 treatment ( trastuzumab or lapatinib ) after 2nd progression ( N=52 ) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents ( N=88 ) ( HR 0.63 ; p=0.02 ) . CONCLUSIONS Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab . However , in a post-hoc analysis , patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment BACKGROUND Trastuzumab emtansine ( T-DM1 ) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1 . The antibody and the cytotoxic agent are conjugated by means of a stable linker . METHODS We r and omly assigned patients with HER2-positive advanced breast cancer , who had previously been treated with trastuzumab and a taxane , to T-DM1 or lapatinib plus capecitabine . The primary end points were progression-free survival ( as assessed by independent review ) , overall survival , and safety . Secondary end points included progression-free survival ( investigator-assessed ) , the objective response rate , and the time to symptom progression . Two interim analyses of overall survival were conducted . RESULTS Among 991 r and omly assigned patients , median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine ( hazard ratio for progression or death from any cause , 0.65 ; 95 % confidence interval [ CI ] , 0.55 to 0.77 ; P<0.001 ) , and median overall survival at the second interim analysis crossed the stopping boundary for efficacy ( 30.9 months vs. 25.1 months ; hazard ratio for death from any cause , 0.68 ; 95 % CI , 0.55 to 0.85 ; P<0.001 ) . The objective response rate was higher with T-DM1 ( 43.6 % , vs. 30.8 % with lapatinib plus capecitabine ; P<0.001 ) ; results for all additional secondary end points favored T-DM1 . Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 ( 57 % vs. 41 % ) . The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1 , whereas the incidences of diarrhea , nausea , vomiting , and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine . CONCLUSIONS T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane . ( Funded by F. Hoffmann-La Roche/Genentech ; EMILIA Clinical Trials.gov number , NCT00829166 . )

Adverse events were generally mild to moderate , rarely led to withdrawal , and did not differ in frequency between groups . A single dose of parecoxib 20 mg or 40 mg provided effective analgesia for 50 to 60 % of those treated compared to about 15 % with placebo , and was well tolerated . Duration of analgesia was longer , and significantly fewer participants required rescue medication over 24 hours with the higher dose

BACKGROUND Parecoxib was the first COX-2 available for parenteral administration , and may , given intravenously or intramuscularly , offer advantages over oral medication when patients have nausea and vomiting or are unable to swallow , such as in the immediate postoperative period . OBJECTIVES Assess the efficacy of single dose intravenous or intramuscular parecoxib in acute postoperative pain , the requirement for rescue medication , and any associated adverse events .

OBJECTIVE : The aim of this study was to compare the upper GI mucosal effects of i.v . parecoxib sodium with i.v . ketorolac tromethamine and placebo in healthy elderly subjects . METHODS : This was a two-center , double-blind , r and omized , placebo-controlled study . Healthy subjects aged 65–75 yr who were shown at baseline endoscopy to have no gastric or duodenal lesions received either parecoxib sodium 40 mg b.i.d . for 7 days , ketorolac 15 mg q.i.d . for 5 days , or placebo for 7 days . Endoscopy was repeated at the end of dosing . Measures of upper GI effects were : 1 ) ulceration , 2 ) incidence of an ulcer and /or any erosions , and 3 ) incidence of an ulcer and /or ≥11 erosions in the stomach , duodenum , or both . RESULTS : No gastric or duodenal ulcers occurred in any subjects receiving parecoxib sodium ( n = 29 ) or placebo ( n = 32 ) . In contrast , seven ( 23 % ) of the 31 ketorolac subjects had at least one ulcer ; five ( 16 % ) had gastric ulcers , and two ( 6 % ) had duodenal ulcers ( p < 0.05 vs parecoxib sodium and placebo for gastroduodenal ulcers and for gastric ulcers ) . A total of 28 ( 90 % ) ketorolac subjects had an ulcer or at least one erosion in the stomach , compared with incidences of four ( 14 % ) and two ( 6 % ) for parecoxib sodium and placebo , respectively . Incidences of duodenal ulcers/erosions were 45 % ( n = 14 ) for ketorolac , 10 % ( n = 3 ) for parecoxib sodium , and none for placebo . The differences between ketorolac and both other treatment groups were statistically significant for both stomach and duodenum . No parecoxib sodium or placebo subjects had an ulcer or ≥11 erosions in the stomach , compared with eight ( 26 % ) ketorolac subjects ( p < 0.05 vs both parecoxib sodium and placebo ) . No subject in any group had ≥11 duodenal erosions . CONCLUSIONS : These results indicate that multiple dose administration of parecoxib sodium is safe and well tolerated in healthy elderly subjects , with a decreased risk of gastroduodenal mucosal injury compared with ketorolac Background : The gastrointestinal safety of the novel injectable cyclooxygenase-2 selective inhibitor , parecoxib sodium , was compared with the nonselective nonsteroidal anti-inflammatory drug , ketorolac , and placebo in healthy subjects . Study : In a multicenter , r and omized , double-blind , placebo-controlled design , 123 adults with endoscopically-confirmed normal upper gastrointestinal mucosae received parecoxib sodium 40 mg twice daily ( 7 days ) ; placebo ( 2 days ) followed by ketorolac 30 mg 4 times daily ( 5 days ) ; or placebo ( 7 days ) ( each group n = 41 ) . Posttreatment endoscopy scores were analyzed at 3 levels of severity : ulcers ( scores of 7 ) , ≥11 erosions/ulcers ( scores of 5–7 ) , and any erosions/ulcers ( scores of 3–7 ) . Results : No subjects treated with parecoxib sodium or placebo developed gastroduodenal ulcers or ≥11 erosions/ulcers . Parecoxib sodium was comparable to placebo with respect to the combined incidence of erosions/ulcers ( 12 % vs. 7 % , P = 0.419 ) . In contrast , in the ketorolac group , 11 ( 28 % ) subjects developed ulcers , 19 ( 48 % ) subjects developed ≥11 gastroduodenal erosions/ulcers , and the rate of combined ulcers/erosions was 85 % ( P < 0.001 vs. placebo and parecoxib sodium ) . Conclusions : Parecoxib sodium 40 mg twice daily for 7 days has a gastrointestinal safety profile superior to ketorolac 30 mg 4 times daily for 5 days , and comparable to placebo Abstract Variability in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size BACKGROUND : This multicenter , multiple-dose , r and omized , double-blind , parallel-group study compared the analgesic efficacy and safety of two dosing regimens of parecoxib sodium ( parecoxib ) versus placebo after total hip arthroplasty . METHODS : On study Day 1 , 490 patients received a postoperative initial loading dose of IV parecoxib 40 mg , followed by a re-dose of parecoxib 20 mg in 484 of 490 patients . Subsequently , 479 r and omized patients received double-blind treatment with parecoxib 20 mg bid ( n = 159 ) , parecoxib 20 mg qd ( n = 159 ) followed by placebo , or placebo ( n = 161 ) on Day 2 . RESULTS : Patients treated with parecoxib 20 mg bid reported significantly lower summed pain intensity over 24 h ( SPI-24 ) scores and improved patients ’ global evaluation of study medication ( PGESM ) ratings compared with placebo-treated patients on Days 2 to 5 ( P < 0.05 ) . For patients treated with parecoxib 20 mg qd , SPI-24 scores were significantly lower on Days 3 and 4 ( P < 0.05 ) , and PGESM ratings significantly improved on Day 5 compared with placebo . The incidence of adverse events was similar in all treatment groups with the exception of fever , vomiting and impaired concentration , which were significantly more common in the placebo group compared with one or other of the parecoxib treatment groups ( P < 0.05 ) . CONCLUSION : Multiple-day administration of parecoxib 20 mg once or twice daily is effective and generally well tolerated after total hip arthroplasty & NA ; There is uncertainty over whether the patient group in which acute pain studies are conducted ( pain model ) has any influence on the estimate of analgesic efficacy . Data from four recently up date d systematic review s of aspirin 600/650 mg , paracetamol 600/650 mg , paracetamol 1000 mg and ibuprofen 400 mg were used to investigate the influence of pain model . Area under the pain relief versus time curve equivalent to at least 50 % maximum pain relief over 6 h was used as the outcome measure . Event rates with treatment and placebo , and relative benefit ( RB ) and number needed to treat ( NNT ) were used as outputs from the meta‐analyses . The event rate with placebo was systematic ally statistically lower for dental than postsurgical pain for all four treatments . Event rates with analgesics , RB and NNT were infrequently different between the pain models . Systematic difference in the estimate of analgesic efficacy between dental and postsurgical pain models remains unproven , and , on balance , no major difference is likely Background : Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting . The authors conducted a r and omized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures . Methods : The trial was r and omized and double-blind , with 10 days of treatment and 30 days of follow-up . Patients ( n = 1,062 ) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout . The frequency of predefined adjudicated postr and omization adverse events , including cardiovascular thromboembolism , renal dysfunction , gastroduodenal ulceration , and wound-healing complications , was assessed in each group . Secondary efficacy endpoints included patients ' pain ratings , opioid analgesic consumption ( recorded as morphine equivalents ) , and reports of opioid-related adverse effects . Results : Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib ( 2.7 % ) and placebo patients ( 3.2 % ) ( P = 0.58 ) , including cardiovascular thromboembolic events ( 1.0 % in each group ; P = 1.0 ) . Placebo patients consumed more morphine equivalents ( 66.2 ± 92.4 mg ) than did patients receiving parecoxib and valdecoxib ( 43.2 ± 65.7 mg ) ( P < 0.001 ) . Placebo patients had higher mean pain ratings on each of study days 2–10 ( P < 0.01 ) and reported more opioid-related symptom distress on days 2–6 ( P < 0.01 ) . Conclusions : Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients . Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery BACKGROUND This multicentre , double-blind , placebo-controlled study compared the opioid-sparing effectiveness and clinical safety of parecoxib sodium over 48 h , in 195 postoperative patients after routine total knee replacement surgery . METHODS Elective total primary knee arthroplasty was performed under spinal anaesthesia , with a single dose of spinal bupivacaine 10 - 20 mg , and intraoperative sedation with midazolam 0.5 - 1.0 mg i.v . , or propofol < 6 mg kg(-1)h(-1 ) . Patients were r and omized to receive either parecoxib sodium 20 mg twice daily ( bd ) i.v . ( n=65 ) , parecoxib sodium 40 mg bd i.v . ( n=67 ) , or placebo ( n=63 ) at the completion of surgery , and after 12 , 24 , and 36 h. Morphine ( 1 - 2 mg ) was taken by patient-controlled analgesia or by bolus doses after 30 min . RESULTS Patients receiving parecoxib sodium 20 mg bd and 40 mg bd consumed 15.6 % and 27.8 % less morphine at 24 h than patients taking placebo ( both P<0.05 ) . Both doses of parecoxib sodium administered with morphine provided significantly greater pain relief than morphine alone from 6 h ( P<0.05 ) . A global evaluation of study medication demonstrated a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo . Parecoxib sodium administered in combination with morphine was well tolerated . However , a reduction in opioid-type side-effects was not demonstrated in the parecoxib sodium groups . CONCLUSION Parecoxib sodium provides opioid-sparing analgesic effects in postoperative patients Background Clinical trials suggest that cyclo-oxygenase-2 specific inhibitors ( coxibs ) are an effective treatment for acute postoperative pain . The aims of this systematic review were to examine the evidence for oral valdecoxib and injected parecoxib , and quantify efficacy and adverse effects . Methods Information from r and omized , double-blind studies in acute postoperative pain was sought . The area under the pain relief versus time curve over four to six hours was dichotomized using vali date d equations to derive the proportion of patients with treatment and placebo with at least 50 % pain relief over four to six hours and calculate the number-needed-to-treat ( NNT ) . Information on duration of analgesia and adverse events was also collected . Results The NNT for one patient to experience at least 50 % relief over six hours following a single oral dose of valdecoxib 20 mg and 40 mg was 1.7 ( 1.4 to 2.0 ) and 1.6 ( 1.4 to 1.8 ) respectively . The NNT for one patient to have at least 50 % relief over four to six hours with parecoxib 20 mg IV and 40 mg IV was 3.0 ( 2.3 to 4.1 ) and 2.3 ( 2.0 to 2.6 ) respectively . Mean time to remedication ( weighted by trial size ) was > 24 hours with valdecoxib 40 mg , 8.7 hours with parecoxib 40 mg IV and 1.7 to 1.8 hours with placebo . There were no statistical differences between treatment and placebo for any adverse effect . Conclusion Both oral valdecoxib and injected parecoxib are effective treatments for acute postoperative pain Background The analgesic efficacy and side effect profile of intravenous parecoxib , a novel cyclooxygenase type-2 ( COX-2 ) inhibitor , was assessed in a double-blinded , placebo-controlled study involving patients undergoing major gynecologic surgical procedures . Methods After Institutional Review Board approval , 60 consenting women , American Society of Anesthesiologists ( ASA ) physical status I – III , undergoing lower abdominal surgery with a st and ardized general anesthetic technique were r and omly assigned to receive one of three study medications : group 1 ( control ) received normal saline ; group 2 received intravenous parecoxib , 20 mg ; and group 3 received intravenous parecoxib , 40 mg . The initial dose of study medication was administered when the patient first requested pain medication after surgery . All patients had access to patient-controlled analgesia ( PCA ) with intravenous morphine , 1 or 2 mg , with a 6-min lockout period . Subsequent doses of the same study medication were administered at 12-h and 24-h intervals after the initial dose . The postoperative opioid analgesic requirement ( PCA morphine usage ) , pain scores , pain relief scores , side effects , and need for supplemental medications ( e.g. , antiemetics , antipruritics , laxatives ) were recorded . Results Compared with saline , intravenous parecoxib , 20 mg and 40 mg every 12 h , significantly decreased the PCA morphine usage during the first 6 h postoperatively ( group 1 , 25 ± 13 mg ; group 2 , 16 ± 11 mg ; group 3 , 17 ± 10 mg ) and at 12 h ( group 1 , 34 ± 18 mg ; group 2 , 24 ± 14 mg ; group 3 , 23 ± 13 mg ) and 24 h ( group 1 , 51 ± 27 mg ; group 2 , 34 ± 20 mg ; group 3 , 33 ± 21 mg ) after surgery . However , there were no significant differences in the patients ’ global evaluation of the study medications at 12 h and 24 h between those who received intravenous parecoxib ( 20 or 40 mg ) and saline . Moreover , the postoperative pain scores and side effect profiles were similar in the three treatment groups . Conclusion Intravenous parecoxib ( 20 or 40 mg ) was effective in decreasing the PCA opioid requirement after lower abdominal surgical procedures . However , it failed to improve pain management or reduce opioid-related side effects in the early postoperative period Objective To determine the analgesic efficacy of 1-day and multiple-day dosing regimens of parecoxib sodium ( parecoxib ) after bunionectomy in 2 r and omized placebo-controlled studies . Methods The first double-blind study assessed the efficacy of intravenous parecoxib 40 mg followed by an additional dose of parecoxib 20 mg , parecoxib 40 mg followed by placebo , or 2 placebo doses over 1 day . In the second study , all patients received parecoxib 40 mg and a second dose of 20 mg on day 1 . On days 2 and 3 , patients were r and omized to parecoxib 20 mg once daily and placebo once daily , parecoxib 20 mg twice daily , or placebo twice daily . Rescue medication ( hydrocodone 5 mg/acetaminophen 500 mg ) was available throughout both studies . Results In the single-day study , patients receiving parecoxib had significantly improved summed pain intensity difference through 24 hours , time-weighted sum of total pain relief through 24 hours , and Patient 's Global Evaluation of Study Medication ( PGESM ) scores compared with those given placebo . In the multiday study , patients given parecoxib had significantly improved summed pain intensity through 24 hours and PGESM scores compared with patients receiving placebo . The incidence of adverse events was lower in the parecoxib groups than in the placebo group on days 2 and 3 . Conclusions Parecoxib treatment , in conjunction with supplemental analgesia given as needed , provided effective pain relief over 1 to 3 days in the bunionectomy model of postoperative analgesia . Bunionectomy is a useful model for testing multiple-day analgesic therapy & NA ; Previous retrospective studies have suggested that patient demographics may influence analgesic administration . These studies have not taken physicians ’ impression of patient pain into account . This prospect i ve study investigates the influence of ( i ) physician impression of the degree of pain and ( ii ) patient demographics on the use of analgesic . A convenience sample of adults with non‐traumatic lower back pain was studied . Possible predictors of analgesic administration included physician pain scores ( assessed by visual analogue scale ) , patient ethnicity , gender , age , and insurance . These variables were tested individually and then using logistic regression . For the total of 91 patients enrolled , only physician pain scale was found to be associated with analgesic use . Median scores were 68 mm ( interquartile range=62–80 mm ) for those receiving treatment versus 48 mm ( interquartile range=30–58 mm ) for those who did not ( P<0.001 ) . This study therefore suggests that physician impression of patient pain rather than patient demographics influences analgesic use Study Design . A bicenter r and omized , patients , healthcare providers , and data collectors blind placebo-controlled trial in multimodal analgesia for postoperative lumbar spine surgery was conducted . Objective . To assess the efficacy and safety of parecoxib on postoperative pain management after posterior lumbar spine surgery . Summary of Background Data . Systematic review s suggest that cyclo-oxygenase-2 inhibitors are an effective treatment for acute postoperative pain . However , previous trials on lumbar spine surgery showed equivocal efficacy of cyclo-oxygenase-2 inhibitors for postoperative pain relief . Methods . In this study , 120 patients undergoing posterior lumbar discectomy , spinal decompression , or spinal fusion were stratified based on the surgical procedure to 3 groups ( n = 40 ) and r and omly allocated to receive multidoses of parecoxib 40 mg/dose or placebo . Efficacy was assessed by total morphine used from patient-controlled analgesic pump , pain intensity , pain relief , and the patient ’s subjective rating of the medication . Results . Parecoxib 40 mg reduced the total amount of morphine required over 48 hours by 39 % relative morphine reduction compared with placebo ( P = 0.0001 ) . Pain at rest was reduced by 30 % ( P = 0.0001 ) . Ninety percent of patients given parecoxib experienced at least 50 % maximum total pain relief compared with 58 % treated with placebo . The number-needed-to-treat for 1 patient to have at least half pain relief was 3.1 ( 2.0–4.6 ) . Patients ’ subjective rating of the medication was described as “ excellent , good , and fair ” by 48 % , 43 % , and 8 % in the parecoxib group , respectively , compared with 21 % , 50 % , and 28 % of placebo patients ( P = 0.004 ) . Overall adverse effects of patients receiving parecoxib and morphine were comparable to those receiving morphine alone . Conclusion . The present study demonstrates that the perioperative administration of parecoxib with patient-controlled analgesic morphine after lumber spine surgery result ed in significantly improved postoperative analgesic management as defined by reduction in opioid requirement , lower pain scores , and higher patients ’ subjective rating of the medication BACKGROUND Parecoxib sodium is an injectable cyclooxygenase-2-specific inhibitor developed for the treatment of acute pain . The analgesic efficacy of IV and IM parecoxib has been demonstrated in previous pilot studies using the post-oral surgery pain model . OBJECTIVE This study was conducted to characterize the analgesic efficacy of parecoxib in healthy adults after oral surgery while comparing the efficacy and tolerability of the IV and IM routes of administration . METHODS This was a double-blind , r and omized , parallel-group , placebo- and active-controlled , single-dose , single-center trial . Patients experiencing moderate to severe post-operative pain after the extraction of > or = 2 impacted third molars were r and omized to receive parecoxib sodium 20 mg IM , 20 mg IV , 40 mg IM , or 40 mg IV ; ketorolac tromethamine 60 mg IM ; or placebo . Patients assessed pain intensity and pain relief ( PR ) at baseline and at design ated intervals for 24 hours after administration of study medication or until rescue medication was taken . Analgesic efficacy was assessed in terms of time-specific pain intensity difference ( PID ) and PR , time to onset of analgesia , and time to use of rescue medication . RESULTS Three hundred four patients were r and omized to treatment . Parecoxib sodium 20 and 40 mg IM or IV and ketorolac 60 mg IM were significantly superior to placebo in PID , PR , time to onset of analgesia , and time to use of rescue medication ( P < or = 0.05 ) . Equal IV and IM doses of parecoxib were comparable on these measures ; however , time to use of rescue medication was longer with IM compared with IV administration . Both doses of parecoxib were comparable to ketorolac 60 mg IM in time to onset of analgesia , but parecoxib 40 mg had a significantly longer duration of action ( P < or = 0.05 ) . The few statistically significant differences in PID and PR between parecoxib 40 mg and ketorolac favored ketorolac versus parecoxib 40 mg IV at earlier time points and parecoxib 40 mg IM versus ketorolac at later time points ( P < or = 0.05 ) . All treatments were well tolerated . CONCLUSIONS Parecoxib IV and IM provided effective analgesia . The 40-mg dose was comparable to ketorolac 60 mg on most measures of analgesia but had a longer duration of action Abstract A previously established relationship for deriving dichotomous from continuous information in r and omised controlled trials ( RCTs ) of analgesics has been tested using an independent data set . Individual patient information from 18 RCTs of parallel‐group design in acute postoperative pain ( after abdominal , gynaecological and oral surgery ) was used to calculate the percentage of the maximum possible pain relief score ( % maxTOTPAR ) and the proportion of patients with > 50%maxTOTPAR for the different treatments . The relationship between the measures was investigated in 85 treatments with over 3400 patients . In 80 of 85 treatments ( 94 % ) agreement between calculated and actual number of patients with > 50%maxTOTPAR was within four patients per treatment and in 72 ( 85 % ) was within three ( average of 40 patients per treatment , range 21–58 patients ) . Summing the positive and negative differences between actual and calculated numbers of patients with > 50%maxTOTPAR gave an average difference of 0.30 patients per treatment arm . Reports of RCTs of analgesics frequently describe results of studies in the form of mean derived indices , rather than using discontinuous events , such as number or proportion of patients with 50 % pain relief . Because mean data inadequately describe information with a non‐normal distribution , combining mean data in systematic review s may compromise the results . Showing that dichotomous data can reliably be derived from mean data in acute pain studies enables data published as means to be used for quantitative systematic review s which require data in dichotomous form We assessed the quality of assessment and reporting of adverse effects in r and omized , double-blind clinical trials of single-dose acetaminophen or ibuprofen compared with placebo in moderate to severe postoperative pain . Reports were identified by systematic search ing of a number of bibliographic data bases ( e.g. , MEDLINE ) . Information on adverse effect assessment , severity and reporting , patient withdrawals , and anesthetic used was extracted . Compliance with former guidelines for adverse effect reporting was noted . Fifty-two studies were included ; two made no mention of adverse effects . No method of assessment was given in 19 studies . Twenty trials failed to report the type of anesthetic used , eight made no mention of patient withdrawals , and nine did not state the severity of reported adverse effects . Only two studies described the method of assessment of adverse effect severity . When all adverse effect data were pooled , significantly more adverse effects were reported with active treatment than with placebo . For individual adverse effects , there was no difference between active ( acetaminophen 1000 mg or ibuprofen 400 mg ) and placebo ; the exception was significantly more somnolence/drowsiness with ibuprofen 400 mg . Ninety percent of trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain . All studies published after 1994 complied with former guidelines for adverse effect reporting . Different methods of assessing adverse effects produce different reported incidence : patient diaries yielded significantly more adverse effects than other forms of assessment . We recommend guidelines for reporting adverse effect information in clinical trials BACKGROUND The parenteral cyclo-oxygenase , or COX , -2 selective inhibitor parecoxib sodium in a 40-milligram dose for intravenous/intramuscular , or i.v./i.m . , administration is approved for postoperative pain in Europe , but not yet in the United States . However , previous trials in dental surgical patients have indicated that lower doses may be as effective . METHODS The authors enrolled 353 patients in a single-center , double-blind , placebo-controlled , dose-ranging study to compare the efficacy and tolerability of single i.m . doses of parecoxib ( 1 - 20 mg ) with ketorolac tromethamine 30 mg i.m . after dental surgery . Pain assessment s occurred at baseline and through 24 hours postdose . RESULTS A 20-mg dose of parecoxib was significantly more effective than were 1-mg to 10-mg doses and than placebo . The analgesic onset of a 20-mg dose of parecoxib was similar to that of a 30-mg dose of ketorolac . The magnitude of analgesia with a 20-mg dose of parecoxib was significantly lower than that with ketorolac , according to the mean pain intensity difference , or PID , scores from one and one-half to four hours postdose or summed PID , or SPID , -categorical scores at six hours postdose . However , there was no significant difference in mean pain relief ; total pain relief , or TOTPAR ; and SPID-visual analog scale , or VAS , scores six hours postdose . Mean PID scores for parecoxib 20 mg from 12 to 24 hours postdose were significantly higher than and SPID-VAS mean scores were not statistically significantly different from eight hours onward . CONCLUSIONS Parecoxib 20 mg i.m . is an effective analgesic dose with an onset and magnitude of analgesic effect approaching that of ketorolac 30 mg i.m . after dental surgery . It also is well-tolerated . CLINICAL IMPLICATION S These findings support the use of parecoxib 20 mg i.m . as an initial dosing option for postoperative pain management in countries in which it is approved & NA ; Reports of RCTs of analgesics frequently describe results of studies in the form of mean derived indices , rather than using discontinuous events — such as number or proportion of patients with 50 % pain relief . Because mean data inadequately describe information with a non‐normal distribution , combining mean data in systematic review s may compromise the results . Showing that dichotomous data can reliably be derived from mean data , at least in acute pain models , indicates that more meaningful overviews or meta‐ analysis may be possible . This study investigated the relationship between continuous and dichotomous analgesic measures in a set of individual patient data , and then used that relationship to derive dichotomous from continuous information in r and omised controlled trials ( RCTs ) of analgesics . Individual patient information from 13 RCTs of parallel‐group and crossover design in acute postoperative pain was used to calculate the percentage of the maximum possible pain relief score ( % maxTOTPAR ) and the proportion of patients with greater than 50 % pain relief ( > 50%maxTOTPAR ) for the different treatments . The relationship between the measures was investigated in 45 actual treatments and 10 000 treatments simulated using the underlying actual distribution ; 1283 patients had 45 separate treatments . Mean % maxTOTPAR correlated with the proportion of patients with > 50%maxTOTPAR ( r2 = 0.90 ) . The relationship calculated from all the 45 treatments predicted to within three patients the number of patients with more than 50 % pain relief in 42 of 45 treatments , and 98.8 % of 10 000 simulated treatments . For seven effective treatments , actual numbers‐needed‐to‐treat ( NNT ) to achieve > 50%maxTOTPAR compared with placebo were very similar to those derived from calculated data OBJECTIVE The purpose of this study was to compare the analgesic activity of 2 doses of parecoxib sodium , ketorolac , and morphine with placebo after gynecologic surgery that requires laparotomy . STUDY DESIGN In a r and omized , controlled , double-blind , parallel-group study , 208 patients , after surgical hysterectomy , received single-dose intravenous placebo , parecoxib sodium 20 mg or 40 mg , ketorolac 30 mg , or morphine 4 mg followed by multiple-dose parecoxib sodium or ketorolac as needed . Primary efficacy variables were time to onset of analgesia , pain intensity differences , pain relief , time to first rescue/remedication , and global evaluation of study medication . RESULTS Single-dose parecoxib sodium 40 mg provided significantly better pain responses to placebo or morphine 4 mg and was comparable to ketorolac 30 mg . Multiple-dose parecoxib sodium 20 mg , 4 times daily , or 40 mg , twice daily , was comparable to ketorolac 30 mg , 4 times daily . Parecoxib sodium was well tolerated . CONCLUSION Parecoxib sodium is an effective analgesic in the management of acute postoperative pain after laparotomy surgery PURPOSE Our goal was to compare the analgesic efficacy and safety of single doses of intravenous parecoxib sodium , a prodrug of the novel cyclooxygenase (COX)-2-selective inhibitor valdecoxib , with intravenous ketorolac and placebo in postoperative oral surgery patients . PATIENTS AND METHODS Eligible patients experiencing moderate to severe pain within 6 hours of surgery to extract 2 or more impacted third molars were r and omized to receive a single dose of parecoxib sodium 1 , 2 , 5 , 10 , 20 , 50 , or 100 mg ; ketorolac 30 mg ; or placebo . Analgesic efficacy was assessed over a 24-hour treatment period or until rescue analgesia was required . RESULTS Parecoxib sodium doses ( particularly 50 and 100 mg ) had a rapid onset of analgesia ( within 11 minutes ) . The analgesic efficacy of parecoxib sodium 20 to 100 mg was similar to that of ketorolac 30 mg . Parecoxib sodium doses below 20 mg had suboptimal analgesic activity compared with placebo and ketorolac . A plateau of efficacy was observed at the parecoxib sodium 50-mg dose . Parecoxib sodium 50 and 100 mg had a significantly longer duration of analgesia than ketorolac 30 mg . All doses of parecoxib sodium were well tolerated . CONCLUSIONS Parecoxib sodium , a novel parenteral prodrug of the COX-2-selective inhibitor valdecoxib , is as effective and longer acting at 50- and 100-mg intravenous doses than a st and ard dose of ketorolac 30 mg intravenously . Parecoxib sodium appears to be safe and well tolerated and , therefore , merits further evaluation in other models of postsurgical pain Background A recent article in the New Scientist argued that women were under-represented in clinical trials which , until now , had masked the finding that ibuprofen 400 mg was ineffective in women . Methods Meta- analysis of r and omised , double-blind placebo-controlled trials of ibuprofen 400 mg in acute pain , and use of individual patient information were planned to test the hypothesis that ibuprofen is ineffective in women . For each trial the proportion of women participating , the number of patients with at least 50 % pain relief and the overall event rate for ibuprofen 400 mg and placebo was calculated . For each patient percentage pain relief was calculated , and the numbers of women and men achieving at least 50 % pain relief used to calculate number-needed-to-treat ( NNT ) for ibuprofen 400 mg compared to placebo . Results Thirty-seven included trials had 3,577 patients , 67 % of whom were women . The proportion with at least 50 % pain relief was unaffected by how many women were included . In an analysis of 678 individual patients the proportion of women and men with at least 50 % pain relief was the same , NNT 3.4 ( 2.6 to 4.6 ) and 2.5 ( 2.0 to 3.3 ) respectively . Conclusion There is no clinical ly meaningful difference in the efficacy of ibuprofen 400 mg between men and women experiencing moderate to severe postoperative pain and women were well represented BACKGROUND Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting ( CABG ) . We conducted a r and omized trial to assess the safety of these drugs after CABG . METHODS In this r and omized , double-blind study involving 10 days of treatment and 30 days of follow-up , 1671 patients were r and omly assigned to receive intravenous parecoxib for at least 3 days , followed by oral valdecoxib through day 10 ; intravenous placebo followed by oral valdecoxib ; or placebo for 10 days . All patients had access to st and ard opioid medications . The primary end point was the frequency of predefined adverse events , including cardiovascular events , renal failure or dysfunction , gastroduodenal ulceration , and wound-healing complications . RESULTS As compared with the group given placebo alone , both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event ( 7.4 percent in each of these two groups vs. 4.0 percent in the placebo group ; risk ratio for each comparison , 1.9 ; 95 percent confidence interval , 1.1 to 3.2 ; P=0.02 for each comparison with the placebo group ) . In particular , cardiovascular events ( including myocardial infa rct ion , cardiac arrest , stroke , and pulmonary embolism ) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo ( 2.0 percent vs. 0.5 percent ; risk ratio , 3.7 ; 95 percent confidence interval , 1.0 to 13.5 ; P=0.03 ) . CONCLUSIONS The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events , arousing serious concern about the use of these drugs in such circumstances Parecoxib sodium , the injectable prodrug of valdecoxib , is a cyclooxygenase-2-specific inhibitor that is effective in the treatment of postoperative pain . In this r and omized , double-blind , placebo-controlled study , we compared the efficacy of a single dose of parecoxib sodium 40 mg IM with single doses of morphine 6 and 12 mg IM in treating postoperative pain after gynecologic surgery requiring a laparotomy incision . By nearly all efficacy measures ( including total pain relief and patient 's global evaluation of study medication ) , parecoxib sodium 40 mg IM demonstrated pain relief and a decrease in pain intensity that was statistically similar to that with morphine 12 mg IM and superior to that with morphine 6 mg IM . Parecoxib sodium 40 mg IM-treated patients also demonstrated a longer time to use of rescue medication than patients treated with both morphine doses , and this dose provided sustained pain relief over the 12-h study period . The incidence of adverse events in the active treatment groups was similar to that observed with placebo . Parecoxib sodium , 40 mg IM , has been shown to be as effective as clinical ly relevant doses of morphine in patients after gynecologic laparotomy surgery & NA ; A data base of r and omised clinical trials ( RCTs ) in pain research published from 1950 to 1990 was created following an extensive literature search . By applying a refined MEDLINE search strategy from 1966 to 1990 and by h and ‐ search ing more than 1 000 000 pages of a total of 40 biomedical journals published during the period 1950–1990 , more than 8000 RCTs were identified . The RCTs were published in more than 800 journals and over 85 % appeared between 1976 and 1990 . If the trend of the last 15 years persists , a total of more than 15 000 RCTs will be published in pain relief by the year 2000 . A detailed description of methods to ensure efficient use of re sources during the identification , retrieval and management of the information in pain relief and other fields is given . Emphasis is made on the importance of refining MEDLINE search strategies , on the use of volunteers to h and ‐ search journals and on careful monitoring of each of the steps of the process . The potential uses of the data base to guide clinical and research decisions are discussed BACKGROUND Based on a PubMed search of the literature using the terms parecoxib , platelets , thromboxane , bleeding , and platelet aggregation , the effects of parecoxib on platelet function have not fully been established under clinical conditions . OBJECTIVE The aim of this study was to determine platelet aggregation , thromboxane B(2 ) ( TxB(2 ) ) formation , and plasma concentrations with the use of parecoxib in postoperative pain management . METHODS This double-blind , r and omized , parallel-group trial was conducted at the University Hospital for Orthopedic Surgery , Friedrichsheim , Frankfurt , Germany . Male and female patients aged 18 to 55 years and scheduled to undergo routine partial meniscectomy ( or a similar arthroscopic procedure ) were eligible . All patients received dose-adjusted enoxaparin before surgery and parecoxib 40 mg BID or dipyrone 1000 mg QID . Blood sample s were drawn before first injection ( predose ) and at 0.5 , 2 , and 6 hours after injection . Platelet aggregation ( expressed as percentage of the maximal light transmittance [ A(max ) ] ) was induced with arachidonic acid ( A(max)AA ) and collagen ( A(max)CO ) . TxB(2 ) formation was determined using enzyme-linked immunosorbent assay . RESULTS This study included 26 patients . In both treatment groups , 8 males and 5 females , all white , were enrolled . In the dipyrone group , the mean age was 48 years ( range , 32 - 61 years ) and the mean weight was 85 kg ( range , 63 - 122 kg ) ; in the parecoxib group , the mean age was 47 years ( range , 31 - 61 years ) and the mean weight was 81 kg ( range , 57 - 100 kg ) . Median ( interquartile range [ IQR ] ) predose values for A(max)AA were 76 % ( 65%-83 % ) in the parecoxib group and 87 % ( 80%-89 % ) in the dipyrone group . At 0.5 hour after injection , A(max)AA was 52 % ( 5%-77 % ) with parecoxib and 8 % ( 0%-11 % ) with dipyrone ( P=0.004 ) . At 2 hours after injection , A(max)AA was 78 % ( 72%-80 % ) in the parecoxib group versus 7 % ( 5%-11 % ) in the dipyrone group ( P<0.001 ) . At 6 hours after study drug administration , no treatment differences were found . For A(max)CO , no statistically significant differences were found . Consistent with the stronger inhibition of aggregation , patients who received dipyrone had lower TxB(2 ) formation values . Six hours after parecoxib administration , mean TxB(2 ) formation was significantly enhanced compared with predose values ( 132 ng/mL [ IQR , 62 - 228 ng/mL ] vs 185 ng/mL [ IQR , 135 - 239 ng/mL ] ; P=0.05 ) . CONCLUSIONS Platelet aggregation and TxB(2 ) formation were significantly lower for 6 hours in dipyronetreated patients compared with parecoxib-treated patients . In contrast , TxB(2 ) formation was increased with parecoxib 6 hours after administration compared with pretreatment values . In this small study , parecoxib did not affect platelet aggregation in a population of patients undergoing routine partial meniscectomy ( or a similar arthroscopic procedure ) under clinical conditions Background This study tested the hypothesis that an injectable cyclooxygenase (COX)-2–specific inhibitor will be at least as effective and well tolerated as a COX-nonspecific conventional nonsteroidal antiinflammatory drug ( NSAID ) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium , an injectable prodrug of the novel COX-2–specific inhibitor , valdecoxib , with ketorolac and placebo in postoperative laparotomy surgery patients . Intravenous morphine , 4 mg , was studied as a positive analgesic control . Methods In this multicenter , double-blinded , placebo-controlled study , women experiencing moderate-to-severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium , 20 or 40 mg , ketorolac , 30 mg , morphine , 4 mg , or placebo . Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients , whose pain was not adequately controlled , opted to receive rescue analgesia . Results Two hundred two patients were enrolled . All treatment groups had comparable demographics and baseline pain status . All active treatments had an equally rapid time to onset of analgesia ( 10–23 min ) . Overall , each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points , including a significantly longer ( two- to threefold ) time to rescue analgesia ( P ≤ 0.05 ) . All treatments were well tolerated . Conclusions Single intravenous doses of parecoxib sodium , 20 mg and 40 mg , have comparable analgesic effects and are well tolerated after laparotomy surgery . Parecoxib sodium appears to be as effective as intravenous ketorolac , 30 mg , and superior to intravenous morphine , 4 mg Abstract One way to ensure adequate sensitivity for analgesic trials is to test the intervention on patients who have established pain of moderate to severe intensity . The usual criterion is at least moderate pain on a categorical pain intensity scale . When visual analogue scales ( VAS ) are the only pain measure in trials we need to know what point on a VAS represents moderate pain , so that these trials can be included in meta‐ analysis when baseline pain of at least moderate intensity is an inclusion criterion . To investigate this we used individual patient data from 1080 patients from r and omised controlled trials of various analgesics . Baseline pain was measured using a 4‐point categorical pain intensity scale and a pain intensity VAS under identical conditions . The distribution of the VAS scores was examined for 736 patients reporting moderate pain and for 344 reporting severe pain . The VAS scores corresponding to moderate or severe pain were also examined by gender . Baseline VAS scores recorded by patients reporting moderate pain were significantly different from those of patients reporting severe pain . Of the patients reporting moderate pain 85 % scored over 30 mm on the corresponding VAS , with a mean score of 49 mm . For those reporting severe pain 85 % scored over 54 mm with a mean score of 75 mm . There was no difference between the corresponding VAS scores of men and women . Our results indicate that if a patient records a baseline VAS score in excess of 30 mm they would probably have recorded at least moderate pain on a 4‐point categorical scale OBJECTIVE Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients . We prospect ively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a r and omized clinical trial . METHODS A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States , Canada , Germany , and the United Kingdom participated in this multicenter , phase III , placebo-controlled , double-blind , r and omized , parallel-group trial . Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or st and ard care ( control ) groups , respectively . Intravenous study drug ( 40 mg ) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days . Subsequently , oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days . Patient-controlled analgesia with morphine , oral opioids , or acetaminophen was available as required . Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use . Additional efficacy evaluations included daily pain intensity , patient and physician global evaluation of study medication , and pain effect on quality of life . Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period . RESULTS Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour ( P = .009 ) , 24- to 48-hour ( P = .017 ) , 72- to 96-hour ( P = .002 ) , 96- to 120-hour ( P = .004 ) , and 120- to 144-hour ( P = .037 ) periods . Both patients ( P < .001 ) and physicians ( P < .001 ) evaluated the study medication as significantly better than control therapy . The modified Brief Pain Inventory question naire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested ( eg , current pain , worst pain , and mood ) beginning on day 4 and continuing for at least 4 days . Although there were no differences between the groups in overall adverse events , serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients ( 19.0 % , 59/311 patients ) than in control patients ( 9.9 % , 15/151 patients ; P = .015 ) . Regarding individual serious adverse events , a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients ( 10 [ 3.2 % ] ) versus control patients ( 0 [ 0 % ] ) ( P = .035 ) . The incidences of other individual serious adverse events , including cerebrovascular complications , myocardial infa rct ion , and renal dysfunction , were proportionally greater but not significantly different between the groups . CONCLUSIONS In patients undergoing coronary artery bypass grafting surgery , the cyclooxygenase 2 inhibitor combination , parecoxib/valdecoxib , was effective for postoperative analgesia . However , the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular . Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery Our objective in a r and omized , multicenter , double-blind , parallel-group , placebo- and active-controlled study was to evaluate and compare the analgesic effectiveness of single intravenous ( IV ) doses of parecoxib sodium 20 and 40 mg , morphine 4 mg , and ketorolac 30 mg in the postsurgical orthopedic pain model . After undergoing unilateral total knee replacement surgery , 208 healthy adult patients were r and omized to receive placebo or a study drug within 6 hours of discontinuation of patient-controlled analgesia on postoperative day 1 . Onset of analgesia was similarly rapid with IV parecoxib sodium 40 mg , morphine , and ketorolac . Level and duration of analgesia were significantly superior with parecoxib sodium than with morphine and were similar for parecoxib sodium and ketorolac . Parecoxib sodium was safe and well tolerated . In conclusion , IV parecoxib sodium 40 mg is as effective as ketorolac 30 mg and is more effective than morphine 4 mg and therefore has potential widespread utility in acute postoperative pain management

In general , annual citation rate appeared to gradually increase during the first 2 - 3 years after publication before reaching high levels . However , areas such as quality of life , side effects , and end-of-life care were underrepresented .

High and continuously increasing research activity related to different aspects of pathogenesis , epidemiology , diagnosis and treatment of glioblastoma has been performed between 2006 and 2010 . Different measures of impact , visibility and quality of published research are available , each with its own pros and cons .

PURPOSE Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma ( GBM ) by increasing the therapeutic index , overcoming common mechanisms of temozolomide resistance , or both . The goal of this r and omized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM . PATIENTS AND METHODS Adult patients with newly diagnosed GBM were r and omly assigned to receive st and ard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense ( 150 mg/m(2 ) days 1 to 7 and 15 to 21 ) or metronomic ( 50 mg/m(2 ) continuous daily ) temozolomide . Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression . The primary end point was overall survival ( OS ) at 1 year . Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . RESULTS Eighty-five eligible patients were enrolled ; 42 were r and omly assigned to dose-dense and 43 to metronomic temozolomide . The 1-year survival rate was 80 % for the dose-dense arm and 69 % for the metronomic arm ; median OS was 17.1 months ( 95 % CI , 14.0 to 28.1 months ) and 15.1 months ( 95 % CI , 12.3 to 18.9 months ) , respectively . The most common toxicities were myelosuppression ( leukopenia , neutropenia , and thrombocytopenia ) and elevated liver enzymes . Pseudoprogression was observed in 37 % of assessable patients and may have had an impact on estimates of progression-free survival ( 6.6 months in the dose-dense arm and 5.0 months in the metronomic arm ) . CONCLUSION Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity . The dose-dense regimen appears promising , with 1-year survival of 80 % PURPOSE Approximately 50 % of glioblastomas ( GBMs ) are characterized by overexpression of the epidermal growth factor receptor ( EGFR ) and EGFR gene amplification . In approximately 25 % of instances , constitutively activated EGFR mutants are present . These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM . PATIENTS AND METHODS In a r and omized , controlled , phase II trial , 110 patients with progressive GBM after prior radiotherapy were r and omly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine ( BCNU ) . The primary end point was 6-month progression-free survival ( PFS ) . Tumor specimens obtained at first surgery were investigated for EGFR expression ; EGFRvIII mutants ; EGFR amplification ; EGFR mutations in exons 18 , 19 , and 21 ; and pAkt . These results were correlated with outcome . Pharmacokinetic analysis was part of the study . RESULTS ; Treatment was well tolerated in general ; skin toxicity was the most frequent adverse effect of erlotinib . The 6-month PFS rate in the erlotinib arm was 11.4 % ( 95 % CI , 4.6 % to 21.5 % ) , and it was 24 % in the control arm . Of all explored biomarkers , only low pAkt expression appeared to be of borderline significance to an improved outcome . None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS . The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance , but pharmacokinetic findings were not related to outcome . CONCLUSION Erlotinib has insufficient single-agent activity in unselected GBM . No clear biomarker associated with improved outcome to erlotinib was identified BACKGROUND In this r and omized phase III study , the effectiveness as well as the side-effects of intraarterial [ i.a . ] ( 17 patients ) versus intravenous [ i.v . ] ( 16 patients ) ACNU [ Nimustine ] administration in newly diagnosed glioblastoma , were compared . PATIENTS AND METHODS All patients undenwent extensive surgical resection , and both groups were homogeneous for the other known risk factors . Thirty-three patients with glioblastoma were treated with ACNU at the dose of 80 - 100 mg/m2 . Treatment was repeated every 5 - 8 weeks for a minimum of 2 and maximum of 14 cycles . Total survival time ( TST ) and to time to progression were chosen as outcome variables . RESULTS AND CONCLUSION No significant differences in systemic and hematological toxicity between the i.a . and iv . ACNU administration routes were detected . In both groups , tolerance of the procedure was excellent . Analysis of the main outcome measured showed no significant differences between i.a . and i.v . ACNU administration : time to progression was 6 months for i.a . ACNU and 4 months for i.v . ACNU and total survival time was 17 months for i.a . ACNU and 20 months for i.v . ACNU . In spite of ACNU dose incrementation , obtained through i.a . route administration , and subsequent higher concentration in the tumor bed , no improvement could be achieved in effectiveness Using MRI techniques , we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset , is prolonged but reversible , and has the significant clinical benefit of alleviating edema . Reversal of normalization began by 28 days , though some features persisted for as long as four months . Basic FGF , SDF1alpha , and viable circulating endothelial cells ( CECs ) increased when tumors escaped treatment , and circulating progenitor cells ( CPCs ) increased when tumors progressed after drug interruption . Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor Summary Purpose Because raised matrix metalloprotease ( MMP ) levels are associated with glioma invasion and angiogenesis , we tested the efficacy of marimastat ( MT ) an orally active drug that can reduce MMP levels , in patients with gliomas . Patients and Methods A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter , double-blind , placebo-controlled , parallel group study conducted at 20 institutions . Seventy-nine patients ( 57 male , 22 female , median age 58 years ) were r and omized to receive placebo ( PB ) , and 83 patients ( 51 male , 32 female , median age 57 years ) were r and omized to receive MT , 10 mg orally twice daily , until tumor progression . Results This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival ( P=0.38 , log rank test ) . The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group , with a hazard ratio of 1.16 ( 95 % CI 0.83 to 1.60 ) . There were no statistically significant differences in quality of life between the PB and MT groups , as assessed by the FACT-BR question naire . Musculoskeletal toxicities led to dose modification or withdrawal in 20 % of MT-treated and 1.2 % of PB-treated patients . Conclusion MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy . Therefore , single-agent MT appears unwarranted ; however , MT in combination with cytotoxic chemotherapy may be warranted , as suggested by observations in our study and other studies PURPOSE This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma ( WHO grade 4 ) . PATIENTS AND METHODS Patients were r and omly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d ( 1,125-mg loading dose , day 1 ) or lomustine ( 100 to 130 mg/m(2 ) , day 1 ) . Assuming a 45 % improvement in progression-free survival ( PFS ) , 397 patients were required to provide 80 % power to achieve statistical significance at a one-sided level of .025 . RESULTS Enrollment was terminated at 266 patients ( enzastaurin , n = 174 ; lomustine , n = 92 ) after a planned interim analysis for futility . Patient characteristics were balanced between arms . Median PFS ( 1.5 v 1.6 months ; hazard ratio [ HR ] = 1.28 ; 95 % CI , 0.97 to 1.70 ) , overall survival ( 6.6 v 7.1 months ; HR = 1.20 ; 95 % CI , 0.88 to 1.65 ) , and 6-month PFS rate ( P = .13 ) did not differ significantly between enzastaurin and lomustine , respectively . Stable disease occurred in 38.5 % and 35.9 % of patients and objective response occurred in 2.9 % and 4.3 % of patients , respectively . Time to deterioration of physical and functional well-being and symptoms did not differ between arms ( HR = 1.12 ; P = .54 ) . Four patients discontinued enzastaurin because of drug-related serious adverse events ( AEs ) . Eleven patients treated with enzastaurin died on study ( four because of AEs ; one was drug-related ) . All four deaths that occurred in patients receiving lomustine were disease-related . Grade 3 to 4 hematologic toxicities were significantly higher with lomustine ( 46 events ) than with enzastaurin ( one event ; P < or = .001 ) . CONCLUSION Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma CONTEXT The relative merits of various study design s and their placement in hierarchies of evidence are often discussed . However , there is limited knowledge about the relative citation impact of articles using various study design s. OBJECTIVE To determine whether the type of study design affects the rate of citation in subsequent articles . DESIGN AND SETTING We measured the citation impact of articles using various study design s -- including meta-analyses , r and omized controlled trials , cohort studies , case-control studies , case reports , non systematic review s , and decision analysis or cost-effectiveness analysis --published in 1991 and in 2001 for a sample of 2646 articles . MAIN OUTCOME MEASURE The citation count through the end of the second year after the year of publication and the total received citations . RESULTS Meta-analyses received more citations than any other study design both in 1991 ( P<.05 for all comparisons ) and in 2001 ( P<.001 for all comparisons ) and both in the first 2 years and in the longer term . More than 10 citations in the first 2 years were received by 32.4 % of meta-analyses published in 1991 and 43.6 % of meta-analyses published in 2001 . R and omized controlled trials did not differ significantly from epidemiological studies and non systematic review articles in 1991 but clearly became the second-cited study design in 2001 . Epidemiological studies , non systematic review articles , and decision and cost-effectiveness analyses had relatively similar impact ; case reports received negligible citations . Meta-analyses were cited significantly more often than all other design s after adjusting for year of publication , high journal impact factor , and country of origin . When limited to studies addressing treatment effects , meta-analyses received more citations than r and omized trials . CONCLUSION Overall , the citation impact of various study design s is commensurate with most proposed hierarchies of evidence PURPOSE To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma . PATIENTS AND METHODS Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks . After tumor progression , patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2 ) or 125 mg/m(2 ) every 2 weeks , depending on use of enzyme-inducing antiepileptic drugs . Complete patient evaluations were repeated every 4 weeks . RESULTS Forty-eight heavily pretreated patients were accrued to this study . Thromboembolic events ( 12.5 % ) , hypertension ( 12.5 % ) , hypophosphatemia ( 6 % ) , and thrombocytopenia ( 6 % ) were the most common drug-associated adverse events . Six patients ( 12.5 % ) were removed from study for drug-associated toxicity ( five thromboembolic events , one bowel perforation ) . Thirty-four patients ( 71 % ) and 17 patients ( 35 % ) achieved radiographic response based on Levin and Macdonald criteria , respectively . Median progression-free survival ( PFS ) was 16 weeks ( 95 % CI , 12 to 26 weeks ) . The 6-month PFS was 29 % ( 95 % CI , 18 % to 48 % ) . The 6-month overall survival was 57 % ( 95 % CI , 44 % to 75 % ) . Median overall survival was 31 weeks ( 95 % CI , 21 to 54 weeks ) . Early magnetic resonance imaging response ( first 96 hours and 4 weeks ) was predictive of long-term PFS , with the Levin criteria being more predictive than Macdonald criteria . Of 19 patients treated with bevacizumab plus irinotecan at progression , there were no objective radiographic responses . Eighteen patients ( 95 % ) experienced disease progression by the second cycle , and the median PFS was 30 days . CONCLUSION We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma PURPOSE In patients with newly diagnosed glioblastoma multiforme , to determine whether cisplatin plus carmustine ( BCNU ) administered before and concurrently with radiation therapy ( RT ) improves survival compared with BCNU and RT and whether survival using accelerated RT ( ART ) is equivalent to survival using st and ard RT ( SRT ) . PATIENTS AND METHODS After surgery , patients were stratified by age , performance score , extent of surgical resection , and histology ( glioblastoma v gliosarcoma ) and then r and omly assigned to arm A ( BCNU plus SRT ) , arm B ( BCNU plus ART ) , arm C ( cisplatin plus BCNU plus SRT ) , or arm D ( cisplatin plus BCNU plus ART ) . RESULTS Four hundred fifty-one patients were r and omly assigned , and 401 were eligible . Frequent toxicities included myelosuppression , vomiting , sensory neuropathy , and ototoxicity and were worse with cisplatin . There was no difference in toxicity between SRT and ART . Median survival times and 2-year survival rates for patients who received BCNU plus RT ( arms A and B ) compared with cisplatin , BCNU , and RT ( arms C and D ) were 10.1 v 11.5 months , respectively , and 11.5 % v 13.7 % , respectively ( P = .19 ) . Median survival times and 2-year survival rates for patients who received SRT ( arms A and C ) compared with ART ( arms B and D ) were 11.2 v 10.5 months , respectively , and 13.8 % v 11.4 % , respectively ( P = .33 ) . CONCLUSION Cisplatin administered concurrently with BCNU and RT result ed in more toxicity but provided no significant improvement in survival . SRT and ART produced similar toxicity and survival Convection-enhanced delivery ( CED ) of cintredekin besudotox ( CB ) was compared with Gliadel wafers ( GW ) in adult patients with glioblastoma multiforme ( GBM ) at first recurrence . Patients were r and omized 2:1 to receive CB or GW . CB ( 0.5 microg/mL ; total flow rate 0.75 mL/h ) was administered over 96 hours via 2 - 4 intraparenchymal catheters placed after tumor resection . GW ( 3.85%/7.7 mg carmustine per wafer ; maximum 8 wafers ) were placed immediately after tumor resection . The primary endpoint was overall survival from the time of r and omization . Prestated interim analyses were built into the study design . Secondary and tertiary endpoints were safety and health-related quality -of-life assessment s. From March 2004 to December 2005 , 296 patients were enrolled at 52 centers . Demographic and baseline characteristics were balanced between the 2 treatment arms . Median survival was 36.4 weeks ( 9.1 months ) for CB and 35.3 weeks ( 8.8 months ) for GW ( P = .476 ) . For the efficacy evaluable population , the median survival was 45.3 weeks ( 11.3 months ) for CB and 39.8 weeks ( 10 months ) for GW ( P = .310 ) . The adverse-events profile was similar in both arms , except that pulmonary embolism was higher in the CB arm ( 8 % vs 1 % , P = .014 ) . This is the first r and omized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients . There was no survival difference between CB administered via CED and GW . Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics PURPOSE The prognosis for patients with recurrent glioblastoma multiforme is poor , with a median survival of 3 to 6 months . We performed a phase II trial of bevacizumab , a monoclonal antibody to vascular endothelial growth factor , in combination with irinotecan . PATIENTS AND METHODS This phase II trial included two cohorts of patients . The initial cohort , comprising 23 patients , received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks . The dose of irinotecan was based on the patient 's anticonvulsant : Patients taking enzyme-inducing antiepileptic drugs ( EIAEDs ) received 340 mg/m2 , and patients not taking EIAEDs received 125 mg/m2 . After this regimen was deemed safe and effective , the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks , in anticipation of a phase III r and omized trial of irinotecan versus irinotecan and bevacizumab . The second cohort , comprising 12 patients , received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1 , 8 , 22 , and 29 . Each cycle was 6 weeks long and concluded with patient evaluations , including magnetic resonance imaging . RESULTS The 6-month progression-free survival among all 35 patients was 46 % ( 95 % CI , 32 % to 66 % ) . The 6-month overall survival was 77 % ( 95 % CI , 64 % to 92 % ) . Twenty of the 35 patients ( 57 % ; 95 % CI , 39 % to 74 % ) had at least a partial response . One patient developed a CNS hemorrhage , which occurred in his 10th cycle . Four patients developed thromboembolic complications ( deep venous thrombosis and /or pulmonary emboli ) . CONCLUSION Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity Glioblastoma multiforme ( GBM ) carries dismal prognosis and can not be eradicated surgically because of its wide brain invasion . The objective of this prospect i ve r and omised controlled trial was to evaluate ALA and Photofrin ® fluorescence-guided resection ( FGR ) and repetitive photodynamic therapy ( PDT ) in GBM . We recruited 27 patients ; 13 were in the study group and 14 were in the control group . The mean survival of the study group was 52.8 weeks compared to 24.6 weeks in the control group ( p < 0.01 ) . The study group gained on average 20 points on the Karnofsky performance score ( p < 0.05 ) . There were no differences in complications or hospital stay between the two groups . The mean time to tumour progression was 8.6 months in the study group compared to 4.8 months in the control group ( p < 0.05 ) . Therefore , ALA and Photofrin ® fluorescence-guided resection and repetitive PDT offered a worthwhile survival advantage without added risk to patients with GBM . A multicentre r and omized controlled trial is warranted to confirm these results PURPOSE We evaluated the efficacy of bevacizumab , alone and in combination with irinotecan , in patients with recurrent glioblastoma in a phase II , multicenter , open-label , noncomparative trial . PATIENTS AND METHODS One hundred sixty-seven patients were r and omly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2 ) or 125 mg/m(2 ) ( with or without concomitant enzyme-inducing antiepileptic drugs , respectively ) once every 2 weeks . Primary end points were 6-month progression-free survival and objective response rate , as determined by independent radiology review . Secondary end points included safety and overall survival . RESULTS In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups , estimated 6-month progression-free survival rates were 42.6 % and 50.3 % , respectively ; objective response rates were 28.2 % and 37.8 % , respectively ; and median overall survival times were 9.2 months and 8.7 months , respectively . There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time . Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan , 46.4 % and 65.8 % , respectively , experienced grade > or = 3 adverse events , the most common of which were hypertension ( 8.3 % ) and convulsion ( 6.0 % ) in the bevacizumab-alone group and convulsion ( 13.9 % ) , neutropenia ( 8.9 % ) , and fatigue ( 8.9 % ) in the bevacizumab-plus-irinotecan group . Intracranial hemorrhage was noted in two patients ( 2.4 % ) in the bevacizumab-alone group ( grade 1 ) and in three patients ( 3.8 % ) patients in the bevacizumab-plus-irinotecan group ( grade s 1 , 2 , and 4 , respectively ) . CONCLUSION Bevacizumab , alone or in combination with irinotecan , was well tolerated and active in recurrent glioblastoma BACKGROUND There is no community st and ard for the treatment of glioblastoma in patients 70 years of age or older . We conducted a r and omized trial that compared radiotherapy and supportive care with supportive care alone in such patients . METHODS Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were r and omly assigned to receive supportive care only or supportive care plus radiotherapy ( focal radiation in daily fractions of 1.8 Gy given 5 days per week , for a total dose of 50 Gy ) . The primary end point was overall survival ; secondary end points were progression-free survival , tolerance of radiotherapy , health-related quality of life , and cognition . RESULTS We r and omly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone . The trial was discontinued at the first interim analysis , which showed that with a preset boundary of efficacy , radiotherapy and supportive care were superior to supportive care alone . A final analysis was carried out for the 81 patients with glioblastoma ( median age , 73 years ; range , 70 to 85 ) . At a median follow-up of 21 weeks , the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks , as compared with 16.9 weeks for the 42 patients who received supportive care alone . The hazard ratio for death in the radiotherapy group was 0.47 ( 95 % confidence interval , 0.29 to 0.76 ; P=0.002 ) . There were no severe adverse events related to radiotherapy . The results of quality -of-life and cognitive evaluations over time did not differ significantly between the treatment groups . CONCLUSIONS Radiotherapy results in a modest improvement in survival , without reducing the quality of life or cognition , in elderly patients with glioblastoma . ( Clinical Trials.gov number , NCT00430911 [ Clinical Trials.gov ] . ) A r and omized , multicenter , open-label , phase 3 study of patients with progressive , recurrent glioblastoma multiforme ( GBM ) for whom front-line therapy had failed was conducted . This study was design ed to determine whether combination therapy with imatinib and hydroxyurea ( HU ) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM . The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0–2 who had completed previous treatment comprising surgical resection , irradiation therapy , and first-line chemotherapy ( preferably temozolomide ( TMZ ) containing regimen ) and who have progressed despite treatment . If first-line chemotherapy did not contain TMZ , a second completed chemotherapy was acceptable . The primary efficacy parameter was progression-free survival ( PFS ) . The primary comparison of combination therapy versus monotherapy for PFS was not significant ( adjusted P = 0.56 ) . The hazard ratio ( HR ) ( adjusted HR = 0.93 ) was not clinical ly relevant . The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm ( 6 weeks ) . The 6-month PFS for the two treatment groups was very similar ( 5 % in the combination arm vs. 7 % in the monotherapy arm ) . No clinical ly meaningful differences were found between the two treatment arms , and the primary study end point was not met . Among the patients receiving imatinib , no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease Context The median survival for patients with glioblastoma multiforme is 1 year despite aggressive treatment . Chloroquine interferes with cellular mechanisms that might cause treatment resistance . Content In this single-center , r and omized , double-blind , placebo-controlled trial , 30 patients receiving surgery , chemotherapy , and radiotherapy for glioblastoma multiforme were r and omly assigned to receive chloroquine or placebo for 12 months . Median survival was 24 months for patients who received chloroquine and 11 months for patients who received placebo . No patient stopped therapy because of toxicity . Limitations The number of patients was small , and the difference in survival was not statistically significant ( P= 0.139 ) . Implication s Chloroquine , in conjunction with other treatments , may prolong survival in patients with glioblastoma multiforme . Larger clinical trials are needed . The Editors Despite numerous advances in the diagnosis of glioblastoma multiforme , there have been relatively few advances in therapy , and the prognosis of patients with this disorder has not changed considerably during the past decades . Recent studies have shown that median survival after aggressive treatment combining surgery , radiotherapy , and chemotherapy is approximately 1 year ( 1 - 4 ) . Even the most sophisticated approaches , such as stereotactic radiosurgery , have failed to improve survival or quality of life ( 5 ) . There are 2 main reasons that explain the high rate of therapeutic failure : the infiltrative nature of glioblastoma multiforme and the presence of cancer cells resistant to radiotherapy and chemotherapy . The latter might be due to the unrestricted growth of resistant cell clones within the original tumor , which replace those cells initially susceptible , or to the emergence of new mutant cell clones resistant to the treatment . This phenomenon could be prompted by the high rate of mutagenesis of malignant glial cells , which is increased by both ionizing radiation and antineoplastic drugs ( 1 , 2 , 4 , 6 ) . Antimalarial drugs , particularly chloroquine and quinacrine , are strong DNA-intercalating agents and are lysosomotropic ; both actions in eukaryotic cells modify several cell functions . In cells with a high mitotic rate , such as cancer cells , chloroquine and quinacrine are antimutagenic ( 7 , 8) ; however , they are not cytotoxic or antimitotic and do not exhibit a substantial antineoplastic effect ( 9 ) . In cultured glioma cells and in malignant glioma in rats , we have shown that these substances have a strong potentiating effect on the antineoplastic action of carmustine and maintain the long-term susceptibility of malignant glioma cells to chemotherapy ( 10 ) . On the basis of these experimental findings , we conducted a preliminary , open-label trial on patients with glioblastoma multiforme by administering chloroquine in addition to surgery and to the st and ard courses of radiotherapy and chemotherapy ; when compared with concurrent controls , survival was statistically significantly longer in chloroquine-treated patients ( 6 ) . After that initial experience , we conducted the present double-blind , placebo-controlled study of chloroquine as adjuvant therapy for patients with glioblastoma multiforme . Methods Patient Recruitment , Enrollment , and Follow-up During a 40-month period ( October 2000 to January 2004 ) , 120 patients with clinical suspicion of a malignant brain tumor were screened at the National Institute of Neurology and Neurosurgery of Mexico . Of these patients , 30 participated in the present study . All patients fulfilled the following inclusion criteria : glioblastoma multiforme , which was confirmed by 2 independent pathologists on the histologic specimen obtained at surgery ; fair clinical neurologic status with a Karnofsky performance score of 70 or higher at the time of diagnosis ; absence of associated severe disorders , such as diabetes and hypertension ; evidence on magnetic resonance imaging ( MRI ) scans that the tumor was restricted to 1 hemisphere of the brain ; and age younger than 60 years . Intervention All patients participating in the study received the same conventional scheme of chemotherapy and radiotherapy : extensive tumor ablation by surgery ; 4 courses of carmustine at 200 mg/m2 , one given every 5 weeks and the first given 8 weeks after surgery ; and radiotherapy that began 3 weeks after surgery , for a total radiation dose of 60 Gy ( 6000 rads ) separated in 30 to 32 courses with daily fractionated doses . All patients and their legal guardians signed the informed consent document , clearly stating their willingness to participate in a r and omized , double-blind , placebo-controlled trial . Chloroquine tablets ( Aralen , Sanofi-Synthelabo , Mexico City , Mexico ) , 150 mg , were commercially purchased , and identical placebo tablets were formulated ; treatments were r and omly distributed into 15 chloroquine and 15 placebo sets ( each set was design ed for 1-year treatment ) and were coded at the laboratory of an independent investigator at another institution . We received the 30 sets coded and numbered , and they were administered in sequential order as the patients entered the trial . The study monitor sealed and kept the code until the end of the study . Therefore , the participants , those administering the treatment , and those assessing the outcomes were blinded to group assignment . Chloroquine was administered at 150 mg/d , starting on day 5 after surgery , and was continued for 12 months ; in a nontrial setting , chemotherapy and radiotherapy would have been completed before 12 months had passed . The dose of chloroquine used in this study was selected on the basis of several pharmacologic studies on toxicity , long-term administration , and antimalarial effectiveness ( 6 , 7 ) ; it is also identical to the dose used in our preliminary study ( 6 ) . The assignment of treatments was decodified in January 2005 , when all patients had had surgery at least 1 year previously , and the follow-up continued until October 2005 . Our institutional review board of research and the institutional board of ethics both approved the study . This study complied with the Consoli date d St and ards for Reporting Trials ( CONSORT ) items for a r and omized trial ( 11 ) . Primary and Secondary Outcomes Clinical evaluation after hospital discharge was done every 2 weeks , and MRI studies were done every 2 months . Tumor size was measured on the MRI scan taken before surgery ; the largest diameter of the tumor on the axial planes was considered as a single value . Primary outcome was survival after surgery . Karnofsky score was determined at the time of diagnosis , 1 month after surgery , and 5 months after surgery . Signs of systemic toxicity induced by the therapy were studied monthly by routine analysis of peripheral blood , which included hematic biometry , blood chemistry , and hepatic tests . In addition , potential signs of drug toxicity in the retina as a result of chloroquine treatment were monitored monthly by ophthalmoscopic evaluation in all patients . Statistical Analysis KaplanMeier survival curves were plotted . Survival times in the 2 groups were compared by using the hazard ratio and 95 % CI from a bivariate Cox regression . Statistical significance was assessed with the log-rank test . Other statistical comparisons were made by using the unpaired t-test and the Fisher exact test ( SPSS , version 10.0 , SPSS Inc. , Chicago , Illinois ) . Role of the Funding Source This work was conducted at the National Institute of Neurology and Neurosurgery of Mexico , which is a public institution without any commercial interests . Partial support was obtained by a grant from Consejo Nacional de Ciencia y Tecnologa ( CONACyT ) , which is the federal agency for support of scientific research in Mexico . The agency did not participate in the design , conduct , analysis , or reporting of this study . No pharmaceutical companies participated in any part of the study . Results Patient Characteristics and Follow-up In the chloroquine group , the duration of symptoms and the diameter of the tumor were greater but the average age of the patients was slightly lower than in the placebo group ; otherwise , the characteristics of patients were similar in the 2 groups ( Table ) . Maximum , minimum , and median follow-ups were 59 , 5 , and 15 months , respectively . Radiotherapy or chemotherapy was not stopped in any surviving patient during the study period . Table . Characteristics of Patients with Glioblastoma Multiforme Survival Median survival over the entire study period was 24 months for the patients in the chloroquine-treated group and 11 months for controls . At the end of the observation period , 6 patients ( 40 % ) from the chloroquine-treated group and 3 patients from the control group ( 20 % ) were still alive ( Figure 1 ) . Figure 1 . KaplanMeier estimates of survival in 30 patients with glioblastoma multiforme who received chloroquine ( n = 15 ) or placebo ( n = 15 ) in addition to conventional therapy . Secondary Outcomes In October 2005 , 6 patients from the chloroquine-treated group were alive . Of these , 1 had survived 59 months after surgery ( Figure 2 ) ; 1 patient each had survived 45 , 30 , and 20 months , respectively , and 2 additional patients had survived 27 months . The patients from the control group had survived 32 , 25 , and 22 months , respectively . Although not statistically significantly different , the rate of death over time was approximately half as large in patients receiving chloroquine as in patients receiving placebo ( hazard ratio , 0.52 [ 95 % CI , 0.21 to 1.26 ] ; P= 0.139 ) . The observed data are consistent with proportional hazards assumption ( P= 0.92 ) . Figure 2 . Magnetic resonance imaging scan of a patient with glioblastoma multiforme treated with chloroquine in addition to surgery , chemotherapy , and radiotherapy . Top . Bottom . Adverse Events During the trial , no signs of retinopathy related to chloroquine toxicity were found in any patient . Follow-up hematologic results were similar between chloroquine-treated patients and control BACKGROUND In 2004 , a r and omised phase III trial by the European Organisation for Research and Treatment of Cancer ( EORTC ) and National Cancer Institute of Canada Clinical Trials Group ( NCIC ) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy . We report the final results with a median follow-up of more than 5 years . METHODS Adult patients with newly diagnosed glioblastoma were r and omly assigned to receive either st and ard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide . The methylation status of the methyl-guanine methyl transferase gene , MGMT , was determined retrospectively from the tumour tissue of 206 patients . The primary endpoint was overall survival . Analyses were by intention to treat . This trial is registered with Clinical trials.gov , number NCT00006353 . FINDINGS Between Aug 17 , 2000 , and March 22 , 2002 , 573 patients were assigned to treatment . 278 ( 97 % ) of 286 patients in the radiotherapy alone group and 254 ( 89 % ) of 287 in the combined-treatment group died during 5 years of follow-up . Overall survival was 27.2 % ( 95 % CI 22.2 - 32.5 ) at 2 years , 16.0 % ( 12.0 - 20.6 ) at 3 years , 12.1 % ( 8.5 - 16.4 ) at 4 years , and 9.8 % ( 6.4 - 14.0 ) at 5 years with temozolomide , versus 10.9 % ( 7.6 - 14.8 ) , 4.4 % ( 2.4 - 7.2 ) , 3.0 % ( 1.4 - 5.7 ) , and 1.9 % ( 0.6 - 4.4 ) with radiotherapy alone ( hazard ratio 0.6 , 95 % CI 0.5 - 0.7 ; p<0.0001 ) . A benefit of combined therapy was recorded in all clinical prognostic subgroups , including patients aged 60 - 70 years . Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy . INTERPRETATION Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up . A few patients in favourable prognostic categories survive longer than 5 years . MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide . FUNDING EORTC , NCIC , Nélia and Amadeo Barletta Foundation , Schering-Plough PURPOSE Cilengitide , an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors , demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme ( GBM ) in a prior phase I study . The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence . PATIENTS AND METHODS Eligible patients were r and omly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis . Patients were assessed every 4 weeks . The primary end point was 6-month progression-free survival ( PFS ) rate . Secondary end points included PFS , overall survival ( OS ) , and radiographic response , as well as quality -of-life and pharmacokinetic assessment s. RESULTS Eighty-one patients were enrolled , including 41 on the 500-mg arm and 40 on the 2,000-mg arm . The safety profile of cilengitide was excellent , with no significant reproducible toxicities observed on either arm . Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg , including a 6-month PFS of 15 % and a median OS of 9.9 months . CONCLUSION Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients . Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted PURPOSE To report a prospect i ve , r and omized , Phase II trial of radiotherapy with and without topotecan for the treatment of glioblastoma . PATIENTS AND METHODS Inclusion criteria were histology of glioblastoma , age < 60 years , and Eastern Cooperative Oncology Group status 0 - 2 . Patients were stratified according to recursive partitioning analysis class , center , and enzyme-inducing antiepileptic medication . Magnetic resonance imaging scans , neurologic examinations , and quality of life assessment s were done every 3 months . The primary endpoint was the progression-free survival rate at 6 months ( 6-m-PFS ) . This trial was design ed as an exploratory , r and omized , Phase II trial with an accrual of 140 patients to detect a difference of 15 - 20 % in 6-m-PFS . An interim analysis was scheduled after 60 patients . Median follow-up was 14 months ( range , 1 - 50 months ) . RESULTS The 6-m-PFS was 56 % and 40 % for patients with and without topotecan , respectively . This benefit disappeared within 2 months . Mean ( range ) progression-free survival time was 8 ( 5 - 10.9 ) months and 6.7 ( 4 - 9.5 ) months for patients with and without topotecan , respectively . The corresponding 2-year-overall survival rates were 28 % vs. 22 % ( nonsignificant difference ) , and mean ( range ) survival time was 20.7 ( 13.9 - 27.5 ) months vs. 18.9 ( 13.5 - 24.4 ) months ( nonsignificant difference ) . CONCLUSIONS A slight but measurable increase of 16 % was detected in 6-m-PFS for patients receiving topotecan with radiation as compared with patients having radiotherapy alone . These data might support further investigations into topotecan for the treatment of glioblastoma Purpose : To evaluate the efficacy of simultaneous postoperative temozolomide radiochemotherapy in glioblastoma patients . Patients and Methods : From February 2002 to July 2004 , n = 65 patients from 11 German centers with macroscopic complete tumor resection were r and omized to receive either postoperative radiotherapy alone ( RT , n = 35 ) or postoperative radiotherapy with simultaneous temozolomide ( RT + TMZ , n = 30 ) . Patients were stratified according to age ( ≤/>50 years ) and WHO performance score ( 0–1 vs. 2 ) . RT consisted of 60 Gy in 30 fractions . In the RT + TMZ arm , oral TMZ was administered daily at a dose of 75 mg/m2 including weekends ( 40–42 doses ) . Adjuvant treatment was not given , but in both arms , patients with recurrent tumors and in good condition ( WHO 0–2 ) were scheduled for salvage chemotherapy with TMZ . Results : The trial was stopped early due to the results of EORTC- study 26981 - 22981 that showed a survival benefit for the combination of concomitant and adjuvant TMZ compared to radiotherapy alone . In total , 62/65 patients were evaluable . Stratification variables were well balanced ( ≤ 50 years 26 % vs. 20 % , WHO 0–1 91 % vs. 100 % ) . Neither overall survival ( median 17 vs. 15 months ) nor progression-free survival ( median 7 vs. 6 months ) differed significantly between the two arms . In the RT ( RT + TMZ ) arm , 76 % ( 62 % ) of the progressing patients received salvage chemotherapy with TMZ , 36 % ( 50 % ) had a second resection . There was a time-constant trend for increased general quality of life ( EORTC question naire QLQ C30 ) and brain-specific quality of life ( EORTC question naire B20 ) in the combined arm . Lymphopenia G3–4 was more frequent ( 33 vs. 6 % ) in the RT + TMZ arm . Conclusion : After early closure of this trial , a benefit for progression-free survival for simultaneous TMZ radiochemotherapy alone could not be demonstrated . In both arms , salvage therapies were frequently used and probably had a major effect on overall survival . Ziel : Bestimmung der Effektivität einer alleinigen simultanen , postoperativen Radiochemotherapie mit Temozolomid bei Patienten mit Glioblastom . Patienten und Method ik : Von Februar 2002 bis Juli 2004 wurden n = 65 Patienten aus 11 Zentren nach makroskopischer Tumorresektion r and omisiert und erhielten entweder eine postoperative lokale Strahlenbeh and lung ( RT , n = 35 ) oder eine simultane Radiochemotherapie mit Temozolomid ( RT + TMZ , n = 30 ) . Die Stratifizierung erfolgte anh and des Alters ( ≤/>50 Jahre ) und des Allgemeinzust and s ( AZ ) nach WHO ( 0–1 vs. 2 ) . Die Bestrahlung wurde mit 60 Gy in 30 Fraktionen durchgeführt . I m RT + TMZ-Arm wurde TMZ oral in einer täglichen Dosis von 75 mg/m2 an allen Bestrahlungstagen und am Wochenende verabreicht ( 40–42 Dosen ) . Eine adjuvante Therapie mit TMZ erfolgte nicht , stattdessen war für die Patienten in gutem AZ ( WHO 0–2 ) i m Falle einer Tumorprogression in beiden Armen eine Rezidiv-Chemotherapie mit TMZ vorgesehen . Ergebnisse : Die Studie wurde vorzeitig nach der Veröffentlichung der EORTC-Studie 26981 - 22981 abgebrochen , die eine Verlängerung der Überlebenszeit durch eine simultane und adjuvante Radiochemotherapie mit TMZ gezeigt hatte . Insgesamt waren 62/65 Patienten auswertbar . Die Arme ( RT vs. RT + TMZ ) waren bezüglich der Stratifikationsvariablen ausgeglichen ( ≤ 50 Jahre 26 % vs. 20 % , WHO 0–1 91 % vs. 100 % ) . Weder das Gesamtüberleben ( Median 17 vs. 15 Monate ) noch das progressionsfreie Überleben ( Median 7 vs. 6 Monate ) unterschieden sich signifikant . In dem RT-(RT + TMZ-)Arm erhielten 76 % ( 62 % ) der progredienten Patienten eine Rezidiv-Chemotherapie mit Temodal , 36 % ( 50 % ) wurden nochmals operiert . Für die allgemeine und hirnfunktionsbezogene Lebensqualität ( EORTC-Fragebögen QLQ C30 und BN20 ) zeigte sich in dem RT + TMZ-Arm ein zeitkonstanter Trend für bessere Werte . I m RT + TMZ-Arm war die Häufigkeit einer Lymphopenie Grad 3–4 erhöht ( 33 % vs. 6%).Schlussfolgerung : Nach dem vorzeitigen Abbruch der Studie konnte ein Vorteil bezüglich des progressionsfreien Überlebens für die alleinige simultane Radiochemotherapie mit Temozolomid nicht gezeigt werden . In beiden Armen wurden Rezidivtherapien häufig eingesetzt , diese hatten wahrscheinlich einen erheblichen Einfluss auf das Gesamtüberleben Objectives : ( 1 ) Examine the tendency of peer- review ed surgical journals to publish positive reports or negative and inconclusive outcome articles as a function of the journals ’ impact factor ( IF ) . ( 2 ) Examine the frequency with which surgical journal editors/publishers adhere to the International Committee of Medical Journal Editors statement on sources of funding and /or conflicts of interest ( COI ) . Background : Evidence -based medicine is often used as a template for measuring quality of medical care . Clinicians put their faith in peer- review ed articles as quality -assured and reliable information . However , peer- review ed literature does not provide balanced access to positive , negative , and inconclusive reports . Funding may also influence the decision to publish certain articles and can thus add to the reported bias in the literature . Methods : Articles from 15 surgical journals comprising 3 separate journal groups based upon 2006 impact factor ( IF ) rankings were review ed . All were published in 2007 . Manuscripts were classified by 5 independent review ers as having positive , negative , or inconclusive primary and secondary outcomes and for statements on funding /COI . Positive reports were defined as P < 0.05 , null hypothesis rejected ; negative reports defined as P < 0.05 , null hypothesis accepted ; and inconclusive reports defined as P > 0.05 . Inter-observer consistency was affirmed . Separate analysis of r and omized controlled trials ( RCT ) was performed to assess for the quality of published positive and negative trials . Results : We evaluated 2457 published articles . Positive primary outcomes were reported in 67 % to 100 % of studied articles in selected journals . Negative and inconclusive primary outcomes were less likely to be reported , except for one journal that reported a high of 33 % negative articles . Higher-ranked journals published fewer negative and inconclusive studies ( 5%–7 % ) than both medium- and lowly-ranked journals ( P < 0.0001 ) . The proportion of RCTs published varied , constituting 18 % to 21 % of articles in the 5 high-ranked journals compared to 6 % to 14 % in the 5 more lowly ranked journals ( P < 0.0001 ) . Reporting of COIs and funding were more frequent in high-IF compared to low-IF journals ( P < 0.0001 ) . Conclusions : Quality rather than outcome should be the measure on which a publication decision is made ; commercial bias may further complicate this balance . Lower IF-rated journals may serve a decidedly useful purpose by publishing more negative and inconclusive outcome studies . The practice of focusing disproportionately on the positive outcomes of most studies may result in unbalanced evidence OBJECT The goal of this study was to assess the impact of neuronavigation on the cytoreductive treatment of solitary contrast-enhancing intracerebral tumors and outcomes of this treatment in cases in which neuronavigation was preoperatively judged to be redundant . METHODS The authors conducted a prospect i ve r and omized study in which 45 patients , each harboring a solitary contrast-enhancing intracerebral tumor , were r and omized for surgery with or without neuronavigation . Peri- and postoperative parameters under investigation included the following : duration of the procedure ; surgeon 's estimate of the usefulness of neuronavigation ; quantification of the extent of resection , determined using magnetic resonance imaging ; and the postoperative course , as evaluated by neurological examinations , the patient 's quality -of-life self- assessment , application of the Barthel index and the Karnofsky Performance Scale score , and the patient 's time of death . The mean amount of residual tumor tissue was 28.9 % for st and ard surgery ( SS ) and 13.8 % for surgery involving neuronavigation ( SN ) . The corresponding mean amounts of residual contrast-enhancing tumor tissue were 29.2 and 24.4 % , respectively . These differences were not significant . Gross-total removal ( GTR ) was achieved in five patients who underwent SS and in three who underwent SN . Median survival was significantly shorter in the SN group ( 5.6 months compared with 9 months , unadjusted hazard ratio = 1.6 ) ; however , this difference may be attributable to the coincidental early death of three patients in the SN group . No discernible important effect on the patients ' 3-month postoperative course was identified . CONCLUSIONS There is no rationale for the routine use of neuronavigation to improve the extent of tumor resection and prognosis in patients harboring a solitary enhancing intracerebral lesion when neuronavigation is not already deemed advantageous because of the size or location of the lesion

These elements were distilled into 5 primary categories and conceptually referred to as the 5 Ms : mission-clearly defined policy/st and ards for PAaN ; motivate-providing choices , developmentally appropriate activities , feedback , and encouragement ; manage-structuring and managing the environment for safety , routines , and discipline ; monitor-ongoing evaluation of PAaN ; and maximize-incorporating all former Ms. CONCLUSIONS The application of this training framework should lead to improved implementation and eventual achievement of policy goals for PAaN in ASPs .

BACKGROUND After-school programs ( ASPs , 3 pm to 6 pm ) have been called upon to increase the amount of daily physical activity children accumulate and improve the nutritional quality of the snacks served . To this end , state and national physical activity and nutrition ( PAaN ) policies have been proposed . Frontline staff who directly interact with children on a daily basis are charged with the responsibility to meet policy goals . Without appropriate skills , staffers ' ability to achieve such goals is limited . The gap between policies and improvements in PAaN must be bridged through professional development training . This article describes the development of an ASP staff professional development training program .

Background Underst and ing the correlates of dietary intake is necessary in order to effectively promote healthy dietary behavior among children and adolescents . A literature review was conducted on the correlates of the following categories of dietary intake in children and adolescents : Fruit , Juice and Vegetable Consumption , Fat in Diet , Total Energy Intake , Sugar Snacking , Sweetened Beverage Consumption , Dietary Fiber , Other Healthy Dietary Consumption , and Other Less Healthy Dietary Consumption in children and adolescents . Methods Cross-sectional and prospect i ve studies were identified from PubMed , PsycINFO and PsycArticles by using a combination of search terms . Quantitative research examining determinants of dietary intake among children and adolescents aged 3–18 years were included . The selection and review process yielded information on country , study design , population , instrument used for measuring intake , and quality of research study . Results Seventy-seven articles were included . Many potential correlates have been studied among children and adolescents . However , for many hypothesized correlates substantial evidence is lacking due to a dearth of research . The correlates best supported by the literature are : perceived modeling , dietary intentions , norms , liking and preferences . Perceived modeling and dietary intentions have the most consistent and positive associations with eating behavior . Norms , liking , and preferences were also consistently and positively related to eating behavior in children and adolescents . Availability , knowledge , outcome expectations , self-efficacy and social support did not show consistent relationships across dietary outcomes . Conclusion This review examined the correlates of various dietary intake ; Fruit , Juice and Vegetable Consumption , Fat in Diet , Total Energy Intake , Sugar Snacking , Sweetened Beverage Consumption , Dietary Fiber , Other Healthy Dietary Consumption , and Other Less Healthy Dietary Consumption in cross-sectional and prospect i ve studies for children and adolescents . The correlates most consistently supported by evidence were perceived modeling , dietary intentions , norms , liking and preferences . More prospect i ve studies on the psychosocial determinants of eating behavior using broader theoretical perspectives should be examined in future research OBJECTIVE To evaluate the feasibility , acceptability , and efficacy of an after-school team sports program for reducing weight gain in low-income overweight children . DESIGN Six-month , 2-arm , parallel-group , pilot r and omized controlled trial . SETTING Low-income , racial/ethnic minority community . PARTICIPANTS Twenty-one children in grade s 4 and 5 with a body mass index at or above the 85th percentile . INTERVENTIONS The treatment intervention consisted of an after-school soccer program . The " active placebo " control intervention consisted of an after-school health education program . MAIN OUTCOME MEASURES Implementation , acceptability , body mass index , physical activity measured using accelerometers , reported television and other screen time , self-esteem , depressive symptoms , and weight concerns . RESULTS All 21 children completed the study . Compared with children receiving health education , children in the soccer group had significant decreases in body mass index z scores at 3 and 6 months and significant increases in total daily , moderate , and vigorous physical activity at 3 months . CONCLUSION An after-school team soccer program for overweight children can be a feasible , acceptable , and efficacious intervention for weight control BACKGROUND Policies to require afterschool programs ( ASPs , 3 PM to 6 PM ) to provide children a minimum of 30 minutes of moderate-to-vigorous physical activity ( MVPA ) exist . With few low-cost , easy-to-use measures of MVPA available to the general public , ASP providers are limited in their ability to track progress toward achieving this policy- goal . Pedometers may fill this gap , yet there are no step-count guidelines for ASPs linked to 30 minutes of MVPA . METHODS Steps and accelerometer estimates of MVPA were collected concurrently over multiple days on 245 children ( 8.2 years , 48 % boys , BMI -percentile 68.2 ) attending 3 community-based ASPs . R and om intercept logit models and receiver operating characteristic ( ROC ) analyses were used to identify a threshold of steps that corresponded with attaining 30 minutes of MVPA . RESULTS Children accumulated an average of 2876 steps ( st and ard error [ SE ] 79 ) and 16.1 minutes ( SE0.5 ) of MVPA over 111 minutes ( SE1.3 ) during the ASP . A threshold of 4600 steps provided high specificity ( 0.967 ) and adequate sensitivity ( 0.646 ) for discriminating children who achieved the 30 minutes of MVPA ; 93 % of the children were correctly classified . The total area under the curve was 0.919 . Children accumulating 4600 steps were 25times more likely to accumulate 30 minutes of MVPA . CONCLUSIONS This step threshold will provide ASP leaders with an objective , low-cost , easy-to-use tool to monitor progress toward policy-related goals PURPOSE This intervention compares the effectiveness of daily step count targets with time-based prescription for increasing the health-related physical activity of low-active adolescent girls . METHODS We assigned participants ( N = 85 , mean age 15.8 + /- 0.8 yr ) depending on school attended to a control ( CON ) , pedometer ( PED ) , or minutes ( MIN ) group . The intervention groups were involved in a 12-wk physical activity self-monitoring and educative program . The only difference between the intervention groups was that the PED group set daily step count targets whereas the MIN group set daily time-based goals for physical activity involvement . Pre- , mid- , and postintervention changes in physical activity ( 4-d blinded step count and 3-d physical activity recall ) and body mass index ( BMI ) were assessed using a series of 3 ( group assignment ) x 3 ( time ) ANOVA . Where significant interactions were found , separate follow-up simple main effects tests were used . RESULTS At postintervention , only the PED group had significantly increased their total activity as measured by a 4-d step count , when compared with the control ( P = 0.03 , ES = 0.13 ) . The group , time , and interaction effects for 4-d step count were significant , indicating that although both the participants in the PED and the MIN groups significantly increased their step count across the 12-wk intervention ( P = 0.00 - 0.01 ) , the participants in the PED group had a greater increase at the midintervention time point ( P = 0.04 , ES = 0.10 ) . No pre- , mid- , or postintervention changes were reported in any group for BMI ( F = 1.18 , P = 0.32 ) . CONCLUSION The use of pedometers and daily step count targets with low-active adolescent girls may result in short-term ( 6 wk ) enhanced physical activity related outcomes when compared with traditional time-based physical activity prescriptions . However , both interventions appear to result in similar improvements in physical activity when duration of the observation is extended to 12 wk PURPOSE This study evaluated the effects of a classroom-based physical activity program on children 's in-school physical activity levels and on-task behavior during academic instruction . METHODS Physical activity of 243 students was assessed during school hours . Intervention-group students ( N = 135 ) received a classroom-based program ( i.e. , Energizers ) . The control group ( N = 108 ) did not receive Energizers . On-task behavior during academic instruction time was observed for 62 third- grade ( N = 37 ) and fourth- grade students ( N = 25 ) before and after Energizers activities . An independent groups t-test compared in-school physical activity levels between intervention and control classes . A multiple-baseline across-classrooms design was used to evaluate the effectiveness of the Energizers on on-task behavior . Additionally , a two-way ( time [ pre- vs postobservation ] x period [ baseline vs intervention ] ) repeated- measures analysis of variance compared on-task behavior between observation periods . Magnitudes of mean differences were evaluated with Cohen 's delta ( ES ) . RESULTS Students in the intervention group took significantly ( P < 0.05 ) more in-school steps ( 5587 + /- 1633 ) than control-group students ( 4805 + /- 1543 ) , and the size of this difference was moderate ( ES = 0.49 ) . The intervention was effective in improving on-task behavior ; after the Energizers were systematic ally implemented , on-task behavior systematic ally improved . The improvement in on-task behavior of 8 % between the pre-Energizers and post-Energizers observations was statistically significant ( P < 0.017 ) , and the difference was moderate ( ES = 0.60 ) . Likewise , the least on-task students improved on-task behavior by 20 % after Energizers activities . This improvement was statistically significant ( P < 0.001 ) and meaningful ( ES = 2.20 ) . CONCLUSION A classroom-based physical activity program was effective for increasing daily in-school physical activity and improving on-task behavior during academic instruction BACKGROUND Policies now recommend afterschool programs ( ASP , 3 - 6 pm ) provide children a minimum amount of physical activity daily . We examined the extent to which children attending ASPs meet existing national and state-level policies that specify expected levels of physical activity ( PA ) . METHODS Accelerometer-derived physical activity ( light and moderate-to-vigorous , MVPA ) of 253 children ( 5 - 13 years ) was compared to policies that recommend varying amounts of PA children should achieve during an ASP . RESULTS The proportion of children achieving a policy ranged from 0.0 % ( California 60 min MVPA and North Carolina 20 % of daily program time devoted to MVPA ) , 1.2 % ( California 30 min MVPA ) , to 48.2 % ( National Afterschool Association 30 min light plus MVPA ) . R and om effects logistic models indicated boys ( odds ratio [ OR ] range 2.0 to 6.27 ) and children from a minority background ( Black/Hispanic , OR range 1.87 to 3.98 ) were more likely to achieve a recommended level of physical activity , in comparison to girls and White children . Neither age nor BMI were related to achieving a policy . CONCLUSIONS The PA of children attending ASP falls below policy recommended levels ; however , these policies were developed in absence of data on expected PA levels during ASPs . Thus , concerted effort towards building a stronger ASP evidence -base for policy refinement is required BACKGROUND Substantial differences exist in how and where physical education ( PE ) is conducted in elementary schools throughout the United States . Few effectiveness studies of large-scale interventions to improve PE have been reported . DESIGN Multicenter r and omized trial . SETTING / PARTICIPANTS The Child and Adolescent Trial for Cardiovascular Health ( CATCH ) was implemented in PE classes in 96 schools ( 56 intervention , 40 control ) in four study centers : California , Louisiana , Minnesota , and Texas . INTERVENTION The 2.5-year PE intervention consisted of professional development sessions , curricula , and follow-up consultations . MAIN OUTCOME MEASURES Intervention effects on student physical activity and lesson context in PE were examined by teacher type ( PE specialists and classroom teachers ) and lesson location ( indoors and outdoors ) . RESULTS Differential effects by teacher type and lesson location were evidence d for both physical activity and lesson context . Observations of 2016 lessons showed that intervention schools provided more moderate-to-vigorous physical activity ( p=0.002 ) and vigorous physical activity ( p=0.02 ) than controls . Classroom teachers improved physical activity relatively more than PE specialists , but PE specialists still provided longer lessons and more physical activity . Classroom teachers increased lesson length ( p=0.02 ) and time for physical fitness ( p=0.03 ) . CONCLUSIONS The intervention improved PE of both specialists ' and classroom teachers ' lessons . States and districts should ensure that the most qualified staff teaches PE . Interventions need to be tailored to meet local needs and conditions , including teacher type and location of lessons PURPOSE School physical education ( PE ) is highly recommended as a means of promoting physical activity , and r and omized studies of health-related PE interventions in middle schools have not been reported . We developed , implemented , and assessed an intervention to increase physical activity during middle-school PE classes . METHODS Twenty-four middle schools ( approximately 25,000 students , 45 % nonwhite ) in Southern California participated in a r and omized trial . Schools were assigned to intervention ( N = 12 ) or control ( N = 12 ) conditions , and school was the unit of analysis . A major component of the intervention was a 2-yr PE program , which consisted of curricular material s , staff development , and on-site follow-up . Control schools continued usual programs . Student activity and lesson context were observed in 1849 PE lessons using a vali date d instrument during baseline and intervention years 1 and 2 . RESULTS The intervention significantly ( P = 0.02 ) improved student moderate to vigorous physical activity ( MVPA ) in PE , by approximately 3 min per lesson . Effects were cumulative ; by year 2 intervention schools increased MVPA by 18 % . Effect sizes were greater for boys ( d = 0.98 ; large ) than girls ( d = 0.68 ; medium ) . CONCLUSIONS A st and ardized program increased MVPA in middle schools without requiring an increase in frequency or duration of PE lessons . Program components were well received by teachers and have the potential for generalization to other schools . Additional strategies may be needed for girls OBJECTIVES This study evaluated a health-related physical education program for fourth- and fifth- grade students design ed to increase physical activity during physical education classes and outside of school . METHODS Seven schools were assigned to three conditions in a quasi-experimental design . Health-related physical education was taught by physical education specialists or trained classroom teachers . Students from these classes were compared with those in control classes . Analyses were conducted on 955 students with complete data . RESULTS Students spent more minutes per week being physically active in specialist-led ( 40 min ) and teacher-led ( 33 min ) physical education classes than in control classes ( 18 min ; P < .001 ) . After 2 years , girls in the specialist-led condition were superior to girls in the control condition on abdominal strength and endurance ( P < .001 ) and cardiorespiratory endurance ( P < .001 ) . There were no effects on physical activity outside of school . CONCLUSIONS A health-related physical education curriculum can provide students with substantially more physical activity during physical education classes . Improved physical education classes can potentially benefit 97 % of elementary school students Abstract The purpose of this study was to evaluate the impact of an extra-curricular school sport programme to promote physical activity among adolescents . One hundred and sixteen students ( mean age 14.2 years , s = 0.5 ) were assigned to an intervention ( n = 50 ) or comparison group ( n = 66 ) . The 8-week intervention involved structured exercise activities and information sessions . Four days of pedometer monitoring and time spent in non-organized physical activity and sedentary behaviours were measured at baseline and post-test . At baseline , participants were classified using steps per day as low-active ( girls < 11,000 , boys < 13,000 ) or active ( girls ≥ 11,000 , boys ≥ 13,000 ) and the effects of the intervention were assessed using these subgroups . Adolescents in the intervention group classified as low-active at baseline increased their step counts across the 8-week intervention ( baseline : 7716 steps/day , s = 1751 ; post-test : 10,301 steps/day , s = 4410 ; P < 0.05 ) and accumulated significantly more steps ( P < 0.05 ) than their peers in the comparison group ( baseline : 8414 steps/day , s = 2460 ; post-test : 8248 steps/day , s = 3674 ; P = 0.879 ) . The results of the present study provide further evidence that physical activity monitoring using pedometers is an effective strategy for increasing activity among low-active adolescents Complex interventions are more than the sum of their parts , and interventions need to be better theorised to reflect this Many people think that st and ardisation and r and omised controlled trials go h and in h and . Having an intervention look the same as possible in different places is thought to be paramount . But this may be why some community interventions have had weak effects . We propose a radical departure from the way large scale interventions are typically conceptualised . This could liberate interventions to be responsive to local context and potentially more effective while still allowing meaningful evaluation in controlled design s. The key lies in looking past the simple elements of a system to embrace complex system functions and processes . The suitability of cluster r and omised trials for evaluating interventions directed at whole communities or organisations remains vexed.1 It need not be.2 Some health promotion advocates ( including the WHO European working group on health promotion evaluation ) believe r and omised controlled trials are inappropriate because of the perceived requirement for interventions in different sites to be st and ardised or look the same.1 3 4 They have ab and oned r and omised trials because they think context level adaptation , which is essential for interventions to work , is precluded by trial design s. An example of context level adaptation might be adjusting educational material s to suit various local learning styles and literacy levels . Lead thinkers in complex interventions , such as the UK 's Medical Research Council , also think that trials of complex interventions must “ consistently provide as close to the same intervention as possible ” by “ st and ardising the content and delivery of the intervention.”5 By contrast , however , they do not see this as a reason to reject r and omised controlled trials . These divergent views have led to problems on two fronts . Firstly , the field of health promotion is being turned away from r and omised

Moderate evidence supports the use of decision support and clinical pharmacy interventions to increase provision of patient self-education/asthma action plans . Moderate evidence supports use of decision support tools to reduce emergency department visits , and low- grade evidence suggests there is no benefit for this outcome with organizational change , education only , and quality improvement/pay-for-performance . : Decision support tools , feedback and audit , and clinical pharmacy support were most likely to improve provider adherence to asthma guidelines , as measured through health care process outcomes .

BACKGROUND AND OBJECTIVE : Health care provider adherence to asthma guidelines is poor . The objective of this study was to assess the effect of interventions to improve health care providers ’ adherence to asthma guidelines on health care process and clinical outcomes .

Abstract Objective : To evaluate the use of a computerised support system for decision making for implementing evidence based clinical guidelines for the management of asthma and angina in adults in primary care . Design : A before and after pragmatic cluster r and omised controlled trial utilising a two by two incomplete block design . Setting : 60 general practice s in north east Engl and . Participants : General practitioners and practice nurses in the study practice s and their patients aged 18 or over with angina or asthma . Main outcome measures : Adherence to the guidelines , based on review of case notes and patient reported generic and condition specific outcome measures . Results : The computerised decision support system had no significant effect on consultation rates , process of care measures ( including prescribing ) , or any patient reported outcomes for either condition . Levels of use of the software were low . Conclusions : No effect was found of computerised evidence based guidelines on the management of asthma or angina in adults in primary care . This was probably due to low levels of use of the software , despite the system being optimised as far as was technically possible . Even if the technical problems of producing a system that fully supports the management of chronic disease were solved , there remains the challenge of integrating the systems into clinical encounters where busy practitioners manage patients with complex , multiple conditions Objective . We evaluated the effectiveness of a continuing medical education program , Physician Asthma Care Education , in improving pediatricians ’ asthma therapeutic and communication skills and patients ’ health care utilization for asthma . Methods . We conducted a r and omized trial in 10 regions in the United States . Primary care providers were recruited and r and omly assigned by site to receive the program provided by local faculty . The program included 2 interactive seminar sessions ( 2.5 hours each ) that review ed national asthma guidelines , communication skills , and key educational messages . Format included short lectures , case discussion s , and a video modeling communication techniques . We collected information on parent perceptions of physicians ’ communication , the child ’s asthma symptoms , and patients ’ asthma health care utilization . We used multivariate regression models to determine differences between control and intervention groups . Results . A total of 101 primary care providers and a r and om sample of 870 of their asthma patients participated . After 1 year , we completed follow-up telephone interviews with the parents of 731 of the 870 patients . Compared to control subjects , parents reported that physicians in the intervention group were more likely to inquire about patients ’ concerns about asthma , encourage patients to be physically active , and set goals for successful treatment . Patients of physicians that attended the program had a greater decrease in days limited by asthma symptoms ( 8.5 vs 15.6 days ) , as well as decreased emergency department asthma visits ( 0.30 vs 0.55 visits per year ) . Conclusions . The Physician Asthma Care Education program was used in a range of locations and was effective in improving parent-reported provider communication skills , the number of days affected by asthma symptoms , and asthma health care use . Patients with more frequent asthma symptoms and higher health care utilization at baseline were more likely to benefit from their physician ’s participation in the program OBJECTIVE : Asthma continues to be 1 of the most common chronic diseases of childhood and affects ∼6 million US children . Although National Asthma Education Prevention Program guidelines exist and are widely accepted , previous studies have demonstrated poor clinician adherence across a variety of population s. We sought to determine if clinical decision support ( CDS ) embedded in an electronic health record ( EHR ) would improve clinician adherence to national asthma guidelines in the primary care setting . METHODS : We conducted a prospect i ve cluster-r and omized trial in 12 primary care sites over a 1-year period . Practice s were stratified for analysis according to whether the site was urban or suburban . Children aged 0 to 18 years with persistent asthma were identified by International Classification of Diseases , Ninth Revision codes for asthma . The 6 intervention- practice sites had CDS alerts imbedded in the EHR . Outcomes of interest were the proportion of children with at least 1 prescription for controller medication , an up-to- date asthma care plan , and the performance of office-based spirometry . RESULTS : Increases in the number of prescriptions for controller medications , over time , was 6 % greater ( P = .006 ) and 3 % greater for spirometry ( P = .04 ) in the intervention urban practice s. Filing an up-to- date asthma care plan improved 14 % ( P = .03 ) and spirometry improved 6 % ( P = .003 ) in the suburban practice s with the intervention . CONCLUSION : In our study , using a cluster-r and omized trial design , CDS in the EHR , at the point of care , improved clinician compliance with National Asthma Education Prevention Program guidelines OBJECTIVES This study was conducted to assess the impact of an interactive seminar based on self-regulation theory on 1 ) the treatment practice s and communications and education behavior of physicians , 2 ) the health status and medical care utilization of their pediatric patients with asthma , and 3 ) the satisfaction with care of the subjects ' parents . METHODS A total of 74 general practice pediatricians were assigned to either a program or a control group in a r and omized controlled study . Data were collected from physicians at baseline , and 69 ( 93 % ) provided follow-up data 5 months after the program . Data were also collected from 637 of their patients at baseline , and in a 22-month window after the intervention , 472 ( 74 % ) of this number provided follow-up data . RESULTS After the seminar , physicians in the program group were more likely than were control group physicians to address patients ' fears about medicines , review written instructions , provide a sequence of educational messages , write down how to adjust the medicines at home when symptoms change , and report that they spent less time with their patients . Parents of the children treated by program physicians were significantly more likely than were control group parents to report that the physician had been reassuring , described as a goal that the child be fully active , and gave information to relieve specific worries . After a visit with the physician , these parents were also more likely to report that they knew how to make management decisions at home . After the intervention compared to controls , patients of physicians in the program group were more likely to have received a prescription for inhaled antiinflammatory medicine and to have been asked by the physician to demonstrate how to use a metered-dose inhaler . After the intervention , children seen by program physicians made significantly fewer nonemergency office visits and visits for follow-up of an episode of symptoms ; however , there were no differences in emergency department visits and hospitalizations . Among children who were placed on inhaled corticosteroids during this study , however , children treated by physicians who had received education had significantly fewer symptoms and fewer follow-up office visits , nonemergency physician office visits , emergency department visits , and hospitalizations . CONCLUSIONS The interactive seminar based on theories of self-regulation led to patient-physician encounters that were of shorter duration , had significant impact on the prescribing and communications behavior of physicians , led to more favorable patient responses to physicians ' actions , and led to reductions in health care utilization Abstract Objectives : To evaluate the effectiveness of an asthma re source centre in improving treatment and quality of life for asthmatic patients Design : Community based r and omised controlled trial Setting : 41 general practice s in Greenwich with a practice nurse Subjects : All registered patients aged 15 - 50 years Intervention : Nurse specialists in asthma who educated and supported practice nurses , who in turn educated patients in the management of asthma according to the British Thoracic Society 's guidelines Main outcome measures : Quality of life of asthmatic patients , attendance at accident and emergency departments , admissions to local hospitals , and steroid prescribing by general practitioners Results : Of 24 400 patients r and omly selected and surveyed in 1993 , 12 238 replied ; 1621 were asthmatic of whom 1291 were sent a repeat question naire in 1996 and 780 replied . Of 24 400 patients newly surveyed in 1996 , 10 783 ( 1616 asthmatic ) replied . No evidence was found for an improvement in asthma related quality of life among newly surveyed patients in intervention practice s compared with control practice s. Neither was there evidence of an improvement in other measures of the quality of asthma care . Weak evidence was found for an improvement in quality of life in intervention practice s among asthmatics registered with study practice s in 1993 and followed up in 1996 . Neither attendances at accident and emergency departments nor admissions for asthma showed any tendency to diverge in intervention and control practice s over the study period . Steroid prescribing rates rose steadily during the study period . The average annual increase in steroid prescribing was 3 % per year higher in intervention than control practice s ( 95 % confidence interval −1 % to 6 % , P=0.10 ) Conclusions : This model of service delivery is not effective in improving the outcome of asthma in the community . Further development is required if cost effective management of asthma is to be OBJECTIVE To test a quality improvement intervention , a learning collaborative based on the Institute for Healthcare Improvement 's Breakthrough Series methodology , specifically intended to improve care and outcomes for patients with childhood asthma . DESIGN R and omized trial in primary care practice s. SETTING Practice s in greater Boston , Mass , and greater Detroit , Mich. PARTICIPANTS Forty-three practice s , with 13 878 pediatric patients with asthma , r and omized to intervention and control groups . Intervention Participation in a learning collaborative project based on the Breakthrough Series methodology of continuous quality improvement . MAIN OUTCOME MEASURES Change from baseline in the proportion of children with persistent asthma who received appropriate medication therapy for asthma , and in the proportion of children whose parent received a written management plan for their child 's asthma , as determined by telephone interviews with parents of 631 children . RESULTS After adjusting for state , practice size , child age , sex , and within- practice clustering , no overall effect of the intervention was found . CONCLUSIONS This method ologically rigorous assessment of a widely used quality improvement technique did not demonstrate a significant effect on processes or outcomes of care for children with asthma . Potential deficiencies in program implementation , project duration , sample selection , and data sources preclude making the general inference that this type of improvement program is ineffective . Additional rigorous studies should be undertaken under more optimal setting s to assess the efficacy of this method for improving care Objective . To evaluate effects on the process and outcomes of care brought about by use of a h and held , computer-based system that implements the American Academy of Pediatrics guideline on office management of asthma exacerbations . Design . A before – after trial with r and omly selected , office-based Connecticut pediatricians . In both the control and intervention phases , physicians collected data from 10 patient encounters for acute asthma exacerbations . During the intervention phase , the computer provided for structured encounter documentation and offered recommendations based on the guideline of the American Academy of Pediatrics . Patients were contacted by telephone 7 to 14 days after the visit to assess outcomes . Results . Nine study -physicians enrolled 91 patients in the control phase and 74 in the intervention phase . Follow-up information was available for 93 % of encounters . Use of the intervention was associated with increased mean frequency/visit of : 1 ) measurements of peak expiratory flow rate ( 2.18 vs 1.57 ) and oxygen saturation ( 1.12 vs .42 ) , and 2 ) administration of nebulized β2-agonists ( 1.25 vs .71 ) . Visits in the intervention phase lasted longer and fees were higher ( $ 145.61 vs $ 103.11 ) . There were no significant differences in immediate disposition or subsequent emergency department visits , hospitalizations , missed school , or caretaker 's missed work during the 7 days post visit . Conclusion . Use of h and held computers that provide guideline -based decision support was associated with increased physician adherence to guideline recommendations ; however , visits were prolonged , fees were higher , and no improvement could be demonstrated with regard to the observed intermediate-term patient outcomes . Guideline implementers ( and users ) should be cautious about putting unvali date d recommendations into practice OBJECTIVE : Outpatient asthma management remains suboptimal . We previously reported significant improvements in asthma guideline adherence and outcomes in children by using quality -improvement processes and community health workers . We hypothesized that a larger project could achieve comparable outcome improvements with streamlined quality -improvement processes and decreased technical assistance . METHODS : Seventeen clinics treating 12 000 children with asthma were evaluated through interviews of a subset of patients with persistent or high-risk asthma ( n = 761 ) at baseline and at 12 and 21 months and chart review s r and omly selected from all patients with asthma at baseline and 12 and 24 months ( n = 2040 ) . Multidisciplinary teams developed data -driven continuous quality -improvement activities . Asthma coordinators provided patient education and were active team members . RESULTS : Study children were predominantly Hispanic ( 77 % ) and black ( 11 % ) ; 60 % were enrolled in Medicaid , and 9 % were uninsured . Comparing results between baseline and the 21-month follow-up , significantly fewer families reported emergency-department visits ( 29.6 % vs 9.3 % ) , hospitalizations ( 10.9 % vs 3.4 % ) , frequent daytime symptoms ( 44.0 % vs 11.7 % ) , and missed school days ( 28.7 % vs 13.6 % ) ; significantly more reported confidence in asthma management ( 70.6 % vs 95.5 % ) ; and quality -of-life scores increased significantly for both children and caregivers ( all P < .05 ) . Cross-sectional data revealed significant clinic-wide improvements in symptom documentation , health care use , and review of action plans . CONCLUSIONS : On a larger scale , this approach realized impressive changes in provider clinical practice associated with major improvements in health outcomes . It holds great potential for significantly reducing asthma-related morbidity among low-income children Background : Despite national disease management plans , optimal asthma management remains a challenge in Australia . Community pharmacists are ideally placed to implement new strategies that aim to ensure asthma care meets current st and ards of best practice . The impact of the Pharmacy Asthma Care Program ( PACP ) on asthma control was assessed using a multi-site r and omised intervention versus control repeated measures study design . Methods : Fifty Australian pharmacies were r and omised into two groups : intervention pharmacies implemented the PACP ( an ongoing cycle of assessment , goal setting , monitoring and review ) to 191 patients over 6 months , while control pharmacies gave their usual care to 205 control patients . Both groups administered question naires and conducted spirometric testing at baseline and 6 months later . The main outcome measure was asthma severity/control status . Results : 186 of 205 control patients ( 91 % ) and 165 of 191 intervention patients ( 86 % ) completed the study . The intervention result ed in improved asthma control : patients receiving the intervention were 2.7 times more likely to improve from “ severe ” to “ not severe ” than control patients ( OR 2.68 , 95 % CI 1.64 to 4.37 ; p<0.001 ) . The intervention also result ed in improved adherence to preventer medication ( OR 1.89 , 95 % CI 1.08 to 3.30 ; p = 0.03 ) , decreased mean daily dose of reliever medication ( difference −149.11 μg , 95 % CI −283.87 to −14.36 ; p = 0.03 ) , a shift in medication profile from reliever only to a combination of preventer , reliever with or without long-acting β agonist ( OR 3.80 , 95 % CI 1.40 to 10.32 ; p = 0.01 ) and improved scores on risk of non-adherence ( difference −0.44 , 95 % CI −0.69 to −0.18 ; p = 0.04 ) , quality of life ( difference −0.23 , 95 % CI −0.46 to 0.00 ; p = 0.05 ) , asthma knowledge ( difference 1.18 , 95 % CI 0.73 to 1.63 ; p<0.01 ) and perceived control of asthma question naires ( difference −1.39 , 95 % CI −2.44 to −0.35 ; p<0.01 ) . No significant change in spirometric measures occurred in either group . Conclusions : A pharmacist-delivered asthma care programme based on national guidelines improves asthma control . The sustainability and implementation of the programme within the healthcare system remains to be investigated Abstract Objective : To determine whether locally developed guidelines on asthma and diabetes disseminated through practice based education improve quality of care in non-training , inner city general practice s. Design : R and omised controlled trial with each practice receiving one set of guidelines but providing data on the management of both conditions . Subjects:24 inner city , non-training general practice s. Setting : East London . Main outcome measures : Recording of key variables in patient records ( asthma : peak flow rate , review of inhaler technique , review of asthma symptoms , prophylaxis , occupation , and smoking habit ; diabetes : blood glucose concentration , glycaemic control , funduscopy , feet examination , weight , and smoking habit ) ; size of practice disease registers ; prescribing in asthma ; and use of structured consultation “ prompts . ” Results : In practice s receiving diabetes guidelines , significant improvements in recording were seen for all seven diabetes variables . Both groups of practice s showed improved recording of review of inhaler technique , smoking habit , and review of asthma symptoms . In practice s receiving asthma guidelines , further improvement was seen only in recording of review of inhaler technique and quality of prescribing in asthma . Sizes of disease registers were unchanged . The use of structured prompts was associated with improved recording of four of seven variables on diabetes and all six variables on asthma . Conclusions : Local guidelines disseminated via practice based education improve the management of diabetes and possibly of asthma in inner city , non-training practice s. The use of simple prompts may enhance this improvement OBJECTIVE To assess the practice -level effects of ( 1 ) a physician peer leader intervention and ( 2 ) peer leaders in combination with the introduction of asthma education nurses to facilitate care improvement . And , to compare findings with previously reported patient-level outcomes of trial enrollees . STUDY SETTING Data were included on children 5 - 17 years old with asthma in 40 primary care practice s , affiliated with managed health care plans enrolled in the Pediatric Asthma Care Patient Outcomes Research Team ( PORT ) r and omized trial . STUDY DESIGN Primary care practice s were r and omly assigned to one of two care improvement arms or to usual care . Automated cl aims data were analyzed for 12-month periods using a repeated cross-sectional design . The primary outcome was evidence of at least one controller medication dispensed among patients with persistent asthma . Secondary outcomes included controller dispensing among all identified asthmatics , evidence of chronic controller use , and the dispensing of oral steroids . Health service utilization outcomes included numbers of ambulatory visits and hospital-based events . PRINCIPAL FINDINGS The proportion of children with persistent asthma prescribed controllers increased in all study arms . No effect of the interventions on the proportion receiving controllers was detected ( peer leader intervention effect 0.01 , 95 percent confidence interval [ CI ] : -0.07 , 0.08 ; planned care intervention effect -0.03 , 95 percent CI : -0.09 , 0.02 ) . A statistical trend was seen toward an increased number of oral corticosteroid bursts dispensed in intervention practice s. Significant adjusted increases in ambulatory visits of 0.08 - 0.10 visits per child per year were seen in the first intervention year , but only a statistical trend in these outcomes persisted into the second year of follow-up . No differences in hospital-based events were detected . CONCLUSIONS This analysis showed a slight increase in ambulatory asthma visits as a result of asthma care improvement interventions , using automated data . The absence of detectable impact on medication use at the practice level differs from the positive intervention effect observed in patient self-reported data from trial enrollees . Analysis of automated data on nonenrollees adds information about practice -level impact of care improvement strategies . Benefits of practice -level interventions may accrue disproportionately to the subgroup of trial enrollees . The effect of such interventions may be less apparent at the level of practice s or health plans Abstract Objectives To assess the feasibility and effectiveness of a general practice based , proactive system of asthma care in children . Design R and omised controlled trial with cluster sampling by general practice . Setting General practice s in the northern region of the Australian Capital Territory . Participants 174 children with moderate to severe asthma who attended 24 general practitioners . Intervention System of structured asthma care ( the 3 + visit plan ) , with participating families reminded to attend the general practitioner . Main outcome measures Process measures : rates for asthma consultations with general practitioner , written asthma plans , completion of the 3 + visit plan ; clinical measures : rates for emergency department visits for asthma , days absent from school , symptom-free days , symptoms over the past year , activity limitation over the past year , and asthma drug use over the past year ; spirometric lung function measures before and after cold air challenge . Results Intervention group children had significantly more asthma related consultations ( odds ratio for three or more asthma related consultations 3.8 ( 95 % confidence interval 1.9 to 7.6 ; P = 0.0001 ) , written asthma plans ( 2.2 ( 1.2 to 4.1 ) ; P = 0.01 ) , and completed 3 + visit plans ( 24.2 ( 5.7 to 103.2 ) ; P = 0.0001 ) than control children and a mean reduction in measurements of forced expiratory volume in one second after cold air challenge of 2.6 % ( 1.7 to 3.5 ) ; P = 0.0001 ) less than control children . The number needed to treat ( benefit ) for one additional written asthma action plan was 5 ( 3 to 41 ) children . Intervention group children had lower emergency department attendance rates for asthma ( odds ratio 0.4 ( 0.2 to 1.04 ) ; P = 0.06 ) and less speech limiting wheeze ( 0.2 ( 0.1 to 0.4 ) ; P = 0.0001 ) than control children and were more likely to use a spacer ( 2.8 ( 1.6 to 4.7 ) ; P = 0.0001 ) . No differences occurred in number of days absent from school or symptom-free day scores . Conclusions Proactive care with active recall for children with moderate to severe asthma is feasible in general practice and seems to be beneficial OBJECTIVE : To study the effectiveness of an intensive small group education and peer review programme aim ed at implementing national guidelines on asthma/chronic obstructive pulmonary disease ( COPD ) on care provision by general practitioners ( GPs ) and on patient outcomes . DESIGN : A r and omised experimental study with pre-measurement and post-measurement ( after one year ) in an experimental group and a control group in Dutch general practice . SUBJECTS AND INTERVENTION : Two groups of GPs were formed and r and omised . The education and peer review group ( 17 GPs with 210 patients ) had an intervention consisting of an interactive group education and peer review programme ( four sessions each lasting two hours ) . The control group consisted of 17 GPs with 223 patients ( no intervention ) . MAIN OUTCOME MEASURES : Knowledge , skills , opinion about asthma and COPD care , presence of equipment in practice ; actual performance about peakflow measurement , non-pharmacological and pharmacological treatment ; asthma symptoms ( Dutch Medical Research Council ) , smoking habits , exacerbation ratio , and disease specific quality of life ( QOL-RIQ ) . Data were collected by a written question naire for GPs , by self recording of consultations by GPs , and by a written self administered question naire for adult patients with asthma/ COPD . RESULTS : Data from 34 GP question naires , 433 patient question naires , and recordings from 934 consultations/visits and 350 repeat prescriptions were available . Compared with the control group there were only significant changes for self estimated skills ( + 16 % , 95 % confidence interval 4 % to 26 % ) and presence of peakflow meters in practice ( + 18 % , p < 0.05 ) . No significant changes were found for provided care and patient outcomes compared with the control group . In the subgroup of more severe patients , the group of older patients , and in the group of patients not using anti-inflammatory medication at baseline , no significant changes compared with the control group were seen in patient outcomes . CONCLUSION : Except for two aspects , intensive small group education and peer review in asthma and COPD care do not seem to be effective in changing relevant aspects of the provided care by GPs in accordance with guidelines , nor in changing patients ' health status Our aim was to evaluate effects on prescribing for urinary tract infection ( UTI ) and asthma , of an education with messages based on national guidelines , aim ed at improving prescribing in primary care in Sweden . The study is part of the European Drug Education Project . A r and omized controlled trial , with groups of general practitioners ( GPs ) allocated to education on UTI ( 18 groups , 104 GPs ) or asthma ( 18 groups , 100 GPs ) , the two parallel intervention arms being controls for each other . Feedback was provided on the GP 's judgments of simulated cases and prescribing . Prescribing indicators were developed and measured before and after the intervention . Analysis was performed by multi-level technique . Prescribing of first choice UTI drugs increased in the intervention arm from 52 % to 70 % and remained constant in the control arm ( P < 0.001 ) . The proportion of patients receiving an inhaled corticosteroid increased insignificantly in both study arms . The educational model can be used to improve prescribing . Further studies are needed to define when the model is effective OBJECTIVE The purpose of this study was to show the association between changes in clinician self-efficacy and readiness to change and implementation of an asthma management program ( Easy Breathing ) . METHODS A 36 month r and omized , controlled trial was conducted involving 24 pediatric practice s ( 88 clinicians ) . R and omized clinicians received interventions design ed to enhance clinician self-efficacy and readiness to change which were measured at baseline and 3 years . Interventions consisted of an educational toolbox , seminars , teleconferences , mini-fellowships , opinion leader visits , clinician-specific feedback , and pay for performance . The primary outcome was program utilization ( number of children enrolled in Easy Breathing/year ) ; secondary outcomes included development of a written treatment plan and severity-appropriate therapy . RESULTS At baseline , clinicians enrolled 149 ± 147 ( mean ± SD ) children/clinician/year ; 84 % of children had a written treatment plan and 77 % of plans used severity-appropriate therapy . At baseline , higher self-efficacy scores were associated with greater program utilization ( relative rate [ RR ] , 1.34 ; 95 % confidence interval [ CI ] , 1.04 - 1.72 ; P = .04 ) but not treatment plan development ( RR , 0.63 ; 95 % CI , 0.29 - 1.35 ; P = .23 ) or anti-inflammatory use ( RR , 1.76 ; 95 % CI , 0.92 - 3.35 ; P = .09 ) . Intervention clinicians participated in 17 interventions over 36 months . At study end , self-efficacy scores increased in intervention clinicians compared to control clinicians ( P = .01 ) and more clinicians were in an action stage of change ( P = .001 ) but these changes were not associated with changes in primary or secondary outcomes . CONCLUSIONS Self-efficacy scores correlated with program use at baseline and increased in the intervention arm , but these increases were not associated with greater program-related activities . Self-efficacy may be necessary but not sufficient for behavior change Rationale and aims Quality circles ( QCs ) are well established as a means of aiding doctors . New quality improvement strategies include benchmarking activities . The aim of this paper was to evaluate the efficacy of QCs for asthma care working either with general feedback or with an open benchmark . Methods Twelve QCs , involving 96 general practitioners , were organized in a r and omized controlled trial . Six worked with traditional anonymous feedback and six with an open benchmark ; both had guided discussion from a trained moderator . Forty-three primary care practice s agreed to give out question naires to patients to evaluate the efficacy of QCs . Results A total of 256 patients participated in the survey , of whom 185 ( 72.3 % ) responded to the follow-up 1 year later . Use of inhaled steroids at baseline was high ( 69 % ) and self-management low ( asthma education 27 % , individual emergency plan 8 % , and peak flow meter at home 21 % ) . Guideline adherence in drug treatment increased ( P = 0.19 ) , and asthma steps improved ( P = 0.02 ) . Delivery of individual emergency plans increased ( P = 0.008 ) , and unscheduled emergency visits decreased ( P = 0.064 ) . There was no change in asthma education and peak flow meter usage . High medication guideline adherence was associated with reduced emergency visits ( OR 0.24 ; 95 % CI 0.07–0.89 ) . Use of theophylline was associated with hospitalization ( OR 7.1 ; 95 % CI 1.5–34.3 ) and emergency visits ( OR 4.9 ; 95 % CI 1.6–14.7 ) . There was no difference between traditional and benchmarking QCs . Conclusions Quality circles working with individualized feedback are effective at improving asthma care . The trial may have been underpowered to detect specific benchmarking effects . Further research is necessary to evaluate strategies for improving the self-management of asthma patients Background It is difficult to keep control over prescribing behaviour in general practice s. The purpose of this study was to assess the effects of a dissemination strategy of multidisciplinary guidelines on the volume of drug prescribing . Methods The study included two design s , a quasi-experimental pre/post study with concurrent control group and a r and om sample of GPs within the intervention group . The intervention area with 53 GPs was compared with a control group of 54 r and omly selected GPs in the south and centre of the Netherl and s. Additionally , a r and omisation was executed in the intervention group to create two arms with 27 GPs who were more intensively involved in the development of the guideline and 26 GPs in the control group . A multidisciplinary committee developed prescription guidelines . Subsequently these guidelines were disseminated to all GPs in the intervention region . Additional effects were studied in the subgroup trial in which GPs were invited to be more intensively involved in the guideline development procedure . The guidelines contained 14 recommendations on antibiotics , asthma/ COPD drugs and cholesterol drugsThe main outcome measures were prescription data of a three-year period ( one year before and 2 years after guideline dissemination ) and proportion of change according to recommendations . Results Significant short-term improvements were seen for one recommendation : mupirocin . Long-term changes were found for cholesterol drug prescriptions . No additional changes were seen for the r and omised controlled study in the subgroup . GPs did not take up the invitation for involvement . Conclusion Disseminating multidisciplinary guidelines that were developed within a region , has no clear effect on prescribing behaviour even though GPs and specialists were involved more intensively in their development . Apparently , more effort is needed to bring about change To assess the effectiveness of an intervention design ed to increase compliance with national asthma care guidelines in primary care safety net health centers serving high-disparity patient population s , we conducted a group-r and omized controlled trial ( seven intervention sites and nine control sites ) in federally funded community health centers in eight southeastern states . There were three components involved in the intervention : re sources ( asthma kits including peak flow meter , MDI spacer device , plus educational material s ) , training of all health center staff in asthma care guidelines , and tools or templates for practice -level systems change ( asthma flow sheets and st and ing orders ) . Control group sites received only copies of the national asthma guidelines . Chart review s were performed to determine practitioner 's compliance with national guidelines for asthma care . Clinicians practicing in intervention health centers showed significantly ( p < 0.01 ) greater improvement on some measures than did the control health centers , although postintervention compliance with guidelines was still suboptimal . Disseminating national guidelines is not enough . Providing training and guideline -specific re sources , in combination with tools for practice change , improved care significantly even in safety net health centers serving high-disparity patient population OBJECTIVE Clinical asthma guidelines recommend spirometry for asthma diagnosis , but there is inconsistent evidence about benefits to patients in using it for ongoing management . Our aim was to determine whether training in the use of spirometry for management of asthma provided better health outcomes and improved the quality of care in the primary care setting . DESIGN Pragmatic , cluster r and omized controlled trial . SETTING General practice s in two states of Australia . PARTICIPANTS Forty practice s and 397 adults with asthma . INTERVENTION The staff of 26 intervention practice s received comprehensive spirometry training . Fourteen control practice s provided usual care . MAIN OUTCOME MEASURES Primary outcome measures were quality of life , self-reported asthma symptoms and lung function . Secondary measures related to the process of care ( e.g. performance of spirometry , preparation of a written asthma action plan ) and patient and general practitioner rating of the acceptability and usefulness of spirometry . RESULTS There were no statistically significant differences between the groups at 12 months for quality of life ( mean difference = -0.23 ; 95 % CI : -0.44 , -0.01 ) , days off work ( rate ratio = 1.52 ; 95 % CI : 0.91 , 2.54 ) , exacerbations ( rate ratio = 1.09 ; 95 % CI : 0.85 , 1.41 ) , asthma on waking ( rate ratio = 1.21 ; 95 % CI : 0.79 , 1.85 ) , nocturnal asthma ( rate ratio = 0.98 ; 95 % CI : 0.63 , 1.51 ) and post-bronchodilator FEV(1)/FVC ratio ( mean difference = -0.01 , 95 % CI : -0.03 , 0.02 ) . There was no improvement in the quality of care provided . CONCLUSIONS Training in spirometry did not result in any measurable improvement in the use of spirometry , quality of management of asthma or patient outcomes in primary care BACKGROUND The Canadian Clinical Practice Guidelines ( CPGs ) for the management of asthmatic patients were last published in 1999 , with up date s in 2001 and June 2004 . Large disparities exist in the implementation of these guidelines into clinical practice . OBJECTIVE The present study evaluated the knowledge of Quebec-based primary care physicians regarding the CPGs , as well as patient outcomes before and after introducing physicians to a new clinical tool -- a memory aid in the form of a self-inking paper stamp checklist summarizing CPG criteria and guidelines for assessing asthmatic patient control and therapy . The primary objective of the present study was to assess whether the stamp would improve physicians ' knowledge of the CPGs , and as a secondary objective , to assess whether it would decrease patient emergency room visits and hospitalizations . METHODS A prospect i ve , r and omized , controlled study of 104 primary care physicians located in four Quebec regions was conducted . Each physician initially responded to questions on their knowledge of the CPGs , and was then r and omly assigned to one of four groups that received information about the CPGs while implementing an intervention ( the stamp tool ) aim ed at supporting their decision-making process at the point of care . Six months later , the physicians were retested , and patient outcomes for approximately one year were obtained from the Régie de l'assurance maladie du Québec . RESULTS The stamp significantly improved physicians ' knowledge of the CPGs in all Quebec regions tested , and reduced emergency room visits and hospitalizations in patients who were followed for at least one year . CONCLUSION A paper stamp summarizing CPGs for asthma can be used effectively to increase the knowledge of physicians and to positively affect patient outcomes STUDY OBJECTIVES To determine whether an interactive physician seminar that has been shown to improve patient/parent satisfaction and to decrease emergency department visits for children with asthma was also effective for those children from low-income families . DESIGN Seventy-four pediatricians and 637 of their patients were r and omized to receive two asthma seminars or no educational programs and were observed for 2 years . SETTING Physicians in the New York , NY , and Ann Arbor , MI , areas were enrolled , and , on average , 10 patients with asthma per provider were surveyed and observed for 2 years . PATIENTS OR PARTICIPANTS A total of 637 subjects were enrolled , and 369 subjects remained in the study after 2 years . Of these , 279 had complete medical and survey information . INTERVENTIONS Physicians were r and omized , and then a r and om sample of their patients was enrolled and surveyed regarding the physician 's communication style , the child 's asthma symptoms , medical needs , and asthma care . Low income was defined as annual income of < 20,000 dollars . MEASUREMENTS AND RESULTS The families of 36 children ( 13 % ) had an income of < 20,000 dollars , and they were treated by 23 physicians . Low-income children in the treatment group tended to have higher levels of use of controller medications , to receive a written asthma action plan , and to miss fewer days of school , although these differences were not statistically significant compared to low-income children in the control group . However , low-income treatment group children were significantly less likely to be admitted to an emergency department ( annual rate , 0.208 vs 1.441 , respectively ) or to a hospital ( annual rate , 0 vs 0.029 , respectively ) for asthma care compared to children in the control group . CONCLUSIONS The educational program for physicians improved asthma outcomes for their low-income patients . Provider interventions targeted to these high-risk patients may diminish hospital and emergency department asthma care CONTEXT . Barriers impede translating recommendations for asthma treatment into practice , particularly in inner cities where asthma morbidity is highest . METHODS . The purpose of this study was to test the effectiveness of timely patient feedback in the form of a letter providing recent patient-specific symptoms , medication , and health service use combined with guideline -based recommendations for changes in therapy on improving the quality of asthma care by inner-city primary care providers and on result ant asthma morbidity . This was a r and omized , controlled clinical trial in 5- to 11-year-old children ( n = 937 ) with moderate to severe asthma receiving health care in hospital- and community-based clinics and private practice s in 7 inner-city urban areas . The caretaker of each child received a bimonthly telephone call to collect clinical information about the child 's asthma . For a full year , the providers of intervention group children received bimonthly computer-generated letters based on these calls summarizing the child 's asthma symptoms , health service use , and medication use with a corresponding recommendation to step up or step down medications . We measured the number and proportion of scheduled visits result ing in stepping up of medications , asthma symptoms ( 2-week recall ) , and health care use ( 2-month recall ) . RESULTS . In this population , only a modest proportion of children whose symptoms warranted a medication increase actually had a scheduled visit to reevaluate their asthma treatment . However , in the 2-month interval after receipt of a step-up letter , 17.1 % of the letters were followed by scheduled visits in the intervention group compared with scheduled visits 12.3 % of the time by the control children with comparable clinical symptoms . Asthma medications were stepped up when indicated after 46.0 % of these visits in the intervention group compared with 35.6 % in the control group , and when asthma symptoms warranted a step up in therapy , medication changes occurred earlier among the intervention children . Among children whose medications were stepped up at any time during the 12-month study period , those in the intervention group experienced 22.1 % fewer symptom days and 37.9 % fewer school days missed . The intention-to-treat analysis showed no difference over the intervention year in the number of symptom days , yet there was a trend toward fewer days of limited activity and a significant decrease in emergency department visits by the intervention group compared with controls . This 24 % drop in emergency department visits result ed in an intervention that was cost saving in its first year . CONCLUSIONS . Patient-specific feedback to inner-city providers increased scheduled asthma visits , increased asthma visits in which medications were stepped up when clinical ly indicated , and reduced emergency department visits OBJECTIVE It is difficult to control drug-prescribing behaviour in general practice , despite the development and distribution of guidelines . The purpose of this study was to assess the effect on drug-prescribing behaviour of implementing prescribing guidelines by means of a reactive computer reminder system ( CRS ) . DESIGN Cluster-r and omised controlled trial with an incomplete block design in the south of the Netherl and s : 25 GPs ( 7 GP practice s ) received reminders about antibiotics and asthma/ COPD prescriptions , 28 GPs ( 7 GP practice s ) received reminders about cholesterol prescriptions . Prescription guidelines were integrated into the computerised GP information system . MEASUREMENTS Both performance indicators and prescription volumes were calculated as the main outcome measures . Next to individual volume measure , sum scores were constructed on the volume measures per drug group ( antibiotics , asthma/ COPD and cholesterol ) . RESULTS Variation between GPs turned out to be larger and more skewed than expected . No differences between groups were found for indicators and volumes related to recommendations advocating certain drugs . Although there was a tendency towards clinical ly relevant results for prescription volumes that were supposed to drop , the difference in sum score between the groups was not significant . For antibiotic prescriptions that were supposed to drop , the sum score for the intervention group was 28.2 ( 95 % CI : 20.8 - 44.5 ) prescriptions per 1000 patients per GP , while this was 39.7 ( 95 % CI : 29.7 - 64.1 ) for the control group ( p 0.2 ) . For prescriptions asthma/ COPD that were supposed to drop , the sum score for the intervention group was 1.1 ( 95 % CI : 0.6 - 2.6 ) prescriptions per 1000 patients per GP , while this was 2.2 ( 95 % CI : 1.4 - 4.3 ) for the control group ( p 0.1 ) . On three specific recommendations ( on quinolones for cystitis , corticosteroids for CPOD , and antibiotics for acute sore throat ) significant differences were found . CONCLUSIONS This study turned out to be underpowered due to high inter doctor variation in prescribing behaviour . Nevertheless , computerised reminders sometimes have a favourable effect on restricting certain drugs that are not or no longer indicated in general practice OBJECTIVE . The purpose of this work was to improve asthma-related health outcomes in an ethnically and geographically disparate population of economically disadvantaged school-aged children by using a team-based approach using continuous quality improvement and community health workers . PATIENTS AND METHODS . A demonstration project was conducted with 7 community clinics treating ∼3000 children with asthma 5 to 18 years of age . The overall clinic population with asthma was assessed for care-process changes through r and om cross-sectional chart review s at baseline and 24 months ( N = 560 ) . A subset of patients with either moderate or severe persistent asthma or poorly controlled asthma ( N = 405 ) was followed longitudinally for specific asthma-related clinical outcomes , satisfaction with care , and confidence managing asthma by family interview at baseline and at 12 or 24 months . Patient-centered and care-process outcomes included patient/parent assessment of quality of care and confidence in self-management , asthma action plan review , and documentation of guideline -based indicators of quality of care . Direct clinical outcomes included daytime and nighttime symptoms , use of rescue medications , acute care and emergency department visits , hospitalizations , and missed school days . Each clinic site 's degree of adherence to the intervention model was evaluated and ranked to examine the correlation between model adherence and outcomes . RESULTS . Cross-sectional data showed clinic-wide improvements in the documentation of asthma severity , review of action plans , health services use , and asthma symptoms . At follow-up in the longitudinal sample , fewer patients reported acute visits , emergency department visits , hospitalizations , frequent daytime and nighttime symptoms , and missed school days compared with baseline . More patients reported excellent or very good quality of care and confidence in asthma self-management . Linear regression analysis of the clinical sites ’ model adherence ranks against site-level combined scores estimating overall outcomes , clinical outcomes , and improvements in clinical care processes showed significant linear correlations with R2 ≥ 0.60 . CONCLUSIONS . The demonstration produced major improvements in asthma-related care processes and clinical outcomes . Closer adherence to the demonstration model was directly associated with better outcomes OBJECTIVES To describe the use of antiasthma drugs among the study patients and to evaluate whether therapeutic outcomes monitoring ( TOM ) is associated with improved quality of drug therapy . DESIGN Prospect i ve , controlled , multicenter study . Consumption of antiasthma medications was measured as the number of defined daily doses ( DDDs ) purchased . Data were collected from the pharmacies ' computer systems for a period beginning 6 months before the start of the study ( period 1 ) and during its first and second half-years ( periods 2 and 3 ) . Treatment changes for TOM patients were classified on the basis of drug regimens at periods 1 and 3 . SETTING Community pharmacies in Denmark ( 16 intervention , 15 control ) . PATIENTS Five hundred patients with asthma aged 16 to 60 years who were being treated in primary health care ; this study used data from 350 patients from this sample . INTERVENTION TOM . MAIN OUTCOME MEASURES Changes in the use of individual drugs and changes in therapeutic patterns -- distribution of purchased drugs ; proportion of corticosteroid users ; frequency of drug regimens used ; treatment changes for TOM patients . RESULTS TOM patients ' consumption of beta2-agonists decreased by 12 % overall from period 1 through period 3 , while control patients ' consumption of these medications decreased by only 1 % . TOM patients ' use of inhaled corticosteroids increased by more than 50 % compared with 9 % among controls . In both groups , about one-half of all purchased DDDs were for inhaled beta2-agonists . The proportion of inhaled corticosteroids increased from 27 % to 42 % of total DDDs for the TOM group and remained constant for controls . Of patients using beta2-agonists , 68 % also used inhaled steroids initially in both the TOM and control groups . The proportion of inhaled steroid users in the TOM group increased to 84 % , and to 70 % among controls . The most common regimen was inhaled short-acting beta2-agonists and corticosteroids in combination , and the second most common regimen was monotherapy with short-acting beta2-agonists . With time , the regimens changed more toward consensus guidelines among TOM patients . Changes in drug therapy totaled 451 , averaging 2.4 changes per TOM patient . The largest number of changes ( 49 % ) involved inhaled corticosteroids . CONCLUSION Changes in medication use among TOM patients were toward improved asthma treatment . Our results show that community pharmacists , physicians , and patients , working together , can improve prescribing , solve drug therapy problems , and improve outcomes for patients with moderate-to-severe asthma BACKGROUND AND OBJECTIVES This project focused on increasing compliance , in a large family practice group , with quality indicators for the management of asthma . The objective was to determine if use of a flow sheet incorporating the Global Initiative for Asthma ( GINA ) guidelines could improve compliance with those guidelines if the flow sheet was placed in patients ' medical records . METHODS After review and selection of 14 clinical quality indicators , physicians in the practice implemented a flow sheet as an intervention . These flow sheets were inserted into the records of 122 r and omly selected patients with asthma . Medical records were review ed before the flow sheets were placed in the records , and again approximately 6 months later , to determine if there was a change in compliance with the quality indicators . RESULTS Improvement of documentation was demonstrated in 13 of the 14 quality indicators . CONCLUSIONS The results indicate that compliance with asthma management quality indicators can improve with the use of a flow sheet OBJECTIVE To assess the effect of a structured program of pharmaceutical care on changes in disease control , functional status , and health services utilization for pediatric and adolescent patients with moderate-to-severe asthma . DESIGN R and omized , controlled trial . SETTING Community and clinic pharmacies ( 14 intervention and 18 usual care pharmacies ) in western Washington State . PATIENTS Three hundred thirty children , aged 6 to 17 years , with asthma . INTERVENTION Structured training for the intervention group pharmacists to provide individualized asthma management services during patient-pharmacist encounters for up to 1 year following the patient 's enrollment into the study . MAIN OUTCOME MEASURES The primary outcome measure was change in pulmonary function as measured by peak expiratory flow rate and spirometry . Secondary outcome measures included changes in functional status and use of asthma-related health care services . RESULTS The intervention had no significant effect on the health or health services use outcomes of study subjects . When compared with the usual care group , there was no evidence that patients from the intervention group experienced improvements in pulmonary function , functional status , quality of life , asthma management , or satisfaction with care . In addition , there were no differences between groups in use of anti-inflammatory medications , total or asthma-related medical care utilization , or total or asthma-related school days lost . CONCLUSION This pharmaceutical care intervention had no significant effect on the health or health services use outcomes of pediatric patients with asthma . The intervention may not have been powerful enough to significantly affect pharmacists ' behaviors and asthma patients ' outcomes in community pharmacy setting s , and there is evidence that the pharmacists ' compliance with the study protocol was low due , in part , to patient- and practice -related obstacles OBJECTIVE To improve health outcomes of children and adolescents with asthma using a multifaceted intervention for GPs . METHODS The design of the study was a cluster r and omized controlled trial . GPs were r and omized at a practice level in general practice clinics in Melbourne , Australia . Participants were children/adolescents aged 2 - 14 years with asthma and their caregivers identified from the medical records of participating clinics . Question naires were completed by 411 at baseline and 341 at follow-up . The intervention arm ( n = 18 GPs ) participated in a small group asthma education programme and was provided with locally adapted paediatric asthma guidelines . One control arm ( n = 18 GPs ) received only the adapted paediatric asthma guidelines , while the other control arm ( n = 15 GPs ) received an unrelated educational intervention . The outcome measures of the study were children/adolescents and caregivers completed question naires about asthma management and control , asthma knowledge and quality of life at recruitment and 6 months later . Ownership of a written asthma action plan ( WAAP ) was the primary outcome . RESULTS There was no evidence for changes in ownership of WAAPs between the three study arms . Adolescents in the intervention group reported an improvement in quality of life subscale score ' positive effects ' ( mean difference = 2.64 , P = 0.01 ) , but there was no evidence for an effect of the intervention on other study outcomes among the three study arms . CONCLUSIONS The intervention was associated with some improvement in quality of life for adolescents . However , overall , the intervention did not translate into increased ownership of WAAPs , control of asthma or improved quality of life Abstract Objective . To evaluate the effects of postal feedback with clinical ly relevant data on general practitioners ' prescribing compared with feedback with aggregate data on prescribing patterns of asthma drugs . Methods . The study was a r and omised , controlled trial . The general practitioners ( GPs ) in the County of Funen , Denmark ( 292 GPs representing 178 practice s ) were r and omised to one of three groups receiving different forms of prescriber feedback . The first group received detailed and clinical ly relevant data on asthma drug prescribing patterns and a guideline statement . These data included tables with counts of asthma patients following classification of each individual 's consumption of inhaled β2-agonists and use of inhaled steroids . The second group received aggregate data on asthma drug prescribing patterns and a guideline statement , and the third group received feedback on an unrelated subject and served as control for the other groups . Each GP received prescriber feedback three times within a 6-month period . The last two letters with prescriber feedback had up date d information with the purpose of showing changes in prescribing patterns . Effects were followed for a period of 1 year . The main outcome measures were change in fraction of asthmatics treated with inhaled steroids and incidence rate of treatment with inhaled steroids . Results . The three groups had similar baseline characteristics . None of the two types of feedback on prescribing of asthma drugs had a statistically significant impact on GPs ' prescribing patterns . Conclusion . Mailed prescriber feedback of detailed and clinical ly relevant data with a guideline statement , without revealing patient identities , has little or no impact on prescribing patterns Aims : To evaluate the effect of the implementation of an asthma clinical pathway on asthma in children in general practice . Methods : A r and omized , controlled trial involving 270 general practitioners . One group of general practitioners implemented the asthma clinical pathway for children ( intervention group ) and the control group continued with their usual asthma medical care management . The main outcome measures were admissions to hospital for asthma and attendance at the Children 's Emergency Department . Compliance with the guidelines was assessed by examining asthma drug prescriptions . Results : Admissions to hospital for asthma dropped 40 % in the intervention group , by 33 % in the control group and by 22 % in general practitioners not participating in the trial . The differences between the intervention and control and between the intervention and non‐participating general practitioners were not statistically significant . The decrease in attendance at the Children 's Emergency Department decreased by 25 % , 30 % and 19 % , respectively , but this was not statistically significant . There was a significant decrease in prescriptions for oral relievers , dry powder relievers in the under 6s , mast cell stabilizers and methylxanthines in both control and intervention groups . However , only for oral relievers was there a significant difference between the intervention group and control , with the decrease larger in the intervention group ( p<0.001 ) OBJECTIVE To assess improvement in documentation of asthma indicators using the Asthma Toolbox , an asthma decision-making tool developed in accord with National Asthma Education and Prevention Program guidelines . DESIGN Retrospective medical record review using cross-sectional , independent , r and om sample s. Review s were conducted for 1-year periods before and after implementation and after revision reflecting 2007 guideline modifications . SETTING Two inner-city , federally qualified health center programs providing pediatric primary care to housed and homeless population s. PARTICIPANTS A total of 1246 patients aged 6 months to 18 years with at least 1 asthma visit to a community health center using paper records ( n = 600 ) or a mobile medical program serving family homeless shelters using an electronic health record ( EHR ; n = 646 ) . INTERVENTION Implementation of the Asthma Toolbox incorporated into paper encounter forms and embedded in the EHR to guide providers ( ie , physicians and nurse practitioners ) through pediatric asthma assessment and management . MAIN OUTCOME MEASURES Documentation of a subset of asthma severity/control measures , emergency department visits , hospitalizations , and percentage of persistent asthmatic patients prescribed controller medications . RESULTS Documentation of each asthma indicator increased significantly after implementation ( χ(2 ) tests ; P < .001 all comparisons ) for both programs . Documentation of severity/control increased from 25.5 % to 77.5 % in paper records and from 11.7 % to 85.1 % in the EHR ( P < .001 ) . Increases were sustained after Asthma Toolbox revision for all indicators . The percentage of patients with persistent/uncontrolled asthma prescribed controller medications reached 96 % to 97 % in both programs . CONCLUSION Use of the Asthma Toolbox , an asthma decision-making tool , significantly increased documentation of pediatric asthma management among providers working in high-disparity , urban primary care setting OBJECTIVE To evaluate a family-focused asthma intervention design ed for inner-city children 5 to 11 years old with moderate to severe asthma . STUDY DESIGN R and omized , multisite , controlled trial to minimize symptom days ( wheeze , loss of sleep , reduction in play activity ) measured by a 2-week recall assessed at 2-month intervals over a 2-year follow-up period . The intervention was tailored to each family 's individual asthma risk profile assessed at baseline . RESULTS Averaged over the first 12 months , participants in the intervention group ( n = 515 ) reported 3.51 symptom days in the 2 weeks before each follow-up interview compared with 4.06 symptom days for the control group ( n = 518 ) , a difference of 0.55 ( 95 % CI , 0.18 to 0.92 , P = .004 ) . The reduction among children with severe asthma was approximately 3 times greater ( 1.54 d/2 wk ) . More children in the control group ( 18.9 % ) were hospitalized during the intervention compared with children in the intervention group ( 14 . 8 % ) , a decrease of 4.19 % ( CI , -8.75 to 0.36 , P = .071 ) . These improvements were maintained in the intervention group during the second year of follow-up , during which they did not have access to the asthma counselor . CONCLUSIONS We demonstrated that an individually tailored , multifaceted intervention carried out by Masters-level social workers trained in asthma management can reduce asthma symptoms among children in the inner city OBJECTIVE To evaluate the effectiveness of the Practitioner Asthma Communication and Education ( PACE ) Australia program , an innovative communication and paediatric asthma management program for general practitioners . DESIGN R and omised controlled trial . SETTING General practice s from two regions in metropolitan Sydney . PARTICIPANTS 150 GPs , who were recruited between 2006 and 2008 , and 221 children with asthma in their care . INTERVENTION GPs in the intervention group participated in two 3-hour workshops , focusing on communication and education strategies to facilitate quality asthma care . MAIN OUTCOME MEASURES Patient outcomes included receipt of a written asthma action plan ( WAAP ) , appropriate medication use , parent days away from work , and child days away from school or child care . GP outcomes included frequency of providing a WAAP and patient education , communication and teaching behaviour , and adherence to national asthma guidelines regarding medication use . RESULTS More patients of GPs in the intervention group reported receipt of a WAAP ( difference , 15 % ; 95 % CI , 2 % to 28 % ; adjusted P=0.046 ) . In the intervention group , children with infrequent intermittent asthma symptoms had lower use of inhaled corticosteroids ( difference , 24 % ; 95 % CI , -43 % to -5 % ; P=0.03 ) and long-acting bronchodilators ( difference , 19 % ; 95 % CI , -34 % to -5 % ; P=0.02 ) . GPs in the intervention group were more confident when communicating with patients ( difference 22 % ; 95 % CI , 3 % to 40 % ; P=0.03 ) . A higher proportion of GPs in the intervention group reported providing a WAAP more than 70 % of the time ( difference , 23 % ; 95 % CI , 11 % to 36 % ; adjusted P=0.002 ) and prescribing spacer devices more than 90 % of the time ( difference , 29 % ; 95 % CI , 16 % to 42 % ; adjusted P=0.02 ) . CONCLUSIONS The PACE Australia program improved GPs ' asthma management practice s and led to improvements in some important patient outcomes . TRIAL REGISTRATION Australian New Zeal and Clinical Trials Registry ACTRN12607000067471 BACKGROUND Guidelines recommend preventive medications for all children with persistent asthma , yet young urban children often receive inadequate therapy . This may occur in part because primary care providers are unaware of the severity of their patients ' symptoms . OBJECTIVE To determine whether systematic school-based asthma screening , coupled with primary care provider notification of asthma severity , will prompt providers to take preventive medication action ( prescribe a new preventive medication or change a current dose ) . DESIGN Children aged 3 to 7 years with mild persistent to severe persistent asthma were identified at the start of the 2002 - 2003 school year in Rochester . Children were assigned r and omly to a provider notification group ( child 's primary care provider notified of asthma severity ) or a control group ( provider not notified of severity ) . Primary care providers of children in the provider notification group were sent a facsimile indicating the child 's symptoms and recommending medication action based on national criteria . Interviewers blinded to the child 's group assignment called parents 3 to 6 months later to determine if preventive actions were taken . RESULTS Of 164 eligible children with mild persistent or more severe asthma , 151 ( 92.1 % ) were enrolled . Children in the provider notification group were not more likely to receive a preventive medication action than were children in the control group ( 21.9 % vs 26.0 % ; P = .57 ) . Additional preventive measures , including encouraging compliance with medications ( 33.3 % vs 31.3 % ; P = .85 ) , recommending environmental modifications ( 39.3 % vs 42.4 % ; P = .86 ) , and referrals for specialty care ( 6.6 % vs 6.0 % ; P > .99 ) , also did not differ between the provider notification and control groups . At the end of the study , 52.4 % of children in both groups with no medication changes were still experiencing persistent symptoms . CONCLUSIONS School-based asthma screening identified many symptomatic children in need of medication modification . Provider notification , however , did not improve preventive care . Findings suggest that more powerful interventions are needed to make systematic asthma screening effective OBJECTIVE To evaluate the cost-effectiveness of an educational outreach intervention to improve primary respiratory care by South African nurses . METHODS Cost-effectiveness analysis alongside a pragmatic cluster r and omised controlled trial , with individual patient data . The intervention , the Practical Approach to Lung Health in South Africa ( PALSA ) , comprised educational outreach based on syndromic clinical practice guidelines for tuberculosis , asthma , chronic obstructive pulmonary disease , pneumonia and other respiratory diseases . The study included 1999 patients aged 15 or over with cough or difficult breathing , attending 40 primary care clinics staffed by nurses in the Free State province . They were interviewed at first presentation , and 1856 ( 93 % ) were interviewed 3 months later . RESULTS The intervention increased the tuberculosis case detection rate by 2.2 % and increased the proportion of patients appropriately managed ( that is , diagnosed with tuberculosis or prescribed an inhaled corticosteroid for asthma or referred with indicators of severe disease ) by 10 % . It costs the health service $ 68 more for each extra patient diagnosed with tuberculosis and $ 15 more for every extra patient appropriately managed . Analyses were most sensitive to assumptions about how long training was effective for and to inclusion of household and tuberculosis treatment costs . CONCLUSION This educational outreach method was more effective and more costly than usual training in improving tuberculosis , asthma and urgent respiratory care . The extra cost of increasing tuberculosis case detection was comparable to current costs of passive case detection . The syndromic approach increased cost-effectiveness by also improving care of other conditions . This educational intervention was sustainable , reaching thous and s of health workers and hundreds of clinics since the trial CONTEXT It is not known whether patient outcomes are enhanced by effective pharmacist-patient interactions . OBJECTIVE To assess the effectiveness of a pharmaceutical care program for patients with asthma or chronic obstructive pulmonary disease ( COPD ) . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at 36 community drugstores in Indianapolis , Ind. We enrolled 1113 participants with active COPD or asthma from July 1998 to December 1999 . Outcomes were assessed in 947 ( 85.1 % ) participants at 6 months and 898 ( 80.7 % ) at 12 months . INTERVENTIONS The pharmaceutical care program ( n = 447 ) provided pharmacists with recent patient-specific clinical data ( peak expiratory flow rates [ PEFRs ] , emergency department [ ED ] visits , hospitalizations , and medication compliance ) , training , customized patient educational material s , and re sources to facilitate program implementation . The PEFR monitoring control group ( n = 363 ) received a peak flow meter , instructions about its use , and monthly calls to elicit PEFRs . However , PEFR data were not provided to the pharmacist . Patients in the usual care group ( n = 303 ) received neither peak flow meters nor instructions in their use ; during monthly telephone interviews , PEFR rates were not elicited . Pharmacists in both control groups had a training session but received no components of the pharmaceutical care intervention . MAIN OUTCOME MEASURES Peak expiratory flow rates , breathing-related ED or hospital visits , health-related quality of life ( HRQOL ) , medication compliance , and patient satisfaction . RESULTS At 12 months , patients receiving pharmaceutical care had significantly higher peak flow rates than the usual care group ( P = .02 ) but not than PEFR monitoring controls ( P = .28 ) . There were no significant between-group differences in medication compliance or HRQOL . Asthma patients receiving pharmaceutical care had significantly more breathing-related ED or hospital visits than the usual care group ( odds ratio , 2.16 ; 95 % confidence interval , 1.76 - 2.63 ; P<.001 ) . Patients receiving pharmaceutical care were more satisfied with their pharmacist than the usual care group ( P = .03 ) and the PEFR monitoring group ( P = .001 ) and were more satisfied with their health care than the usual care group at 6 months only ( P = .01 ) . Despite ample opportunities to implement the program , pharmacists accessed patient-specific data only about half of the time and documented actions about half of the time that records were accessed . CONCLUSIONS This pharmaceutical care program increased patients ' PEFRs compared with usual care but provided little benefit compared with peak flow monitoring alone . Pharmaceutical care increased patient satisfaction but also increased the amount of breathing-related medical care sought In the international Drug Education Project , an educational program involving auditing and feedback in peer groups to improve the treatment of asthma and urinary tract infections ( UTI ) was developed and tested in primary care . Individualized feedback was provided and discussed in 24 Dutch peer groups showing doctors their prescribing practice s and underlying reasons for treatment . A parallel , r and omized controlled design was used to test the effect on competence and actual prescribing ; in one study arm doctors received feedback on asthma treatment and in the other on UTI treatment . Especially the messages to treat asthma exacerbations with oral corticosteroids ( 17 % increase ) and to prescribe short courses for UTI ( decrease duration of 1.8 days ) brought about large improvements . Both messages concerned acute situations , and were clear and relatively easy for GPs to implement . GPs will experience more barriers when changing maintenance treatment of an asthma patient , which could explain the more limited success of this part of the educational program : the proportion of patients treated with inhaled corticosteroids increased 5 % . A ceiling effect was experienced regarding drug choice for UTI Abstract Objective : To test whether an audit facilitator could alter the pattern of diagnosis and treatment of childhood asthma . Design : R and omised stratified controlled trial . Setting : 12 general practice s in Tayside . Subjects : 3373 children aged 1 - 15 inclusive who had symptoms suggestive of asthma or possible asthma drawn from a systematic review of 10 725 general practice case records . Intervention : Children were targeted for a clinical review by their general practitioner or practice nurses . Main outcome measures : Asthma related consultations , precriptions , hospital attendances , and health service costs 12 months before and after study . Results : Compared with controls ( n=1563 ) the intervention group ( n=1585 ) had more practice initiated consultations for asthma ( relative risk 2.18 ( 95 % confidence interval 1.74 to 2.73 ) ) , new diagnoses of asthma ( 2.83 ( 2.26 to 3.54 ) ) , and past diagnoses reaffirmed ( 1.30 ( 1.08 to 1.58 ) ) , and they were more frequently prescribed inhaled cromoglycate ( 1.52 ( 1.02 to 2.25 ) ) . Hospital inpatient day rates fell from 152 to 122 in the intervention group and rose from 69 to 117 in the control group between the year before and the year after study . Total primary care costs rose from pounds sterling30118 to pounds sterling37243 in the intervention group and fell from pounds sterling29131 to pounds sterling27990 in the control group . Hospital care cost fell in the intervention group from pounds sterling25406 to pounds sterling20727 and rose in the control group from pounds sterling12699 to pounds sterling19650 . Conclusion : An audit facilitator can favourably influence the pattern of diagnosis and treatment of childhood asthma in general practice . This may have an impact on health service costs . Key messages Key messages Controlled trial of an audit facilitator is feasible in primary care Intervention of an audit facilitator result ed in desirable changes in the diagnosis and treatment of asthma in children in general practice Such intervention may also have had an impact on the use of hospital re sources and on health care AIM The aim of the study was to assess , in a r and omised , controlled design , the efficacy of different strategies to improve childhood asthma management . METHOD Three interventions directed to three groups of general practitioners were compared : Group A - dissemination of a guideline ; Group B - guideline dissemination plus an educational session ; Group C - guideline dissemination , educational session , plus individualised treatment advice based on airway hyperresponsiveness ( AHR ) and symptoms . Efficacy of the three strategies was assessed by evaluating change in AHR in 362 children after one year . RESULTS The overall between-group effect of the severity of AHR was not significantly different ( P=0.09 ) . In Groups A and C an improvement was seen in nocturnal symptoms ( P=0.02 ) and in Group C an improvement was seen in the prescription of inhaled corticosteroids ( P=0.03 ) . CONCLUSION In this study , the combined implementation strategy did not show a clear improvement in the management of children with asthma in general practice BACKGROUND Information that enhances expectations about drug effectiveness improves the response to placebos for pain . Although asthma symptoms often improve with placebo , it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit . OBJECTIVE The study objective was to determine whether response to placebo or a leukotriene antagonist ( montelukast ) can be augmented by messages that increase expectation of benefit . METHODS A r and omized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups . Participants were r and omly assigned to one of 4 treatment groups in a factorial design ( ie , placebo with enhanced messages , placebo with neutral messages , montelukast with enhanced messages , or montelukast with neutral messages ) or to usual care . Assignment to study drug was double masked , assignment to message content was single masked , and usual care was not masked . The enhanced message aim ed to increase expectation of benefit from the drug . The primary outcome was mean change in daily peak flow over 4 weeks . Secondary outcomes included lung function and asthma symptom control . RESULTS Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo ; no differences were noted between the neutral placebo and usual care groups . Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants ; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference . Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect . CONCLUSIONS Optimistic drug presentation augments the placebo effect for patient-reported outcomes ( asthma control ) but not lung function . However , the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness

Conclusions CT measurements of emphysema or peripheral airways are significantly related to airflow obstruction in COPD patients . CT provides a morphological method to investigate airway obstruction in COPD .Key Points• Computed tomography is widely performed in patients with chronic obstructive pulmonary disease ( COPD ) • CT provides quantitative morphological methods to investigate airflow obstruction in COPD • CT measurements correlate significantly with the degree of airflow obstruction in COPD • Expiratory CT measurements correlate more strongly with airflow obstruction than inspiratory CT• Low-dose CT decreases the radiation dose for diagnosis and quantitative emphysema

Objectives To determine the correlation between CT measurements of emphysema or peripheral airways and airflow obstruction in chronic obstructive pulmonary disease ( COPD ) .

PURPOSE The purpose of this study was to directly and prospect ively compare the capability of dynamic O(2)-enhanced MRI and quantitatively assessed thin-section MDCT to assess smokers ' COPD in a large prospect i ve cohort . MATERIAL S AND METHODS The GOLD criteria for smokers were used to classify 187 smokers into four clinical stage groups as follows : smokers without COPD ( n=56 ) and with mild ( n=54 ) , moderate ( n=52 ) and severe or very severe COPD ( n=24 ) . All smokers underwent dynamic O(2)-enhanced MRI , MDCT and pulmonary function tests . Mean relative enhancement ratio and mean wash-in time on MRI and CT-based functional lung volume ( CT-based FLV ) as well as the ratio of airway wall area to total airway area on MDCT were computationally calculated . Then , all indexes were significantly correlated with functional parameters . To determine the efficacy of all indexes for clinical stage classification , the indexes for the four clinical groups were statistically compared by using Tukey 's honestly significant difference multiple comparison test . RESULTS All indexes had significant correlations with functional parameters ( p<0.0001 ) . All indexes except CT-based FLV in all groups had significant differences each other ( p<0.05 ) . CONCLUSIONS Dynamic O(2)-enhanced MRI for assessment of COPD in smokers is potentially as efficacious as quantitatively assessed thin-section MDCT Computed Tomography ( CT ) has been proved to be the most accurate imaging modality to diagnose emphysema in vivo . Our study was aim ed at comparing different CT methods for pulmonary emphysema quantification in patients with severe chronic obstructive pulmonary disease ( COPD ) . Forty-six consecutive in patients affected with COPD underwent high resolution CT ( H RCT ) . Three scans were acquired at 3 preselected anatomic levels at both full inspiration and expiration . Three different observers were asked to subjectively evaluate , under blind conditions , the extent alone and both the severity and the extent of emphysema on the 6 scans . H RCT findings were also analyzed quantitatively by measuring the mean CT number in Hounsfield Units ( HU ) and the % of lung area with CT numbers < -900 HU ( pixel index ) . Quantitative CT data were compared with reference values obtained in 7 normal nonsmokers . The CT visual score of emphysema exhibited medium-high interobserver reproducibility with correlation coefficients ranging from 0.80 to 0.96 and a good correlation with pulmonary function tests , particularly relative to the assessment of the extent of emphysema alone as expressed by one observer . CT quantification demonstrated an excellent correlation with functional indices of expiratory airflow , lung volumes and diffusion coefficients ( p < 0.001 ) . The expiratory measurements were better than the inspiratory ones while the analysis of both CT number and pixel index gave comparable results . Only the CT expiratory quantitative data allowed to differentiate the patients affected with COPD from the controls . In conclusion , the severity of emphysema as expressed by CT correctly reflects the functional impairment of patients with severe COPD . ( ABSTRACT TRUNCATED AT 250 WORDS

Conclusions The HADS anxiety subscale performed worse than the total and the depression subscales for both indicators . Diagnostic accuracy varied widely by threshold but was consistently superior for depression screening than for screening of any mental disorder

Purpose The Hospital Anxiety and Depression Scale ( HADS ) is the most extensively vali date d scale for screening emotional distress in cancer patients . However , thresholds for clinical decision making vary widely across studies . A meta- analysis was conducted with the aim of identifying optimal , empirically derived cut-offs .

Abstract The psychometric properties of the Italian version of the Hospital Anxiety and Depression Scale and its utility as a screening instrument for anxiety and depression in a non-psychiatric setting were evaluated . The question naire was administered twice to 197 breast cancer patients r and omised in a phase III adjuvant clinical trial : before the start of chemotherapy and at the first follow-up visit . The presence of psychiatric disorders was evaluated at the follow-up visit using the Structured Clinical Interview for DSM-III-R in 132 patients . Factor analyses identified two strictly correlated factors . Crohnbach 's alpha for the anxiety and depression scales ranged between 0.80 and 0.85 . At follow-up , 50 patients ( 38 % ) were assigned a current DSM-III-R diagnosis , in most cases adjustment disorders ( 24 % ) or major depressive disorder ( 10 % ) . Receiver operating characteristics ( ROC ) analysis was used to test the discriminant validity for both anxiety and depressive disorders . The comparison of the areas under the curve ( AUC ) between the two scales did not show any difference in identifying either anxiety ( P=0.855 ) or depressive disorders ( P=0.357 ) . The 14-item total scale showed a high internal consistency ( alpha=0.89 and 0.88 ) and a high discriminating power for all the psychiatric disorders ( AUC=0.89 ; 95 % CI=0.83–0.94 ) . The cut-off point that maximised sensitivity ( 84 % ) and specificity ( 79 % ) was 10 . These results suggest that the total score is a valid measure of emotional distress , so that the Italian version of HADS can be used as a screening question naire for psychiatric disorders . The use of the two subscales as a ' case identifier ' or as an outcome measure should be considered with caution The Hospital Anxiety and Depression ( HAD ) scale , a self-report question naire , was tested as a method of identifying mood disorder among patients with operable breast cancer during the year after diagnosis . In a cohort of 91 patients anxiety and depression were assessed preoperatively , and at 3 and 12 months post-operatively , using a st and ardised psychiatric interview and diagnostic rating criteria . The patients also completed the HAD scale at each assessment . Fifty out of 91 ( 55 % ) patients were full or borderline cases of depression and /or anxiety at one or more assessment points . Using a receiver operator characteristic curve analysis , the optimum threshold for the preoperative HAD scale total score to identify psychiatric disorder either preoperatively or at 3 and 12 months post-operatively was 11 . With this threshold 70 % of both full and borderline cases occurring at any of the assessment points were correctly identified . The false-positive rate was 12 % . This approach was particularly sensitive to full cases , correctly identifying 90 % of them . The potential for the preoperative HAD scale total score to identify mood disorder in the year after diagnosis was influenced by age . Among women aged less than 50 years , a preoperative HAD scale total score > or = 11 provided a highly sensitive indicator of mood disorder ( full and borderline cases ) at any time in the year after diagnosis ( sensitivity = 90 % ) . The false-positive rate was 40 % . Among women older than 50 who experienced a mood disorder , only 57 % were correctly identified by a HAD scale total score of > or = 11 ( sensitivity = 57 % ) . However , the false-positive rate among older women was low ( 3 % ) . This simple preoperative screening approach can be used to identify patients who have or are at high risk of developing severe mood disorder in the year after diagnosis . The HAD scale is also sensitive to the detection of borderline mood disorder in patients under the age of 50 . It is a specific screening tool among patients over 50 , but is not sensitive to the detection of borderline mood disorder in this age group BACKGROUND This study aim ed to determine the prevalence of psychiatric morbidity and distress among 189 consecutively recruited cancer patients upon admission to surgical oncology wards , and to investigate the recognition of distressed patients by medical staff . PATIENTS AND METHODS Assessment consisted of a diagnostic psychiatric interview ( SCID , DSM-IV ) , patient-reported distress using a st and ardised question naire ( Hospital Anxiety and Depression Scale ) , and physicians ' and nurses ' estimates of patients ' distress . Twenty-eight per cent of patients were assigned a psychiatric diagnosis , with adjustment disorder predominating . RESULTS Surgeons accurately recognised marked distress in 77 % of patients with a psychiatric disorder and nurses did so in 75 % . Because of low specificity , the positive predictive value was only 39 % in surgeons and 40 % in nurses . However , recognition of distress translated into referral to the psychosocial liaison service for only a minor proportion of distressed patients . CONCLUSIONS Since a remarkable proportion of distressed patients remained unrecognised by the medical staff , only systematic screening of patients upon admission allows timely support to those who are most in need Prediction of delayed psychiatric disorders in breast cancer patients by using a screening procedure was investigated . Two question naires , the Psychological Distress Inventory and the Hospital Anxiety and Depression Scale , were administered before and during chemotherapy , and at the first follow-up visit . A psychiatric diagnosis was assigned to 50 of the 132 patients ( 38 % ) evaluated at follow-up . Including a set of clinical and demographic variables in a logistic regression , increasing age ( P=0.001 ) and psychiatric history ( P<0.001 ) were associated with psychiatric morbidity at follow-up . The accuracy of the two question naires in predicting delayed psychiatric disorders increased from the evaluation before chemotherapy to the evaluation during chemotherapy . The most accurate prediction was observed for the concurrent evaluation at follow-up . The accuracy of three predictive models developed for each evaluation point by including age , psychiatric history and psychological distress measured with each of the two question naires was not significantly better than that observed using only the question naires ' scores as predictors PURPOSE Distress has been recognized as the sixth vital sign in cancer care and several guidelines recommend routine screening . Despite this , screening for distress is rarely conducted and infrequently evaluated . METHODS A program of routine online screening for distress was implemented for new patients with breast and lung cancer . Patients were r and omly assigned to one of three conditions : ( 1 ) minimal screening : the distress thermometer ( DT ) only plus usual care ; ( 2 ) full screening : DT , problem checklist , Psychological Screen for Cancer part C measuring anxiety and depression , a personalized report summarizing concerns and the report on the medical file ; or ( 3 ) triage : full screening plus optional personalized phone triage with referral to re sources . Patients in all conditions received an information packet and were reassessed 3 months later with the full screening battery . RESULTS Five hundred eighty-five patients with breast cancer and 549 patients with lung cancer were assessed at baseline ( 89 % of all patients ) , and 75.5 % retained for follow-up . High prevalence of baseline distress was found across patients . Twenty percent fewer patients with lung cancer in triage continued to have high distress at follow-up compared to those in the other two groups , and patients with breast cancer in the full screening and triage conditions showed lower distress at follow-up than those in minimal screening . The best predictor of decreased anxiety and depression in full screening and triage conditions was receiving a referral to psychosocial services . CONCLUSION Routine online screening is feasible in a large cancer center and may help to reduce future distress levels , particularly when coupled with uptake of appropriate re sources The aim of this prospect i ve study was to identify the psychiatric morbidity associated with the diagnosis and treatment of early breast cancer . At each of five time points , 269 women were interviewed using a shortened version of the Present State Examination ( PSE ) and 266 completed self- assessment question naires , the Hospital and Anxiety Depression Scale ( HADS ) and the Rotterdam Symptom Checklist ( RSCL ) . This paper compares the ability of the question naires to detect psychiatric morbidity with that of the PSE . The majority of women who experienced anxiety and /or depression did so within 3 months of their initial surgery . The clinical interview identified anxiety disorder in 132 of 266 women ( 49.6 % ) and depressive illness in 99/266 ( 37.2 % ) during the first 3 months . Using the recommended threshold of > or = 11 for caseness , the sensitivities for both tests were very low at 24.2 % ( HADS anxiety ) and 14.1 % ( HADS depression ) and 30.6 % ( RSCL psychological distress scale ) . Lowering the threshold value to > or = 7 on the HADS improved the sensitivity to 72 % for the anxiety subscale , but it remained low at 37.4 % for the depression subscale . A threshold of > or = 7 for the RSCL scale raised sensitivity to 66.7 % . Lowering the threshold values raised the sensitivity of both the instruments but decreased their specificity : the lower the threshold , the greater the number of women who were identified as false positives which would increase the work load for clinic staff if used as a screening tool . Given that the HADS was inadequate in discriminating for depressive illness , it was not surprising that its use as a unitary scale with a threshold value as low as 12 result ed in a sensitivity of only 42.7 % . In the light of these findings , we question the use of both the HADS and the RSCL as suitable research or screening instruments for detection of psychological morbidity in early breast cancer Two hundred fifteen r and omly accessed cancer patients who were new admissions to three collaborating cancer centers were examined for the presence of formal psychiatric disorder . Each patient was assessed in a common protocol via a psychiatric interview and st and ardized psychological tests . The American Psychiatric Association 's DSM-III diagnostic system was used in making the diagnoses . Results indicated that 47 % of the patients received a DSM-III diagnosis , with 44 % being diagnosed as manifesting a clinical syndrome and 3 % with personality disorders . Approximately 68 % of the psychiatric diagnoses consisted of adjustment disorders , with 13 % representing major affective disorders ( depression ) . The remaining diagnoses were split among organic mental disorders ( 8 % ) , personality disorders ( 7 % ) , and anxiety disorders ( 4 % ) . Approximately 85 % of those patients with a positive psychiatric condition were experiencing a disorder with depression or anxiety as the central symptom . The large majority of conditions were judged to represent highly treatable disorders

A single oral dose of 2 g of amoxicillin before lower third molar osteotomy surgical extraction significantly decreased the incidence of SSI . A single dose of 0.8 g of penicillin V before lower third molar osteotomy surgical extraction significantly decreased the incidence of alveolar osteitis

PURPOSE We conducted a systematic review of r and omized controlled trials ( RCTs ) to evaluate the effectiveness of a single dose of preoperative antibiotic administered perorally , intravenously , intramuscularly , or topically for preventing infection and alveolar osteitis in lower third molar surgical extraction applying osteotomy .

Abstract The use of systemic prophylactic antibiotics in third molar surgery is still a controversial issue . A double-blind study has been conducted with 75 selected patients r and omized into two groups . After exclusions , 68 patients requiring removal of 133 bone impacted m and ibular third molars remained . Surgery was carried out under general anesthesia and a St and ard operative technique used . Postoperative raorbidity was assessed by recording trismus , swelling , pain , and the incidence of infection . In the group given an antibiotic 15.1 % of patients and 7.8 % of sockets became infected ; in the control group the incidence was 14.3 % and 8.7 % , respectively . Difficult extraction s were more likely to give rise to postoperative infection , but neither the state of eruption nor the occurrence of previous pericoronitis appeared to predispose to dry socket . Trismus and swelling were associated with increased difficulty of extraction , but increased pain did not usually occur unless a socket became infected , Differences of overall morbidity between the groups were slight and not statistically significant . The main conclusion from the study is that the use of prophylactic antibiotics in third molar surgery is unnecessary unless specific systemic factors are present Treatment of osteitis after surgical removal of the third molar of the m and ible is still a clinical problem . A total of 140 patients undergoing operations for removal of an impacted third molar of the m and ible , were included in a double-blind study . Placebo or antibiotics - azidocillin , erythromycin , clindamycin and doxycycline - were given to the patients preoperatively and for the following 7 days . The concentrations in serum , alveolar serum and m and ibular bone were measured and the postoperative courses - pain , trismus , swelling and wound-healing - were recorded . No correlation was obtained between the antibiotic concentration and the postoperative complaints , except in the azidocillin group on day 2 , in which fewer complaints were noticed in patients with high concentrations of the drug at the time of operations . The 80 patients in the antibiotic groups responded significantly better with respect to wound-healing than the 60 patients in the placebo groups . Only 15 operations lasted more than 15 min and the three of them which subsequently result ed in alveolitis were in the placebo groups . Antibiotics significantly reduced pain on day 7 postoperatively . In general , no statistically significant differences in trismus and swelling could be demonstrated between the patient groups . However , there was a significant difference between the placebo and doxycycline groups with respect to swelling ( day 2 postoperative , P < 0.01 ; day 5 postoperative , P < 0.05 ) . Thus systemically administered antibiotics offered only slight advantages in routine operations of impacted third m and ibular molars , but could decrease the rate of infections after traumatic operations A prospect i ve r and omized crossover , within-patient , controlled study was performed in 26 healthy patients to test the effect of the prophylactic local use of gauze drain impregnated with chlortetracycline ( Aureomycin 3 % , Lederle ) ointment on postoperative alveolitis formation after surgical removal of 52 bilaterally impacted m and ibular third molars . The teeth were removed on two separate occasions ; on one side drain was inserted in the socket , and on the other side no drain treatment was used for control . The influence on postoperative pain , swelling , and mouth opening ability was investigated . The results indicated a statistically significant reduction ( P = 0.02 ) in the incidence of postoperative inflammatory complications , defined as postoperative alveolitis , from 35 % in the no-drain group to 4 % in the drain group . No statistically significant difference was found between the two treatment methods with regard to pain and mouth opening reduction . There was a significant difference between the drain and no-drain treatment with regard to swelling on the 1st postoperative day in favor of the no-drain method . It is concluded that insertion of a chlortetracycline-impregnated drain may be an effective method for reducing postoperative alveolitis formation but has no beneficial effect on pain , swelling , and mouth opening reduction after impacted m and ibular third-molar surgery PURPOSE This study evaluated the influence of antibiotic prophylaxis on postoperative complications after inferior third molar removal in young patients . PATIENTS AND METHODS We extracted 59 m and ibular third molars from 59 patients with a mean age of 15 years ( range , 12 - 19 years ) . The patients were included in the study when radiographs at the time of surgery showed that only the crown of the tooth germ was formed . Patients were r and omized into 2 groups , the test group and the control group . The test group received 2-g amoxicillin tablets 1 hour before surgery , and the control group received no antibiotic therapy . The test group included 32 patients , 20 of whom were female and 12 were male ; the mean age was 15 years . The control group included 27 patients , 12 of whom were female and 15 were male ; the mean age was 15 years . Postoperative complications such as pain , swelling , wound infection , and fever were recorded by use of a question naire completed by the patient for the week after the extraction . Suture removal and question naire evaluation were performed by a surgeon who did not know the preoperative regimen . RESULTS The mean operating time was 34 minutes in the control group and 31 minutes in the test group . This difference was not significant . In the test group there was a statistically significant reduction of postoperative pain in the 7 days after the extraction , and the patients had a consistent minor consumption of analgesics . Swelling was always present in the control and test groups in the postoperative week , but in the test group it was a minor sequela and was absent in 2 patients . Wound infection was a sequela reported in 4 patients in the control group and in 1 patient in the test group ; this difference was statistically significant ( P < .01 ) . Fever was present in 2 patients in the control group and in 1 patient in the test group ; this difference was not statistically significant . CONCLUSIONS A statistically significant difference was found between patients receiving preoperative amoxicillin and the control group in the incidence of postoperative pain , fever , and wound infection . Another important finding was the statistically minor consumption of analgesics in the test group in the postoperative week AIM To test the efficacy of two dosing regimens of antimicrobial prophylaxis during the removal of impacted lower third molars . DESIGN Double blind , prospect i ve , placebo-controlled trial . SETTING Teaching hospital , India . SUBJECTS 151 patients aged 19 - 36 having impacted lower third molars removed . METHODS R and om allocation into three groups : placebo ( n= 34 ) , metronidazole 1 g orally , 1 hour preoperatively ( n= 44 ) , or metronidazole 400 mg orally eight hourly for 5 days postoperatively ( n= 47 ) . Patients were recalled on the sixth postoperative day for assessment of pain scores on the second and sixth days , swelling , differences in mouth opening between preoperative and the sixth postoperative day , and the state of the wound . RESULTS There were no significant differences in the outcome between the three groups ( P= 0.09 ) . CONCLUSION Antimicrobial prophylaxis does not seem to reduce morbidity after removal of lower third molars PURPOSE We sought to compare recovery for clinical and health-related quality of life ( HRQOL ) outcomes after third molar surgery in patients treated with or without intravenous antibiotics at surgery . PATIENTS AND METHODS Fifty-six patients at least 18 years of age and with all 4 third molars below the occlusal plane , treated at 3 clinical centers , were given intravenous antibiotics just before third molar surgery . Clinical and HRQOL outcomes of these patients were compared with those of a nonconcurrent control group ( n = 60 patients ) who did not receive antibiotics . The control group was selected using the same criteria and treated under the same surgical protocol as the antibiotic group . Differences between the groups were assessed with Cochran-Mantel-Haenszel row mean score statistics . RESULTS The incidence of delayed clinical recovery defined as a postsurgery visit with treatment was higher in the control group compared with the antibiotic group . In the antibiotic group , 4 % had 1 postsurgery visit with treatment ; no patient had 2 visits . In the control group without antibiotics , 28 % had at least 1 postsurgery visit with treatment ( P < .0001 ) and 13 % had at least 2 postsurgery visits with treatment . No statistically significant differences in HRQOL outcomes were found between the 2 groups . CONCLUSIONS Administration of intravenous antibiotics before third molar surgery may improve clinical recovery in healthy adult patients with all 4 third molars below the occlusal plane , a presenting characteristic that has been suggested as a risk factor for delayed recovery . The findings from this exploratory trial indicate that evaluation of the effectiveness of systemic antibiotic administration with third molar surgery in a r and omized , multi-intervention , explanatory clinical trial is warranted A double blind trial , was design ed , in which 118 patients undergoing the removal of impacted wisdom teeth were r and omly divided into the following groups ; 41 patients received Metronidazole , 39 patients received Arnica Montana , 38 patients received the placebo . Metronidazole was more effective in pain control than Arnica ( p less than 0.001 ) and placebo ( p less than 0.01 ) . It prevented swelling better than Arnica ( p less than 0.01 ) and placebo ( p less than 0.05 ) and was more effective in promoting healing than Arnica ( p less than 0.01 ) and placebo ( p greater than 0.02 ) . Arnica Montana appeared to give rise to greater pain than placebo ( p less than 0.05 ) and caused more swelling than the placebo ( p less than 0.01 ) The effect of a single preoperative dose of metronidazole in the prevention of alveolitis sicca dolorosa ( ASD ) after surgical removal of one impacted , non-infected m and ibular third molar was investigated . A patient sample of 270 were given either 1000 mg of metronidazole or placebo at least 30 min before surgery . The preoperative recordings included gender , age , tooth to be removed , experience of surgeon , time of test medication , and duration of surgery . No difference was found between the metronidazole and placebo groups in the occurrence of ASD . The duration of surgery and the experience of the operating surgeons had no effect on the occurrence of ASD . The present study failed to demonstrate any preventive effect of a single dose of metronidazole on the development of ASD PURPOSE We evaluated the need for prophylactic postoperative oral antibiotic treatment in the removal of asymptomatic third molars . MATERIAL S AND METHODS In a prospect i ve study of more than 30 months , a total of 528 impacted lower third molars were surgically removed in 288 patients . All patients were referred to our department by a dentist or a general practitioner . No patient showed any sign of pain , inflammation , or swelling at the time of removal . Three groups were established . In the first group , antibiotic treatment with amoxicillin/clavulanic acid as an oral medication was carried out for 5 days postoperatively . In the second group , we used clindamycin . In the third group , the patients received no antibiotic treatment . Clinical and radiologic factors were recorded for each case , and the rationale for assigning the patients to the groups was strictly r and om . The surgical technique was the same in all cases , and the follow-up period was 4 weeks . Parameters that were evaluated were pain , differences in mouth opening , infection , the occurrence of dry socket , and adverse postoperative side effects . RESULTS We could not find any significant difference between the 3 groups regarding the evaluated parameters , but in 69.6 % of the patients with dry socket , the teeth were partially erupted , which showed a significant difference . CONCLUSIONS The results of our study show that specific postoperative oral prophylactic antibiotic treatment after the removal of lower third molars does not contribute to a better wound healing , less pain , or increased mouth opening and could not prevent the cases of inflammatory problems after surgery , respectively , and therefore is not recommended for routine use Background The aim of this study was to assess the efficacy of a single prophylactic dose of amoxicillin and /or dexamethasone in preventing postoperative complications ( PC ) after a surgical removal of a single m and ibular third molar ( M3 ) . Methods This study is a r and omized , placebo controlled clinical trial . Four groups were included : Group 1 ( G1 ) included a prophylactic dose of 2 g of amoxicillin and 8 mg of dexamethasone ; Group 2 ( G2 ) included a prophylactic dose of 2 g of amoxicillin and 8 mg of placebo ; Group 3 ( G3 ) included a prophylactic dose of 8 mg of dexamethasone and 2 g of placebo and ; Group 4 ( G4 ) placebo . Results Fifty patients were included . It was observed one case of alveolar infection ( 2 % ) and two of alveolar osteitis ( 4 % ) result ing in three PC ( 6 % ) . No statistical differences were observed between therapeutic groups for development of PC , trismus , pain and edema . The use of antibiotics showed an absolute risk reduction ( ARR ) for PC development of 3.52 % and the number needed to treat ( NNT ) was 29 . Conclusion Prophylactic antibiotics and corticoid in a single dose regimen did not bring any benefit on M3 surgeries Clindamycin and other agents were compared for efficacy in preventing the entity " dry socket . " A total 765 patients were treated with clindamycin , per os , and 408 patients were treated with other antibiotics or were non-treated controls . All patients underwent surgical removal of impacted m and ibular third molars . The incidence of dry socket in untreated control and in non-clindamycin antibiotic-treated patients varied from 15 to 31 percent , while in those patients receiving clindamycin , the incidence was 0.65 percent . The results demonstrate a remarkable effectiveness of clindamycin in reducing the incidence of dry socket following surgical removal of impacted m and ibular third molar Aims and Objectives : To evaluate the role of prophylactic antibiotics , if any , in the removal of m and ibular impacted third molars . Patients and Methods : A total of 89 patients were r and omly allocated in 3 groups ( group 1 , placebo ; group 2 , amoxicillin 1 g orally 1 h before surgery ; and group 3 , metronidazole 800 mg orally 1 h before surgery ) . Results : Of the 89 patients , 5 had surgical wound infection ( 3 [ 10.33 % ] in group 1 , 2 [ 6.45 % ] in group 2 , and none [ 0 % ] in group 3 ) , leading to an overall infection rate of 5.61 % . There was no statistically significant difference found in surgical wound infection between the groups . Conclusions : Our study failed to show any advantage in the routine use of prophylactic antibiotics because we found no statistically significant difference between the groups A clinical double-blind placebo controlled trial was carried out in 136 patients to test the value of the prophylactic use of phenoxymethylpenicillin and tinidazole in m and ibular third molar surgery . The three patient groups were uniform with regard to the background data such as age and weight of the patients and the clinical status of the operated tooth , as well as to the observations made at surgery . No statistically significant differences were found between the study groups in the parameters used for evaluation . The results indicate that neither penicillin nor tinidazole have more effect on postoperative complications following operative extraction of wisdom teeth , than placebo tablets We r and omised 119 patients who had been referred for removal of partially impacted m and ibular third molars to be given either metronidazole 1600 mg or placebo as a single dose 45 min before operation . Ten of the fifty-nine patients who were given metronidazole and 13 of the 60 given placebo developed dry sockets . Two variables were significantly associated with the development of a dry socket : pericoronitis and oral contraceptives Abstract The investigation was performed on a r and om material consisting of 329 patients in whom impacted m and ibular third molars had been removed surgically . The effectiveness of generally administered antibiotics ( lincomycin and V-penicillin ) and a local b and age ( gauze sponge ) saturated with Whitehead 's varnish in preventing postoperative symptoms was evaluated . The results revealed a most significant improvement among patients treated with a local b and age in comparison with a control group . Lincomycin and V-penicillin also improved the results significantly . Lincomycin tended to be somewhat more effective . However , the local b and age was significantly more effective than the antibiotics and consequently must be preferred , especially in view of the drawbacks of these drugs . Another observation in this investigation was that an operation time longer than 10 min result ed in significantly more postoperative discomfort . The same effect was noticed when unerupted teeth were extirpated compared to partly erupted ones The use of prophylactic antibiotics to reduce postoperative complications in third molar surgery remains controversial . The study was a prospect i ve , r and omized , double blind , placebo-controlled clinical trial . 100 patients were r and omly assigned to two groups . Each patient acted as their own control using the split-mouth technique . Two unilateral impacted third molars were removed under antibiotic cover and the other two were removed without antibiotic cover . The first group received antibiotics on the first surgical visit . On the second surgical visit ( after 3 weeks ) , placebo capsules were given or vice versa . The second group received antibiotics with continued therapy for 2 days on the first surgical visit and on the second surgical visit ( after 3 weeks ) placebo capsules were given or vice versa . Pain , swelling , infection , trismus and temperature were recorded on days 3 , 7 and 14 after surgery . Of 380 impactions , 6 sockets ( 2 % ) became infected . There was no statistically significant difference in the infection rate , pain , swelling , trismus , and temperature between the two groups ( p>0.05 ) . Results of the study showed that prophylactic antibiotics did not have a statistically significant effect on postoperative infections in third molar surgery and should not be routinely administered when third molars are removed in non-immunocompromised patients Postoperative complications after surgical removal of m and ibular third molars are still a clinical problem . Sixty patients undergoing operations for removal of an impacted third m and ibular molar , were included in a double blind study . Phenoxymethylpenicillin 800 mg , azidocillin 750 mg , or placebo were given to the patients pre-operatively and then twice per day for the following seven days . The concentrations of phenoxymethylpenicillin and azidocillin in serum and alveolar serum were measured and the postoperative courses - pain , trismus , swelling and wound-healing - were recorded . The 40 patients in the antibiotic groups responded significantly better with respect to wound-healing than the 20 patients in the placebo group , and there were no differences between phenoxymethylpenicillin and azidocillin . Antibiotics significantly reduced pain on day 7 postoperatively . There were no differences between antibiotic groups and placebo with respect to trismus and swelling . When the dental alveolar serum concentrations of phenoxymethylpenicillin 3.0 microgram/ml and azidocillin 7.9 microgram/ml were related to their range of inhibitory concentrations for microorganisms isolated from orofacial infections , it was noticed that the two drugs achieved levels sufficient to inhibit most strains . The effect of phenoxymethylpenicillin and azidocillin on postoperative infections can be of value after traumatic oral surgery or after operations on patients especially susceptible to infections PURPOSE The purpose of this study was to identify the risk factors for severe discomfort after m and ibular third molar surgery and to assess the validity of the Postoperative Symptom Severity ( PoSSe ) scale . PATIENTS AND METHODS In a 2-year prospect i ve study , a total of 255 unilateral impacted m and ibular third molar teeth were surgically removed under local anesthesia by 3 surgeons . St and ardized surgical and analgesic protocol s were followed . At the review appointment , 1 week after surgery , all patients returned a completed follow-up question naire ( PoSSe scale ) and were evaluated clinical ly for postoperative pain ( number of painkillers taken ) and trismus ( differences in mouth opening ) . Sixteen predictive variables were evaluated using stepwise logistic regression analysis to identify the risk factors associated with severe discomfort . RESULTS Severe postoperative discomfort was predicted by these independent variables : gender , tobacco use , ramus relationship/space available , and antibiotic prophylaxis . Oral contraceptive use and operation time were not identified as risk factors . The patients ' perceptions of the severity of symptoms ( PoSSe scale score ) was strongly correlated with clinical assessment of trismus ( r = 0.54 ) and pain ( r = 0.42 ) . CONCLUSION The PoSSe scale result ed in a valid and responsive measure of the severity of symptoms after surgical extraction of lower third molars and reflected the clinical severity of the postoperative discomfort . From a patient 's perspective , operative factors had little bearing on the quality of life after removal of m and ibular third molars One hundred and forty eight patients with bilateral symmetrically impacted lower third molars entered a clinical crossover trial to compare the effects on postoperative recovery of a Bismuth Iodoform Paraffin Paste ( BIPP ) socket dressing , primary closure using a resorbable suture ( Softgut ) and to ascertain if prophylactic metronidazole influenced the outcome . The results reaffirm the surgical principle that contaminated surgical wounds such as third molar sockets are best kept open with a dressing . Attempts at primary closure should be resisted if there is no intention to prescribe antibiotic cover . However , if a suitable antibiotic is taken then primary closure using a resorbable suture can be carried out with confidence . This may reduce the need for outpatient follow up OBJECTIVE The purpose of this study was to evaluate the use of a 0.2 % chlorhexidine gluconate and amoxicillin plus clavulanic acid combination as a prophylactic therapy for the prevention of alveolar osteitis after m and ibular third molar extraction s and to investigate adverse reactions to chlorhexidine . STUDY DESIGN This r and omized , placebo-controlled , parallel group study was conducted in a group of 177 subjects , from which 3 groups were formed . The first group ( n = 62 ) received 0.2 % chlorhexidine gluconate , the second group ( n = 56 ) received a 0.2 % chlorhexidine gluconate and amoxicillin plus clavulanic acid combination , and the third group ( n = 59 ) received 0.09 % sterile saline solution . All patients were recalled for the diagnosis of alveolar osteitis on the third and seventh postoperative days . RESULTS When patients in the antibiotic group were compared with those in the other 2 groups , a significant reduction in alveolar osteitis was noted ( P < .05 ) . An alteration in taste , the bad taste of the solution , and staining of dentures and oral tissues were the major complaints about chlorhexidine . CONCLUSION It would be more beneficial to use chlorhexidine solution with a beta-lactamase inhibitor-containing antibiotic to enhance its effectiveness for the prevention of alveolar osteitis The goal of this study was to evaluate the efficacy of single- and multi-dose ( 5-day ) clindamycin therapy for the prevention of inflammatory complications in patients undergoing lower third molar surgical extraction with bone removal . Patients who qualified for the prospect i ve , r and omized , double-masked , placebo-controlled trial were r and omly divided into three groups : ( 1 ) single dose of oral clindamycin administered preoperatively ( single-dose group ) ; ( 2 ) clindamycin administered preoperatively with continued therapy for 5 days ( 5-day group ) ; and ( 3 ) a placebo group . The following parameters were evaluated on the first , second and seventh days postsurgery : trismus , facial swelling , body temperature , lymphadenopathy , alveolar osteitis and subjective pain sensations . There were 86 patients ( 31 in the single-dose group , 28 in the 5-day group and 27 in the placebo group ) enrolled in the study . There were no statistically significant differences in postoperative inflammatory complications in patients during the first and second days postsurgery . A statistically significant variation in body temperature was reported on the seventh day . Analysis of the postoperative analgesic intake did not show statistically significant differences between examined groups . Clindamycin applied in a single preoperative dose of 600 mg with or without subsequent 5-day therapy does not demonstrate efficacy in prophylaxis for postoperative inflammatory complications after third molar surgery PURPOSE To analyze the impact of the postoperative administration of moxifloxacin ( MXF ) on oral function and quality of life after third molar ( TM ) surgery . MATERIAL S AND METHODS A single-center , prospect i ve , r and omized , double-blind , controlled clinical trial was design ed . The study population consisted of 100 patients who underwent impacted TM extraction s. Patients were distributed into 2 groups of 50 individuals each . Postoperatively , one group was administered MXF ( 400 mg/24 hours for 5 days ) ; the positive control group received amoxicillin and clavulanic acid ( AMX-CLV ) ( 500/125 mg/8 hours for 5 days ) . Follow-up was performed for 7 postoperative days , during which the patient recorded information on pain , the use of rescue analgesia , undesirable effects of the medication , difficulty in speaking , difficulty in chewing , diet consistency , difficulty performing oral hygiene , asthenia , time in bed , going out of the house , and returning to work . RESULTS The administration of MFX was significantly associated with headache , and AMX-CLV was significantly associated with diarrhea . Greater difficulty in chewing and performing oral hygiene was observed in the AMX-CLV group compared with the MXF group . The percentage of patients who tolerated a diet of normal consistency was significantly higher in the MXF group compared with the AMX-CLV group . During the first 4 days of follow-up , the percentage of patients who returned to work was significantly higher in the MXF group than in the AMX-CLV group . CONCLUSIONS Moxifloxacin shortens the period of postoperative recovery in terms of oral function and return to work . Therefore , MXF could be a useful option in TM surgery when antibiotics are indicated , particularly if patients are allergic to beta-lactams , their oral flora is resistant to macrolides , or they are intolerant of either of these antibiotics A double-blind r and omised placebo-controlled study of the value of systemic penicillin in preventing pain , swelling and trismus following the removal of impacted m and ibular third molars and indicates that penicillin may be used justifiably in the more difficult cases Postoperative infections in the oral region are usually caused by anaerobic bacteria . While some authors cl aim that routine antibiotic prophylaxis is necessary after third molar surgery , others do not recommend this practice . The major subject of controversy is what constitutes postoperative infection . Previous studies that have examined the benefit of routine antibiotic prophylaxis have used several clinical symptoms ( pain , swelling , and trismus ) as indicators of infection ; however , these clinical symptoms may be vague and unreliable , and can not be evaluated scientifically . As a result , their use has only sparked more debate in this area of research . The present study assessed the value of routine antibiotic prophylaxis in impacted m and ibular third molar surgery using acute-phase protein levels as potential indicators of early and late postoperative infection . Specifically , serum levels of C-reactive protein and alpha-1 antitrypsin were measured preoperatively and postoperatively in patients who received either prophylactic antibiotics or placebos . The results revealed no statistically significant difference between treated and control patients in terms of incidence of postoperative infection Metronidazole , used for prevention and treatment of infections in oral and maxillofacial surgery is frequently prescribed three times daily , but research into its pharmacokinetics has shown that a twelve hourly dosage regimen achieves and maintains therapeutic serum concentrations . No clinical data is available to support this and consequently a single blind , prospect i ve , r and omised trial was carried out to compare rates of postoperative infection following m and ibular third molar excision under general anaesthesia . Sixty-two patients were r and omly allocated to receive either 400 mg of metronidazole twice or three times daily for 5 days and all were assessed by the same surgeon for postoperative infection 7 days later . There was no statistically significant difference between rates of infection in either group and of potential side effects only nausea occurred statistically more frequently in the three times daily group . It would appear that a 12-hourly dose interval of metronidazole is no different from an 8-hourly dose interval , in prevention of local wound infection following minor oral surgery OBJECTIVE To find out whether the frequency of postoperative infectious and inflammatory complications ( IC ) in subjects treated with placebo ( Pl ) is greater than those treated with antibiotic ( Ab ) after extraction of an impacted m and ibular third molar ( M3 ) . Our hypothesis is there are more IC in Pl than in Ab , with a maximum ratio difference of 0.067 . STUDY DESIGN A double-blind placebo-controlled r and omized clinical trial . The sample was derived from the population of subjects attending Cruces Hospital for evaluation and extraction of 1 M3 under local anesthesia . Patients were treated with postoperative placebo or amoxicillin/clavulanic acid 500/125 mg 3 times a day during 4 days . The outcome variable was infectious and inflammatory complications . Sex , age , smoking , molar depth , angulation , need for sectioning , ostectomy , and operation time were recorded . Analysis was by intention to treat , risk measures , and logistic regression . RESULTS In 490 subjects ( 259 Ab and 231 Pl ) , the frequency of IC was 1.9 % in the Ab and 12.9 % in the Pl group ( OR 7.6 , 95%CI 2.9 - 19.9 ; P < .001 ) . The number needed to treat was 10 ( 7 - 16 ) . Unadjusted relative risk was 0.15 ( 0.06 - 0.38 ) ( P < .001 ) . Absolute reduction risk was 0.11(0.066 - 0.155 ) ] . Therefore , the hypothesis can not be rejected . Multivariate analysis shows treatment with antibiotic ( OR = 8.66 ( 3.17 - 23.67 ) ; P < .001 ) and age ( OR = 1.08 ( 1.00 - 1.16 ) ; P = .029 ) are the only variables to be included in the logistic regression model . CONCLUSION Amoxicillin/clavulanic acid is efficacious in reducing the incidence of IC following third molar extraction but should not be prescribed in all cases OBJECTIVES This study was carried out to compare the efficacy of preoperative single bolus antibiotics with a 5 day- postoperative antibiotic regimen in reducing pain , swelling , and trismus , surgical site infection ( SSI ) and alveolar osteitis ( AO ) after third molar surgery . PATIENTS AND METHODS A r and omised experiment was done involving eighty-four patients . The patients were divided into two groups consisting of 42 patients each . A preoperative group was given an oral bolus of 2 g amoxycillin capsules and 1 g metronidazole tablets one hour before extraction , while those in the postoperative group were given a five-day regimen oral 500 mg amoxycillin capsules thrice daily and 400 mg metronidazole tablets thrice daily . The occurrence of postoperative pain , swelling , trismus , SSI and AO were compared between the groups . RESULTS Seventy-nine patients completed the study ; 38 patients in the preoperative group and 41 patients in the postoperative group . There was no difference between the groups in respect of the inflammatory complications . The four cases of AO occurred in the preoperative group . CONCLUSION Single bolus antibiotic prophylaxis should be adequate for most cases of third molar surgery as the degree of degree of postoperative pain , swelling and trismus was similar in both groups . The use of single bolus antibiotic prophylaxis would also help reduce the cost of treatment in developing countries as well as reduce the risk of development of resistant strains . However , a five-day postoperative antibiotic regimen is advised in patient with risk factors for AO This study aim ed at testing the clinical efficacy of a topical prevention of FA , the sample comprising 300 cases of extraction s. A sponge was inserted in the socket of each of them , dividing the sample into 3 equal groups : group A ( gelatine ) , group B ( gelatine + Solcoseryl ) and group C ( gelatine + Solcoseryl + propyl-hydroxy-benzoic-acid ) . The global incidence of FA was a comparatively high , 7.6 % , which could be related to the pool of patients included in the study as to the presence of teeth and techniques more prone to complications . No specific clinical characteristic has been isolated ( distribution within sex , age , teeth , etc . ) which could contradict data collected from other authors . The incidence was lower in the groups B ( 3 % ) and C ( 7 % ) as compared to group A ( 13 % ) , but only sponges of group B demonstrated a clinical and statistical efficacy , according to the high number of lower third molar extraction s. In contrast , the addition of Solcoseryl proves efficient and does not delay healing , according to previous histological studies . This last characteristic has to be confirmed in the experimental conditions described in our study , as has its mode of action . The ultimate mechanism of FA has still , in our opinion , to be better defined well before the restatement of a topical prevention of FA A r and om material of 112 patients , was investigated after surgical removal of impacted lower third molars . 2 experimental groups and 1 control group were studied . Prophylactic medication with penicillin V combined with preoperative rinsing using 0.2 % chlorhexidine gluconate ( Hibitane ) was found to reduce postoperative symptoms , when compared with preoperative rinsing alone . In both cases , patients were compared with the control group The purpose of this study was to evaluate the efficacy of antibiotic prophylaxis during removal of impacted third molars . We studied 150 patients with impacted m and ibular or maxillary third molars who were divided r and omly into three groups . The first was given amoxicillin 2 g combined with clavulanic acid , orally daily for 5 days postoperatively ; starting at the end of the operation . The second group was given the same drugs but the regimen started 5 days before the operation . The third was given no antibiotics . Pain , infection , swelling , alveolar osteitis , and interincisal mouth opening ( mm ) were evaluated . There were no significant differences among the groups in the incidence of these complications . We can not recommend routine oral antibiotic prophylaxis in third molar surgery A controlled clinical trial of prophylactic tinidazole for chemoprophylaxis in third molar A double-blind , placebo-controlled trial was carried out to study the value of cones containing sulfanilamide and sulfathiazole in the healing of third molar sockets . On the seventh postoperative day , 94 patients were examined regarding pain , swelling and the overall effect of the operation . Trials were run to compare sulfa cones directly with a placebo : in addition , the placebo and sulfa drugs were each compared with the effects of no medication . Pairs were made of the left and right m and ibular third molars in the same patient and the results assessed by sequential analysis . It was found that although sulfa cones were better than the placebo , they themselves were no better or worse than leaving the socket alone There is an increasing body of evidence implicating oral anaerobic bacteria in the aetiology of post-surgical dentoalveolar infections . This information has lead to several studies demonstrating the usefulness of specific anaerobicidal drugs in the prevention and treatment of dento-alveolar infection . One such study utilised a single 2 g preoperative oral dose of tinidazole which was found to be significantly better than placebo in preventing infective sequelae after removal of impacted m and ibular third molars . The present study was design ed to compare a high-dose short-term broad spectrum penicillin , ( pivampicillin ) , with the previously described regimen , using tinidazole in order to discern the existence or otherwise of any practical difference between an anaerobicidal and a broad spectrum antibiotic when local infection was considered Combined treatments with non-steroidal anti-inflammatory drugs and antibiotics may offer significant benefits in the prevention of pain and infections associated with oral surgery . In this study , piroxicam and azithromycin were administered to patients undergoing dental extraction to examine the efficacy of piroxicam in the prevention of post-operative pain and inflammatory complications , either in the absence or in the presence of a concomitant antibiotic treatment . Thirty patients were r and omly assigned to three groups and treated for 3 days , before impacted lower third molar removal , as follows : ( 1 ) sublingual piroxicam-FDDF ( fast dissolving dosage formulation ) 20 mg/day ; ( 2 ) oral azithromycin 500 mg/day ; ( 3 ) piroxicam-FDDF 20 mg/day plus azithromycin 500 mg/day . Oral acetaminophen ( 500 mg tablets ) was allowed as rescue analgesic medication . Pain intensity was evaluated on a 100-mm visual-analogue scale after dental extraction ( day 1 ) , and at days 2 , 3 , 7 after surgery . Edema and trismus were estimated at days 2 and 7 . At days 1 and 2 , pain intensity was significantly lower in patients treated with piroxicam-FDDF , either alone ( p < 0.05 ) or in combination with azithromycin ( p < 0.05 ) , than in patients administered with azithromycin alone . A higher acetaminophen consumption was also recorded in the latter group ( p < 0.01 ) . Pain intensity values did not differ among treatment groups at days 3 and 7 . At day 2 , the facial edema was significantly less intense in patients exposed to piroxicam-FDDF alone , as compared to patients treated with azithromycin , either alone ( p < 0.05 ) or in combination with piroxicam-FDDF ( p < 0.05 ) . No significant differences were detected when comparing groups for trismus at days 2 and 7 . The present results indicate that , when given alone in the pre-operative period , piroxicam-FDDF effectively counteracts post-surgical pain and inflammatory reactions in oral tissues . Upon combined treatment with piroxicam-FDDF and azithromycin , the macrolide antibiotic may reduce the influence of piroxicam on post-operative inflammation , without affecting its beneficial effect on surgical pain PURPOSE The aim of the present study was to evaluate and compare the occurrence of postoperative complications in patients receiving either pre- or postoperative amoxicillin versus placebo after third molar surgery . PATIENTS AND METHODS A r and omized , double-blind , placebo-controlled clinical trial was performed in 123 patients undergoing third molar surgery . The patients were r and omized to 3 groups , according to the treatment regimen : preoperative amoxicillin , postoperative amoxicillin , and placebo . Both surgeon and patients were unaware of the treatment assignment . The clinical outcomes , including pain , wound infection , trismus , temperature , intra- and extraoral swelling , dysphagia , side effects , and postoperative complications , were assessed . RESULTS Statistically significant differences were found in the incidence of pain , wound infection , temperature , trismus , and dysphagia between the groups receiving amoxicillin versus placebo . Suture dehiscence and infection of 5 sockets were only found in the placebo group . No cases of alveolitis were observed in the 3 groups studied . No significant differences in swelling were found among the different groups . No statistically significant differences in side effects were found between the groups . The efficacy was greatest in the group receiving postoperative amoxicillin compared with the group receiving a prophylactic preoperative dose . CONCLUSION Amoxicillin administered pre- or postoperatively demonstrated greater efficacy than placebo in preventing postoperative complications in patients undergoing third molar surgery . The best results were obtained using the postoperative protocol A longitudinal prospect i ve trial was carried out on 146 patients to evaluate which factors can have an effect on postoperative recovery after extraction of impacted third molars or wisdom teeth . The following factors were considered : ( 1 ) age , ( 2 ) sex , ( 3 ) smoking habits , ( 4 ) use of the birth control pill , ( 5 ) previous history of pericoronitis , ( 6 ) degree of difficulty of the extraction , ( 7 ) expertise of the surgeon , ( 8) length of surgery , and ( 9 ) antibiotic prophylaxis . The following results were obtained and statistically significant differences were noted with respect to the pain in the context of ( 1 ) sex-males noted more pain on the 1st and 3rd days ( p < 0.05 ) compared with females ; ( 2 ) expertise of the surgeon-- patients treated by surgeons with considerable or average expertise reported less pain on the first and third days ( p < 0.05 ) compared with patients treated by surgeons with little expertise ; and ( 3 ) age -- a direct correlation was noted between age and pain ( p < 0.05 )

Few studies reported on pain , therefore , at best , there was very low quality evidence of little or no difference in pain relief between the different techniques . When the working mechanism for pain relief and functional improvement is fusion of the motion segment , there is low quality evidence that iliac crest autograft appears to be the better technique . When ignoring fusion rates and looking at complication rates , a cage has a weak evidence base over iliac crest autograft , but not over discectomy alone .

BACKGROUND The number of surgical techniques for decompression and solid interbody fusion as treatment for cervical spondylosis has increased rapidly , but the rationale for the choice between different techniques remains unclear . OBJECTIVES To determine which technique of anterior interbody fusion gives the best clinical and radiological outcomes in patients with single- or double-level degenerative disc disease of the cervical spine .

OBJECTIVE After 40 years of experience with anterior cervical operations , whether to fuse is still controversial . This study seeks to answer this question . METHODS In this prospect i ve r and omized study , we operated on 91 patients with single-level cervical root compression using three different methods : 1 ) discectomy without fusion , 2 ) fusion with autologous bone graft , and 3 ) fusion with autologous bone graft plus plating . RESULTS After 4 years of follow-up , the radiological results indicated that complete bony union was achieved in almost all cases . A slight kyphosis developed in 62.5 % of the patients who had undergone discectomy , 40 % of the patients who had undergone fusion , and 44 % of the patients who had undergone fusion plus plating ( not significant ) . The clinical outcomes were good for 76 % of the patients who had undergone discectomy , 82 % who had undergone fusion , and 73 % who had undergone fusion plus plating . The outcomes were poor in 0 , 4 , and 4 % , respectively ( not significant ) . CONCLUSION According to this study , satisfactory results can be achieved by performing simple discectomy to treat single-level cervical root compressive disease OBJECT The authors have previously reported that the results of using cadaveric fibula and locking plate ( CF/LP ) fusion following anterior cervical discectomy ( ACD ) for cervical spondylotic radiculopathy and myelopathy are superior to those obtained using autologous iliac crest ( AIC ) grafts in the short term . The long-term results of using this construct are important in substantiating this improvement . The authors report on 246 consecutive patients ( 54 % smokers ) who underwent ACD with CF/LP fusion ( 175 with allogeneic bone matrix [ ABM ] ) and compare them with 111 consecutive patients in whom AIC fusions ( 49 % smokers ) were performed by the same surgeons . METHODS The study is a retrospective nonr and omized analysis , and chi-square statistics were used . Bone densitometric studies of AIC grafts and CF grafts were performed . A paired t-test was used for statistical analysis of the results . Disease in the group of patients undergoing CF/LP fusion included soft-disc herniation with radiculopathy in 14 , soft-disc hemiation with myelopathy in seven , cervical spondylotic radiculopathy in 144 , cervical spondylotic myelopathy in 75 , AIC graft collapse pseudarthrosis in five , and ACD with no fusion collapse/kyphosis in one . Operations consisted of single-level CF/LP fusion in 142 patients and multilevel CF/LP fusion in 104 . Perioperative complications in the CF/LP group included three cases of transient hoarseness . There were no transfusions , infections , neurological injuries , or deaths . The mean hospital length of stay was 1.2 days ( 28 % outpatient and 66 % 23-hour stay ) . The mean follow-up period was 60 months ( range 12 - 94 months ) . Ten patients were lost to follow up after 1 year . Long-term complications included one traumatic plate fracture and one symptomatic pseudarthrosis with plate fracture . At 1 year and beyond , in 245 ( 99.6 % ) of 246 patients radiographically documented fusion with no motion at the fused level on flexion-extension films was demonstrated . There was no kyphosis , no symptomatic screw plate backout , and no CF/LP graft collapse ( 100 % in the ABM group ) . In the 111 consecutive patients with AIC fusions , however , there was a 17 % graft-related complication rate . There were significantly fewer graft-related complications in the CF/LP group ( p < 0.001 ) . There was no difference in neurological outcome for any of the groups . In the groups undergoing single-level ACD there was a significantly greater chance of complete relief of neck pain CF/LP fusion compared with those undergoing AIC fusion ( p < 0.02 ) . There was a significantly greater chance of AIC collapse with the passage of time compared with CF graft ( p < 0.02 ) . Time until return to work was shorter for the CF/LP group by 5 to 6 weeks ( p < 0.02 ) . There was a higher rate of radiographically documented pseudarthrosis in the AIC group ( p < 0.006 ) . The mean bone densitometry for the CF/LP group was 0.7 g/cm2 , significantly greater than that of the AIC group , which was 0.2 g/cm2 ( paired t-test p < 0.001 ) . CONCLUSIONS When fusion is necessary following ACD , the results of CF/LP fusion are significantly superior in the first 5 years after surgery compared with those for AIC fusions . It remains to be determined if demineralized ABM has a significant effect in enhancing fusion OBJECT The authors compare clinical outcome and fusion rates after iliac crest autograft (ICAG)- and rectangular titanium cage (RTC)-augmented fusion in patients undergoing anterior cervical discectomy ( ACD ) . METHODS One hundred consecutive patients with 127 levels of cervical disc disease refractory to conservative treatment were r and omized into one of the two treatment groups ( ICAG/RTC fusion ) . The visual analog scale was used by the patient to rate overall pain and head , neck , arm , and donor site pain separately . Myelopathy was documented according to Japanese Orthopaedic Association and Nurick grading systems . Outcome was analyzed using Odom criteria , the 36-Item Short Form ( SF-36 ) , and Patient Satisfaction Index scales . Fusion rates were assessed on st and ard and flexion-extension radiographs . Follow-up data of at least 12 months ' duration were available for 95 patients . More residual overall pain after 12 months was documented in patients who underwent ICAG fusion ( 3.3 + /- 2.5 [ ICAG ] and 2.2 + /- 2.4 [ RTC ] ; p < 0.05 ) . Although arm and head pain were minimal in both groups , neck pain proved to be the predominant symptom ( 2.7 + /- 2.5 [ ICAG ] and 1.9 + /- 2.1 [ RTC ] ) , which resolved in only 67 and 48 % of RTC- and ICAG-treated patients , respectively ( p < 0.05 ) . Myelopathy improved comparably in both groups . Regardless of increased pain in ICAG-treated patients , PSI and SF-36 scores were not significantly different between groups ( only four [ 8 % ] of 47 ICAG-treated patients and five [ 10 % ] of 48 RTC-treated patients were unsatisfied ) . Good to excellent functional recovery according to Odom criteria was observed in 75 and 79 % of ICAG- and RTC-treated patients , respectively . Fusion rates were 81 and 74 % , respectively ( p = 0.51 ) . CONCLUSIONS Fusion rates and clinical outcome at 12 months after ACD were comparable between patients who underwent ICAG and RTC fusion . The use of rectangular cages , however , avoids donor site morbidity and reduces overall pain and , thus , seems to be an advantageous treatment alternative Study Design . This study analyzed the fusion results of an allograft-demineralized bone matrix composite versus autograft in a prospect i ve series of patients undergoing surgery for cervical disc disease . Objectives . To determine the fusion rates of allograft-demineralized bone matrix composite in anterior cervical fusion as compared with the gold st and ard autograft . Summary of Background Data . For the anterior cervical fusion , the use of freeze-dried allograft is well documented in the literature , citing its effectiveness and inferior fusion rates . The use of demineralized bone matrix in conjunction with freeze-dried allograft in anterior cervical fusion has not been reported . Methods . This study was done in a prospect i ve fashion in two medical centers . One group received autograft from the anterior iliac crest , whereas others received freeze-dried allograft augmented with demineralized bone matrix ( Grafton , Osteotech , inc , Shrewsbury , New Jersey ) . For the autograft group , the st and ard Smith-Robinson grafting technique was used . For the allograft composite group , demineralized bone matrix was pasted onto the freeze-dried allograft and into the disc space before graft insertion . The autograft group consisted of 38 patients with age ranging 26–71 years ( mean , 46.1 years ) and follow-up periods of 12–33 months ( mean , 18.4 months ) . There were 19 onelevel , 17 two-level , and two three-level fusions , Similarly , the allograft group consisted of 39 patients with age ranging 28–80 years ( mean , 48.0 years ) with follow-up period of 12–31 months ( mean , 17.5 months ) . There were 19 one-level , 16 two-level , and four three level fusions . Clinical and radiographic follow-up evaluations were completed at 3-month intervals . Radio graphs taken 12 months after surgery were analyzed blindly . Results . Pseudarthrosis developed in 46.2 % of patients ( 33.3 % of levels ) in the allograft-demineralized bone matrix group compared with 26.3 % ( 22 % of levels ) in the autograft group ( p = 0.11 for patients , p = 0.23 for levels ) . For patients undergoing two-level fusions , 37.5 % of allograft-demineralized bone matrix failed compared with 23.5 % of of autografts , for singlelevel fusions , 47.4 % of allograft patients developed a pseudarthrosis compared with 26.3 % in the autograft group . Graft collapse of ≥ 3 mm was noted in 11 % of the autograft group versus 19 % in the allograft-demineralized bone matrix group ( p = 0.32 ) . Graft collapse of ≥ 2 mm occurred in 24.4 % of autograft patients compared with 39.7 % of the allograft-demineralized bone matrix group ( p = 0.09 ) . Smokers had an increased rate of pseudarthrosis ( 47.1 % ) compared with nonsmokers ( 27.9 % , p = 0.13 ) . Conclusions . The study revealed that the allograft-demineralized bone matrix construct gives a higher rate of graft collapse and pseudarthrosis when compared with autograft in a prospect i ve series , although the differences were not statistically significant , The pseudar-throsis rate in the series may be high because of the large percentage of smokers and radiographic evaluation techniques . For the purpose of solid radiographic fusion , the use of autograft is recommended in anterior cervical surgery until other acceptable osteoinductive material s are developed Anterior cervical discectomy and interbody grafting provide excellent results in treating cervical radiculopathy . This prospect i ve study compares the results of the technique obtaining autogenous bone from the cervical vertebrae for grafting to the modified Smith-Robinson technique using autogenous iliac crest graft . Seven levels in six patients were fused using the vertebral body autograft technique and 43 levels in 40 patients using the st and ard technique . All patients had radiculopathy and neck pain . Statistically significant differences in fusion rate ( 4/7 vertebral body autograft ; 40/43 modified Smith-Robinson ) ( p = 0.029 ) , disc height maintenance ( p = 0.001 ) , and neck pain improvement ( p = 0.05 ) occurred between the techniques . We do not recommend vertebral body autograft over the modified Smith-Robinson technique for anterior cervical fusion following discectomy Abstract This study evaluated whether addition of a cervical spine locking plate ( CSLP ) in two-level disc fusions improved the postoperative stability and reduced the time to healing . Radiostereometric analysis was used to obtain precise recordings of the three-dimensional motion between the fused vertebrae . Eighteen consecutive patients were operated on with excision of two adjacent cervical discs and anterior horseshoe grafting with autologous bone ( Smith Robinson technique ) . Nine patients were r and omized to stabilization with autologous bone grafting and CSLP plate fixation and nine patients to grafting without fixation . Clinical symptoms in terms of pain in the neck and the arm were analysed preoperatively and after 1 year using a visual analogue scale ( VAS ) . The patients operated without a plate displayed increased rotations around the transverse axis , corresponding to the development of a kyphosis [ mean value no plate/plate 14.4 ° /0.8 ° ( repeated measure ANOVA : P < 0.01 ) ] . The mean compression was 3.2 mm larger in patients operated without a plate ( repeated measure ANOVA : P < 0.01 ) . Patients operated without a plate had more arm pain at the 1-year follow up ( P < 0.05 , Mann-Whitney U test ) . The VAS score for neck pain did not differ significantly between the two groups . Plate fixation could not be demonstrated to increase the healing rate , promote more rapid fusion or influence the frequency of graft complications Study Design . In this study , 43 patients scheduled for a single-level cervical Cloward procedure for disc disease were r and omized prospect ively to fusion with autograft , allograft , or xenograft . Objective . To outline any differences in fusion over time in terms of final mobility and clinical outcome between the three bone grafts . Summary of Background Data . Fusion is used to relieve pain from a spinal segment . The bovine xenograft gives a fibrous fusion in contrast to the solid bone fusion obtained with autograft from the iliac crest , but no definite differences in clinical outcome have been shown previously after surgery at a single level . Methods . By use of radiostereometric analysis , 33 patients were observed after 6 , 12 , and 24 to 50 ( mean , 37 ) months . All 43 patients underwent clinical examination , which involved pain rating before and after surgery , with a final follow-up assessment by an unbiased observer . Results . Mobility could be demonstrated in 9 patients after 1 year and in 6 patients at the final follow-up assessment , without pain , and with no difference between bone grafts . The patients who received autograft experienced a greater reduction of pain than the patients treated with xenograft . Conclusions . Most of the patients healed with a rigid fusion no matter which graft was used , but the healing process took longer than expected . The clinical results were not influenced by whether mobility could be demonstrated . There was a tendency toward better clinical results in the patients treated with autograft The authors performed a prospect i ve study of 63 patients with cervical radiculopathy treated with Robinson anterior cervical discectomy and fusion and compared the traditional or st and ard and reverse graft techniques . Modifications of the st and ard Robinson grafting techniques have been proposed . The reverse graft technique has theoretical advantages , including limiting the deleterious effects of graft extrusion and maintaining rigid middle column support . A radiographic evaluation and an assessment of clinical outcome based on the criteria of Odom were performed prospect ively for as long as 1 year after surgery . Thirty-one patients were treated with the st and ard grafting technique and 32 with the reverse graft orientation . The radiographic evaluation showed no significant differences between the two techniques with regard to sagittal alignment and disk heights . The overall fusion grade was higher in the reverse graft technique ( p < 0.05 ) . There were 93 % and 96 % good to excellent results in the st and ard graft and reverse graft groups , respectively . The authors report no significant differences associated with the st and ard or reverse anterior cervical grafting techniques in terms of radiographic alignment or disk height loss over time or at early clinical outcome . However , improved fusion grade was noted with the reverse graft technique , which may be related to end plate and intervertebral space preparation . The reverse grafting technique is an acceptable alternative to the st and ard graft orientation Introduction : Intervertebral carbon fiber cages may reduce graft collapse and promote bony fusion . Their safety and efficacy in the cervical spine have been investigated ; however , no study has compared the outcomes of anterior cervical decompression and placement of a carbon fiber cage with placement of allograft and plate . Methods : Forty consecutive patients who met inclusion criteria were enrolled and r and omized to anterior cervical discectomy with carbon fiber cage alone ( n=20 ) or with allograft with plating ( n=20 ) . Clinical and radiographic evaluations were performed at baseline and at 6 weeks , 3 , 6 , 12 and 24 months . Neck and arm pain as well as neck disability index ( NDI ) were assessed at every visit . The Short Form (SF)-36 was completed prior to operation and at 12-month intervals . Cervical radiographs were evaluated pre-op and at every follow-up for evidence of fusion and instability . Results : No significant difference was found between the two r and omized groups with respect to pre-operative age ( mean 50 years ) , sex , employment status , duration of pain or cervical levels affected . The mean follow-up period was 14 months ( range , 6–26 months ) . The clinical pain and disability improvements were similar for both treatments . Post-operative donor site pain was only present in the cage group , but not of significant long-term disability . At up to 24 months , NDI scores were significantly improved in both groups when compared with baseline . At 12 and 24 months , all SF-36 question naire responses were also improved in both the treatment groups . However , there was no statistically significant difference in outcomes between the two groups at any time . The fusion rate was 100 % in both groups by 12 and 24 months , without evidence of instability . There were no differences in complications between both groups . Conclusions : The outcomes after cervical decompression and placement of a carbon fiber cage appear to be similar to cervical decompression with allograft and plating by the Smith – Robinson technique Abstract A prospect i ve r and omised 2-year study was performed to compare the conservative and operative treatment of mild and moderate forms of spondylotic cervical myelopathy ( SCM ) . Forty-eight patients presenting with the clinical syndrome of SCM , with a modified Japanese Orthopaedic Association ( mJOA ) score of 12 points or more , were r and omised into two groups . Group A , treated conservatively , consisted of 27 patients , mean age 55.6 ± 8.6 years , while group B was treated surgically ( 21 patients , mean age 52.7 ± 8.1 years ) . The clinical outcome was measured by the mJOA score , recovery rate ( RR ) , timed 10 m walk , score of daily activities ( recorded by video and evaluated by two observers blinded to the therapy ) , and by the subjective assessment of the patients at 6 , 12 , and 24 months of the follow-up . There was , on average , no significant deterioration in mJOA score , recovery ratio , or timed 10 m walk within either group during the 2 years of follow-up . In the surgery group there was a slight decline in the scores for daily activities and subjective evaluation . A comparison of the two groups showed no significant differences in changes over time in mJOA score or quantified gait , but there were significant differences in the score of daily activities recorded by video at 24 months , which was a little lower in the surgical group , and also in RR and subjective evaluation , which were both worse in the surgical group at months 12 and 24 . However , at month 6 , this last parameter was significantly better in the surgical than in conservative group . Surgical treatment of mild and moderate forms of SCM in the present study design , comprising the patients with no or very slow , insidious progression and a relatively long duration of symptoms , did not show better results than conservative treatment over the 2-year follow-up Anterior cervical plate fixation is an approved surgical technique for cervical spine stabilization in the presence of anterior cervical instability . Rigid plate design with screws rigidly locked to the plate is widely used and is thought to provide a better fixation for the treated spinal segment than a dynamic design in which the screws may slide when the graft is settling . Recent biomechanical studies showed that dynamic anterior plates provide a better graft loading possibly leading to accelerated spinal fusion with a lower incidence of implant complications . This , however , was investigated in vitro and does not necessarily mean to be the case in vivo , as well . Thus , the two major aspects of this study were to compare the speed of bone fusion and the rate of implant complications using either rigid- or dynamic plates . The study design is prospect i ve , r and omized , controlled , and multi-centric , having been approved by respective ethic committees of all participating sites . One hundred and thirty-two patients were included in this study and r and omly assigned to one of the two groups , both undergoing routine level-1- or level-2 anterior cervical discectomy with autograft fusion receiving either a dynamic plate with screws being locked in ap - position ( ABC , Aesculap , Germany ) , or a rigid plate ( CSLP , Synthes , Switzerl and ) . Segmental mobility and implant complications were compared after 3- and 6 months , respectively . All measurements were performed by an independent radiologist . Mobility results after 6 months were available for 77 patients ( 43 ABC/34 CSLP ) . Mean segmental mobility for the ABC group was 1.7 mm at the time of discharge , 1.4 mm after 3 months , and 0.8 mm after 6 months . For the CSLP- group the measurements were 1.0 , 1.8 , and 1.7 mm , respectively . The differences of mean segmental mobility were statistically significant between both groups after 6 months ( P = 0.02 ) . Four patients of the CSLP-group demonstrated surgical hardware complications , whereas no implant complications were observed within the ABC-group ( P = 0.0375 ) . Dynamic plate design s provided a faster fusion of the cervical spine compared with rigid plate design s after prior spinal surgery . Moreover , the rate of implant complications was lower within the group of patients receiving a dynamic plate . These interim results refer to a follow-up period of 6 months after prior spinal surgery . Further investigations will be performed 2 years postoperatively Study Design This is a prospect i ve , r and omized , and controlled study , approved by the local ethical committee of Saarl and ( Germany ) , no. 209/06 . Objective The aim of this study was to compare clinical results , segmental motility , magnetic resonance imaging ( MRI ) compatibility , and change of the bone density of a cervical spine segment that was treated with either bioresorbable or titanium plates in single level . Summary and Background Data Anterior cervical discectomy and fusion including plate fixation is an accepted technique for treatment of symptomatic degenerative disc disease . Titanium plates have been used but cause imaging artifacts . Radiolucent bioresorbable plates and screws were developed to reduce the imaging artifacts associated with titanium . Methods Forty patients with single level cervical radiculopathy were r and omized to anterior discectomy and fusion with bioresorbable plate ( 19 patients , study group ) or titanium plate ( 18 patients , control group ) . Follow-up used a visual analog scale ( VAS ) with regard to brachial pain and Neck Disability Index ( NDI ) for neck pain . Radiostereometry was performed immediately postoperative and after 6 weeks , 3 , and 6 months . MRI of the cervical spine was obtained immediately postoperatively at 3 and 6 months to assess hematoma , infection , and swelling . Computed tomography of the operated cervical spine segment was performed to assess bone density , expressed in Hounsfield units . Results Three-dimensional analysis of segmental motion ( medio-lateral , cranio-caudal and anterior-posterior ) did not reveal any statistical difference between both groups at any time postoperatively ( P>0.05 ) . Fusion rate and speed evaluated on Radiostereometric analysis and computed tomography of cervical spine segment were similar in both groups . MRI of cervical spine did not show any pathology , especially hematoma and infection . The VAS and NDI did not differ between both groups after 6 months ( P>0.05 ) . Conclusions Anterior plate fixation by using a bioresorbable plate has the same fusion progress and stability as titanium . During the study , no complications like soft tissue swelling and infection occurred In a prospect i ve study , 103 patients were r and omised to anterior cervical decompression and fusion ( ACDF ) with a cervical carbon-fibre intervertebral fusion cage or the Cloward procedure . Preoperative background variables , active range of neck motion , h and grip strength , radiological evaluation and subjective variables were used in a multiple regression model to find the strongest predictors of postoperative outcome as measured by current pain intensity and the Neck Disability Index ( NDI ) . Male sex , greater kyphosis at the level operated on , non-smoking , a greater neck mobility in right rotation , low disability on NDI , and older age were predictors of pain reduction and explained 30 % of current pain intensity at follow-up . Higher educational level , non-smoking , greater kyphosis at the level operated on , a greater flexion mobility , greater right h and grip strength and lower current pain intensity were predictors of improvement , and explained 28 % of the postoperative outcome on NDI . The most important predictor for postoperative pain intensity was the magnitude of the preoperative kyphosis . Preoperative pain intensity was the most important predictor for improved NDI . At follow-up about 70 % of the patients still had deficit based on current pain intensity and NDI , and 44 % had remaining dysfunction based on Odom 's criteria . In conclusion , the multivariate analysis shows that male sex , non-smoking , greater segmental kyphosis and a low pain and disability level are preoperative predictors of a good outcome in ACDF . In addition , the study suggests the importance of other predictive variables than those studied for the outcome of ACDF Study Design . A prospect i ve r and omized clinical study . Objective . To compare 2 surgical methods in the treatment of cervical radiculopathy caused by hard or soft disc herniation ; namely , simple discectomy versus discectomy with an additional interbody fusion with a Ray titanium cage . Summary of Background Data . Although an interbody fusion after anterior decompressive surgery for hard or soft disc herniation is widely accepted , there is no scientific evidence that convincingly demonstrates that insertion of graft material for interbody fusion is necessary after discectomy and decompression of the nervous elements have been performed . To date , no r and omized studies have compared simple discectomy with discectomy followed by an interbody fusion with a titanium cage . Methods . Eighty-six patients with symptoms of nerve root compression at 1 level were r and omly allocated to either discectomy followed by fusion with a Ray titanium cage ( 40 patients ) or to discectomy alone ( 46 patients ) . Clinical and radiologic follow-up was performed 3 , 12 , and 24 months after surgery . Results . There was no statistically significant difference between the 2 groups concerning self-reported satisfaction or severity of pain in the neck and arm . Two years after the operation , 86.1 % of the patients treated with cage stated a good outcome versus 76.7 % in the discectomy group ( P = 0.44 ) . The rate of fusion was 83.3 % in the cage group versus 81.0 % in the discectomy group ( P = 0.30 ) . Furthermore , after 2 years , also the rates of new adjacent disc degeneration or spondylosis were the same in both groups . Conclusion . This study showed no statistically significant difference between simple discectomy and discectomy followed by interbody fusion with a titanium cage in the surgical treatment of cervical radiculopathy caused by disc herniation Study Design One hundred fifteen patients having symptomatic cervical disc disease were recruited prospect ively for this study . They were allocated r and omly for either autologous iliac bone graft or biocompatible osteoconductive polymer implants . Both groups were compared clinical ly and radiologically . Objectives Complications , long‐term clinical and radiologic outcome , and hospital stay were compared to determine if biocompatible osteoconductive polymer was an improvement on iliac bone graft in terms of reduced donor site pain and shortened hospital stay . Summary of Background Data Donor site morbidity is a significant problem in anterior cervical fusion . Hospital stay is another factor in the recent era of cost consciousness . Biocompatible osteoconductive polymer has been used in many centers as a biodegradable implant to circumvent these problems . Methods Smith‐Robinson technique was used in 74 patients , and Cloward technique was used in 41 patients . Sixty‐five patients had biocompatible osteoconductive polymer implants , and 50 patients had iliac bone graft . Patients were followed‐up routinely in the outpatient clinic where pain visual analogue scale and Odom 's criteria were used for outcome evaluation . Plain radiography , computed tomography scan , and magnetic resonance imaging were used for radiologic evaluation . Results The mean hospital stay was 4.8 days for those with iliac bone graft and 4.7 days for those with biocompatible osteoconductive polymer . Clinical outcome was identical in both groups . The incidence of partial graft protrusion and postoperative intersegmental kyphosis was statistically higher with iliac bone graft ( P = 0.018 and P = 0.02 , respectively ) . “ Sclerosis ” started to form around biocompatible osteoconductive polymer like a “ halo ” at 2 months . It increased with time , and sometimes was associated with new osteophyte formation ; however , there was no biocompatible osteoconductive polymer incorporation or biodegradation . Conclusions Biocompatible osteoconductive polymer acts as a good “ spacer ” that reduces graft collapse and intersegmental kyphosis . However , it did not show any radiologic evidence of biodegradation or incorporation during the follow‐up period of 24 months Study Design . A prospect i ve r and omized trial with independent clinical and radiographic outcome review of patients receiving either hydroxyapatite or tricortical iliac crest graft for cervical interbody fusion was conducted . Objective . To determine whether coralline-derived hydroxyapatite is a suitable bone graft substitute in cervical interbody fusion . Summary of Background Data . Tricortical iliac crest bone is the “ gold st and ard ” graft material for cervical interbody fusion . Various bone substitutes have been used for this procedure to avoid potential donor site morbidity . ProOsteon 200 is a coralline-derived hydroxyapatite product , the use of which remains unclear for cervical interbody fusion . Methods . In this study , 29 patients undergoing anterior cervical fusion and plating were r and omized to receive either ProOsteon 200 or iliac crest grafts . The SF-36 and Oswestry Disability Index were used to measure clinical outcome . Postoperative radiographs were analyzed for graft fragmentation , loss of height , angular alignment , and hardware failure to assess structural integrity of the graft material . Plain radiographs and computed tomography scans were used to evaluate fusion . Results . Both the ProOsteon 200 and iliac crest groups demonstrated significant improvement in clinical outcome scores . There was no significant difference in clinical outcome or fusion rates between the two groups . Graft fragmentation occurred in 89 % of the hydroxyapatite grafts and 11 % of the autografts ( P = 0.001 ) . Significant graft settling occurred in 50 % of the hydroxyapatite grafts , as compared with 11 % of the autografts ( P = 0 . 009 ) . One patient in the ProOsteon 200 group required revision surgery for graft failure . Conclusions . ProOsteon 200 does not possess adequate structural integrity to resist axial loading and maintain disc height or segmental lordosis during cervical interbody fusion The method of anterior mono- or bisegmental cervical spine fusion is a well-established procedure for degenerative conditions of the cervical spine . While the early reports promote fusion with bone graft alone , recent studies report superior results with the addition of anterior plating . The objective of this study was to evaluate the influence of using plates in anterior cervical spine fusion in a prospect i ve study . Fifty c and i date s for anterior mono- or bisegmental cervical spine fusion were r and omly and prospect ively selected and assigned to a plated and a non-plated group . After a minimum follow-up of 22 months , patients were clinical ly and radiologically examined . The reduction in pain , improvement in neurology and functional assessment showed a significant improvement in both groups compared to the preoperative values . The total neurological score improved significantly in both groups , but the changes were greater in the group with plates . There was no significant difference between the groups for fusion rating , but graft quality ( graft height ) was significantly better in the plated group . We conclude that the overall data do not suggest better results with plating in mono- or bisegmental anterior spine fusions . Indications for additional internal fixation are restricted to special conditions with increased instability , insufficient bone quality or inappropriate graft placing OBJECT The authors report the preservation of motion at surgically treated and adjacent spinal segments after placing an artificial cervical joint ( ACJ ) and they describe the influence of interbody fusion on changes in angulation occurring in the sagittal plane at adjacent levels in the treatment of cervical spondylosis . METHODS The authors conducted a prospect i ve nonr and omized study of patients in whom an ACJ was placed or autologous bone graft interbody fusion was performed . Angular measurements at levels adjacent to that surgically treated were calculated using plain flexion-extension radiographs obtained at 6-month intervals . Analyses of qualitative data , such as increase or decrease in adjacent-level motion , and the degree of disc degeneration were performed . Quantitative data were also analyzed . In the fusion group a significant increase in adjacent-level movement was demonstrated at the 12-month follow-up visit compared with the group of patients in whom ACJs were placed ( p < 0.001 ) . The increase in movement occurred predominantly at intervertebral discs that were preoperatively regarded as normal ( p < 0.02 ) . An overall reduction in adjacent-level movement was observed in patients who underwent joint replacement , although this was compensated for by the movement provided by the ACJ itself . CONCLUSIONS Fusion results in increased motion at adjacent levels . The increase in adjacent-level motion derives from those discs that appear radiologically normal prior to surgery . It remains unknown whether ACJs have a protective influence on adjacent intervertebral discs OBJECT The authors prospect ively evaluated cervical foraminal height changes after anterior cervical discectomy and fusion . To their knowledge , this prospect i ve study is the first in which foraminal height changes over time are compared following the placement of a tricortical graft or a polyetheretherketone ( PEEK ) cage . METHODS The patients were r and omly divided in two groups . In one group , 30 patients underwent anterior cervical microdiscectomy and free bone graft ( FBG ) insertion at 46 levels via the Smith-Robinson technique . The FBG was harvested from the right iliac crest . Another 35 patients underwent the same operation , but fusion was provided by the insertion of PEEK intervertebral cages at 41 levels . Fusion status and the C2 - 7 Cobb angle , interspace height , and foraminal height changes were observed on anterior , lateral , and oblique radiographs obtained at the 18-month follow-up examination . There were no differences between the groups with regard to clinical recovery , fusion status , and Cobb angle . A significant interspace height reduction was observed in the FBG group during the 1st postoperative month . In the FBG group , the mean heights ( + /- st and ard deviation ) of the foramina were 8.2 + /- 2.7 mm preoperatively , 10.8 + /- 2.6 mm on postoperative Day 2 , and 8.1 + /- 1.5 mm after 18 months of follow up . In the PEEK cage group , the mean heights were 8.4 + /- 2.8 mm preoperatively , 10.3 + /- 1.1 mm on postoperative Day 2 , and 9.6 + /- 1.2 mm after 18 months of follow up . The increase in foraminal height was significantly preserved at the 6th , 12th , and 18th months in the cage group . CONCLUSIONS In both groups the foraminal height increased sufficiently and the nerve root was decompressed postoperatively . The PEEK cages may provide sufficient preservation of foraminal height even 1.5 years after the operation A primary object with a fusion cage is avoidance of graft collapse with subsequent subsidence and malalignment of the cervical spine that is observed after bone grafting alone . No r and omized studies exist that demonstrate the difference between these two methods in terms of graft subsidence and angulation of the fused segment . The size of the study population was calculated to be 24 patients to reach a significant difference at the 95 % CI level . Patients with one-level cervical radiculopathy scheduled for surgery were r and omized to anterior discectomy and fusion ( ACDF ) with autograft or to fusion cage , both without plate fixation . Tantalum markers were inserted in the two adjacent vertebrae at the end of surgery . Radiostereometry was performed immediately postoperatively and at regular intervals for 2 years . Question naires were used to evaluate the clinical outcome and an unbiased observer grade d the outcome after 2 years . No significant differences were found between the two methods after 2 years in regard of narrowing of the disc space ( mean 1.7 and 1.4 mm , respectively ) or deformation of the fused segment into flexion ( mean 7.7 ° and 4.6 ° , respectively ) . Patients in the cage group had a significantly better clinical outcome . The findings of subsidence and flexion deformation of the fused segment after 2 years seem to be of no clinical importance after one-level cervical disc surgery . However , in multi-level surgery using the same methods , an additive effect of the deformations of the fused segments may affect the clinical outcome A variety of bone graft substitutes , interbody cages , and anterior plates have been used in cervical interbody fusion , but no controlled study was conducted on the clinical performance of β-tricalcium phosphate ( β-TCP ) and the effect of supplemented anterior plate fixation . The objective of this prospect i ve , r and omized clinical study was to evaluate the effectiveness of implanting interbody fusion cage containing β-TCP for the treatment of cervical radiculopathy and /or myelopathy , and the fusion rates and outcomes in patients with or without r and omly assigned plate fixation . Sixty-two patients with cervical radiculopathy and /or myelopathy due to soft disc herniation or spondylosis were treated with one- or two-level discectomy and fusion with interbody cages containing β-TCP . They were r and omly assigned to receive supplemented anterior plate ( n = 33 ) or not ( n = 29 ) . The patients were followed up for 2 years postoperatively . The radiological and clinical outcomes were assessed during a 2-year follow-up . The results showed that the fusion rate ( 75.0 % ) 3 months after surgery in patients treated without anterior cervical plating was significantly lower than that ( 97.9 % ) with plate fixation ( P < 0.05 ) , but successful bone fusion was achieved in all patients of both groups at 6-month follow-up assessment . Patients treated without anterior plate fixation had 11 of 52 ( 19.2 % ) cage subsidence at last follow-up . No difference ( P > 0.05 ) was found regarding improvement in spinal curvature as well as neck and arm pain , and recovery rate of JOA score at all time intervals between the two groups . Based on the findings of this study , interbody fusion cage containing β-TCP following one- or two-level discectomy proved to be an effective treatment for cervical spondylotic radiculopathy and /or myelopathy . Supplemented anterior plate fixation can promote interbody fusion and prevent cage subsidence but do not improve the 2-year outcome when compared with those treated without anterior plate fixation OBJECTIVE To evaluate anterior cervical plating in short-level anterior discectomy and autograft bone fusion . METHODS Eighty-one patients who underwent one- and two-level anterior cervical discectomy and fusion were r and omized to 2 groups , with or without instrumentation . Among them , 55 patients were followed up . The mean follow-up time was ( 22 + /- 7 ) months . Fusion rate , disc height and cervical lordotic alignment were assessed by radiographs . RESULTS The improving rates were 68 % in non-instrumented group and 58 % in instrumented group , respectively ( P > 0.05 ) . The fusion rate was 93 % in the non-instrumented group and 100 % in the later one . The disc height was decreased ( 0.7 + /- 1.0 ) mm in the former group and increased ( 1.2 + /- 0.6 ) mm in the later one ( P < 0.01 ) . Although the postoperative cervical lordotic alignment was maintained better in instrumented group , the difference was not significant . CONCLUSION Anterior cervical plating can make good influence on the result of anterior cervical discectomy and fusion in some degree OBJECT The need for interbody fusion or stabilization after anterior cervical microdiscectomy is still debated . The objectives of this prospect i ve r and omized study were 1 ) to examine whether combined interbody fusion and stabilization is more beneficial than microdiscectomy only ( MDO ) and 2 ) if fusion is found to be more beneficial than MDO , to determine which is the best method of fusion by comparing the results achieved using autologous bone graft ( ABG ) , polymethylmethacrylate ( PMMA ) interposition , and threaded titanium cage ( TTC ) . METHODS A total of 125 patients with a single-level cervical disc disease were included in this prospect i ve study . All patients were r and omized and assigned to one of the four following groups : Group 1 ( 33 patients ) , MDO ; Group 2 ( 30 patients ) , microdiscectomy followed by ABG ; Group 3 ( 26 patients ) , microdiscectomy followed by injection of PMMA ; and Group 4 ( 36 patients ) , microdiscectomy followed by placement of a TTC . Clinical outcome according to Odom criteria was summarized as 1 ) excellent and good or 2 ) satisfactory and poor . One-year follow-up examination was performed in 123 patients . Patients in the TTC group experienced a significantly better outcome 6 months after surgery ( 92 % excellent and good results ) compared with those in the MDO and ABG groups ( 72.7 and 66.6 % excellent and good results , respectively ) . Twelve months after surgery there was still a significant difference in outcomes between the TTC group ( 94.4 % excellent and good results ) and the MDO group ( 75.5 % excellent and good results ) . Outcome in patients treated with PMMA was comparable with that in those treated with TCC after 6 ( 91.6 % ) and 12 months ( 87.5 % ) , but no segmental fusion was achieved . Differences compared with MDO and ABG were , however , not significant , which may be related to the smaller number of patients in the PMMA group . CONCLUSIONS Interbody cage-assisted fusion yields a significantly better short- and intermediate-term outcome than MDO in terms of return to work , radicular pain , Odom criteria , and earlier fusion . In addition , the advantages of interbody cages over ABG fusion included better results in terms of return to work , Odom criteria , and earlier fusion after 6 months . These results suggest that interbody cage-assisted fusion is a promising therapeutic option in patients with single-level disc disease . Polymethylmethacrylate seems to be a good alternative to interbody cage fusion but is hindered by the absence of immediate fusion Background Anterior cervical microdiscectomy ( ACD ) is commonly applied in the surgical treatment of cervical disc herniation . However , following discectomy procedure to perform a fusion process is still controversial . Therefore , a controlled , multicentric , prospect i ve , r and omized study was design ed . Material and Method Totally 20 patients were operated . Eleven patients were operated with applying simple anterior microdiscectomy technique . Nine patients were operated via ACD and fusion with a semirigid plate technique . Preoperative and postoperative [ immediate ; postoperative first day and postoperative 1 y ( mean 13.95 mo ) ] computed tomography studies and plain x-rays were obtained . The cervical disc and bilateral neural foramen heights of the operated level and adjacent segments were calculated . Pain assessment was performed using visual analog pain scale . Mann-Whitney statistical analysis method was applied to compare the outcomes for both groups . Results Satisfactory result was achieved in both groups . The pain scores for major complaint ( arm pain ) were decreased significantly in all patients after surgery regardless of the type of technique applied . The improvement in neck pain scores was significant only in patients who were treated with fusion procedure . There were no significant changes in disc height and neural foramen height measurements for both groups in adjacent levels in immediate and 1-year postoperative periods . The patients who were operated with simple ACD technique showed no significant decrease at postoperative first day in disc height and neural foramen height . However , the 1-year postoperative radiologic studies showed a significant decrease in disc height and neural foramen dimensions compared with preoperative values . The patients who were treated with fusion process showed a significant increase in disc height and nonsignificant increase in neural foramen heights at immediate postoperative study . However , with time , all dimensions showed significant decrease compared with preoperative values . Conclusions ACD technique offers satisfactory outcome regardless of whether fusion process is applied or not . Fusion with semirigid plate offers an advantage at operated level in immediate postoperative period in regard of disc height and neural foramen height . However , semirigid anterior plates by definition do not stop subsidence and the advantage that is offered by this technique is not persistent . On the other h and , to apply fusion process with semirigid plate system offers significantly less narrowing in disc height compared with simple ACD technique BACKGROUND CONTEXT Conflicting views exist according to the individual philosophy about various plate design s that can be used in anterior cervical discectomy and fusion ( ACDF ) to achieve clinical and radiological improvement within shortest time period . No prospect i ve r and omized study has ever been conducted to clarify the relationship between clinical outcomes , fusion rates , and the choice of plate ( static vs. dynamic design ) . PURPOSE To compare the clinical and radiological outcomes of patients treated with one-level or multiple levels ACDF using cervical plates of dynamic ( slotted-holes ) versus static ( fixed-holes ) design . STUDY DESIGN Single masked , prospect i ve , r and omized study . PATIENT SAMPLE Over a 4-year period , 66 patients ( M : F=37:29 ) had ACDF using either dynamic ( n=33 ) or static ( n=33 ) plates for intractable radiculopathy as the result of degenerative cervical spine disease . Overall , 28 patients had single-level fusion and 38 had two or three levels fused . OUTCOME MEASURES Visual Analogue Pain scores ( VASs ) , Neck Disability Index ( NDI ) , and radiological criteria of established fusion . METHODS The qualifying subjects were r and omized to receive ACDF using either fixed-holes ( static ) or the slotted-holes ( dynamic ) anterior cervical plates . Clinical and radiographic data were collected and analyzed . Paired- sample t test was used to correlate clinical and radiological outcomes and General Linear Model Analysis of Variance ( GLM ANOVA ) with repeated measures was used to detect outcome differences between the two groups for single and multiple fusions . RESULTS At a mean follow-up of 16 months ( range , 12 - 24 ) , 49 patients ( 73.7 % ) had clinical success and 56 ( 85 % ) showed radiological fusion . Although clinical success was a predictor of fusion ( p=.043 ) , the reverse was not true ( p=.61 ) . In single-level fusion , no statistical difference of outcome was observed between the two groups but multilevel fusions with dynamic plate showed significantly lower VAS and NDI than those with static plates ( p=.050 ) . CONCLUSIONS Although clinical improvement is a good predictor of successful ACDF , radiological evidence of fusion alone is not reliable as a parameter of success . The design of plate does not affect the outcomes in single-level fusions but statistics indicate that multiple-level fusions may have better clinical outcome when a dynamic plate design is used PURPOSE To describe and explore the relationships between pain , emotional state and coping strategies in patients with chronic radicular neck pain before and after surgery or conservative treatments . METHODS We r and omize 81 conseutive patients with cervical radicular pain and nerve root compression , verified by MRI , to either surgical decompression with fusion or physiotherapy or neck collar . Emotional state was both measured with Mood Adjective Check List . Hospital Anxiety and Depression Scale and with a Coping Strategies Question naire . Pain was measured with VAS and function with Disability Index Rating . Measurements were made before treatment , and follow ups after 3 and 12 months post treatment . RESULTS We found generally a low emotional state with anxiety , depression and sleep-disturbances not only connected to pain . Pain improved faster in the surgery group but after one year no differences were seen . Surgery and physiotherapy improved function with heavy work compared to collar after 3 months . Many patients used active coping before treatment , but after treatment more passive coping strategies were found . CONCLUSION We recommend a multidisciplinary rehabilitation with cognitive behavioural therapy and psychological interventions Summary The Cloward procedure is a routine approach to decompress and fuse the cervical spine . This paper looks at two aspects of the operation . Firstly the morbidity due to the hip wound is assessed , and alternatives to the use of autologous bone graft discussed . Secondly one Neurosurgical Unit 's experience in the use of surgibone — an animal bone substitute harvested from steers and fashioned in dowels — is described . In this trial it was not found to be a satisfactory substitute to autologous bone The authors conducted a prospect i ve study of 132 patients requiring interbody fusion without instrumentation following anterior cervical discectomy to compare the efficacy of tricortical iliac crest allograft versus autograft fusion substrates . The objectives of the study were to assess the potential differences in interspace collapse , angulation , maintenance of cervical alignment and lordosis , and clinical and radiographic fusion success rates between the two fusion substrates . The impact of habitual cigarette smoking on fusion rates was also examined . Autograft tricortical iliac crest bone was found to be superior to allograft bone as an interbody fusion substrate after both single- and multiple-level anterior cervical decompression procedures with respect to maintenance of cervical interspace height , interspace angulation , and radiographic and clinical fusion success rates . Cigarette consumption had a significant adverse effect on successful anterior cervical interbody fusion for both autograft and allograft substrate , an effect that was most pronounced among smokers treated with allograft bone ( p = 0.004 ) UNLABELLED This study investigated the radiographic and scintigraphic courses of union in cervical interbody fusion using hydroxyapatite ( HA ) grafts or iliac bone autografts . METHODS Twelve patients underwent both serial plain radiography and bone scintigraphy during the 12 mo after surgery . Serial plain radiographs were obtained every month until the end of the study period . Bone scintigrams with 99mTc-hydroxymethylene diphosphonate ( HMDP ) were obtained at 2 wk and at 1 , 2 , 3 , and 6 mo . Uptake of 99mTc-HMDP in the graft was expressed as a ratio of the counts in the graft to those in the axis . RESULTS In the HA graft group , the plain radiographs of all patients showed a radiolucent stripe that disappeared 7.3 + /- 1.5 ( mean + /- SD ) months after surgery . In the autograft group , a radiolucent stripe around the graft was not seen for any patient , and union was confirmed by follow-up radiographs within 6 mo after surgery . The serial changes in the 99mTc-HMDP uptake ratio showed no difference between the 2 groups . The 99mTc-HMDP uptake ratio peaked 1 mo after surgery and decreased rapidly to a plateau within 2 mo . CONCLUSION In the HA graft group , despite the presence of a radiolucent stripe around the graft for more than 6 mo , the scintigraphic course of union was not different from that in the autograft group . The likelihood is that the presence of a radiolucent stripe around the HA graft in the early months after surgery is not always a sign of pseudoarthrosis BACKGROUND Anterior cervical discectomy and fusion ( ACDF ) using bone graft or a cage with plate fixation is an accepted technique for the treatment of symptomatic degenerative disc disease . It is , however , debatable whether a plate is really necessary to increase the progress of fusion . Thus , the aim of this r and omized and controlled prospect i ve study was to evaluate whether ACDF with a cage and anterior plate fixation results in a greater progress of fusion compared with ACDF using a st and -alone cage . METHODS 37 c and i date s for ACDF were treated either with a st and -alone cage ( study group ) or with a cage+plate fixation ( control group ) . 19 patients were r and omized to be stabilized with a st and -alone cage and 18 patients were treated with a cage and additional anterior plate fixation . The progress of cervical fusion over time was compared by radiostereometric analysis ( RSA ) . Follow-up examinations pre- and postoperatively were done using the Visual Analogue Scale ( VAS ) for neck and arm pain . Radiographic assessment of fusion using an RSA-control was done after one , six and twelve weeks , as well as after six months , and one and two years postoperatively . Mann-Whitney test for unpaired values was used to determine the statistical differences in residual intervertebral motion . RESULTS Three-dimensional analysis of segmental motion ( left-right , cranio-caudal , and posterior-anterior ) did not reveal any statistical differences between both groups at any examination time postoperatively ( P>0.05 ) . The VAS score did not differ between the groups ( P>0.05 ) . CONCLUSION Anterior plate fixation did not demonstrate an improvement in the progress of fusion in one-level ACDF OBJECTIVE The need for interbody fusion after anterior cervical discectomy for radiculopathy remains controversial . The purpose of this study was to assess clinical and radiographic outcomes in patients with cervical radiculopathy after discectomy without fusion ( ACD ) , discectomy with intervertebral fusion ( ACDF ) , and discectomy with intervertebral fusion and instrumentation ( ACDFI ) . METHODS Forty-two consecutive patients with cervical radiculopathy who failed medical management were r and omized to one of three treatment groups : ACD , ACDF , or ACDFI . Indices including symptoms , work status , Short Form-36 , McGill pain scores , and anteroposterior/lateral flexion/extension x-rays were obtained preoperatively and during the follow-up period . RESULTS There were no inter-group differences observed during the 2-year follow-up period with respect to neck pain , interscapular pain , or arm pain ( P > 0.05 ) . Short Form-36 scores demonstrated a dramatic postoperative improvement followed by further gradual improvement in both physical and mental components as well as other subscale scores in all groups during the follow-up period ( P < 0.05 ) . Fusion occurred in 67 % of the ACD patients compared with 93 % of the ACDF patients and 100 % of the ACDFI patients ( P < 0.05 ) . Segmental kyphosis was noted in 75 % of the ACD patients postoperatively compared with 17 % preoperatively . There was no change in sagittal balance in the ACDF or ACDFI groups ( P > 0.05 ) . CONCLUSION Patient selection and surgical decompression remain the key to achieving desirable clinical outcomes after cervical discectomy for radiculopathy . Within a 2-year follow-up period , the technique of reconstruction plays no role in clinical results . However , ACD alone results in segmental kyphosis compared with ACDF and ACDFI Summary This study was conducted on 90 patients with symptomatic cervical disc disease with one or two-level disc pathology . Clinical and radiological outcome was compared to determine which technique was advantageous for patients with disc disease . Problems related to donor site as well as those related to fusion bed and grafts have stimulated investigators to avoid fusion . Patients were allocated at r and om for either the ACF ( n=50 ) or the ACD ( n=40 ) procedures . The st and ard Smith-Robinson technique was performed on all patients in this study . Patients were followed-up clinical ly and radiologically according to the study protocol . The clinical long-term outcome was comparable in both groups , though those who had ACF were more satisfied . There was significant incidence of kyphosis in the ACD group ( P=0.02 ) . Osseous union was slow and less satisfactory with ACD ( 64 % ) than with ACF ( 94 % ) . Pain at the donor site was not a significant problem in the long-term . Hospital stay and operative time was shortened in ACD patients though not significantly . Spondylotic patients were less satisfied with ACD though not significantly . Conclusions . The issue of whether to fuse or not to fuse has not come to an end yet . The technique is still in need of more refinement of disc excision and graft harvesting and shaping , as well as more adequately controlled studies . Until that , ACD has to be limited to those patients with a soft single disc without spondylosis Background The purpose of this prospect i ve semi-r and omised comparative study was to compare fusion rates , course of fusion , and occurrence of collapse and subsidence of autologous and allogenic bone grafts in instrumented anterior cervical fusion . The number of fused levels and the smoking status were investigated as potential factors influencing the bone-healing process . No similar prospect i ve study on instrumented anterior cervical discectomy and fusion was found in the literature . Methods Seventy-nine consecutive patients were operated on using the Smith – Robinson technique with a single instrumentation system at one or two levels . Seventy-six cadaverous fibular bone grafts and 37 autologous iliac-crest bone grafts were inserted . All patients were followed up for at least 2 years . Results The radiographs obtained during the follow-up were analysed , and showed no statistical difference in fusion and collapse rate between autografts and allografts . Allografts showed significantly longer time to union . No case of graft migration was observed . No difference was found between fusion and collapse rate with respect to the number of fused levels in general , but greater time to union was seen in two-level fusions . When one- and two-level subgroups were compared , there was no evidence of any significant difference in fusion or collapse rates between autografts and allografts , and the healing process took longer in allogenic grafts . Smoking status did not alter any of the fusion or collapse rates , or the course of bone fusion . Conclusions This study demonstrates that allografts are suitable substitutes for autografts in instrumented ACDF . Prolonged time to union observed in allogenic bone grafts does not seem to be an important factor in instrumented procedures . Two-level grafting does not imply a significantly lower fusion rate , but longer time to union can be expected than with single-level instrumented procedures in both allograft and autograft subgroups . Our relatively small number of patients may not have been sufficient to decipher significant differences between smokers and non-smokers in the rate or course of fusion as previously reported Anterior cervical decompression and fusion ( ACDF ) is the st and ard for cervical discectomies . With the full-endoscopic anterior cervical discectomy ( FACD ) a minimally invasive procedure is available . The objective of this prospect i ve , r and omised , controlled study was to compare the results of FACD with those of ACDF in mediolateral soft disc herniations . A total of 103 patients with ACDF or FACD were followed up for two years . In addition to general parameters specific measuring instruments were used . Postoperatively 85.9 % of the patients no longer had arm pain , and 10.1 % had occasional pain . There were no significant clinical differences between the decompression with or without fusion . The full-endoscopic technique afforded advantages in operation technique , rehabilitation and soft tissue injury . The recorded results show that FACD is a sufficient and safe alternative to conventional procedures when the indication criteria are fulfilled . At the same time , it offers the advantages of a minimally invasive intervention . RésuméLa décompression cervicale antérieure avec greffe ( ACDF ) est un st and ard de la chirurgie cervicale avec discectomies . La discectomie endoscopique FACD par voie mini-invasive est également possible . L’objectif de cette étude prospect i ve r and omisée est de comparer les résultats de cette technique endoscopique mini-invasive FACD avec la technique classique ACDF . 103 patients ayant bénéficié soit d’une ACDF soit d’une FACD ont été suivis pendant une moyenne de deux ans . après l’intervention , 85,9 % des patients ne présentent aucune douleur au niveau brachial et 10,1 % des douleurs occasionnelles . Il n’y a pas de différence significative que l’on ait réalisé ou non une greffe . La technique par endoscopie présente des avantages pratiques notamment en ce qui concerne la rééducation et les lésions des tissus en post-opératoires . le résultat montre que la technique FACD est une technique suffisamment sûre et es-t une alternative valable à la technique conventionnelle lorsque les critères d’indication ont été respectés . Cette technique a par ailleurs les avantages de la voie mini-invasive Study Design . A prospect i ve , r and omized , pilot clinical trial compared recombinant human bone morphogenetic protein-2 ( rhBMP-2 ) with iliac crest autograft bone for the treatment of human cervical disc disease . Objective . To examine the safety and effectiveness of using INFUSE ™ Bone Graft ( rhBMP-2 applied to an absorbable collagen sponge ) , as compared with an autogenous iliac crest bone graft placed inside the CORNERSTONE-SR ™ fibular allograft , in anterior cervical discectomy and interbody fusion . Summary of Background Data . Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that induces a reliable fusion in the lumbar spine , but it has not been studied in patients with degenerative cervical disc disease . Methods . For this study , 33 patients with degenerative cervical disc disease were r and omly assigned to investigational or control groups . The investigational group received a fibular allograft ( CORNERSTONE-SR ™ Allograft Ring ) with an rhBMP-2–laden collagen carrier inside the graft along with an ATLANTIS ™ anterior cervical plate . The control group received a fibular allograft with cancellous iliac crest autograft placed inside it , along with an ATLANTIS anterior cervical plate . The patients underwent plain radiographs at 6 weeks , then at 3 , 6 , 12 , and 24 months , and CT scans at 3 and 6 months after surgery . They also completed general health profiles and self-evaluation scales . Adverse events were evaluated for severity , duration , association with the implant , and the need for a second surgical procedure . Results . All the patients evaluated had solid fusions 6 , 12 , and 24 months after surgery . There were no device-related adverse events . At 24 months , the investigational group had mean improvement superior to that of the control group in neck disability and arm pain scores ( P < 0.03 each ) . Conclusions . This pilot study demonstrates the feasibility of using rhBMP-2 safely and effectively in the cervical spine We conducted a prospect i ve , r and omised study of 42 cervical interbody fusions undertaken with either an autologous tricortical graft or a cage . The factors assessed in the two groups were : ( 1 ) time taken to achieve fusion ; ( 2 ) neck disability index ; ( 3 ) pain score ; ( 4 ) interbody height ratio ; ( 5 ) interbody angle and ( 6 ) the influence of smoking on fusion . No statistical difference was seen in the time taken to achieve fusion , neck disability index , interbody height ratio , or interbody angles . Smoking did not have any effect on the fusion process . The pain score was significantly lower in the tricortical graft group at six months . We conclude that both methods of fusion give similar results , although tricortical graft fusion is cheaper than cage fusion , and is more effective in reducing the pain score Study Design . This prospect i ve , r and omized study compares the efficacy of surgical and conservative treatments in patients with long-lasting cervical radicular pain . Objectives . To compare the effects of surgery , physiotherapy , and a cervical collar . Summary of Background Data . There are no previous controlled outcome studies that have compared surgical treatment with nonsurgical treatment of patients with cervical radicular pain . Methods . The study group comprised 81 patients with cervicobrachial pain of at least 3 months ' duration , in whom the distribution of the arm pain corresponded to a nerve root that was significantly compressed by spondylotic encroachment with or without an additional bulging disc , as verified by magnetic resonance imaging or computed tomographic myelography . The patients were r and omly allocated to surgery ( Cloward technique ) , individually adapted physiotherapy , or a cervical collar . The therapeutic effects were evaluated with respect to pain intensity by the visual analogue scale , function by the Sickness Impact Profile , and mood by the Mood Adjective Check List . The measurements were performed before treatment ( control 1 ) , shortly after treatment ( control 2 ) , and after a further 12 months ( control 3 ) . Results . At control 1 , the groups were uniform . At control 2 , the surgery group reported less pain ( visual analogue scale ) and , like the physiotherapy group , better function ( Sickness Impact Profile ) than the collar group . At control 3 , there was no difference in visual analogue scale , Sickness Impact Profile , and Mood Adjective Check List measurements among the groups . Conclusions . In the treatment of patients with long-lasting cervical radicular pain , it appears that a cervical collar , physiotherapy , or surgery are equally effective in the long term A prospect i ve r and omised study . To compare the long-term outcome of anterior cervical decompression and fusion ( ACDF ) with a cervical intervertebral fusion cage ( CIFC ) and the Cloward procedure ( CP ) . We have previously shown that the 2 year outcome of ACDF with the CIFC is the same as for the CP . The fusion rate in CIFC group was , however , only 55 % , compared to 85 % in CP group . The long-term outcome of CIFC is poorly documented . Ninety-five patients with at least 6 months duration of neck pain and radicular arm pain were r and omly allocated for ACDF with the CIFC or the CP . Radiographs were obtained at 2 years . Question naires about pain , disability ( Neck Disability Index , NDI ) , distress , quality of life and global outcome were obtained from 83 patients ( 87 % ) ( 43 CIFC , 40 CP ) at a mean follow-up time of 6 years ( range 56–94 months ) . There were no significant differences in any outcome variable between the two treatments . For both CP and CIFC the pain intensity improved ( P<0.0001 ) whereas the NDI was unchanged at long-term follow-up compared to preoperatively . In the CIFC group patients with a healed fusion had significantly less mean pain ( 24 mm ) and NDI ( 26 % ) than patients with pseudarthrosis ( 42 and 41 , respectively ) . Furthermore , the mean pain and NDI reported by CIFC patients with a healed fusion was significantly less than in healed CP patients ( 37 and 38 , respectively ) . The long-term outcome is the same for the CIFC and the CP , with similar improvements of pain but with considerable remaining functional disability . However , in the subgroup of patients with healed CIFC the outcome was clearly better than for the non-healed CIFC group , and also clearly better than for the healed CP group . Thus , if the healing problem associated with the CIFC can be solved the results indicate that a better outcome can be expected with the cage than with the CP In 200 patients with either isolated protrusion of disc or with spondylosis a cervical discectomy in one or two levels was performed from a ventral approach . In 100 patients the removed disc was replaced with an implant of polymethylmethacrylat ( PMMA ) . In 100 patients interbodyfusion was done with a titanium cage . Both groups were analysed in a prospect i ve study . Clinical outcome was assessed after surgery . Results were similar in terms of complications and clinical outcome . As the PMMA surgery took longer and the costs of titanium are higher , there is no marked advantage of one implant material over the other OBJECT A prospect i ve , r and omized trial was performed to compare the efficacy of anterior cervical discectomy ( ACD ) with ACD and fusion ( ACDF ) for the treatment of cervical spondylosis in patients with neurological compromise . METHODS Forty-four patients underwent ACD and 40 underwent ACDF . Operative time and length of hospital stay were shorter and there was less need for analgesia in the ACD group . It was found that whereas the incidence of fusion was greater in the ACDF group compared to the ACD group ( 97 compared with 70 % , respectively ; p<0.01 ) , patient satisfaction and a return to preoperative activity level was similar between groups . CONCLUSIONS Analysis of the results suggests that the addition of a fusion procedure may be unnecessary Fifty-one patients with symptomatic cervical disc disease refractory to conservative management were allocated at r and om to one of two treatment groups . The st and ard anterior approach devised by Cloward was used for 25 patients , and radical discectomy and foraminotomy for the other 26 . All patients were followed for 6 months or longer with interview , physical examination , and radiographic evaluation . There was no difference in the success rate between the two groups . The large majority ( 92 % ) of patients in both groups were pleased with results of their operation . Because of technical factors related to operative exposure of the spinal canal and nerve roots , we prefer the Cloward procedure for patients symptomatic from advanced spondylosis and reserve discectomy without bone graft insertion for those with minimal spondylosis or soft disc herniations Study Design . Prospect i ve , controlled , r and omized , multicenter study . Objective . To analyze implant complications and speed . Summary of Background Data . Rigid plate design s , in which the screws are locked to the plate , are in common use and thought to provide more fixation than dynamic design s , in which the screws may glide when the graft is settling . The aim of the study is to analyze ( 1 ) implant complications , ( 2 ) speed of fusion , ( 3 ) loss of lordosis , and ( 4 ) clinical outcome in both types of plates . Methods . One hundred thirty-two patients were included and assigned by r and omization to one of the groups in which they received a routine anterior cervical discectomy and autograft fusion with either a dynamic plate ( ABC , study group ) or a rigid plate ( CSLP , control group ) . At discharge , after 3 and 6 months and finally after 2 years , implant complications , segmental mobility , absence of radiolucencies , absence of bone sclerosis , evidence of bridging trabecular bone , loss of lordosis , Visual Analog Scale ( VAS ) and Neck Disability Score were recorded . All radiographic measurements were performed by an independent radiologist . Results . There have been 4 patients with implant complications within the control group and no implant complications within the study group , P = 0.045 . Mean segmental mobility before discharge for the study group was 1.7 mm , 1.4 mm after 3 months , 0.8 mm after 6 months , and 0.4 mm after 2 years . For the control group , these values were 1.0 , 1.8 , 1.6 , and 0.5 mm . The difference at 6 months between both groups was significant ( P = 0.024 ) . Neither absence of radiolucencies , nor absence of sclerosis , nor evidence of bridging bone showed significant differences between the 2 groups through the postoperative follow-up ( P > 0.05 ) . The loss of segmental lordosis for the study group with respect to intraoperative radiograph was 1.3 ° at discharge and 4.3 ° after 2 years . For the controlgroup , these values were 0.9 ° , 0.7 ° . The difference at 2 years was significant ( P = 0.003 ) . Clinical postoperative outcome ( VAS and ODI ) was not different between the 2 groups through the postoperative follow-up ( P > 0.05 ) . Conclusion . Dynamic cervical plate design s provide less implant complications ( no patient ) compared with rigid plate design s ( 4 patients ) . Speed of fusion was faster in the presence of a dynamic plate . However , loss of segmental lordosis is significantly higher if dynamic plates are used , which did not result in differences regarding clinical outcome between dynamic and constrained plates after 2 years . Thus , dynamic plates should be considered to be the preferred treatment option because of the lower risk for implant failure-related revision surgery Abstract Forty-six consecutive patients with neck pain and arm radiculopathy were treated with anterior cervical discectomy and fusion . All patients had neurological symptoms corresponding to a herniated disc and /or spondylosis at one or two cervical levels , verified by magnetic resonance imaging . The patients were stabilized with an anterior graft and r and omized to either fixation with a CSLP plate or no internal fixation . Preoperatively and 2 years postoperatively the patients filled in a question naire that included a modified Million Index , a modified Oswestry Index and the Zung Depression Scale . They were also asked to register their pain in the arm and in the neck on a vertical visual analogue scale ( VAS ) . At the 2-year follow-up , an unbiased observer grade d the patients ’ clinical outcome using Odom ’s criteria . A test-retest procedure was carried out to examine the question naire reproducibility . In the group that was operated at one level , there was no significant improvement in any of the scores . Nevertheless , 81 % of the patients were satisfied with the outcome of the surgery . All scores improved in the group operated at two levels . The pain in the neck and arm , as measured on a VAS , decreased in both groups . The improvement in arm pain was significantly more pronounced in patients operated with a plate at two levels compared to those who were operated without a plate . At the 2-year follow-up , patients with an excellent or good result according to Odom ’s criteria had a lower Million Index ¶(P < 0.0005 ) , Oswestry Index ( P < 0.0005 ) , and Zung ( P = 0.024 ) score , than the group classified as fair or poor . There was a significant correlation ( P < 0.0001 for all scores ) between the test and retest results . We conclude that the modified Million Index and Oswestry Index are clinical ly useful tools in the evaluation of outcome after degenerative cervical disc surgery . The clinical benefits of plate fixation were minimal . The outcome after surgery , measured with the Oswestry Index , Million Index and VAS for arm and neck pain , seems to correlate well with the classification of outcome by Odom INTRODUCTION Nonautologous interbody fusion material s are utilised in increasing numbers after anterior cervical disc surgery to overcome the problem of donor site morbidity of autologous bone grafts . This study investigates the performance of two nonautologous material s , the bone cement Polymethylmethacrylate ( PMMA ) and titanium cages . This prospect i ve r and omised trial , with assessment of the results by an independent observer , evaluates whether a Polymethylmethacrylate ( PMMA ) spacer or a titanium cage provides a better fusion rate around the implant and a better clinical outcome . PATIENTS / MATERIAL AND METHODS Between 2000 and 2002 , 115 patients with monoradicular cervical nerve root compression syndrome caused by soft cervical disc herniation were eligible for this study . Myelopathy , excessive osteophyte formation , and adjacent level degeneration were exclusion criteria . A block-restricted r and omisation was applied . The 2-year clinical outcome served as the primary endpoint of the study . Clinical outcome was assessed according to the Odom scale by an independent observer at the follow-up examination . Preoperative , postoperative , and follow-up radiographs were taken . RESULTS The study was completed by 107 patients ( 53 with PMMA and 54 with titanium cage ) . No significant difference between the two groups could be established with respect to the clinical outcome . In each group , 26 patients scored excellent . Good results were found in 19 PMMA patients and 16 titanium cage patients ; satisfactory results were found in 8 PMMA patients and 9 titanium cage patients ; bad results were found in 3 titanium cage patients . In 47 titanium cage cases ( 87 % ) , fusion occurred radiologically as bony bridging around the implant . The fusion rate was significantly lower ( p=0.011 ) in the PMMA group , with 35 cases ( 66 % ) united at follow-up . CONCLUSION The radiological result of the titanium cage is superior to that of PMMA with respect to the fusion rate . Although the titanium cage achieves a better fusion rate , there is no difference between titanium cages and PMMA with respect to the clinical outcome BACKGROUND CONTEXT The success of arthrodesis for anterior cervical fusion depends on several factors , including the number of surgical levels . Internal fixation putatively improves the arthrodesis rate and outcome . PURPOSE To provide medium-term follow-up data on the surgical success and patient outcome of one- and two-level anterior cervical discectomies and fusions and to determine the effect that plate fixation has on results . STUDY DESIGN A prospect i ve study of 40 patients who underwent modified Smith-Robinson anterior cervical discectomy and fusion at one or two operative levels . PATIENT SAMPLE Forty patients . OUTCOME MEASURES Odom criteria , Nurick grading system , radiographs . METHODS Forty patients , with an average age of 44 years ( range , 27 to 82 ) , were followed for an average of 51 months ( range , 24 to 85 ) . All had an anterior discectomy , burring of the end plates and placement of an autogenous tricortical iliac crest graft at one ( 20 patients ) or two levels ( 20 patients ) . Twenty-three were stabilized with the Cervical Spine Locking Plate ( Synthes Spine , Paoli , PA ) , 4 single level , 19 two level . All patients had follow-up office visits with examinations and radiographs . Radiographic union , postoperative pain relief and neurologic recovery were evaluated . RESULTS Successful arthrodesis of single-level procedures occurred in 11 of 16 unplated and 2 of 4 plated fusions . Primary bony union in the two-level group was achieved in 15 of 19 plated patients and did not occur in the single unplated procedure . Clinical ly , there were 12 excellent , 5 good , 3 satisfactory and 0 poor outcomes among the single-level procedures . Among the dual-level procedures , there were 10 excellent , 5 good , 3 satisfactory and 2 poor results . Nine of 16 who developed adjacent-level degeneration had pain . Five of the 9 also had nonunions . Of the 40 , 3 had fibrous union at final follow-up , and 10 had revision surgery . CONCLUSIONS The Cervical Spine Locking Plate improved the outcome of two-level procedures to that of uninstrumented one-level fusions . Adjacent-level degeneration is associated with persistent pain , especially if there is also a nonunion . Primary bony union is paralleled by a better clinical outcome We r and omized 27 consecutive patients undergoing 1-level cervical disc surgery to surgery with or without anterior plate fixation . The patients were studied with radiostereometry and clinical ly with visual analogue scores ( VAS ) for arm and neck pain . After 2 years , 1 patient had developed pseudoarthrosis , all other fusions were healed , but 1 patient showed substantial motions in the fusion area between the 1- and 2-year follow-ups . The 12 patients operated on without a plate had increased rotations around the transverse axis , corresponding to deformation towards kyphosis . Clinical ly , there was no difference in outcome between the two groups , as assessed by VAS . The use of an anterior plate in 1-level degenerative disc surgery in the cervical spine seems to prevent rotational deformation , without affecting the clinical outcome or fusion healing Study Design . A prospect i ve r and omized study was conducted . Objective . To determine whether the use of a cervical carbon fiber intervertebral fusion cage improves the outcome of anterior cervical decompression and fusion , as compared with the Cloward procedure using autograft . Summary of Background Data . Despite the theoretical advantages of using intervertebral cages , including reduced donor site morbidity and prevention of graft collapse , an improved clinical outcome has not yet been documented . Methods . For this study , 103 patients were r and omized to anterior cervical decompression and fusion with a carbon fiber intervertebral fusion cage ( n = 52 ) or the Cloward procedure ( n = 51 ) . An independent observer quantified pain and functional disability . Fusion rate , segmental kyphosis , and disc height were assessed by radiographs . Results . During a mean follow-up period of 36 months ( range , 24–72 months ) for 89 patients ( 86 % ) , the pain and disability were similar for both treatments . Postoperative donor site pain was significantly less in the carbon fiber intervertebral fusion cage group . The fusion rate was 86 % in the Cloward procedure group and 62 % in the carbon fiber intervertebral fusion cage group ( P < 0.05 ) . In the latter group , patients with pseudarthrosis reported more severe pain than fused patients ( 51 and 33 visual analog scores , respectively ) , but the difference was not significant . The segmental kyphosis was less and the disc height increased in the carbon fiber intervertebral fusion cage group , as compared with the Cloward procedure group . Disc height was not correlated with outcome . Segmental kyphosis showed a weak ( r = −0.3 ) but significant ( P < 0.05 ) correlation with improvement of the Cervical Spine Functional Score , but not with other outcome variables . Conclusions . Except for reduced donor site pain , the clinical outcome for the carbon fiber intervertebral fusion cage is the same as for the Cloward procedure . Use of the cage results in a more lordotic alignment and an increased disc height , but in a higher pseudarthrosis rate than use of the Cloward procedure A prospect i ve r and omized study to compare discectomy without ( DE ) and with fusion ( DEF ) included 63 patients operated on with DE returned to work during the first 9 weeks postoperatively than patients operated on with DEF ( p less than 0.005 to 0.05 ) . The prognosis is significantly better for men than for women after DEF ( p less than 0.005 ) , while no difference can be shown after DE OBJECT Despite variations in technique , inherent problems persist with current approaches to anterior cervical fusion . This study was performed to determine whether anterior cervical fusion performed using an investigational device was safe and effective in the treatment of degenerative cervical disc disorders and whether this device offered advantages over current techniques . METHODS Fifty-four patients with radiculopathy with or without mild myelopathy due to one- or two-level cervical degenerative disc disease were r and omized as part of a Food and Drug Administration device study . Following microsurgical discectomy , the control group was treated with iliac crest graft fusion ; the experimental study group underwent insertion of an interspace cage and placement of a local autograft . All patients received postoperative follow-up care for at least 2 years . Good or excellent results were found in approximately 97 % of the experimental group and 88 % of the control group . A solid fusion was achieved in all patients who underwent one-level cage placement , and a solid fusion at one or both levels was achieved in over 90 % of both groups . Chronic donor site pain was reported by 31 % of the control group . CONCLUSIONS In this study , the use of an interbody fusion cage avoided donor site morbidity and placement of autograft achieved a high rate of good or excellent results . Interbody fusion cages appear safe and effective , and their use helps to avoid some of the inherent problems in performing current anterior cervical fusion techniques A prospect i ve r and omized study was undertaken to evaluate the radiological appearance and clinical effectiveness of two porous tantalum ( Hedrocel ) implants in achieving a stable cervical interbody fusion . A prer and omization protocol was used to allocate patients to the three arms of the study : a ring implant containing autologous cancellous bone graft , a solid block implant or autologous tricortical iliac crest bone graft . Patients were followed for 2 years with plain radiological studies , SF-36 , and Neck Disability Index question naires and neurological assessment . Early in the study the postoperative radiographs of four patients receiving Hedrocel implants showed inferior end-plate lucency raising concerns about delayed or non-fusion . Recruitment to the study was halted by the investigators to allow longer-term follow-up of the implanted patients when only 24 patients had been recruited to the study . Although fusion was subsequently noted in all patients at 12 months there was no further enrolment to the study . At 2 years the radiological and clinical outcomes of the three groups appeared comparable , but the study numbers were too small for any statistical analysis . This study highlights the difficulties that can arise when clinical caution takes precedence over objective measures of clinical progress during a study . In the absence of an independent safety monitoring committee , the investigators were under an ethical obligation to suspend recruitment to this study , until it was clear that the radiological features were not associated with poor clinical outcomes . The use of safety monitoring committees and the clarification of stopping criteria in relation to outcome measures should be considered in open r and omized trials of spinal surgical techniques and implants In a prospect i ve r and omised study with a 2-year follow-up , 103 patients were r and omised to anterior cervical decompression and fusion ( ACDF ) with a cervical carbon-fibre intervertebral fusion cage ( CIFC ) or the Cloward procedure ( CP ) . The purpose of the present study was to report predictors for fusion and also to investigate the importance of radiological variables for the clinical outcome . Gender , age , smoking habits , disc height , segmental kyphosis and type of surgical procedure were used as independent ( before surgery ) variables in a multiple regression model . Male gender , one-level surgery and CP treatment were significant predictors of fusion and explained 14 % of the variability of fusion status at follow-up . Number of levels operated on , however , did not influence the clinical outcome . Fifty-two per cent of the women and 17 % of the men in the CIFC group , and 25 % of the women and 8 % of the men in the CP group , had pseudarthrosis . Although patients with a healed fusion had significantly less pain intensity than patients with pseudarthrosis , radiological variables explained only 4 % of the variability of pain at follow-up . Apart from a significant correlation between preoperative kyphosis and neck disability index at follow-up , no significant correlation between either postoperative kyphosis or preoperative or postoperative disc height and clinical outcome was found . Neither degree of segmental kyphosis nor disc height was different between patients with healed fusion and pseudarthrosis . One can conclude that male gender and type of surgery were significant predictors for a healed fusion and that pseudarthrosis affected outcome . In contrast to the commonly held view based mainly on theoretical considerations , no effect on clinical outcome could be demonstrated for segmental kyphosis and disc height at follow-up . Overall , the study shows that the importance of radiological factors as predictors for fusion as well as clinical outcome is limited Study Design A prospect i ve r and omized trial with assessment of treatment results by an independent observer and by patient question naire . Objectives This study evaluated whether implantation of polymethylmethacrylate after anterior cervical discectomy improved clinical results and whether polymethylmethacrylate provided a solid bony union with preservation of anatomical relations of the cervical spine . Summary of Background Data Discectomy without fusion disturbs anatomical relations of the cervical spine . Use of an autologous bone graft frequently causes donor‐site complications . Therefore , synthetic material s such as polymethylmethacrylate have been used instead of bone to obtain spinal fusion . Whether these implants improve the clinical results of anterior discectomy is unknown . In addition , the radiological follow‐up of discectomy with polymethylmethacrylate has hardly been investigated . Methods Between April , 1986 , and April , 1990 , all patients with radiologically proven cervical disc pathology and a radicular syndrome were eligible for this study . The primary endpoint of the study was the clinical result after 2 years . Assessment of the result was rated both by an independent observer using Odom 's criteria and by the patient using a written question naire . Before surgery and during follow‐up , radiographs were obtained . Results Two patients died during follow‐up . A good result was obtained in 28 of 42 patients ( 70 % ) treated with polymethylmethacrylate and in 30 of 39 patients ( 77 % ) of patients treated with discectomy only . Pre‐operative neck pain subsided earlier if polymethylmethacrylate was used , but the difference was temporary and clinical ly insignificant . The use of polymethylmethacrylate result ed in a significant lower bony union rate . Polymethylmethacrylate frequently migrated into adjacent vertebrae . Conclusions No relevant clinical differences between treatments were found . The radiological results of anterior discectomy with polymethylmethacrylate were inferior to those of discectomy only . Based on these results , the use of polymethylmethacrylate to obtain fusion after anterior discectomy is not recommended Study Design . A longitudinal cohort study ( n = 448 ) comparing functionally restored discectomy ( n = 123 ) and fusion ( n = 101 ) workers ' compensation patients to matched , unoperated control patients ( n = 123 and n = 101 , respectively ) . Objectives . To determine successful treatment outcomes uniquely important in a workers ' compensation environment when spine surgery is combined with comprehensive tertiary rehabilitation , to optimize anatomic and social sequelae . Summary of Background Data . Multiple recent studies confirm suboptimal socioeconomic outcomes for spinal surgery for degenerative conditions in a workers ' compensation venue . In other musculoskeletal regions , there is a clear relationship between the quality of postsurgical rehabilitation and the impact on disability , recurrent injury , and future health care use . It is hypothesized that poor surgical outcomes in compensation injuries may result from outmoded postoperative methods , rather than failures of patient selection or surgical technique . No previous combination of surgery plus rehabilitation has been carefully evaluated with disabled workers undergoing spine surgery . Functional restoration is an individualized medically directed , interdisciplinary program using quantitatively directed exercise progression , psychotherapeutic interventions , and monitoring of specific socioeconomic outcomes for chronically disabled workers . Methods . This study prospect ively evaluated a cohort of consecutive functional restoration program graduates ( n = 1202 ) . Two surgical groups , discectomy ( n = 123 ) and fusion ( n = 101 ) were matched to two groups of unoperated control patients , control/discectomy and control/fusion , selected from the same cohort of patients with chronic spinal disorders based on age , gender , race , length of disability , and workers ' compensation jurisdiction . A structured clinical interview was administered 12 months after program completion , with a contact rate of 95 % to 98 % . Results . Socioeconomic outcomes for work return , health care use , and recurrent lost‐time injury were assessed . All groups demonstrated a return‐to‐work incidence of more than 85 % , but work retention at 1 year was higher for the fusion group than for the discectomy or control/fusion groups . Health care use was significantly higher for the discectomy group than the control/discectomy or fusion groups for reoperation ( 8 % vs. 4%/2 % ) , as well as other factors . All groups showed comparable recurrent lost‐time injury rates ( 2‐3.3 % ) , and made comparable improvements in prospect ively collected physical and psychological measures . Conclusions . Discectomy patients had work , health care utilization , and recurrent injury outcomes comparable with those for unoperated control patients . Fusion patients had better outcomes of work retention , reoperation , and health care use compared with the unoperated control patients and even with discectomy patients , in spite of more cases of previous surgery and greater duration of disability . The discectomy and fusion cohorts of operated chronic spinal disorder compensation patients with subsequent functional restoration had the best documented outcomes found in the literature for this population . In spite of the common presumption that spine surgery patients fare poorly in a workers ' compensation environment , these results demonstrate that such patients can show remarkably successful objective outcomes if accompanied by effective rehabilitation , documenting efficacy and clinical utility . A new clinical approach is required to evaluate prospect ively the combination of surgery and rehabilitation in chronic pain/disability workers ' compensation patients , in which the surgical role is to correct an anatomic lesion , but the socioeconomic outcomes either occur spontaneously or are effected through some form of rehabilitation OBJECT In a double-blind r and omized study , platelet concentrate was used to treat 50 patients who underwent anterior cervical fusion with allograft bone and internal fixation , predominantly for degenerative disc disease or soft herniated cervical disc . The goal in this study was to compare the outcomes in patients treated with and without the platelet gel . METHODS Patients were assessed radiographically at 6 , 12 , and 52 weeks and at 2 years if needed . Clinical ly , patients were evaluated with the visual analog scale , Neck Disability Index , Short Form-36 , and a modified Prolo Scale . RESULTS Follow-up included 90 % of the patients at 1 year and 84 % at 2 years . The overall fusion rate was 84 % . CONCLUSIONS Whereas patients with degenerative discs treated with platelet gel demonstrated early fusion at the 12-week follow-up interval , no consistent early fusion was obtained with the use of the platelet gel preparation in patients with a soft disc herniation BACKGROUND Cervical disc herniation causing neurological compromise is a common affliction . Sophisticated surgical treatments have been developed throughout the twentieth century and are largely successful . Although each procedure has its supporters , it is still unclear if one surgical technique is superior . METHODS A prospect i ve trial was design ed to evaluate the efficacy of three surgical procedures for the treatment of cervical radiculopathy caused by a unilateral acute herniated cervical disc . Patients were r and omized to posterior cervical foraminotomy ( FOR ) , and anterior cervical discectomy with ( ACDF ) , and without ( ACD ) fusion . Perioperative data , office follow-up and long-term follow-up were used to compare the procedures . RESULTS All of the procedures yielded excellent relief of symptoms and signs postoperatively and during follow-up . Operative time and hospital stay were slightly shorter for ACD compared with ACDF and FOR . Reoperations occurred in all groups but there was a trend for higher recurrence at the same level with FOR and recurrence at other levels with ACDF . CONCLUSION All three of the procedures were successful for treatment of cervical radiculopathy caused by a herniated cervical disc . Although the numbers in this study were small , none of the procedures could be considered superior to the others . This study suggests that the selection of surgical procedure may reasonably be based on the preference of the surgeon and tailored to the individual patient Study Design . A prospect i ve r and omized controlled study was carried out . Objective . To determine the effectiveness and safety of a tantalum implant in achieving anterior cervical fusion following 1-level discectomy as treatment of degenerative cervical disc disease with radiculopathy . Summary of Background Data . The gold st and ard for the treatment of degenerative cervical disc disease could not be already identified . The morbidity of autologous graft and plating , and the doubt about the mechanical efficacy of plate fixation and the clinical benefits in 1-level fusion have promoted the use of other constructs . Methods . Sixty-one patients were r and omized to anterior cervical discectomy and fusion with interbody implant of tantalum ( n = 28 ) or by means of autologous iliac bone graft and plating ( n = 33 ) . Fusion rate and segmental height and alignment were blind assessed by radiographs by 2 independent review ers . Clinical status was evaluated using pain visual analogue scale , the Neck Disability Index , and the Zung Depression Scale . Patient ’s subjective satisfaction was recorded . Complications and operative parameters were also taken into account . Results . With an endpoint of 24 months , radiologic and clinical outcomes were similar for both treatments without significant difference . The safety of fusion with tantalum implant was obvious , based on the analysis of complications . Complication rate was considerably higher for the autologous graft plus plating procedure than for implant tantalum ( P < 0.005 ) . Conclusion . The efficacy to achieve fusion after 1-level anterior cervical discectomy , with a good radiologic and clinical outcome , using tantalum implant is equivalent to that of autologous graft and anterior plate , being safer as avoids donor-site graft harvesting and plating complications

This review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes . A recent Cochrane review suggests that calcium channel blockers ( mainly nifedipine ) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics .

BACKGROUND Preterm birth , defined as birth before 37 completed weeks , is the single most important cause of perinatal mortality and morbidity in high-income countries . Oxytocin receptor antagonists have been proposed as effective tocolytic agents for women in preterm labour to postpone the birth , with fewer side-effects than other tocolytic agents . OBJECTIVES To assess the effects on maternal , fetal and neonatal outcomes of tocolysis with oxytocin receptor antagonists for women with preterm labour compared with placebo or no intervention and compared with any other tocolytic agent .

OBJECTIVES To compare the efficacy and safety of nifedipine and ritodrine in preventing preterm labor , and to evaluate maternal side effects and neonatal outcome . STUDY DESIGN Non-blind , r and omized controlled trial RESULTS A r and omized trial of 102 pregnant women with gestational ages under 34 weeks , including 24 with twin pregnancies and 45 on betasympathicomimetic drugs , who had regular uterine contractions with either observed cervical changes or preterm rupture of membranes . After stratification women were r and omly assigned to receive either ritodrine intravenously or nifedipine orally . Fifty-five women were r and omized to the nifedipine group and 47 to the ritodrine group . As expected , both groups were comparable in terms of several entry variables , including mean gestational age , ruptured membranes , treatment with tocolytic drugs , cervical examination , contraction frequency , age , and twin gestation . Delivery of women in the nifedipine group was delayed for 48 h , 7 days , and until 34 weeks gestation in 33 ( 60 % ) , 26 ( 47 % ) and 21(38 % ) cases , respectively , compared with 31 ( 66 % ) , 21(45 % ) and 11(23 % ) women in the ritodrine group ( no significant difference ) . Maternal side effects were significantly less common in the nifedipine group than in the ritodrine group , however after 7 days of therapy there was no difference between the two groups . Neonatal outcome was similar in the two groups , with four neonatal deaths in the nifedipine and five in the ritodrine group . CONCLUSIONS Nifedipine seems to be as effective as ritodrine in the treatment of preterm labor and is associated with less frequent side effects OBJECTIVE The objective was to compare the effectiveness , efficacy , and safety of atosiban and nifedipine in preventing or delaying premature labor . DESIGN An interventional , r and omized , controlled trial of 63 women experiencing preterm labor varying from 24 to 35 completed weeks of gestation . The women were r and omized to receive either atosiban intravenously ( group I , n=31 ) , or nifedipine orally ( group II , n=32 ) . RESULTS There were no significant differences in effectiveness and efficacy of tocolysis between the two groups . Women with a history of preterm labor responded significantly better to atosiban than those with no such history . Those at 28 weeks or less responded significantly better to nifedipine , while those at more than 28 weeks ' gestation showed an equal response in the two groups . Nifedipine achieved uterine quiescence in a significantly shorter time than atosiban . The maternal side effects were higher with nifedipine . Neonatal complications were comparable in both groups . CONCLUSIONS Both drugs are equally effective and efficacious in acute tocolysis . Subgrouping of patients according to gestational age and history of preterm labor may be applied in selecting the line of treatment . The maternal side effects were higher with nifedipine OBJECTIVE To perform a comparison between atosiban ( oxytocin antagonist ) and nifedipin ( calcium channel blocker ) for acute treatment of preterm labor and their maternal safety . METHODS A r and omized controlled trial study was performed on 80 pregnant women with preterm labor , between 26 and 34 weeks of pregnancy , in Akbar Abadi Teaching Hospital in Tehran , Iran . 40 women ( the atosiban group ) were compared with another 40 women ( the nifedipin group ) for the drugs ' efficacy in delaying delivery for more than 48 h in order to undergo steroid therapy , and for more than 7 days or more , and also to assess their maternal safety . The duration between the drugs ' administration and delivery were compared . The statistical analysis was performed using the Statistical Package for Social Science ( SPSS ) . RESULTS There was no statistically significant difference between the two groups in the treatment of preterm labor . Atosiban was effective in 82.5 % of cases , and nifedipin in 75 % of the cases ( p=1.000 ) , for delaying delivery for 48 h. Atosiban was effective in 75 % of the cases , and nifedipin in 65 % of the cases , for delaying delivery for more than 7 days . The maternal side effects in the atosiban group were 17.5 % , and in the nifedipin group they were 40 % , which had a statistically significant difference ( p=0.027 ) . The duration between treatment and delivery was 29.03+/-16.12 days in the atosiban group and 22.85+/-13.9 days in the nifedipin group with no statistically significant difference ( p=0.79 ) . CONCLUSION Atosiban is an effective and safe drug for the acute treatment of preterm labor with minimal side effects , and it can be an option in the treatment of preterm labor , especially in patients with heart disease and multi-fetal pregnancies The purpose of this study was to describe the course of preterm labor in patients receiving a st and ard intravenous infusion of the oxytocin antagonist atosiban . An open-labeled , non-r and omized study was conducted at 4 sites . Successful tocolysis was defined as delay of delivery larger than 48 hours from starting atosiban and no need for an alternate tocolytic . Atosiban was administered by continuous intravenous infusion at a rate of 300 micrograms per minute until uterine contractions were absent for 6 hours , or up to a maximum infusion time of 12 hours . Sixty-two patients of between 20 and 36 weeks ' gestation were enrolled over 6 months . One had rupture of membranes and was excluded . Successful tocolysis was noted in 43 of 61 ( 70.5 % ) . Four delivered spontaneously within 48 hours and 14 ( 23.0 % ) required an alternate tocolytic agent . The chance of successful tocolysis was related to the degree of cervical dilation at the start of therapy . Cessation of uterine contractions was noted in 38 patients ( 62.3 % ) . A decrease in uterine contraction frequency of 50 % or more was noted in 50 of 61 patients ( 82.0 % ) . Four patients reported side effects ( nausea , vomiting , headache , dysguesia , chest pain ) , but in no case did side effects require discontinuation of the medication . Intravenous administration of atosiban is associated with a delay in delivery comparable to that seen with other tocolytics . If this effect is confirmed in planned placebo-controlled trials , its favorable side effect profile may give it a place in the armamentarium A phase IV multinational , multicentre study has been design ed -- the Tractocile Efficacy Assessment Survey in Europe ( TREASURE ) . The aim is to assess atosiban in the clinical setting , which is associated with fewer restrictions than in phase III trials . Atosiban is to be compared with ' usual care ' in women eligible for treatment , and will also be evaluated as deferred or immediate treatment in women who have not yet fulfilled the diagnostic criteria for pre-term labour . Exploring the use of atosiban beyond the normal indications may allow the identification of additional sub population s of women who will benefit from early treatment . TREASURE will offer data on new diagnostic tools , investigate respiratory distress syndrome according to severity and record the use of antenatal steroids . It is hoped that additional information concerning the subtle differences in clinical practice will broaden our underst and ing of how to manage pre-term labour and offer the chance to revise treatment guidelines Abstract Objective : To compare the efficacy of atosiban with usual management of threatened preterm labor . Methods : In this prospect i ve , open-label , r and omized controlled trial , women admitted to the hospital in threatened preterm labor ( between 24 and 34 weeks ' gestation ) were r and omized to receive atosiban or usual care ( β-agonists , calcium channel blockers , magnesium sulphate , or any other tocolytic , alone or in combination , and /or bed rest ) . Results : In women r and omized to receive atosiban ( n=295 ) or usual care ( n=290 ) , significantly more women receiving atosiban remained undelivered at 48 h with no alternative tocolytic compared with usual care ( 77.6 % vs. 56.6 % ; P<0.001 ) . The proportion of women remaining undelivered after 48 h was comparable between the treatment groups . However , more women in the atosiban group required no additional tocolytics ( 85.1 % vs. 62.8 % ; P<0.001 ) . Maternal and fetal safety was significantly superior with atosiban . Neonatal safety was comparable . Conclusions : These findings support the use of atosiban to delay preterm birth and are consistent with previously conducted , r and omized , controlled trials . Atosiban was associated with fewer maternal and fetal adverse events compared with other tocolytics , and presented no safety concerns for either the mother or the unborn baby Objective To compare the effects of four methods of analysis on the results of r and omised controlled trials that recruit women with multiple pregnancies and measure outcomes on their babies OBJECTIVE Our aims were to develop a risk assessment system for the prediction of spontaneous preterm delivery using clinical information available at 23 to 24 weeks ' gestation and to determine the predictive value of such a system . STUDY DESIGN A total of 2929 women were evaluated between 23 and 24 weeks ' gestation at 10 centers . Demographic factors , socioeconomic status , home and work environment , drug and alcohol use , and medical history were evaluated . Information regarding symptoms , cultures , and treatments in the current pregnancy were ascertained . Anthropomorphic and cervical examinations were performed . Univariate analysis and multivariate logistic regression were performed in a r and om selection , constituting 85 % of the study population . The derived risk assessment system was applied to the remaining 15 % of the population to evaluate its validity . RESULTS A total of 10.4 % of women were delivered of preterm infants . The multivariate models for spontaneous preterm delivery were highly associated with spontaneous preterm delivery ( p < 0.0001 ) . A low body mass index ( < 19.8 ) and increasing Bishop scores were significantly associated with spontaneous preterm delivery in nulliparous and multiparous women . Black race , poor social environment , and work during pregnancy were associated with increased risk for nulliparous women . Prior obstetric outcome overshadowed socioeconomic risk factors in multiparous women with a twofold increase in the odds of spontaneous preterm delivery for each prior spontaneous preterm delivery . Current pregnancy symptoms , including vaginal bleeding , symptomatic contractions within 2 weeks , and acute or chronic lung disease were variably associated with spontaneous preterm delivery in nulliparous and multiparous women . When the system was applied to the remainder of the population , women defined to be at high risk for spontaneous preterm delivery ( > or = 20 % risk ) carried a 3.8-fold ( nulliparous women ) and 3.3-fold ( multiparous women ) higher risk of spontaneous preterm delivery than those predicted to be at low risk . However , the risk assessment system identified a minority of women who had spontaneous preterm deliveries . The sensitivities were 24.2 % and 18.2 % and positive predictive values were 28.6 % and 33.3 % , respectively , for nulliparous and multiparous women . CONCLUSIONS Although it is possible to develop a grade d risk assessment system that includes factors that are highly associated with spontaneous preterm delivery in nulliparous and multiparous women , such a system does not identify most women who subsequently have a spontaneous preterm delivery . This system has investigational value as the basis for evaluating new technologies design ed to identify at-risk sub population OBJECTIVES This study was design ed to evaluate the efficacy and safety of the oxytocin receptor antagonist atosiban in the treatment of preterm labor . STUDY DESIGN A multicenter , double-blind , placebo-controlled trial with tocolytic rescue was design ed . Five hundred thirty-one patients were r and omized to receive , and 501 received , either intravenous atosiban ( n = 246 ) or placebo ( n = 255 ) , followed by subcutaneous maintenance with the assigned agent . St and ard tocolytics as rescue tocolysis were permitted after 1 hour of either placebo or atosiban if preterm labor continued . The primary end point was the time from the start of study drug to delivery or therapeutic failure . Secondary end points were the proportion of patients who remained undelivered and did not receive an alternate tocolytic at 24 hours , 48 hours , and 7 days . RESULTS No significant difference was found in the time from start of treatment to delivery or therapeutic failure between atosiban and placebo ( median , 25.6 days vs 21.0 days , respectively ; P = .6 ) . The percentages of patients remaining undelivered and not requiring an alternate tocolytic at 24 hours , 48 hours , and 7 days were significantly higher in the atosiban group than in the control group ( all P < or = .008 ) . A significant treatment-by-gestational age interaction existed for the 48-hour and 7-day end points . Atosiban was consistently superior to placebo at a gestational age of > or = 28 weeks . Fourteen atosiban-treated patients and 5 placebo-treated patients were r and omized at < 24 weeks ; the incidence of fetal-infant deaths was higher for the atosiban group at < 24 weeks . Maternal-fetal adverse events were similar except for injection-site reactions , which occurred more often with atosiban . CONCLUSIONS In this trial the treatment of patients in preterm labor with atosiban result ed in prolongation of pregnancy for up to 7 days for those at a gestational age > or = 28 weeks , and this occurred with a low rate of maternal-fetal adverse effects . In addition , at a gestational age > or = 28 weeks , the infant morbidity and mortality of atosiban-initiated st and ard care were similar to those with placebo-initiated st and ard care . Given that all patients in this study were eligible for tocolysis and that , in practice , nearly all patients who are eligible for a tocolytic receive one , the benefit of using atosiban is the placebo-like maternal-fetal side effect profile . These observations support the use of this oxytocin receptor antagonist in the treatment of patients in preterm labor with intact membranes . Efficacy and infant outcome data at < 28 weeks are inconclusive Objective Atosiban has been shown to be an effective tocolytic agent with a low rate of side effects during 24 to 33 weeks of gestation . Atosiban acts through selective , competitive inhibition of both oxytocin and vasopressin , so that there are reasons to assume that a tocolytic effect can also be achieved earlier in the pregnancy . Study design In this prospect i ve , r and omized pilot study , 20 women in the 18th through 24th week of gestation who presented at our hospital with preterm labor were treated with atosiban . In the control group 20 women received saline infusions . All patients received antibiotic therapy . A cervical cerclage was performed when indicated as was correction of the vaginal pH. Results The tocolytic effect began after 3–10 min ( median : 6.5 min ) . Treatment time until the complete absence of contractions was 3–12 h ( median : 7.5 h ) . Pregnancies were prolonged between 11.1 and 21.7 weeks ( median : 15.6 weeks ) in the atosiban group vs. 10.5–19.1 weeks in the control group . If well tolerated , atosiban was continued . There were no significant alterations in the routine laboratory parameters , circulation parameters , and fluid balance . Conclusion In summary , atosiban showed itself to be effective for tocolytic treatment for premature labor , even during 18 and 24 weeks of pregnancy , while exhibiting its known , favorable profile of side effects OBJECTIVE To compare the efficacy and safety of atosiban and terbutaline for the inhibition of preterm labor . METHODS Two hundred and forty-nine women diagnosed with preterm labor at 23 - 33 weeks of gestation were enrolled of whom 245 women received treatment , 116 with atosiban and 129 with terbutaline . At r and omization , women were stratified by gestational age ( < or = 28 weeks and > 28 weeks ) . Atosiban ( iv bolus dose of 6.75 mg , then 300 microg/min for 3 h and 100 microg/min thereafter ) and terbutaline ( 5 - 20 microg/min ) were administered by iv infusion for 13 - 18 h. Re-treatment with study drug or an alternative tocolytic agent was allowed . Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and 7 days and efficacy and tolerability in terms of the number of women remaining undelivered and not requiring alternative tocolytic therapy after 48 hours and 7 days of starting therapy . Safety was assessed in terms of maternal side effects and neonatal morbidity . RESULTS Tocolytic effectiveness at 48 hours was 86.1 % vs 85.3 % ; p=0.783 , and after 7 days it was 76.5 % vs 67.4 % ; p=0.067 , in the atosiban and terbutaline groups , respectively . Tocolytic efficacy and tolerability after 48 hours was 72.2 % vs 68.2 % ; p=0.51 and after 7 days was 55.6 % vs 43.4 % ; p=0.08 in the atosiban and terbutaline groups , respectively . Overall , there were fewer clinical ly important adverse events with atosiban than with terbutaline . CONCLUSIONS The efficacy of atosiban in the inhibition of preterm labor was shown to be comparable to terbutaline . Atosiban had a superior safety profile compared with terbutaline in terms of maternal and fetal adverse events , and comparable infant outcomes OBJECTIVES Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age , birth weight , and gender . STUDY DESIGN Perinatal data were collected prospect ively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports . Sociodemographic factors , perinatal events , and the neonatal course to 120 days of life , discharge , or death were evaluated . RESULTS Eighty-three percent of infants survived until discharge to home or to a long- term care facility ( compared with 74 % in 1988 ) . Survival to discharge was 49 % for infants weighing 501 to 750 g at birth , 85 % for those 751 to 1000 g , 93 % for those 1001 to 1250 g , and 96 % for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life . Mortality rates were greater for male than for female infants . Respiratory distress syndrome was the most frequent pulmonary disease ( 52 % ) . Chronic lung disease ( defined as an oxygen requirement at 36 weeks after conception ) developed in 19 % . Thirty-two percent of infants had evidence of intracranial hemorrhage . Periventricular leukomalacia was noted in 6 % of infants who had ultrasonography after 2 weeks . The average duration of hospitalization for survivors was 68 days ( 122 days for surviving infants weighing 501 to 750 g , compared with an average of 43 days for surviving infants 1251 to 1500 g ) . Among infants who died , the average length of stay was 19 days . CONCLUSIONS The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline . This increase in survival is not accompanied by an increase in medical morbidity . There are interactions between birth weight , gestational age , sex , and survival rates OBJECTIVES Patients admitted with an acute episode of preterm labor who respond to early intravenously administered tocolysis remain at risk of having subsequent episodes of preterm labor and preterm delivery . Several pharmacologic agents have been used in an attempt to reduce subsequent episodes of preterm labor , and all are associated with significant side effects . Atosiban , an oxytocin receptor antagonist , is effective in the treatment of an acute episode of preterm labor . This study was design ed to compare the efficacy and safety of atosiban with those of placebo maintenance therapy in women with preterm labor who achieved uterine quiescence with intravenous atosiban . STUDY DESIGN A multicenter , double-blind , placebo-controlled trial was design ed for patients in preterm labor who responded to early intravenous treatment with atosiban . Five hundred thirteen patients were r and omly assigned to receive maintenance therapy , 252 to receive atosiban , and 251 to receive matching placebo . Maintenance therapy was administered as a continuous subcutaneous infusion , via pump , of 30 microg/min to the end of 36 weeks ' gestation . The primary end point was the number of days from the start of maintenance therapy until the first recurrence of labor . A secondary end point was the percentage of patients receiving subsequent intravenous atosiban therapy . RESULTS The time ( median ) from the start of maintenance treatment to the first recurrence of labor was 32.6 days with atosiban and 27.6 days with placebo ( P = .02 ) . At least one subsequent intravenous atosiban treatment was needed by 61 atosiban patients ( 23 % ) and 77 placebo patients ( 31 % ) . Except for injection site reactions , adverse event profiles of atosiban and placebo were comparable . There were 4 neonatal deaths reported in the atosiban group and 5 in the placebo group after the start of maintenance therapy . Infant outcomes ( including birth weight ) were comparable between maintenance and treatment groups . CONCLUSIONS Maintenance therapy with the oxytocin receptor antagonist atosiban can prolong uterine quiescence after successful treatment of an acute episode of preterm labor with atosiban . Treatment was well tolerated Relcovaptan ( SR 49059 ) is a non-peptide , orally active vasopressin V1a receptor inhibitor . The effect on uterine contractions in 18 women with preterm labor in pregnancy weeks 32–36 was assessed in a double-blind investigation . The inclusion criterion was at least four regular uterine contractions over 30 min as measured by external tocodynamometry . Twelve patients received at r and om a single oral dose of 400 mg relcovaptan and six received placebo , and contractions were monitored up to 6 h thereafter . Rescue medication ( β-adrenoceptor-stimulating drug ) was allowed after 2 h. Before drug administration a mean ( ± SE ) of 8.2 ± 1.4 and 9.7 ± 1.6 contractions/30 min were recorded in the relcovaptan- and placebo-treated groups , respectively . In the former group , the frequency of uterine contractions started to decrease within the first half hour , and 1.5–2 h after dosing it was steady at 3.2 ± 0.9 contractions/30 min . Correspondingly , after placebo , 7.8 ± 2.2 contractions/30 min were recorded , a statistically significant difference ( p = 0.017 ) . The activity in the relcovaptan-treated women remained low , whereas in the placebo group inhibited uterine contractions were observed only in women receiving ‘ rescue ’ tocolytic treatment . It is concluded that relcovaptan inhibits preterm labor OBJECTIVE The purpose of this study was to test the hypothesis that infusion of the oxytocin antagonist atosiban results in decreased preterm uterine activity in the human . STUDY DESIGN A r and omized , double-blind , placebo-controlled trial was performed . One hundred twenty women from 20 to 36 weeks ' gestation with a complaint of labor who had more than four uterine contractions per hour after intravenous hydration but no evidence of cervical changes were r and omized to receive a 2-hour intravenous infusion of atosiban at a rate of 300 micrograms/min or placebo . Ond hundred-twelve subjects ( 56 in each arm ) were suitable for analysis of efficacy . Both groups remained at bed rest and received hydration . RESULTS The mean percent decrease in contraction frequency was greater in atosiban subjects compared with controls ( 55.3 % + /- 36.3 % vs 26.7 % + /- 40.4 % , mean + /- SD , p < 0.001 ) . A minimal ( < 20 % ) decrease or an increase in contraction frequency was noted in 25 placebo subjects ( 45 % ) and seven atosiban subjects ( 13 % ) . There was no clinical ly or statistically significant change in maternal blood pressure or heart rate during the infusion . The only adverse experiences possibly related to the drug were nausea and vomiting in one atosiban patient . CONCLUSION A 2-hour infusion of the oxytocin antagonist atosiban result ed in a significantly greater decline in contraction frequency compared with controls . Oxytocin appears to play a role in the maintenance of preterm uterine activity in the human OBJECTIVE To compare the efficacy and safety of atosiban and salbutamol in the treatment of preterm labor . STUDY DESIGN A multicenter , double-blind , double-placebo , r and omized , controlled trial . Women ( n=241 ) diagnosed with preterm labor at 23 - 33 gestational weeks were enrolled and received either atosiban ( n=119 ) or salbutamol ( n=122 ) . At r and omization , women were stratified by gestational age ( < or = 28 weeks and > 28 weeks ) . Atosiban ( i.v . bolus dose of 6.75 mg , then 300 microg/min for 3h and 100 microg/min for up to 48h ) and salbutamol ( 2.5 - 45 microg/min ) were administered by i.v . infusion for up to 48h . Retreatment with study drug or an alternative tocolytic agent was allowed . Main outcome measures included tocolytic effectiveness which was assessed in terms of the number of women undelivered after 48h and 7 days . Tocolytic efficacy and tolerability were assessed in terms of the proportion of women undelivered and who did not require alternative tocolytic therapy at 48h and 7 days of starting treatment . Safety was assessed in terms of maternal side effects and neonatal morbidity . RESULTS Tocolytic effectiveness at 48h was 93.3 versus 95.0 % ( P=0.67 ) and after 7 days was 89.9 versus 90.1 % ( P=0.93 ) in the atosiban and salbutamol groups , respectively . Tocolytic efficacy and tolerability within 48h was 79.8 versus 75.2 % ( P=0.15 ) , and after 7 days was 58.8 versus 46.3 % ( P=0.021 ) in the atosiban and salbutamol groups , respectively . Maternal adverse events , including serious events , occurred more frequently in the salbutamol group . Neonatal outcomes were comparable between the study groups . CONCLUSIONS The oxytocin antagonist atosiban was found to be better tolerated by both mother and fetus than salbutamol , with a comparable neonatal and infant safety profile , and atosiban was as effective as salbutamol in delaying threatened preterm birth . This study supports the clinical use of atosiban in the treatment of preterm labor OBJECTIVE This study was undertaken to compare the efficacy and safety of intravenous administration of atosiban versus ritodrine for the treatment of preterm labor . STUDY DESIGN Women with preterm labor and intact membranes diagnosed at 23 to 33 gestational weeks ( n = 247 ) were r and omly assigned to treatment arms and received atosiban ( 6.75 mg intravenous bolus , 300 microg/min for 3 hours , then 100 microg/min intravenously ) or ritodrine ( 0.10 - 0.35 mg/min intravenously ) for as long as 18 hours . Tocolytic effectiveness was assessed in terms of the numbers of women who had not been delivered after 48 hours and after 7 days . Safety was assessed in terms of maternal side effects and neonatal morbidity . Secondary outcomes included mean gestational age at delivery and mean birth weight . An intent-to-treat analysis was performed with the Cochran-Mantel-Haenszel test . RESULTS The proportion of women who had not been delivered at 48 hours was 84.9 % ( n = 107 ) in the atosiban group and 86.8 % ( n = 105 ) in the ritodrine group . At 7 days 92 women had still not been delivered in both the atosiban ( 73.0 % ) and ritodrine ( 76.0 % ) groups . Neither of these differences was statistically significant . The incidence of maternal cardiovascular side effects was substantially lower in the atosiban group ( 4.0 % vs 84.3 % , P < .001 ) . In addition , intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group ( 29.8 % ) than in the atosiban group ( 0.8 % ) . The overall occurrences of fetal adverse events in the two treatment groups were comparable . Neonatal morbidity was similar between the treatment groups after adjustment for unbalanced enrollment of women with multiple pregnancies and for gestational ages within treatment groups . CONCLUSION Atosiban was comparable in clinical effectiveness to conventional ritodrine therapy but was better tolerated than ritodrine , with no evidence of significant maternal or fetal adverse events . Neonatal morbidity , which was similar between the two treatment arms , was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent Objective . To evaluate the outcome for all infants born before 26 weeks of gestation in the United Kingdom and the Republic of Irel and . This report is of survival and complications up until discharge from hospital . Methodology . A prospect i ve observational study of all births between March 1 , 1995 and December 31 , 1995 from 20 to 25 weeks of gestation . Results . A total of 4004 births were recorded , and 811 infants were admitted for intensive care . Overall survival was 39 % ( n = 314 ) . Male sex , no reported chorioamnionitis , no antenatal steroids , persistent bradycardia at 5 minutes , hypothermia , and high Clinical Risk Index for Babies ( CRIB ) score were all independently associated with death . Of the survivors , 17 % had parenchymal cysts and /or hydrocephalus , 14 % received treatment for retinopathy of prematurity ( ROP ) , and 51 % needed supplementary oxygen at the expected date of delivery . Failure to administer antenatal steroids and postnatal transfer for intensive care within 24 hours of birth were predictive of major scan abnormality ; lower gestation was predictive of severe ROP , while being born to a black mother was protective . Being of lower gestation , male sex , tocolysis , low maternal age , neonatal hypothermia , a high CRIB score , and surfactant therapy were all predictive of oxygen dependency . Intensive care was provided in 137 units , only 8 of which had > 5 survivors . There was no difference in survival between institutions when divided into quintiles based on their numbers of extremely preterm births or admissions . Conclusions . This study provides outcome data for this geographically defined cohort ; survival and neonatal morbidity are consistent with previous data from the United Kingdom and facilitate comparison with other geographically based data

Qualitative analyses showed lower volumes of WB , prefrontal regions , temporal lobe , hippocampus , thalamus and cerebellum , and higher volumes of lateral ventricles , amygdala , and putamen in violent vs. non-violent people with schizophrenia . Conclusions : We review ed evidence for differences in brain volume correlates of aggression in persons with schizophrenia . Our results point toward a reduced whole brain volume in violent as opposed to non-violent persons with schizophrenia .

Background : Aggression in psychoses is of high clinical importance , and volumetric MRI techniques have been used to explore its structural brain correlates .

The profile of brain structural abnormalities in schizophrenia is still not fully understood , despite decades of research using brain scans . To vali date a prospect i ve meta- analysis approach to analyzing multicenter neuroimaging data , we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls , assessed with st and ardized methods at 15 centers worldwide . We identified subcortical brain volumes that differentiated patients from controls , and ranked them according to their effect sizes . Compared with healthy controls , patients with schizophrenia had smaller hippocampus ( Cohen ’s d=−0.46 ) , amygdala ( d=−0.31 ) , thalamus ( d=−0.31 ) , accumbens ( d=−0.25 ) and intracranial volumes ( d=−0.12 ) , as well as larger pallidum ( d=0.21 ) and lateral ventricle volumes ( d=0.37 ) . Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients . Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia , which is consistent with that based on traditional meta-analytic approaches . This first ENIGMA Schizophrenia Working Group study vali date s that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our underst and ing of severe mental illness In this work , we address an important but unexplored topic , namely the neural correlates of hate . In a block- design fMRI study , we scanned 17 normal human subjects while they viewed the face of a person they hated and also faces of acquaintances for whom they had neutral feelings . A hate score was obtained for the object of hate for each subject and this was used as a covariate in a between-subject r and om effects analysis . Viewing a hated face result ed in increased activity in the medial frontal gyrus , right putamen , bilaterally in premotor cortex , in the frontal pole and bilaterally in the medial insula . We also found three areas where activation correlated linearly with the declared level of hatred , the right insula , right premotor cortex and the right fronto-medial gyrus . One area of deactivation was found in the right superior frontal gyrus . The study thus shows that there is a unique pattern of activity in the brain in the context of hate . Though distinct from the pattern of activity that correlates with romantic love , this pattern nevertheless shares two areas with the latter , namely the putamen and the insula BACKGROUND Reduced amygdala volume has been implicated in the development of severe and persistent aggression and the development of psychopathic personality . With longitudinal data , the current study examined whether male subjects with lower amygdala volume have a history of aggression and psychopathic features dating back to childhood and are at increased risk for engaging in future aggression/violence . METHODS Participants were selected from a longitudinal study of 503 male subjects initially recruited when they were in the first grade in 1986 - 1987 . At age 26 , a sub sample of 56 men with varying histories of violence was recruited for a neuroimaging sub study . Automated segmentation was used to index individual differences in amygdala volume . Analyses examined the association between amygdala volume and levels of aggression and psychopathic features of participants measured in childhood and adolescence . Analyses also examined whether amygdala volume was associated with violence and psychopathic traits assessed at a 3-year follow-up . RESULTS Men with lower amygdala volume exhibited higher levels of aggression and psychopathic features from childhood to adulthood . Lower amygdala volume was also associated with aggression , violence , and psychopathic traits at a 3-year follow-up , even after controlling for earlier levels of these features . All effects remained after accounting for several potential confounds . CONCLUSIONS This represents the first prospect i ve study to demonstrate that men with lower amygdala volume have a longst and ing history of aggression and psychopathic features and are at increased risk for committing future violence . Studies should further examine whether specific amygdala abnormalities might be a useful biomarker for severe and persistent aggression This study aim ed to identify the incidence and clinical correlates of aggression and violence in first episode psychosis . We prospect ively recruited subjects with a first episode of DSM-psychosis presenting from a geographically defined catchment area to a secondary referral psychiatric service over a four-year period ( n = 157 ) . We used the Modified Overt Aggression Scale to retrospectively assess aggression ( a hostile or destructive mental attitude , including verbal aggression , physical aggression and /or violence ) and violence ( the exercise of physical force ) , blind to diagnosis . One in three patients with psychosis was aggressive at the time of presentation . One patient in 14 engaged in violence that caused , or was likely to cause , injury to other people . Aggression was independently associated with drug misuse ( odds ratio ( OR ) 2.80 , 95 % confidence interval 1.12 - 6.99 ) and involuntary admission status ( OR = 3.62 , 95 % CI 1.45 - 9.01 ) . Violence in the week prior to presentation was associated with drug misuse ( OR = 2.75 , CI 1.04 - 7.24 ) and involuntary admission status ( OR = 3.21 , CI 1.21 - 8.50 ) . Violence in the week following presentation was associated with poor insight ( OR 2.97 , CI 1.03 - 8.56 ) and pre-contact violence ( OR 3,82 , CI 1.34 - 10.88 ) . In patients with schizophrenia , violence in the week following presentation was associated with drug misuse ( OR = 7.81 , CI 1.33 - 45.95 ) and high psychopathology scores ( OR = 20.59 , CI 1.66 - 254.96 ) . Overall , despite a high rate of verbal aggression , physical violence towards other people is uncommon in individuals presenting with first episode psychosis OBJECTIVE Aggression , suicidality and involuntary treatment constitute severe clinical problems in first-episode psychosis ( FEP ) . Although there are studies on prevalence and clinical predictors of these conditions , little is known on the influence of psychopathology and neuropsychological dysfunction . METHOD 152 FEP in patients were prospect ively assessed using the Brief Psychiatric Rating Scale ( BPRS ) and a neuropsychological examination covering the domains ' processing speed ' , ' concentration and attention ' , ' executive function ' , ' working memory ' , ' verbal memory ' , ' verbal comprehension ' , ' logical reasoning ' , ' global cognition ' , and ' general intelligence ' . Clinical data were collected retrospectively in a structured file audit trial . RESULTS Patients were aged 24.5±4.9years , and 112 ( 74 % ) were male . At admission , 13 ( 9 % ) patients presented with severe aggression , and 28 ( 18 % ) with severe suicidality . 31 patients ( 20 % ) received involuntary treatment . In multivariate analyses , aggression was predicted by BPRS-Excited Component ( BPRS-EC ; p=.001 ) , suicidality was predicted by BPRS-EC ( p=.013 ) and general intelligence ( p=.016 ) , and predictors for involuntary treatment were BPRS-EC ( p=.001 ) and neuropsychological dysfunction in the domain ' concentration and attention ' ( p=.016 ) . CONCLUSION Psychopathology and neuropsychological functioning independently predict dangerous behavior in FEP patients . Some correlations with neuropsychology ( e.g. , of aggression with concentration/attention ) are absent in multivariate analyses and may thus constitute a proxy of psychopathological features . In addition to clinical data , BPRS-EC can be used as a predictor of dangerous behavior . Patients with severe aggression and suicidality show different patterns of neuropsychological dysfunction , indicating that suicidality should not be conceptualized as subtype of aggressive behavior OBJECTIVE Agitation , aggression , and violence are increased in psychotic disorders . Additionally , an earlier age at onset may be associated with aggressive behavior . However , the relationship of age at onset , an agitated-aggressive syndrome as measured with the Positive And Negative Syndrome Scale for Schizophrenia - Excited Component ( PANSS-EC ) , and its potential correlates in first-episode psychosis ( FEP ) has not been studied . METHOD This study assessed the association between age at onset , an agitated-aggressive syndrome , and its potential correlates in a prospect i ve sample of 52 FEP patients with early-onset and adult-onset followed up for 12months . RESULTS Twenty-six patients conformed to the criteria of early-onset psychosis . Early age at onset was associated with antisocial personality disorder ( p=0.004 ; φc=0.39 ) , a history of legal involvement ( p=0.005 ; φc=0.39 ) , and higher rates of lifetime substance use disorder ( SUD ; p=0.002 ; φc=0.42 ) . Early-onset patients had significantly higher PANSS-EC scores over the course of observation ( F(1,44.4)=5.39 ; p=0.025 ; d=0.656 ) , but no significant group differences emerged for the remaining PANSS subscores . PANSS-EC scores were correlated positively with antisocial personality disorder and forensic history at 6weeks , 3months , 6months , and 12months , and with lifetime substance use disorder at 3months and 6months . CONCLUSIONS Patients with early onset psychosis may have increased levels of agitation/aggressiveness , and , more likely , antisocial personality disorder , forensic history , and lifetime substance use disorder . These variables were linked to suicidality , aggressiveness , and involuntary treatment

Conclusion RIC was associated with lower myocardial edema levels , myocardial salvage index and incidence of MACCE , while non-significant beneficial effect on infa rct size , TIMI flow grade III or LVEF . These findings suggest that RIC is a promising adjunctive treatment to PCI for the prevention of reperfusion injury in STEMI patients

Objective This systematic review was design ed to evaluate the efficacy of remote ischemic conditioning ( RIC ) with primary percutaneous coronary intervention ( PCI ) versus primary PCI alone for ST-segment elevation myocardial infa rct ion ( STEMI ) .

OBJECTIVES This study sought to evaluate whether remote ischemic post-conditioning ( RIPC ) could reduce enzymatic infa rct size in patients with anterior ST-segment elevation myocardial infa rct ion undergoing primary percutaneous coronary intervention ( pPCI ) . BACKGROUND Myocardial reperfusion injury may attenuate the benefit of pPCI . In animal models , RIPC mitigates myocardial reperfusion injury . METHODS One hundred patients with anterior ST-segment elevation myocardial infa rct ion and occluded left anterior descending artery were r and omized to pPCI + RIPC ( n = 50 ) or conventional pPCI ( n = 50 ) . RIPC consisted of 3 cycles of 5 min/5 min ischemia/reperfusion by cuff inflation/deflation of the lower limb . The primary endpoint was infa rct size assessed by the area under the curve of creatinine kinase-myocardial b and release ( CK-MB ) . Secondary endpoints included the following : infa rct size assessed by cardiac magnetic resonance delayed enhancement volume ; T2-weighted edema volume ; ST-segment resolution > 50 % ; TIMI ( Thrombolysis In Myocardial Infa rct ion ) frame count ; and myocardial blush grading . RESULTS Four patients ( 2 RIPC , 2 controls ) were excluded due to missing sample s of CK-MB . A total of 96 patients were analyzed ; median area under the curve CK-MB was 8,814 ( interquartile range [ IQR ] : 5,567 to 11,325 ) arbitrary units in the RIPC group and 10,065 ( IQR : 7,465 to 14,004 ) arbitrary units in control subjects ( relative reduction : 20 % , 95 % confidence interval : 0.2 % to 28.7 % ; p = 0.043 ) . Seventy-seven patients underwent a cardiac magnetic resonance scan 3 to 5 days after r and omization , and 66 patients repeated a second scan after 4 months . T2-weighted edema volume was 37 ± 16 cc in RIPC patients and 47 ± 22 cc in control subjects ( p = 0.049 ) . ST-segment resolution > 50 % was 66 % in RIPC and 37 % in control subjects ( p = 0.015 ) . We observed no significant differences in TIMI frame count , myocardial blush grading , and delayed enhancement volume . CONCLUSIONS In patients with anterior ST-segment elevation myocardial infa rct ion , RIPC at the time of pPCI reduced enzymatic infa rct size and was also associated with an improvement of T2-weighted edema volume and ST-segment resolution > 50 % . ( Remote Postconditioning in Patients With Acute Myocardial Infa rct ion Treated by Primary Percutaneous Coronary Intervention [ PCI ] [ RemPostCon ] ; NCT00865722 ) BACKGROUND Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty . We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infa rct ion , and done before primary percutaneous coronary intervention , increases myocardial salvage . METHODS 333 consecutive adult patients with a suspected first acute myocardial infa rct ion were r and omly assigned in a 1:1 ratio by computerised block r and omisation to receive primary percutaneous coronary intervention with ( n=166 patients ) versus without ( n=167 ) remote conditioning ( intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff ) . Allocation was concealed with opaque sealed envelopes . Patients received remote conditioning during transport to hospital , and primary percutaneous coronary intervention in hospital . The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention , measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment ; analysis was per protocol . This study is registered with Clinical Trials.gov , number NCT00435266 . FINDINGS 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria , 32 were lost to follow-up , and 77 did not complete the follow-up with data for salvage index . Median salvage index was 0.75 ( IQR 0.50 - 0.93 , n=73 ) in the remote conditioning group versus 0.55 ( 0.35 - 0.88 , n=69 ) in the control group , with median difference of 0.10 ( 95 % CI 0.01 - 0.22 ; p=0.0333 ) ; mean salvage index was 0.69 ( SD 0.27 ) versus 0.57 ( 0.26 ) , with mean difference of 0.12 ( 95 % CI 0.01 - 0.21 ; p=0.0333 ) . Major adverse coronary events were death ( n=3 per group ) , reinfa rct ion ( n=1 per group ) , and heart failure ( n=3 per group ) . INTERPRETATION Remote ischaemic conditioning before hospital admission increases myocardial salvage , and has a favourable safety profile . Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes . FUNDING Fondation Leducq Background — In animal models , brief periods of ischemia performed just at the time of reperfusion can reduce infa rct size , a phenomenon called postconditioning . In this prospect i ve , r and omized , controlled , multicenter study , we investigated whether postconditioning may protect the human heart during coronary angioplasty for acute myocardial infa rct ion . Methods and Results — Thirty patients , su bmi tted to coronary angioplasty for ongoing acute myocardial infa rct ion , contributed to the study . Patients were r and omly assigned to either a control or a postconditioning group . After reperfusion by direct stenting , control subjects underwent no further intervention , whereas postconditioning was performed within 1 minute of reflow by 4 episodes of 1-minute inflation and 1-minute deflation of the angioplasty balloon . Infa rct size was assessed by measuring total creatine kinase release over 72 hours . Area at risk and collateral blood flow were estimated on left ventricular and coronary angiograms . No adverse events occurred in the postconditioning group . Determinants of infa rct size , including ischemia time , size of the area at risk , and collateral flow , were comparable between the 2 groups . Area under the curve of creatine kinase release was significantly reduced in the postconditioning compared with the control group , averaging 208 984±26 576 compared with 326 095±48 779 ( arbitrary units ) in control subjects , ie , a 36 % reduction in infa rct size . Blush grade , a marker of myocardial reperfusion , was significantly increased in postconditioned compared with control subjects : 2.44±0.17 versus 1.95±0.27 , respectively ( P<0.05 ) . Conclusions — This study suggests that postconditioning by coronary angioplasty protects the human heart during acute myocardial infa rct ion Remote ischemic conditioning ( RIC ) is known to improve microcirculation in various setting s , but little is known about the impact of the amount of ischemic tissue mass or the limb itself . Since ischemia and subsequent necrosis of flaps is one of the most dreaded complications in reconstructive surgery , adjuvant methods to improve microcirculation are desirable . We therefore performed a r and omized trial to compare the effect of arm versus leg ischemia for RIC of the cutaneous microcirculation of the antero-lateral thigh . Forty healthy volunteers were r and omized to undergo 5 min of ischemia of either the upper or lower extremity , followed by 10 min of reperfusion . Ischemia was induced by a surgical tourniquet applied to the proximal limb , which was inflated to 250 mmHg for the upper and 300 mgHg for the lower extremity . This cycle was repeated a total of three times . Cutaneous microcirculation was assessed by combined laser doppler spectrophotometry on the antero-lateral aspect of the thigh to measure cutaneous blood flow ( BF ) , relative hemoglobin content ( rHb ) , and oxygen saturation ( StO2 ) . Baseline measurements were performed for 10 min , after which the ischemia/reperfusion cycles were begun . Measurements were performed continuously and were afterwards pooled to obtain a mean value per minute . Both groups showed significant increases in all three measured parameters of cutaneous microcirculation after three cycles of ischemia/reperfusion when compared to baseline ( BF : 95.1 % ( P < 0.001 ) and 27.9 % ( P = 0.002 ) ; rHb : 9.4 % ( P < 0.001 ) and 5.9 % ( P < 0.001 ) , StO2 : 8.4 % ( P = 0.045 ) and 9.4 % ( P < 0.001 ) . When comparing both groups , BF was significantly higher in the arm group ( P = 0.019 after 11 min . , P = 0.009 after 45 min ) . In conclusions , both ischemic conditioning of the upper and lower extremity is able to improve cutaneous BF on the ALT donor site . However , RIC of the upper extremity seems to be a superior trigger for improvement of cutaneous BF BACKGROUND Contrast medium-induced acute kidney injury ( CI-AKI ) is a cardiovascular complication after myocardial infa rct ion treated with emergency percutaneous coronary intervention . The aim of this r and omized , sham-controlled trial was to evaluate the impact of remote ischemic preconditioning ( RIPC ) on CI-AKI in patients with ST-elevation myocardial infa rct ion who received emergency primary percutaneous coronary intervention . METHODS AND RESULTS Patients with a suspected ST-elevation myocardial infa rct ion were r and omly assigned at a 1:1 ratio to receive percutaneous coronary intervention either with ( n=63 ) or without ( n=62 ) RIPC ( intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a blood pressure cuff ) . A total of 47 RIPC patients and 47 control patients met all study criteria . The primary endpoint was the incidence of CI-AKI , which was defined as an increase in serum creatinine > 0.5mg/dL or > 25 % over the baseline value 48 - 72h after administration of contrast medium . The incidence of CI-AKI was 10 % ( n=5 ) in the RIPC group and 36 % ( n=17 ) in the control group ( p=0.003 ) . The odds ratio of CI-AKI in patients who received RIPC was 0.18 ( 95 % confidence interval : 0.05 - 0.64 ; p=0.008 ) . CONCLUSIONS In patients with ST-elevation myocardial infa rct ion , RIPC before percutaneous coronary intervention reduced the incidence of CI-AKI Background The aim of this study was to evaluate the role of remote ischemic postconditioning ( RIPC ) of the upper arm on protection from cardiac ischemia-reperfusion injury following primary percutaneous coronary intervention ( PCI ) in patients with acute ST-segment elevation myocardial infa rct ion ( STEMI ) . Material / Methods Eighty patients with STEMI were r and omized into two groups : primary PCI ( N=44 ) and primary PCI+RIPC ( N=36 ) . RIPC consisted of four cycles of 5 minutes of occlusion and five minutes of reperfusion by cuff inflation and deflation of the upper arm , commencing within one minute of the first PCI balloon dilatation . Peripheral venous blood sample s were collected before PCI and at 0.5 , 8 , 24 , 48 , and 72 hours after PCI . Levels of creatine kinase-MB ( CK-MB ) , serum creatinine ( Cr ) , nitric oxide ( NO ) , and stromal cell-derived factor-1α ( SDF-1α ) were measured . The rates of acute kidney injury ( AKI ) and the estimated glomerular filtration rate ( eGFR ) were calculated . Results Patients in the primary PCI+RIPC group , compared with the primary PCI group , had significantly lower peak CK-MB concentrations ( P<0.01 ) , a significantly increased left ventricular ejection fraction ( LVEF ) ( P=0.01 ) , a significantly lower rate of AKI ( P<0.01 ) a significantly increased eGFR ( P<0.01 ) , and decreased area under the curve ( AUC ) of CK-MB , NO and SDF-1α . Conclusions RIPC of the upper arm following primary PCI in patients with acute STEMI might provide cardiac and renal protection from ischemia-reperfusion injury via the actions of SDF-1α , and NO Importance Ischemic postconditioning of the heart during primary percutaneous coronary intervention ( PCI ) induced by repetitive interruptions of blood flow to the ischemic myocardial region immediately after reopening of the infa rct -related artery may limit myocardial damage . Objective To determine whether ischemic postconditioning can improve the clinical outcomes in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) . Design , Setting , And Participants In this multicenter , r and omized clinical trial , patients with onset of symptoms within 12 hours , STEMI , and thrombolysis in myocardial infa rct ion ( TIMI ) grade 0 - 1 flow in the infa rct -related artery at arrival were r and omized to conventional PCI or postconditioning . Inclusion began on March 21 , 2011 , through February 2 , 2014 , and follow-up was completed on February 2 , 2016 . Analysis was based on intention to treat . Interventions Patients were r and omly allocated 1:1 to conventional primary PCI , including stent implantation , or postconditioning performed as 4 repeated 30-second balloon occlusions followed by 30 seconds of reperfusion immediately after opening of the infa rct -related artery and before stent implantation . Main Outcome and Measures A combination of all-cause death and hospitalization for heart failure . Results During the inclusion period , 1234 patients ( 975 men [ 79.0 % ] and 259 women [ 21.0 % ] ; mean [ SD ] age , 62 [ 11 ] years ) underwent r and omization in the trial . Median follow-up was 38 months ( interquartile range , 24 - 58 months ) . The primary outcome occurred in 69 patients ( 11.2 % ) who underwent conventional primary PCI and in 65 ( 10.5 % ) who underwent postconditioning ( hazard ratio , 0.93 ; 95 % CI , 0.66 - 1.30 ; P = .66 ) . The hazard ratios were 0.75 ( 95 % CI , 0.49 - 1.14 ; P = .18 ) for all-cause death and 0.99 ( 95 % CI , 0.60 - 1.64 ; P = .96 ) for heart failure . Conclusions and Relevance Routine ischemic postconditioning during primary PCI failed to reduce the composite outcome of death from any cause and hospitalization for heart failure in patients with STEMI and TIMI grade 0 - 1 flow at arrival . Trial Registration clinical trials.gov Identifier : Background —We have found that remote ischemic conditioning ( rIC ) , adjunctive to primary angioplasty , increases myocardial salvage in patients with ST-segment elevation myocardial infa rct ion ( STEMI ) and extensive myocardial area at risk ( AAR ) . The present sub study aim ed to evaluate the short-term effects of rIC on left ventricular ( LV ) function . Methods and Results — Patients with a first STEMI were r and omized to rIC ( 4 cycles of 5 minutes upper-limb ischemia ) during transfer to primary percutaneous coronary intervention ( pPCI ) ( n=123 ) versus pPCI alone ( n=119 ) . Ejection fraction ( EF ) , LV volumes , ( 2D and 3D echocardiography and myocardial perfusion imaging ) , and speckle-tracking global longitudinal strain were compared between treatment groups . There was no significant difference in LV function at day 1 ( EF-2D , 0.51±0.10 versus 0.49±0.10 ; P=0.22 ) and after 30 days ( EF-2D , 0.54±0.08 versus 0.53±0.10 ) between the rIC and the pPCI-alone groups . In patients with extensive AAR ≥35 % of LV ( n=53 ) , EF after 30 days was higher after rIC than after pPCI alone ( EF-2D , 0.51±0.07 versus 0.46±0.09 ; P=0.05 ) . In patients with anterior infa rct ion ( n=97 ) , rIC preserved LV function on day 1 ( EF-2D , 0.51±0.11 versus 0.46±0.11 ; P=0.03 ) and persistently after 30 days ( EF-2D , 0.55±0.08 versus 0.50±0.11 ; P=0.04 ; EF-myocardial perfusion imaging , 0.55±0.10 versus 0.49±0.12 ; P=0.02 ) . These patients had similar AAR , whereas rIC reduced infa rct size from 16 % to 7 % of LV ( P=0.01 ) . Conclusions —Although no significant overall effect was observed , rIC seemed to result in modest improvement in LV function in high-risk patients prone to develop large myocardial infa rcts . These results need to be confirmed in larger trials . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00435266 OBJECTIVES This study aim ed to determine whether remote ischemic conditioning ( RIC ) initiated prior to primary percutaneous coronary intervention ( PPCI ) could reduce myocardial infa rct ( MI ) size in patients presenting with ST-segment elevation myocardial infa rct ion . BACKGROUND RIC , using transient limb ischemia and reperfusion , can protect the heart against acute ischemia-reperfusion injury . Whether RIC can reduce MI size , assessed by cardiac magnetic resonance ( CMR ) , is unknown . METHODS We r and omly assigned 197 ST-segment elevation myocardial infa rct ion patients with TIMI ( Thrombolysis In Myocardial Infa rct ion ) flow grade 0 to receive RIC ( four 5-min cycles of upper arm cuff inflation/deflation ) or control ( uninflated cuff placed on upper arm for 40 min ) protocol s prior to PPCI . The primary study endpoint was MI size , measured by CMR in 83 subjects on days 3 to 6 after admission . RESULTS RIC reduced MI size by 27 % , when compared with the MI size of control subjects ( 18.0 ± 10 % [ n = 40 ] vs. 24.5 ± 12.0 % [ n = 43 ] ; p = 0.009 ) . At 24 h , high-sensitivity troponin T was lower with RIC ( 2,296 ± 263 ng/l [ n = 89 ] vs. 2,736 ± 325 ng/l [ n = 84 ] ; p = 0.037 ) . RIC also reduced the extent of myocardial edema measured by T2-mapping CMR ( 28.5 ± 9.0 % vs. 35.1 ± 10.0 % ; p = 0.003 ) and lowered mean T2 values ( 68.7 ± 5.8 ms vs. 73.1 ± 6.1 ms ; p = 0.001 ) , precluding the use of CMR edema imaging to correctly estimate the area at risk . Using CMR-independent coronary angiography jeopardy scores to estimate the area at risk , RIC , when compared with the control protocol , was found to significantly improve the myocardial salvage index ( 0.42 ± 0.29 vs. 0.28 ± 0.29 ; p = 0.03 ) . CONCLUSIONS This r and omized study demonstrated that in ST-segment elevation myocardial infa rct ion patients treated by PPCI , RIC , initiated prior to PPCI , reduced MI size , increased myocardial salvage , and reduced myocardial edema Local ischemic postconditioning ( IPost ) and remote ischemic perconditioning ( RIPer ) are promising cardioprotective therapies in ST-elevation myocardial infa rct ion ( STEMI ) . We aim ed : ( 1 ) to investigate whether RIPer initiated at the catheterization laboratory would reduce infa rct size , as measured using serum creatine kinase-MB isoenzyme ( CK-MB ) release as a surrogate marker ; ( 2 ) to assess if the combination of RIPer and IPost would provide an additional reduction . Patients ( n = 151 ) were r and omly allocated to one of the following groups : ( 1 ) control group , percutaneous transluminal coronary angioplasty ( PTCA ) alone ; ( 2 ) RIPer group , PTCA combined with RIPer , consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion ; ( 3 ) RIPer+IPost group , PTCA combined with RIPer and IPost , consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon . The CK-MB area under the curve ( AUC ) over 72 h was reduced in RIPer , and RIPer+IPost groups , by 31 and 29 % , respectively , compared to the Control group ; however , CK-MB AUC differences between the three groups were not statistically significant ( p = 0.06 ) . Peak CK-MB , CK-MB AUC to area at risk ( AAR ) ratio , and peak CK-MB level to AAR ratio were all significantly reduced in the RIPer and RIPer+IPost groups , compared to the Control group . On the contrary , none of these parameters was significantly different between RIPer+IPost and RIPer groups . To conclude , starting RIPer therapy immediately prior to revascularization was shown to reduce infa rct size in STEMI patients , yet combining this therapy with an IPost strategy did not lead to further decrease in infa rct size Abstract The role of remote ischemic postconditioning ( RIPostC ) in improving left ventricular ( LV ) remodeling after primary percutaneous coronary intervention ( PCI ) is not well established . To determine the efficacy and safety of RIPostC in improving LV remodeling and cardiovascular outcomes after primary PCI for anterior ST‐elevation myocardial infa rct ion ( STEMI ) . Seventy‐one patients with anterior STEMI were r and omized to primary PCI with RIPostC protocol ( n = 36 ) versus conventional primary PCI ( n = 35 ) . Primary outcomes included LV remodeling and LV ejection fraction ( LVEF ) at 6 month follow‐up using transthoracic echocardiography . Secondary outcomes included infa rct size , ST‐segment resolution ( STR ) ≥70 % , Thrombolysis in Myocardial Infa rct ion ( TIMI ) flow grade , and myocardial blush grade ( MBG ) . Major adverse cardiac events ( MACEs ) were also assessed at 6 months . Safety outcome included incidence of acute kidney injury ( AKI ) post primary PCI . Sixty patients completed the study . At 6 months , there was no significant decrease in the incidence of LV remodeling with RIPostC group ( p = 0.42 ) . Similarly , RIPostC failed to show significant improvement in LVEF . However , STR ≥ 70 % after primary PCI was achieved more in the RIPostC group ( p = 0.04 ) , with a trend toward less AKI in the RIPostC group ( p = 0.08 ) . All other secondary end points , including MACEs at 6 months , were similar in both groups . RIPostC might be associated with better STR after reperfusion as well as less incidence of AKI in patients undergoing primary PCI for anterior wall STEMI , indicating potential benefit in those patients . Whether this role can be translated to better outcomes after primary PCI warrants further investigation We have previously shown that remote ischemic preconditioning by limb ischemia ( rIPC ) or intra-arterial adenosine releases a dialyzable cardioprotective circulating factor(s ) , the release of which requires an intact neural connection to the limb and is blocked by pretreatment with S-nitroso-N-acetylpenicillamine ( SNAP ) . Remote cardioprotection can be induced by other forms of peripheral stimulation including topical capsaicin , but the mechanisms of their signal transduction are incompletely understood . Rabbits were anesthetized by intravenous pentobarbital , intubated and ventilated , then r and omized ( 4–7 animals in each group ) to receive sham procedure , rIPC ( 4 cycles of 5 min lower limb ischemia , 5 min reperfusion ) , direct femoral nerve stimulation , topical capsaicin , pretreatment with intra-arterial SNAP + capsaicin , pretreatment with topical DMSO ( a sensory nerve blocker ) + topical capsaicin , or pretreatment with intra-arterial SNAP + femoral nerve stimulation , topical DMSO alone , or intra-arterial SNAP alone . Blood was then rapidly drawn from the carotid artery to produce the plasma dialysate which was used to perfuse a naïve heart from an untreated donor rabbit . The infa rct size and recovery of LV-developed pressure and end-diastolic pressure were measured after 30 min of global ischemia and 120 min of reperfusion . Compared to sham , dialysate from rIPC , femoral nerve stimulation , and topical capsaicin groups all produced significant cardioprotection with significantly reduced infa rct size , and improved the post-ischemic cardiac performance . Cardioprotection was not seen in the topical DMSO-capsaicin , SNAP + capsaicin , and SNAP + FNS groups . These results confirm the central role of peripheral nerves in the local signal transduction of remote cardioprotection . Direct electrical or peripheral neural stimulation evokes the release of cardioprotective substances into the bloodstream , with comparable effects to that of rIPC induced by limb ischemia AIMS Remote ischaemic conditioning ( RIC ) and postconditioning ( PostC ) are both potent activators of innate protection against ischaemia-reperfusion injury and have demonstrated cardioprotection in experimental and clinical ST-elevation myocardial infa rct ion ( STEMI ) trials . However , their combined effects have not been studied in detail . The aim of this study was to evaluate if the co-application of intrahospital RIC and PostC has a more powerful effect on myocardial salvage compared with either PostC alone or control . METHODS AND RESULTS This prospect i ve , controlled , single-centre study r and omized 696 STEMI patients to one of the following three groups : ( i ) combined intrahospital RIC + PostC in addition to primary percutaneous coronary intervention ( PCI ) ; ( ii ) PostC in addition to PCI ; and ( iii ) conventional PCI ( control ) . The primary endpoint myocardial salvage index was assessed by cardiac magnetic resonance ( CMR ) imaging within 3 days after infa rct ion . Secondary endpoints included infa rct size and microvascular obstruction ( MVO ) assessed by CMR . The combined clinical endpoint consisted of death , reinfa rct ion , and new congestive heart failure within 6 months . The primary endpoint myocardial salvage index was significantly greater in the combined RIC + PostC group when compared with the control group ( 49 [ interquartile range 30 - 72 ] vs. 40 [ interquartile range 16 - 68 ] , P = 0.02 ) . Postconditioning alone failed to improve myocardial salvage when compared with conventional PCI ( P = 0.39 ) . The secondary endpoints , including infa rct size and MVO , showed no significant differences between groups . Clinical follow-up at 6 months revealed no differences in the combined clinical endpoint between groups ( P = 0.44 ) . CONCLUSION Combined intrahospital RIC + PostC in conjunction with PCI in STEMI significantly improves myocardial salvage in comparison with control and PostC. CLINICAL TRIALSGOV NCT02158468 AIMS Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infa rct ion increases myocardial salvage . We investigated the effect of remote ischaemic conditioning on long-term clinical outcome . METHODS AND RESULTS From February 2007 to November 2008 , 333 patients with a suspected first acute ST-elevation myocardial infa rct ion were r and omized to receive primary percutaneous coronary intervention with ( n = 166 ) or without ( n = 167 ) remote ischaemic conditioning ( intermittent arm ischaemia through four cycles of 5-min inflation followed by 5-min deflation of a blood-pressure cuff ) . Patient follow-up extended from the r and omization date until an outcome , emigration or January 2012 ( median follow-up = 3.8 years ) . The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE)-a composite of all-cause mortality , myocardial infa rct ion , readmission for heart failure , and ischaemic stroke/transient ischaemic attack . The individual components of the primary endpoint comprised the secondary endpoints . Outcomes were obtained from Danish nationwide medical registries and vali date d by medical record review and contact to patients ' general practitioner . In the per- protocol analysis of 251 patient fulfilling trial criteria , MACCE occurred for 17 ( 13.5 % ) patients in the intervention group compared with 32 ( 25.6 % ) patients in the control group , yielding a hazard ratio ( HR ) of 0.49 ( 95 % confidence interval : 0.27 - 0.89 , P = 0.018 ) . The HR for all-cause mortality was 0.32 ( 95 % confidence interval : 0.12 - 0.88 , P = 0.027 ) . Although lower precision , the HRs were also directionally lower for all other secondary endpoints . CONCLUSION Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infa rct ion OBJECTIVES We sought to determine the potential of remote ischemic periconditioning ( RIPC ) , and its combination with morphine , to reduce reperfusion injury in primary percutaneous coronary interventions . BACKGROUND Remote ischemic post-conditioning is implemented by applying cycles of ischemia and reperfusion on a remote organ , which result in release of circulating factors inducing the effects of post-conditioning on the myocardium . METHODS A total of 96 patients ( 59 men ) were enrolled . The patients were r and omized to groups as follows : 33 to each treatment group ( Group A : RIPC ; Group B : RIPC and morphine ) and 30 to the control group ( Group C ) . Measures of efficacy were achievement of full ST-segment resolution ( primary ) , and reduction of ST-segment deviation score and peak troponin I during hospitalization . RESULTS A higher proportion of patients in Groups A ( 73 % ) and B ( 82 % ) achieved full ST-segment resolution after percutaneous coronary intervention , compared with control patients ( 53 % ) ( p = 0.045 ) . Peak troponin I was lowest in Group B , 103.3 + /- 13.3 ng/ml , in comparison to peak levels in Group A , 166.0 + /- 28.0 ng/ml , and the control group , 255.5 + /- 35.5 ng/ml ( p = 0.0006 ) . ST-segment deviation resolution was 87.3 + /- 2.7 % in Group B , compared with 69.9 + /- 5.1 % in Group A and 53.2 + /- 6.4 % in the control group ( p = 0.00002 ) . In paired comparisons between groups , Group B did better than the control group in terms of both ST-segment reduction ( p = 0.0001 ) and peak troponin I ( p = 0.004 ) , whereas Group A differences from the control group did not achieve statistical significance ( p = 0.054 and p = 0.062 , respectively ) . CONCLUSIONS These findings demonstrate a cardioprotective effect of RIPC and morphine during primary percutaneous coronary intervention for the prevention of reperfusion injury . This is in agreement with observations that the beneficial effect of RIPC is inhibited by the opioid receptor blocker naloxone BACKGROUND Previous studies indicate that remote ischemic conditioning performed before percutaneous coronary intervention ( PCI ) reduces infa rct size in patients with ST-elevation myocardial infa rct ion ( STEMI ) . It remains unclear whether remote conditioning affords protection when performed in adjunct to primary PCI . We aim ed to study whether remote ischemic per-postconditioning ( RIperpostC ) initiated after admission to the catheterization laboratory attenuates myocardial infa rct size in patients with anterior STEMI . METHODS In this prospect i ve multicenter trial 93 patients with anterior STEMI were r and omized to RIperpostC or sham procedure as adjunct to primary PCI . RIperpostC was started on arrival in the catheterization laboratory by 5-minute cycles of inflation and deflation of a blood pressure cuff around the left thigh and continued throughout the PCI procedure . Infa rct size and myocardium at risk were determined by cardiac magnetic resonance at day 4 to 7 . The primary outcome was myocardial salvage index . RESULTS There was no significant difference in myocardial salvage index between the RIperpostC and control group ( median 48.5 % and interquartile range 30.9%-60.8 % vs 49.2 % [ 42.1%-58.8 % ] ) . Neither did absolute infa rct size in relation to left ventricular myocardial volume differ significantly ( RIperpostC 20.6 % [ 14.1%-31.7 % ] vs control 17.9 % [ 13.4%-25.0 % ] ) . The RIperpostC group had larger myocardial area at risk than the control group ( 43.1 % ( 35.4%-49.7 % ) vs 37.0 % ( 30.8%-44.1 % ) of the left ventricle , P=.03 ) . Peak value and area under the curve for troponin T did not differ significantly between the study groups . CONCLUSIONS RIperpostC initiated after admission to the catheterization laboratory in patients with anterior STEMI did not confer protection against reperfusion injury

Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term ; however the magnitude of the risk is uncertain .

BACKGROUND Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000 . In this review we focus on gliomas with low aggressive potential in the short term , i.e. low- grade gliomas . Most people with low- grade gliomas are treated with surgery and may receive radiotherapy thereafter . However , there is concern about the possible long-term effects of radiotherapy , especially on neurocognitive functioning . OBJECTIVES To evaluate the long-term neurocognitive and other side effects of radiotherapy ( with or without chemotherapy ) compared with no radiotherapy , or different types of radiotherapy , among people with glioma ( where ' long-term ' is defined as at least two years after diagnosis ) ; and to write a brief economic commentary .

PURPOSE A prospect i ve , open-label phase II study was conducted to determine whether donepezil , a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer 's type dementia , improved cognitive functioning , mood , and quality of life ( QOL ) in irradiated brain tumor patients . PATIENTS AND METHODS Thirty-four patients received donepezil 5 mg/d for 6 weeks , then 10 mg/d for 18 weeks , followed by a washout period of 6 weeks off drug . Outcomes were assessed at baseline , 12 , 24 ( end of treatment ) , and 30 weeks ( end of wash-out ) . All tests were administered by a trained research nurse . RESULTS Of 35 patients who initiated the study , 24 patients ( mean age , 45 years ) remained on study for 24 weeks and completed all outcome assessment s. All 24 patients had a primary brain tumor , mostly low- grade glioma . Scores significantly improved between baseline ( pretreatment ) and week 24 on measures of attention/concentration , verbal memory , and figural memory and a trend for verbal fluency ( all P < .05 ) . Confused mood also improved from baseline to 24 weeks ( P = .004 ) , with a trend for fatigue and anger ( all P < .05 ) . Health-related QOL improved significantly from baseline to 24 weeks , particularly , for brain specific concerns with a trend for improvement in emotional and social functioning ( all P < .05 ) . CONCLUSION Cognitive functioning , mood , and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil . Toxicities were minimal . We are planning a double blinded , placebo-controlled , phase III trial of donepezil to confirm these favorable results From 1990 to 1994 , patients with newly diagnosed malignant gliomas were enrolled and r and omized between hyperfractionated radiation ( HFX ) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily . All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1–3 q8 weeks for 1 year . Patients were stratified by age , KPS , and histology . The primary endpoint was overall survival ( OS ) , with secondary endpoints including progression-free survival ( PFS ) and toxicity . Out of the 712 patients accrued , 694 ( 97.5 % ) were analyzable cases ( 350 HFX , 344 st and ard arm ) . There was no significant difference between the arms on overall acute or late treatment-related toxicity . No statistically significant effect for HFX , as compared to st and ard therapy , was found on either OS , with a median survival time ( MST ) of 11.3 versus 13.1 months ( p = 0.20 ) or PFS , with a median PFS time of 5.7 versus 6.9 months ( p = 0.18 ) . The treatment effect on OS remained insignificant based on the multivariate analysis ( hazard ratio 1.16 ; p = 0.0682 ) . When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme ( MST : 10.3 vs. 11.2 months ; p = 0.34 ) , anaplastic astrocytoma ( MST : 69.8 vs. 50.0 months ; p = 0.91 ) or anaplastic oligodendroglioma ( MST : 92.1 vs. 66.5 months ; p = 0.33 ) . Though this trial provided many invaluable secondary analyses , there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients Background Outcome of low- grade glioma ( LGG , WHO grade II ) is highly variable reflecting molecular heterogeneity of the disease . We compared two different single modality treatment strategies : st and ard radiotherapy ( RT ) versus primary temozolomide ( TMZ ) chemotherapy with the aim of tailoring treatment and identifying predictive molecular factors . Methods 477 patients ( 2005 – 2012 , median FU 48 months ) with a low- grade glioma ( astrocytoma , oligoastrocytoma , oligodendroglioma , WHO grade II ) with at least one high-risk feature ( age > 40 years , progressive disease , tumor > 5 cm or crossing the midline , neurological symptoms ( e.g. focal or mental deficits , increased intracranial pressure or intractable seizures ) ) were , after stratification by chromosome 1p-status , r and omized to either conformal RT ( 50.4 Gy/28 fractions ) or dose-dense TMZ ( 75 mg/m2 daily × 21 days , q28 days , max . 12 cycles ) . R and om treatment allocation was performed online using a minimization technique . A planned analysis was performed after 246 progression events . All analyses are intent to treat . Primary clinical endpoint was progression-free survival ( PFS ) , correlative analyses included molecular markers ( 1p/19q co-deletion , MGMT methylation status , IDH1 + 2 mutations ) . The trial has been registered at the European Trials Registry ( EudraCT 2004 - 002714 - 11 ) and at Clinical Trials.gov ( NCT00182819 ) . Findings Four hundred seventy-seven patients were r and omized . Severe hematological toxicity occurred in 14 % of TMZ-treated patients , infections in 3 % of TMZ-treated patients , and 1 % of RT-treated patients . Moderate to severe fatigue was recorded in 3 % of patients in the RT group and 7 % in the TMZ group . At a median follow-up of 48 months ( IQR:31–56 ) , median PFS was 39 months ( IQR:16–46 ) in the TMZ arm and 46 months ( IQR:19–48 ) in the RT group ( hazard ratio 1.16 , 95 % CI , 0.9–1.5 ; p=0.22 ) . Median OS has not been reached . Exploratory analyses identified treatment-dependent variation in outcome of molecular LGG subgroups ( n=318 ) . Interpretation There was no significant difference in outcome of the overall patient population treated with either radiotherapy alone or TMZ chemotherapy alone . Further data maturation is needed for overall survival analyses and evaluation of the full predictive impact of the molecular subtypes for individualized treatment choices . Funding Merck & Co , Swiss-Bridge Award 2011 , Swiss Cancer League We characterized health-related quality of life ( HRQoL ) , cognitive , and functional status in newly diagnosed glioblastoma ( GBM ) patients receiving Tumor treating fields ( TTFields ) with temozolomide ( TMZ ) versus TMZ alone in a planned interim analysis of a r and omized phase III trial [ NCT00916409 ] , which showed significant improvement in progression-free and overall survival with TTFields/TMZ . After radiotherapy with concomitant TMZ , newly diagnosed GBM patients were r and omized ( 2:1 ) to TTFields/TMZ ( n = 210 ) or TMZ ( n = 105 ) . Interim analysis was performed in 315 patients with ≥18 months of follow-up . HRQoL , a secondary endpoint , was evaluated in per- protocol patient population and expressed as change from baseline ( CFB ) at 3 , 6 , and 9 months for each subscale in the EORTC QLQ-C30/BN20 . Karnofsky performance scores ( KPS ) and Mini-Mental State Examination scores ( MMSE ) were assessed . CFB in HRQoL was balanced in treatment groups at the 12-month time point . Initially , HRQoL improved in patients treated with TTFields/TMZ ( CFB3 : 24 % and CFB6 : 13 % ) versus TMZ ( CFB3 : −7 % and CFB6 : −17 % ) , though this difference was no longer evident at the 9-month point . General scales , including physical and social functioning , showed no difference at 9 and 12 months . TTFields/TMZ group reported higher concerns of “ itchy skin ” . KPS over 12 months was just below 90 in both groups . Cognitive status ( MMSE ) was stable over time . HRQoL , KPS , and MMSE were balanced in both groups over time . There was no preliminary evidence that HRQoL , cognitive , and functional status is adversely affected by the continuous use of TTFields BACKGROUND Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low- grade glioma has been shown to have no significant effect on progression-free survival . If these treatments have a different effect on health-related quality of life ( HRQOL ) , it might affect the choice of therapy . We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy . METHODS We did a prospect i ve , phase 3 , r and omised controlled trial at 78 medical centres and large hospitals in 19 countries . We enrolled adult patients ( aged ≥18 years ) with histologically confirmed diffuse ( WHO grade II ) astrocytoma , oligodendroglioma , or mixed oligoastrocytoma , with a WHO performance status of 2 or lower , without previous chemotherapy or radiotherapy , who needed active treatment other than surgery . We r and omly assigned eligible patients ( 1:1 ) using a minimisation technique , stratified by WHO performance status ( 0 - 1 vs 2 ) , age ( < 40 years vs ≥40 years ) , presence of contrast enhancement on MRI , chromosome 1p status ( deleted vs non-deleted vs indeterminate ) , and the treating medical centre , to receive either radiotherapy ( 50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks ) or temozolomide chemotherapy ( 75 mg/m2 daily , for 21 of 28 days [ one cycle ] for 12 cycles ) . The primary endpoint was progression-free survival ( results published separately ) ; here , we report the results for two key secondary endpoints : HRQOL ( assessed using the European Organisation for Research and Treatment of Cancer 's [ EORTC ] QLQ-C30 [ version 3 ] and the EORTC Brain Cancer Module [ QLQ-BN20 ] ) and global cognitive functioning ( assessed using the Mini-Mental State Examination [ MMSE ] ) . We did analyses on the intention-to-treat population . This study is closed and is registered at EudraCT , number 2004 - 002714 - 11 , and at Clinical Trials.gov , number NCT00182819 . FINDINGS Between Dec 6 , 2005 , and Dec 21 , 2012 , we r and omly assigned 477 eligible patients to either radiotherapy ( n=240 ) or temozolomide chemotherapy ( n=237 ) . The difference in HRQOL between the two treatment groups was not significant during the 36 months ' follow-up ( mean between group difference [ averaged over all timepoints ] 0·06 , 95 % CI -4·64 to 4·75 , p=0·98 ) . At baseline , 32 ( 13 % ) of 239 patients who received radiotherapy and 32 ( 14 % ) of 236 patients who received temozolomide chemotherapy had impaired cognitive function , according to the MMSE scores . After r and omisation , five ( 8 % ) of 63 patients who received radiotherapy and three ( 6 % ) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function , according to the MMSE scores . No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up . INTERPRETATION The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low- grade glioma . These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low- grade glioma . FUNDING Merck Sharp & Dohme-Merck & Co , National Cancer Institute , Swiss Cancer League , National Institute for Health Research , Cancer Research UK , Canadian Cancer Society Research Institute , National Health and Medical Research Council , European Organisation for Research and Treatment of Cancer Cancer Research Fund Background The addition of bevacizumab to temozolomide-based chemoradiotherapy ( TMZ/RT → TMZ ) did not prolong overall survival ( OS ) in patients with newly diagnosed glioblastoma in phase III trials . Elderly and frail patients are underrepresented in clinical trials , but early reports suggested preferential benefit in this population . Patients and methods ARTE was a 2 : 1 r and omized , multi-center , open-label , non-comparative phase II trial of hypofractionated RT ( 40 Gy in 15 fractions ) with bevacizumab ( 10 mg/kg × 14 days ) ( arm A , N = 50 ) or without bevacizumab ( arm B , N = 25 ) in patients with newly diagnosed glioblastoma aged ≥65 years . The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT . Response was assessed by RANO criteria . Quality of life ( QoL ) was monitored by the EORTC QLQ-C30/BN20 modules . Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses . Results Median PFS was longer in arm A than in arm B ( 7.6 and 4.8 months , P = 0.003 ) , but OS was similar ( 12.1 and 12.2 months , P = 0.77 ) . Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase ( RTK ) I methylation subtype ( HR 0.25 , P = 0.014 ) and proneural gene expression ( HR 0.29 , P = 0.025 ) . In a Cox model of OS controlling for established prognostic factors , associations with more favorable outcome were identified for age < 70 years ( HR 0.52 , P = 0.018 ) and Karnofsky performance score 90%-100 % ( HR 0.51 , P = 0.026 ) . Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS ( HR 1.73 , P = 0.076 ) . Conclusion Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients . Molecular biomarkers may identify patients with preferential benefit from bevacizumab . Clinical trial registration number NCT01443676 PURPOSE Cerebral low- grade gliomas ( LGG ) in adults are mostly composed of astrocytomas , oligodendrogliomas , and mixed oligoastrocytomas . There is at present no consensus in the policy of treatment of these tumors . We sought to determine the efficacy of radiotherapy and the presence of a dose-response relationship for these tumors in two multicentric r and omized trials conducted by the European Organization for Research and Treatment of Cancer ( EORTC ) . The dose-response study is the subject of this article . METHODS AND MATERIAL S For the dose-response trial , 379 adult patients with cerebral LGGs were r and omized central ly at the EORTC Data Center to receive irradiation postoperatively ( or postbiopsy ) with either 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks with quality -controlled radiation therapy . All known parameters with possible influences on prognosis were prospect ively recorded . Conventional treatment techniques were recommended . RESULTS With 343 ( 91 % ) eligible and evaluable patients followed up for at least 50 months with a median of 74 months , there is no significant difference in terms of survival ( 58 % for the low-dose arm and 59 % for the high-dose arm ) or the progression free survival ( 47 % and 50 % ) between the two arms of the trial . However , this prospect i ve trial has revealed some important facets about the prognostic parameters : The T of the TNM classifications as proposed in the protocol appears to be one of the most important prognostic factors ( p < 0.0001 ) on multivariate analysis . Other prognostic factors , most of which are known , have now been quantified and confirmed in this prospect i ve study . CONCLUSION The EORTC trial 22844 has not revealed the presence of radiotherapeutic dose-response for patients with LGG for the two dose levels investigated with this conventional setup , but objective prognostic parameters are recognized . The tumor size or T parameter as used in this study appears to be a very important factor Background Assumptions about the damaging effects of radiotherapy ( XRT ) are based on studies in which total dose , dose fraction , treatment volume , degree of malignancy , chemotherapy , tumor recurrence , and neurologic comorbidity interact with XRT effects . This is a prospect i ve , long-term study of XRT effects in adults , in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity ( e.g. , hypertension ) were excluded . Methods The effects of XRT on the cognitive and radiographic outcomes of 26 patients with low- grade , supratentorial , brain tumors yearly from baseline ( 6 weeks after surgery and immediately before XRT ) and yearly to 6 years were examined . Radiographic findings were examined regionally . Results Selective cognitive declines ( in visual memory ) emerged only at 5 years , whereas ratings of clinical MRI ( T2 images ) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years , with no further progression . White matter atrophy and total hyperintensities demonstrated this effect , with subcortical and deep white matter , corpus callosum , cerebellar structures , and pons accounting for these changes over time . About half of the patients demonstrated cognitive decline and treatment-related hyperintensities . Conclusions There was no evidence of a general cognitive decline or progression of white matter changes after 3 years . Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors BACKGROUND Despite aggressive st and ard of care ( SOC ) treatment , survival of malignant gliomas remains very poor . This Phase II , prospect i ve , matched controlled , multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec ( AdV-tk ) plus valacyclovir ( gene-mediated cytotoxic immunotherapy [ GMCI ] ) in combination with SOC for newly diagnosed malignant glioma patients . METHODS Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010 . The preplanned , matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution . AdV-tk was administered at surgery followed by SOC radiation and temozolomide . Subset analyses were preplanned , based on prognostic factors : pathological diagnosis ( glioblastoma vs others ) and extent of resection . RESULTS Forty-eight patients completed SOC + GMCI , and 134 met control cohort criteria . Median overall survival ( OS ) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone ( P = .0417 ) . Survival at 1 , 2 , and 3 years was 67 % , 35 % , and 19 % versus 57 % , 22 % , and 8 % , respectively . The greatest benefit was observed in gross total resection patients : median OS of 25 versus 16.9 months ( P = .0492 ) ; 1 , 2 , and 3-year survival of 90 % , 53 % , and 32 % versus 64 % , 28 % and 6 % , respectively . There were no dose-limiting toxicities ; fever , fatigue , and headache were the most common GMCI-related symptoms . CONCLUSIONS GMCI can be safely combined with SOC in newly diagnosed malignant gliomas . Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection . These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas . CLINICAL TRIAL REGISTRY Clinical Trials.gov NCT00589875 PURPOSE To compare survival and toxicity in adult patients treated with low-dose ( 50.4 Gy/28 fractions ) versus high-dose ( 64.8 Gy/36 fractions ) localized radiation therapy ( RT ) for supratentorial low- grade astrocytoma , oligodendroglioma , and mixed oligoastrocytoma . PATIENTS AND METHODS From 1986 to 1994 , 203 eligible/analyzable patients were r and omized : 101 to low-dose RT , 102 to high-dose RT . Almost half were younger than 40 years , and 95 % had grade 2 tumors . Histologic subtype was astrocytoma ( or mixed oligo-astrocytoma with astrocytoma dominant ) in 32 % of patients and oligodendroglioma ( or oligoastrocytoma with oligodendroglioma dominant ) in 68 % . Tumor diameter was less than 5 cm in 35 % of patients , and 41 % of tumors showed some degree of contrast enhancement . Extent of resection was gross total in 14 % of patients , subtotal in 35 % , and biopsy only in 51 % . RESULTS At the time of the present analysis , 83 patients ( 41 % ) are dead , and median follow-up is 6.43 years in the 120 who are still alive . Survival at 2 and 5 years is nonsignificantly better with low-dose RT ; survival at 2 and 5 years was 94 % and 72 % , respectively , with low-dose RT and 85 % and 64 % , respectively , with high-dose RT ( log rank P = .48 ) . Multivariate analysis identified histologic subtype , tumor size , and age as the most significant prognostic factors . Survival is significantly better in patients who are younger than 40 years and in patients who have oligodendroglioma or oligo-dominant histology . Grade 3 to 5 radiation neurotoxicity ( necrosis ) was observed in seven patients , with one fatality in each treatment arm . The 2-year actuarial incidence of grade 3 to 5 radiation necrosis was 2.5 % with low-dose RT and 5 % with high-dose RT . CONCLUSION This phase III prospect i ve r and omized trial of low- versus high-dose radiation therapy for adults with supratentorial low- grade astrocytoma , oligodendroglioma , and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm . The most important prognostic factors for survival are histologic subtype , tumor size , and age . The study design of the ongoing intergroup trial in this population will be discussed Abstract The Radiation Therapy Oncology Group ( RTOG ) embarked on a phase I/II study of patients suffering from glioblastoma multiforme ( protocol 98 - 03 ) to assess the impact of dose escalation with 3-D conformal techniques . The primary endpoints were feasibility and survival . This report describes the outcome of secondary endpoints ( quality of life and neurocognitive function ) . Patients with supratentorial GBM were treated with a combination of carmustine ( BCNU ) and conformal irradiation ( dose levels : 66 , 72 , 78 , 84 Gy , respectively ) . Quality of Life was assessed with the Spitzer Quality of Life Index . Neurocognitive function was determined by the Mini Mental Status Examination . The latter tests were administered at the start of irradiation , at the end of irradiation and then at 4 month intervals . Relatively high compliance was achieved with both of the tools ( SQLI ; MMSE ) . Overall rates of survival between baseline SQLI scores < 7 and 7–10 were statistically significantly different [ HR = 1.72 , 95 % CI ( 1.22 , 2.4 ) , P = 0.0015 ] . The significant impact of high SQLI score on survival was preserved in multivariate analysis . The component of this index which made the greatest contribution was the patient ’s independence . There was continual deterioration of neurocognitive function within the population s studied . No correlation was seen between dose escalation and the secondary endpoints studied . Radiation dose escalation and assessment of its impact on life quality and neurocognition can be carried out in a large international trial . Baseline SQLI is a statistically significant determinant of survival . Those who maintain independence have superior survival to those who are reliant on others Outcome after radiochemotherapy ( RCHT ) with temozolomide ( TMZ ) versus radiotherapy ( RT ) for WHO grade III astrocytic tumors was evaluated . No significant difference in overall survival or progression-free survival between both groups was calculated . RCHT seems not to result in an improved outcome . Further r and omized studies are needed to support these results The purpose of this prospect i ve phase II/III trial was to study the effect of therapy intensification when combining procarbazine , lomustine , and vincristine ( PCV ) chemotherapy with a st and ard course of radiation therapy ( RT ) on cognitive functioning for patients with World Health Organization grade 2 low- grade gliomas ( LGGs ) . Initial results of the trial demonstrated a progression-free survival benefit with adjuvant PCV , but no overall survival benefit in the intention-to-treat analysis . Because patients with LGGs have favorable prognostic indicators , the five-year overall survival rates range from 60%-70 % . The effect of cancer treatment on neurocognitive function is a topic of increasing interest to healthcare providers and patients . The negative effect is commonly called " chemobrain " and refers to diminished concentration and compromised short-term memory following treatment . Chemobrain has been studied in other population s of patients with cancer ( e.g. , breast cancer ) with associated statistically significant chemotherapy-associated compromised cognitive function when chemotherapy was added to RT PURPOSE The st and ard of care for anaplastic gliomas is surgery followed by radiotherapy . The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas . PATIENTS AND METHODS Patients ( N = 318 ) were r and omly assigned 2:1:1 ( A : B1:B2 ) to receive conventional radiotherapy ( arm A ) ; procarbazine , lomustine ( CCNU ) , and vincristine ( PCV ; arm B1 ) ; or temozolomide ( arm B2 ) at diagnosis . At occurrence of unacceptable toxicity or disease progression , patients in arm A were treated with PCV or temozolomide ( 1:1 r and om assignment ) , whereas patients in arms B1 or B2 received radiotherapy . The primary end point was time to treatment failure ( TTF ) , defined as progression after radiotherapy and one chemotherapy in either sequence . RESULTS Patient characteristics in the intention-to-treat population ( n = 274 ) were balanced between arms . All histologic diagnoses were central ly confirmed . Median TTF ( hazard ratio [ HR ] = 1.2 ; 95 % CI , 0.8 to 1.8 ) , progression-free survival ( PFS ; HR = 1.0 ; 95 % CI , 0.7 to 1.3 , and overall survival ( HR = 1.2 ; 95 % CI , 0.8 to 1.9 ) were similar for arms A and B1/B2 . Extent of resection was an important prognosticator . Anaplastic oligodendrogliomas and oligoastrocytomas share the same , better prognosis than anaplastic astrocytomas . Hypermethylation of the O(6)-methylguanine DNA-methyltransferase ( MGMT ) promoter ( HR = 0.59 ; 95 % CI , 0.36 to 1.0 ) , mutations of the isocitrate dehydrogenase ( IDH1 ) gene ( HR = 0.48 ; 95 % CI , 0.29 to 0.77 ) , and oligodendroglial histology ( HR = 0.33 ; 95 % CI , 0.2 to 0.55 ) reduced the risk of progression . Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm . CONCLUSION Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas . IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas , with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation PURPOSE There is no consensus on the treatment strategy for adult patients with cerebral low- grade glioma . The diagnosis and primary treatment are usually undertaken by surgery . Some investigators doubt the efficacy of postoperative radiotherapy ( RT ) , whereas others advise routine postoperative RT . We report the primary results of a multicenter r and omized trial on this controversy . METHODS AND MATERIAL S From 24 European centers , 311 adult patients with low- grade glioma were r and omized central ly after surgery from March 1986 through September 1997 , between the two arms of the trial . The irradiated group received 54 Gy in 6 weeks . The other patients did not receive any treatment after surgery until the tumor showed progression , defined as clinical -neurologic deterioration and evidence of progressive tumor on imaging . RESULTS Of 290 eligible and assessable patients ( 93 % ) , the irradiated group showed a significant ( log-rank p = 0.02 ) improvement in time to progression but not in overall survival , with a median follow-up of 5 years . The 5-year estimate was , respectively , 63 % vs. 66 % ( overall survival ) and 44 % vs. 37 % ( time to progression ) for the treated and control arms . Different treatment modalities , including RT , were undertaken for the 85 controls when a progressive tumor was noted . CONCLUSION Early postoperative conventional RT such as that used for this protocol appears to improve the time to progression or progression-free survival , but not overall survival , for patients with low- grade glioma Sixty adult patients with incompletely excised low- grade gliomas were r and omly assigned to receive radiotherapy ( 55 Gy over a total of 6 1/2 to 7 weeks ) either alone or with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea ( CCNU ; 100 mg/sq m every 6 weeks ) . Pathological review showed that six patients were ineligible for the study . Evaluation of patient age , extent of surgery , tumor grade , and performance status showed no significant differences between the treatment arms . The response rate , as judged by the disappearance or reduction in size of the tumor on computerized tomography scans , was 79 % for radiation therapy alone versus 54 % for irradiation plus CCNU . The median survival time was 4.45 years for all patients , with no significant difference between treatment arms ( p = 0.7 ) . For the group as a whole , patient age and performance status were the most important prognostic parameters . The majority of patients receiving chemotherapy experienced moderate hematological toxicity . This study demonstrates that CCNU chemotherapy does not improve the results of radiation therapy in the treatment of incompletely excised low- grade gliomas PURPOSE To evaluate the effects of cranial radiotherapy ( RT ) on cognitive function in patients with supratentorial low- grade glioma . METHODS AND MATERIAL S Twenty adult patients with supratentorial low- grade glioma were treated with 50.4 Gy ( 10 patients ) or 64.8 Gy ( 10 patients ) localized RT . The patients then were evaluated with an extensive battery of psychometric tests at baseline ( before RT ) and at approximately 18-month intervals for as long as 5 years after completing RT . To allow patients to serve as their own controls , cognitive performance was evaluated as change in scores over time . All patients underwent at least two evaluations . RESULTS Baseline test scores were below average compared with age-specific norms . At the second evaluation , the groups ' mean test scores were higher than their initial performances on all psychometric measures , although the improvement was not statistically significant . No changes in cognitive performance were seen during the evaluation period when test scores were analyzed by age , treatment , tumor location , tumor type , or extent of resection . CONCLUSIONS Cognitive function was stable after RT in these patients evaluated prospect ively during 3 years of follow-up . Slight improvements in some cognitive areas are consistent with practice effects attributable to increased familiarity with test procedures and content Investigations of the effects of radiation on neuropsychological functions have revealed variable outcomes , ranging from no effect to severe cognitive impairment . However , many of the previous studies have relied on retrospective data or have been limited by method ological problems . In this study , prospect i ve neuropsychological assessment s were compared at baseline ( after surgery and before radiotherapy ) and within 4 months of completion of radiotherapy ( except one case ) , to examine early-delayed effects of radiation on intellectual and cognitive functioning . Sixteen adult patients with either low- or high- grade brain tumours , 15 of whom were treated with radiotherapy , were compared with 8 control participants with nonmalignant brain tumours whom did not undergo radiotherapy . All participants had lesions situated mainly in the frontal lobes . All groups of patients had evidence of intellectual and cognitive impairment at baseline . The low- and high- grade brain tumour groups showed a differential pattern of performance following radiotherapy , with the low- grade tumour group 's performance being more competent on all of the five main neuropsychological measures . Their pattern of improvement was very similar to that of the nonmalignant brain tumour group who had not undergone radiotherapy . The present study provides some preliminary information about the neuropsychological deficits associated with primary brain tumours , their severity , and the relationship between neuropsychological functioning and brain tumours and radiotherapy To underst and neurocognitive effects of proton radiation therapy ( PRT ) in patients with low- grade glioma , we evaluated 20 patients who received this therapy prospect ively and over 5 years with a comprehensive neuropsychological battery . 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual , attention , executive , visuospatial and memory functions as well as mood and functional status . We evaluated change in cognitive functioning over time . We analyzed the relationship between cognitive performance and tumor location and also examined whether patients ’ performance differed from that reported in a study of normative practice effects . Overall , patients exhibited stability in cognitive functioning . Tumor location played a role in performance ; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures ( p < .05 ) . However , we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors ( p < .05 ) . Results of our study , the first to investigate , in depth , neurocognitive effects of PRT in adults with low- grade gliomas , are promising . We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning , although larger sample sizes and a longer period of study are required . Our study also highlights the need to consider normative practice effects when study ing neurocognitive functioning in response to treatment over time , and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors PURPOSE To prospect ively evaluate the association between hippocampal dose and long-term neurocognitive function ( NCF ) impairment for benign or low- grade adult brain tumors treated with fractionated stereotactic radiotherapy ( FSRT ) . METHODS AND MATERIAL S Adult patients with benign or low- grade adult brain tumors were treated with FSRT per institutional practice . No attempt was made to spare the hippocampus . NCF testing was conducted at baseline and 18 months follow-up , on a prospect i ve clinical trial . Regression-based st and ardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval . NCF impairment was defined as a z score ≤-1.5 . After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas , dose-volume histograms were generated for the left and right hippocampi and for the composite pair . Biologically equivalent doses in 2-Gy fractions ( EQD(2 ) ) assuming an α/β ratio of 2 Gy were computed . Fisher 's exact test and binary logistic regression were used for univariate and multivariate analyses , respectively . Dose-response data were fit to a nonlinear model . RESULTS Of 29 patients enrolled in this trial , 18 completed both baseline and 18-month NCF testing . An EQD(2 ) to 40 % of the bilateral hippocampi > 7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List ( WMS-WL ) delayed recall ( odds ratio [ OR ] 19.3 ; p = 0.043 ) . The association between WMS-WL delayed recall and EQD(2 ) to 100 % of the bilateral hippocampi > 0.0 Gy trended to significance ( OR 14.8 ; p = 0.068 ) . CONCLUSION EQD(2 ) to 40 % of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low- grade adult brain tumors . Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold , patients should be enrolled in ongoing prospect i ve trials of hippocampal sparing during cranial irradiation to confirm these preliminary results Summary Endocrine functions were studied in long-term survivors of low- grade glioma treated with radiotherapy . Hypothalamic-pituitary dysfunction has recently been reported to occur more frequently than generally considered . Because endocrine dysfunction is a treatable condition , careful testing and , if necessary , supplementary treatment may enhance quality of life . Thirteen adult patients treated with radiotherapy because of supratentorial low- grade glioma at least one year before ( range 1–11.5 years ) were tested . Focal brain radiotherapy ( 45–61.2 Gy ) , with calculated dose to the hypothalamic-pituitary area ranging from 0 to 50 Gy ( mean 36.1 ) had been applied to all patients . Serum levels of pituitary hormones , cortisol and thyroid hormone were determined before and after stimulation with hypothalamic hormones . In 10 out of 13 patients one or more hormonal values were out of the normal range . Most disturbances were demonstrated in the pituitary-adrenal axis ( 8 patients ) and the GH-axis ( 4 patients ) . None of the patients had clinical symptomatology of adrenal , thyroid or gonadal dysfunction . Careful endocrine testing after cranial radiotherapy may reveal ( sub clinical ) hypothalamic-pituitary dysfunction in long-term survivors . Follow-up testing in these patients seems warranted PURPOSE To evaluate the effects of limited field conventional cerebral radiotherapy ( RT ) on cognitive functions of adults . METHODS AND MATERIAL S A prospect i ve neuropsychological study was performed on 17 patients who underwent conventional limited field RT for a low- grade glioma or for a good-prognosis anaplastic glioma . Results were compared with 14 control patients with low- grade gliomas who did not receive radiotherapy . RESULTS A transient significant decrease of performances for the Reaction Time test was observed at 6 months in the irradiated group with return to baseline values 12 months post-RT . Subsequently , no other significant changes were observed over a 48-month follow-up period in the irradiated and nonirradiated groups . Nonetheless , when the scores of each patient were considered over time instead of the mean values of the group , one irradiated patient ( 5.8 % ) experienced progressive deterioration while two irradiated patients ( 11.7 % ) experienced long-lasting improvement . Individual changes did not occur in the control group . CONCLUSION This study suggests that a transient early delayed drop of neuropsychological performances at 6 months is frequent following limited field conventional RT , but the risk of long-term cognitive dysfunction after irradiation is low , at least in the first 4 years after RT and when it is administered alone in young adults Purpose In cancer research , outcome measures may co-vary . Treatment and treatment related impairment of health-related quality of life ( HRQoL ) may affect survival . When these effects are analyzed separately , bias may arise . Therefore , we investigated the combined effect of treatment and longitudinally measured HRQoL on survival . Methods Patients with anaplastic oligodendrogliomas ( n = 288 ) who were r and omized ( EORTC 26951 ) to radiotherapy ( RT ) alone or RT plus procarbazine , lomustine , and vincristine ( PCV ) chemotherapy were analyzed . HRQoL [ appetite loss ( AP ) ] was assessed with the EORTC QLQ-C30 . We compared survival results from different analysis strategies : Cox model with treatment only [ model 1 ( M1 ) ] or with treatment and time-dependent AP score [ model 2 ( M2 ) ] and the joint model combining longitudinal AP score and survival [ model 3 ( M3 ) ] . Results The estimated hazard ratio ( HR ) for RT plus PCV was 0.76 ( 95 % CI 0.58–1.00 ) for M1 , 0.72 ( 0.55–0.96 ) for M2 , and 0.69 ( 0.52–0.92 ) for M3 . This corresponds to a lower risk of death of 24 % in M1 , 28 % in M2 , and 31 % in M3 , for patients treated with RT plus PCV chemotherapy . AP result ed in an increased risk of death , with estimated HR of 1.06 ( 1.01–1.12 ) for M2 and 1.13 ( 1.03–1.23 ) for M3 : Every 10-point increase of AP result ed in a 13 % increased risk of death in M3 as compared to 6 % in M2 . Conclusion Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients ’ HRQoL. In our study , up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling Background In patients with low- grade glioma ( LGG ) , the tumor and its treatment with conformal radiation therapy ( RT ) and chemotherapy can disrupt cognitive function . However , the contribution of disease and treatment to long-term cognitive outcome remains to be eluci date d. In this study , we performed longitudinal cognitive follow-up in a subgroup of patients who received RT , chemotherapy , or no treatment . Methods Twenty-five LGG patients underwent neuropsychological evaluations at study entry , and 6 and 12 months subsequently ; 9 patients had RT ± chemotherapy prior to enrollment and 16 had no treatment . Results At the initial evaluation , treated patients had impaired performance on motor speed only , but scored 1 st and ard deviation below normative values on tests of executive functions ; untreated patients had no cognitive impairment . Repeated measures analyses of variance showed a significant variation over time ( P = 0.03 ) in nonverbal memory ( delayed recall ) ; treated patients ’ performance improved at the 6-month follow-up to a level comparable to untreated patients , but both groups declined slightly by the 12-month evaluation . In a subset of patients ( N = 16 ) available for an additional cognitive evaluation , significant changes between the 12-month and the long-term follow-up were seen in phonemic verbal fluency , mood and quality of life ; untreated patients seen at short intervals improved slightly while treated patients seen at longer intervals declined . Conclusions Longitudinal follow-up showed that both disease duration and treatment with RT ± chemotherapy contributed to a mild decrement in nonverbal recall and in some aspects of executive functions and quality of life in this group of LGG patients Purpose The treatment of low- grade glioma is still debated . Surgery is the first-line approach , and the correct timing of radiation therapy has not yet been defined since “ early ” radiation therapy improves relapse-free survival but not overall survival . Since a longer progression-free survival is desirable , the main issue related to radiotherapy is the incidence of late neurocognitive toxicity . Material s and methods Ninety-five patients with low- grade glioma were consecutively treated with early ( within 3 months ) or late ( at disease progression ) post-surgical radiation therapy . Clinical and therapeutic factors were entered into the analysis overall ( OS ) and progression-free ( PFS ) survival , and the distribution in two accrual periods identified based on the evolution of imaging procedures and radiotherapy techniques were compared . For 6/18 long survivors ( LS ) without evidence of disease , neurocognitive evaluation was obtained and the dose to the hippocampus region was retrospectively calculated . Results Univariate analysis of OS showed a statistically significant advantage for grade 1 and oligodendroglioma histology , better performance status [ Karnofsky index ( KI ) ] , age < 40 years , radical surgery , no steroid treatment ; PFS was significantly related with younger age , better KI and “ early ” radiotherapy . Multivariate analysis of OS confirmed the significance of all variables except surgery ; for PFS , only “ early ” radiotherapy and better KI retained significance . Memory impairment was evident in 4/6 of the LS tested ; quality of life was good and executive functions were normal . Conclusion Radiotherapy remains an essential component in the treatment of low- grade glioma . Prospect i ve studies are needed to evaluate the relative contributions of the disease itself and of surgery , radiation and chemotherapy to long-term neurocognitive damage PURPOSE The addition of PCV ( procarbazine , lomustine , and vincristine ) chemotherapy to radiotherapy ( RT ) for patients with WHO grade 2 glioma improves progression-free survival ( PFS ) . The effect of therapy intensification on cognitive function ( CF ) remains a concern in this population with substantial long-term survival . PATIENTS AND METHODS A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were r and omly assigned to RT ( 54 Gy ) or RT plus PCV . We observed 111 patients age < 40 years with gross total resection . CF was assessed by Mini-Mental State Examination ( MMSE ) at baseline and years 1 , 2 , 3 , and 5 . RESULTS Overall , few patients experienced significant decline in MMSE score . There were no significant differences in the proportion of patients experiencing MMSE score decline between the r and omized study arms at any time point . Both study arms experienced a significant gain in average MMSE score longitudinally over time , with no difference between arms . CONCLUSION The MMSE is a relatively insensitive tool , and subtle changes in CF may have been missed . However , the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up . Patients in both r and omly assigned arms experienced a statistically significant average MMSE score increase over time , with no difference between arms . The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low- grade glioma PURPOSE Little is known about the health-related quality of life ( HRQOL ) of patients treated for anaplastic oligodendrogliomas . The impact of combined procarbazine , CCNU ( lomustine ) , and vincristine ( PCV ) chemotherapy after radiotherapy ( RT ) compared with RT alone on HRQOL in the r and omized European Organisation for Research and Treatment of Cancer ( EORTC ) 26951 trial was studied . PATIENTS AND METHODS Adult patients with anaplastic oligodendrogliomas received RT alone or RT plus PCV chemotherapy . HRQOL was assessed with the EORTC Quality of Life Question naire C30 and Brain Cancer Module . Seven prespecified HRQOL end points were selected . We hypothesized that chemotherapy would impair HRQOL during treatment but that there would be a similar HRQOL between treatment arms once off treatment . Assessment s were performed at r and omization , at the end of RT , and then every 3 to 6 months until progression . RESULTS A total of 368 patients were r and omly assigned to one of the two arms ; overall , 58 % were male , and the median age was 49 years . Compliance with HRQOL was 78 % at baseline and dropped to 55 % to 72 % up to 2.5 years post-RT . Baseline scores demonstrated considerable impairments in HRQOL for both treatment groups . The longitudinal analysis showed a significant increase in nausea/vomiting in the RT plus PCV chemotherapy arm during and shortly after chemotherapy . Because of a difference in baseline scores for fatigue and physical functioning , the differences between treatment arms during PCV did not reach significance . The nonselected scales of appetite loss and drowsiness demonstrated significant differences between treatment arms during chemotherapy in favor of the RT arm . The long-term results showed no difference between arms . CONCLUSION The major impact of PCV on HRQOL is on nausea/vomiting , loss of appetite , and drowsiness during and shortly after treatment . There are no long-term effects of PCV chemotherapy Importance Evidence for application of stereotactic and other conformal radiotherapy techniques in treating brain tumors is largely based on data derived from dosimetric , retrospective , or small prospect i ve studies . Therefore , we conducted a r and omized clinical trial of stereotactic conformal radiotherapy ( SCRT ) compared with conventional radiotherapy ( ConvRT ) evaluating clinical ly meaningful end points . Objective To compare neurocognitive and endocrine functional outcomes and survival at 5 years in young patients with residual and /or progressive benign or low- grade brain tumors treated with SCRT and ConvRT techniques . Design , Setting , and Participants This phase 3 r and omized clinical trial enrolled 200 young patients ( ages 3 - 25 years ) with residual or progressive benign or low- grade brain tumors at a single center between April 2001 to March 2012 . Patients were r and omly allocated ( 1:1 ) to either SCRT ( n = 104 ) or ConvRT ( n = 96 ) arms . Interventions Patients were r and omly assigned to either high-precision SCRT or ConvRT to a dose of 54 Gy in 30 fractions over 6 weeks . Main Outcomes and Measures Detailed neuropsychological and neuroendocrine assessment s were performed at preradiotherapy baseline , at 6 months , and annually thereafter until 5 years on longitudinal follow-up . Change in these functional parameters was compared between the 2 arms as the primary end point and overall survival ( OS ) as the secondary end point . Results In total , 200 young patients ( median [ interquartile range ] age , 13 [ 9 - 17 ] years ; 133 males and 67 females ) were enrolled . Mean full-scale or global intelligence quotient ( IQ ) and performance IQ scores over a period of 5 years were significantly superior in patients treated with SCRT compared with those treated with ConvRT ( difference in slope = 1.48 ; P = .04 vs difference in slope = 1.64 ; P = .046 , respectively ) . Cumulative incidence of developing new neuroendocrine dysfunction at 5 years was significantly lower in patients treated with SCRT compared with ConvRT ( 31 % vs 51 % ; P = .01 ) while developing a new neuroendocrine axis dysfunction in patients with preexisting dysfunction in at least 1 axis at baseline was also significantly lower in the SCRT arm compared with the ConvRT arm ( 29 % vs 52 % ; P = .02 ) . Five-year OS in SCRT and ConvRT arms was 86 % and 91 % , respectively ( P = .54 ) . Conclusions and Relevance In young patients with residual and /or progressive benign or low- grade brain tumors requiring radiotherapy for long-term tumor control , SCRT compared with ConvRT achieves superior neurocognitive and neuroendocrine functional outcomes over 5 years without compromising survival . Trial Registration clinical trials.gov Identifier : PURPOSE Anaplastic oligodendrogliomas are more responsive to chemotherapy than high- grade astrocytomas . We investigated , in a multicenter r and omized controlled trial , whether adjuvant procarbazine , lomustine , and vincristine ( PCV ) chemotherapy improves overall survival ( OS ) in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas . PATIENTS AND METHODS The primary end point of the study was OS ; secondary end points were progression-free survival ( PFS ) and toxicity . Patients were r and omly assigned to either 59.4 Gy of radiotherapy ( RT ) in 33 fractions only or to the same RT followed by six cycles of st and ard PCV chemotherapy ( RT/PCV ) . 1p and 19q deletions were assessed with fluorescent in situ hybridization . RESULTS A total of 368 patients were included . The median follow-up time was 60 months , and 59 % of patients have died . In the RT arm , 82 % of patients with tumor progression received chemotherapy . In 38 % of patients in the RT/PCV arm , adjuvant PCV was discontinued for toxicity . OS time after RT/PCV was 40.3 months compared with 30.6 months after RT only ( P = .23 ) . RT/PCV increased PFS time compared with RT only ( 23 v 13.2 months , respectively ; P = .0018 ) . Twenty-five percent of patients were diagnosed with combined 1p/19q loss ; 74 % of this subgroup was still alive after 60 months . RT/PCV did not improve survival in the subgroup of patients with 1p/19q loss . CONCLUSION Adjuvant PCV chemotherapy does not prolong OS but does increase PFS in anaplastic oligodendroglioma . Combined loss of 1p/19q identifies a favorable subgroup of oligodendroglial tumors . No genetic subgroup could be identified that benefited with respect to OS from adjuvant PCV In a pilot study , two groups of patients with malignant glioma underwent sequential neuropsychological evaluations after successful tumor treatment . Group 1 included nine patients treated from 1981 to 1985 ; all patients received irradiation and eight underwent chemotherapy . The baseline neuropsychological assessment was performed 1 to 63 months after tumor diagnosis , with follow-up evaluations at irregular intervals over the next 3 to 7 years . Six patients in Group 1 exhibited impairment on most measures at baseline ; subsequently , two patients developed profound cognitive impairment . Initially , three patients functioned in the average range on most tasks ; thereafter , two deteriorated on one measure each . Group 2 was ascertained prospect ively and included 16 patients treated from 1985 to 1987 , all of whom received irradiation and chemotherapy . The first evaluation was performed 18 months after diagnosis , then every 6 months for 2 years , and then yearly . Compared to a control group , those in Group 2 had significant cognitive impairment at baseline . Cognitive performance did not change over the next 12 months in 10 patients who remained free of tumor , but within 2 years of baseline testing , deterioration on specific tasks was evident in two of seven disease-free survivors . When last tested , five of six disease-free survivors had deteriorated on one or more measures . Unlike Group 1 , severe global cognitive impairment was not seen , perhaps because Group 2 was followed for a shorter time . Verbal and nonverbal composite scores derived from intelligence quotient ( IQ ) tests showed less impairment at baseline than did other measures and were more likely to remain stable subsequently . Verbal memory and sustained attention were the most impaired at baseline , and verbal learning and flexibility in thinking showed the greatest tendency to decline over time . Cognitive functioning in survivors of high- grade glioma is best measured and monitored by tests that probe a broader spectrum of abilities than IQ . Neuropsychological measures used in this analysis lacked sensitivity at the lower end of the impaired range . Future studies should use tests better able to discern cognitive differences at low performance levels . Based on this experience , the authors conclude that most long-term survivors of high- grade glioma will have significant cognitive difficulties , usually evident by the first assessment ; some patients will develop profound impairment years later , and few are capable of fully independent living PURPOSE Anaplastic oligodendroglioma ( AO ) and anaplastic oligoastrocytoma ( AOA ) are treated with surgery and radiotherapy ( RT ) at diagnosis , but they also respond to procarbazine , lomustine , and vincristine ( PCV ) , raising the possibility that early chemotherapy will improve survival . Furthermore , better outcomes in AO have been associated with 1p and 19q allelic loss . PATIENTS AND METHODS Patients with AO and AOA were r and omly assigned to PCV chemotherapy followed by RT versus postoperative RT alone . The primary end point was overall survival . The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization . RESULTS Two hundred eighty-nine eligible patients were r and omly assigned to either PCV plus RT ( n = 147 ) or RT alone ( n = 142 ) . At progression , 80 % of patients r and omly assigned to RT had chemotherapy . With 3-year follow-up on most patients , the median survival times were similar ( 4.9 years after PCV plus RT v 4.7 years after RT alone ; hazard ratio [ HR ] = 0.90 ; 95 % CI , 0.66 to 1.24 ; P = .26 ) . Progression-free survival time favored PCV plus RT ( 2.6 years v 1.7 years for RT alone ; HR = 0.69 ; 95 % CI , 0.52 to 0.91 ; P = .004 ) , but 65 % of patients experienced grade 3 or 4 toxicity , and one patient died . Patients with tumors lacking 1p and 19q ( 46 % ) compared with tumors not lacking 1p and 19q had longer median survival times ( > 7 v 2.8 years , respectively ; P < or = .001 ) ; longer progression-free survival was most apparent in this subset . CONCLUSION For patients with AO and AOA , PCV plus RT does not prolong survival . Longer progression-free survival after PCV plus RT is associated with significant toxicity . Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both BACKGROUND Glioblastoma , the most common primary brain tumor in adults , is usually rapidly fatal . The current st and ard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible , followed by adjuvant radiotherapy . In this trial we compared radiotherapy alone with radiotherapy plus temozolomide , given concomitantly with and after radiotherapy , in terms of efficacy and safety . METHODS Patients with newly diagnosed , histologically confirmed glioblastoma were r and omly assigned to receive radiotherapy alone ( fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks , for a total of 60 Gy ) or radiotherapy plus continuous daily temozolomide ( 75 mg per square meter of body-surface area per day , 7 days per week from the first to the last day of radiotherapy ) , followed by six cycles of adjuvant temozolomide ( 150 to 200 mg per square meter for 5 days during each 28-day cycle ) . The primary end point was overall survival . RESULTS A total of 573 patients from 85 centers underwent r and omization . The median age was 56 years , and 84 percent of patients had undergone debulking surgery . At a median follow-up of 28 months , the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone . The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 ( 95 percent confidence interval , 0.52 to 0.75 ; P<0.001 by the log-rank test ) . The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone . Concomitant treatment with radiotherapy plus temozolomide result ed in grade 3 or 4 hematologic toxic effects in 7 percent of patients . CONCLUSIONS The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma result ed in a clinical ly meaningful and statistically significant survival benefit with minimal additional toxicity PURPOSE To assess the neurocognitive effects of cranial radiotherapy on patients with low- grade gliomas , we analyzed cognitive performance data collected in a prospect i ve , intergroup clinical trial . METHODS Patients included 203 adults with supratentorial low- grade gliomas r and omly assigned to a lower dose ( 50.4 Gy in 28 fractions ) or a higher dose ( 64.8 Gy in 36 fractions ) of localized radiotherapy . Folstein Mini-Mental State Examination ( MMSE ) scores and neurologic function scores ( NFS ) at baseline and key evaluations were analyzed . Median follow-up was 7.4 years in 101 patients still alive . A change of more than three MMSE points was considered clinical ly significant . RESULTS In patients without tumor progression , significant deterioration from baseline occurred at years 1 , 2 , and 5 in 8.2 % , 4.6 % , and 5.3 % of patients , respectively . Most patients with an abnormal baseline MMSE score ( < 27 ) experienced significant increases . Baseline variables such as radiation dose , conformal versus conventional radiotherapy , number of radiation fields , age , sex , tumor size , NFS , seizures , and seizure medications did not predict cognitive function changes . CONCLUSION In this population , most low- grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE . Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy . Only a small percentage of patients had cognitive deterioration after radiotherapy . However , more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE PURPOSE A prior Radiation Therapy Oncology Group ( RTOG ) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine , lomustine , and vincristine ( PCV ) chemotherapy in addition to radiation therapy ( RT ) , as have smaller trials in low- grade glioma ( LGG ) . PATIENTS AND METHODS Eligibility criteria included supratentorial WHO grade 2 LGG , age 18 to 39 years with subtotal resection/biopsy , or age ≥ 40 years with any extent resection . Patients were r and omly assigned to RT alone or RT followed by six cycles of PCV . Survival was compared by using the modified Wilcoxon and log-rank tests . RESULTS In all , 251 patients were accrued from 1998 to 2002 . Median overall survival ( OS ) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63 % versus 72 % , respectively ( hazard ratio [ HR ] ; 0.72 ; 95 % CI , 0.47 to 1.10 ; P = .33 ; log-rank P = .13 ) . Median progression-free survival ( PFS ) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46 % versus 63 % , respectively ( HR , 0.6 ; 95 % CI , 0.41 to 0.86 ; P = .06 ; log-rank P = .005 ) . OS and PFS were similar for all patients between years 0 and 2 . After 2 years , OS and PFS curves separated significantly , favoring RT + PCV . For 2-year survivors ( n = 211 ) , the probability of OS for an additional 5 years was 74 % with RT + PCV versus 59 % with RT alone ( HR , 0.52 ; 95 % CI , 0.30 to 0.90 ; log-rank P = .02 ) . CONCLUSION PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone . On post hoc analysis , for 2-year survivors , the addition of PCV to RT conferred a survival advantage , suggesting a delayed benefit for chemotherapy PURPOSE The effect of radiotherapy on the long-term cognitive performance of patients treated for intracranial neoplasm is a major concern to clinicians and patients , particularly as long-term survival or cure is possible for a small minority of patients . To assess the effects of cranial radiotherapy and chemotherapy on the cognitive performance of high- grade glioma patients , we analyzed cognitive performance data collected in a series of prospect i ve clinical trials . METHODS We studied 701 high- grade brain tumor patients entered onto two consecutive North Central Cancer Treatment Group ( NCCTG ) r and omized treatment trials design ed to compare radiotherapy and carmustine ( BCNU ) versus radiotherapy and 1-(2-chloroethyl)-3(2,6 dioxo-l-piperidyl)-1-nitro source a ( PCNU ) ( first trial ) and radiotherapy and BCNU and interferon alfa ( IFN ) versus radiotherapy and BCNU ( second trial ) . Folstein Mini-Mental Status Exam ( MMSE ) score and Eastern Cooperative Oncology Group ( ECOG ) performance score ( PS ) recorded at baseline and 6 , 12 , 18 , and 24 months were analyzed to assess cognitive and physical function over time . Patients who did not demonstrate tumor progression within 60 days of the assessment time were considered nonprogressors at that evaluation . A loss of greater than 3 points on the MMSE was considered significant deterioration . RESULTS The number of patients who experienced a greater than 3-point decrease in MMSE from baseline was 13 of 119 nonprogressors ( 10.9 % ; 95 % confidence interval [ CI ] , 6.3 % to 18.9 % ) at 6 months , three of 54 nonprogressors ( 5.5 % ; 95 % CI , 0.5 % to 12.8 % ) at 12 months , three of 30 nonprogressors ( 10 % ; 95 % CI , 2.1 % to 26.5 % ) at 18 months , and four of 22 nonprogressors ( 18.2 % ; 95 % CI , 5.2 % to 40.3 % ) at 24 months . The CIs at all times overlapped , which indicates no statistically significant increase in the percentage of patients who experienced a significant decrease in their MMSE score . Patients who demonstrated a significant decrease in their MMSE score were significantly older than those who did not ( P = .0017 ) at 6 months and remained so throughout follow-up ; moreover , they had a significantly shorter time to progression and death . ECOG PS was strongly negatively correlated with MMSE score throughout the study , and MMSE score at all time intervals was correlated with baseline PS . CONCLUSION In this population of glioma patients who received radiotherapy , there is no clear trend to cognitive worsening . Factors such as older age , poorer PS , and sub clinical tumor progression may be more significant factors in those patients who did demonstrate a significant cognitive decline Objective : In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline , dose volume histogram ( DVH ) analyses of specific brain regions of interest ( ROI ) are correlated to neurocognitive performance in 57 primary brain tumor survivors . Methods : Neurocognitive assessment at baseline included Trail Making Tests A/B , a modified Rey-Osterreith Complex Figure , California or Hopkins Verbal Learning Test , Digit Span , and Controlled Oral Word Association . DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition . The % v10 ( percent of ROI receiving 10 Gy ) , % v40 , and % v60 were calculated for each ROI . Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests . Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI . Results : Regions that predicted global cognitive outcomes at doses < 60 Gy included the corpus callosum , left frontal white matter , right temporal lobe , bilateral hippocampi , subventricular zone , and cerebellum . Regions of adult neurogenesis primarily predicted cognition at % v40 except for the right hippocampus which predicted at % v10 . Regions that did not predict global cognitive outcomes at any dose include total brain volume , frontal pole , anterior cingulate , right frontal white matter , and the right pre central gyrus . Conclusions : Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible . A prospect i ve trial is necessary to vali date these data PURPOSE Anaplastic oligodendrogliomas , pure ( AO ) and mixed ( anaplastic oligoastrocytoma [ AOA ] ) , are chemosensitive , especially if codeleted for 1p/19q , but whether patients live longer after chemoradiotherapy is unknown . PATIENTS AND METHODS Eligible patients with AO/AOA were r and omly assigned to procarbazine , lomustine , and vincristine ( PCV ) plus radiotherapy ( RT ) versus RT alone . The primary end point was overall survival ( OS ) . RESULTS Two hundred ninety-one eligible patients were r and omly assigned : 148 to PCV plus RT and 143 to RT . For the entire cohort , there was no difference in median survival by treatment ( 4.6 years for PCV plus RT v 4.7 years for RT ; hazard ratio [ HR ] = 0.79 ; 95 % CI , 0.60 to 1.04 ; P = .1 ) . Patients with codeleted tumors lived longer than those with noncodeleted tumors ( PCV plus RT : 14.7 v 2.6 years , HR = 0.36 , 95 % CI , 0.23 to 0.57 , P < .001 ; RT : 7.3 v 2.7 years , HR = 0.40 , 95 % CI , 0.27 to 0.60 , P < .001 ) , and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT ( 14.7 v 7.3 years ; HR = 0.59 ; 95 % CI , 0.37 to 0.95 ; P = .03 ) . For those with noncodeleted tumors , there was no difference in median survival by treatment arm ( 2.6 v 2.7 years ; HR = 0.85 ; 95 % CI , 0.58 to 1.23 ; P = .39 ) . In Cox models that included codeletion status , the adjusted OS for all patients was prolonged by PCV plus RT ( HR = 0.67 ; 95 % CI , 0.50 to 0.91 ; P = .01 ) . CONCLUSION For the subset of patients with 1p/19q codeleted AO/AOA , PCV plus RT may be an especially effective treatment , although this observation was derived from an unplanned analysis BACKGROUND Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death . Early results of this trial showed that treatment with procarbazine , lomustine ( also called CCNU ) , and vincristine after radiation therapy at the time of initial diagnosis result ed in longer progression-free survival , but not overall survival , than radiation therapy alone . We now report the long-term results . METHODS We included patients with grade 2 astrocytoma , oligoastrocytoma , or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor . Patients were stratified according to age , histologic findings , Karnofsky performance-status score , and presence or absence of contrast enhancement on preoperative images . Patients were r and omly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy . RESULTS A total of 251 eligible patients were enrolled from 1998 through 2002 . The median follow-up was 11.9 years ; 55 % of the patients died . Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone ( 13.3 vs. 7.8 years ; hazard ratio for death , 0.59 ; P=0.003 ) . The rate of progression-free survival at 10 years was 51 % in the group that received radiation therapy plus chemotherapy versus 21 % in the group that received radiation therapy alone ; the corresponding rates of overall survival at 10 years were 60 % and 40 % . A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival . CONCLUSIONS In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older , progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00003375 . ) Abstract Introduction : A pilot study of temozolomide ( TMZ ) given before radiotherapy ( RT ) for anaplastic astrocytoma ( AA ) and glioblastoma ( GBM ) result ed in prolonged survival compared to historical controls receiving RT alone . We therefore investigated neoadjuvant TMZ ( NeoTMZ ) in a r and omized trial . During enrollment , concomitant and adjuvant radio-chemotherapy with TMZ became st and ard treatment . The trial was amended to include concurrent TMZ . Patients and methods : Patients , after surgery for GBM or AA , age ≤60 years and performance status ( PS ) 0–2 , were r and omized to either 2–3 cycles of TMZ , 200 mg/m2 days 1–5 every 28 days , followed by RT 60 Gy in 30 fractions or RT only . Patients without progressive disease after two TMZ cycles , received the third cycle . From March 2005 , TMZ 75 mg/m2 was administered daily concomitant with RT . TMZ was recommended first-line treatment at progression . Primary endpoint was overall survival and secondary safety . Results : The study closed prematurely after enrolling 144 patients , 103 with GBM and 41 with AA . Median age was 53 years ( range 24–60 ) and 89 ( 62 % ) were male . PS was 0–1 for 133 ( 92 % ) patients , 53 ( 37 % ) had complete surgical resection and 18 ( 12 % ) biopsy . Ninety-two ( 64 % ) received TMZ concomitant with RT . Seventy-two ( 50 % ) were r and omized to neoadjuvant treatment . For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ ( p = .76 ) , this not reaching the primary objective . For the preplanned subgroup analysis , we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT ( p = .022 ) . For patients with GBM , no difference in survival was observed ( p = .10 ) . MGMT and IDH status affected outcome . Conclusions : No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM , while NeoTMZ result ed in 5 years longer median survival for patients diagnosed as AA BACKGROUND The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas , which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours , is unclear . We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas . METHODS This was a phase 3 , r and omised , open-label study with a 2 × 2 factorial design . Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0 - 2 . The r and omisation schedule was generated with the electronic EORTC web-based ORTA system . Patients were assigned in equal numbers ( 1:1:1:1 ) , using the minimisation technique , to receive radiotherapy ( 59·4 Gy in 33 fractions of 1·8 Gy ) alone or with adjuvant temozolomide ( 12 4-week cycles of 150 - 200 mg/m2 temozolomide given on days 1 - 5 ) ; or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day , with or without adjuvant temozolomide . The primary endpoint was overall survival adjusted for performance status score , age , 1p loss of heterozygosity , presence of oligodendroglial elements , and MGMT promoter methylation status , analysed by intention to treat . We did a planned interim analysis after 219 ( 41 % ) deaths had occurred to test the null hypothesis of no efficacy ( threshold for rejection p<0·0084 ) . This trial is registered with Clinical Trials.gov , number NCT00626990 . FINDINGS At the time of the interim analysis , 745 ( 99 % ) of the planned 748 patients had been enrolled . The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 ( 99·145 % CI 0·45 - 0·93 ) . Overall survival at 5 years was 55·9 % ( 95 % CI 47·2 - 63·8 ) with and 44·1 % ( 36·3 - 51·6 ) without adjuvant temozolomide . Grade 3 - 4 adverse events were seen in 8 - 12 % of 549 patients assigned temozolomide , and were mainly haematological and reversible . INTERPRETATION Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma . Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed . FUNDING Schering Plough and MSD

PARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease . Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC . More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease

BACKGROUND Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide . Three-quarters of women present when the disease has spread throughout the abdomen ( stage III or IV ) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy . Although initial responses to chemotherapy are good , most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy . PARP ( poly ( ADP-ribose ) polymerase ) inhibitors , are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents . It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer , with respect to survival , side effects and quality of life . OBJECTIVES To determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer ( EOC ) .

BACKGROUND Olaparib is a poly(ADP-ribose ) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor ( VEGFR ) 1 , VEGFR2 , and VEGFR3 . Both oral agents have antitumour activity in women with recurrent ovarian cancer , and their combination was active and had manageable toxicities in a phase 1 trial . We investigated whether this combination could improve progression-free survival ( PFS ) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer . METHODS In our r and omised , open-label , phase 2 study , we recruited women ( aged ≥18 years ) who had measurable platinum-sensitive , relapsed , high- grade serous or endometrioid ovarian , fallopian tube , or primary peritoneal cancer , or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres . We r and omly allocated participants ( 1:1 ) according to permuted blocks , stratified by germline BRCA status and previous anti-angiogenic therapy , to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily . The primary endpoint was progression-free survival analysed in the intention-to-treat population . The phase 2 trial is no longer accruing patients . An interim analysis was conducted in November , 2013 , after 50 % of expected events had occurred and efficacy results were unmasked . The primary analysis was performed on March 31 , 2014 , after 47 events ( 66 % of those expected ) . The trial is registered with Clinical Trials.gov , number NCT01116648 . FINDINGS Between Oct 26 , 2011 , and June 3 , 2013 , we r and omly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib . Median PFS was 17·7 months ( 95 % CI 14·7-not reached ) for the women treated with cediranib plus olaparib compared with 9·0 months ( 95 % CI 5·7 - 16·5 ) for those treated with olaparib monotherapy ( hazard ratio 0·42 , 95 % CI 0·23 - 0·76 ; p=0·005 ) . Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy , including fatigue ( 12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group ) , diarrhoea ( ten vs none ) , and hypertension ( 18 vs none ) . INTERPRETATION Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high- grade serous or endometrioid ovarian cancer , and warrants study in a phase 3 trial . The side-effect profile suggests such investigations should include assessment s of quality of life and patient-reported outcomes to underst and the effects of a continuing oral regimen with that of intermittent chemotherapy . FUNDING American Recovery and Reinvestment Act grant from the National Institutes of Health ( NIH ) ( 3 U01 CA062490 - 16S2 ) ; Intramural Program of the Center for Cancer Research ; and the Division of Cancer Treatment and Diagnosis , National Cancer Institute , NIH BACKGROUND Olaparib ( AZD2281 ) is an oral poly(adenosine diphosphate [ADP]-ribose ) polymerase inhibitor that has shown antitumor activity in patients with high- grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations . METHODS We conducted a r and omized , double-blind , placebo-controlled , phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive , relapsed , high- grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen . Patients were r and omly assigned to receive olaparib , at a dose of 400 mg twice daily , or placebo . The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines . RESULTS Of 265 patients who underwent r and omization , 136 were assigned to the olaparib group and 129 to the placebo group . Progression-free survival was significantly longer with olaparib than with placebo ( median , 8.4 months vs. 4.8 months from r and omization on completion of chemotherapy ; hazard ratio for progression or death , 0.35 ; 95 % confidence interval [ CI ] , 0.25 to 0.49 ; P<0.001 ) . Subgroup analyses of progression-free survival showed that , regardless of subgroup , patients in the olaparib group had a lower risk of progression . Adverse events more commonly reported in the olaparib group than in the placebo group ( by more than 10 % of patients ) were nausea ( 68 % vs. 35 % ) , fatigue ( 49 % vs. 38 % ) , vomiting ( 32 % vs. 14 % ) , and anemia ( 17 % vs. 5 % ) ; the majority of adverse events were grade 1 or 2 . An interim analysis of overall survival ( 38 % maturity , meaning that 38 % of the patients had died ) showed no significant difference between groups ( hazard ratio with olaparib , 0.94 ; 95 % CI , 0.63 to 1.39 ; P=0.75 ) . CONCLUSIONS Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive , relapsed , high- grade serous ovarian cancer . Interim analysis showed no overall survival benefit . The toxicity profile of olaparib in this population was consistent with that in previous studies . ( Funded by AstraZeneca ; Clinical Trials.gov number , NCT00753545 . ) BACKGROUND The inhibition of poly(adenosine diphosphate [ADP]-ribose ) polymerase ( PARP ) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects , including those arising in carriers of a BRCA1 or BRCA2 mutation . We conducted a clinical evaluation in humans of olaparib ( AZD2281 ) , a novel , potent , orally active PARP inhibitor . METHODS This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib . Selection was aim ed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation . RESULTS We enrolled and treated 60 patients ; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing . The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously . Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily ( grade 3 mood alteration and fatigue ) and two of five patients receiving 600 mg twice daily ( grade 4 thrombocytopenia and grade 3 somnolence ) . This led us to enroll another cohort , consisting only of carriers of a BRCA1 or BRCA2 mutation , to receive olaparib at a dose of 200 mg twice daily . Other adverse effects included mild gastrointestinal symptoms . There was no obvious increase in adverse effects seen in the mutation carriers . Pharmacokinetic data indicated rapid absorption and elimination ; pharmacodynamic studies confirmed PARP inhibition in surrogate sample s ( of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles ) and tumor tissue . Objective antitumor activity was reported only in mutation carriers , all of whom had ovarian , breast , or prostate cancer and had received multiple treatment regimens . CONCLUSIONS Olaparib has few of the adverse effects of conventional chemotherapy , inhibits PARP , and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation . ( Clinical Trials.gov number , NCT00516373 . Purpose : Veliparib , a PARP inhibitor , demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial . To define the relative contribution of PARP inhibition to the observed clinical activity , we conducted a r and omized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal , fallopian tube , or high- grade serous ovarian cancers ( HGSOC ) . Experimental Design : Adult patients were r and omized to receive cyclophosphamide alone ( 50 mg orally once daily ) or with veliparib ( 60 mg orally once daily ) in 21-day cycles . Crossover to the combination was allowed at disease progression . Results : Seventy-five patients were enrolled and 72 were evaluable for response ; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen . Treatment was well tolerated . One complete response was observed in each arm , with three partial responses ( PR ) in the combination arm and six PRs in the cyclophosphamide alone arm . Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair ; none of the detected genetic alterations were significantly associated with treatment benefit . Conclusion : This is the first trial that evaluated single-agent , low-dose cyclophosphamide in HGSOC , peritoneal , fallopian tube , and BRCA-mutant ovarian cancers . It was well tolerated and clinical activity was observed ; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival . Clin Cancer Res ; 21(7 ) ; 1574–82 . © 2015 AACR 5003 Background : Olaparib ( AZD2281 ) is an oral PARP inhibitor that has shown antitumor activity in patients ( pts ) with high- grade serous ovarian cancer ( SOC ) with and without BRCA1 or BRCA2 mutations . This r and omized , double-blind , multicenter , placebo-controlled Phase II study evaluated maintenance treatment with olaparib in pts with high- grade PSR SOC ( clinical trials.gov ; NCT00753545 ) . METHODS Pts with PSR SOC who had received ≥2 previous platinum regimens and were in a maintained partial or complete response following their last platinum-containing regimen were r and omized to oral olaparib 400 mg bid or placebo . The primary endpoint was progression-free survival ( PFS ) by RECIST . Secondary endpoints included time to progression ( TTP ) by CA-125 ( GCIG criteria ) or RECIST , overall survival ( OS ) and safety . RESULTS 265 pts were r and omized ( 136 to olaparib and 129 to placebo ) . Demographics and baseline characteristics were generally well balanced . At data cut-off there were 153 ( 58 % ) progression events . PFS by RECIST was significantly longer in the olaparib than the placebo group ( HR , 0.35 ; 95 % CI 0.25 - 0.49 ; P<0.00001 ; median 8.4 vs 4.8 months ) . TTP by CA-125 or RECIST was also significantly longer in the olaparib than the placebo group ( HR , 0.35 ; 95 % CI 0.25 - 0.47 ; P<0.00001 ; median 8.3 vs 3.7 months ) . At data cut-off OS data were too immature for analysis . 68 ( 50 % ) and 21 ( 16 % ) remain on olaparib or placebo , respectively . AEs more commonly reported on olaparib than placebo ( by > 10 % ) were nausea ( 68 % vs 35 % ) , fatigue ( 49 % vs 38 % ) , vomiting ( 32 % vs 14 % ) and anemia ( 17 % vs 5 % ) ; the majority of AEs were CTCAE grade 1 or 2 . The most frequently reported CTCAE grade ≥3 events were fatigue ( 9 pts ) and anemia ( 7 pts ) for olaparib , and abdominal pain and fatigue ( 4 pts each ) for placebo . 3 ( 2.2 % ) pts on olaparib and 1 ( 0.8 % ) on placebo had AEs that led to treatment discontinuation . 31 pts ( 23 % ) in the olaparib group and 9 ( 7 % ) in the placebo group had both dose reductions and interruptions . CONCLUSIONS In pts with PSR SOC , maintenance treatment with olaparib 400 mg bid provided a significant improvement in PFS . Olaparib was well tolerated , and toxicities were consistent with previous studies ABSTRACT Aim : PARP inhibitors ( PARPi ) such as oral rucaparib are thought to be effective in cancers with homologous recombination deficiency ( HRD ) , best shown to date in patients ( pts ) with a germline BRCA1/2 mutation ( gBRCAmut ) . The Cancer Genome Atlas ( TCGA ) estimated ∼50 % of pts with high- grade serous ovarian carcinoma ( OC ) have HRD tumors . Multiple mechanisms can lead to HRD , which in turn can lead to genomic loss of heterozygosity ( LOH ) . Currently , the best molecular predictors of PARPi response ( other than BRCA mutation ) are not known and platinum-sensitivity , a surrogate predictive indicator for PARPi response , is inadequate . Molecular analysis of tumor tissue to assess BRCA mutations as well as genomic LOH , a phenotypic endpoint of HRD , could be a more inclusive method for selection of pts for PARPi therapy . Methods : The primary objective of Phase 2 study ARIEL2 is to identify a molecular HRD signature associated with clinical benefit from rucaparib treatment . This signature will be prospect ively applied to the final analysis of the “ all-comer ” Phase 3 r and omized pivotal trial ( ARIEL3 ) . ARIEL2 is an ongoing single-arm , open-label biomarker study design ed to refine the molecular HRD signature associated with rucaparib response . Eligible pts ( n = 180 ) have relapsed , platinum-sensitive , high- grade OC and measurable disease . Tumor HRD status is assessed using Foundation Medicine 's next generation sequencing platform with the current HRD algorithm , based on BRCA status and genomic LOH , developed using in vitro/in vivo and TCGA ( and similar ) bioinformatic data . PFS and response by RECIST will be correlated with tumor HRD status . Enrollment of gBRCAmut pts is limited to maximize non-gBRCAmut response predictors . Results : Preliminary efficacy data from ARIEL2 indicate RECIST responses in patients who are BRCA wild-type and have high tumor genomic LOH as well as in BRCAmut pts . Data for approximately 75 pts is anticipated to be available in late September . Conclusions : Preliminary data indicate tumor genomic LOH as well as BRCA mutation analysis may predict OC pts likely to respond to rucaparib . Disclosure : I. McNeish : Interactions with Clovis relevant to rucaparib . Advisory Boards for AZ and Roche within the past 2 years also ; R. Coleman : Membership on Clovis advisory board and clinical trial funding from Sponsor ( Clovis ) ; A.M. Oza : Clinical Trial Funding from Sponsor ( Clovis ) to Princess Margaret Cancer Centre ; D. O'Malley : Clinical trial support from Sponsor ( Clovis ) Participated in an advisory board for Sponsor ( Clovis ) ; C. Scott : Corporate-Sponsored Research : Provision of drug and in-kind molecular analyses by Clovis Oncology of laboratory research not associated with these clinical trials Other Substantive Relationships : Clinical trial support for ARIEL2/3 at my site ; A. Oaknin and A. Floquet : Clinical Trial support from Sponsor ( Clovis ) ; J. Brenton : Travel funding from Clovis Oncology for clinical trials meetings ; K. Lin , S. Shetty , H. Giordano , M. Raponi and L. Rolfe : Clovis Employment and Stock Ownership . All other authors have declared no conflicts of interest ABSTRACT Background : Niraparib is an oral PARP-1/2 inhibitor with efficacy in both germline BRCA mutated ( gBRCA ) ovarian cancer ( OvCa ) and high grade serous OvCa ( HGSC ) patients ( pts ) who are non-gBRCA . Phase I data established a RP2D of 300 mg . At the recommended dose , 75 % platinum sensitive patients achieved RECIST response in phase 1 . Trial design : ENGOT-OV16/NOVA study ( n = 360 ) is a double-blind , 2:1 r and omized , placebo controlled phase III study of oral niraparib versus placebo in pts with platinum ( plat ) sensitive recurrent OvCa . Primary objective is to evaluate efficacy of niraparib as maintenance therapy assessed by the prolongation of progression free survival ( PFS ) . PFS will be independently evaluated in a cohort of gBRCA pts and in HGSC pts who are non-gBRCA . Secondary objectives : overall survival in each cohort ; bridge the central ized BRCA mutation test method to the c and i date companion diagnostic test ; patient-reported outcomes ; PFS2 ; chemotherapy free interval ; safety/tolerability ; QTc in a subset of niraparib-treated pts . Study eligibility includes : histologically confirmed OvCa , HGSC histology or known gBRCA , plat sensitive recurrence , at least 2 prior courses of plat-containing therapy with no/minimal radiological residual disease , and normal CA125 or decrease by 90 % after last plat , PS 0 - 1 , and normal organ function . The study is powered to assess PFS and OS in both cohorts ( gBRCA & non-gBRCA ) . The trial is being conducted in 126 sites in collaboration with European Network of Gynaecological Oncological Trials Groups ( NSGO Denmark-Norway-Sweden , AGO Austria , AGO Germany , BGOG Belgium , ISGO Israel , GEICO Spain , GINECO France , MaNGO Italy , MITO Italy , NCRI UK ) , US , Canada , Hungary & Pol and . The pt . enrolment is according to the timelines . Clinical Trials.gov Identifier : NCT01847274 Disclosure : S. Agarwal : Medical Officer , Tesaro Bio Inc. ( sponsor of the trial ) ; R.E. Martell : Chief Medical Officer , Tesaro Bio Inc. ( Sponsor of the trial ) . All other authors have declared no conflicts of interest BACKGROUND The poly(ADP-ribose ) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive , recurrent , high- grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations . The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy , followed by olaparib maintenance monotherapy , versus chemotherapy alone in patients with platinum-sensitive , recurrent , high- grade serous ovarian cancer . METHODS In this r and omised , open-label , phase 2 study , adult patients with platinum-sensitive , recurrent , high- grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before r and omisation received either olaparib ( 200 mg capsules twice daily , administered orally on days 1 - 10 of each 21-day cycle ) plus paclitaxel ( 175 mg/m(2 ) , administered intravenously on day 1 ) and carboplatin ( area under the curve [ AUC ] 4 mg/mL per min , according to the Calvert formula , administered intravenously on day 1 ) , then olaparib monotherapy ( 400 mg capsules twice daily , given continuously ) until progression ( the olaparib plus chemotherapy group ) , or paclitaxel ( 175 mg/m(2 ) on day 1 ) and carboplatin ( AUC 6 mg/mL per min on day 1 ) then no further treatment ( the chemotherapy alone group ) . R and omisation was done by an interactive voice response system , stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen . The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 , analysed by intention to treat . Prespecified exploratory analyses included efficacy by BRCA mutation status , assessed retrospectively . This study is registered with Clinical Trials.gov , number NCT01081951 , and has been completed . FINDINGS Between Feb 12 and July 30 , 2010 , 173 patients at 43 investigational sites in 12 countries were enrolled into the study , of whom 162 were eligible and were r and omly assigned to the two treatment groups ( 81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group ) . Of these r and omised patients , 156 were treated in the combination phase ( 81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group ) and 121 continued to the maintenance or no further treatment phase ( 66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group ) . BRCA mutation status was known for 107 patients ( either at baseline or determined retrospectively ) : 41 ( 38 % ) of 107 had a BRCA mutation ( 20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group ) . Progression-free survival was significantly longer in the olaparib plus chemotherapy group ( median 12.2 months [ 95 % CI 9.7 - 15.0 ] ) than in the chemotherapy alone group ( median 9.6 months [ 95 % CI 9.1 - 9.7 ) ( HR 0.51 [ 95 % CI 0.34 - 0.77 ] ; p=0.0012 ) , especially in patients with BRCA mutations ( HR 0.21 [ 0.08 - 0.55 ] ; p=0.0015 ) . In the combination phase , adverse events that were reported at least 10 % more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia ( 60 [ 74 % ] of 81 vs 44 [ 59 % ] of 75 ) , nausea ( 56 [ 69 % ] vs 43 [ 57 % ] ) , neutropenia ( 40 [ 49 % ] vs 29 [ 39 % ] ) , diarrhoea ( 34 [ 42 % ] vs 20 [ 27 % ] ) , headache ( 27 [ 33 % ] vs seven [ 9 % ] ) , peripheral neuropathy ( 25 [ 31 % ] vs 14 [ 19 % ] ) , and dyspepsia ( 21 [ 26 % ] vs 9 [ 12 % ] ) ; most were of mild-to-moderate intensity . The most common grade 3 or higher adverse events during the combination phase were neutropenia ( in 35 [ 43 % ] of 81 patients in the olaparib plus chemotherapy group vs 26 [ 35 % ] of 75 in the chemotherapy alone group ) and anaemia ( seven [ 9 % ] vs five [ 7 % ] ) . Serious adverse events were reported in 12 ( 15 % ) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 ( 21 % ) patients in the chemotherapy alone group . INTERPRETATION Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone , with the greatest clinical benefit in BRCA-mutated patients , and had an acceptable and manageable tolerability profile . FUNDING AstraZeneca BACKGROUND Olaparib ( AZD2281 ) is a small-molecule , potent oral poly(ADP-ribose ) polymerase ( PARP ) inhibitor . We aim ed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high- grade serous and /or undifferentiated ovarian cancer . METHODS In this phase 2 , multicentre , open-label , non-r and omised study , women with advanced high- grade serous and /or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day . Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not . The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors ( RECIST ) . All patients who received treatment were included in the analysis of toxic effects , and patients who had measurable lesions at baseline were included in the primary efficacy analysis . This trial is registered at Clinical Trials.gov , number NCT00679783 . FINDINGS 91 patients were enrolled ( 65 with ovarian cancer and 26 breast cancer ) and 90 were treated between July 8 , 2008 , and Sept 24 , 2009 . In the ovarian cancer cohorts , 64 patients received treatment . 63 patients had target lesions and therefore were evaluable for objective response as per RECIST . In these patients , confirmed objective responses were seen in seven ( 41 % ; 95 % CI 22 - 64 ) of 17 patients with BRCA1 or BRCA2 mutations and 11 ( 24 % ; 14 - 38 ) of 46 without mutations . No confirmed objective responses were reported in patients with breast cancer . The most common adverse events were fatigue ( 45 [ 70 % ] of patients with ovarian cancer , 13 [ 50 % ] of patients with breast cancer ) , nausea ( 42 [ 66 % ] and 16 [ 62 % ] ) , vomiting ( 25 [ 39 % ] and nine [ 35 % ] ) , and decreased appetite ( 23 [ 36 % ] and seven [ 27 % ] ) . INTERPRETATION Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed . FUNDING AstraZeneca BACKGROUND Olaparib , a novel , orally active poly(ADP-ribose ) polymerase ( PARP ) inhibitor , induced synthetic lethality in BRCA-deficient cells . A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported . We therefore assessed the efficacy , safety , and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer . METHODS Women ( aged > or=18 years ) with confirmed BRCA1 or BRCA2 mutations and recurrent , advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia , Germany , Spain , Sweden , the UK , and the USA . The first cohort ( n=27 ) was given continuous oral olaparib at the maximum tolerated dose ( 400 mg twice daily ) , and the second ( n=27 ) was given a lower dose ( 100 mg twice daily ) . The primary efficacy endpoint was objective response rate ( ORR ) . This study is registered with Clinical Trials.gov , number NCT00494234 . FINDINGS Patients had been given a median of three previous chemotherapy regimens ( range 1 - 5 in cohort 1 , and 2 - 4 in cohort 2 ) . ORR was 11 ( 41 % ) of 27 patients ( 95 % CI 25 - 59 ) in the cohort assigned to 400 mg twice daily , and six ( 22 % ) of 27 ( 11 - 41 ) in the cohort assigned to 100 mg twice daily . Toxicities were mainly at low grade s. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue ( grade 1 or 2 , 11 [ 41 % ] ; grade 3 or 4 , four [ 15 % ] ) , nausea ( grade 1 or 2 , 11 [ 41 % ] ; grade 3 or 4 , four [ 15 % ] ) , vomiting ( grade 1 or 2 , three [ 11 % ] ; grade 3 or 4 , three [ 11 % ] ) , and anaemia ( grade 1 or 2 , one [ 4 % ] ; grade 3 or 4 , three [ 11 % ] ) . The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea ( grade 1 or 2 , 11 [ 41 % ] ; none grade 3 or 4 ) and fatigue ( grade 1 or 2 , seven [ 26 % ] ; grade 3 or 4 , one [ 4 % ] ) . INTERPRETATION The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair . Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations . FUNDING AstraZeneca PURPOSE Olaparib ( AZD2281 ) , an orally active poly ( ADP-ribose ) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells , has shown promising clinical efficacy in nonr and omized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency . We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin ( PLD ) in this patient population . PATIENTS AND METHODS In this multicenter , open-label , r and omized , phase II study , patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled . Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m(2 ) intravenously every 28 days . The primary efficacy end point was Response Evaluation Criteria in Solid Tumors ( RECIST ) -assessed progression-free survival ( PFS ) . Secondary end points included objective response rate ( ORR ) and safety . RESULTS Ninety-seven patients were r and omly assigned . Median PFS was 6.5 months ( 95 % CI , 5.5 to 10.1 months ) , 8.8 months ( 95 % CI , 5.4 to 9.2 months ) , and 7.1 months ( 95 % CI , 3.7 to 10.7 months ) for the olaparib 200 mg , olaparib 400 mg , and PLD groups , respectively . There was no statistically significant difference in PFS ( hazard ratio , 0.88 ; 95 % CI , 0.51 to 1.56 ; P = .66 ) for combined olaparib doses versus PLD . RECIST-assessed ORRs were 25 % , 31 % , and 18 % for olaparib 200 mg , olaparib 400 mg , and PLD , respectively ; differences were not statistically significant . Tolerability of both treatments was as expected based on previous trials . CONCLUSION The efficacy of olaparib was consistent with previous studies . However , the efficacy of PLD was greater than expected . Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population

The data of 14 reports disclosed enhanced antiadhesive and antibiofilm activity by the plant extracts obtained from Vitis vinifera , Pinus spp . , Overall , a positive correlation was revealed between herb-based therapies and elimination rates of all types of multispecies oral biofilms . In that context , integrating or even replacing conventional dental therapy protocol s with herbal-inspired treatments can allow effective antimicrobial control of oral biofilms and thus , dental diseases

Oral diseases such as caries and periodontitis are mainly caused by microbial biofilms . Antibiotic therapy has reached its limits with regard to antimicrobial resistance , and new therapeutic measures utilizing natural phytochemicals are currently a focus of research . Hence , this systematic review provides a critical presentation of the antimicrobial effects of various medicinal herbs against in vitro , ex vivo , and in situ formed multispecies oral biofilms .

UNLABELLED This study determined the changes of calcium concentration in a medium containing teeth/biofilm exposed to Coffea canephora extract ( CCE ) . Enamel fragments were r and omly fixed into two 24-well polystyrene plates containing BHI . Pooled human saliva was added to form biofilm on fragments . Specimens were divided into treatment groups ( G , n = 8 per group ) and treated with 50 μl daily for 1 min per week , as follows : G1 , 20 % CCE ; G2 , Milli-Q water ( negative control ) ; G3 , antibiotic ( positive control ) . Six fragments represented the blank control ( G4 ) . The calcium content was observed at baseline , 4 and 7 days of treatment by atomic-absorption spectrophotometry . Cross-sectional hardness of enamel was a demineralization indicator . Calcium increased in the medium after 4 and 7 days of treatment in G1 ( 3·80 ± 1·3 mg l(-1 ) and 4·93 ± 2·1 mg l(-1 ) , respectively ) and G3 ( 4th day = 5·7 ± 1·8 mg l(-1 ) ; 7th day = 6·7 ± 3·5 mg l(-1 ) ) ( P > 0·05 ) . Calcium from G2 decreased after 7 days , which was different from G3 ( P < 0·05 ) . The lower calcium content , at the end of the experiment , was represented by G4 , 2·16 ± 0·2 mg l(-1 ) . The increase in calcium after treatment with CCE is probably due to its antibacterial effect , which caused the bacterial lysis and consequent release of calcium in the medium . SIGNIFICANCE AND IMPACT OF THE STUDY This study revealed an inhibitory action of Coffea canephora against dental biofilm . This coffee species caused bacterial lysis and consequent release of calcium into the medium . Furthermore , the advantage of coffee as an antibacterial beverage is that it is consumed in a concentrated form ( 6 - 10 % ) as opposed to various medicinal infusions that have shown such effect in vitro and are usually consumed at 1 - 2 % . Therefore , a light roasted C. canephora aqueous extract can be considered as a potential anticariogenic substance In the present work , we studied the effect of the hydro-alcoholic extract ( HAE ) from Punica granatum ( pomegranate ) fruits on dental plaque microorganisms . The study was conducted on 60 healthy patients ( 33 females and 27 males , with age ranging from 9 to 25 years ) using fixed orthodontic appliances , and r and omly distributed into 3 groups of 20 patients each . The first group ( control ) used distilled water , while the second and third groups used chlorhexidine ( st and ard ) and HAE as mouth-rinses , respectively . The dental plaque material was collected from each patient , before and after a 1-min mouth-rinse with 15 ml of either distilled water , chlorhexidine or HAE . In both dental plaque collection s , the material was removed from patients without oral hygiene , for 24 h ( no tooth brushing ) . Dental plaque sample s were diluted in phosphate buffered saline ( PBS ) plated on Mueller-Hinton agar , and incubated for 48 h , at 37 ° C . Results , expressed as the number of colony forming units per milliliter ( CFU/mL ) , show that the HAE was very effective against dental plaque microorganisms , decreasing the CFU/ml by 84 % ( CFU X105 , before mouth-rinse : 154.0 ±41.18 ; after mouth-rinse : 25.4 ±7.76 ) . While similar values were observed with chlorhexidine , used as st and ard and positive control ( 79 % inhibition ) , only an 11 % inhibition of CFU/ml was demonstrated in the distilled water group , negative control ( CFUX 105 , before mouth-rinse : chlorhexidine , 208.7 ±58.81 and distilled water , 81.1 ±10.12 ; after mouth-rinse : chlorhexidine , 44.0 ±15.85 and distilled water , 71.9 ±8.68 ) . The HAE presented also an antibacterial activity against selected microorganisms , and may be a possible alternative for the treatment of dental plaque bacteria OBJECTIVES The present study focused on isolation , characterization and evaluation of purified compounds from Morus alba against Streptococcus mutans biofilm formation . METHODS The effect of crude extract from M. alba leaves was evaluated against oral pathogens , chiefly S. mutans . MICs were determined by the microdilution method . The compound was purified by employing silica gel chromatography and critically analysed with GC-MS , NMR and IR spectroscopy . The S. mutans traits of adherence and biofilm formation were assessed at sub-MIC concentrations of the crude extract and purified compound . Both water-soluble and alkali-soluble polysaccharide were estimated to determine the effect of the purified compound on the extracellular polysaccharide secretion of S. mutans . Its effect on biofilm architecture was also investigated with the help of confocal microscopy . RESULTS The purified compound of M. alba showed an 8-fold greater reduction of MIC against S. mutans than the crude extract ( MICs , 15.6 and 125 mg/L , respectively ) . The extract strongly inhibited biofilm formation of S. mutans at its active accumulation and plateau phases . The purified compound led to a 22 % greater reduction in alkali-soluble polysaccharide than in water-soluble polysaccharide . The purified compound was found to be 1-deoxynojirimycin ( DNJ ) . Confocal microscopy revealed that DNJ distorts the biofilm architecture of S. mutans . CONCLUSIONS The whole study reflects a prospect i ve role of DNJ as a therapeutic agent by controlling the overgrowth and biofilm formation of S. mutans This double-blind , r and omized control trial sought to evaluate the clinical effects of 3 mouthrinses against salivary mutans streptococci ( MS ) . Ninety high-caries risk volunteers were r and omly assigned to 3 groups , each group using a selected mouthrinse BID for 30 days . Subjects in Group 1 rinsed with 10 ml of 50 % Acacia nilotica , Group 2 subjects rinsed with 10 ml of 0.2 % chlorhexidine ( active control ) , and subjects in Group 3 rinsed with saline water ( passive control ) . Unstimulated saliva sample s were collected at baseline , 30 , and 60 days . MS were cultured on mitis salivarius bacitracin agar , and colony counts were obtained . The margin of error was fixed at 5 % . ANOVA and post hoc least significant difference tests were performed . There were significant decreases in the MS colony count in the A. nilotica and chlorhexidine groups at 30 days ( 85 % and 83 % , respectively ) and at 60 days ( 65 % and 63 % , respectively ) ( P < 0.0001 ) . The antibacterial action of A. nilotica against MS was similar to that of chlorhexidine Aim : To determine the anti-carious effect of coffee in humans . Coffee represents one of the most consumed products by the population . Material s and Methods : A r and om sample of 1000 individuals , of both sexes , who consumed only coffee as a beverage and who visited the Out-Patient Department of KLE Society 's Institute of Dental Sciences , with a dental complaint and no history of any major illness , were considered as subjects . The patients ' histories with regard to the coffee intake , such as , period of consumption , frequency of consumption , whether taken with milk or wihout milk , with sugar or without sugar , and the br and make , was noted . History of the type of diet , consumption of sweets , periodicity of brushing , and whether they had undergone fluoride applications were also noted . A thous and patients who consumed beverages other than coffee were taken as the control . Results : The results showed that coffee most consumed was roasted coffee , and the frequency on an average was about three cups per day , for an average period of 35 years . The Decayed/Missing/Filled Surface ( DMFS ) scores varied from 2.9 , in subjects who drank black coffee , to 5.5 in subjects who consumed coffee together with sweeteners and creaming agents . The DMFS score was 3.4 in subjects who consumed coffee together with milk but no sugar . The DMFS score of the control subjects was 4 , indicating that coffee if consumed alone had anticaries action , but in the presence of additives the antibacterial and anticaries action was totally minimized . Conclusion : Thus coffee can help in prevention of dental caries if consumed without additives

We did not find strong or consistent evidence that quasi-r and omization is associated with selection bias more often than true r and omization . High risk of bias judgements for quasi-r and omized emergency studies should therefore not be assumed in systematic review s. Clinical heterogeneity across trials within review s , coupled with limited availability of relevant trial accrual data , meant it was not possible to adequately explore the possibility that true r and omization might result in slower trial recruitment rates , or the recruitment of less representative population

BACKGROUND Quasi-r and omization might expedite recruitment into trials in emergency care setting s but may also introduce selection bias .

Objective . Birth asphyxia represents a serious problem worldwide , result ing in ∼1 million deaths and an equal number of serious sequelae annually . It is therefore important to develop new and better ways to treat asphyxia . Resuscitation after birth asphyxia traditionally has been carried out with 100 % oxygen , and most guidelines and textbooks recommend this ; however , the scientific background for this has never been established . On the contrary , theoretic considerations indicate that resuscitation with high oxygen concentrations could have detrimental effects . We have performed a series of animal studies as well as one pilot study indicating that resuscitation can be performed with room air just as efficiently as with 100 % oxygen . To test this more thoroughly , we organized a multicenter study and hypothesized that room air is superior to 100 % oxygen when asphyxiated newborn infants are resuscitated . Methodology . In a prospect i ve , international , controlled multicenter study including 11 centers from six countries , asphyxiated newborn infants with birth weight > 999 g were allocated to resuscitation with either room air or 100 % oxygen . The study was not blinded , and the patients were allocated to one of the two treatment groups according to date of birth . Those born on even date s were resuscitated with room air and those born on odd date s with 100 % oxygen . Informed consent was not obtained until after the initial resuscitation , an arrangement in agreement with the new proposal of the US Food and Drug Administration 's rules governing investigational drugs and medical devices to permit clinical research on emergency care without the consent of subjects . The protocol was approved by the ethical committees at each participating center . Entry criterion was apnea or gasping with heart rate < 80 beats per minute at birth necessitating resuscitation . Exclusion criteria were birth weight < 1000 g , lethal anomalies , hydrops , cyanotic congenital heart defects , and stillbirths . Primary outcome measures were death within 1 week and /or presence of hypoxic – ischemic encephalopathy , grade II or III , according to a modification of Sarnat and Sarnat . Secondary outcome measures were Apgar score at 5 minutes , heart rate at 90 seconds , time to first breath , time to first cry , duration of resuscitation , arterial blood gases and acid base status at 10 and 30 minutes of age , and abnormal neurologic examination at 4 weeks . The existing routines for resuscitation in each participating unit were followed , and the ventilation techniques described by the American Heart Association were used as guidelines aim ing at a frequency of manual ventilation of 40 to 60 breaths per minute . Results . Forms for 703 enrolled infants from 11 centers were received by the steering committee . All 94 patients from one of the centers were excluded because of violation of the inclusion criteria in 86 of these . Therefore , the final number of infants enrolled in the study was 609 ( from 10 centers ) , with 288 in the room air group and 321 in the oxygen group . Median ( 5 to 95 percentile ) gestational ages were 38 ( 32.0 to 42.0 ) and 38 ( 31.1 to 41.5 ) weeks ( NS ) , and birth weights were 2600 ( 1320 to 4078 ) g and 2560 ( 1303 to 3900 ) g ( NS ) in the room air and oxygen groups , respectively . There were 46 % girls in the room air and 41 % in the oxygen group ( NS ) . Mortality in the first 7 days of life was 12.2 % and 15.0 % in the room air and oxygen groups , respectively ; adjusted odds ratio ( OR ) = 0.82 with 95 % confidence intervals ( CI ) = 0.50–1.35 . Neonatal mortality was 13.9 % and 19.0 % ; adjusted OR = 0.72 with 95 % CI = 0.45–1.15 . Death within 7 days of life and /or moderate or severe hypoxic – ischemic encephalopathy ( primary outcome measure ) was seen in 21.2 % in the room air group and in 23.7 % in the oxygen group ; OR = 0.94 with 95 % CI = 0.63–1.40 . Heart rates did not differ between the two groups at any time point and were ( mean ± SD ) 90 ± 31 versus 93 ± 33 beats per minute at 1 minute and 110 ± 27 versus 113 ± 30 beats per minute at 90 seconds in the room air and oxygen groups , respectively . Apgar scores at 1 minute ( median and 5 to 95 percentiles ) were significantly higher in the room air group ( 5 [ 1 to 6.7 ] ) than in the oxygen group ( 4 [ 1 to 7 ] ) ; however , at 5 minutes there were no significant differences , with 8 ( 4 to 9 ) versus 7 ( 3 to 9 ) . There were significantly more infants with very low 1-minute Apgar scores ( < 4 ) in the oxygen group ( 44.4 % ) than in the room air group ( 32.3 % ) . There also were significantly more infants with 5-minute Apgar score < 7 in the oxygen group ( 31.8 % ) than in the room air group ( 24.8 % ) . There were no differences in acid base status or Sao 2during the observation period between the two groups . Mean ( SD ) Pao 2 was 31 ( 17 ) versus 30 ( 22 ) mm Hg in cord blood in the room air and oxygen groups , respectively ( NS ) . At 10 minutes Pao 2 was 76 ( 32 ) versus 87 ( 49 ) mm Hg ( NS ) , and at 30 minutes , the values were 74 ( 29 ) versus 89 ( 42 ) mm Hg in the room air and oxygen groups , respectively . Median ( 95 % CI ) time to first breath was 1.1 ( 1.0–1.2 ) minutes in the room air group versus 1.5 ( 1.4 to 1.6 ) minutes in the oxygen group . Time to the first cry also was in mean 0.4 minute shorter in the room air group compared with the oxygen group . In the room air group , there were 25.7 % so-called resuscitation failures ( bradycardia and /or central cyanosis after 90 seconds ) that were switched to 100 % oxygen after 90 seconds . The percentage of resuscitation failures in the oxygen group was 29.8 % . Conclusions . This study with patients enrolled primarily from developing countries indicates that asphyxiated newborn infants can be resuscitated with room air as efficiently as with pure oxygen . In fact , time to first breath and first cry was significantly shorter in room air- versus oxygen-resuscitated infants . Resuscitation with 100 % oxygen may depress ventilation and therefore delay the first breath . More studies are needed confirming these results before resuscitation guidelines are changed ABSTRACT : To test the hypothesis that room air is superior to 100 % oxygen when asphyxiated newborns are resuscitated , 84 neonates ( birth weight > 999 g ) with heart rate < 80 and /or apnea at birth were allocated to be resuscitated with either room air ( n = 42 ) or 100 % oxygen ( n = 42 ) . Serial , unblinded observations of heart rates at 1 , 3 , 5 , and 10 min and Apgar scores at 1 min revealed no significant differences between the two groups . At 5 min , median ( 25th and 75th percentile ) Apgar scores were higher in the room air than in the oxygen group [ 8 ( 7–9 ) versus 7 ( 6–8 ) , p = 0.03 ] . After the initial resuscitation , arterial partial pressure of oxygen , pH , and base excess were comparable in the two groups . Assisted ventilation was necessary for 2.4 ( 1.5–3.4 ) min in the room air group and 3.0 ( 2.0–4.0 ) min in the oxygen group ( p = 0.14 ) . The median time to first breath was 1.5 ( 1.0–2.0 ) min in both the room air and oxygen groups ( p = 0.59 ) , and the time to first cry was 3.0 ( 2.0–4.0 ) min and 3.5 ( 2.5–5.5 ) min in the room air and oxygen groups , respectively ( p = 0.19 ) . Three neonates in the room air group and four in the oxygen group died in the neonatal period . At 28 d , 72 of the 77 surviving neonates were available for follow-up ( 36 in each group ) , and none had any neurologic sequelae . This preliminary study did not provide conclusive evidence that room air is superior to 100 % oxygen in the resuscitation of asphyxiated newborns , although it indicated that room air is as effective as 100 % oxygen . Additional trials with increased numbers of patients are necessary before deciding whether room air or oxygen should be used in clinical practice BACKGROUND Traditional fluid resuscitation strategy in the actively hemorrhaging trauma patient emphasizes maintenance of a normal systolic blood pressure ( SBP ) . One human trial has demonstrated improved survival when fluid resuscitation is restricted , whereas numerous laboratory studies have reported improved survival when resuscitation is directed to a lower than normal pressure . We hypothesized that fluid resuscitation titrated to a lower than normal SBP during the period of active hemorrhage would improve survival in trauma patients presenting to the hospital in hemorrhagic shock . METHODS Patients presenting in hemorrhagic shock were r and omized to one of two fluid resuscitation protocol s : target SBP > 100 mm Hg ( conventional ) or target SBP of 70 mm Hg ( low ) . Fluid therapy was titrated to this endpoint until definitive hemostasis was achieved . In-hospital mortality , injury severity , and probability of survival were determined for each patient . RESULTS One hundred ten patients were enrolled over 20 months , 55 in each group . The study cohort had a mean age of 31 years , and consisted of 79 % male patients and 51 % penetrating trauma victims . There was a significant difference in SBP observed during the study period ( 114 mm Hg vs. 100 mm Hg , p < 0.001 ) . Injury Severity Score ( 19.65 + /- 11.8 vs. 23.64 + /- 13.8 , p = 0.11 ) and the duration of active hemorrhage ( 2.97 + /- 1.75 hours vs. 2.57 + /- 1.46 hours , p = 0.20 ) were not different between groups . Overall survival was 92.7 % , with four deaths in each group . CONCLUSION Titration of initial fluid therapy to a lower than normal SBP during active hemorrhage did not affect mortality in this study . Reasons for the decreased overall mortality and the lack of differentiation between groups likely include improvements in diagnostic and therapeutic technology , the heterogeneous nature of human traumatic injuries , and the imprecision of SBP as a marker for tissue oxygen delivery BACKGROUND Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment . We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation . METHODS In this multicenter trial with blinded assessment of the outcome , patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were r and omly assigned to undergo therapeutic hypothermia ( target temperature , 32 degrees C to 34 degrees C , measured in the bladder ) over a period of 24 hours or to receive st and ard treatment with normothermia . The primary end point was a favorable neurologic outcome within six months after cardiac arrest ; secondary end points were mortality within six months and the rate of complications within seven days . RESULTS Seventy-five of the 136 patients in the hypothermia group for whom data were available ( 55 percent ) had a favorable neurologic outcome ( cerebral-performance category , 1 [ good recovery ] or 2 [ moderate disability ] ) , as compared with 54 of 137 ( 39 percent ) in the normothermia group ( risk ratio , 1.40 ; 95 percent confidence interval , 1.08 to 1.81 ) . Mortality at six months was 41 percent in the hypothermia group ( 56 of 137 patients died ) , as compared with 55 percent in the normothermia group ( 76 of 138 patients ; risk ratio , 0.74 ; 95 percent confidence interval , 0.58 to 0.95 ) . The complication rate did not differ significantly between the two groups . CONCLUSIONS In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation , therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality BACKGROUND Fluid resuscitation may be detrimental when given before bleeding is controlled in patients with trauma . The purpose of this study was to determine the effects of delaying fluid resuscitation until the time of operative intervention in hypotensive patients with penetrating injuries to the torso . METHODS We conducted a prospect i ve trial comparing immediate and delayed fluid resuscitation in 598 adults with penetrating torso injuries who presented with a pre-hospital systolic blood pressure of < or = 90 mm Hg . The study setting was a city with a single central ized system of pre-hospital emergency care and a single receiving facility for patients with major trauma . Patients assigned to the immediate-resuscitation group received st and ard fluid resuscitation before they reached the hospital and in the trauma center , and those assigned to the delayed-resuscitation group received intravenous cannulation but no fluid resuscitation until they reached the operating room . RESULTS Among the 289 patients who received delayed fluid resuscitation , 203 ( 70 percent ) survived and were discharged from the hospital , as compared with 193 of the 309 patients ( 62 percent ) who received immediate fluid resuscitation ( P = 0.04 ) . The mean estimated intraoperative blood loss was similar in the two groups . Among the 238 patients in the delayed-resuscitation group who survived to the postoperative period , 55 ( 23 percent ) had one or more complications ( adult respiratory distress syndrome , sepsis syndrome , acute renal failure , coagulopathy , wound infection , and pneumonia ) , as compared with 69 of the 227 patients ( 30 percent ) in the immediate-resuscitation group ( P = 0.08 ) . The duration of hospitalization was shorter in the delayed-resuscitation group . CONCLUSIONS For hypotensive patients with penetrating torso injuries , delay of aggressive fluid resuscitation until operative intervention improves the outcome CONTEXT Endotracheal intubation ( ETI ) is widely used for airway management of children in the out-of-hospital setting , despite a lack of controlled trials demonstrating a positive effect on survival or neurological outcome . OBJECTIVE To compare the survival and neurological outcomes of pediatric patients treated with bag-valve-mask ventilation ( BVM ) with those of patients treated with BVM followed by ETI . DESIGN Controlled clinical trial , in which patients were assigned to interventions by calendar day from March 15 , 1994 , through January 1 , 1997 . SETTING Two large , urban , rapid-transport emergency medical services ( EMS ) systems . PARTICIPANTS A total of 830 consecutive patients aged 12 years or younger or estimated to weigh less than 40 kg who required airway management ; 820 were available for follow-up . INTERVENTIONS Patients were assigned to receive either BVM ( odd days ; n = 410 ) or BVM followed by ETI ( even days ; n = 420 ) . MAIN OUTCOME MEASURES Survival to hospital discharge and neurological status at discharge from an acute care hospital compared by treatment group . RESULTS There was no significant difference in survival between the BVM group ( 123/404 [ 30 % ] ) and the ETI group ( 110/416 [ 26 % ] ) ( odds ratio [ OR ] , 0.82 ; 95 % confidence interval [ CI ] , 0.61 - 1.11 ) or in the rate of achieving a good neurological outcome ( BVM , 92/404 [ 23 % ] vs ETI , 85/416 [ 20 % ] ) ( OR , 0.87 ; 95 % CI , 0.62 - 1.22 ) . CONCLUSION These results indicate that the addition of out-of-hospital ETI to a paramedic scope of practice that already includes BVM did not improve survival or neurological outcome of pediatric patients treated in an urban EMS system BACKGROUND The role of fluids in trauma resuscitation is controversial . We compared resuscitation with 0.9 % saline vs hydroxyethyl starch , HES 130/0.4 , in severe trauma with respect to resuscitation , fluid volume , gastrointestinal recovery , renal function , and blood product requirements . METHODS R and omized , controlled , double-blind study of severely injured patients requiring > 3 litres of fluid resuscitation . Blunt and penetrating trauma were r and omized separately . Patients were followed up for 30 days . RESULTS A total of 115 patients were r and omized ; of which , 109 were studied . For patients with penetrating trauma ( n=67 ) , the mean ( sd ) fluid requirements were 5.1 ( 2.7 ) litres in the HES group and 7.4 ( 4.3 ) litres in the saline group ( P<0.001 ) . In blunt trauma ( n=42 ) , there was no difference in study fluid requirements , but the HES group required significantly more blood products [ packed red blood cell volumes 2943 ( 1628 ) vs 1473 ( 1071 ) ml , P=0.005 ] and was more severely injured than the saline group ( median injury severity score 29.5 vs 18 ; P=0.01 ) . Haemodynamic data were similar , but , in the penetrating group , plasma lactate concentrations were lower over the first 4 h ( P=0.029 ) and on day 1 with HES than with saline [ 2.1 ( 1.4 ) vs 3.2 ( 2.2 ) mmol litre⁻¹ ; P=0.017 ] . There was no difference between any groups in time to recovery of bowel function or mortality . In penetrating trauma , renal injury occurred more frequently in the saline group than the HES group ( 16 % vs 0 % ; P=0.018 ) . In penetrating trauma , maximum sequential organ function scores were lower with HES than with saline ( median 2.4 vs 4.5 , P=0.012 ) . No differences were seen in safety measures in the blunt trauma patients . CONCLUSIONS In penetrating trauma , HES provided significantly better lactate clearance and less renal injury than saline . No firm conclusions could be drawn for blunt trauma . STUDY REGISTRATION IS RCT N 42061860 OBJECTIVE To compare the short-term efficacy of room air versus 100 % oxygen for resuscitation of asphyxic newborns at birth . DESIGN Multicentric quasi r and omized controlled trial . SETTING Teaching hospitals . INCLUSION CRITERIA Asphyxiated babies weighing greater than 1000 grams , with heart rate less than 100 per min and /or apnea , unresponsive to nasopharyngeal suction and tactile stimuli and having no lethal abnormalities . INTERVENTION Asphyxiated neonates born on odd date s were given oxygen and those on even date s room air for resuscitation . OUTCOME MEASURES Primary : Apgar score at 5 minutes ; Secondary : Mortality and Hypoxic ischaemic encephalopathy ( HIE ) during first 7 days of life . RESULTS A total of 431 asphyxiated babies , 210 in the room air and 221 in 100 % oxygen group were enrolled for the study . Both the groups were comparable for maternal , intrapartum and neonatal characteristics . The heart rates in room air and 100 % oxygen groups were comparable at 1 minute ( 94 bpm and 88 bpm ) , 5 minutes ( 131 bpm and 131 bpm ) and 10 minutes ( 135 bpm and 136 bpm ) . Median apgar scores at 5 min [ 7 versus 7 ] and 10 minutes [ 8 versus 8 ] , in the room air and oxygen groups respectively , were found to be comparable . Median time to first breath ( 1.5 versus 1.5 minutes ) was similar in the room air and oxygen group . Median time to first cry ( 2.0 versus 3.0 minutes ) and median duration of resuscitation ( 2.0 versus 3 minutes ) were significantly shorter in the room air group . The number of babies with HIE during first seven days of life in the two treatment groups ( 35.7 % babies in room air and 37.1 % in the 100 % oxygen group ) were similar . There was also no statistically significant difference in the overall and asphyxia related mortality in the two treatment groups ( 12.4 % and 10.0 % in room air versus 18.1 % and 13.6 % in oxygen group ) . CONCLUSION Room air appears as good as 100 % oxygen for resuscitation of asphyxic newborn babies at birth We evaluated the efficacy of the esophageal airway ( EA ) by prospect ively r and omizing 175 prehospital cardiopulmonary arrest patients to receive either an esophageal gastric tube airway ( EGTA ) or an endotracheal tube ( ET ) . If attempts with the initial airway failed , the alternate airway was attempted . The cost of training paramedics in EA use was considerably less than the ET ( $ 80 vs $ 1,000 ) . Survival to the emergency room , to hospitalization and to discharge in ET and EGTA groups were 64.4 percent , 25.6 percent , 11.1 percent , and 54.1 percent , 27.1 percent , 12.9 percent , respectively -- differences not statistically significant . The incidence of neurologic residual ( ET 50 percent , EGTA 36.4 percent ) and congestive heart failure ( ET 40 percent , EGTA 45.5 percent ) in surviving ET and EGTA patients did not differ ( NS ) . An additional 125 consecutive patients with only the opportunity to receive an EA were also evaluated and did not differ in mortality , neurologic residual , or congestive heart failure from ET patients . We conclude that the EA is a satisfactory alternative to the ET for short-term prehospital use in cardiopulmonary arrest patients This paper examines the two principal justifications that have been offered for the st and ard conditions that clinical trials be r and omized and controlled , with the conclusion that , strictly speaking , neither justification is valid . It is argued , on the other h and , that a Bayesian analysis of clinical trials affords a valid , intuitively plausible rationale for selective controls , and marks out a more limited role for r and omization than it is generally accorded . The feasibility of retrospective trials is then considered in the light of these conclusions Objective : To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock . Background : Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion , with a smaller volume , and modulation of the inflammatory response , to reduce subsequent organ injury . Methods : Multicenter , r and omized , blinded clinical trial , May 2006 to August 2008 , 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium . Inclusion criteria : injured patients , age ≥ 15 years with hypovolemic shock ( systolic blood pressure ⩽ 70 mm Hg or systolic blood pressure 71–90 mm Hg with heart rate ≥ 108 beats per minute ) . Initial resuscitation fluid , 250 mL of either 7.5 % saline per 6 % dextran 70 ( hypertonic saline/dextran , HSD ) , 7.5 % saline ( hypertonic saline , HS ) , or 0.9 % saline ( normal saline , NS ) administered by out-of-hospital providers . Primary outcome was 28-day survival . On the recommendation of the data and safety monitoring board , the study was stopped early ( 23 % of proposed sample size ) for futility and potential safety concern . Results : A total of 853 treated patients were enrolled , among whom 62 % were with blunt trauma , 38 % with penetrating . There was no difference in 28-day survival — HSD : 74.5 % ( 0.1 ; 95 % confidence interval [ CI ] , −7.5 to 7.8 ) ; HS : 73.0 % ( −1.4 ; 95 % CI , −8.7–6.0 ) ; and NS : 74.4 % , P = 0.91 . There was a higher mortality for the postr and omization subgroup of patients who did not receive blood transfusions in the first 24 hours , who received hypertonic fluids compared to NS [ 28-day mortality — HSD : 10 % ( 5.2 ; 95 % CI , 0.4–10.1 ) ; HS : 12.2 % ( 7.4 ; 95 % CI , 2.5–12.2 ) ; and NS : 4.8 % , P < 0.01 ] . Conclusion : Among injured patients with hypovolemic shock , initial resuscitation fluid treatment with either HS or HSD compared with NS , did not result in superior 28-day survival . However , interpretation of these findings is limited by the early stopping of the trial . Clinical Trial Registration : Clinical Trials.gov , OBJECTIVE To evaluate the use of 250 mL of a 7.5 % sodium chloride solution , both with and without added dextran 70 , for the prehospital resuscitation of hypotensive trauma patients . DESIGN Double-blind r and omized trial . SETTING Six trauma systems served by helicopter transport . PATIENTS Injured patients with systolic blood pressures less than 90 mm Hg at any time in the field or during helicopter transport . INTERVENTIONS Infusion of study solution , in the field or during transport , followed by conventional isotonic solutions as needed . Solutions studied in four cohorts were as follows : ( 1 ) lactated Ringer 's ; ( 2 ) 7.5 % sodium chloride ( hypertonic saline ) ; ( 3 ) 7.5 % sodium chloride combined with 6 % dextran 70 ; and ( 4 ) 7.5 % sodium chloride combined with 12 % dextran 70 . MAIN OUTCOME MEASURES Blood pressure response ; survival to time of hospital discharge among the treatment groups ; and survival compared with that predicted by norms from the Major Trauma Outcome Study ( MTOS ) . RESULTS The mean ( + /- SD ) change in systolic blood pressure on arrival in the emergency department was significantly higher in the hypertonic saline solution group than that in the lactated Ringer 's solution group ( 34 + /- 46 vs 11 + /- 49 mm Hg , P < .03 ) . Overall survival in the four treatment groups was 49 % , 60 % , 56 % , and 45 % ( not statistically significant ) . Survival in the hypertonic saline solution group , however , was significantly higher than that predicted by the MTOS norms ( 60 % vs 48 % , P < .001 ) . Survival to hospital discharge in patients with baseline Glasgow Coma Scale scores of 8 or less was correlated with treatment group ( P < .05 by logistic regression and P < .01 by Cox proportional-hazards analysis ; with survival in the hypertonic saline solution group [ 34 % ] vs lactated Ringer 's solution group [ 12 % ] ) . CONCLUSIONS Prehospital infusion of 250 mL of 7.5 % sodium chloride is associated with an increase in blood pressure and an increase in survival to hospital discharge compared with survival predicted by the MTOS norms . Patients with low baseline Glasgow Coma Scale scores seem to benefit the most from 7.5 % sodium chloride resuscitation . Hypertonic saline solution without added dextran 70 is as effective as the more expensive solutions that contain dextran 70 RATIONALE Pure oxygen causes more oxidative stress than room air in resuscitation of asphyctic neonates , and consequently could be associated with increased tissue damage . OBJECTIVES To compare damage caused to heart and kidneys on reoxygenation in severely asphyctic term neonates resuscitated with room air ( RAR ) or 100 % oxygen ( OxR ) . Nonasphyctic term newborn infants served as a control group . METHODS AND MEASUREMENTS This is a prospect i ve r and omized clinical trial masked for the gas mixture . Reduced glutathione ( GSH ) , oxidized glutathione ( GSSG ) , and superoxide dismutase ( SOD ) activity were measured to assess oxidative stress . Plasma cardiac troponin T ( cTnT ) and urinary N-acetyl-glucosaminidase ( NAG ) assessed cardiac and renal damage , respectively . Daily determinations of NAG for a 2-wk period were performed to monitor postasphyctic renal damage . MAIN RESULTS Both asphyctic groups showed oxidative stress when compared with the control group as evidence d by diminished GSH/GSSG ratios , adaptive increases in SOD activity , and higher values of NAG and cTnT ( markers of tissue damage ) . However , the OxR group showed significantly higher values of NAG and cTnT , lower GSH/GSSG ratios , and higher SOD activity than the RAR group . Moreover , NAG values persisted in being higher than normal in the OxR group for 2 wk after birth , whereas NAG in the RAR group dropped to normal within the first week . A linear correlation between cTnT or NAG and GSSG was found . CONCLUSIONS The use of room air on resuscitation causes less oxidative stress and damage to heart and kidney than pure oxygen BACKGROUND Cardiac arrest outside the hospital is common and has a poor outcome . Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome , but there have been no conclusive studies in humans . In a r and omized , controlled trial , we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest . METHODS The study subjects were 77 patients who were r and omly assigned to treatment with hypothermia ( with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours ) or normothermia . The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility . RESULTS The demographic characteristics of the patients were similar in the hypothermia and normothermia groups . Twenty-one of the 43 patients treated with hypothermia ( 49 percent ) survived and had a good outcome --that is , they were discharged home or to a rehabilitation facility -- as compared with 9 of the 34 treated with normothermia ( 26 percent , P=0.046 ) . After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation , the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 ( 95 percent confidence interval , 1.47 to 18.76 ; P=0.011 ) . Hypothermia was associated with a lower cardiac index , higher systemic vascular resistance , and hyperglycemia . There was no difference in the frequency of adverse events . CONCLUSIONS Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest OBJECTIVES The study examined the effect of isovolumic high-volume hemofiltration ( HF ) alone or combined with mild hypothermia ( HT ) on survival after out-of-hospital cardiac arrest ( OHCA ) with initial ventricular fibrillation or asystole . BACKGROUND Global inflammation in response to whole-body ischemia-reperfusion is common after OHCA and may worsen the overall prognosis . METHODS Sixty-one patients admitted between May 2000 and March 2002 in the intensive care units of two hospitals in France were r and omized to one of three groups : control , HF ( 200 ml/kg/h over 8 h ) or HF+HT ( 32 degrees C for 24 h ) induced by cooling the HF substitution fluid . St and ard supportive care was provided in all three groups . The primary end point was survival with a follow-up time of six months . The effect of HF on death by intractable shock was the secondary end point . RESULTS The six-month survival curves of the three groups were significantly different , with better survival in the HF group ( p = 0.026 ) and in the HF+HT group ( p = 0.018 ) . After adjustment on baseline characteristics of cardiac arrest , HF ( with or without HT ) was associated with improved survival ( logistic regression odds ratio , 4.4 ; 95 % confidence interval [ CI ] , 1.1 to 16.6 ) . Compared to control group , the relative risk of death by intractable shock was 0.29 ( 95 % CI , 0.09 to 0.91 ) in the HF+HT group and 0.21 ( 95 % CI , 0.05 to 0.85 ) in the HF group . CONCLUSIONS The HF may improve the overall prognosis after resuscitation from OHCA . Combination of HF with mild HT is feasible and should be evaluated in larger trials A key component of the Cochrane Collaboration 's risk of bias tool for critically evaluating r and omised trials is the consideration of whether baseline characteristics of the treatment groups being compared are systematic ally different . Considered under the domain of ' selection bias ' , this is currently evaluated by looking at the methods of r and omisation and specifically at the generation of the r and omised allocation sequence and the concealment of this sequence during the process of r and omisation . Assessment of the actual similarity of baseline variables across groups in demographic and clinical characteristics is seldom performed . Even when performed , the link with selection bias is sometimes not considered . Methods of r and omisation and allocation concealment are often poorly reported in published trials , yet baseline data tables are presented in a large majority of trial reports . In this article , we propose that assessment of trial baseline data should form a key and prominent part of selection bias judgements when using the risk of bias tool . We outline the possible benefits from using this approach , including reduced uncertainty in systematic review conclusions , reduced risk of chance findings being ascribed to treatment effects and better use of available evidence by a more considered approach to evaluating studies using imperfect r and omisation and allocation methods OBJECTIVE Disagreement exists concerning the appropriate delivery room management of the airway of vigorous meconium-stained infants . Some suggest a universal approach to intubation and suctioning of the airway in all such neonates , whereas others advocate a selective approach . We performed this investigation : 1 ) to assess whether intubation and suctioning of apparently vigorous , meconium-stained neonates would reduce the incidence of meconium aspiration syndrome ( MAS ) ; and 2 ) to determine the frequency of complications from delivery room intubation and suctioning of such infants . METHODS Inclusion criteria included : 1 ) gestational age > /=37 weeks ; 2 ) birth through meconium-stained amniotic fluid of any consistency ; and 3 ) apparent vigor immediately after birth . Subjects were r and omized to be intubated and suctioned ( INT ) or to expectant management ( EXP ) . Primary outcome measures included : 1 ) the incidence of respiratory distress , including MAS , and 2 ) the incidence of complications from intubation . RESULTS A total of 2094 neonates were enrolled from 12 participating centers ( 1051 INT and 1043 EXP ) . Meconium-stained amniotic fluid consistency was similar in both groups . Of the 149 ( 7.1 % ) infants that subsequently demonstrated respiratory distress , 62 ( 3.0 % ) had MAS and 87 ( 4.2 % ) had findings attributed to other disorders . There were no significant differences between groups in the occurrence of MAS ( INT = 3.2 % ; EXP = 2.7 % ) or in the development of other respiratory disorders ( INT = 3.8 % ; EXP = 4.5 % ) . Of 1098 successfully intubated infants , 42 ( 3.8 % ) had a total of 51 complications of the procedure . In all cases , the complications were mild and transient in nature . CONCLUSIONS Compared with expectant management , intubation and suctioning of the apparently vigorous meconium-stained infant does not result in a decreased incidence of MAS or other respiratory disorders . Complications of intubation are infrequent and short-lived This prospect i ve r and omised study was performed to compare the use of the Esophageal-Tracheal Combitube(R ) ( ETC ; Tyco Healthcare , Mansfield , MA ; http://www.combitube.org ) with a conventional tracheal airway ( ETA ) for airway management by experienced physicians of the Emergency Medical Services System of the City of Vienna in the prehospital setting . Access to the patient 's head , time of arrival of the ambulance , ease of insertion , time of insertion , potential substitution by the alternate airway , efficacy of adrenaline ( epinephrine ) administered via the airway , survival to the intensive care unit ( ICU ) ward and survival to discharge from the hospital were evaluated . One hundred and seventy-two non-traumatic cardiac arrest patients ( 131 males , 41 females ) were enrolled in this study during a 12 months period . In 83 patients ( 48.3 % ) , the conventional ETA ( group 1 ) was used for the initial intubation attempt which was successful in 78 patients ( 94 % ) . The remaining five patients of group 1 could not be intubated with an ETA , but were successfully managed with the ETC . Eighty-nine patients ( 51.7 % ) were intubated with the ETC ( group 2 ) as first choice ( 79 in oesophageal position ( 89 % ) ; eight in tracheal position : ( 9 % ) ) , which was successful in 87 ( 98 % ) patients . The remaining two patients in group 2 ( 2 % ) were successfully managed with the ETA . Success of intubation and ventilation with ETC was comparable to the ETA . Recorded time of insertion was shorter with the ETC versus ETA ( P<0.05 ) . The Combitube worked well in cases of difficult access to the patient 's head and in bleeding and vomiting patients . Both devices served as successful substitutes for each other . Adrenaline ( epinephrine ) applied via ETC with a 10-fold dosage was as effective as via the conventional ETA . To our knowledge this is the first study using physicians comparing ETC and ETA in the prehospital setting Haemaccel is widely used throughout Europe and South Africa in the resuscitation of trauma patients " . Although it is very effective when used as the sole volume exp and er , it is usually used in conjunction with a crystalloid which has been shown both experimentally and clinical ly to increase its benefits " . The colloid within Haemaccel is chemically modified bovine bone gelatine preparation . The gelatine is subjected to thermal degradation to produce a gelatine hydrolysate in the form of small polypeptides of molecular weight 12000 to 15000 . These are then cross linked to form larger molecules which have an average molecular weight of 35000 ( range 25000 - 50000 ) . In addition , the solution contains a number of other solutes including Ca2 + ( 6.2 mM ) , and exerts an oncotic pressure of 3.4 - 3.8 kaPa at 37 ° C . It is isoncotic with plasma and it has a half life in the body of approximately 5 h. Recent anecdotal reports from the Department of Surgery at the University Hospital Bloemfontein ( Orange Free State , South Africa ) suggested that trauma patients who had received Haemaccel for shock exhibited an increased bleeding tendency in the form of wound oozing , both intra and post-operatively . The aim of the present study , therefore , was to perform a controlled investigation of the effects of Hacmacccl on bleeding time in vivo in trauma victims at the Trauma Unit of Johannesburg Hospital In a prospect i ve study , we determined whether routine immediate tracheal aspiration at birth is necessary in meconium-stained but otherwise normal infants delivered vaginally and having a 1-minute Apgar score greater than 8 . A total of 572 newborn infants who met these criteria were r and omly allocated to one of two groups . All infants underwent oropharyngeal suctioning with a DeLee catheter while the head was still on the perineum . In group I ( n = 308 ) suctioning of the trachea under direct vision was performed instantly at birth ; in group II ( n = 264 ) this procedure was not done . There was no mortality among infants in the study , but morbidity , mainly pulmonary and laryngeal disorders , occurred in six of 308 group I infants and in none of the group II infants ( P less than 0.025 ) . Immediate tracheal suction is not a harmless intervention , and should be considered superfluous in a vigorous term neonate born with meconium-stained amniotic fluid RESULTS In total 1309 patients were entered in the study : 699 ( 53.4 % ) were treated by paramedics operating protocol A and 610 ( 46.6 % ) were treated by paramedics operating protocol B. The r and omisation worked well and there were no significant differences between treatment groups in incident characteristics , ambulance performance times , or patient or injury characteristics , apart from slightly more moderate or severe head injuries in the protocol A group ( 25.3 % versus 20.3 % ) . Protocol compliance was poor , with only 31 % of protocol A patients receiving prehospital fluids and only 80 % of protocol B patients not given fluids . The estimated odds ratio for being given prehospital fluids when treated by protocol A compared to protocol B was 2.09 ( 95 % confidence interval ( CI ) , 1.53 to 2.81 ) . MORTALITY There were 73 deaths within 6 months in the 699 patients in the protocol A group ( 10.4 % ) , and 60/610 ( 9.8 % ) in the protocol B group . Thus the crude odds ratio for deaths when managed by protocol A was 1.07 ( 95 % CI , 0.73 to 1.54 ) . Excluding 26 patients whose cause of death may not have been trauma related , the odds ratio was 1.04 ( 95 % CI , 0.69 to 1.55 ) . Excluding 17 patients who may have been dead on arrival of the ambulance at the scene the odds ratio was 1.04 ( 95 % CI , 0.70 to 1.53 ) . Adjustment for age , injury severity and whether the patient was unconscious at the scene did not significantly alter these odds ratios . COMPLICATIONS A total of 106 patients were identified from hospital notes as having at least one of eight major complications ( adult respiratory distress syndrome , sepsis , acute renal failure , coagulopathy , wound infection , pneumonia , fat embolism or pulmonary embolism ) . The proportions with recorded complications were similar in the two groups : 60/699 ( 8.5 % ) in the protocol A group versus 46/610 ( 7.5 % ) in the protocol B group . HEALTH STATUS : A total of 878 question naires were sent to patients , and 559 ( 64 % ) usable replies were received . The response rate was similar in the two groups ( 62.9 % versus 64.6 % ) . In all eight dimensions of the SF-36 health status measure patients who had been managed by paramedics operating protocol A reported better average health than did patients in the protocol B group . However , none of the differences were at a level considered clinical ly important and only for one of the eight dimensions was the difference statistically significant . COMPOSITE OUTCOMES : No significant differences in outcome were found between the two protocol groups in terms of patients who either died or had serious complications , nor for patients who either died or had known poor health . SUBGROUPS : Subgroups of patients were defined on eight characteristics ( ambulance service area , whether a doctor was on scene , paramedic-patient contact time , injury severity , whether taken to theatre for emergency surgery , type of injuries , type of area , and whether the patient was treated before or after protocol cross-over ) . There was no evidence of any difference in mortality rates or composite outcomes between any subgroups , or between protocol s within any subgroup . Time to A&E department The analysis suggests that patients given fluids spent 12 - 13 minutes longer at the accident scene than did patients not given fluids . However , because only one-quarter of patients were given fluids , and the specific protocol used made little difference to this , average on-scene times were largely unaffected by protocol s. COSTS In the prehospital and immediate-care phase ( including A&E treatment ) , the mean costs of the protocol A and protocol B groups were ¿ 419 and ¿ 416 , respectively . This small difference reflects two small and off setting effects of protocol B : reduced on-scene time ( p = 0.08 ) and increased use of blood in the A&E department ( p = 0.03 ) . There were no other statistically significant differences in costs , with the mean total costs being ¿ 2706 and ¿ 2678 in the protocol A and protocol B groups , respectively ( p = 0.52 ) . ( ABSTRACT The authors present a new central ized r and omization method for multicenter emergency treatment clinical trials . With this step-forward method , treatment r and omization for the next subject is performed immediately after the enrollment of the current subject . This design ensures the readiness of the treatment assignment for each subject at the point of study enrollment , and it simultaneously provides effective control on treatment assignments balance and distributions of covariates . The authors also discuss procedures of the step-forward r and omization method along with its implementation for two National Institute of Neurological Disorders and Stroke-funded multicenter acute stroke trials , one double-blinded and one open-labeled . Advantages and limitations are presented based on experience gained in these two trials CONTEXT Prehospital hypertonic saline ( HTS ) resuscitation of patients with traumatic brain injury ( TBI ) may increase survival but whether HTS improves neurological outcomes is unknown . OBJECTIVE To determine whether prehospital resuscitation with intravenous HTS improves long-term neurological outcome in patients with severe TBI compared with resuscitation with conventional fluids . DESIGN , SETTING , AND PATIENTS Double-blind , r and omized controlled trial of 229 patients with TBI who were comatose ( Glasgow Coma Scale score , < 9 ) and hypotensive ( systolic blood pressure , < 100 mm Hg ) . The patients were enrolled between December 14 , 1998 , and April 9 , 2002 , in Melbourne , Australia . INTERVENTIONS Patients were r and omly assigned to receive a rapid intravenous infusion of either 250 mL of 7.5 % saline ( n = 114 ) or 250 mL of Ringer 's lactate solution ( n = 115 ; controls ) in addition to conventional intravenous fluid and resuscitation protocol s administered by paramedics . Treatment allocation was concealed . MAIN OUTCOME MEASURE Neurological function at 6 months , measured by the extended Glasgow Outcome Score ( GOSE ) . RESULTS Primary outcomes were obtained in 226 ( 99 % ) of 229 patients enrolled . Baseline characteristics of the groups were equivalent . At hospital admission , the mean serum sodium level was 149 mEq/L for HTS patients vs 141 mEq/L for controls ( P<.001 ) . The proportion of patients surviving to hospital discharge was similar in both groups ( n = 63 [ 55 % ] for HTS group and n = 57 [ 50 % ] for controls ; P = .32 ) ; at 6 months , survival rates were n = 62 ( 55 % ) in the HTS group and n = 53 ( 47 % ) in the control group ( P = .23 ) . At 6 months , the median ( interquartile range ) GOSE was 5 ( 3 - 6 ) in the HTS group vs 5 ( 5 - 6 ) in the control group ( P = .45 ) . There was no significant difference between the groups in favorable outcomes ( moderate disability and good outcome survivors [ GOSE of 5 - 8 ] ) ( risk ratio , 0.99 ; 95 % confidence interval , 0.76 - 1.30 ; P = .96 ) or in any other measure of postinjury neurological function . CONCLUSION In this study , patients with hypotension and severe TBI who received prehospital resuscitation with HTS had almost identical neurological function 6 months after injury as patients who received conventional fluid Children with thermal burns covering 30 % or more of the body surface area were alternately resuscitated with either hypertonic lactated saline ( HLS ) or lactated Ringer 's solution ( LRS ) . Parameters sequentially measured and calculated included : 1 ) serum and urine electrolyte concentrations , 2 ) serum and urine osmolalities , 3 ) arterial blood gases , 4 ) total and fractional serum proteins , 5 ) blood urea nitrogen , complete blood count and blood sugar concentration , 6 ) changes in body weight , 7 ) sodium , potassium and water balance . The water load received by the HLS group was significantly less through 48 hours postburn ( 49 % at 8 hours , 44 % at 24 hours and 38 % at 48 hours postburn ) . Although the HLS group received significantly more sodium than the LRS group , there was no difference in sodium balance at 48 hours postburn . This is explained by the fact that the HLS group , at 48 hours postburn , retained significantly less of the administered sodium load ( 69 % vs. 83 % ) . Positive water balance was significantly greater in the LR group for the first 48 hours postburn . This study suggests that current hypotonic fluid regimens for burn resuscitation contain water in excess of that required for proper resuscitation . Severely burned children may be safely and efficiently resuscitated with conventional salt loads and one-third less than usual water loads Evidence -based medicine is a new approach to improve the transfer process of knowledge from research to medical practice . The assumption that only results of r and omized controlled studies are evident is true for many but by far not for all clinical problems . As is demonstrated from one historical and many recent examples , there exists another but equally stringent method of proof which is based on an implicit historical comparison . This kind of evidence still has to be defined exactly in order to protect it from misuse by alternative medicine . The statement that only 20 % of methods used in conventional medicine are [ corrected ] evidence -based can not be substantiated . Methods and importance of meta-analyses are critically discussed as well as the meaning of the term publication bias . The new documentation- and information techniques will improve some steps in the transfer process . At the end it will be crucial whether the last step , the improvement of rationality in patient care , will be successful . This evidence still has to be demonstrated OBJECTIVE To test the hypothesis that resuscitation of asphyxiated infants with pure oxygen causes hyperoxemia and oxidative stress . Study design Asphyxiated term newborn infants ( n = 106 ) were r and omly resuscitated with room air ( RAR = 51 ) or 100 % oxygen ( OxR = 55 ) . The Apgar score , time of the first cry , and establishment of a sustained pattern of respiration were recorded . Assays performed included : blood gases ; reduced glutathione ( GSH ) and oxidized glutathione ( GSSG ) in whole blood ; glutathione-related enzyme activities ; and superoxide dismutase activity ( SOD ) in erythrocytes . RESULTS The RAR group needed less time of ventilation for resuscitation ( 5.3 + /- 1.5 vs 6.8 + /- 1.2 min ; P < .05 ) . Pure oxygen caused hyperoxemia ( PO(2 ) , 126.3 + /- 21.8 mm Hg ) that did not occur with the use of room air ( PO(2 ) , 72.2 + /- 6.8 mm Hg ) . GSH was decreased and GSSG , the glutathione cycle enzymes , and SOD activities were increased in both asphyxiated groups . However , the 100 % oxygen-resuscitated group showed significantly greater alterations that correlated positively with hyperoxemia . CONCLUSIONS Asphyxia causes oxidative stress in the perinatal period , and resuscitation with 100 % oxygen causes hyperoxemia and increased oxidative stress . Because there are no advantages to resuscitation with 100 % oxygen , room air may be preferred under certain circumstances for the resuscitation of asphyxiated neonates The aim of the study was to determine whether neonates resuscitated with room air compared with 100 per cent oxygen in the delivery room were less likely to have hypoxic ischemic encephalopathy and /or death before discharge . A controlled clinical trial was carried out at a tertiary care institute . All newborns weighing 1000 g or more with apnea or gasping respiration and /or heart rate less than 100 beats/min requiring positive pressure ventilation after initial steps of resuscitation were included . All eligible neonates were r and omized to receive room air or 100 per cent oxygen for the first 90 s after birth if they required positive pressure ventilation . The composite primary outcome variable was hypoxic ischemic encephalopathy ( HIE ) and /or death before discharge . A total of 204 neonates fulfilling the inclusion criteria were enrolled . Of these , 107 neonates received room air and 97 neonates received 100 per cent oxygen for resuscitation . The composite primary outcome occurred in 41.1 per cent of the neonates assigned to receive room air and 43.3 per cent of those in the 100 per cent oxygen group ( odds ratio in the group assigned to room air , 0.92 ; 95 per cent confidence interval , 0.52 - 1.60 ) . Resuscitation of a newborn baby with room air instead of the current practice of 100 per cent oxygen does not confer a benefit in terms of reduced HIE and /or mortality . Significantly , there is no increase in adverse outcome with the use of room air , which can be recommended for resuscitation if oxygen is not available The safety and efficacy of 7.5 % sodium chloride in 6 % dextran 70 ( HSD ) in posttraumatic hypotension was evaluated in Houston , Denver , and Milwaukee . Multicentered , blinded , prospect i ve r and omized studies were developed comparing 250 mL of HSD versus 250 mL of normal crystalloid solution administered before routine prehospital and emergency center resuscitation . During a 13-month period , 422 patients were enrolled , 211 of whom subsequently underwent operative procedures . Three hundred fifty-nine patients met criteria for efficacy analysis , 51 % of whom were in the HSD group . Seventy-two per cent of all patients were victims of penetrating trauma . The mean injury severity score ( 19 ) , Trauma Score plus Injury Severity Score ( TRISS ) probability of survival , revised trauma scores ( 5.9 ) , age , ambulance times , preinfusion blood pressure , and etiology distribution were identical between groups . The total amount of fluid administered , white blood cell count , arterial blood gases , potassium , or bicarbonate also were identical between groups . The HSD group had an improved blood pressure ( p = 0.024 ) . Hematocrit , sodium chloride , and osmolality levels were significantly elevated in the Emergency Center . Although no difference in overall survival was demonstrated , the HSD group requiring surgery did have a better survival ( p = 0.02 ) , with some variance among centers . The HSD group had fewer complications that the st and ard treatment group ( 7 versus 24 ) . A greater incidence of adult respiratory distress syndrome , renal failure , and coagulopathy occurred in the st and ard treatment group . No anaphylactoid nor Dextran-related coagulopathies occurred in the HSD group . Although this trial demonstrated trends supportive of HSD in hypotensive hemorrhagic shock patients requiring surgery , a larger sample size will be required to establish which subgroups of trauma patients might maximally benefit from the prehospital use of a small volume of hyperosmolar solution . This study demonstrates the safety of administering 250 mL 7.5 % HDS to this group of patients

There is some evidence of improvement in metabolic control in people with diabetes , after treating periodontal disease .

BACKGROUND Glycaemic control is a key issue in the care of people with diabetes mellitus ( DM ) . Some studies have suggested a bidirectional relationship between glycaemic control and periodontal disease . OBJECTIVES To investigate the relationship between periodontal therapy and glycaemic control in people with diabetes and to identify the appropriate future strategy for this question .

Purpose This study aim ed to investigate the effects of oral hygiene care by oral professionals on periodontal health in type 2 diabetes mellitus patients . Material s and Methods Diabetic participants were recruited at a university hospital and matched at a 1:1 ratio by age and gender , and r and omly allocated into intervention ( 40 people ) and control groups ( 35 people ) . Tooth brushing instruction , oral health education , and supra-gingival scaling were implemented in all patients at baseline . This program was repeatedly conducted in intervention patients every month for 6 months , and twice at baseline and the sixth month in the control . Oral health was measured by decayed , missing , and filled teeth ( DMFT ) , plaque index , calculus index , bleeding index , patient hygiene performance ( PHP ) index , tooth mobility , Russel 's periodontal index , and community periodontal index ( CPI ) . Diabetes-related factors , oral and general health behaviors , and sociodemographic factors were interviewed as other confounding factors . An analysis of covariance ( ANCOVA ) was used with SPSS for Windows 14.0 . Results At baseline , there were no significant differences between the two groups in average of periodontal health ( calculus index , bleeding index , Russel 's periodontal index , CPI , and tooth mobility ) , diabetes-related factors ( fasting blood glucose , postpr and ial blood glucose , and HbA1c ) , and in distribution of sociodemographic factors and health behaviors . In intervention group , plaque index , dental calculus index , bleeding index , and PHP index were reduced fairly and steadily from the baseline . There were significant differences in plaque index , dental calculus index , bleeding index , PHP index , and Russel 's periodontal index between the two groups at sixth month after adjusted for baseline status . Conclusion Intensive oral hygiene care can persistently improve oral inflammation status and could slow periodontal deterioration A controlled cross-sectional study with the aim of study ing oral health in patients with type 2 diabetes was carried out in a health care district in Sweden . The study included 102 r and omly sample d diabetic patients and 102 age- and gender-matched non-diabetic subjects from the same geographical area , treated at the same Public Dental Service clinics . Oral conditions were measured at clinical and X-ray examinations . Diabetes-related variables were extracted from medical records . Diabetic patients suffered from xerostomia ( dry mouth ) to a significantly higher degree than non-diabetic controls did ( 53.5 vs. 28.4 % ; P=0.0003 ) . Sites with advanced periodontitis were more frequent in the diabetic group ( P=0.006 ) as were initial caries lesions ( P=0.02 ) . Diabetic subjects showed a greater need of periodontal treatment ( P=0.05 ) , caries prevention ( P=0.002 ) and prosthetic corrections ( P=0.004 ) . Diabetes duration or metabolic control of the disease was not related to periodontal status . However , patients with longer duration of diabetes had more manifest caries lesions ( P=0.05 ) as had those on insulin treatment when compared with patients on oral/diet or combined treatment ( P=0.0001 ) . The conclusion is that individuals with type 2 diabetes in some oral conditions exhibited poorer health . Close collaboration between the patient , the primary health care and oral health professionals could be a way of improving the diabetic patient 's general and oral health Abstract Objective : To examine the value of glycated haemoglobin ( HbA1c ) concentration , a marker of blood glucose concentration , as a predictor of death from cardiovascular and all causes in men . Design : Prospect i ve population study . Setting : Norfolk cohort of European Prospect i ve Investigation into Cancer and Nutrition ( EPIC-Norfolk ) . Subjects : 4662 men aged 45 - 79 years who had had glycated haemoglobin measured at the baseline survey in 1995 - 7 who were followed up to December 1999 . Main outcome measures : Mortality from all causes , cardiovascular disease , ischaemic heart disease , and other causes . Results : Men with known diabetes had increased mortality from all causes , cardiovascular disease , and ischaemic disease ( relative risks 2.2 , 3.3 , and 4.2 , respectively , P < 0.001 independent of age and other risk factors ) compared with men without known diabetes . The increased risk of death among men with diabetes was largely explained by HbA1c concentration . HbA1c was continuously related to subsequent all cause , cardiovascular , and ischaemic heart disease mortality through the whole population distribution , with lowest rates in those with HbA1c concentrations below 5 % . An increase of 1 % in HbA1c was associated with a 28 % ( P<0.002 ) increase in risk of death independent of age , blood pressure , serum cholesterol , body mass index , and cigarette smoking habit ; this effect remained ( relative risk 1.46 , P=0.05 adjusted for age and risk factors ) after men with known diabetes , a HbA1c concentration ≥7 % , or history of myocardial infa rct ion or stroke were excluded . 18 % of the population excess mortality risk associated with a HbA1c concentration ≥5 % occurred in men with diabetes , but 82 % occurred in men with concentrations of 5%-6.9 % ( the majority of the population ) . Conclusions : Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution . Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA1c through behavioural means Despite long-st and ing critiques of the conduct of underpowered clinical trials , the practice not only remains widespread , but also has garnered increasing support . Patients and healthy volunteers continue to participate in research that may be of limited clinical value , and authors recently have offered 2 related arguments to support the validity and value of underpowered clinical trials : that meta- analysis may " save " small studies by providing a means to combine the results with those of other similar studies to enable estimates of an intervention 's efficacy , and that although small studies may not provide a good basis for testing hypotheses , they may provide valuable estimates of treatment effects using confidence intervals . In this article , we examine these arguments in light of the distinctive moral issues associated with the conduct of underpowered trials , the disclosures that are owed to potential participants in underpowered trials so they may make autonomous enrollment decisions , and the circumstances in which the prospect s for future meta-analyses may justify individually underpowered trials . We conclude that underpowered trials are ethical in only 2 situations : small trials of interventions for rare diseases in which investigators document explicit plans for including their results with those of similar trials in a prospect i ve meta- analysis , and early-phase trials in the development of drugs or devices , provided they are adequately powered for defined purpose s other than r and omized treatment comparisons . In both cases , investigators must inform prospect i ve subjects that their participation may only indirectly contribute to future health care benefits Measurement of glycohemoglobin ( GHb ) is widely used in patients with diabetes mellitus as a monitor of long-term glycemic control (1)(2)(3 ) . In addition , prospect i ve r and omized clinical trials , most notably the Diabetes Control and Complications Trial ( DCCT ) and the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) , have demonstrated that GHb is a measure of the risk for the development of diabetes complications (4)(5 ) . GHb is therefore an integral component of the management of patients with diabetes . GHb comprises several different hemoglobin-glucose adducts , including hemoglobin A1a ( HbA1a ) , HbA1b , and HbA1c . More than 30 different methods are commercially available to measure GHb . Together these factors have led to considerable variation in reference intervals and results reported by different laboratories . When the DCCT was published in 1993 , the lack of st and ardization of GHb methods produced very wide variability among methods , with values ranging from 4.0 % to 8.1 % on the same blood sample ( 6 ) . In the United States , the NGSP ( previously known as the National Glycohemoglobin St and ardization Program ) has reduced interlaboratory variation ( 7 ) . Using a st and ardization process based on the DCCT reference method , the NGSP has promoted a dramatic improvement in comparability of GHb values among laboratories ( 3 ) . Data from the 2003 GH2 survey from the College of American Pathologists indicated that ≥98 % of participating laboratories use NGSP-certified methods and report results as HbA1c or HbA1c equivalents ( 3 ) . Analogous st and ardization programs in Sweden and Japan (8)(9 ) , established to harmonize GHb results , have also reduced variability among GHb results . More recently , the IFCC Working Group on HbA1c St and ardization prepared primary reference material s of pure HbA1c and HbA0 and developed a reference method for HbA1c ( 10 ) . They defined HbA1c as the stable adduct of glucose to the N-terminal valine of the β-chain of hemoglobin . In the reference method , hemoglobin is cleaved Background Periodontitis is a common , chronic inflammatory disease caused by gram-negative bacteria leading to destruction of tissues supporting the teeth . Epidemiological studies have consistently shown increased frequency , extent and severity of periodontitis among diabetic adults . More recently , some controlled clinical trials have also suggested that periodontal treatment could improve glycaemic control in diabetic patients . However current evidence does not provide sufficient information on which to confidently base any clinical recommendations . The main objective of this clinical trial is to assess whether periodontal treatment could lead to a decrease in glycated haemoglobin levels in metabolically unbalanced diabetic patients suffering from chronic periodontitis . Methods The DIAPERIO trial is an open-label , 13-week follow-up , r and omized , controlled trial . The total target sample size is planned at 150 participants , with a balanced ( 1:1 ) treatment allocation ( immediate treatment vs delayed treatment ) . Periodontal treatment will include full mouth non-surgical scaling and root planing , systemic antibiotherapy , local antiseptics ( chlorhexidine 0.12 % ) and oral health instructions . The primary outcome will be the difference in change of HbA1c between the two groups after the 13-weeks ' follow-up . Secondary outcomes will be the difference in change of fructosamine levels and quality of life between the two groups . Discussion The DIAPERIO trial will provide insight into the question of whether periodontal treatment could lead to an improvement in glycaemic control in metabolically unbalanced diabetic patients suffering from periodontitis . The results of this trial will help to provide evidence -based recommendations for clinicians and a draft framework for design ing national health policies . Trial registration Current Controlled Trials IS RCT Periodontal disease is a common infection-induced inflammatory disease among individuals suffering from diabetes mellitus . The purpose of this study was to assess the effects of treatment of periodontal disease on the level of metabolic control of diabetes . A total of 113 Native Americans ( 81 females and 32 males ) suffering from periodontal disease and non-insulin dependent diabetes mellitus ( NIDDM ) were r and omized into 5 treatment groups . Periodontal treatment included ultrasonic scaling and curettage combined with one of the following antimicrobial regimens : 1 ) topical water and systemic doxycycline , 100 mg for 2 weeks ; 2 ) topical 0.12 % chlorhexidine ( CHX ) and systemic doxycycline , 100 mg for 2 weeks ; 3 ) topical povidone-iodine and systemic doxycycline , 100 mg for 2 weeks ; 4 ) topical 0.12 % CHX and placebo ; and 5 ) topical water and placebo ( control group ) . Assessment s were performed prior to and at 3 and 6 months after treatment and included probing depth ( PD ) , clinical attachment level ( CAL ) , detection of Porphyromonas gingivalis in subgingival plaque and determination of serum glucose and glycated hemoglobin ( HbA1c ) . After treatment all study groups showed clinical and microbial improvement . The doxycycline-treated groups showed the greatest reduction in probing depth and subgingival Porphyromonas gingivalis compared to the control group . In addition , all 3 groups receiving systemic doxycycline showed , at 3 months , significant reductions ( P < or = 0.04 ) in mean HbA1c reaching nearly 10 % from the pretreatment value . Effective treatment of periodontal infection and reduction of periodontal inflammation is associated with a reduction in level of glycated hemoglobin . Control of periodontal infections should thus be an important part of the overall management of diabetes mellitus patients BACKGROUND Periodontitis is a major cause of tooth loss among adults . Several studies have shown a possible systemic impact of periodontal infection , including poor glycemic control in patients with diabetes . Recently , photodynamic therapy ( PDT ) was used to successfully treat periodontal infection . PDT provides a broad spectrum antimicrobial efficacy with no local or systemic side effects . The objective of this study was to examine the effect of the adjunctive use of PDT on periodontal status and glycemic control of patients with diabetes and periodontitis . METHODS Forty-five patients with type 2 diabetes and moderate to severe chronic periodontitis were selected and r and omly assigned to one of the following three treatment modalities ( 15 subjects each ) : scaling and root planing ( SRP ) only , SRP plus systemic doxycycline , and SRP plus PDT . The plaque and bleeding scores , probing depth , clinical attachment level , and glycosylated hemoglobin ( HbA1c ) level were recorded at baseline and 3 months after periodontal treatment . Descriptive statistics , the paired t test , and analysis of variance ( ANOVA ) were used for data analysis . RESULTS Statistically significant differences in the mean probing depth , clinical attachment level , plaque deposit , and bleeding on probing were found between baseline and 12 weeks post-treatment for all groups . No significant differences in periodontal parameters and glucose levels were detected among the three groups . Reduction in the mean HbA1c level after treatment was observed in all groups but was only significant for the SRP plus doxycycline group . CONCLUSION The results of the present study indicate that PDT does not benefit conventional non-surgical periodontal therapy in patients with diabetes BACKGROUND , AIMS This study was design ed to explore the effect of periodontal therapy on glycemic control in persons with type 2 diabetes mellitus ( DM ) . METHODS 36 patients with type 2 DM ( treatment group ) received therapy for adult periodontitis during an 18-month period . A 36-person control group was r and omly selected from the same population of persons with type 2 DM who did not receive periodontal treatment . RESULTS These groups were well matched for most of the parameters investigated . During the nine-month observation period , there was a 6.7 % improvement in glycemic control in the control group when compared to a 17.1 % improvement in the treatment group , a statistically significant difference . Several parameters that could confound or moderate this glycemic control were explored . These included the treatment of non-dental infections , weight and medication changes . No moderating effect was associated with any of these variables . However , there were too few subjects in the study to have the statistical power necessary to assess these possible moderators of glycemic control . CONCLUSIONS We interpret the data in the study to suggest that periodontal therapy was associated with improved glycemic control in persons with type 2 DM Abstract Objective : To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes . Design : Prospect i ve observational study . Setting : 23 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Participants : 4585 white , Asian Indian , and Afro-Caribbean UKPDS patients , whether r and omised or not to treatment , were included in analyses of incidence ; of these , 3642 were included in analyses of relative risk . Outcome measures : Primary predefined aggregate clinical outcomes : any end point or deaths related to diabetes and all cause mortality . Secondary aggregate outcomes : myocardial infa rct ion , stroke , amputation ( including death from peripheral vascular disease ) , and microvascular disease ( predominantly retinal photo-coagulation ) . Single end points : non-fatal heart failure and cataract extraction . Risk reduction associated with a 1 % reduction in up date d mean HbA1c adjusted for possible confounders at diagnosis of diabetes . Results : The incidence of clinical complications was significantly associated with glycaemia . Each 1 % reduction in up date d mean HbA1c was associated with reductions in risk of 21 % for any end point related to diabetes ( 95 % confidence interval 17 % to 24 % , P<0.0001 ) , 21 % for deaths related to diabetes ( 15 % to 27 % , P<0.0001 ) , 14 % for myocardial infa rct ion ( 8 % to 21 % , P<0.0001 ) , and 37 % for microvascular complications ( 33 % to 41 % , P<0.0001 ) . No threshold of risk was observed for any end point . Conclusions : In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia . Any reduction in HbA1c is likely to reduce the risk of complications , with the lowest risk being in those with HbA1c values in the normal range ( < 6.0 % ) UNLABELLED The AIM of this study was to evaluate the effect of non-surgical therapy on clinical variables and glycemic control on type 2 diabetics with chronic periodontitis . PATIENTS AND METHODS Forty six type 2 diabetics with chronic periodontitis were r and omized into two groups ( group A and group B ) . Treatment included scaling and root planning for group A plus systematic use of doxycycline in both groups . Assessment was made prior to and 16 weeks following the therapy . RESULTS Analysis of data showed that both groups had clinical and glycated hemoglobin ( HbAlc ) improvement after the treatment . Group A had a statistically significant reduction of plaque index and bleeding on probing scores compared with controls ( P < 0.05 ) at 16 weeks . CONCLUSION These results suggest that non-surgical therapy is of value in maintaining periodontal health and may be beneficial in reducing blood glucose level in type 2 diabetics with chronic periodontitis OBJECTIVES The purpose of this study was to evaluate the effect of subgingival administration of doxycycline as an adjunct to periodontal therapy in type 1 diabetes mellitus ( DM ) patients . MATERIAL AND METHODS Twenty-two paired periodontal defects > or = 5.0 mm were treated in 11 patients ( 35 - 55 years old ) . After initial therapy the sites were r and omly assigned into test ( scaling and root planing+subgingival administration of 10 % doxycycline hyclate gel ) or control ( scaling and root planing+subgingival placebo gel ) groups . The clinical parameters of clinical attachment level ( CAL ) , probing depth ( PD ) and gingival margin level ( GML ) for recession determination were assessed at baseline , after 6 weeks , and 6 , 9 and 12 months , using a computerized probe . Data were statistically evaluated using Duncan and F tests . RESULTS Between study group comparisons indicated PD reduction and CAL gain were greater in the test group than in the control group at 6 weeks and 6 , 9 and 12 months but only statistically significant at 12 months ( p<0.05 ) . Within study group comparisons indicated statistically significant differences were found for CAL and PD values favouring the adjunctive doxycycline group from baseline to 6 weeks and 6 , 9 and 12 months ( p<0.05 ) . CONCLUSIONS These findings suggest that subgingivally delivered doxycycline hyclate produces additional favorable clinical results to periodontal therapy in type 1 DM patients BACKGROUND The literature suggests that an alteration in glucose metabolism occurs as a result of antibacterial periodontal therapy . The objective of this study was to monitor the effect of non-surgical periodontal therapy on glycemic control in patients with type 2 diabetes mellitus ( DM ) . METHODS Thirty type 2 DM subjects with periodontitis were r and omly divided into two groups . Group 1 ( G1 ) , 15 subjects , received one-stage full-mouth scaling and root planing ( FMSRP ) plus amoxicillin/clavulanic acid 875 mg ; group 2 ( G2 ) , 15 patients , received only FMSRP . At baseline and after 3 months , the glycated hemoglobin ( HbA1c ) values , fasting glucose , and clinical parameters ( with computerized probing and individualized acrylic stents ) were recorded . Following therapy , the subjects were enrolled in a 2-week interval maintenance program for 3 months . RESULTS After treatment , both groups showed clinical improvements . A probing depth ( PD ) reduction of 0.8 + /- 0.6 mm ( P < 0.05 ) occurred in G1 and 0.9 + /- 0.4 mm in G2 ( P < 0.05 ) , but there were no significant changes in attachment level . Treatment reduced the HbA1c values after the 3-month observation period in both groups ; however , the reduction in HbA1c values for the G2 group was statistically significant , but not for the G1 group . The changes in fasting glucose levels were not significant for either group . CONCLUSIONS Periodontal therapy improved glycemic control in patients with type 2 DM in both groups ; however , the reduction in HbA1c values reached statistical significance only in the group receiving scaling and root planing alone [ correction ] AIM The purpose of this study was to assess the response of diabetics to scaling and root planing treatment and subgingival oral irrigation as adjunctive therapy . METHOD A total of 52 type 1 and 2 diabetics ( mean age 51.3+/-14 ) with adult periodontitis were r and omized to two groups . Treatment included ultrasonic scaling and scaling and root planing in both groups ( control and test ) plus subgingival water irrigation 2x daily for the test group . Assessment s were made prior to and at 6 and 12 weeks after treatment . Parameters measured were modified gingival index ( MGI ) , probing pocket depth ( PPD ) , plaque index ( PI ) , clinical attachment level ( CAL ) , and bleeding on probing ( BOP ) . Systemic measurement of Reactive Oxygen Species ( ROS ) generation , cytokines ( TNF-alpha , IL-1beta , IL-10 , and PGE2 ) , and glycated hemoglobin ( HbA1C ) . RESULTS After treatment , analysis of data showed that both groups had clinical and systemic improvement . The test group had a statistically significant reduction for MGI , PI , and BOP compared to controls ( p<0.03 ) at 12 weeks and for ROS generation at 12 weeks ( p<0.012 ) . Unlike controls , systemic analysis of cytokines showed a statistically significant reduction from baseline for IL-1beta at 6 weeks and PGE2 at 6 and 12 weeks ( p<0.05 ) within test group . CONCLUSION These results suggest that scaling and root planing and adjunctive therapy may be of value in establishing a healthy periodontium in diabetics OBJECTIVES Report results of a r and omized- clinical trial of the efficacy of periodontal care in the improvement of glycemic control in 165 veterans with poorly controlled diabetes over 4 months . METHODS Outcomes were change in Haemoglobin A1c ( HbA1c ) in the Early Treatment versus untreated ( Usual Care ) groups and percent of participants with decreases in HbA1c . Analyses included simple/multiple variable linear/logistic regressions , adjusted for baseline HbA1c , age , and duration of diabetes . RESULTS Unadjusted analyses showed no differences between groups . After adjustment for baseline HbA1c , age , and diabetes duration , the mean absolute HbA1c change in the Early Treatment group was -0.65 % versus -0.51 % in the Usual Care group ( p=0.47 ) . Adjusted odds for improvement by 0.5 % in the Early Treatment group was 1.67 ( 95 % confidence interval : 0.84 , 3.34 , p=0.14 ) . Usual Care subjects were twice as likely to increase insulin from baseline to 4 months ( 20 % versus 11 % , p=0.12 ) and less likely to decrease insulin ( 1 % versus 6 % , p=0.21 ) than Early Treatment subjects . Among insulin users at baseline , more increased insulin in the Usual Care group ( 40 % versus 21 % , p=0.06 ) . CONCLUSIONS No significant benefit was found for periodontal therapy after 4 months in this study ; trends in some results were in favour of periodontal treatment AIM The present investigation was performed to study how type 1 diabetics responded to non-surgical periodontal treatment with and without adjunctive doxycycline . METHOD Sixty diabetic type 1 patients ( mean age 35.3+/-9 years ) with moderate-to-severe periodontal disease were selected and divided into two groups of 30 patients each . Both groups were sex and age matched and had similar amounts of periodontal destruction . Plaque index ( PI ) , bleeding on probing ( BOP ) , probing depth ( PD ) and clinical attachment levels ( CAL ) were recorded . Group 1 ( 30 patients ) was treated with oral hygiene instruction , scaling and root planing , chlorhexidine rinses twice a day and doxycycline ( 100 mg/day for 15 days ) . Group 2 ( 30 patients ) had the same treatment but without doxycycline . After 12 weeks their periodontal condition was reevaluated . RESULTS After treatment , both groups had a significant improvement in all periodontal parameters , since PI , BOP , probing pocket depth ( PPD ) and CAL were significantly reduced . However , the reduction in PD in pockets > or = 6 mm and in BOP were more evident when doxycycline was used ( group 1 ) . Differences between groups for these parameters were statistically significant ( p=0.03 ) . CONCLUSION Although both periodontal treatment regimens are effective in type 1 diabetics , the use of doxycycline as an adjunct , provided more significant results when good plaque control was achieved BACKGROUND Alendronate ( ALN ) is an aminobisphosphonate commonly used for osteoporosis in postmenopausal women . We studied the effect of ALN on bone loss prevention in type 2 diabetes mellitus patients with periodontal disease . METHODS In a controlled double-blind , r and omized study we evaluated prospect ively diabetic patients paired by gender and years since diagnosis for 6 months . The study included 40 patients ( 20 men and 20 women ) , 50 to 60 years old , with more than 5 years since diagnosis of diabetes and established periodontitis . They were r and omly allocated to alendronate ( 10 mg/daily ) or placebo treatment for 6 months . The endpoints of treatment were : the distance between the alveolar bone border and the cemento-enamel-junction ( CEJ ) evaluated by means of digital radiographic imaging , a biochemical marker of bone resorption ( urine N-telopeptide ) ( Ntx ) , and periodontal parameters . Metabolic control was assessed at baseline and after 6 months . RESULTS Baseline and 6-month glycated hemoglobin levels were similar in both groups . Alendronate induced a significant decrease in NTx at 6 months ( P = 0.006 ) . Periodontal parameters improved in both groups . However , they were significantly better for the ALN treated group . Alveolar bone border-CEJ distance increased in the placebo , but decreased in the ALN group ( P = 0.0003 ) . CONCLUSIONS In type-2 diabetic patients , alendronate induced more improvement in alveolar bone crest height than control therapy . No differences in urinary N-telopeptide or glycated hemoglobin were observed in this short-term r and omized controlled pilot trial

Conclusions The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter .

Background Aromatase inhibitors ( AIs ) have been associated with cardiovascular disease in adjuvant r and omized controlled trials ( RCTs ) comparing these drugs to tamoxifen . However , it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen . To address this question , we conducted a systematic review and meta- analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting .

Tamoxifen is associated with a reduced risk of coronary heart disease ( CHD ) . However , there are few reports on long-term effects . Using data from a large Swedish r and omized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer , we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment . A total of 4,150 patients were breast cancer recurrence-free after 2 years . Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease . Hazard ratios were estimated using Cox regression . Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [ hazard ratio ( HR ) , 0.83 ; 95 % CI 0.70–1.00 ] , especially apparent during the active treatment period ( HR 0.65 ; 95 % CI 0.43–1.00 ) . The mortality from CHD was significantly reduced ( HR 0.72 ; 95 % CI 0.53–0.97 ) . During the active treatment , the morbidity of other heart diseases was also significantly reduced ( HR 0.40 ; 95 % CI 0.25–0.64 ) but not after treatment stopped ( HR 1.06 ; 95 % CI 0.87–1.30 ) . Similar results were seen for both heart failure and atrial fibrillation/flutter . As compared to 2 years of therapy , 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases . The risk reduction is most apparent during the active treatment period , and later tends to diminish Abstract Objective : To determine any cardiac or vascular morbidity associated with long term treatment with tamoxifen given after mastectomy for primary breast cancer . Design : Cohort study using linkage between data base of a r and omised trial and statistics of Scottish hospital in patients to identify episodes of cardiac and vascular morbidity . Setting : NHS hospitals in Scotl and . Subjects : 1312 women who had undergone mastectomy for breast cancer and who were r and omised either to a treatment group to receive adjuvant tamoxifen or to a control group to be given tamoxifen only on first relapse of disease . Maximum duration of tamoxifen treatment was 14 years . Total woman years of follow up were 9943 . Main outcome measures : R and omised and observational comparisons of risk ( expressed as hazard ratios ) of myocardial infa rct ion , other cardiac event , cerebrovascular disease , or thromboembolic event according to treatment allocated and between non-users , former users , and current users of tamoxifen . Results : Use of tamoxifen was associated with lower rates of myocardial infa rct ion . Hazard ratio for women in control group was 1.92 ( 95 % confidence interval 0.99 to 3.73 ) compared with women allocated to adjuvant treatment . The association was stronger for current use : hazard ratio for non-users was 3.49 ( 1.52 to 8.03 ) compared with current users . Current users of tamoxifen , however , had higher rates of thromboembolic events : hazard ratio for non-users was 0.40 ( 0.18 to 0.90 ) compared with current users . Conclusions : Our results provide further evidence that tamoxifen reduces the risk of myocardial infa rct ion . Thromboembolic events should be carefully monitored in trials of tamoxifen , particularly those of prophylactic treatment , in which tamoxifen is given to healthy women www.thelancet.com/oncology Vol 17 July 2016 e275 Postmenopausal women with hormone-receptor-positive early breast cancer could benefit by extending adjuvant therapy with aromatase inhibitors from 5 years to 10 years , a new double-blind , phase 3 , placebo-controlled trial study suggests . Paul Goss ( Massachusetts General Hospital Cancer Centre , MA , USA ) and colleagues ’ study enrolled postmenopausal women with primary breast cancer who had received 4·5 - 6·0 years of adjuvant therapy with an aromatase inhibitor , most of whom had previously been treated with tamoxifen and who were disease-free at the time of enrolment . 1918 patients were r and omly assigned to receive 25 mg letrozole or placebo daily for a further 5 years . At a median follow-up of 6·3 years , 67 ( 7 % ) of 959 patients in the letrozole group had disease recurrence or contralaleral breast cancer compared with 98 ( 10 % ) of 959 patients in the placebo group . 5-year disease-free survival ( the primary endpoint ) was 95 % ( 95 % CI 93–96 ) in the letrozole group and 91 % ( 89–93 ) in the placebo group , ( 0·66 hazard ratio [ 95 % CI 0·48–0·91 ] ; p=0·01 ) . 5-year overall survival was similar between groups : 93 % ( 95 % CI 92–95 ) with letrozole and 94 % ( 92–95 ) with placebo ( HR 0·97 , 95 % CI 0·73–1·28 ; p=0·83 ) . Except for bone-related toxic eff ects , which occurred more frequently in the letrozole group compared with the placebo group , the toxic eff ects were similar . Commenting on the study , Miguel Martin ( Hospital General Universitario Gregorio Maranon , Madrid , Spain ) , said that “ this [ study ] is very relevant clinical ly , is practice changing , and should be discussed with our patients as a new option , taking into consideration the pros ( reduction of contralateral breast cancers and local-regional and distant metastases ) and the cons ( lack of survival benefi t and negative bone eff ects of letrozole ) of the therapy . ” He continued , “ Avoiding a contralateral breast cancer , regardless of the lack of benefit on survival , is a goal by itself . ” Goss told The Lancet Oncology , “ We are conducting deeper analyses to determine which patients should or should not continue [ alignment therapy ] . We have reduced recurrences or occurrences by 34 % which is clinical ly very significant . ” However , he concluded , “ Extending a therapy clinical ly for 5 years is important and my opinion is that ... a sober judgment by properly appointed guideline committees is needed ” before such changes are instituted Introduction Extended adjuvant endocrine therapy for breast cancer with aromatase inhibitors may potentially alter the lipid profile of postmenopausal patients and thus increase the risk of developing cardiovascular disease . In this study , a sub protocol of the ATENA ( Adjuvant post-Tamoxifen Exemestane versus Nothing Applied ) trial , we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal patients with operable breast cancer , in the adjuvant setting , with that of observation alone after completion of 5 to 7 years of primary treatment with tamoxifen . Methods In this open-label , r and omized , parallel-group study , 411 postmenopausal patients with operable breast cancer , who had been treated with tamoxifen for 5 to 7 years , were r and omized to either 5 additional years of exemestane ( 25 mg/day ; n = 211 ) or observation only ( n = 200 ) . Assessment s of total cholesterol ( TC ) , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , and total serum triglycerides ( TRG ) were performed at baseline and then during each follow-up visit , performed at either 6 or 12 months , according to the center 's clinical practice , until completing 24 months in the study . Results TC and LDL levels increased significantly across time for both arms ; TC increase was more pronounced for the observation arm , and that was sustained up to 24 months . HDL levels decreased significantly across time for the exemestane arm , whereas no significant change was detected across time for the observation arm . Triglyceride levels decreased significantly across time on both arms , with no difference detected in changes from baseline between the exemestane and the observation arms . Conclusions Exemestane lacks the beneficial effect of tamoxifen on lipids ; however , sequential adjuvant treatment with exemestane in postmenopausal breast cancer patients after cessation of 5 to 7 years of tamoxifen does not appear to alter the lipid profile significantly compared with that of an observational arm . Trial Registration Clinical Trials.gov ID : NCT00810706 PURPOSE This study analyzes the long-term results and causes of death in elderly women with node-positive breast cancer who participated in a double-blind adjuvant trial that compared tamoxifen with placebo to determine the benefit of 2 years of treatment . PATIENTS AND METHODS One hundred eighty-one women 65 to 84 years old were given 20 mg of tamoxifen or placebo daily for 2 years after stratification by estrogen receptor status , tumor size , and degree of lymph node involvement . Approximately 30 % of patients were older than 70 years and 20 % were older than 75 years . Eighty-five percent were estrogen receptor-positive . Median follow-up was 10 years . RESULTS Among the 168 eligible patients , there have been 98 recurrences ( 59 placebo v 39 tamoxifen ) , with reduced distant and bone-only first sites in patients treated with tamoxifen . Median time to failure was 4.4 years for placebo versus 7.4 years for tamoxifen ( log-rank P = .001 ) . A similar number of new nonbreast cancers occurred in each arm ( seven placebo v six tamoxifen ) , but a reduced number of opposite-breast cancers ( five placebo v one tamoxifen ) was noted . Overall , there were 102 deaths ( 57 placebo v 45 tamoxifen ) . Median survivals were 8.0 years with placebo and 8.5 years with tamoxifen ( log-rank P = .063 ) ; 50 % of the tamoxifen patients and 33 % of the placebo patients are still alive . Sixty-one percent of the deaths were reported to have been caused by breast cancer recurrence , 4 % by other cancers , and 22 % by the sequelae of non-cancer-related illness , with equal distributions for cardiovascular and cerebrovascular disease . There was no increase in the number of endometrial or other types of cancer , or thrombotic or orthopedic complications in this older group . CONCLUSION Tamoxifen currently is the treatment of choice for elderly women with breast cancer . It extends the time to treatment failure by 3 years and reduces the number of recurrences , deaths , distant and bone-only first recurrences , and second breast cancers BACKGROUND Adjuvant tamoxifen therapy for breast cancer has been given for a period of several years . Cardiovascular diseases increased in incidence rapidly in women older than 60 years . Favorable changes in cardiovascular risk factors have been seen with 2 years of tamoxifen therapy , and lower rates of myocardial infa rct ion and of hospitalization for heart disease have been observed in tamoxifen-treated women . PURPOSE We sought to evaluate changes in risk factors for cardiovascular diseases in postmenopausal women after therapy with tamoxifen for 5 years . METHODS Five years after their initial entry in a 2-year r and omized , placebo-controlled toxicity study , we re-examined 62 of the original 140 disease-free , axillary node-negative postmenopausal breast cancer patients . These 62 patients were women available for study because they had not suffered major illness and had continued on either the tamoxifen or no-tamoxifen regimen to which they had been originally r and omly assigned for the entire 5 years . Patient and control blood sample s were analyzed for total cholesterol , low-density lipoprotein ( LDL ) cholesterol , high-density lipoprotein ( HDL ) cholesterol and subfractions , triglycerides , apolipoprotein AI , apolipoprotein B , lipoprotein(a ) , fibrinogen , glucose , and platelets . RESULTS At base line for all measurements except atherogenic lipoprotein [ lipoprotein(a ) ] , the 30 long-term tamoxifen recipients and the 32 long-term no-tamoxifen recipients were not significantly different . After 5 years , levels of total serum cholesterol ( P < .001 ) , LDL cholesterol ( P < .001 ) , and lipoprotein(a ) ( P = .001 ) were significantly lower , and apolipoprotein AI levels were significantly higher ( P < .001 ) in the tamoxifen-treated group compared with the no-tamoxifen group . Apolipoprotein B levels increased to a greater extent in the no-tamoxifen than in the tamoxifen group ( P < .001 ) . After 5 years , fibrinogen level decrease and triglyceride level increases in the tamoxifen group compared with the no-tamoxifen group were of borderline statistical significance and HDL cholesterol levels were not different in the two groups . CONCLUSION Favorable changes in lipid , lipoprotein , and fibrinogen levels seen early in tamoxifen therapy in postmenopausal women persist with treatment of 5 years . IMPLICATION S The types and magnitude of changes in cardiovascular risk factors seen here with tamoxifen are similar to a certain extent with those seen with estrogen supplements . Further risk-factor and ethnic-group data are needed to estimate the magnitude of expected benefits of tamoxifen treatment on incidence of heart disease PURPOSE In postmenopausal women with estrogen receptor-positive early breast cancer , surgery is usually followed by a 5-year course of tamoxifen . This report presents results of a prospect i ve , open-label , r and omized study , design ed to evaluate the benefits of switching to anastrozole after 2 years of tamoxifen treatment , compared with continuing on tamoxifen for 5 years . PATIENTS AND METHODS After receiving tamoxifen treatment for 2 years , eligible patients ( n = 979 ) were r and omly assigned to switch to anastrozole ( 1 mg/d ) or continue tamoxifen ( 20 or 30 mg/d ) for an additional 3 years . Patients were monitored every 6 months during years 1 to 3 and annually thereafter . The primary efficacy variable was disease-free survival , including local or distant recurrence , new contralateral breast cancer , or death . Secondary variables were overall survival and assessment of safety . RESULTS Switching to anastrozole result ed in a significant reduction in the risk of disease recurrence ( hazard ratio [ HR ] , 0.66 ; 95 % CI , 0.44 to 1.00 ; P = .049 ) , and improved overall survival ( HR , 0.53 ; 95 % CI , 0.28 to 0.99 ; P = .045 ) compared with continuing on tamoxifen . Fewer patients who switched to anastrozole reported serious adverse events ( 22.7 % v 30.8 % ) compared with those who continued on tamoxifen , mainly due to more patients in the tamoxifen group with endometrial events . The overall safety profile for anastrozole was consistent with previous reports and no new safety issues were identified . CONCLUSION Postmenopausal women who have taken tamoxifen for 2 years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing to receive tamoxifen BACKGROUND The purpose of this study was to evaluate changes in serum lipid parameters { cholesterol , high-density lipoprotein ( HDL ) cholesterol , low-density lipoprotein ( LDL ) cholesterol , triglycerides and lipoprotein(a ) [ Lp(a ) ] } , in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer ( NCIC CTG MA.17L ) . PATIENTS AND METHODS MA.17L is a sub study of MA.17 , a r and omized , double-blind , placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen . Patients consenting to participate in this companion study had blood drawn and lipid parameters ( total cholesterol , HDL cholesterol , LDL cholesterol , Lp(a ) , triglycerides ) evaluated at baseline , 6 months , 12 months and yearly thereafter until completion of protocol therapy . It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial . RESULTS Three hundred and forty seven women were enrolled in the study . The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months ( P=0.049 ) , in LDL cholesterol at 12 months ( P=0.033 ) and triglycerides at 24 months ( P=0.036 ) . All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups . No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups . CONCLUSIONS The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen . Results from this study suggests that letrozole does not significantly alter serum cholesterol , HDL cholesterol , LDL cholesterol , triglycerides or Lp(a ) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy . These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following st and ard tamoxifen therapy Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Health-related quality of life ( HRQOL ) , symptoms of depression , and adverse events ( AEs ) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer ( BC ) who received adjuvant tamoxifen , exemestane , or anastrozole in an open-labeled , r and omized , multicenter trial design ated as the National Surgical Adjuvant Study of Breast Cancer ( N-SAS BC ) 04 sub study of the Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) trial . During the first year of treatment , HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast ( FACT-B ) and its Endocrine Symptom Subscale ( ES ) , and the Center for Epidemiologic Studies Depression Scale ( CES-D ) , respectively . In addition , predefined AEs were analyzed . A total of 166 eligible patients were r and omly assigned to receive adjuvant tamoxifen , exemestane , or anastrozole . FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year ( P = 0.045 ) . FACT-B scores were similar in the exemestane group and anastrozole group . ES scores and CES-D scores were similar in all treatment groups . Arthralgia and fatigue were less frequent , but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group . HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole . HRQOL and AEs were similar with exemestane and anastrozole . Given the results of the TEAM trial , upfront use of tamoxifen followed by an aromatase inhibitor ( AI ) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival ( DFS ) than tamoxifen in postmenopausal early breast cancer . Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences , assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted . This open-label , r and omized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer , who had received tamoxifen for 1 to 4 years as adjuvant therapy . This study was closed early after entry of ~28 % of the initially planned patients . They were r and omly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years . Primary endpoints were DFS and adverse events . At a median follow-up of 42 months , the unadjusted hazard ratio was 0.69 ( 95 % confidence interval , 0.42–1.14 ; P = 0.14 ) for DFS and 0.54 ( 95 % CI , 0.29–1.02 ; P = 0.06 ) for relapse-free survival ( RFS ) , both in favor of anastrozole . The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high . Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients . Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese Summary Background For women with oestrogen receptor (ER)-positive early breast cancer , treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis . We aim ed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years . Methods In the worldwide Adjuvant Tamoxifen : Longer Against Shorter ( ATLAS ) trial , 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were r and omly allocated to continue tamoxifen to 10 years or stop at 5 years ( open control ) . Allocation ( 1:1 ) was by central computer , using minimisation . After entry ( between 1996 and 2005 ) , yearly follow-up forms recorded any recurrence , second cancer , hospital admission , or death . We report effects on breast cancer outcomes among the 6846 women with ER-positive disease , and side-effects among all women ( with positive , negative , or unknown ER status ) . Long-term follow-up still continues . This study is registered , number IS RCT N19652633 . Findings Among women with ER-positive disease , allocation to continue tamoxifen reduced the risk of breast cancer recurrence ( 617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls , p=0·002 ) , reduced breast cancer mortality ( 331 deaths vs 397 deaths , p=0·01 ) , and reduced overall mortality ( 639 deaths vs 722 deaths , p=0·01 ) . The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 ( recurrence rate ratio [ RR ] 0·90 [ 95 % CI 0·79–1·02 ] during years 5–9 and 0·75 [ 0·62–0·90 ] in later years ; breast cancer mortality RR 0·97 [ 0·79–1·18 ] during years 5–9 and 0·71 [ 0·58–0·88 ] in later years ) . The cumulative risk of recurrence during years 5–14 was 21·4 % for women allocated to continue versus 25·1 % for controls ; breast cancer mortality during years 5–14 was 12·2 % for women allocated to continue versus 15·0 % for controls ( absolute mortality reduction 2·8 % ) . Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease , and an intermediate effect among 4800 women with unknown ER status . Among all 12 894 women , mortality without recurrence from causes other than breast cancer was little affected ( 691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls ; RR 0·99 [ 0·89–1·10 ] ; p=0·84 ) . For the incidence ( hospitalisation or death ) rates of specific diseases , RRs were as follows : pulmonary embolus 1·87 ( 95 % CI 1·13–3·07 , p=0·01 [ including 0·2 % mortality in both treatment groups ] ) , stroke 1·06 ( 0·83–1·36 ) , ischaemic heart disease 0·76 ( 0·60–0·95 , p=0·02 ) , and endometrial cancer 1·74 ( 1·30–2·34 , p=0·0002 ) . The cumulative risk of endometrial cancer during years 5–14 was 3·1 % ( mortality 0·4 % ) for women allocated to continue versus 1·6 % ( mortality 0·2 % ) for controls ( absolute mortality increase 0·2 % ) . Interpretation For women with ER-positive disease , continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality , particularly after year 10 . These results , taken together with results from previous trials of 5 years of tamoxifen treatment versus none , suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis . Funding Cancer Research UK , UK Medical Research Council , AstraZeneca UK , US Army , EU-Biomed In a trial that began in 1978 , 1312 evaluable patients under 80 years of age who either had negative axillary nodes or were postmenopausal with positive axillary nodes were r and omised to receive adjuvant tamoxifen 20 mg daily for 5 years , or tamoxifen for the treatment of first relapse . Estimates of oestrogen receptor ( ER ) content of primary tumour specimens were made in 57 % . There has been a highly significant delay in relapse in the adjuvant arm of the trial . This benefit supersedes that from tamoxifen given as treatment for recurrent disease in control-arm patients ( 93 % received this ) so that benefit from adjuvant tamoxifen was maintained in the overall survival comparisons . This improvement seems to be independent of nodal and menopausal status . It does not differ significantly with ER level , although the greatest benefit in disease-free survival is in patients with levels of 100 fmol/mg protein or more Long-term endocrine therapy for breast cancer may have clinical implication s as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease . In this study , a companion sub protocol to the ATENA ( Adjuvant post-Tamoxifen Exemestane versus Nothing Applied ) trial , we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of post-menopausal women with operable breast cancer in the adjuvant setting to that of observation alone following deprivation of 5–7 years primary treatment with tamoxifen . In this open-label , r and omized , parallel group study , 340 post-menopausal patients with operable breast cancer who had been treated with tamoxifen for 5–7 years were r and omized to either 5 additional years of exemestane ( 25 mg/day ; n=172 ) or observation alone ( n=168 ) . Assessment s of total cholesterol , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) and total serum triglycerides ( TRG ) were performed at baseline , and at 6 and 12 months . Total TRG levels were significantly reduced compared with baseline for the exemestane and the observational arm . Both total cholesterol and LDL levels were significantly increased above that of baseline values by 6 months , maintained through to 12 months , with no significant difference between the two treatment arms . There was no significant alteration observed for HDL over time or between the two arms . We conclude that sequential adjuvant treatment with exemestane in post-menopausal operable breast cancer patients following cessation of 5–7 years of tamoxifen does not appear to significantly alter the lipidemic profile for at least 12 months compared with an observational arm BACKGROUND Tamoxifen , taken for five years , is the st and ard adjuvant treatment for postmenopausal women with primary , estrogen-receptor-positive breast cancer . Despite this treatment , however , some patients have a relapse . METHODS We conducted a double-blind , r and omized trial to test whether , after two to three years of tamoxifen therapy , switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment . The primary end point was disease-free survival . RESULTS Of the 4742 patients enrolled , 2362 were r and omly assigned to switch to exemestane , and 2380 to continue to receive tamoxifen . After a median follow-up of 30.6 months , 449 first events ( local or metastatic recurrence , contralateral breast cancer , or death ) were reported--183 in the exemestane group and 266 in the tamoxifen group . The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 ( 95 percent confidence interval , 0.56 to 0.82 ; P<0.001 by the log-rank test ) , representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent ( 95 percent confidence interval , 2.6 to 6.8 ) at three years after r and omization . Overall survival was not significantly different in the two groups , with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group . Severe toxic effects of exemestane were rare . Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group ( P=0.04 ) . CONCLUSIONS Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the st and ard five years of tamoxifen treatment Our study demonstrates that tamoxifen , when administered to postmenopausal women at a conventional dosage , reduces LDL levels and protects LDL from oxidation . The protective effect of tamoxifen against the development of breast cancer in women considered at risk is being investigated in a placebo-controlled trial sponsored by the National Institutes of Health . Whether tamoxifen also protects against the development of cardiovascular disease in this trial is also of considerable interest BACKGROUND Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2 - 3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer . We therefore compared the long-term effects of exemestane monotherapy with sequential treatment ( tamoxifen followed by exemestane ) . METHODS The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries . Postmenopausal women ( median age 64 years , range 35 - 96 ) with hormone-receptor-positive breast cancer were r and omly assigned in a 1:1 ratio to open-label exemestane ( 25 mg once a day , orally ) alone or following tamoxifen ( 20 mg once a day , orally ) for 5 years . R and omisation was by use of a computer-generated r and om permuted block method . The primary endpoint was disease-free survival ( DFS ) at 5 years . Main analyses were by intention to treat . The trial is registered with Clinical Trials.gov , NCT00279448 , NCT00032136 , and NCT00036270 ; NTR 267 ; Ethics Commission Trial27/2001 ; and UMIN , C000000057 . FINDINGS 9779 patients were assigned to sequential treatment ( n=4875 ) or exemestane alone ( n=4904 ) , and 4868 and 4898 were analysed by intention to treat , respectively . 4154 ( 85 % ) patients in the sequential group and 4186 ( 86 % ) in the exemestane alone group were disease free at 5 years ( hazard ratio 0·97 , 95 % CI 0·88 - 1·08 ; p=0·60 ) . In the safety analysis , sequential treatment was associated with a higher incidence of gynaecological symptoms ( 942 [ 20 % ] of 4814 vs 523 [ 11 % ] of 4852 ) , venous thrombosis ( 99 [ 2 % ] vs 47 [ 1 % ] ) , and endometrial abnormalities ( 191 [ 4 % ] vs 19 [ < 1 % ] ) than was exemestane alone . Musculoskeletal adverse events ( 2448 [ 50 % ] vs 2133 [ 44 % ] ) , hypertension ( 303 [ 6 % ] vs 219 [ 5 % ] ) , and hyperlipidaemia ( 230 [ 5 % ] vs 136 [ 3 % ] ) were reported more frequently with exemestane alone . INTERPRETATION Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer . FUNDING Pfizer BACKGROUND Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer . Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer . METHODS In a r and omized , placebo-controlled , double-blind trial of exemestane design ed to detect a 65 % relative reduction in invasive breast cancer , eligible postmenopausal women 35 years of age or older had at least one of the following risk factors : 60 years of age or older ; Gail 5-year risk score greater than 1.66 % ( chances in 100 of invasive breast cancer developing within 5 years ) ; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ ; or ductal carcinoma in situ with mastectomy . Toxic effects and health-related and menopause-specific qualities of life were measured . RESULTS A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3 % were r and omly assigned to either exemestane or placebo . At a median follow-up of 35 months , 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo , with a 65 % relative reduction in the annual incidence of invasive breast cancer ( 0.19 % vs. 0.55 % ; hazard ratio , 0.35 ; 95 % confidence interval [ CI ] , 0.18 to 0.70 ; P=0.002 ) . The annual incidence of invasive plus noninvasive ( ductal carcinoma in situ ) breast cancers was 0.35 % on exemestane and 0.77 % on placebo ( hazard ratio , 0.47 ; 95 % CI , 0.27 to 0.79 ; P=0.004 ) . Adverse events occurred in 88 % of the exemestane group and 85 % of the placebo group ( P=0.003 ) , with no significant differences between the two groups in terms of skeletal fractures , cardiovascular events , other cancers , or treatment-related deaths . Minimal quality -of-life differences were observed . CONCLUSIONS Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer . During a median follow-up period of 3 years , exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life . ( Funded by Pfizer and others ; NCIC CTG MAP.3 Clinical Trials.gov number , NCT00083174 . ) BACKGROUND In the adjuvant setting , tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer . However , it is associated with several side-effects including endometrial cancer and thromboembolic disorders . We aim ed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years . METHODS Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy . The primary endpoints were disease-free survival and occurrence of adverse events . Analysis for efficacy was by intention to treat . FINDINGS 9366 patients were recruited , of whom 3125 were r and omly assigned anastrozole , 3116 tamoxifen , and 3125 combination . Median follow-up was 33.3 months . 7839 ( 84 % ) patients were known to be hormone-receptor-positive . Disease-free survival at 3 years was 89.4 % on anastrozole and 87.4 % on tamoxifen ( hazard ratio 0.83 [ 95 % CI 0.71 - 0.96 ] , p=0.013 ) . Results with the combination were not significantly different from those with tamoxifen alone ( 87.2 % , 1.02 [ 0.89 - 1.18 ] , p=0.8 ) . The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients , but not the receptor-negative patients . Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen ( odds ratio 0.42 [ 0.22 - 0.79 ] , p=0.007 ) . Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer ( p=0.02 ) , vaginal bleeding and discharge ( p<0.0001 for both ) , cerebrovascular events ( p=0.0006 ) , venous thromboembolic events ( p=0.0006 ) , and hot flushes ( p<0.0001 ) . Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures ( p<0.0001 for both ) . INTERPRETATION Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer . Longer follow-up is required before a final benefit : risk assessment can be made PURPOSE The Cancer Research UK " Over 50s " trial compared 5 and 2 years of tamoxifen in women with early breast cancer . Results are reported after median follow-up of 10 years . PATIENTS AND METHODS Between 1987 and 1997 , 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were r and omly assigned to either stop or continue for an additional 3 years , if they were alive and recurrence free . Data on recurrences , new tumors , deaths , and cardiovascular events were obtained ( April 2010 ) . RESULTS There were 1,103 recurrences , 755 deaths as a result of breast cancer , 621 cardiovascular ( CV ) events , and 236 deaths as a result of CV events . Fifteen years after starting treatment , for every 100 women who received tamoxifen for 5 years , 5.8 fewer experienced recurrence , compared with those who received tamoxifen for 2 years . The risk of contralateral breast cancer was significantly reduced ( hazard ratio , 0.70 ; 95 % CI , 0.48 to 1.00 ) . Among women age 50 to 59 years , there was a 35 % reduction in CV events ( P = .005 ) and 59 % reduction in death as a result of a CV event ( P = .02 ) ; in older women , the effect was much smaller and not statistically significant . CONCLUSION Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment . It also lowers the risk of CV disease and death as a result of a CV event , particularly among those age 50 to 59 years . Women should therefore be encouraged to complete the full course . Although aromatase inhibitors improve disease-free survival , tamoxifen remains a cheap and highly effective alternative , particularly in developing countries The use of tamoxifen as a breast cancer preventive agent may be contraindicated by an increased risk of endometrial cancer and venous thromboembolic events , particularly in postmenopausal women . Since these estrogenic effects may be dose-related , a dose reduction may reduce toxicity . We have recently shown a comparable activity of lower doses of tamoxifen on putative surrogate biomarkers of cardiovascular disease and breast cancer . To provide further insight into the effect of tamoxifen at low doses on the cardiovascular system , we compared the effect of three different doses on circulating levels of C-reactive protein ( CRP ) , an independent risk marker for cardiovascular disease ( CVD ) , which was lowered by tamoxifen at the st and ard dose of 20 mg day-1 in previous studies . We compared the changes in CRP after 2 months of either placebo ( n = 24 ) , or tamoxifen 10 mg alternate daily ( n = 26 ) , or 10 mg day-1 ( n = 22 ) , or 20 mg day-1 ( n = 19 ) in healthy women aged 35 - 70 years . The median percent change was -2.2 % ( 95 % CI , -23.3 to 42.8 ) with placebo , -39.1 ( 95 % CI , -59.9 to -28.7 ) with 10 mg alternate daily , -56.9 % ( 95 % CI , -68.6 to -38.4 ) with 10 mg day-1 and -42.9 % ( 95 % CI , -62.6 to 1.6 ) with 20 mg day-1 ( P = 0.291 for the linear dose-response trend ) . Similar results were obtained when the data were classified according to blood tamoxifen concentrations , with a median reduction of 47 % ( 95 % CI , 65.5 - 36.3 ) for women with low tamoxifen concentrations ( < 30 ng mL-1 ) . We conclude that tamoxifen at low doses is able to lower ultrasensitive CRP and that this might be associated with a beneficial effect on CVD Abstract —Tamoxifen reduces the incidence of breast cancer in women at risk for that disease . Because heart disease is the leading cause of death in women and because tamoxifen is also associated with venous thrombosis , an improved underst and ing of the association of tamoxifen with cardiovascular disease risk factors is required . In 111 healthy women at a single center , who were participating in a r and omized double-blind breast cancer prevention trial , the 6-month effects of oral tamoxifen ( 20 mg/d ) compared with placebo on factors related to inflammation , hemostasis , and lipids were studied . Tamoxifen was associated with reductions of 26 % in median C-reactive protein , 22 % in median fibrinogen , and 9 % in cholesterol ( all P < 0.01 compared with placebo ) . There were no differences in treatment effects on factor VII coagulant activity , fragment 1 - 2 , and triglycerides . In secondary analyses , the effect of tamoxifen on C-reactive protein was larger in postmenopausal women and in women with higher waist-to-hip ratios . The effect on fibrinogen was larger in women with higher baseline cholesterol . Tamoxifen demonstrated effects on inflammatory markers that were consistent with reduced cardiovascular risk . These findings are in contrast to recent reports of increased C-reactive protein associated with postmenopausal estrogen . The potential for beneficial cardiovascular effects of tamoxifen in healthy women is suggested BACKGROUND Although trials of post-surgical tamoxifen therapy for patients with breast cancer have convincingly demonstrated reductions in relapse rates and improvements in survival , the optimal duration of therapy is as yet unclear . PURPOSE Our objective is to determine whether 2 or 5 years of tamoxifen therapy ( 20 mg/day orally ) is preferable in the treatment of patients with early breast cancer . METHODS A r and omized trial that was pragmatic in policy , allowing flexibility in primary treatment ( i.e. , type of surgery ) and adjuvant therapy other than tamoxifen ( i.e. , radiotherapy or chemotherapy ) , was used to encourage maximum participation of clinicians and patients . This design allowed comparison of the two duration s of tamoxifen therapy under conditions in which they would subsequently be applied in clinical practice . The patients were recruited from the oncology departments of participating hospitals in the U.K. , Belgium , Pol and , and Hong Kong . Those women who had completed an initial 2-year course of tamoxifen therapy after primary surgery and had not experienced a recurrence of breast cancer were asked to consider r and om assignment either to no further therapy or to an additional 3 years of tamoxifen . Follow-up reports ( every 6 months for 3 years after r and om assignment and then annually ) were required for all surviving study subjects . These reports recorded all breast cancer-related events ( i.e. , locoregional relapse and distant metastasis ) or the development of new primary tumors ( in the opposite breast or at any other site ) . For patients who died , the date and cause of death were recorded . Event-free survival ; overall survival ; and time to locoregional relapse , distant metastasis , or the development of new primary cancers were end points for the analysis . Survival comparisons were made by use of life tables and the logrank test . Reported P values are two-sided . RESULTS By December 31 , 1994 , 2937 patients had accepted r and om assignment to treatment ; 1470 were assigned to stop tamoxifen therapy after having received it for 2 years and 1467 were assigned to continue therapy for an additional 3 years ( total , 5 years ) . An analysis was performed when the target for patient accrual had been reached , although the trial remains open . At a median follow-up of 2 years since the r and omization , no difference in survival between the two treatment groups was detected ( relative risk = 0.89 ; 95 % confidence interval = 0.69 - 1.15 ) , but a statistically significant delay in the time to relapse for patients receiving the longer treatment was demonstrated ( relative risk = 0.81 ; 95 % confidence interval = 0.69 - 0.98 ) . CONCLUSIONS AND IMPLICATION S Our results suggest that 5 years may be better than 2 years of tamoxifen therapy , but more evidence regarding the optimal duration of tamoxifen therapy must be obtained Summary Background Four previously published r and omised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up . We report the long-term follow-up of the IBIS-I trial , in which the participants and investigators remain largely masked to treatment allocation . Methods In the IBIS-I r and omised controlled trial , premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were r and omly assigned ( 1:1 ) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years . Patients were r and omly assigned to the two treatment groups by telephone or fax according to a block r and omisation schedule ( permuted block sizes of six or ten ) . Patients and investigators were masked to treatment assignment by use of central r and omisation and coded drug supply . The primary endpoint was the occurrence of breast cancer ( invasive breast cancer and ductal carcinoma in situ ) , analysed by intention to treat . Cox proportional hazard models were used to assess breast cancer occurrence and mortality . The trial is closed to recruitment and active treatment is completed , but long-term follow-up is ongoing . This trial is registered with controlledtrials.com , number IS RCT N91879928 . Findings Between April 14 , 1992 , and March 30 , 2001 , 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were r and omly allocated to the two treatment groups : 3579 to tamoxifen and 3575 to placebo . After a median follow up of 16·0 years ( IQR 14·1–17·6 ) , 601 breast cancers have been reported ( 251 [ 7·0 % ] in 3579 patients in the tamoxifen group vs 350 [ 9·8 % ] in 3575 women in the placebo group ; hazard ratio [ HR ] 0·71 [ 95 % CI 0·60–0·83 ] , p<0·0001 ) . The risk of developing breast cancer was similar between years 0–10 ( 226 [ 6·3 % ] in 3575 women in the placebo group vs 163 [ 4·6 % ] in 3579 women in the tamoxifen group ; hazard ratio [ HR ] 0·72 [ 95 % CI 0·59–0·88 ] , p=0·001 ) and after 10 years ( 124 [ 3·8 % ] in 3295 women vs 88 [ 2·6 % ] in 3343 , respectively ; HR 0·69 [ 0·53–0·91 ] , p=0·009 ) . The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer ( HR 0·66 [ 95 % CI 0·54–0·81 ] , p<0·0001 ) and ductal carcinoma in situ ( 0·65 [ 0·43–1·00 ] , p=0·05 ) , but no effect was noted for invasive oestrogen receptor-negative breast cancer ( HR 1·05 [ 95 % CI 0·71–1·57 ] , p=0·8 ) . Interpretation These results show that tamoxifen offers a very long period of protection after treatment cessation , and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention . Funding Cancer Research UK ( UK ) and the National Health and Medical Research Council ( Australia ) PURPOSE To up date the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment , particularly adjuvant tamoxifen . METHODS ASCO convened the Up date Committee and conducted a systematic review of r and omized clinical trials from January 2009 to June 2013 and analyzed three historical trials . Guideline recommendations were based on the Up date Committee 's review of the evidence . Outcomes of interest included survival , disease recurrence , and adverse events . RESULTS This guideline up date reflects emerging data on duration of tamoxifen treatment . There have been five studies of tamoxifen treatment beyond 5 years of therapy . The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year duration s of tamoxifen use . In addition to modest gains in survival , extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer . RECOMMENDATIONS Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen , and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor ( in sequence ) . If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen , they should be offered 10 years total duration of tamoxifen . If women are postmenopausal and have received 5 years of adjuvant tamoxifen , they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy BACKGROUND The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen . We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women . METHODS The Breast International Group ( BIG ) 1 - 98 study is a r and omized , phase 3 , double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer : letrozole , letrozole followed by tamoxifen , tamoxifen , and tamoxifen followed by letrozole . This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially ; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched . RESULTS A total of 8010 women with data that could be assessed were enrolled , 4003 in the letrozole group and 4007 in the tamoxifen group . After a median follow-up of 25.8 months , 351 events had occurred in the letrozole group and 428 events in the tamoxifen group , with five-year disease-free survival estimates of 84.0 percent and 81.4 percent , respectively . As compared with tamoxifen , letrozole significantly reduced the risk of an event ending a period of disease-free survival ( hazard ratio , 0.81 ; 95 percent confidence interval , 0.70 to 0.93 ; P=0.003 ) , especially the risk of distant recurrence ( hazard ratio , 0.73 ; 95 percent confidence interval , 0.60 to 0.88 ; P=0.001 ) . Thromboembolism , endometrial cancer , and vaginal bleeding were more common in the tamoxifen group . Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia . CONCLUSIONS In postmenopausal women with endocrine-responsive breast cancer , adjuvant treatment with letrozole , as compared with tamoxifen , reduced the risk of recurrent disease , especially at distant sites . ( Clinical Trials.gov number , NCT00004205 . BACKGROUND Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years . The MA.17 trial , which was design ed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences , was stopped early after an interim analysis showed that letrozole improved disease-free survival . This report presents up date d findings from the trial . METHODS Postmenopausal women completing 5 years of tamoxifen treatment were r and omly assigned to a planned 5 years of letrozole ( n = 2593 ) or placebo ( n = 2594 ) . The primary endpoint was disease-free survival ( DFS ) ; secondary endpoints included distant disease-free survival , overall survival , incidence of contralateral tumors , and toxic effects . Survival was examined using Kaplan-Meier analysis and log-rank tests . Planned subgroup analyses included those by axillary lymph node status . All statistical tests were two-sided . RESULTS After a median follow-up of 30 months ( range = 1.5 - 61.4 months ) , women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm ( DFS : hazard ratio [ HR ] for recurrence or contralateral breast cancer = 0.58 , 95 % confidence interval [ CI ] = 0.45 to 0.76 ; P < .001 ; distant DFS : HR = 0.60 , 95 % CI = 0.43 to 0.84 ; P = .002 ) . Overall survival was the same in both arms ( HR for death from any cause = 0.82 , 95 % CI = 0.57 to 1.19 ; P = .3 ) . However , among lymph node-positive patients , overall survival was statistically significantly improved with letrozole ( HR = 0.61 , 95 % CI = 0.38 to 0.98 ; P = .04 ) . The incidence of contralateral breast cancer was lower in women receiving letrozole , but the difference was not statistically significant . Women receiving letrozole experienced more hormonally related side effects than those receiving placebo , but the incidences of bone fractures and cardiovascular events were the same . CONCLUSION Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival , except in node-positive patients BACKGROUND There is debate about the value of assessing levels of C-reactive protein ( CRP ) and other biomarkers of inflammation for the prediction of first cardiovascular events . METHODS We analyzed data from 52 prospect i ve studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk . We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implication s of initiation of statin therapy after the assessment of CRP or fibrinogen . RESULTS The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age , sex , smoking status , blood pressure , history of diabetes , and total cholesterol level increased the C-index , a measure of risk discrimination , by 0.0050 . The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027 , respectively ( P<0.001 ) , and yielded a net reclassification improvement of 1.52 % and 0.83 % , respectively , for the predicted 10-year risk categories of " low " ( < 10 % ) , " intermediate " ( 10 % to < 20 % ) , and " high " ( ≥20 % ) ( P<0.02 for both comparisons ) . We estimated that among 100,000 adults 40 years of age or older , 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk . Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines ( i.e. , for persons with a predicted risk of ≥20 % and for those with certain other risk factors , such as diabetes , irrespective of their 10-year predicted risk ) , additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years . CONCLUSIONS In a study of people without known cardiovascular disease , we estimated that under current treatment guidelines , assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened . ( Funded by the British Heart Foundation and others . ) thyrotrophin , and treatment was continued for 12 - 15 months . One patient became hypothyroid while taking carbimazole and remained hypothyroid after drug withdrawal . He remained well on long term thyroxine replacement . Three further patients remained well and euthyroid 6 - 18 months after withdrawal of carbimazole . One patient 's thyrotoxicosis relapsed 12 months after carbimazole was stopped ; he was treated for a further 15 months and was euthyroid without carbimazole nine months later BACKGROUND The Arimidex ( anastrozole ) , Tamoxifen , Alone or in Combination ( ATAC ) trial was design ed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer . After an extended follow-up beyond the 5 years of treatment , we aim ed to assess the safety , tolerability , and risk-benefit indices of these compounds . METHODS We analysed postmenopausal women ( mean age 64 years [ SD 9 ] ) with localised breast cancer r and omly assigned to anastrozole ( n=3125 ) or tamoxifen ( n=3116 ) . Efficacy measures , including death and risk-benefit indices , were analysed by intention to treat . Safety analyses were based on treatment first received ( n=3092 for anastrozole and n=3094 tamoxifen ) . We calculated a risk-benefit analysis using the two global indices for the Women 's Health Initiative and for Disease-Free Survival and Serious Adverse Events . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N18233230 . FINDINGS At median follow-up of 68 months ( range 1 - 93 ) , treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen ( 1884 [ 61 % ] vs 2117 [ 68 % ] ; p<0.0001 ) , as did treatment-related serious adverse events ( 146 [ 5 % ] vs 277 [ 9 % ] ; p<0.0001 ) and adverse events leading to withdrawal ( 344 [ 11 % ] vs 442 [ 14 % ] ; p=0.0002 ) . Patients given anastrozole had significantly fewer overall events for the Global Index of the Women 's Health Initiative ( 744 [ 24 % ] vs 851 [ 27 % ] ; hazard ratio 0.85 [ 95 % CI 0.77 - 0.94 ] , p=0.001 ) and the Global Index of Disease-Free Survival and Serious Adverse Events ( 1453 [ 46 % ] vs 1594 [ 51 % ] ; 0.88 [ 0.82 - 0.94 ] ; p=0.0004 ) . INTERPRETATION Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer , and results in fewer serious adverse events . Furthermore , it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen PURPOSE Tamoxifen , which is actually the gold st and ard adjuvant treatment in estrogen receptor-positive early breast cancer , is associated with an increased risk of endometrial cancer and other life-threatening events . Moreover , many women relapse during or after tamoxifen therapy because of the development of resistance . Therefore new approaches are required . PATIENTS AND METHODS We conducted a prospect i ve r and omized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole . After 2 to 3 years of tamoxifen treatment , patients were r and omly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d , for a total duration of treatment of 5 years . Disease-free survival was the primary end point . Event-free survival , overall survival , and safety were secondary end points . RESULTS Four hundred forty-eight patients were enrolled . All women had node-positive , estrogen receptor-positive tumors . At a median follow-up time of 36 months , 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group ( P = .0002 ) . Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group ( hazard ratio [ HR ] = 0.35 ; 95 % CI , 0.18 to 0.68 ; P = .001 and HR = 0.15 ; 95 % CI , 0.03 to 0.65 ; P = .003 , respectively ) . Overall , more adverse events were recorded in the anastrozole group compared with the tamoxifen group ( 203 v 150 , respectively ; P = .04 ) . However , more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group ( 33 of 150 events v 28 of 203 events , P = .04 ) . CONCLUSION Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer PURPOSE To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer . PATIENTS AND METHODS Women with breast carcinoma T1 - 3 , N0 - 3 , M0 , who were between 50 and 70 years of age , were eligible irrespective of menopausal status , tumor grade , or estrogen receptor ( ER ) status . Patients who were event-free after 2 years of tamoxifen therapy were r and omly assigned to stop or continue tamoxifen therapy for an additional 3 years . The primary end point was length of disease-free survival ( DFS ) . Secondary end points included overall survival ( OS ) and toxicity . RESULTS From 1989 through 1996 , 1,901 patients were r and omly assigned either to stop treatment ( n = 958 ) or to receive tamoxifen for 3 additional years ( n = 943 ) . The median duration of postr and omization follow-up was 52 months . We found no statistically significant differences between the 5-year arm and the 2-year arm in terms of DFS ( hazard ratio [ HR ] , 0.91 ; 95 % confidence interval [ CI ] , 0.76 to 1.08 ) and OS ( HR , 1.16 ; 95 % CI , 0.92 to 1.46 ) . In ER-positive patients , a statistically significant prolongation of DFS related to longer treatment duration was observed ( HR , 0.74 ; 95 % CI , 0.59 to 0.93 ) , whereas no difference in OS could be detected ( HR , 0.98 ; 95 % CI , 0.72 to 1.32 ) . No differences in terms of endometrial cancers , cardiac or cerebrovascular events , or fractures were detected , whereas a doubling in the risk of thromboembolic events was found in the 5-year arm . CONCLUSION Our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years in patients with ER-positive tumors PURPOSE Among postmenopausal women with endocrine-responsive breast cancer , the aromatase inhibitor letrozole , when compared with tamoxifen , has been shown to significantly improve disease-free survival ( DFS ) and time to distant recurrence ( TDR ) . We investigated whether letrozole monotherapy prolonged overall survival ( OS ) compared with tamoxifen monotherapy . PATIENTS AND METHODS Of 8,010 postmenopausal women with hormone receptor-positive , early breast cancer enrolled on the Breast International Group ( BIG ) 1 - 98 study , 4,922 were r and omly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen . Of 2,459 patients enrolled in the tamoxifen treatment arm , 619 ( 25.2 % ) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005 . To gain better estimates of relative treatment effects in the presence of selective crossover , we used inverse probability of censoring weighted ( IPCW ) modeling . RESULTS Weighted Cox models , by using IPCW , estimated a statistically significant , 18 % reduction in the hazard of an OS event with letrozole treatment ( hazard ratio [ HR ] , 0.82 ; 95 % CI , 0.70 to 0.95 ) . Estimates of 5-year OS on the basis of IPCW were 91.8 % and 90.4 % for letrozole and tamoxifen , respectively . The HRs of DFS and TDR events by using IPCW modeling were 0.83 ( 95 % CI , 0.74 to 0.94 ) and 0.80 ( 95 % CI , 0.67 to 0.94 ) , respectively ( P < .05 for DFS , OS , and TDR ) . Median follow-up was 74 months . CONCLUSION Adjuvant treatment with letrozole , compared with tamoxifen , significantly reduces the risk of death , the risk of recurrent disease , and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer BACKGROUND AND METHODS The Scottish Adjuvant Tamoxifen Trial ( main trial ) was initiated in April 1978 to assess the effect of tamoxifen given to patients with breast cancer immediately after mastectomy ( or mastectomy plus radiation therapy ) ( adjuvant arm ) or only after the patients had had a relapse ( control arm ) ; 1323 patients were r and omly assigned ( 667 to the adjuvant arm and 656 to the control arm ) . Results have been reported for the follow-up period from 2.5 through 8 years . In this article , we report up date d results after a median follow-up of 15 years . If agreeable and eligible , patients who were disease free at 5 years in the adjuvant arm of the main trial were entered into a duration trial and r and omly assigned either to stop taking tamoxifen ( 169 patients ) or to continue taking it indefinitely until relapse or death ( 173 patients ) . For this up date , we analyzed information on death , recurrence , survival , and other malignancies for all but 21 of the 560 living patients from the original and duration trials to determine the probabilities of total survival , systemic relapse of disease , and death from breast cancer . All statistical tests are two-sided . RESULTS The beneficial effect of adjuvant tamoxifen given for 5 years on the probability of total survival ( P = .006 ) , systemic relapse ( P = .007 ) , and death from breast cancer ( P = .002 ) has been maintained through 15 years . No additional benefit was observed in those r and omly assigned to continue taking tamoxifen beyond 5 years . CONCLUSION Information from this study suggests that , if adjuvant tamoxifen is given to women with operable breast cancer , it need not be for more than 5 years BACKGROUND In 1982 , the National Surgical Adjuvant Breast and Bowel Project initiated a r and omized , double-blinded , placebo-controlled trial ( B-14 ) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement . The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease . However , questions arose about how long the observed benefit would persist , about the duration of therapy necessary to maintain maximum benefit , and about the nature and severity of adverse effects from prolonged treatment . PURPOSE We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up . In addition , the effects of 5 years versus more than 5 years of tamoxifen therapy were compared . METHODS In the trial , patients were initially assigned to receive either tamoxifen at 20 mg/day ( n = 1404 ) or placebo ( n = 1414 ) . Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen ( n = 322 ) or 5 years of placebo ( n = 321 ) . After the study began , another group of patients who met the same protocol eligibility requirements as the r and omly assigned patients were registered to receive tamoxifen ( n = 1211 ) . Registered patients who were disease free after 5 years of treatment were also r and omly assigned to another 5 years of tamoxifen ( n = 261 ) or to 5 years of placebo ( n = 249 ) . To compare 5 years with more than 5 years of tamoxifen therapy , data relating to all patients reassigned to an additional 5 years of the drug were combined . Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study . Survival , disease-free survival , and distant disease-free survival ( relating to failure at distant sites ) were estimated by use of the Kaplan-Meier method ; differences between the treatment groups were assessed by use of the logrank test . The relative risks of failure ( with 95 % confidence intervals [ CIs ] ) were determined by use of the Cox proportional hazards model . Reported P values are two-sided . RESULTS Through 10 years of follow-up , a significant advantage in disease-free survival ( 69 % versus 57 % , P < .0001 ; relative risk = 0.66 ; 95 % CI = 0.58 - 0.74 ) , distant disease-free survival ( 76 % versus 67 % , P < .0001 ; relative risk = 0.70 ; 95 % CI = 0.61 - 0.81 ) , and survival ( 80 % versus 76 % , P = .02 ; relative risk = 0.84 ; 95 % CI = 0.71 - 0.99 ) was found for patients in the group first assigned to receive tamoxifen . The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older . Tamoxifen therapy was associated with a 37 % reduction in the incidence of contralateral ( opposite ) breast cancer ( P = .007 ) . Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups , advantages in disease-free survival ( 92 % versus 86 % , P = .003 ) and distant disease-free survival ( 96 % versus 90 % , P = .01 ) were found for those who discontinued tamoxifen treatment . Survival was 96 % for those who discontinued tamoxifen compared with 94 % for those who continued tamoxifen treatment ( P = .08 ) . A higher incidence of thromboembolic events was seen in tamoxifen-treated patients ( through 5 years , 1.7 % versus 0.4 % ) . Except for endometrial cancer , the incidence of second cancers was not increased with tamoxifen therapy . CONCLUSIONS AND IMPLICATION S The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up . No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years

Results For dalteparin and tinzaparin , no accumulation was observed . Enoxaparin , on the other h and , did lead to accumulation in patients with renal insufficiency , although not in patients undergoing renal replacement therapy . Bemiparin and certoparin also did show accumulation . Conclusions In this systematic review , we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation . However , prophylactic dosages of enoxaparin , bemiparin , and certoparin did show accumulation in patients with a creatinine clearance ( CrCl ) below 30 ml/min , and therefore , dose reduction is required . The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs

Purpose Although therapeutic dosages of most low-molecular-weight heparins ( LMWHs ) are known to accumulate in patients with renal insufficiency , for the lower prophylactic dosages this has not been clearly proven . Nevertheless , dose reduction is often recommended . We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients .

The efficacy and safety of a low molecular weight heparin ( LMWH ) given as a single predialysis bolus injection was compared to st and ard heparin ( SH ) administered with a continuous infusion in a r and omized , 6 month , open follow-up study in 70 patients undergoing hemodialysis . No major bleeding or adverse events were encountered during a total of 4,000 dialysis procedures ( 2,000 with LMWH ) . Clot formation in the extracorporeal circuit was minimal and comparable between the groups at 4 , 13 , and 26 weeks after the start of the study . No accumulation of LMWH anticoagulant activity was noted . It is concluded that the use of LMWH is a safe , effective , and less complex alternative to SH STUDY OBJECTIVE To evaluate the relationship between impaired renal function and antifactor Xa activity in patients receiving dalteparin . DESIGN Open-label prospect i ve study . SETTING Inpatient and outpatient units of a large teaching hospital . SUBJECTS Eleven patients with renal impairment and 11 control subjects with normal renal function . INTERVENTION Subjects were administered dalteparin at a dosage of approximately 100 U/kg subcutaneously every 12 hours . MEASUREMENTS AND MAIN RESULTS Peak steady-state antifactor Xa levels were compared between the groups . Mean + /- SD levels were similar for patients with and without renal impairment : 0.47 + /- 0.25 and 0.55 + /- 0.20 U/ml , respectively . A test of equivalency showed statistical significance ( p=0.0001 ) . CONCLUSION No meaningful difference in peak antifactor Xa activity was found between patients with renal impairment and control subjects . To the extent that peak antifactor Xa levels can be used as markers for adjusting doses of dalteparin , these data suggest that such adjustments are not necessary for patients with renal impairment who are not receiving dialysis BACKGROUND Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk . To challenge this premise , we evaluated if deep vein thrombosis ( DVT ) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency . METHODS We conducted a multicenter , single-arm clinical trial of DVT prophylaxis with dalteparin sodium , 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min ( to convert to milliliters per second , multiply by 0.0167 ) . Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL , measured twice weekly . The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3 , 10 , and 17 . RESULTS We enrolled 156 patients with a mean ( SD ) creatinine clearance of 18.9 ( 6.5 ) mL/min ; 18 were excluded because they died or were discharged before testing ( n = 3 ) or had prevalent DVT ( n = 15 ) . Of 138 patients included , the median ( interquartile range [ IQR ] ) duration of dalteparin exposure was 7 ( 4 - 12 ) days . In 120 patients who had at least 1 trough anti-Xa level ( 427 total measurements ) , no patient had bioaccumulation ( 0 % ; 95 % confidence interval [ CI ] : 0%-3.0 % ) ; the median ( IQR ) trough anti-Xa level was undetectable ( < 0.10 IU/mL [ < 0.10 to < 0.10 IU/mL ] ) . Based on serial measurements , peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients ( 5.1 % ; 95 % CI , 2.5%-10.1 % ) ; major bleeding occurred in 10 patients ( 7.2 % ; 95 % CI , 4.0%-12.8 % ) , all with trough anti-Xa levels of 0.18 IU/mL or lower . CONCLUSION In critically ill patients with severe renal insufficiency , DVT prophylaxis with dalteparin sodium , 5000 IU once daily , is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00138099 BACKGROUND Enoxaparin dosage for obese patients and patients with renal impairment remains controversial . OBJECTIVE To compare anti-factor Xa activity ( anti-Xa ) among obese and renal impairment patients to patients with healthy weight and adequate renal function . DESIGN Open , prospect i ve , nonr and omized clinical trial . SETTING A major community teaching hospital . PATIENTS A total of 233 patients with prescription of enoxaparin . INTERVENTIONS Enoxaparin 1.5 mg/kg once daily or 1 mg/kg twice daily except those on dialysis , who received 75 % of the dose . MEASUREMENTS Anti-Xa was measured 4 h post-injection on day 2 or 3 . RESULTS Mean ( 95 % confidence interval ( 95 % CI ) ) anti-Xa was equal to 1.14 IU/mL ( 1.07 - 1.21 ) and 1.14 IU/mL ( 1.08 - 1.20 ) among patients who received one ( n=92 ) and two injections ( n=122 ) per day , respectively . Anti-Xa increases with body mass index ( BMI ) ( 0.01 IU/mL for each kg/m2 ; 95 % CI : 0.002 - 0.017 ) , but the increase is insufficient to reach supratherapeutic anti-Xa . Anti-Xa decreases with higher creatinine clearance ( CrCl ) ( -0.003 IU/mL for each mL/min ; 95 % CI : -0.006 to -0.001 ) . On the twice-daily regimen , this is sufficient to reach supratherapeutic anti-Xa . The odd ratio ( OR ) ( 95 % CI ) of having a nontherapeutic anti-Xa is equal to 2.28 ( 1.25 - 4.16 ) when enoxaparin is administered twice daily and to 3.03 ( 1.16 - 7.86 ) among severe renal impairment patients ( < or = 30 mL/min ) . CONCLUSIONS Based on Anti-Xa , no dosage adjustments are required in obese patients . In renally impaired patients , adjustments may be necessary when enoxaparin is administered twice daily Enoxaparin is a low molecular weight heparin ( LMWH ) that has been shown to be effective in deep vein thrombosis , pulmonary embolism , and unstable angina . Because renal function plays an important role in the clearance of LMWH , the authors sought to investigate the effect of renal function on enoxaparin . This prospect i ve multiple-dose study evaluated 18 patients with varying degrees of renal function initiated on enoxaparin 1 mg/kg subcutaneously every 12 hours . Peak blood levels of anti-Xa concentrations were obtained 4 + /- 0.5 hours postdose after receiving at least three doses of enoxaparin . The median antifactor Xa levels were higher in patients with creatinine clearance ( CLCr ) < or = 30 mL/min compared to CLCr > or = 31 mL/min ( 1.34 IU/mL vs. 0.91 IU/mL , respectively , p < 0.05 ) . A linear correlation was established between creatinine clearance and anti-Xa concentrations ( p < 0.0005 ) . On the basis of the data , the authors believe that a dose adjustment is necessary in patients receiving repeated doses of enoxaparin with CLCr < or = 30 mL/min Abstract Objectives : Too few very elderly patients with an age-related renal impairment are included in clinical trials . We conducted a study in order to evaluate the safety profile of tinzaparin , a low molecular weight heparin ( LMWH ) , given at a curative dose ( 175 IU/kg once daily ) in very elderly patients treated for up to 30 days . Setting : An 800-bed geriatric hospital . Design : A 1-year prescribing study . Patients : Consecutive in- patients older than age 70 , whose creatinine clearance was above 20 ml/min , and requiring full anticoagulation with LMWH were included . Measurements : Safety parameters ( major bleeding/heparin-induced thrombocytopenia/death ) were recorded . Plasma anti-Xa activity levels were regularly measured throughout the treatment period . Results : Two-hundred in- patients , mean age 85.2 ± 6.9 years ( 70 to 102 ) , mean creatinine clearance 51.2 ± 22.9 ml/min , were given tinzaparin . Six patients died during the treatment period : only one could be related to the anticoagulation treatment . Three major bleeding episodes ( 1.5 % ) were reported . Antithrombotic drug interactions likely contributed to the bleeding event in two of them . Heparin-induced thrombocytopenia was confirmed in two patients ( 1 % ) . No correlation was found between anti-Xa activity and creatinine clearance or age . Conclusions : Tinzaparin can be used safely at a curative dose in very elderly patients as long as ( i ) the accurate bodyweight-adjusted dose is given ; ( ii ) platelet counts and anti-Xa levels are regularly monitored and ; ( iii ) the interaction with other antithrombotic drugs is correctly managed Low-molecular-weight heparins ( LMWHs ) accumulate in patients with impaired renal function . As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination , LMWHs might have different pharmacodynamic profiles . The primary objective was to examine if any accumulation effect of two LMWHs , enoxaparin and tinzaparin , occurred after repeated administration of a prophylactic dose over eight days in elderly patients ( age > 75 years ) with creatinine clearance between 20 and 50 ml/min and body weight < 65Kg . Patients were openly r and omized to two groups ( enoxaparin 4,000 IU or tinzaparin 4,500 IU once daily ) . Anti-Xa was measured on day 1 and day 8 . Blood sample s were taken at 0 , 2 , 4 , 5 , 6 , 9 , 12 , 16 and 24 hours . The primary end point was the accumulation factor calculated as a ratio between the maximal anti-Xa activity on day 1 and day 8 . Fifty-five patients were included ( mean age 87.9 + /- 5.5 ) . The creatinine clearance was 34.7 + /- 11.4 ml/min ; the body weight was 52.3 + /- 8.6 kg . The accumulation factor defined was not significant for tinzaparin ( 1.05 , p = 0.29 ) while it was significantly enhanced for enoxaparin ( 1.22 , p < 0.0001 ) . In this pharmacodynamic study performed in elderly patients with impaired renal function , a statistically significant accumulation effect was observed after eight days of prophylactic treatment with enoxaparin but not with tinzaparin , which are two LMWHs with different chain lengths . Trials based on clinical end points should be conducted to evaluate the clinical relevance of these observations Background The safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined . Methods The primary aim of this study was to analyse , in ‘ real life ’ , the influence of renal function , as assessed by Creatinine clearance ( CLcr ) , on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin . Consecutive hospitalised acutely ill medical patients aged ≥75 years receiving daily dosages of enoxaparin 4000IU for up to 10 days were prospect ively enrolled in two centres . Peak anti-Xa activity was measured at the beginning and during the course of therapy . Results One hundred and twenty-five patients ( 31 men , 94 women ) , mean age 87.5 ± 6.3 years , mean bodyweight 56.4±11.9 kg and mean CLcr 39.8 ± 16.1 mL/min , were enrolled in the study . The mean maximum anti-Xa activity ( day 1 to day 10 ) [ anti-Xamaxl – l0 ] was 0.64 ± 0.23 IU/mL ( range 0.24–1.50 IU/mL ) . Weak negative correlations were found between CLcr and anti-Xamax and between bodyweight and anti-Xamax . Mean anti-Xamax was slightly but significantly higher in patients with CLcr of 20–30 mL/min compared with patients with CLcr of 31–40,41–50 or 51–80 mL/min ( 0.72 versus 0.61 , 0.61 and 0.60 IU/ mL , respectively ) , and in patients weighing < 50 kg compared with patients weighing 50–60 kg or > 60 kg ( 0.74 vs 0.64 and 0.52 IU/mL , respectively ) . Serious bleeding occurred in five patients , but anti-Xamax values in these patients were not different to those in patients without bleeding ( p = 0.77 ) . Individual anti-Xamax at the beginning or during the course of treatment was measured in the subgroup of 58 patients in whom anti-Xa activity was measured at least once during the study . The mean anti-Xamax value was slightly but significantly higher during the course of the therapy than at the beginning of the study ( 0.63 ± 0.26 IU/mL vs 0.56±0.23 IU/mL , p = 0.012 ) . Conclusion Only CLcr < 30 mL/min and bodyweight < 50 kg were associated with significantly higher anti-Xamax values . The clinical relevance of these increases remains question able . No conclusions about the safety of enoxaparin in elderly medical patients can be drawn from these findings A multicentre , double-blind , r and omised trial was conducted to compare the efficacy of a low-molecular-weight ( LMW ) heparin , Logiparin , with that of an unfractionated ( UF ) heparin in the prophylactic treatment of thrombosis in patients undergoing general surgery . A total of 1,290 patients were r and omised to receive a single daily dose of Logiparin ( 2,500 IU : 431 patients ; 3,500 IU : 430 patients ) or UF heparin ( 2 x 5,000 IU : 429 patients ) . The incidence of the main end point , deep venous thrombosis , was found to be significantly different between the groups ( p = 0.03 ) , whereas the incidence of severe haemorrhage was not ( p = 0.05 ) . The plasma anti-Xa activity was found to be correlated with body weight , but correlated only very weakly with antithrombotic activity ( p = 0.045 ) after adjustment in a stepwise multivariate analysis , and did not significantly correlate with the incidence of haemorrhage . Logiparin at 3,500 IU and UF heparin showed similar efficacy . Although a correlation between plasma anti-Xa activity and body weight was observed , there is not sufficient evidence to recommend the adjustment of the Logiparin dose on patient 's weight for prophylaxis in general surgery patients The present trial was design ed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins ( LMMHs ) : dalteparin ( Fragmin ) , nadroparin ( Fraxiparin ) , and enoxaparin ( Lovenox ) given by subcutaneous route . The study was carried out in 20 healthy young volunteers given , according to a cross over design , a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis ( commercial preparations , prefilled syringes ) : dalteparin 2,500 IU (= 2,500 IU anti-Xa ) , nadroparin 7,500 ICU (= 3,075 IU anti-Xa ) , enoxaparin 20 mg (= 2,000 IU anti-Xa ) and enoxaparin 40 mg (= 4,000 IU anti-Xa ) . Of the markers used , activated partial thromboplastin time ( APTT ) , thrombin clotting time ( TCT ) , Heptest , anti-thrombin ( aIIa ) activity and anti-Xa ( aXa ) activity , the most pertinent parameter ( from a biodynamic viewpoint ) is plasma aXa activity . We demonstrated that dalteparin , nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns . Normalized to the same injected dose ( 1,000 IU aXa ) , the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater ( p < 0.001 ) than that of nadroparin and 2.28 times greater ( p < 0.001 ) than that of dalteparin while the plasma amount induced by nadroparin is 1.54 times greater ( p < 0.001 ) than that of dalteparin . The apparent total body clearance of enoxaparin doses ( CL/F = 16.7 + /- 5.5 and 13.8 + /- 3.2 ml/min ) is significantly smaller than those of nadroparin ( CL/F = 21.4 + /- 7.0 ml/min ; p < 0.01 ) and dalteparin ( CL/F = 33.3 + /- 11.8 ml/min ; p < 0.001 ) while dalteparin apparent clearance is about 1.5-fold greater ( p < 0.001 ) than that of nadroparin . These LMMHs also differ by their renal excretion pattern : more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses ( 6.4 and 8.7 % of the dose , respectively ) than following nadroparin ( 3.9 % ) and dalteparin ( 3.4 % ) injection . These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different : dalteparin : 2.8 h ; nadroparin : 3.7 h ; and enoxaparin : 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin ( LMWH ) . The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities . Three groups of 12 subjects were investigated . The first 2 groups were composed of healthy volunteers differing by age ( 25 + /- 4 and 65 + /- 3 yrs ) and creatinine clearance ( 114 + /- 15 and 62 + /- 6 ml x min(-1 ) ) . The third group was composed of patients hospitalized for deep vein thrombosis , having a mean age of 65 + /- 11 yrs and creatinine clearance of 76 + /- 8 ml x min(-1 ) . Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1 ) for 6 to 10 days . Serial sampling on day 1 and on the last day of administration ( day n ) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment . The main findings were the following : ( 1 ) After repeated administration , a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects ( accumulation factor : 1.3 ) . There was no evidence of accumulation of anti-thrombin activity ; ( 2 ) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity ; ( 3 ) In the patients , the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly ; ( 4 ) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients . These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH , predominantly for the anti-thrombin activity BACKGROUND Low-molecular-weight heparins ( LMWHs ) are routinely given without the control of their effect on coagulation . The endogenous thrombin potential ( ETP ) is a sensitive detector of the heparin effect . QUESTION What is the interindividual variation in TG after a fixed dose of LMWH in normal volunteers , is it explained by variation in weight ? METHODS Subcutaneous ( s.c . ) injection , in 12 healthy volunteers , of 9000 aXa-units of unfractionated heparin ( UFH ) and of three heparins with narrow MW distribution around 10.5 , 6.0 and 4.5 kD. Measurement of anti-thrombin ( aIIa ) and antifactor Xa (aXa)-activities and ETP at 11 time points over 24 h. RESULTS The coefficient of variation ( CV ) of the AUCs of aXa- and aIIa-activities is 50 % for UFH and 22 - 37 % for LMWHs . Because of the hyperbolic form of the dose-response curve , the CV of the inhibition of the ETP is lower : 32 % for UFH and 13 - 21 % for the LMWHs . Fixed dosage of LMWH caused under-dosage in 10 - 13 % of the sample s and over-dosage in 5 - 11 % . High or low response is an individual property independent of the type of heparin injected and only partially explained by variation in body weight . CONCLUSION Optimized individual dosage of LMWH is possible through recognition of high and low responders , which requires one measurement of the heparin concentration or , preferably , the heparin effect on the ETP , 2 - 5 h after a first injection BACKGROUND Patients with renal dysfunction who undergo systemic anticoagulation with enoxaparin are at increased risk for bleeding . Although there is decreased renal clearance of enoxaparin in this population , the clinical utility of monitoring antifactor Xa activity is controversial because it is weakly correlated to bleeding . The goal of this study was to investigate the role of other novel anticoagulation markers , such as thrombin generation time , platelet contractile force , and clot elastic modulus , while controlling for antifactor Xa activity in patients with and without renal dysfunction . METHODS Thirty anticoagulant- and antiplatelet-naive subjects completed this trial ( 10 controls , 10 patients with chronic kidney disease , and 10 patients with end-stage renal disease [ ESRD ] ) . Blood sample s were obtained and spiked ex vivo with increasing concentrations of enoxaparin antifactor Xa activity ( 0.25 , 0.5 , 1.0 , and 3.0 IU/mL ) . Thrombin generation time , platelet contractile force , and clot elastic modulus were measured in each group at each antifactor Xa activity concentration . RESULTS Subjects with ESRD had an approximately 50 % greater anticoagulant effect , determined by thrombin generation time prolongation , than controls at antifactor Xa activity concentrations of 0.5 to 3.0 IU/mL. This may explain why subjects with ESRD with seemingly therapeutic antifactor Xa levels still experience adverse bleeding . There were no intergroup differences in platelet function , determined by platelet contractile force and clot elastic modulus . CONCLUSION Antifactor Xa poorly predicts the degree of anticoagulation in patients with ESRD administered low-molecular-weight heparin ( LMWH ) . Thrombin generation time may be a clinical ly useful anticoagulation monitoring tool to monitor LMWH therapy , especially in patients with renal dysfunction . Additional r and omized prospect i ve studies are needed to corroborate these findings BACKGROUND Low-molecular-weight heparin ( LMWH ) is cleared predominantly by the kidneys and hence there is uncertainty about the safety of its use in hemodialysis ( HD ) patients . Our primary objective was to compare whether tinzaparin and dalteparin differentially accumulate in HD patients . STUDY DESIGN Open-label r and omized controlled trial . SETTING & PARTICIPANTS HD patients undergoing periprocedure bridging anticoagulation . INTERVENTION After warfarin therapy was discontinued , participants were r and omly assigned to either 3 daily doses of tinzaparin ( 175 IU/kg ) or dalteparin ( 200 IU/kg ) , with 2 intervening HD treatments between the first dose of study drug and their procedure . OUTCOMES The primary outcome was predialysis anti-Xa levels 20 to 24 hours after the third LMWH dose ( therapeutic target , < 0.2 IU/mL ) . Secondary outcomes included thromboembolic events and major bleeding . RESULTS Of 29 eligible and consenting patients , 17 patients received tinzaparin and 12 patients received dalteparin . Mean predialysis anti-Xa level 20 - 24 hours after the third LMWH dose was 0.37 ± 0.23 ( SD ) IU/mL for tinzaparin and 0.62 ± 0.41 IU/mL for dalteparin ( P = 0.1 ) , indicating clinical ly important accumulation for both drugs . No invasive procedures were canceled due to study drug accumulation . 4 patients experienced serious adverse events ( 1 major bleed after traumatic arteriovenous fistula puncture in the tinzaparin arm , 2 non-ST-elevation myocardial infa rct ions [ 1 in each group ] , and 1 upper-extremity deep venous thrombosis [ dalteparin group ] ) . LIMITATIONS Small sample size . CONCLUSIONS Dalteparin and tinzaparin significantly accumulate in HD patients at therapeutic doses . " Bridging therapy " with LMWHs at therapeutic doses in HD patients who require temporary interruption of warfarin therapy has the potential for complications and is of uncertain benefit . Other anticoagulation strategies , including no bridging therapy or intravenous heparin , need comparative evaluation in this unique patient population The pharmacokinetics of the low-molecular-weight heparin enoxaparin were evaluated in 12 healthy volunteers and 36 patients with mild , moderate or severe renal impairment . Enoxaparin was administered once daily by subcutaneous injections at a dose of 40 mg for 4 days and venous blood sample s were taken over a 5-day period to determine antifactor Xa and antifactor IIa activity and the activated partial thromboplastin time . Adverse events were also recorded . The results for anti-Xa activity showed that the rate of absorption of enoxaparin was similar across the four groups of study participants . The elimination half-life increased with the degree of renal impairment , and this relationship was more evident after repeated dosing . Anti-Xa exposure was not significantly different between healthy volunteers and patients with mild or moderate renal impairment , but was significantly increased in patients with severe renal impairment ( creatinine clearance < or = 30 ml/min ) . Anti-Xa clearance decreased with the degree of renal impairment after repeated dosing , but only the difference between patients with severe renal impairment and healthy volunteers was statistically significant , the clearance on Day 4 being 39 % lower in patients with severe renal impairment than in healthy volunteers ( P=.0001 ) . Anti-IIa activity was low in all study participants , and the activated partial thromboplastin time was not significantly different between the study groups . In conclusion , the clearance of enoxaparin is reduced in patients with severe renal impairment . Dose adjustment of enoxaparin may need to be recommended in these patients , but no recommendation can be made in patients with mild or moderate renal impairment The aim of this prospect i ve cohort study was to determine the incidence of dalteparin bioaccumulation ( measured using anti-Xa levels ) , and bleeding during thromboprophylaxis in elderly patients with renal failure who were admitted to hospital with an acute medical illness . Patients who met the criteria for being at high thromboembolic risk received dalteparin 5,000 IU subcutaneously once daily while the other patients ( low risk ) received 2,500 IU daily . Thromboprophylaxis was administered for at least 6 days . Anti-Xa activity was determined before the first dalteparin dose and again on day 6 , 4 hours after the administration of the dalteparin dose . Bleeding was assessed daily . Compression ultrasonography was performed to identify any deep vein thromboses . There was no evidence of bioaccumulation on day 6 of therapy , irrespective of renal function . No episodes of major bleeding or venous thromboembolism occurred . Larger , r and omized studies are warranted to confirm the safety of dalteparin in this patient population BACKGROUND Heparin-induced thrombocytopenia , defined by the presence of heparin-dependent IgG antibodies , typically occurs five or more days after the start of heparin therapy and can be complicated by thrombotic events . The frequency of heparin-induced thrombocytopenia and of heparin-dependent IgG antibodies , as well as the relative risk of each in patients given low-molecular-weight heparin , is unknown . METHODS We obtained daily platelet counts in 665 patients in a r and omized , double-blind clinical trial comparing unfractionated heparin with low-molecular-weight heparin as prophylaxis after hip surgery . Heparin-induced thrombocytopenia was defined as a decrease in the platelet count below 150,000 per cubic millimeter that began five or more days after the start of heparin therapy , and a positive test for heparin-dependent IgG antibodies . We also tested a representative subgroup of 387 patients for heparin-dependent IgG antibodies regardless of their platelet counts . RESULTS Heparin-induced thrombocytopenia occurred in 9 of 332 patients who received unfractionated heparin and in none of 333 patients who received low-molecular-weight heparin ( 2.7 percent vs. 0 percent ; P = 0.0018 ) . Eight of the 9 patients with heparin-induced thrombocytopenia also had one or more thrombotic events ( venous in 7 and arterial in 1 ) , as compared with 117 of 656 patients without heparin-induced thrombocytopenia ( 88.9 percent vs. 17.8 percent ; odds ratio , 36.9 ; 95 percent confidence interval , 4.8 to 1638 ; P < 0.001 ) . In the subgroup of 387 patients , the frequency of heparin-dependent IgG antibodies was higher among patients who received unfractionated heparin ( 7.8 percent , vs. 2.2 percent among patients who received low-molecular-weight heparin ; P = 0.02 ) . CONCLUSIONS Heparin-induced thrombocytopenia , associated thrombotic events , and heparin-dependent IgG antibodies are more common in patients treated with unfractionated heparin than in those treated with low-molecular-weight heparin The pharmacokinetics of the low-molecular weight heparin ( LMWH ) , dalteparin , was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers , 8 patients with moderate/severe renal failure ( Cl(crea ) 13.1 - 56.5 ml/min ) and 8 hemodialysis patients . Venous blood sample s were taken over a 1-day period to determine anti-Xa activity , anti-IIa activity and plasma levels of free tissue factor pathway inhibitor ( free TFPI ) . Plasma anti-Xa and anti-IIa activities were measured using chromogenic assays and free TFPI levels using an ELISA technique . The anti-Xa clearance was significantly decreased ( p < 0.05 ) in both groups with renal insufficiency when compared with healthy volunteers . There was a positive correlation between creatinine clearance and anti-Xa clearance in the healthy volunteers and patients with moderate/severe renal failure . The anti-Ila activity was characterized by 3- to 4-fold lower plasma concentrations and faster elimination compared with the anti-Xa activity . In patients with moderate/severe renal failure the elimination of anti-lla was only slightly decreased , whereas in hemodialysis patients anti-Ila clearance was significantly decreased ( p < 0.01 ) . There was no correlation between creatinine clearance and anti-IIa clearance . The baseline mean free TFPI plasma levels in the two groups with renal insufficiency were significantly higher ( p < 0.01 ) than in healthy volunteers . Dalteparin administration induced a transient , 6.0- to 8.1-fold increase in the free TFPI values in the three study groups . Dalteparin induced an increase in C(max ) and AUC(0 - infinity ) values of free TFPI in the two groups with renal insufficiency that was higher than in healthy volunteers . No bleeding complications occurred during the study . In conclusion , this is the first report showing retarded elimination of dalteparin and enhanced free TFPI plasma levels induced by a LMWH in patients with renal insufficiency BACKGROUND Low molecular weight heparins ( LMWHs ) and danaparoid are an alternative to unfractionated heparin ( UH ) for anticoagulation during hemodialysis . Few data are available concerning their duration of action and whether drug accumulation occurs with continued use . We performed a prospect i ve r and omized study of the pharmacokinetics of dalteparin and enoxaparin plus danaparoid in 21 hemodialysis patients . METHODS Patients were r and omly assigned to administration of enoxaparin , 40 mg ; dalteparin , 2,500 U ; or danaparoid , 34 U/kg , for 4 weeks . Antifactor Xa levels were measured at the end of weeks 1 and 4 immediately before the injection and at prescribed intervals up to 48 hours postinjection . RESULTS No bleeding or thrombotic episodes occurred during the study . Mean antifactor Xa activities 4 hours postinjection were 0.2 + /- 0.035 ( SEM ) , 0.38 + /- 0.028 , and 0.54 + /- 0.051 U/mL week 1 and 0.26 + /- 0.038 , 0.40 + /- 0.055 , and 0.64 + /- 0.050 U/mL week 4 for dalteparin , enoxaparin , and danaparoid , respectively . Both weeks 1 and 4 , antifactor Xa activity 3 hours postdose was significantly greater for danaparoid sodium compared with enoxaparin and dalteparin . There were no significant differences between antifactor Xa activity week 4 versus week 1 for enoxaparin and dalteparin ; however , danaparoid sodium levels during dialysis were significantly greater after 4 weeks of treatment ( P = 0.0328 , 1 hour ; P = 0.003 , 2 hours ; P = 0.0128 , 3 and 4 hours ) . CONCLUSION Dalteparin and enoxaparin provide adequate anticoagulation for hemodialysis using single bolus injections at relatively low doses . Danaparoid sodium at the current recommended dosage result ed in greater anticoagulation than enoxaparin or dalteparin and may have BACKGROUND Low-molecular-weight heparins ( LMWH ) have been shown to be effective and safe for prophylaxis of thromboembolic diseases . However , issues regarding safety and optimal use of LMWH arise in patients with renal insufficiency ( RI ) . OBJECTIVES To compare pharmacokinetic data of dalteparin for up to 3 weeks in patients with various degrees of RI . PATIENTS AND METHODS Patients from general medical and surgical wards were included in this prospect i ve cohort study and divided into three groups according to renal function : A = normal ( GFR > or=60 mL min(-1)1.73 m(-2 ) ) , B = mild RI ( GFR 30 - 59 mL min(-1)1.73 m(-2 ) ) , C = severe RI ( GFR<30 mL min(-1)1.73 m(-2 ) ) . Dalteparin was injected s.c . once daily at a prophylactic dose . Peak anti-Xa activity levels ( anti-Xa ) were measured 4+/-1 h after injection on day 1 and every third day up to 3 weeks . Primary objectives were peak anti-Xa levels and adjusted anti-Xa levels , adjustment being carried out for dose and body weight . RESULTS A total of 42 patients could be analyzed during a median of 10 days ( interquartile range IQR 4 - 13 , range 1 - 20 ) . In all groups , adjusted peak anti-Xa levels were not different on day 10 compared with day 1 . No bioaccumulation>30 % could be found up to day 10 even in patients with severe RI . CONCLUSION The use of dalteparin at a prophylactic dose was not associated with a bioaccumulation>30 % even in patients with severe renal insufficiency during a median follow-up of 10 days ( IQR 4 - 13 , range 1 - 20 ) who have out-of-hospital cardiac arrests : a prospect i ve , nationwide , population -based cohort study . Lancet 2010 ; 375 : 1347–54 . 39 Anonymous . 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations . Part 2 : Adult basic life support . Resuscitation 2005 ; 67 : 187–201 . 40 Ewy GA . Cardiology patient page . New concepts of cardiopulmonary resuscitation for the lay public : continuous-chest-compression CPR . Circulation 2007 ; 116 : e566– 8 . 41 H and ley AJ . Compression-only CPR – to teach or not to teach ? Resuscitation 2009 ; 80 : 752–4 BACKGROUND Patients with end-stage renal disease are subject to a broad range of thrombotic complications . Low molecular weight heparins ( LMWHs ) are effective antithrombotic agents ; however , they are cleared largely by renal mechanisms , raising uncertainty about their use in renally impaired patients . METHODS Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin , 75 IU/kg , 2 weeks apart : subcutaneously ( SC ) on an off-dialysis day and intravenously ( IV ) just before dialysis . RESULTS Mean maximal anti-factor Xa ( anti-Xa ) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration . Anti-Xa half-lives were 3.89 and 2.31 hours , respectively . Anti-Xa activity returned to baseline within 24 hours of administration by either route . Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment , anti-Xa clearance after tinzaparin administration was reduced 28 % relative to subjects with normal renal function . All 12 study subjects completed hemodialysis without requiring additional anticoagulation . One subject had minimal clotting in the dialyzer drip chamber , and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal . No major bleeding events occurred . CONCLUSION Tinzaparin , 75 IU/kg , SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients . The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation . SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients . The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely

Two broad findings emerged : ( 1 ) disgust appears to be promoting aversion to ( and avoidance of ) CRC screening , and ( 2 ) several known elicitors of disgust are widely apparent in CRC context s. CONCLUSIONS Disgust likely represents a key emotional substrate for avoidance among CRC patients , caregivers , and health professionals . Exposure therapies and mindfulness training may be well suited to treating disgust-generated avoidance .

BACKGROUND The emotion of disgust appears to promote psychological and behavioral avoidance , a dynamic that has significant implication s in physical and psychological outcomes in colorectal cancer ( CRC ) . Patients , caregivers , and health professionals alike are all potentially susceptible to responding with disgust and the associated avoidance . OBJECTIVE This article aim ed to review the early-stage literature related to disgust and CRC , consider the clinical implication s , and suggest an appropriate research agenda .

Delay in follow-up after an abnormal mammogram is associated with advanced disease stage , poorer survival , and increased anxiety . Despite the implementation of many patient navigator programs across the country , there are few published , peer- review ed studies documenting its effectiveness . We tested the effectiveness of a patient navigator in improving timeliness to diagnosis , decreasing anxiety , and increasing satisfaction in urban minority women after an abnormal mammogram . Women with suspicious mammograms were r and omly assigned to usual care ( N = 50 ) or usual care plus intervention with a patient navigator ( N = 55 ) . There were no demographic differences between the two groups . Women in the intervention group had shorter times to diagnostic resolution ( mean 25.0 vs. 42.7 days ; p = .001 ) , with 22 % of women in the control group without a final diagnosis at 60 days vs. 6 % in the intervention group . The intervention group also had lower mean anxiety scores ( decrease of 8.0 in intervention vs. increase of 5.8 in control ; p < .001 ) , and higher mean satisfaction scores ( 4.3 vs. 2.9 ; p < .001 ) . Patient navigation is an effective strategy to improve timely diagnostic resolution , significantly decrease anxiety , and increase patient satisfaction among urban minority women with abnormal mammograms Background We carried out this study to examine the health-related quality of life ( HRQOL ) of patients with advanced colorectal cancer treated with the oral fluoropyrimidine S-1 plus irinotecan ( CPT-11 ) . Methods HRQOL was assessed at baseline ( pretreatment ) and at 5-week intervals during treatment , using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 question naires . The HRQOL data for 12 preselected scales and 21 courses of treatment were then analyzed longitudinally . Results Thirty-seven patients completed the baseline and post-treatment HRQOL assessment s. Statistically significant differences between the baseline and post-treatment HRQOL scores were observed for the global QOL , social function , and pain scales ( all QLQ-C30 ) , as well as the body image , future perspective , gastrointestinal tract symptoms , weight loss , and chemotherapy side effects scales ( all QLQ-CR38 ) ; favorable post-treatment results were observed for all the scales except for body image and chemotherapy side effects , for which post-treatment deteriorations were observed . The changes in body image , future perspective , weight loss , and chemotherapy side effects were each greater than ten points and seemed clinical ly significant . Conclusion Combined treatment with S-1 plus CPT-11 result ed in an acceptable deterioration in HRQOL functioning and symptoms , compared with baseline levels OBJECTIVES This study investigated whether acculturation was associated with the receipt of clinical breast examinations and mammograms among Colombian , Ecuadorian , Dominican , and Puerto Rican women aged 18 to 74 years in New York City in 1992 . METHODS A bilingual , targeted , r and om-digit-dialed telephone survey was conducted among 908 Hispanic women from a population -based quota sample . Outcome measures included ever and recent use of clinical breast examinations and mammograms . Multivariate logistic regression models were used to assess the effect of acculturation on screening use . RESULTS When demographic , socioeconomic , and health system characteristics and cancer attitudes and beliefs were controlled for , women who were more acculturated had significantly higher odds of ever and recently receiving a clinical breast examination ( P < or = .01 ) and of ever ( P < or = .01 ) and recently ( P < or = .05 ) receiving a mammogram than did less acculturated women . For all screening measures , there was a linear increase in the adjusted probability of being screened as a function of acculturation . CONCLUSIONS Neighborhood and health system interventions to increase screening among Hispanic women should target the less acculturated BACKGROUND Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood ( FOB ) tests can lead to a reduction in mortality from colorectal cancer ( CRC ) . The aim of this r and omised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls . METHODS 140,000 people aged 45 - 75 years lived in Funen , Denmark , in August , 1985 , and were considered for inclusion in our study . Before r and omisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study . R and omisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group ( 30,967 ) , three per 14 to the control group ( 30,966 ) , and eight not to be enrolled in the study ( 75,552 ) . Controls were not told about the study and continued to use health-care facilities as normal . Hemoccult-II blood tests ( with dietary restrictions but without rehydration ) were sent to screening-group participants . Only those participants who completed the first screening round were invited for further screening -- five rounds of screening during a 10-year period . Participants with positive tests were asked to attend to full examination and were offered colonoscopy whenever possible . The primary endpoint was death from CRC . FINDINGS Of the 30,967 screening-group participants , 20,672 ( 67 % ) completed the first screening round and were invited for further screening ; more than 90 % accepted repeated screenings . During the 10-year study , 481 people in the screening group had a diagnosis of CRC , compared with 483 unscreened controls . There were 205 deaths attributable to CRC in the screening group , compared with 249 deaths in controls . CRC mortality , including deaths attributable to complications from CRC treatment , was significantly lower in the screening group than in controls ( mortality ratio 0.82 [ 95 % CI 0.68 - 0.99 ] ) p = 0.03 ) . INTERPRETATION Our findings indicate that biennial screening by FOB tests can reduce CRC mortality . This study is being continued to improve its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence Cancer and its treatment are known to cause malnutrition in significant numbers of patients . Although a variety of contributory factors have been identified it is clear that the aetiology of malnutrition is complex and multifactorial . Taste aberrations are believed to be amongst the causative factors and to contribute to the development of food avoidance/aversion in affected patients . The study described investigates the incidence of food avoidance in a r and om sample of 72 patients undergoing cancer chemotherapy . The results show that 59 ( 82 % ) had avoided one or more foods since the instigation of treatment . The foods most commonly affected were coffee , tea , citrus fruit , chocolate and red meat . Changes were noted in the consumption of both sweet and salty foods . In terms of food avoidance no apparent relationships were demonstrated between its incidence and either the type of disease or the drugs used in therapy . In men , the pattern of avoidance showed no differences between the younger ( up to 49 years ) and older ( 50 years and older ) patients ; marked differences were observed between younger and older women . Although the foods avoided in general have little nutritional implication their omission may affect the quality of the patient 's life . Food avoidance per se may , however , affect nutritional status ; suggestions for overcoming its effects are made . The results of this study , obtained by subjective assessment of food acceptability , highlight the individual anture of food avoidance in affected patients and suggest that each must be individually assessed if appropriate nutritional advice is to be given

Occurrence of adverse events was not significantly different between the treated patients the and controls . Limited evidence suggests beneficial effects of propranolol after burn injury , and its use seems safe .

BACKGROUND The hypermetabolic state after severe burns is a major problem that can lead to several pathophysiologic changes and produce multiple sequelae . Adrenergic blockade has been widely used to reverse these changes and improve outcomes in burned patients but has not been rigorously evaluated . The aim of this systematic review was to investigate the efficacy and safety of the use of adrenergic blockade after burn injury .

OBJECTIVE To determine whether propranolol and growth hormone ( GH ) have additive effects to combat burn-induced catabolism . SUMMARY BACKGROUND DATA Both GH and propranolol have been attributed anabolic properties after severe trauma and burn . It is conceivable that the two in combination would have additive effects . METHODS Fifty-six children with more than 40 % TBSA burns were r and omized to one of four anabolic regimens : untreated control , GH treatment , propranolol treatment , or combination GH plus propranolol therapy . Clinical treatment was identical for all groups . Resting energy expenditure was determined by indirect calorimetry and skeletal muscle protein kinetics were measured using stable amino acid isotope infusions before and after each anabolic regimen . RESULTS There were no differences in age , sex , or burn size between groups . Tachycardia and energy expenditure were decreased during propranolol treatment ( < .05 ) . The net balance of muscle protein synthesis and breakdown was improved during propranolol and GH plus propranolol treatment ( < .05 ) . There was no significant benefit of GH alone . No additive effect of combination therapy was seen . CONCLUSIONS Propranolol is a strongly anabolic drug during the early , hypercatabolic period after burn . No synergistic effect between propranolol and GH was identified BACKGROUND The catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism . We hypothesized that blockade of beta-adrenergic stimulation with propranolol would decrease resting energy expenditure and muscle catabolism in patients with severe burns . METHODS Twenty-five children with acute and severe burns ( more than 40 percent of total body-surface area ) were studied in a r and omized trial . Thirteen received oral propranolol for at least two weeks , and 12 served as untreated controls . The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient 's base-line value . Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade ( or no therapy , in controls ) . Body composition was measured serially throughout hospitalization . RESULTS Patients in the control group and the propranolol group were similar with respect to age , weight , percentage of total body-surface area burned , percentage of body-surface area with third-degree burns , and length of time from injury to metabolic study . Beta-blockade decreased the heart rates and resting energy expenditure in the propranolol group , both as compared with the base-line values ( P<0.001 and P=0.01 , respectively ) and as compared with the values in the control group ( P=0.03 and P=0.001 , respectively ) . The net muscle-protein balance increased by 82 percent over base-line values in the propranolol group ( P=0.002 ) , whereas it decreased by 27 percent in the control group ( P not significant ) . The fat-free mass , as measured by whole-body potassium scanning , did not change substantially in the propranolol group , whereas it decreased by a mean ( + /-SE ) of 9+/-2 percent in the control group ( P=0.003 ) . CONCLUSIONS In children with burns , treatment with propranolol during hospitalization attenuates hypermetabolism and reverses muscle-protein catabolism Studies in children with burn injuries have demonstrated that propranolol improves metabolism and reduces muscle protein wasting . However , safety and efficacy in adults are less well established than in children . The purpose of this study was to determine safety of propranolol use in adult patients with burn injuries . Medical records were review ed for burn-injured adults receiving propranolol . Patients between 18 and 65 years old and with ≥20 % TBSA burn were included . Fifty-four patients met the criteria with mean age of 37 years and mean burn size of 38 % TBSA . Propranolol dosages ranged from 0.1 to 3.8 mg/kg/day , with an average maximum dosage of 0.61 mg/kg/day . Mean heart rate decreased by 25 % during 4 weeks . Seventy-two percent of patients experienced at least one episode of hypotension and 15 % experienced bradycardia . Propranolol doses were most frequently held for low blood pressure ; 32 % of patients had at least one dose held for hypotension . This retrospective analysis suggests that modest dosing of propranolol results in frequent episodes of hypotension or bradycardia . Our data suggest that adults do not tolerate the higher doses reported in a pediatric population . Despite potential beneficial anti-catabolic effects of propranolol , burn care providers must recognize potential iatrogenic hemodynamic effects of this intervention . Our data support the need for prospect i ve multicenter studies to delineate the safety and efficacy of propranolol in adult burn-injured patients Burn patients have the highest metabolic rate among critically ill or injured patients . Because propranolol decreases energy expenditure and muscle protein catabolism , in this study , we hypothesized that propranolol would improve healing process and decrease wound-healing time . This study was a double-blind r and omized clinical trial ; a total of 79 burn patients who referred to this center from January 2006 to January 2007 fulfilled the inclusion criteria . Thirty-seven patients were r and omly placed in propranolol group and 42 in control group . The propranolol group received propranolol orally with the dose of 1 mg/kg/d and maximum dose of 1.98 mg/kg/d given in six divided doses . This dose was adjusted to decrease the resting heart rate by 20 % from each patient ’s baseline value . The control group received placebo . The most common cause of burn in both groups was flame followed by flash . Patients with superficial burns in the propranolol group needed less time to heal for acceptable wound healing in superficial burns ( 16.13 ± 7.40 days vs 21.52 ± 7.94 days ; P = .004 ) . We also found that patients with deep burn injury needed less time to be ready for skin graft ( 28.23 ± 8.43 days vs 33.46 ± 9.17 days ; P = .007 ) when compared to that of the control group . The use of propranolol decreased the size of the burn wound that finally needed skin graft . Patients in the propranolol group with an average burn size of 31.42 % TBSA finally needed 13.75 % of TBSA skin graft compared with that of control patients with an average burn size of 33.61 % TBSA who needed 18.72 % of TBSA skin graft , and patients in the control group with an average burn size of 33.61 % TBSA finally needed 18.72 % of TBSA skin graft ( P = .006 ) . Patients in the propranolol group had a shorter hospital stay period than the control group ( 30.95 ± 8.44 days vs 24.41 ± 8.11 days ; P = .05 ) . Administration of propranolol , improved burn wound healing , and decreased healing time and hospital stay period . The use of propranolol decreased the surface area of wounds that needed to be skin grafted BACKGROUND Propranolol , a nonselective beta1 - 2 antagonist , attenuates hypermetabolism and catabolism in severely burned patients . However , recent data suggest that propranolol impairs immune function and enhances inflammation . The purpose of the present study was to determine the effect of propranolol administration on infection , sepsis , and inflammation in severely burned pediatric patients . PATIENTS A prospect i ve , intent-to-treat study was performed ; patient demographics ( age , gender , burn size , and mortality ) ; infectious episodes ( colony count greater then 10 ) ; and sepsis ( guidelines by the society of critical care medicine ) were determined . Hypermetabolic response was determined by resting energy expenditure ( REE ) , and the inflammatory response was determined by measuring serum cytokine expression . RESULTS Two hundred forty-five patients ( 143 controls , 102 propranolol ) were included into the study . There were no differences between the control and propranolol groups for age , gender distribution , burn size , third degree burn , and length of stay . Mortality was 6 % in the control group and 5 % in the propranolol group . Propranolol significantly decreased REE and predicted REE during acute hospital stay . Forty-three patients developed infections in the control group ( 30 % ) , whereas 21 developed infections in the propranolol group ( 21 % ) . The incidence of sepsis was 10 % for controls and 7 % for propranolol . Analysis of the cytokine expression profile in 20 patients in each group revealed that propranolol significantly decreased serum tumor necrosis factor and interleukin-1beta compared with controls ( p < 0.05 ) . CONCLUSION Propranolol treatment attenuates hypermetabolism and does not cause increased incidence of infection and sepsis Background Main contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury . It is currently unknown how long these conditions persist beyond the acute phase post-injury . The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions . Methodology /Principal Findings Patients : Nine-hundred seventy-seven severely burned pediatric patients with burns over 30 % of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned , non-injured children . Demographics and clinical outcomes , hypermetabolism , body composition , organ function , inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn . Statistical analysis was performed using One-way ANOVA , Student 's t-test with Bonferroni correction where appropriate with significance accepted at p<0.05 . Resting energy expenditure , body composition , metabolic markers , cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism , p<0.05 . Along with increased hypermetabolism , significant elevation of cortisol , catecholamines , cytokines , and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05 . Conclusions Severe burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown . Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses , we now identified treatment needs for severely burned patients for a much more prolonged time BACKGROUND There is no direct evidence that beta-blockers improve mortality in burn victims . Beta-blockers attenuate hypermetabolic states in burned children , and perioperative use in elective adult cases has beneficial effects , which suggests that beta-blockers may also improve burn outcomes . However , beta-blockers decrease cardiac output and may decrease oxygen delivery , and theoretically may increase mortality . What is the effect of beta-blockers on healing time and mortality in burn patients ? METHODS This was a retrospective cohort study . We identified three cohorts of adult burn patients between 1996 and 2001 : all who were on beta-blockers ( BB ) before their injury ( PMH BB ) ; all who were initiated on BB during their hospitalization for management of hypertension or tachyarrhythmia ( HOSP BB ) ; and control , who were never treated with beta-blockers . For each patient in the PMH BB and HOSP BB groups , two patients were placed in the control cohort by matching age and total body surface area burn . Premorbid conditions such as diabetes , hypertension , cardiac disease , renal insufficiency , and diuretic and calcium channel blocker use were analyzed . Multivariate regression models were used to identify independent modifiers . RESULTS There were 21 PMH BB , 22 HOSP BB , and 86 control patients . All PMH BB patients remained on their BB regimen in the hospital . HOSP BB patients were initiated on beta-blockers at a mean of 8.8 days postinjury . There were no differences in age ( mean , 58 + /- 17 years ) , total body surface area burned ( mean , 14 + /- 12 % ) , or mechanism of injury among the cohorts . The mortality rate was 5 % for the PMH BB cohort , 27 % for the HOSP BB cohort , and 13 % for controls . The mean healing times were 51 + /- 29 days for PMH BB patients , 79 + /- 54 days for HOSP BB patients , and 60 + /- 39 for controls . In multivariate analyses , PMH BB was associated with a significant decrease in fatal outcome and healing time ( p < or = 0.05 compared with control ) . CONCLUSION Beta-blockers have the potential to improve adult burn outcomes . Postinjury treatment should be studied in a r and omized , clinical trial OBJECTIVE To determine if the cardiovascular effects of excessive catecholamines could be selectively blocked in severely burned patients without adversely affecting protein or fat kinetics . DESIGN Prospect i ve cohort study . SETTING A large tertiary care referral center in Galveston , Tex . PATIENTS Sixteen patients with greater than 40 % body surface area burns . INTERVENTIONS Patients were r and omly selected to receive propranolol hydrochloride , a nonselective beta 1- and beta 2-blocker , or metoprolol tartrate , a selective beta 1-blocker . MAIN OUTCOME MEASURES Heart rate ; rate-pressure product ; rate of appearance of urea , glucose , and leucine ; and leucine oxidation were measured before and after selective or nonselective beta-adrenergic blockade . RESULTS Propranolol and metoprolol caused a significant decrease in heart rate , from a mean ( + /- SD ) of 143 + /- 15 to 115 + /- 11 and from 147 + /- 17 to 120 + /- 9 beats per minute , respectively , during the 5-day study period . Neither the rate of appearance of urea nor the rate of urea production were significantly altered by propranolol or metoprolol therapy . Only propranolol produced a significant decrease ( P < .05 ) in the rate of appearance of glycerol , from a mean ( + /- SD ) of 5.54 + /- 0.62 to 3.07 + /- 0.7 mumol/kg per minute . The rate of appearance of leucine , used as an index of total body protein catabolism , was not significantly altered by either beta-blocker . CONCLUSIONS Selective beta 1-adrenergic blockade did not reduce lipolysis ; however , a beta 1- and beta 2-adrenergic blockade significantly reduced lipolysis . Thus , the increased lipolysis , characteristic of severely burned patients , is caused by stimulation of the beta 2-adrenergic receptors for catecholamines Propranolol has been shown to be effective for as long as 5 days in massively burned children to reduce heart rate and cardiac work . This article describes the use of propranolol given for 10 days to burned children to test whether the drug remains effective and safe in reducing heart rate and cardiac work for longer periods . We prospect ively studied 22 children , 1 to 10 years of age with burns covering > or = 40 % of their total body surface area . These children were treated with 0.5 to 1.0 mg/kg propranolol given orally or intravenously every 8 hours for 10 days . In both septic and nonseptic patients , propranolol significantly decreased their daily average heart rate ( between 10 % and 13 % , p < 0.05 ) and rate-pressure product ( between 10 % and 16 % , p < 0.05 ) compared with their 24-hour mean before propranolol treatment . No significant change in mean arterial blood pressure , or plasma urea nitrogen creatinine or glucose levels could be shown . No hypotension , hypothermia , azotemia , hyperglycemia or hypoglycemia , arrhythmia , bronchospasm , or peripheral ischemia was noted during or after treatment . Whereas propranolol lowered heart rate more per milligram per kilogram body weight when given intravenously , both routes were safe and effective . From these data , we conclude that propranolol can be given to decrease the work of the heart safely and effectively for > or = 10 days BACKGROUND Severe burn is followed by profound cardiac stress . Propranolol , a nonselective β(1 , ) β(2)-receptor antagonist , decreases cardiac stress , but little is known about the dose necessary to cause optimal effect . Thus , the aim of this study was to determine in a large , prospect i ve , r and omized , controlled trial the dose of propranolol that would decrease heart rate ≥15 % of admission heart rate and improve cardiac function . Four-hundred six patients with burns > 30 % total body surface area were enrolled and r and omized to receive st and ard care ( controls ; n = 235 ) or st and ard care plus propranolol ( n = 171 ) . METHODS Dose-response and drug kinetics of propranolol were performed . Heart rate and mean arterial pressure ( MAP ) were measured continuously . Cardiac output ( CO ) , cardiac index , stroke volume , rate-pressure product , and cardiac work ( CW ) were determined at regular intervals . Statistical analysis was performed using analysis of variance with Tukey and Bonferroni corrections and the Student t test when applicable . Significance was accepted at P < .05 . RESULTS Propranolol given initially at 1 mg/kg per day decreased heart rate by 15 % compared with control patients , but was increased to 4 mg/kg per day within the first 10 days to sustain treatment benefits ( P < .05 ) . Propranolol decreased CO , rate-pressure product , and CW without deleterious effects on MAP . The effective plasma drug concentrations were achieved in 30 minutes , and the half-life was 4 hours . CONCLUSION The data suggest that propranolol is an efficacious modulator of the postburn cardiac response when given at a dose of 4 mg/kg per day , and decreases and sustains heart rate 15 % below admission heart rate BACKGROUND Maintaining lean body mass ( LBM ) after a severe burn is an essential goal of modern burn treatment . An accurate determination of LBM is necessary for short- and long-term therapeutic decisions . The aim of this study was to compare 2 measurement methods for body composition , whole-body potassium counting ( K count ) and dual x-ray absorptiometry ( DEXA ) , in a large prospect i ve clinical trial in severely burned pediatric patients . METHODS Two-hundred seventy-nine patients admitted with burns covering 40 % of total body surface area ( TBSA ) were enrolled in the study . Patients enrolled were controls or received long-term treatment with recombinant human growth hormone ( rhGH ) . Near-simultaneous measurements of LBM with DEXA and fat-free mass ( FFM ) with K count were performed at hospital discharge and at 6 , 9 , 12 , 18 , and 24 months post injury . Results were correlated using Pearson 's regression analysis . Agreement between the 2 methods was analyzed with the Bl and -Altman method . RESULTS Age , gender distribution , weight , burn size , and admission time from injury were not significantly different between control and treatment groups . rhGH and control patients at all time points postburn showed a good correlation between LBM and FFM measurements ( R(2 ) between 0.9 and 0.95 ) . Bl and -Altman revealed that the mean bias and 95 % limits of agreement depended only on patient weight and not on treatment or time postburn . The 95 % limits ranged from 0.1 + /- 2.9 kg for LBM or FFM in 7- to 18-kg patients to 16.3 + /- 17.8 kg for LBM or FFM in patients > 60 kg . CONCLUSIONS DEXA can provide a sufficiently accurate determination of LBM and changes in body composition , but a correction factor must be included for older children and adolescents with more LBM . DEXA scans are easier , cheaper , and less stressful for the patient , and this method should be used rather than the K count Objective : To determine the safety and efficacy of propranolol given for 1 year on cardiac function , resting energy expenditure , and body composition in a prospect i ve , r and omized , single-center , controlled study in pediatric patients with large burns . Background : Severe burns trigger a hypermetabolic response that persists for up to 2 years postburn . Propranolol given for 1 month postburn blunts this response . Whether propranolol administration for 1 year after injury provides a continued benefit is currently unclear . Methods : One-hundred seventy-nine pediatric patients with more than 30 % total body surface area burns were r and omized to control ( n = 89 ) or 4 mg/kg/d propranolol ( n = 90 ) for 12 months postburn . Changes in resting energy expenditure , cardiac function , and body composition were measured acutely at 3 , 6 , 9 , and 12 months postburn . Statistical analyses included techniques that adjusted for non-normality , repeated- measures , and regression analyses . P < 0.05 was considered significant . Results : Long-term propranolol treatment significantly reduced the percentage of the predicted heart rate and percentage of the predicted resting energy expenditure , decreased accumulation of central mass and central fat , prevented bone loss , and improved lean body mass accretion . There were very few adverse effects from the dose of propranolol used . Conclusions : Propranolol treatment for 12 months after thermal injury , ameliorates the hyperdynamic , hypermetabolic , hypercatabolic , and osteopenic responses in pediatric patients . This study is registered at clinical trials.gov : NCT00675714

Pneumococcal and influenza vaccination comprise one of the most important preventive approaches for CAP in the elderly

INTRODUCTION Community acquired pneumonia ( CAP ) is a major health problem in elderly persons and is associated with high morbidity and mortality . Areas covered : This article review s the most recent publications relative to CAP in the elderly population , with a focus on epidemiology , prognostic factors , microbial etiology , therapy and prevention . Expert commentary : CAP can occur at any age , but its incidence and risk of death are linked to increasing age . Age-related changes in the immune system make this population more vulnerable to CAP .

Background : An inadequate response to initial empirical treatment of community acquired pneumonia ( CAP ) represents a challenge for clinicians and requires early identification and intervention . A study was undertaken to quantify the incidence of failure of empirical treatment in CAP , to identify risk factors for treatment failure , and to determine the implication s of treatment failure on the outcome . Methods : A prospect i ve multicentre cohort study was performed in 1424 hospitalised patients from 15 hospitals . Early treatment failure ( < 72 hours ) , late treatment failure , and in-hospital mortality were recorded . Results : Treatment failure occurred in 215 patients ( 15.1 % ) : 134 early failure ( 62.3 % ) and 81 late failure ( 37.7 % ) . The causes were infectious in 86 patients ( 40 % ) , non-infectious in 34 ( 15.8 % ) , and undetermined in 95 . The independent risk factors associated with treatment failure in a stepwise logistic regression analysis were liver disease , pneumonia risk class , leucopenia , multilobar CAP , pleural effusion , and radiological signs of cavitation . Independent factors associated with a lower risk of treatment failure were influenza vaccination , initial treatment with fluoroquinolones , and chronic obstructive pulmonary disease ( COPD ) . Mortality was significantly higher in patients with treatment failure ( 25 % v 2 % ) . Failure of empirical treatment increased the mortality of CAP 11-fold after adjustment for risk class . Conclusions : Although these findings need to be confirmed by r and omised studies , they suggest possible interventions to decrease mortality due to CAP BACKGROUND Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia . We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia . METHODS In this double-blind , multicentre , r and omised , placebo-controlled trial , we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerl and within 24 h of presentation . Patients were r and omly assigned ( 1:1 ratio ) to receive either prednisone 50 mg daily for 7 days or placebo . The computer-generated r and omisation was done with variable block sizes of four to six and stratified by study centre . The primary endpoint was time to clinical stability defined as time ( days ) until stable vital signs for at least 24 h , and analysed by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00973154 . FINDINGS From Dec 1 , 2009 , to May 21 , 2014 , of 2911 patients assessed for eligibility , 785 patients were r and omly assigned to either the prednisone group ( n=392 ) or the placebo group ( n=393 ) . Median time to clinical stability was shorter in the prednisone group ( 3·0 days , IQR 2·5 - 3·4 ) than in the placebo group ( 4·4 days , 4·0 - 5·0 ; hazard ratio [ HR ] 1·33 , 95 % CI 1·15 - 1·50 , p<0·0001 ) . Pneumonia-associated complications until day 30 did not differ between groups ( 11 [ 3 % ] in the prednisone group and 22 [ 6 % ] in the placebo group ; odds ratio [ OR ] 0·49 [ 95 % CI 0·23 - 1·02 ] ; p=0·056 ) . The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment ( 76 [ 19 % ] vs 43 [ 11 % ] ; OR 1·96 , 95 % CI 1·31 - 2·93 , p=0·0010 ) . Other adverse events compatible with corticosteroid use were rare and similar in both groups . INTERPRETATION Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications . This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency . FUNDING Swiss National Science Foundation , Viollier AG , Nora van Meeuwen Haefliger Stiftung , Julia und Gottfried Bangerter-Rhyner Stiftung Objectives It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia ( CAP ) . The aim of this prospect i ve , r and omised , double-blind , placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines . Setting A tertiary teaching hospital in Barcelona , Spain . Participants Thirty-four patients were r and omly assigned and included in an intention-to-treat analysis ( 19 to the simvastatin group and 15 to the placebo group ) . Intervention Patients were r and omly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days . Outcome Primary end point was the time from hospital admission to clinical stability . The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen ( PaO2/FiO2 ) at 48 h after treatment administration . Results The trial was stopped because enrolment was much slower than originally anticipated . The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups . No significant differences in the time from hospital admission to clinical stability were found between study groups ( median 3 days , IQR 2–5 vs 3 days , IQR 2–5 ; p=0.47 ) . No significant differences in PaO2/FiO2 ( p=0.37 ) , C reactive protein ( p=0.23 ) , tumour necrosis factor-α ( p=0.58 ) , interleukin 6 ( IL-6 ; p=0.64 ) , and IL-10 ( p=0.61 ) levels at 48 h of hospitalisation were found between simvastatin and placebo groups . Similarly , transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation ( p=0.19 , 0.08 and 0.53 , respectively ) . Conclusions Our results suggest that the use of simvastatin , 20 mg once daily for 4 days , since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP . Trial registration number IS RCT N91327214 Background : In the assessment of severity in community acquired pneumonia ( CAP ) , the modified British Thoracic Society ( mBTS ) rule identifies patients with severe pneumonia but not patients who might be suitable for home management . A multicentre study was conducted to derive and vali date a practical severity assessment model for stratifying adults hospitalised with CAP into different management groups . Methods : Data from three prospect i ve studies of CAP conducted in the UK , New Zeal and , and the Netherl and s were combined . A derivation cohort comprising 80 % of the data was used to develop the model . Prognostic variables were identified using multiple logistic regression with 30 day mortality as the outcome measure . The final model was tested against the validation cohort . Results : 1068 patients were studied ( mean age 64 years , 51.5 % male , 30 day mortality 9 % ) . Age ⩾65 years ( OR 3.5 , 95 % CI 1.6 to 8.0 ) and albumin < 30 g/dl ( OR 4.7 , 95 % CI 2.5 to 8.7 ) were independently associated with mortality over and above the mBTS rule ( OR 5.2 , 95 % CI 2.7 to 10 ) . A six point score , one point for each of Confusion , Urea > 7 mmol/l , Respiratory rate ⩾30/min , low systolic(<90 mm Hg ) or diastolic ( ⩽60 mm Hg ) Blood pressure ) , age ⩾65 years ( CURB-65 score ) based on information available at initial hospital assessment , enabled patients to be stratified according to increasing risk of mortality : score 0 , 0.7 % ; score 1 , 3.2 % ; score 2 , 3 % ; score 3 , 17 % ; score 4 , 41.5 % and score 5 , 57 % . The validation cohort confirmed a similar pattern . Conclusions : A simple six point score based on confusion , urea , respiratory rate , blood pressure , and age can be used to stratify patients with CAP into different management groups Background Community-acquired pneumonia ( CAP ) is generally considered a major cause of morbidity and mortality in the elderly . However , population -based data are very limited and its overall burden is unclear . This study assessed incidence and mortality from CAP among Spanish community-dwelling elderly . Methods Prospect i ve cohort study that included 11,240 individuals aged 65 years or older , who were followed from January 2002 until April 2005 . Primary endpoints were all-cause CAP ( hospitalised and outpatient ) and 30-day mortality after the diagnosis . All cases were radiographically proved and vali date d by checking clinical records . Results Incidence rate of overall CAP was 14 cases per 1,000 person-year ( 95 % confidence interval : 12.7 to 15.3 ) . Incidence increased dramatically by age ( 9.9 in people 65–74 years vs 29.4 in people 85 years or older ) , and it was almost double in men than in women ( 19.3 vs 10.1 ) . Hospitalisation rate was 75.1 % , with a mean length-stay of 10.4 days . Overall 30-days case-fatality rate was 13 % ( 15 % in hospitalised and 2 % in outpatient cases ) . Conclusion CAP remains as a major health problem in older adults . Incidence rates in this study are comparable with rates described in Northern Europe and America , but they largely doubled prior rates reported in other Southern European regions Objective To determine differences in aetiologies , initial antimicrobial treatment choices and outcomes in patients with nursing-home-acquired pneumonia ( NHAP ) compared with patients with community-acquired pneumonia ( CAP ) , which is a controversial issue . Methods Data from the prospect i ve multicentre Competence Network for Community-acquired pneumonia ( CAPNETZ ) data base were analysed for hospitalised patients aged ≥65 years with CAP or NHAP . Potential differences in baseline characteristics , comorbidities , physical examination findings , severity at presentation , initial laboratory investigations , blood gases , microbial investigations , aetiologies , antimicrobial treatment and outcomes were determined between the two groups . Results Patients with NHAP presented with more severe pneumonia as assessed by CRB-65 ( confusion , respiratory rate , blood pressure , 65 years and older ) score than patients with CAP but received the same frequency of mechanical ventilation and less antimicrobial combination treatment . There were no clinical ly relevant differences in aetiology , with Streptococcus pneumoniae the most important pathogen in both groups , and potential multidrug-resistant pathogens were very rare ( < 5 % ) . Only Staphylococcus aureus was more frequent in the NHAP group ( n=12 , 2.3 % of the total population , 3.1 % of those with microbial sampling compared with 0.7 % and 0.8 % in the CAP group , respectively ) . Short-term and long-term mortality in the NHAP group was higher than in the CAP group for patients aged ≥65 years ( 26.6 % vs 7.2 % and 43.8 % vs 14.6 % , respectively ) . However , there was no association between excess mortality and potential multidrug-resistant pathogens . Conclusions Excess mortality in patients with NHAP can not be attributed to a different microbial pattern but appears to result from increased comorbidities , and consequently , pneumonia is frequently considered and managed as a terminal event Background Age-related alterations in the clinical characteristics and performance of severity scoring systems for community-acquired pneumonia ( CAP ) are unknown . Methods Consecutive patients with CAP presenting to the emergency department were prospect ively studied . Patients were classified as younger adults ( age 18–64 years ) , elderly ( age 65–84 years ) and very old subjects ( age ≥85 years ) . Clinical characteristics , complications , outcomes and validity of the pneumonia severity index ( PSI ) and CURB-65 categories were compared across these three age categories . Results Analysis involved 348 ( 35.3 % ) younger adult patients , 438 ( 44.3 % ) elderly patients and 201 ( 20.0 % ) very old patients . Compared with younger adults , elderly and very old patients had a higher burden of comorbidities and a higher incidence of CAP-related complications . The 30-day mortality rate was 5.2 % in younger adults , 7.1 % in elderly patients and 9.5 % in very old patients . The area under the ROC curve ( AUCs ) for PSI were 0.87 ( 95 % CI 0.77 to 0.97 ) , 0.85 ( 95 % CI 0.803 to 0.897 ) and 0.69 ( 95 % CI 0.597 to 0.787 ) and the AUCs for CURB-65 were 0.80 ( 95 % CI 0.67 to 0.93 ) , 0.73 ( 95 % CI 0.65 to 0.82 ) and 0.60 ( 95 % CI 0.47 to 0.73 ) in the younger adult , elderly and very old patients , respectively . A modified PSI or CURB-65 excluding the age variable increased the AUC in most age categories . There was no significant effect of age on 30-day mortality after adjusting for other PSI or CURB-65 variables . Conclusion Elderly patients with CAP have more atypical clinical manifestations and worse outcomes . The underperformance of the PSI in elderly patients may be due to the inappropriate weight given to the age variable . A modification of the cut-off point for PSI or CURB-65 to define severe pneumonia may improve the score performance in elderly patients BACKGROUND Studies suggest that statins and angiotensin-converting enzyme ( ACE ) inhibitors might be beneficial for the treatment of infections . Our purpose was to examine the association of statin , ACE inhibitor , and angiotensin II receptor blocker ( ARB ) use with pneumonia-related outcomes . METHODS We conducted a retrospective cohort study using Department of Veterans Affairs data of patients aged ≥ 65 years hospitalized with pneumonia . We performed propensity-score matching for 3 medication classes simultaneously . RESULTS Of 50119 potentially eligible patients , we matched 11498 cases with 11498 controls . Mortality at 30 days was 13 % ; 34 % used statins , 30 % ACE inhibitors , and 4 % ARBs . In adjusted models , prior statin use was associated with decreased mortality ( odds ratio [ OR ] , 0.74 ; 95 % confidence interval [ CI ] , .68-.82 ) and mechanical ventilation ( OR , 0.81 ; 95 % CI , .70-.94 ) , and inpatient use with decreased mortality ( OR , 0.68 ; 95 % CI , .59-.78 ) and mechanical ventilation ( OR , 0.68 ; 95 % CI , .60-.90 ) . Prior ( OR , 0.88 ; 95 % CI , .80-.97 ) and inpatient ( OR , 0.58 ; 95 % CI , .48-.69 ) ACE inhibitor use was associated with decreased mortality . Prior ( OR , 0.73 ; 95 % CI , .58-.92 ) and inpatient ARB use ( OR , 0.47 ; 95 % CI , .30-.72 ) was only associated with decreased mortality . Use of all 3 medications was associated with reduced length of stay . CONCLUSIONS Statins , and to a lesser extent ACE inhibitors and ARBs , are associated with improved pneumonia-related outcomes . Prospect i ve cohort and r and omized controlled trials are needed to examine potential mechanisms of action and whether acute initiation at the time of presentation with these infections is beneficial BACKGROUND Community acquired pneumonia ( CAP ) in the elderly has unique features and there is little information about the effects of nutrition status on its outcome . AIM To assess the clinical manifestations and prognostic factors of CAP in immunocompetent elderly patients requiring hospitalization . PATIENTS AND METHODS Prospect i ve study of all patients with CAP , admitted to Puerto Montt Hospital , Chile over one year . Epidemiológica ! and clinical information and laboratory results were recorded . A nutritional assessment was also performed . Outcomes of elderly ( > 65 years ) and young patients were compared . RESULTS Two hundred patients aged 63+/- 19 years were studied . Of these , 109 were older than 65 years ( 78.4+/-8 years ) and 91 were younger than 65 years ( 45.5+/-11 years ) . Multiple associated diseases , altered mental status , absence of fever , malnutrition and mortality were more common in the older group . Suspected aspiration pneumonia was more common in younger patients , probably related to alcoholism . Malnutrition was associated with longer hospital stay and mortality at any age . An univariate analysis showed that a low serum albumin ( < 3.4 g/dl ) and a mid arm muscle circumference below the 25th percentile were associated with higher mortality . CONCLUSIONS CAP in the elderly has specific features and malnutrition is associated with a worse prognosis in young and elderly patients Community-acquired pneumonia ( CAP ) is now most frequent in elderly patients . CAP in the younger patient has attracted much less attention . Therefore , we compared patients with CAP aged 18 to < 65 yrs with those aged ≥65 yrs . Data from the prospect i ve multicentre Competence Network for Community Acquired Pneumonia Study Group ( CAPNETZ ) data base were analysed for potential differences in baseline characteristics , comorbidities , clinical presentation , microbial investigations , aetiologies , antimicrobial treatment and outcomes . Overall , 7,803 patients were studied . The proportion of younger patients ( aged < 65 yrs ) was 52.3 % ( 18 to < 30 yrs 6.4 % ; < 40 yrs 17.1 % ; < 50 yrs 29.4 % ) . Comorbidity was present in only half of the younger patients ( 46.6 % versus 88.2 % ) . Fever and chest pain were more common . Most younger patients presented with mild CAP ( 74.0 % had a CURB-65 score of 0 ( confusion of new onset , urea > 7 mmol·L−1 , respiratory rate of ≥30 breaths·min−1 , blood pressure < 90 mmHg or diastolic blood pressure ≤60 mmHg , age ≥65 yrs ) ) . Overall , Streptococcus pneumoniae and Mycoplasma pneumoniae were the most frequent pathogens in the younger patients . Short-term mortality was very low ( 1.7 % versus 8.2 % ) and even lower in patients without comorbidity ( 0.3 % versus 2.4 % ) . Long-term mortality was 3.2 % versus 15.9 % , also lower in patients without comorbidity ( 0.8 % versus 6.1 % ) . Most of the differences found clearly arise after the fifth or within the middle of the sixth decade . CAP in the younger patient is a clinical ly distinct entity BACKGROUND Existing severity assessment tools , such as the pneumonia severity index ( PSI ) and CURB-65 ( tool based on confusion , urea level , respiratory rate , blood pressure , and age > or=65 years ) , predict 30-day mortality in community-acquired pneumonia ( CAP ) and have limited ability to predict which patients will require intensive respiratory or vasopressor support ( IRVS ) . METHODS The Australian CAP Study ( ACAPS ) was a prospect i ve study of 882 episodes in which each patient had a detailed assessment of severity features , etiology , and treatment outcomes . Multivariate logistic regression was performed to identify features at initial assessment that were associated with receipt of IRVS . These results were converted into a simple points-based severity tool that was vali date d in 5 external data bases , totaling 7464 patients . RESULTS In ACAPS , 10.3 % of patients received IRVS , and the 30-day mortality rate was 5.7 % . The features statistically significantly associated with receipt of IRVS were low systolic blood pressure ( 2 points ) , multilobar chest radiography involvement ( 1 point ) , low albumin level ( 1 point ) , high respiratory rate ( 1 point ) , tachycardia ( 1 point ) , confusion ( 1 point ) , poor oxygenation ( 2 points ) , and low arterial pH ( 2 points ) : SMART-COP . A SMART-COP score of > or=3 points identified 92 % of patients who received IRVS , including 84 % of patients who did not need immediate admission to the intensive care unit . Accuracy was also high in the 5 validation data bases . Sensitivities of PSI and CURB-65 for identifying the need for IRVS were 74 % and 39 % , respectively . CONCLUSIONS SMART-COP is a simple , practical clinical tool for accurately predicting the need for IRVS that is likely to assist clinicians in determining CAP severity Background A better underst and ing of potentially modifiable predictors of in-hospital mortality and re-admission to the hospital following discharge may help to improve management of community-acquired pneumonia in older adults . We aim ed to assess the associations of potentially modifiable factors with mortality and re-hospitalization in older adults hospitalized with community-acquired pneumonia . Methods A prospect i ve cohort study was conducted from July 2003 to April 2005 in two Canadian cities . Patients aged 65 years or older hospitalized for community-acquired pneumonia were followed up for up to 30 days from initial hospitalization for mortality and these patients who were discharged alive within 30 days of initial hospitalization were followed up to 90 days of initial hospitalization for re-hospitalization . Separate logistic regression analyses were performed identify the predictors of mortality and re-hospitalization . Results Of 717 enrolled patients hospitalized for community-acquired pneumonia , 49 ( 6.8 % ) died within 30 days of hospital admission . Among these patients , 526 were discharged alive within 30 days of hospitalization of whom 58 ( 11.2 % ) were re-hospitalized within 90 days of initial hospitalization . History of hip fracture ( odds ratio ( OR ) = 4.00 , 95 % confidence interval ( CI ) = ( 1.46 , 10.96 ) , P = .007 ) , chronic obstructive pulmonary disease ( OR = 2.31 , 95 % CI = ( 1.18 , 4.50 ) , P = .014 ) , cerebrovascular disease ( OR = 2.11 , 95 % CI = ( 1.03 , 4.31 ) , P = .040 ) were associated with mortality . Male sex ( OR = 2.35 , 95 % CI = ( 1.13 , 4.85 ) , P = .022 ) was associated with re-hospitalization while vitamin E supplementation was protective ( OR = 0.37 ( 0.16 , 0.90 ) , P = .028 ) . Lower socioeconomic status , prior influenza and pneumococcal vaccinations , appropriate antibiotic prescription upon admission , and lower nutrition risk were not significantly associated with mortality or re-hospitalization . Conclusion Chronic comorbidities appear to be the most important predictors of death and re-hospitalization in older adults hospitalized with community-acquired pneumonia while vitamin E supplementation was protective BACKGROUND Prior retrospective studies suggest that statins may benefit patients with community-acquired pneumonia ( CAP ) due to antiinflammatory and immunomodulatory effects . However , prospect i ve studies of the impact of statins on CAP outcomes are needed . We determined whether statin use was associated with improved outcomes in adults hospitalized with CAP . METHODS Adults aged ≥18 years hospitalized with CAP were prospect ively enrolled at 3 hospitals in Chicago , Illinois , and 2 hospitals in Nashville , Tennessee , from January 2010-June 2012 . Adults receiving statins before and throughout hospitalization ( statin users ) were compared with those who did not receive statins ( nonusers ) . Proportional subdistribution hazards models were used to examine the association between statin use and hospital length of stay ( LOS ) . In-hospital mortality was a secondary outcome . We also compared groups matched on propensity score . RESULTS Of 2016 adults enrolled , 483 ( 24 % ) were statin users ; 1533 ( 76 % ) were nonusers . Statin users were significantly older , had more comorbidities , had more years of education , and were more likely to have health insurance than nonusers . Multivariable regression demonstrated that statin users and nonusers had similar LOS ( adjusted hazard ratio [ HR ] , 0.99 ; 95 % confidence interval [ CI ] , .88 - 1.12 ) , as did those in the propensity-matched groups ( HR , 1.03 ; 95 % CI , .88 - 1.21 ) . No significant associations were found between statin use and LOS or in-hospital mortality , even when stratified by pneumonia severity . CONCLUSIONS In a large prospect i ve study of adults hospitalized with CAP , we found no evidence to suggest that statin use before and during hospitalization improved LOS or in-hospital mortality The etiology of severe pneumonia requiring mechanical ventilation in the very elderly has been imprecise because of lack of comprehensive studies and low yield of diagnostic approach . Overall , 104 patients 75 yr of age and older with severe pneumonia were studied prospect ively at two university-affiliated hospitals . Microbial investigation included blood culture , serology , pleural fluid , and bronchoalveolar secretions . Streptococcus pneumoniae ( 14 % ) , gram-negative enteric bacilli ( 14 % ) , Legionella sp. ( 9 % ) , Hemophilus influenzae ( 7 % ) , and Staphylococcus aureus ( 7 % ) were the predominant pathogens in community-acquired pneumonia ( CAP ) . Staphylococcus aureus ( 29 % ) , gram-negative enteric bacilli ( 15 % ) , Streptococcus pneumoniae ( 9 % ) , and Pseudomonas aeruginosa ( 4 % ) accounted for most isolates of nursing home-acquired pneumonia ( NHAP ) . The case fatality rate was 55 % ( 53 % for CAP and 57 % for NHAP ; p > 0.5 ) . Activity of Daily Living ( ADL ) Index , pulmonary , endocrine and central nervous system ( CNS ) comorbidities were associated with distinct microbial etiology . By multivariate analysis , hospital mortality was associated independently with 24-h urine output ( odds ratio [ OR ] , 5.6 ; 95 % confidence interval [ CI ] , 2.5 to 7.9 ; p < 0.001 ) , septic shock ( OR , 4.3 ; 95 % CI , 1.9 to 8.9 ; p = 0.0059 ) , radiographic multilobar involvement ( OR , 3.7 ; 95 % CI , 1.8 to 15.6 ; p = 0.02 ) , and inadequate antimicrobial therapy ( OR , 2.6 ; 95 % CI , 1.4 to 23.9 ; p = 0.034 ) . Further studies should focus on identifying effective antimicrobial regimens in r and omized trials Little is known about the long-term sequelae of community-acquired pneumonia ( CAP ) . Therefore , we describe the long-term morbidity and mortality of patients after pneumonia requiring hospitalization . We specifically hypothesized that the Pneumonia Severity Index ( PSI ) , design ed to predict 30-day pneumonia-related mortality , would also be associated with longer-term all-cause mortality . Between 2000 and 2002 , 3415 adults with CAP admitted to 6 hospitals in Edmonton , Alberta , Canada , were prospect ively enrolled in a population -based cohort . At the time of hospital admission , demographic , clinical , and laboratory data were collected and the PSI was calculated for each patient . Postdischarge outcomes through to 2006 were ascertained using multiple linked administrative data bases . Outcomes included all-cause mortality , hospital admissions , and re-hospitalization for pneumonia over a maximum of 5.4years of follow-up . Follow-up data were available for 3284 ( 96 % ) patients ; 66%were ≥65 years of age , 53 % were male , and according to the PSI fully 63 % were predicted to have greater than 18 % 30-day pneumonia-related mortality ( that is , PSI class IV-V ) . Median follow-up was 3.8 years . The 30-day , 1-year , and end of study mortality rates were 12 % , 28 % , and 53 % , respectively . Overall , 82(19 % ) patients aged < 45 years died compared with 1456 ( 67 % ) patients aged ≥65 years ( hazard ratio [ HR ] , 5.07 ; 95 % confidence interval [ CI ] , 4.06 - 6.34 ) . Male patients were more likely to die than female patients during follow-up ( 971 [ 56 % ] vs. 767 [ 49 % ] , respectively ; HR , 1.20 ; 95 % CI , 1.13 - 1.37 ) . Initial PSI classification predicted not only 30-day mortality , but also long-term postdischarge mortality , with 92 ( 15 % ) of PSI class I-II patients dying compared with 616 ( 82 % ) PSI class V patients ( HR , 11.80 ; 95 % CI , 4.70 - 14.70 ) . Of 2950 patients who survived the initial CAP hospitalization , 72 % were hospitalized again ( median , 2 admissions over follow-up ) and 16 % were re-hospitalized with pneumonia . In conclusion , long-term morbidity and mortality are high following hospitalization for pneumonia and are strongly correlated with initial PSI class . This suggests that patients with pneumonia , especially those with PSI class IV and V at admission , might need better attention paid to preventive strategies and much closer follow-up due to their elevated risk of subsequent adverse events and increased health re source utilization . Abbreviations : AHW = Alberta Health and Wellness , CAP = community-acquired pneumonia , CI = confidence interval , HR = hazard ratio , ICD = International Classification of Disease , ICD-9-CM = International Classification of Disease , Ninth Revision , Clinical Modification , ICD-10-CA = International Classification of Disease , Tenth Revision , Canadian Version , PHN = personal health number , PORT = Patient Outcomes Research Team , PSI = Pneumonia Severity BACKGROUND Prolonged life expectancy has currently increased the proportion of the very elderly among patients with community-acquired pneumonia ( CAP ) . The aim of this study was to determine the influence of age and comorbidity on microbial patterns in patients over 65 years of age with CAP . METHODS This study was a prospect i ve observational study of adult patients with CAP ( excluding those in nursing homes ) over a 12-year period . We compared patients aged 65 to 74 years , 75 to 84 years , and > 85 years for potential differences in clinical presentation , comorbidities , severity on admission , microbial investigations , causes , antimicrobial treatment , and outcomes . RESULTS We studied a total of 2,149 patients : 759 patients ( 35.3 % ) aged 65 to 74 years , 941 patients ( 43.7 % ) aged 75 to 84 years , and 449 patients ( 20.8 % ) aged > 85 years . At least one comorbidity was present in 1,710 patients ( 79.6 % ) . Streptococcus pneumoniae was the most frequent pathogen in all age groups , regardless of comorbidity . Staphylococcus aureus , Enterobacteriaceae , and Pseudomonas aeruginosa accounted for 9.1 % of isolates , and Haemophilus influenzae , 6.4 % . All these pathogens were isolated only in patients with at least one comorbidity . Mortality increased with age ( 65 - 74 years , 6.9 % ; 75 - 84 years , 8.9 % ; > 85 years , 17.1 % ; P < .001 ) and was associated with increased comorbidities ( neurologic ; OR , 2.1 ; 95 % CI , 1.5 - 2.1 ) , Pneumonia Severity Index IV or V ( OR , 3.2 ; 95 % CI , 1.8 - 6.0 ) , bacteremia ( OR , 1.7 ; 95 % CI , 1.1 - 2.7 ) , the presence of a potential multidrug-resistant ( MDR ) pathogen ( S. aureus , P. aeruginosa , Enterobacteriaceae ; OR , 2.4 ; 95 % CI , 1.3 - 4.3 ) , and ICU admission ( OR , 4.2 ; 95 % CI , 2.9 - 6.1 ) on multivariate analysis . CONCLUSIONS Age does not influence microbial cause itself , whereas comorbidities are associated with specific causes such as H. influenzae and potential MDR pathogens . Mortality in the elderly is mainly driven by the presence of comorbidities and potential MDR pathogens BACKGROUND Appropriate initial antibiotics are essential for the treatment of infectious diseases . However , some patients with pneumonia might develop adverse outcomes , despite receiving appropriate initial antibiotics . We aim ed to clarify the risk factors for 30-day mortality in patients who received appropriate initial antibiotics and to identify potential c and i date s who would benefit from adjunctive therapy . METHODS From March 15 , to Dec 22 , 2010 , we did a prospect i ve , observational study at ten medical institutions in hospitalised patients ( aged ≥20 years ) with pneumonia . We did a multivariable logistic regression analysis to calculate odds ratios ( ORs ) and 95 % CI to assess the risk factors for 30-day mortality . This study was registered with the University Medical Information Network in Japan , number UMIN000003306 . FINDINGS The 30-day mortality was 11 % ( 61 of 579 patients ) in the appropriate initial antibiotic treatment group and 17 % ( 29 of 168 ) in the inappropriate initial antibiotic treatment group . Albumin concentration of less than 30 mg/L ( adjusted OR 3·39 , 95 % CI 1·83 - 6·28 ) , non-ambulatory status ( 3·34 , 1·84 - 6·05 ) , pH of less than 7·35 ( 3·13 , 1·52 - 6·42 ) , respiration rate of at least 30 breaths per min ( 2·33 , 1·28 - 4·24 ) , and blood urea nitrogen of at least 7·14 mmol/L ( 2·20 , 1·13 - 4·30 ) were independent risk factors in patients given appropriate initial antibiotic treatment . The 30-day mortality was 1 % ( one of 126 patients ) , 1 % ( two of 168 ) , 17 % ( 23 of 137 ) , 22 % ( 20 of 89 ) , and 44 % ( 14 of 32 ) for patients with no , one , two , three , and four or five risk factors , respectively . INTERPRETATION Patients with two or more risk factors were at a higher risk of death during the 30 days assessed than were individuals with no or one risk factor , despite appropriate initial antibiotic treatment . Therefore , adjunctive therapy might be important for improving outcomes in patients with two or more risk factors . FUNDING Central Japan Lung Study Group BACKGROUND Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties . We tested the hypothesis that azithromycin would decrease the frequency of exacerbations , increase lung function , and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis . METHODS We undertook a r and omised , double-blind , placebo-controlled trial at three centres in New Zeal and . Between Feb 12 , 2008 , and Oct 15 , 2009 , we enrolled patients who were 18 years or older , had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year , and had a diagnosis of bronchiectasis defined by high-resolution CT scan . We r and omly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio , with a permuted block size of six and sequential assignment stratified by centre . Participants , research assistants , and investigators were masked to treatment allocation . The co primary endpoints were rate of event-based exacerbations in the 6-month treatment period , change in forced expiratory volume in 1 s ( FEV(1 ) ) before bronchodilation , and change in total score on St George 's respiratory question naire ( SGRQ ) . Analyses were by intention to treat . This study is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12607000641493 . FINDINGS 71 patients were in the azithromycin group and 70 in the placebo group . The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period ( rate ratio 0·38 , 95 % CI 0·26 - 0·54 ; p<0·0001 ) . Prebronchodilator FEV(1 ) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group , but the difference was not significant ( 0·04 L , 95 % CI -0·03 to 0·12 ; p=0·251 ) . Additionally , change in SGRQ total score did not differ between the azithromycin ( -5·17 units ) and placebo groups ( -1·92 units ; difference -3·25 , 95 % CI -7·21 to 0·72 ; p=0·108 ) . INTERPRETATION Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year . FUNDING Health Research Council of New Zeal and and Auckl and District Health Board Charitable Trust IMPORTANCE The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial . OBJECTIVE To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia . DESIGN , SETTING , AND PARTICIPANTS Open-label , multicenter , noninferiority , r and omized trial conducted from January 13 , 2009 , through January 31 , 2013 , in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerl and for moderately severe community-acquired pneumonia . Follow-up extended to 90 days . Outcome assessors were masked to treatment allocation . INTERVENTIONS Patients were treated with a β-lactam and a macrolide ( combination arm ) or with a β-lactam alone ( monotherapy arm ) . Legionella pneumophila infection was systematic ally search ed and treated by addition of a macrolide to the monotherapy arm . MAIN OUTCOMES AND MEASURES Proportion of patients not reaching clinical stability ( heart rate < 100/min , systolic blood pressure > 90 mm Hg , temperature < 38.0 ° C , respiratory rate < 24/min , and oxygen saturation > 90 % on room air ) at day 7 . RESULTS After 7 days of treatment , 120 of 291 patients ( 41.2 % ) in the monotherapy arm vs 97 of 289 ( 33.6 % ) in the combination arm had not reached clinical stability ( 7.6 % difference , P = .07 ) . The upper limit of the 1-sided 90 % CI was 13.0 % , exceeding the predefined noninferiority boundary of 8 % . Patients infected with atypical pathogens ( hazard ratio [ HR ] , 0.33 ; 95 % CI , 0.13 - 0.85 ) or with Pneumonia Severity Index ( PSI ) category IV pneumonia ( HR , 0.81 ; 95 % CI , 0.59 - 1.10 ) were less likely to reach clinical stability with monotherapy , whereas patients not infected with atypical pathogens ( HR , 0.99 ; 95 % CI , 0.80 - 1.22 ) or with PSI category I to III pneumonia ( HR , 1.06 ; 95 % CI , 0.82 - 1.36 ) had equivalent outcomes in the 2 arms . There were more 30-day readmissions in the monotherapy arm ( 7.9 % vs 3.1 % , P = .01 ) . Mortality , intensive care unit admission , complications , length of stay , and recurrence of pneumonia within 90 days did not differ between the 2 arms . CONCLUSIONS AND RELEVANCE We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia . Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00818610 OBJECTIVE We herein assessed the utility of computed tomography ( CT ) for the diagnosis and ascertainment of the severity of community-acquired pneumonia ( CAP ) in the elderly . METHODS The utility of CT compared with chest radiography ( CR ) for the diagnosis of CAP was prospect ively studied among elderly in patients with clinical symptoms and signs indicative of CAP at the Department of Respiratory Medicine in Nissan Tamagawa Hospital during the one-year period from January 2013 to December 2013 . Additionally , we evaluated whether the findings of CT were useful as predictive factors related to the mortality rate associated with CAP . RESULTS One hundred and forty-two patients , 65 years of age or older , were surveyed upon hospital admission for suspected CAP . Of the 142 patients included , 127 ( 89.4 % ) had pneumonic infiltration diagnosed by CT , however , CR could not recognize pneumonic infiltration in 9.4 % ( 12/127 ) of these patients . In 127 CAP-positive patients , bilateral pneumonic infiltration was more frequently detected by CT in non-survivors than survivors ( 79.0 % vs. 53.7 % ; p < 0.05 ) . By a multivariable analysis to determine the prognostic factors related to mortality from CAP , oxygen desaturation showed the greatest odds ratio among the other predictive factors , followed by comorbid neoplastic disease , blood urea nitrogen ≥21 mg/dL , male gender , and bilateral pneumonic infiltration diagnosed by CT . CONCLUSION We herein demonstrated that CT was superior to CR for diagnosing and evaluating the severity of CAP in elderly patients BACKGROUND The choice of empirical antibiotic treatment for patients with clinical ly suspected community-acquired pneumonia ( CAP ) who are admitted to non-intensive care unit ( ICU ) hospital wards is complicated by the limited availability of evidence . We compared strategies of empirical treatment ( allowing deviations for medical reasons ) with beta-lactam monotherapy , beta-lactam-macrolide combination therapy , or fluoroquinolone monotherapy . METHODS In a cluster-r and omized , crossover trial with strategies rotated in 4-month periods , we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality , in an intention-to-treat analysis , using a noninferiority margin of 3 percentage points and a two-sided 90 % confidence interval . RESULTS A total of 656 patients were included during the beta-lactam strategy periods , 739 during the beta-lactam-macrolide strategy periods , and 888 during the fluoroquinolone strategy periods , with rates of adherence to the strategy of 93.0 % , 88.0 % , and 92.7 % , respectively . The median age of the patients was 70 years . The crude 90-day mortality was 9.0 % ( 59 patients ) , 11.1 % ( 82 patients ) , and 8.8 % ( 78 patients ) , respectively , during these strategy periods . In the intention-to-treat analysis , the risk of death was higher by 1.9 percentage points ( 90 % confidence interval [ CI ] , -0.6 to 4.4 ) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points ( 90 % CI , -2.8 to 1.9 ) with the fluoroquinolone strategy than with the beta-lactam strategy . These results indicated noninferiority of the beta-lactam strategy . The median length of hospital stay was 6 days for all strategies , and the median time to starting oral treatment was 3 days ( interquartile range , 0 to 4 ) with the fluoroquinolone strategy and 4 days ( interquartile range , 3 to 5 ) with the other strategies . CONCLUSIONS Among patients with clinical ly suspected CAP admitted to non-ICU wards , a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality . ( Funded by the Netherl and s Organization for Health Research and Development ; CAP-START Clinical Trials.gov number , NCT01660204 . ) CONTEXT Azithromycin is recommended as therapy for cystic fibrosis ( CF ) patients with chronic Pseudomonas aeruginosa infection , but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF . OBJECTIVE To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa . DESIGN , SETTING , AND PARTICIPANTS A multicenter , r and omized , double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada . Of the 324 participants screened , 260 were r and omized and received study drug . Eligibility criteria included age of 6 to 18 years , a forced expiratory volume in the first second of expiration ( FEV(1 ) ) of at least 50 % predicted , and negative respiratory tract cultures for P. aeruginosa for at least 1 year . R and omization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center . INTERVENTION The active group ( n = 131 ) received 250 mg ( weight 18 - 35.9 kg ) or 500 mg ( weight > or = 36 kg ) of azithromycin 3 days per week ( Monday , Wednesday , and Friday ) for 168 days . The placebo group ( n = 129 ) received identically packaged placebo tablets on the same schedule . MAIN OUTCOME MEASURES The primary outcome was change in FEV(1 ) . Exploratory outcomes included additional pulmonary function end points , pulmonary exacerbations , changes in weight and height , new use of antibiotics , and hospitalizations . Changes in microbiology and adverse events were monitored . RESULTS The mean ( SD ) age of participants was 10.7 ( 3.17 ) years . The mean ( SD ) FEV(1 ) at baseline and 168 days were 2.13 ( 0.85 ) L and 2.22 ( 0.86 ) L for the azithromycin group and 2.12 ( 0.85 ) L and 2.20 ( 0.88 ) L for the placebo group . The difference in the change in FEV(1 ) between the azithromycin and placebo groups was 0.02 L ( 95 % confidence interval [ CI ] , -0.05 to 0.08 ; P = .61 ) . None of the exploratory pulmonary function end points were statistically significant . Pulmonary exacerbations occurred in 21 % of the azithromycin group and 39 % of the placebo group . Participants in the azithromycin group had a 50 % reduction in exacerbations ( 95 % CI , 31%-79 % ) and an increase in body weight of 0.58 kg ( 95 % CI , 0.14 - 1.02 ) compared with placebo participants . There were no significant differences between groups in height , use of intravenous or inhaled antibiotics , or hospitalizations . Participants in the azithromycin group had no increased risk of adverse events , but had less cough ( -23 % treatment difference ; 95 % CI , -33 % to -11 % ) and less productive cough ( -11 % treatment difference ; 95 % CI , -19 % to -3 % ) compared with placebo participants . CONCLUSION In children and adolescents with CF uninfected with P. aeruginosa , treatment with azithromycin for 24 weeks did not result in improved pulmonary function . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00431964 BACKGROUND Pseudomonas aeruginosa is not a frequent pathogen in community-acquired pneumonia ( CAP ) . However , in patients with severe CAP , P aeruginosa can be the etiology in 1.8 % to 8.3 % of patients , with a case-fatality rate of 50 % to 100 % . We describe the prevalence , clinical characteristics , outcomes , and risk factors associated with CAP result ing from multidrug-resistant ( MDR ) and non-MDR P aeruginosa . METHODS Prospect i ve observational study of 2,023 consecutive adult patients with CAP with definitive etiology . RESULTS P aeruginosa was found in 77 ( 4 % ) of the 2,023 cases with microbial etiology . In 22 ( 32 % ) of the 68 cases of P aeruginosa with antibiogram data , the isolates were MDR . Inappropriate therapy was present in 49 ( 64 % ) cases of P aeruginosa CAP , including 17/22 ( 77 % ) cases of MDR P aeruginosa CAP . Male sex , chronic respiratory disease , C-reactive protein < 12.35 mg/dL , and pneumonia severity index risk class IV to V were independently associated with P aeruginosa CAP . Prior antibiotic treatment was more frequent in MDR P aeruginosa CAP compared with non-MDR P aeruginosa ( 58 % vs 29 % , P = .029 ) , and was the only risk factor associated with CAP result ing from MDR P aeruginosa . In the multivariate analysis , age ≥65 years , CAP result ing from P aeruginosa , chronic liver disease , neurologic disease , nursing home , criteria of ARDS , acute renal failure , ICU admission , and inappropriate empiric treatment were the factors associated with 30-day mortality . CONCLUSIONS P aeruginosa is an individual risk factor associated with mortality in CAP . The risk factors described can help clinicians to suspect P aeruginosa and MDR P aeruginosa RATIONALE To identify pathogens that require different treatments in community-acquired pneumonia ( CAP ) , we propose an acronym , " PES " ( Pseudomonas aeruginosa , Enterobacteriaceae extended-spectrum β-lactamase-positive , and methicillin-resistant Staphylococcus aureus ) . OBJECTIVES To compare the clinical characteristics and outcomes between patients with CAP caused by PES versus other pathogens , and to identify the risk factors associated with infection caused by PES . METHODS We conducted an observational prospect i ve study evaluating only immunocompetent patients with CAP and an established etiological diagnosis . We included patients from nursing homes . We computed a score to identify patients at risk of PES pathogens . MEASUREMENT AND MAIN RESULTS Of the 4,549 patients evaluated , we analyzed 1,597 who presented an etiological diagnosis . Pneumonia caused by PES was identified in 94 ( 6 % ) patients , with 108 PES pathogens isolated ( n = 72 P. aeruginosa , n = 15 Enterobacteriaceae extended-spectrum β-lactamase positive , and n = 21 methicillin-resistant Staphylococcus aureus ) . These patients were older ( P = 0.001 ) , had received prior antibiotic treatment more frequently ( P < 0.001 ) , and frequently presented with acute renal failure ( P = 0.004 ) . PES pathogens were independently associated with increased risk of 30-day mortality ( adjusted odds ratio = 2.51 ; 95 % confidence interval = 1.20 - 5.25 ; P = 0.015 ) . The area under the curve for the score we computed was 0.759 ( 95 % confidence interval , 0.713 - 0.806 ; P < 0.001 ) . CONCLUSIONS PES pathogens are responsible for a small proportion of CAP , result ing in high mortality . These pathogens require a different antibiotic treatment , and identification of specific risk factors could help to identify these microbial etiologies RATIONALE Information on the long-term prognosis after community-acquired pneumonia ( CAP ) is limited . OBJECTIVES To determine if CAP increases adverse long-term outcomes relative to a control population . METHODS Between 2000 and 2002 , 6,078 adults with CAP from six hospitals and seven emergency departments in Edmonton ( AB , Canada ) were prospect ively recruited and matched on age , sex , and site of treatment with five control subjects without pneumonia ( n = 29,402 ) . Mortality , hospitalizations , and emergency department admissions through 2012 were evaluated using multivariable Cox proportional hazards analyses adjusted for socioeconomic status and comorbidities . MEASUREMENTS AND MAIN RESULTS Average age was 59 years ( 2,682 [ 44 % ] ≥ 65 yr ) , 3,214 ( 53 % ) were men , and 3,425 ( 56 % ) were managed as out patients . Over a median of 9.8 years , 2,858 patients with CAP died compared with 9,399 control subjects ( absolute risk difference , 30 per 1,000 patient years [ py ] ; adjusted hazard ratio [ aHR ] , 1.65 ; 95 % confidence interval , 1.57 - 1.73 ; P < 0.001 ) . Patients with CAP who were younger than 25 years old had the lowest absolute rate difference for mortality ( 4 per 1,000 py ; aHR , 2.40 ) , and patients older than 80 years old had the highest absolute rate difference ( 92 per 1,000 py ; aHR , 1.42 ) . Absolute rates of all-cause hospitalization , emergency department visits , and CAP-related visits were all significantly higher in patients with CAP compared with control subjects ( P < 0.001 for all comparisons ) . CONCLUSIONS Our results indicate that an episode of CAP confers a high risk of long-term adverse events compared with the general population who have not experienced CAP , and this is irrespective of age

Conclusions : The Road Sign Recognition , Compass , and TMT B are clinical ly administrable office-based tests that can be used to identify persons with stroke at risk of failing an on-road assessment .

Objective : To identify the best determinants of fitness to drive after stroke , following a systematic review and meta- analysis .

OBJECTIVE To determine the reliability of the road test performed by stroke patients . DESIGN Prospect i ve study of a 6-month predriving evaluation . SETTING Driving safety center in Belgium . PARTICIPANTS Thirty patients with sequelae of stroke . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Results of driving performance as judged by 2 assessors from the Center for Determination of Fitness to Drive and Car Adaptations ( CARA ) , in a car fitted with a video camera . A third assessor also evaluated all the video recordings . Interrater reliability was evaluated by comparing results from real-life performance and video recording , as judged by the CARA assessors and video judgments between CARA assessors and the third assessor . RESULTS Most subitems of the road test showed more than 80 % scoring agreement between the various evaluations . Intraclass correlation coefficients ( ICCs ) of the items varied from -.08 to 1.0 . The ICC of the overall performance was.62 when real-life scores were compared with video evaluations and .80 in video versus video comparison . CONCLUSION The reliability of assessing overall performance of stroke patients in the road test is moderately high and better when assessed using the same evidence . Yet , the reliability of some items needs further attention Background : Neurologically impaired persons seem to benefit from driving-training programs , but there is no convincing evidence to support this notion . The authors therefore investigated the effect of simulator-based training on driving after stroke . Methods : Eighty-three first-ever subacute stroke patients entered a 5-week 15-hour training program in which they were r and omly allocated to either an experimental ( simulator-based training ) or control ( driving-related cognitive tasks ) group . Performance in off-road evaluations and an on-road test were used to assess the driving ability of subjects pre- and post-training . Outcome of an official predriving assessment administered 6 to 9 months poststroke was also considered . Results : Both groups significantly improved in a visual and many neuropsychological evaluations and in the on-road test after training . There were no significant differences between both groups in improvements from pre- to post-training except in the “ road sign recognition test ” in which the experimental subjects improved more . Significant improvements in the three-class decision ( “ fit to drive , ” “ temporarily unfit to drive , ” and “ unfit to drive ” ) were found in favor of the experimental group post-training . Academic qualification and overall disability together determined subjects that benefited most from the simulator-based driving training . Significantly more experimental subjects ( 73 % ) than control subjects ( 42 % ) passed the follow-up official predriving assessment and were legally allowed to resume driving . Conclusions : Simulator-based driving training improved driving ability , especially for well educated and less disabled stroke patients . However , the findings of the study may have been modified as a result of the large number of dropouts and the possibility of some neurologic recovery unrelated to training This paper compares the predictive value of the cognitive test battery developed at the Stroke Research Unit , City Hospital , Nottingham with existing assessment procedures . Subjects were referred from 3 stroke units ( Mansfield , Nottingham and Lincoln ) . Those who had been driving in the three months before the stroke , a minimum of 10 weeks previously , and had a full driving licence were considered . After a road test in a dual controlled , automatic vehicle on a set route around public roads , subjects were grade d by the instructor into pass or fail groups . Subjects were then r and omly allocated into two groups , one of which was tested on the stroke drivers screening assessment . In this group scores from the three tasks were used to predict the likelihood of passing a road test . Details of the tests were sent to the subjects doctors with recommendations as to the fitness to drive . The control group was just instructed to request the advice of their general practitioner . After six months subjects were contacted to ascertain the decisions on fitness to drive . The two types of assessment , cognitive and st and ard procedure were compared to determine which assessment method agreed most closely with the performance on the road tests . The results indicate that the stroke drivers screening assessment correctly predicted road performance significantly better than the st and ard procedure and that this was not due to chance A representation and interpretation of the area under a receiver operating characteristic ( ROC ) curve obtained by the " rating " method , or by mathematical predictions based on patient characteristics , is presented . It is shown that in such a setting the area represents the probability that a r and omly chosen diseased subject is ( correctly ) rated or ranked with greater suspicion than a r and omly chosen non-diseased subject . Moreover , this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic . These two relationships are exploited to ( a ) provide rapid closed-form expressions for the approximate magnitude of the sampling variability , i.e. , st and ard error that one uses to accompany the area under a smoothed ROC curve , ( b ) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area , and ( c ) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques BACKGROUND As the number of older adult drivers increases , distinguishing safe from unsafe older adult drivers will become an increasing public health concern . We report on the medical and functional factors associated with vehicle crashes in a cohort of Alabama drivers , 55 years old and older . METHODS This prospect i ve study involved 174 older adults , on whom demographic , medical , functional , and physical performance data were collected in 1991 . Subjects were then followed through 1996 for incident vehicle crashes . RESULTS Sixty-one subjects experienced between one and four police-reported vehicle crashes during the study period . Following adjustment for age , race , days driven per week , and gender , Cox proportional-hazards models showed the following variables to be associated with crash involvement : reported difficulty with yardwork or light housework ( relative risk [ RR ] = 2.1 ; 95 % confidence interval [ CI ] 1.1 , 4.0 ; p = .02 ) , or opening ajar ( RR = 3 . 1 ; 95 % CI 1.4 , 6.7 ; p = .004 ) ; at least one crash before 1991 ( RR = 2.1 ; 95 % CI 1.2 , 3.7 ; p = .008 ) ; using hypnotic medication ( RR = 2.9 ; 95 % CI 1.3 , 6.6 ; p = .01 ) ; self-reported stroke or transient ischemic attack ( RR = 2.7 ; 95 % CI 1.1 , 6.6 ; p = .03 ) ; scoring within the depressed range on the Geriatric Depression Scale ( RR = 2.5 ; 95 % CI 1.1 , 6.0 ; p = .03 ) , and failing the useful field-of-view test ( RR = 1.9 ; 95 % CI 1.0 , 3.5 ; p = .05 ) . CONCLUSIONS Variables related to function , medication use , affect , neurological disease , and visuocognitive skills were associated with vehicle crash involvement in this cohort . Our findings suggest that multifactorial assessment s are warranted to identify at-risk older drivers OBJECTIVES We sought to determine the criterion validity of the Useful Field of View ( UFOV ) assessment and Stroke Drivers ' Screening Assessment ( SDSA ) through comparison to the results of on-road assessment . METHOD This was a prospect i ve study with people with stroke . Outcome measures used were UFOV , SDSA , and the results of on-road assessment . RESULTS Both the results on UFOV ( Divided Attention subtest , p<.01 ; Selective Attention subtest , p<.05 ) and SDSA ( p<.05 ) were significantly related to the recommendation from on-road assessment . The Divided Attention subtest of the UFOV had the highest sensitivity value ( 88.9 % ) . CONCLUSIONS UFOV and SDSA are valid assessment s of driving ability for stroke . The Divided Attention subtest of the UFOV can guide decision making of occupational therapists in stroke driver rehabilitation and in determining those who require further assessment on road because they pose a safety risk . Screening assists people with stroke to decide whether they are ready to have an on-road assessment Background . No long-term studies have been reported on the effect of training programs on driving after stroke . Objectives . The authors ’ primary aim was to determine the effect of simulator versus cognitive rehabilitation therapy on fitness-to-drive at 5 years poststroke . A second aim was to investigate differences in clinical characteristics between stroke survivors who resumed and stopped driving . Methods . In a previously reported r and omized controlled trial , 83 stroke survivors received 15 hours of simulator training ( n = 42 ) or cognitive therapy ( n = 41 ) . In this 5-year follow-up study , 61 participants were reassessed . Fitness-to-drive decisions were obtained from medical , visual , neuropsychological , and on-road tests ; 44 participants ( simulator group , n = 21 ; cognitive group , n = 23 ) completed all assessment s. The primary outcome measures were fitness-to-drive decision and current driving status . Results . The authors found that 5 years after stroke , 18 of 30 participants ( 60 % ) in the simulator group were considered fit to drive , compared with 15 of 31 ( 48 % ) in the cognitive group ( P = .36 ) ; 34 of 61 ( 56 % ) participants were driving . Current drivers were younger ( P = .04 ) , had higher Barthel scores ( P = .008 ) , had less comorbidity ( P = .01 ) , and were less severely depressed ( P = .02 ) than those who gave up driving . Conclusions . The advantage of simulator-based driving training over cognitive rehabilitation therapy , evident at 6 months poststroke , had faded 5 years later . Poststroke drivers were younger and less severely affected and depressed than nondrivers OBJECTIVE The aim of this prospect i ve study was to confirm the accuracy of a short assessment battery , used previously in a study to predict fitness-to-drive after stroke , in a new cohort of stroke survivors without severe deficits . DESIGN A prospect i ve study . SUBJECTS A total of 43 ( 39 men and 4 women ) consecutive survivors after stroke who were not severely impaired and who performed the pre-driving assessment , which included a st and ardized on-road test at the Belgian Road Safety Institute in Brussels , Belgium . On average , participants were 6 months post-stroke , independently ambulant with or without assistive devices , possessed valid drivers ' licenses and actively drove prior to stroke onset . METHODS Fitness-to-drive decisions based on performance in 15 tests of a full-scale assessment battery were predicted using only the scores from the 3 predictive tests previously identified . RESULTS When the discriminant equation from the previous study including performance in the 3 tests ( figure of Rey , visual neglect ( lateralized mean reaction time ) and on-road test ) was applied , 37 ( 86 % ) of the 43 participants were correctly predicted to pass or fail the pre-driving assessment . The sensitivity and specificity of the predictions were 77 % and 92 % , respectively . CONCLUSION This study shows that the short assessment battery is a good predictor of fitness-to-drive in stroke survivors with moderate physical and cognitive impairments UNLABELLED Crotty M , George S. Retraining visual processing skills to improve driving ability after stroke . OBJECTIVE To evaluate the effectiveness of retraining using the Dynavision on driving performance of people with stroke . DESIGN R and omized controlled trial . SETTING Outpatient rehabilitation clinic in Australia . PARTICIPANTS People with stroke ( N=26 ) referred for driving assessment . INTERVENTIONS Eligible participants were r and omized to either receive retraining with the Dynavision apparatus for 18 sessions or to receive no intervention and go onto a waitlist . MAIN OUTCOME MEASURES The primary outcome was an assessment of on-road ability . Secondary outcomes included measures of response speed , visual scanning , and self-efficacy . All assessment s were conducted by assessors blinded to group assignment . RESULTS No significant difference ( P=.223 ) was found between the intervention and control groups in results of on-road assessment in terms of pass or fail ; the primary outcome measure ; or the results on the secondary outcome measures of response speed , visual scanning , and self-efficacy . CONCLUSIONS In this small trial , training underlying skills ( such as executing a continuous wide scan , combining motor and visual processing into a motor response ) using the Dynavision apparatus did not improve the outcomes of an on-road assessment for people after strokes . Larger trials are needed to evaluate devices that cl aim to retrain underlying skills related to driving OBJECTIVE To compare the effectiveness of a visual attention retraining program using the Useful Field of View ( UFOV ) with a traditional visuoperception treatment program on the driving performance of clients with stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation hospital located in Quebec , Canada . PARTICIPANTS Ninety-seven individuals referred for driving evaluation after a stroke . INTERVENTIONS Participants were r and omized to receive 20 sessions of either UFOV training of visual processing speed , divided attention , and selective attention or traditional computerized visuoperception retraining . MAIN OUTCOME MEASURES Subjects were evaluated with an on-road driving evaluation , visuoperception tests , and the Test of Everyday Attention . An occupational therapist unaware of group assignment conducted all evaluations . RESULTS Eighty-four participants completed the outcome evaluation . There were no significant differences between groups on any of the outcome measures . There was , however , almost a 2-fold increase ( 52.4 % vs 28.6 % ) in the rate of success on the on-road driving evaluation after UFOV training for subjects with right-sided lesions . CONCLUSIONS Rehabilitation that targets visual attention skills was not significantly more beneficial than traditional perceptual training in improving the outcome of an on-road driving evaluation . However , results suggest a potential improvement for subjects with right-sided lesions , indicating that training must target specific skills Objective : To describe the development of the Adelaide Driving Self-Efficacy Scale ( ADSES ) and to report on its reliability and validity . Methods : A set of 12 driving behaviours , developed through literature review , clinical experience and expert review , were rated for self-efficacy using a Likert scale . Internal consistency was investigated using a Cronbach 's alpha coefficient and construct validity by comparing ADSES scores of stroke and non-stroke drivers . Criterion-related validity was examined by comparing ADSES scores with the result on a st and ardized on-road assessment . Setting : A rehabilitation hospital in Adelaide , South Australia . Participants : Staff from the hospital and stroke patients from the rehabilitation unit . Data from a non-stroke sample ( n -/ 79 ) and stroke patients ( n -/ 81 ) were used to test internal consistency and construct validity . A separate group of 45 people recommended for a driving assessment , of whom 34 were stroke patients , were used to test criterion validity . Results : Cronbach 's alpha coefficient was 0.98 , indicating high internal consistency . The non-stroke and stroke groups showed significant differences in ADSES scores ( t(158)-/ 5.5 , P B < 0.05 ) , demonstrating construct validity . Differences in ADSES scores for those participants who passed or failed the on-road assessment were significant for both the entire driving assessment group ( t(43)-/ 3.2 , P B < 0.05 ) and the stroke subgroup ( t(43)-/ 3.2 , P B < 0.05 ) , indicating criterion validity . Conclusion : The ADSES has demonstrated internal consistency and construct validity with the stroke and non-stroke population . The scale demonstrated criterion validity in its relationship with outcome of an on-road driving assessment . It appears to be a reliable and valid measure of driving self-efficacy Smith-Arena L , Edelstein L , Rabadi MH : Predictors of a successful driver evaluation in stroke patients after discharge based on an acute rehabilitation hospital evaluation . Am J Phys Med Rehabil 2006;85:44–52 . Objective : One of the most common concerns of a stroke patient is the ability to drive . We aim ed to determine which neurologic impairments on an acute rehabilitation admission evaluation predict the likelihood of a successful driver evaluation after discharge . Design : Prospect i ve study in an acute stroke rehabilitation unit . Results : A total of 45 stroke patients undertook a driver evaluation at our institution . The mean age ± st and ard deviation was 71.0 ± 9.8 yrs , Mini-Mental State Examination score was 22.7 ± 8.1 , upper limb and lower limb Motricity Index scores were 63.7 ± 34.8 and 71.8 ± 24.3 , Limb Placement Task was 4.6 ± 3.6 inches , and admission total FIM ™ score was 68.5 ± 18 . The admission variables differed between those who failed ( n = 10 ) vs. those who passed the in-clinic driver evaluation ( n = 29 , 75 % ) : Mini-Mental State Examination ( 17.5 ± 9.7 vs. 24.6 ± 6.7 , P = 0.004 ) , and upper limb ( 82 ± 23.7 vs. 57.4 ± 36.1 , P = 0.05 ) and lower limb ( 87.6 ± 11.8 vs. 66.4 ± 25.2 , P = 0.01 ) Motricity Index scores . Conclusions : Patients who undertook and passed the in-clinic driver evaluation had , at admission , higher Mini-Mental State Examination and Motricity Index scores with normal visual field defects OBJECTIVES To determine the validity of a road test performed by stroke patients in Belgium and to reestablish its reliability . DESIGN Prospect i ve study of a predriving evaluation . SETTING University hospital in Belgium . PARTICIPANTS Thirty-eight patients with sequelae of first-ever stroke . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Performance in the Stroke Driver Screening Assessment ( SDSA ) and on a road test . RESULTS Interrater reliability of the road test subitems was moderate to substantial ( weighted kappa range , .44-.78 ) . Item-per-item reliability varied from moderately high ( intraclass correlation coefficient [ICC]=.63 ) to very high ( ICC=.87 ) . The reliability of the overall performance in the road test was very high ( ICC=.83 ) . For the criterion validity of the road test , 78.9 % of the subjects were correctly classified when the judgments of the principal evaluator were compared with outcomes of the SDSA . Agreement in classification between the principal evaluator and a state-registered evaluator 's judgments was 81.6 % . The sensitivity and specificity of the agreement were very high ( 80.6 % ) and perfect ( 100 % ) , respectively . CONCLUSIONS The road test is a reliable and valid test of driving ability after stroke

A small pharmacological effect on clinical histamine dose response was found . After treatment , leukotriene levels in nasal lavage did not increase in the capsaicin group . There is insufficient evidence to assess the use of capsaicin in clinical practice

BACKGROUND Allergic rhinitis represents a global health problem . Non-specific nasal hyperresponsiveness is an important feature of allergic and non-allergic rhinitis . This phenomenon is believed to result from the effect of allergic inflammation on the sensory nerves that supply the upper airway mucosa . A pharmacologic agent that has proved useful in the investigation of effects of neuronal stimulation is capsaicin , the pungent component of hot pepper . Intranasal capsaicin specifically stimulates afferent nerves consisting mostly of unmyelinated C fibers and some myelinated A-delta fibers . As a result it can trigger central and axonal reflexes , the latter being putatively mediated by the release of neuropeptides . Capsaicin as a blocking agent of neuropeptides , blocks the axon reflex and may exert a curative effect on allergic rhinitis . OBJECTIVES To assess the effectiveness of capsaicin for allergic rhinitis in adults .

We have previously shown that capsaicin nasal challenge in subjects with allergic rhinitis produces a dose-dependent increase in the albumin content of nasal lavage fluids . In the present set of studies , we determined whether this observation represents plasma extravasation that is neuronally mediated . To evaluate whether gl and ular secretions contribute to the albumin increase in nasal lavage fluids , volunteers with allergic rhinitis were pretreated with atropine or placebo before capsaicin challenge . Atropine significantly reduced the volume of returned lavage fluids and their lysozyme content but increased their albumin and fibrinogen content . To assess the contribution of sensory nerve stimulation , subjects with allergic rhinitis were pretreated in a second study with lidocaine or placebo before capsaicin challenge . Lidocaine significantly attenuated the capsaicin-induced increases in the volume of nasal lavage fluids , as well as their lysozyme and albumin content . To rule out the possibility of a direct effect of lidocaine on blood vessels rather than on nerves , healthy subjects were pretreated in a third study with lidocaine or placebo before bradykinin nasal challenge . Lidocaine did not affect the bradykinin-induced increase in the albumin content of nasal fluids . We conclude that , in allergic rhinitis , high-dose capsaicin induces plasma extravasation in the human nose and that this effect is neuronally mediated . This provides more definitive evidence that neurogenic inflammation can occur in vivo in the human upper airway Neuronal involvement has been implicated in the pathophysiology of non‐allergic and allergic rhinitis , contributing to the typical exacerbation of these conditions upon exposure to non‐specific environmental irritants BACKGROUND Nerve involvement has been implicated in the pathophysiology of chronic respiratory inflammatory diseases . Peptidergic nerve stimulation has been shown to induce leukocyte activation and plasma extravasation in the airways of various animal species . The occurrence of this phenomenon of neurogenic inflammation in the human airway , however , has not been established . OBJECTIVE We conducted this study to determine whether neuronal stimulation can induce reproducible and dose-dependent inflammatory changes in the human upper airway . METHODS Ten volunteers with active allergic rhinitis participated in the study . Capsaicin , the pungent component of hot pepper that specifically stimulates afferent nerve fibers , was administered by means of nasal spray in doses of 1 microg , 10 microg , and 100 microg in a double-blind , r and omized , crossover manner with 1 week between doses . Symptom scores before and after capsaicin nasal challenge were recorded by using visual analog scales . Nasal lavage fluids collected before and at 30 minutes , 1 hour , and 4 hours after capsaicin challenge were analyzed for leukocyte counts ; albumin and lysozyme levels were measured to evaluate effects on plasma leakage and gl and secretion , respectively . RESULTS Capsaicin nasal challenge produced symptoms of burning , congestion , and rhinorrhea . Leukocyte counts or albumin and lysozyme levels were not significantly increased after administration of 1 microg of capsaicin at any time point . On the other h and , there were significant increases in leukocyte counts 1 hour ( p < 0.05 ) and 4 hours ( p = 0.008 ) after 10 microg of capsaicin and 30 minutes ( p = 0.009 ) , 1 hour ( p = 0.007 ) , and 4 hours ( p = 0.007 ) after 100 microg of capsaicin . Albumin and lysozyme levels were both significantly increased 30 minutes after 10 microg and 100 microg of capsaicin ( p = 0.005 for both ) . Comparison of changes in symptom scores , leukocyte counts , and albumin and lysozyme levels among the three capsaicin challenges indicated generally increasing effects with higher capsaicin doses . CONCLUSION Capsaicin-sensitive nerve stimulation in subjects with active allergic rhinitis produces reproducible and dose-dependent leukocyte influx , albumin leakage , and gl and ular secretion . These results provide in vivo evidence for the occurrence of neurogenic inflammation in the human upper airway with active allergic disease In a recent placebo‐controlled study we demonstrated that capsaicin is an efficacious substance in the treatment of non‐allergic non‐infectious rhinitis . In this study the therapeutic effect lasted more than 9 months . This effect was not based on modulation of inflammation

Hospital readmissions and mortality studies newly included in this up date showed , on average , significantly smaller effects of rehabilitation than were seen in earlier studies .High- quality evidence suggests that pulmonary rehabilitation after an exacerbation improves health-related quality of life . AUTHORS ' CONCLUSIONS Overall , evidence of high quality shows moderate to large effects of rehabilitation on health-related quality of life and exercise capacity in patients with COPD after an exacerbation .

BACKGROUND Guidelines have provided positive recommendations for pulmonary rehabilitation after exacerbations of chronic obstructive pulmonary disease ( COPD ) , but recent studies indicate that postexacerbation rehabilitation may not always be effective in patients with unstable COPD . OBJECTIVES To assess effects of pulmonary rehabilitation after COPD exacerbations on hospital admissions ( primary outcome ) and other patient-important outcomes ( mortality , health-related quality of life ( HRQL ) and exercise capacity ) .

PURPOSE Acute exacerbations of chronic obstructive pulmonary disease ( AE COPD ) impair health-related quality of life ( HRQL ) . We evaluated the effect of an abbreviated repeat pulmonary rehabilitation ( PR ) program on HRQL after an AE COPD . METHODS Patients who had completed PR were followed for up to 12 months to identify an AE COPD and then placed in r and omized groups to receive a 3-week repeat-PR intervention or usual care . Measures of HRQL ( Chronic Respiratory Disease Question naire , CRQ ) and functional exercise capacity ( 6-minute walk distance , 6MWD ) were collected at 2 ( T1 ) , 5 ( T2 ) , and 12 weeks ( T3 ) post-AE COPD . The repeat-PR program was undertaken between T1 and T2 . Between-group differences were examined using repeated- measures analysis of variance or covariance . RESULTS Of the 60 patients ( 30 men , age 69±8 years , forced expiratory volume in 1 second 0.86±0.40 L , 6MWD 367±99 m ) followed , 41 experienced an AE COPD 14 ± 11 weeks after completion of the initial PR program and 33 completed the study . Of these , 16 and 17 were r and omized to the intervention and control groups , respectively . No between-group differences were demonstrated at T2 or T3 . With the exclusion of 5 subjects who experienced a second AE COPD between T1 and T3 , the participants in the intervention group demonstrated greater reduction in dyspnea when compared to those in the control group at T3 ( 0.8±1.6 vs −0.4±1.3 points per item , P = .04 ) . CONCLUSIONS The reduction in dyspnea in those who did not experience a second AE COPD provides preliminary evidence for the role of repeat programs . The application of repeat PR should be refined in larger trials BACKGROUND Pulmonary rehabilitation programmes improve the health of patients disabled by lung disease but their cost effectiveness is unproved . We undertook a cost/utility analysis in conjunction with a r and omised controlled clinical trial of pulmonary rehabilitation versus st and ard care . METHODS Two hundred patients , mainly with chronic obstructive pulmonary disease , were r and omly assigned to either an 18 visit , 6 week rehabilitation programme or st and ard medical management . The difference between the mean cost of 12 months of care for patients in the rehabilitation and control groups ( incremental cost ) and the difference between the two groups in quality adjusted life years ( QALYs ) gained ( incremental utility ) were determined . The ratio between incremental cost and utility ( incremental cost/utility ratio ) was calculated . RESULTS Each rehabilitation programme for up to 20 patients cost £ 12 120 . The mean incremental cost of adding rehabilitation to st and ard care was £ –152 ( 95 % CI –881 to 577 ) per patient , p = NS . The incremental utility of adding rehabilitation was 0.030 ( 95 % CI 0.002 to 0.058 ) QALYs per patient , p=0.03 . The point estimate of the incremental cost/utility ratio was therefore negative . The bootstrapping technique was used to model the distribution of cost/utility estimates possible from the data . A high likelihood of generating QALYs at negative or relatively low cost was indicated . The probability of the cost per QALY generated being below £ 0 was 0.64 . CONCLUSIONS This outpatient pulmonary rehabilitation programme produces cost per QALY ratios within bounds considered to be cost effective and is likely to result in financial benefits to the health service In recent years quality of life instruments have been featured as primary outcomes in many r and omized trials . One of the challenges facing the investigator using such measures is determining the significance of any differences observed , and communicating that significance to clinicians who will be applying the trial results . We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change . Using this approach we have established a plausible range within which the minimal clinical ly important difference ( MCID ) falls . In three studies in which instruments measuring dyspnea , fatigue , and emotional function in patients with chronic heart and lung disease were applied the MCID was represented by mean change in score of approximately 0.5 per item , when responses were presented on a seven point Likert scale . Furthermore , we have established ranges for changes in question naire scores that correspond to moderate and large changes in the domains of interest . This information will be useful in interpreting question naire scores , both in individuals and in groups of patients participating in controlled trials , and in the planning of new trials Background The feasibility of r and omized trials often depends on successful patient recruitment . Although numerous recruitment barriers have been identified it is unclear which of them complicate recruitment most . Also , most surveys have focused on the patients ' perspective of recruitment barriers whereas the perspective of recruiting physicians has received less attention . Therefore , our aim was to conduct a postal survey among recruiting physicians of a multi-center trial to weigh barriers according to their impact on recruitment . Methods We identified any potential recruitment barriers from the literature and from our own experience with a multi-center trial of respiratory rehabilitation in patients with chronic obstructive pulmonary disease . We developed and pilot-tested a self-administered question naire where recruiting physicians were asked to express their agreement with statements about recruitment barriers on a Likert-type scale from 1 ( full agreement with statement = very substantial recruitment barrier ) to 7 ( no agreement with statement = no recruitment barrier ) . Results 38 of 55 recruiting physicians returned question naires ( 69 % response rate ) , of which 35 could be analyzed ( 64 % useable response rate ) . Recruiting physicians reported that " time constraints " ( median agreement of 3 , interquartile range 2–5 ) had the most negative impact on recruitment followed by " difficulties including identified eligible patients " ( median agreement of 5 , IQR 3–6 ) . Other barriers such as " trial design barriers " , " lack of access to treatment " , " individual barriers of recruiting physicians " or " insufficient training of recruiting physicians " were perceived to have little or no impact on patient recruitment . Conclusion Physicians perceived time constraints as the most relevant recruitment barrier in a r and omized trial . To overcome recruitment barriers interventions , that are affordable for both industry- and investigator-driven trials , need to be developed and tested in r and omized trials . Trial registration IS RCT We examined the feasibility of home-based walking training to maintain the benefits of a short-term exercise training in patients with severe chronic obstructive pulmonary disease ( COPD ) . After initial recovery from an exacerbation , 46 patients were r and omized into a training and a control group , and 30 patients completed the programme ( mean + /- SD FEV1 , 36 + /- 7 % predicted ) . The training group performed a 10-day walking training programme in the hospital , followed by a 6-month programme of supervised walking training at home , integrated into daily activities . The control group did not have exercise training in the hospital or at home . Until 6 months after discharge , lung function , exercise performance and symptom scores were assessed . Six-minute walking distance in the training group improved from day 1 to day 10 ( P<0.001 ) and this effect was maintained over 6 months ( P<0.001 ) . On average , daily walking distance at home was 2308 m and walking was reported on 157 days . Quality of life ( QoL ) scores changed significantly over 6 months ( P<0.001 ) . The control group showed no significant changes in exercise performance or QoL scores throughout the whole study period . Therefore , ( i ) significant improvements in exercise performance and Chronic Respiratory Disease Question naire ( CRQ ) scores could be achieved after recovery from an exacerbation and ( ii ) these improvements were maintained after discharge , when supported by a home-based walking training The aim of this study was to assess long-term mortality and predictive factors of death after hospital admission for acute exacerbation of chronic obstructive pulmonary disease ( COPD ) . 1824 patients ( 23.2 % female ; mean age 70.3±11.3 years ) consecutively admitted for acute exacerbation of COPD in the respiratory medicine departments of 68 general hospitals between October 2006 and June 2007 were prospect ively enrolled in a follow-up cohort . Their vital status was documented between October 2010 and April 2011 . Vital status was available for 1750 patients ( 95.9 % ) , among whom 787 ( 45 % ) died during follow-up . Multivariate analysis found that age ( 60–80 years and ≥80 years versus < 60 years , relative risk 2.99 , 95 % CI 2.31–3.89 ) , lower body mass index ( 25–30 kg·m−2 versus ≤20 kg·m−2 , relative risk 0.80 , 95 % CI 0.66–0.97 ) , lung cancer ( relative risk 2.08 , 95 % CI 1.43–3.01 ) , cardiovascular comorbidity ( relative risk 1.35 , 95 % CI 1.16–1.58 ) , previous hospital admissions for acute exacerbation of COPD ( four or more versus none , relative risk 1.91 , 95 % CI 1.44–2.53 ) , use of accessory respiratory muscles ( relative risk 1.19 , 95 % CI 1.01–1.40 ) or lower-limb oedema ( relative risk 1.74 , 95 % CI ( 1.44–2.12 ) ) at admission and treatment by long-term oxygen therapy at discharge ( relative risk 2.09 , 95 % CI 1.79–2.45 ) were independent risk factors of death . Mortality rate during the 4 years following hospital admission for acute exacerbation of COPD was high ( 45 % ) . Simple clinical information relating to respiratory and general status can help in identifying high-risk patients and targeting more intensive follow-up and care . Interestingly , cardiovascular comorbidities and past hospitalisations for acute exacerbation of COPD , but not forced expiratory volume in 1 s , independently predicted the risk of death . Long-term risk of death after hospitalisation for acute exacerbation of COPD is high but can be readily identified Clinical trials identifier NCT02329873 Background Acute exacerbation ( AE ) of COPD is characterized by a sudden worsening of COPD symptoms . Previous studies have explored the effectiveness of respiratory rehabilitation for patients with COPD ; however , no training program specific to acute exacerbation in elderly patients or unstable periods during hospitalization has been developed . Objective To evaluate the effects of a respiratory rehabilitation exercise training package on dyspnea , cough , exercise tolerance , and sputum expectoration among hospitalized elderly patients with AE COPD . Methods A r and omized control trial was conducted . Pretest and posttest evaluations of 61 elderly in patients with AE COPD ( experimental group n=30 ; control group n=31 ) were performed . The experimental group received respiratory rehabilitation exercise training twice a day , 10–30 minutes per session for 4 days . The clinical parameters ( dyspnea , cough , exercise tolerance , and sputum expectoration ) were assessed at the baseline and at the end of the fourth day . Results All participants ( median age = 70 years , male = 60.70 % , and peak expiratory flow 140 L ) completed the study . In the patients of the experimental group , dyspnea and cough decreased and exercise tolerance and sputum expectoration increased significantly compared with those of the patients in the control group ( all P<0.05 ) . Within-group comparisons revealed that the dyspnea , cough , and exercise tolerance significantly improved in the experimental group by the end of the fourth day ( all P<0.05 ) . Conclusion Results of this study suggest that the respiratory rehabilitation exercise training package reduced symptoms and enhanced the effectiveness of the care of elderly in patients with AE COPD Background : Around the world , the timing of referral of chronic obstructive pulmonary disease ( COPD ) patients for pulmonary rehabilitation differs from immediately after exacerbation ( early ) to later on when patients are in a stable state ( late ) . There are no trials comparing the different time points of referral for pulmonary rehabilitation . Objectives : Our aim was to compare the effects of early and late pulmonary rehabilitation on exacerbation rates and health-related quality of life ( HRQOL ) in COPD patients with exacerbations . Methods : We r and omized COPD patients ( Global Initiative for Chronic Obstructive Lung Disease stages II – IV ) with a recent exacerbation to early ( within 2 weeks ) or late pulmonary rehabilitation ( starting 6 months after r and omization and in a stable state ) . The primary outcome was the exacerbation rate over 18 months , and secondary outcomes included HRQOL and mortality . We used multivariate analyses and an intention-to-treat analysis approach . Results : We r and omized 36 patients to pulmonary rehabilitation . On average , patients with early rehabilitation ( n = 19 ) had 2.61 ( SD 2.96 ) exacerbations requiring systemic corticosteroids and /or antibiotics , compared to 2.77 ( SD 3.41 ) in patients with late rehabilitation ( adjusted incidence rate ratio 0.83 , 95 % confidence interval 0.43–1.63 ; p = 0.60 ) . Over the 18-month period , patients with late rehabilitation experienced more dyspnea ( difference on Chronic Respiratory Question naire dyspnea domain 0.74 and on the Medical Research Council dyspnea scale 0.37 ) , but neither these differences nor any difference in HRQOL domains reached statistical significance . Conclusions : We did not find any statistically significant differences between early and late pulmonary rehabilitation . However , our trial indicates that early rehabilitation may lead to faster recovery of HRQOL after exacerbations compared to rehabilitation later on when patients are in a stable state Background Pulmonary rehabilitation ( PR ) is able to improve dyspnea , endurance capacity , and health-related quality of life in chronic obstructive pulmonary disease ( COPD ) patients , but it is rarely used in China . This study aim ed to assess the effectiveness and safety of PR after exacerbation of COPD . Material / Methods Patients admitted to hospital due to an exacerbation of COPD were r and omized to receive either PR or routine care ( control group ) . The PR program was performed from the second day of admission until discharge . The pre-post changes in 6-minute walk distance ( 6MWD ) , self-reported quality of life ( QOL ) assessed by CAT score and CRQ-SAS score , and activity of daily life assessed by ADL-D score were determined . The perceived end-effort dyspnea ( Borg scale ) was measured throughout the study . Results A total of 101 patients were enrolled , of whom 7 withdrew after r and omization , and 94 completed this study . There were 66 patients in the PR group and 28 in the control group . The 6MWD , resting SpO2 , and exercise Borg dyspnea score were significantly improved in the PR group . In addition , the PR group had greater improvement in the total CRQ-SAS score and had a lower CAT score . Significant improvements were also found in the ADL-D and BODE index in the PR group . No adverse events were recorded during exercise . Conclusions Our study provides evidence that it is safe and feasible to apply an early PR in patients with acute exacerbation of COPD OBJECTIVES To identify variables associated with mortality in patients admitted to the hospital for acute exacerbation of COPD . DESIGN Prospect i ve cohort study . SETTING Acute-care hospital in Barcelona ( Spain ) . PATIENTS One hundred thirty-five consecutive patients hospitalized for acute exacerbation of COPD , between October 1996 and May 1997 . MEASUREMENTS AND RESULTS Clinical , spirometric , and gasometric variables were evaluated at the time of inclusion in the study . Socioeconomic characteristics , comorbidity , dyspnea , functional status , depression , and quality of life were analyzed . Mortality at 180 days , 1 year , and 2 years was 13.4 % , 22 % , and 35.6 % , respectively . Sixty-four patients ( 47.4 % ) were dead at the end of the study ( median follow-up duration , 838 days ) . Greater mortality was observed in the bivariate analysis among the oldest patients ( p < 0.0001 ) , women ( p < 0.01 ) , and unmarried patients ( p < 0.002 ) . Hospital admission during the previous year ( p < 0.001 ) , functional dependence ( Katz index ) [ p < 0.0004 ] , greater comorbidity ( Charlson index ) [ p < 0.0006 ] , depression ( Yesavage Scale ) [ p < 0.00001 ] ) , quality of life ( St. George 's Respiratory Question naire [ SGRQ ] ) [ p < 0.01 ] , and PCO(2 ) at discharge ( p < 0.03 ) were also among the significant predictors of mortality . In the multivariate analysis , the activity SGRQ subscale ( p < 0.001 ; odds ratio [ OR ] , 2.62 ; confidence interval [ CI ] , 1.43 to 4.78 ) , comorbidity ( p < 0.005 ; OR , 2.2 ; CI , 1.26 to 3.84 ) , depression ( p < 0.004 ; OR , 3.6 ; CI , 1.5 to 8.65 ) , hospital readmission ( p < 0.03 ; OR , 1.85 ; CI , 1.26 to 3.84 ) , and marital status ( p < 0.0002 ; OR , 3.12 ; CI , 1.73 to 5.63 ) were independent predictors of mortality . CONCLUSIONS Quality of life , marital status , depressive symptoms , comorbidity , and prior hospital admission provide relevant information of prognosis in this group of COPD patients PURPOSE Pulmonary rehabilitation programs are effective in patients with severe chronic obstructive pulmonary disease ( COPD ) in the short term , but their long-term effects are not known . We investigated the short- and long-term effects of a 6-month outpatient rehabilitation program in patients with severe COPD . SUBJECTS AND METHODS One hundred patients were r and omly assigned to receive either an exercise training program that included cycling , walking , and strength training ( n = 50 ) or usual medical care ( n = 50 ) . Thirty-four patients in the training group were evaluated after 6 months ( end of training ) , and 26 were evaluated after 18 months of follow-up . In the control group , 28 patients were evaluated at 6 months and 23 after 18 months . We measured pulmonary function , 6-minute walking distance , maximal exercise capacity , peripheral and respiratory muscle strength , and quality of life ( on a 20 to 140-point scale ) , and estimated the cost-effectiveness of the program . RESULTS At 6 months , the training group showed improvement in 6-minute walking distance [ mean difference ( training - control ) of 52 m ; 95 % confidence interval ( CI ) , 15 to 89 m ] , maximal work load ( 12 W ; 95 % CI , 6 to 19 W ) , maximal oxygen uptake ( 0.26 liters/min ; 95 % CI , 0.07 to 0.45 liters/min ) , quadriceps force ( 18 Nm ; 95 % CI , 7 to 29 Nm ) , inspiratory muscle force ( 11 cm H(2)O ; 95 % CI , 3 to 20 cm H(2)O ) , and quality of life ( 14 points ; 95 % CI , 6 to 21 points ; all P < 0.05 ) . At 18 months all these differences persisted ( P < 0.05 ) , except for inspiratory muscle strength . For 6-minute walking distance and quality of life , the differences between the training group and controls at 18 months exceeded the minimal clinical ly-important difference . CONCLUSION Among patients who completed the 6-month program , outpatient training result ed in significant and clinical ly relevant changes in 6-minute walking distance , maximal exercise performance , peripheral and respiratory muscle strength , and quality of life . Most of these effects persisted 18 months after starting the program In order to describe the outcomes of patients hospitalized with an acute exacerbation of severe chronic obstructive pulmonary disease ( COPD ) and determine the relationship between patient characteristics and length of survival , we studied a prospect i ve cohort of 1,016 adult patients from five hospitals who were admitted with an exacerbation of COPD and a PaCO2 of 50 mm Hg or more . Patient characteristics and acute physiology were determined . Outcomes were evaluated over a 6 mo period . Although only 11 % of the patients died during the index hospital stay , the 60-d , 180-d , 1-yr , and 2-yr mortality was high ( 20 % , 33 % , 43 % , and 49 % , respectively ) . The median cost of the index hospital stay was $ 7,100 ( $ 4,100 to $ 16,000 ; interquartile range ) . The median length of the index hospital stay was 9 d ( 5 to 15 d ) . After discharge , 446 patients were readmitted 754 times in the next 6 mo . At 6 mo , only 26 % of the cohort were both alive and able to report a good , very good , or excellent quality of life . Survival time was independently related to severity of illness , body mass index ( BMI ) , age , prior functional status , PaO2/FI(O2 ) , congestive heart failure , serum albumin , and the presence of cor pulmonale . Patients and caregivers should be aware of the likelihood of poor outcomes following hospitalization for exacerbation of COPD associated with hypercarbia The aim of the study is to explore the experiences of in patients with an acute exacerbation of chronic obstructive pulmonary disease , who participated in a very early exercise programme while acutely unwell . This qualitative study analysed responses from participant interviews as part of a mixed method trial whereby participants were r and omly allocated into three groups : low intensity , moderate to high intensity aerobic and resistance exercises or a control group who received routine physiotherapy . Everyone allocated to the exercise groups were invited to participate in the qualitative study . Interviews were within a week post discharge and the results were analysed thematically . A total of 19 participants were interviewed and described their experience as positive and beneficial and reported an increased motivation towards exercising . These findings converged with the high levels of exercise adherence ( 83 % ) and within-group improvements in walking capacity observed in both exercise groups . Participants also reported commencement of a home exercise programme after discharge but intention to participate in community pulmonary rehabilitation remained low . Participation in a very early exercise programme while acutely unwell can lead to positive attitude towards exercise . The results converge with the quantitative results that provided preliminary evidence of programme feasibility and within-group improvement in exercise tolerance BACKGROUND AND OBJECTIVE In COPD , hospital admissions and readmissions account for the majority of health-care costs . The aim of this prospect i ve r and omized controlled study was to determine if early pulmonary rehabilitation , commenced as an inpatient and continued after discharge , reduced acute health-care utilization . METHODS Consecutive COPD patients ( n = 397 ) , admitted with an exacerbation , were screened : 228 satisfied the eligibility criteria , of whom 97 consented to r and omization to rehabilitation or usual care . Both intention-to-treat and per- protocol analyses are reported with adherence being defined a priori as participation in at least 75 % of rehabilitation sessions . RESULTS The participants were elderly with severe impairment of pulmonary function , poor health-related quality of life and high COPD -related morbidity . The rehabilitation group demonstrated a 23 % ( 95 % CI : 11 - 36 % ) risk of readmission at 3 months , with attendees having a 16 % ( 95 % CI : 0 - 32 % ) risk compared with 32 % ( 95 % CI : 19 - 45 % ) for usual care . These differences were not significant . There were a total of 79 COPD -related readmission days ( 1.7 per patient , 95 % CI : 0.6 - 2.7 , P = 0.19 ) in the rehabilitation group , compared with 25 ( 1.3 per patient , 95 % CI : 0 - 3.1 , P = 0.17 ) for the attendees and 209 ( 4.2 per patient , 95 % CI : 1.7 - 6.7 ) for usual care . The BMI , airflow obstruction , dyspnoea and exercise capacity index showed a non-significant trend to greater improvement among attendees compared with those receiving usual care ( 5.5 ( 2.3 ) and 5.6 ( 2.7 ) at baseline , improving to 3.7 ( 1.9 ) and 4.5 ( 2.5 ) , respectively , at 3 months ) . No adverse effects were identified . CONCLUSIONS Early inpatient-outpatient rehabilitation for COPD patients admitted with an exacerbation was feasible and safe , and was associated with a non-significant trend towards reduced acute health-care utilization RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) acutely reduce skeletal muscle strength and result in long-term loss of functional capacity . OBJECTIVES To investigate whether resistance training is feasible and safe and can prevent deteriorating muscle function during exacerbations of COPD . METHODS Forty patients ( FEV(1 ) 49 + /- 17 % predicted ) hospitalized with a severe COPD exacerbation were r and omized to receive usual care or an additional resistance training program during the hospital admission . Patients were followed up for 1 month after discharge . Primary outcomes were quadriceps force and systemic inflammation . A muscle biopsy was taken in a subgroup of patients to assess anabolic and catabolic pathways . MEASUREMENTS AND MAIN RESULTS Resistance training did not yield higher systemic inflammation as indicated by C-reactive protein levels and could be completed uneventfully . Enhanced quadriceps force was seen at discharge ( + 9.7 + /- 16 % in the training group ; -1 + /- 13 % in control subjects ; P = 0.05 ) and at 1 month follow-up in the patients who trained . The 6-minute walking distance improved after discharge only in the group who received resistance training ( median 34 ; interquartile range , 14 - 61 m ; P = 0.002 ) . In a subgroup of patients a muscle biopsy showed a more anabolic status of skeletal muscle in patients who followed training . Myostatin was lower ( P = 0.03 ) and the myogenin/MyoD ratio tended to be higher ( P = 0.08 ) in the training group compared with control subjects . CONCLUSIONS Resistance training is safe , successfully counteracts skeletal muscle dysfunction during acute exacerbations of COPD , and may up-regulate the anabolic milieu in the skeletal muscle . Clinical trial registered with www . clinical trials.gov ( NCT00877084 ) OBJECTIVE Pulmonary rehabilitation has been shown to be of benefit to clinical ly stable patients with chronic obstructive pulmonary disease ( COPD ) . This study examined the effect of pulmonary rehabilitation on some physiologic variables in COPD patients recovering from an episode of acute respiratory failure . DESIGN A prospect i ve , r and omized study . SETTING A respiratory intensive care unit ( RICU ) . PATIENTS Eighty COPD patients recovering from an episode of acute respiratory failure were r and omized in a 3:1 fashion to receive stepwise pulmonary rehabilitation ( group A , n=60 patients ) or st and ard medical therapy ( group B , n=20 patients ) . MAIN OUTCOME MEASURES Improvements in exercise tolerance , sense of breathlessness , respiratory muscle function , and pulmonary function test values were measured , respectively , by exercise capacity ( 6-minute walking distance [ 6MWD ] ) , dyspnea score ( Visual Analog Scale [ VAS ] ) , maximal inspiratory pressure ( MIP ) , forced expiratory volume in 1 second ( FEV1 ) , and forced vital capacity ( FVC ) . INTERVENTIONS Group A received pulmonary rehabilitation that consisted of passive mobilization ( step I ) , early deambulation ( step II ) , respiratory and lower skeletal muscle training ( step III ) , and if the patients were able , complete lower extremity training on a treadmill ( step IV ) . Group B received st and ard medical therapy plus a basic deambulation program . RESULTS Sixty-one of 80 patients were mechanically ventilated at admission to the unit and most of them were bedridden . Twelve of the 60 group A patients and 4 of the 20 group B patients died during their RICU stay , and 9 patients required invasive mechanical ventilation at home after their discharge . The total length of RICU stay was 38+/-14 days for patients in group A versus 33.2+/-11 days for those in group B. Most patients from both groups regained the ability to walk , either unaided or aided . At discharge , 6 MWD results were significantly improved ( p < .001 ) in Group A only . MIP improved in Group A only ( p < .05 ) , while VAS scores improved in both groups , but the improvement was more marked in group A ( p < .001 ) than in group B ( p < .05 ) . CONCLUSIONS COPD patients who were admitted to a RICU in critical condition after an episode of acute respiratory failure and who , in most cases , required mechanical ventilation benefited from comprehensive early pulmonary rehabilitation , compared with patients who received st and ard medical therapy and progressive ambulation Background Exacerbations of chronic obstructive pulmonary disease ( COPD ) are characterised by increased dyspnoea , reduced quality of life and muscle weakness . Re-exacerbation and hospital admission are common . Pulmonary rehabilitation ( PR ) administered after hospital admission for an exacerbation can improve quality of life and exercise capacity . Objective To determine whether outpatient post-exacerbation PR ( PEPR ) could reduce subsequent hospital admission episodes . Methods Patients admitted to hospital for an exacerbation of COPD were r and omised to receive either usual follow-up care ( UC ) or PEPR after discharge . Hospital admission and emergency department attendances for COPD exacerbations were recorded over a 3-month period and analysed on an intention-to-treat basis . Secondary outcomes included exercise capacity and quadriceps strength . Results 60 patients underwent concealed r and omisation at the time of their hospital discharge ( UC : n=30 , mean ( SD ) age 65 ( 10 ) years , forced expiratory volume in 1 s ( FEV1 ) 52 (22)% predicted ; PEPR : n=30 , 67(10 ) years , 52 (20)% predicted ) . The proportion of patients re-admitted to hospital with an exacerbation was 33 % in the UC group compared with 7 % in those receiving PEPR ( OR 0.15 , 95 % CI 0.03 to 0.72 , p=0.02 ) . The proportion of patients that experienced an exacerbation result ing in an unplanned hospital attendance ( either admission or review and discharge from the emergency department ) was 57 % in the UC group and 27 % in those receiving PEPR ( OR 0.28 , 95 % CI 0.10 to 0.82 , p=0.02 ) . Conclusions Post-exacerbation rehabilitation in COPD can reduce re-exacerbation events that require admission or hospital attendance over a 3-month period . Clinical Trials Registration Number NCT00557115 Objective To investigate whether an early rehabilitation intervention initiated during acute admission for exacerbations of chronic respiratory disease reduces the risk of readmission over 12 months and ameliorates the negative effects of the episode on physical performance and health status . Design Prospect i ve , r and omised controlled trial . Setting An acute cardiorespiratory unit in a teaching hospital and an acute medical unit in an affiliated teaching district general hospital , United Kingdom . Participants 389 patients aged between 45 and 93 who within 48 hours of admission to hospital with an exacerbation of chronic respiratory disease were r and omised to an early rehabilitation intervention ( n=196 ) or to usual care ( n=193 ) . Main outcome measures The primary outcome was readmission rate at 12 months . Secondary outcomes included number of hospital days , mortality , physical performance , and health status . The primary analysis was by intention to treat , with prespecified per protocol analysis as a secondary outcome . Interventions Participants in the early rehabilitation group received a six week intervention , started within 48 hours of admission . The intervention comprised prescribed , progressive aerobic , resistance , and neuromuscular electrical stimulation training . Patients also received a self management and education package . Results Of the 389 participants , 320 ( 82 % ) had a primary diagnosis of chronic obstructive pulmonary disease . 233 ( 60 % ) were readmitted at least once in the following year ( 62 % in the intervention group and 58 % in the control group ) . No significant difference between groups was found ( hazard ratio 1.1 , 95 % confidence interval 0.86 to 1.43 , P=0.4 ) . An increase in mortality was seen in the intervention group at one year ( odds ratio 1.74 , 95 % confidence interval 1.05 to 2.88 , P=0.03 ) . Significant recovery in physical performance and health status was seen after discharge in both groups , with no significant difference between groups at one year . Conclusion Early rehabilitation during hospital admission for chronic respiratory disease did not reduce the risk of subsequent readmission or enhance recovery of physical function following the event over 12 months . Mortality at 12 months was higher in the intervention group . The results suggest that beyond current st and ard physiotherapy practice , progressive exercise rehabilitation should not be started during the early stages of the acute illness . Trial registration Current Controlled Trials IS RCT N05557928 PURPOSE : To determine whether an early rehabilitation program was safe and feasible for patients during an acute exacerbation of chronic obstructive pulmonary disease ( COPD ) . METHODS : In this phase 1 r and omized controlled trial , patients with an acute exacerbation of COPD admitted to the hospital were r and omly allocated to a low-intensity exercise group , a moderate- to high-intensity exercise group , or a control group , who received routine physical therapy . In addition to routine physical therapy , patients in the exercise group had to participate in an exercise program . The program consisted of twice-daily aerobic and resistance exercise sessions . Primary outcomes were the number and classification of adverse events and program adherence . RESULTS : In 174 exercise sessions , there was 1 serious adverse event of arrhythmia in the low-intensity exercise group that resolved within 1 hour . There were 12 other minor adverse events involving 5 patients with no significant differences between groups . Patients completed an average of 80 % of their scheduled sessions with no significant between-group differences . The exercise groups improved significantly in walking distance ; however , no significant between-group differences were observed . CONCLUSIONS : There was preliminary evidence that it was safe and feasible to implement an exercise program for patients during an acute exacerbation of COPD . Additional studies with larger sample sizes are required to accurately evaluate program effectiveness BACKGROUND / OBJECTIVES The chronic respiratory question naire ( CRQ ) , the St. Georges Respiratory Question naire ( SGRQ ) , and the feeling thermometer ( FT ) evaluate change in health-related quality of life ( HRQL ) in patients with chronic airflow limitation ( CAL ) . Although the interpretability , and in particular the minimal important difference ( MID ) in score changes , is well established for the CRQ , this is not the case for the SGRQ and FT . The objective of our study is to explore the interpretation of the SGRQ and FT . METHODS We analyzed data from 84 patients who completed the CRQ , SGRQ , and FT before beginning pulmonary rehabilitation and 3 months later . We calculated correlations between the four CRQ domains ( dyspnea , fatigue , emotional function , and mastery ) and the three SGRQ domains ( symptoms , activities , and impact ) , the SGRQ total score , and the FT . When Pearson 's correlations were > /=0.5 , we constructed regression equations and used the slope to calculate the change in SGRQ and FT score that corresponded to a change in CRQ score of 0.5 ( the MID ) . Having established MID for SGRQ we than used a similar approach to examine the relation between the SGRQ and FT results . RESULTS Comparison with the CRQ dyspnea domain suggested the MID in SGRQ total score is approximately 3.05 with a 95 % confidence interval ( 95 % CI ) ranging from 0.39 to 5.71 and a change of 5.67 ( 95 % CI 3.43 - 7.92 ) represents a moderate change ( 1.0 on the CRQ dyspnea domain ) . The MID for the FT based on the CRQ fatigue domain was 6.1 ( 95 % CI 1.87 - 10.28 ) . The FT MID based on the SGRQ activities domain , impacts domain , and total score were , respectively , 7.4 ( 95 % CI 3.44 - 11.35 ) , 5.6 ( 95 % CI 1.6 - 9.64 ) , and 5.9 ( 95 % CI 1.97 - 9.78 ) . CONCLUSIONS An MID for the SGRQ approximates the previously suggested estimate of 4 on a scale of 0 to 100 . The MID for the FT in patients with CAL is approximately 5 to 8 units on the 0 to 100 scale . These MID estimates should facilitate interpretation of clinical trials in which outcome measures include the SGRQ or FT Patients hospitalised for exacerbations contribute significantly to the total chronic obstructive pulmonary disease ( COPD ) -related healthcare costs . This study aim ed to determine the re source use and costs of exacerbations by exacerbation-severity and to identify risk factors for hospitalisation . Exacerbations and the details of all associated healthcare utilisation were recorded as part of a prospect i ve cost-effectiveness analysis linked to two r and omised controlled trials comparing tiotropium with ipratropium in 519 patients with stable COPD at study entry in the Netherl and s and Belgium . Exacerbation-severity was rated by the physician . A Cox proportional hazards analysis was performed to identify independent risk factors of hospitalisation . Covariates that entered this analysis were smoking status , pack-years , body mass index , number of concomitant diseases , number of concomitant medications , use of inhaled steroids , physician visits prior to trial , FEV1 % predicted , quality of life , baseline dyspnea index ( BDI ) and treatment arm . The mean number of exacerbations per patient was 0.70 ( 95%-CI:0.60 , 0.81 ) . About 10 % of the exacerbations was severe , 47 % moderate and 43 % was mild . The mean costs of these exacerbations were Euro 4007 ( 95%-CI:2004 , 6011 ) , Euro 579 ( 390 , 768 ) and Euro 86 ( 49 , 124 ) , respectively . In addition to treatment arm , a body mass index below 18.5 ( RR:3.62 ) , each additional concomitant diagnosis ( RR:1.40 ) and a decrease of 1 point in the baseline dyspnea index ( RR:1.18 ) were significant risk factors of hospitalisation . Exacerbations that were associated with a hospitalisation accounted for 90 % of the total costs of exacerbations . Underweight , history of concomitant diseases and increased dyspnea ( BDI score ) are factors that are likely to identify patients who are at increased risk for generating high costs due to hospitalisation BACKGROUND Long-term exercise training is capable of improving exercise performance and quality of life in patients with severe COPD . In the present study we examined the effects of an 18-month home-based training on the rate of hospital admissions and bronchodilator use as primary end-points . Secondary end-points were exercise capacity and quality of life . METHODS The study comprised 26 patients with severe COPD ( 20m/6f ; mean + /- SD FEV1 , 37 + /- 6 % pred ) who were recruited in a previous trial and r and omised into a training ( n = 14 ) and a control group ( n = 12 ) . After initial recovery from an exacerbation the training group had performed a 10-day walking training in the hospital . This was followed by 18 months of individually defined , supervised training at home that was integrated into the patients ' daily activities . The control group had no exercise programme , neither in hospital nor at home . RESULTS During the 18-month period patients of the training group showed a lower number of hospital admissions ( total , n = 3 vs n = 14 , p = 0.026 ; disease-related , n = 3 vs n = 12 , p = 0.050 ) and used less short-acting beta 2-agonists ( mean [ 95 % CI ] , 2.4 [ 1.4 - 3.4 ] vs 5.7 [ 4.2 - 7.2 ] puffs per day ; p < 0.001 ) than the control group . Furthermore , the improvements in 6-min treadmill distance and quality of life ( CRQ ) achieved in the hospital were fully maintained in the training group , whereas the control group did not show significant improvements at any time but a tendency toward deterioration . CONCLUSIONS Our data indicate that an individually defined , home-based , long-term walking programme initiated by a short hospital-based training can reduce disease-related medical consumption , in addition to sustained benefits in exercise performance and quality of life The principals of rehabilitation medicine are to prevent muscle atrophy and improve mobility . Exacerbations of chronic obstructive pulmonary disease ( COPD ) are associated with muscle atrophy and yet many patients do not undergo pulmonary rehabilitation until they have been in stable health for some time . We investigated the outcome of a supervised home exercise programme initiated immediately after hospitalisation for an exacerbation of COPD . Thirty-one patients were r and omised into an exercise group ( n=16 , FEV(1 ) 0.94+/-0.34 L ) and a control group ( n=15 , FEV(1 ) 1.08+/-0.33 L ) . The exercise group received a twice-weekly supervised exercise programme , in their homes , for 6 weeks . Spirometry , exercise capacity , isometric muscle strength , dyspnea level , quality of life at baseline and 6 weeks as well as subsequent exacerbations were quantified . At 6 weeks , the exercise group , improved the shuttle walk test ( 198 m+/-95 - 304+/-136 m ) and increased 3 min step test capacity ( 119+/-40 - 163+/-26s ) ( both P<0.001 ) . Knee extensor muscle strength and quality of life scores also increased . Neither exercise capacity nor muscle strength altered in the control group . Follow-up at 3 months showed that three of the control group and none of the exercise group had experienced subsequent exacerbations ( P=0.06 ) . Early rehabilitation via a home from hospital programme improved exercise tolerance , muscle strength , dyspnea scores , quality of life in COPD patients and reduced the number of subsequent exacerbations BACKGROUND AND OBJECTIVE Acute exacerbations of chronic obstructive pulmonary disease ( AE COPD ) incur heavy utilization of health-care re sources for patients who require hospitalization . We evaluated whether an early outpatient pulmonary rehabilitation programme ( PRP ) after hospitalization for AE COPD could reduce acute health-care utilization over the succeeding year . METHODS Sixty patients admitted with AE COPD were r and omized to either PRP or usual care ( UC ) . The PRP group received 8weeks of outpatient rehabilitation programme 2 - 3weeks after discharge from hospital . Lung function , 6min walk test and dyspnoea score were assessed at baseline , 3 , 6 , 9 and 12months , while St George 's respiratory question naire and cardiopulmonary exercise test were assessed at baseline , 3 , 6 and 12months . RESULTS The PRP and UC groups demonstrated a 53.3 % and 43.3 % risk of readmissions at 12months ( incident risk ratio 0.97 ( 95 % CI : 0.57 - 1.60 ) , P=0.90 ) . The mean readmission rates were 1.00±1.20 and 1.03±1.87 ( P=0.47 ) for the PRP versus UC groups respectively . The rates of AE COPD and emergency department visits were similar between the two groups . The St George 's respiratory question naire total score was lower in the PRP group ( 40.15±19.10 vs 46.91±18.21 , P=0.01 and 42.3±20.06 vs 51.44±18.98 P=0.01 at 3 and 6months respectively ) . There were no statistically significant differences in the FEV(1 ) % predicted , dyspnoea score , 6min walk test and maximal oxygen consumption during exercise test between PRP and UC at different time points . CONCLUSIONS An early rehabilitation programme following AE COPD led to improvement in quality of life up to 6months , but did not reduce health-care utilization at 1year Clinical experience suggests that exercise is beneficial for recovery after an acute exacerbation in patients with severe chronic obstructive pulmonary disease ( COPD ) . The aim of this study was to quantify the clinical benefit of exercise in these patients . Twenty-nine in patients were r and omly assigned to a training group ( n = 15 , FEV1 34 % pred ) or a control group ( n = 14 , FEV1 38 % pred ) . On ten consecutive days , patients in the training group performed a 6-min treadmill walking test and , in addition , five walking sessions per day at > or = 75 % of the respective treadmill walking distance . Patients in the control group performed only treadmill walking tests on days 1 , 5 , and 10 . To directly compare the possible benefit of exercise training all patients had an exercise test on day 11 at the same work load as on day 1 . In the training group , 6-min walking distance increased from 237 to 420 m , in the control group from 230 to 255 m over the 10 day period which was significantly different ( P < 0.0001 ) . Minute ventilation and oxygen uptake increased significantly ( P < 0.05 ) in the training but not in the control group . When comparing exercise tests on days 1 and 11 , minute ventilation , oxygen uptake , PaCO2 , lactic acid concentration , and Borg scale were significantly reduced to achieve the same work load ( P < 0.01 ) only in the training group . Intrathoracic gas volume and residual volume decreased , and FEV1 and vital capacity increased in the training ( P < 0.05 ) but not in the control group . Our data demonstrate that exercise training significantly improves the exercise capacity in patients with severe COPD after an acute exacerbation of their disease Objective : To assess the effectiveness of an on-call physical therapy programme in the management of acute exacerbations of chronic obstructive pulmonary diseases . Design : R and omized controlled trial . Setting : Secondary care level , rural hospital . Subjects : Thirty-eight patients with acute exacerbations of chronic obstructive pulmonary disease . Interventions : Regular physical therapy and on-call physical therapy was given to two groups of patients with 19 in each arm . On-call physical therapy included providing respiratory physical therapy as required by the patient out of business hours . Main measures : Peak expiratory flow rate , sustained maximal inspiration , six-minute walk distance and rating of perceived exertion post six-minute walk test . Results : In the group receiving on-call physical therapy , peak expiratory flow rate and six-minute walk test showed a significant difference ( 52.1 L/min and 98.16 m , respectively ) when compared with the control group ( 211.57 ± 51.12 L/min and 159.47 ± 67.78 L/min ; P = 0.01 and 387.89 ± 110.1 m and 289.73 ± 103.2 m ; P=0.004 respectively ) . The difference in peak expiratory flow rate ( Δ peak expiratory flow rate ) was seen to be more in the on-call group ( 120 L/min ) when compared to the control group ( 50 L/min ) , P = 0.002 . Improvements in sustained maximal inspiration and Borg ’s rating of perceived exertion after the six-minute walk test were also observed ( P>0.05 ) . Conclusion : On-call physical therapy brings about a significant increase in peak expiratory flow rates , six-minute walk distance and sustained maximal inspiration OBJECTIVE To evaluate the effects of whole-body resistance training on exercise capacity , health-related quality of life ( HRQOL ) , and muscle strength in patients hospitalized for exacerbation of chronic obstructive pulmonary disease . DESIGN R and omized controlled trial . SETTING University hospital . PARTICIPANTS Patients ( N=46 ) were r and omized to either a control group ( CG ) or training group ( TG ) , and 29 patients completed the study . INTERVENTION Training consisted of weight-lifting exercises for 6 muscle groups in the upper and lower limbs ( 2 sets of 8 repetitions each ) , and the initial load was set at 80 % of the 1-repetition maximum load . MAIN OUTCOME MEASURES Patients were evaluated on the second day of hospitalization , at hospital discharge , and 30 days postdischarge . Patients were evaluated on the basis of the 6-minute walking distance ( 6MWD ) , HRQOL , muscle strength , systemic inflammatory markers , and level of physical activity in daily life ( PADL ) . RESULTS The CG showed a reduction in the strength of lower-limb muscles ( P<.05 ) but not in the 6MWD ( P>.05 ) . In contrast , patients from the TG improved strength in the lower-limb muscles and 6MWD during and 30 days after hospitalization ( P<.05 ) . The TG also improved the impact domain in HRQOL after hospitalization . No improvement in PADL was observed in the TG . Finally , a reduction in the blood levels of inflammatory markers was observed only in the TG after hospitalization . CONCLUSIONS Our results suggest that resistance training during hospitalization improves the 6MWD , HRQOL , and lower-limb muscle strength , without altering the levels of systemic inflammation . However , future research should explore this intervention in larger r and omized trials The objective of this study was to analyze the results of a multimodal therapeutic program during hospitalization in obese AE COPD patients . This was a r and omized , single-blind clinical trial conducted at two university hospitals in Granada , Spain . Forty-nine patients hospitalized due to AE COPD were r and omly allocated to a control group ( CG ) , in which patients received st and ard care , or to an intervention group ( IG ) , in which patients were included in a multimodal therapeutic program , added to the st and ard care . The main outcome measures were pulmonary , physical ( strength and exercise capacity ) and perceived ( dyspnea , quality of life and psychological distress ) variables . Within-group significant improvements ( p < 0.05 ) were found in physical and perceived variables in the IG after the treatment . In the CG , a significant decrease was found in lower limb strength and a significant improvement in dyspnea and in three subscales of the EuroQol-5D question naire . The between-groups analysis showed significant differences after the treatment on lower limb strength and exercise capacity values ( p < 0.05 ) , in three of the EuroQol-5D subscales , and in the total score and the depression subscale of the Hospital Anxiety and Depression Scale . A multimodal therapeutic program has a beneficial effect on physical functioning and perceived variables in hospitalized obese patients with AE COPD Background : The magnitude and time course of effect of an acute exacerbation of chronic bronchitis ( AECB ) on health status are not known . Data from the GLOBE study , a r and omised double blind trial of antibiotic therapy , were used to investigate these effects . Methods : 438 patients with AECB received either gemifloxacin 320 mg once daily for 5 days ( 214 patients ) or clarithromycin 500 mg twice daily for 7 days ( 224 patients ) and were followed up for 26 weeks . St George ’s Respiratory Question naire ( SGRQ ) scores were obtained at baseline and after 4 , 12 , and 26 weeks . Results : At presentation during an exacerbation SGRQ scores were worse ( Total score difference 5.4 units , 95 % CI 1.9 to 8.8 , p=0.002 ) in patients who had a subsequent exacerbation during follow up . The greatest improvement in SGRQ score occurred within the first 4 weeks ( mean 8.9 units , 95 % CI 6.5 to 11.5 , p<0.0001 ) . Subsequently , scores improved more rapidly in patients with no further exacerbations . At 26 weeks the difference between the two groups was 9.6 units ( 95 % CI 5.7 to 13.4 , p<0.0001 ) . In patients with no further exacerbations the SGRQ score improved between 4 and 12 weeks by a further 4.1 units ( 95 % CI 2.2 to 5.9 , p<0.0001 ) . Conclusions : A single infective AECB has a sustained effect on health status . The recovery period is long even in patients who have no further exacerbations . A second episode within 6 months limits recovery markedly . Treatments that reduce exacerbation frequency could have a significant impact on health status BACKGROUND Pulmonary rehabilitation ( PR ) is an evidence -based intervention in patients with chronic obstructive pulmonary disease ( COPD ) which improves the exercise capacity and quality of life ( QoL ) . METHODS We studied 60 patients after an episode of acute exacerbation of COPD ( AE COPD ) . They were r and omised to receive conventional treatment without pulmonary rehabilitation ( CTWPR ) ( n=30 ) or , st and ard treatment plus a 12-week post-exacerbation pulmonary rehabilitation ( PEPR ) programme in addition . Assessment of exercise capacity by six minute walk test ( 6MWT ) and QoL measured by St George 's Respiratory Question naire ( SGRQ ) were carried out initially and at the end of three months . RESULTS The baseline characteristics of both the groups were found to be similar . There was a statistically significant increase in the six minute walk distance ( 6MWD ) ( increase by 37.9 meters , p < 0.001 ) and a significant decline in the total SGRQ score ( by 3.8 units p < 0.001 ) in the PEPR group compared to CTWPR group . CONCLUSION Early pulmonary rehabilitation in patients with an AE COPD has significant benefits on the QoL and exercise capacity BACKGROUND Acute exacerbations form a major component of the socioeconomic burden of COPD . As yet , little information is available about the long-term outcome of patients who have been hospitalized with acute exacerbations , although high mortality rates have been reported . STUDY OBJECTIVE The aim of this study was to investigate prospect ively the outcome for all patients admitted to the hospital with acute exacerbations of COPD during hospital admission and after 1-year of follow-up . Furthermore , patient characteristics related to increased mortality rate were analyzed . DESIGN We investigated prospect ively the 1-year mortality rate and potential determinants of mortality for all patients admitted to the hospital with an acute exacerbation between January 1 and December 31 , 1999 . RESULTS A total of 171 patients were included in the study . The mortality rate during hospital stay was 8 % , increasing to 23 % after 1 year of follow-up . Despite a comparable in-hospital mortality rate ( 6 % ) , the 1-year mortality rate was significantly higher for patients admitted to the ICU for respiratory failure ( 35 % ) . The multivariate Cox proportional hazards model was used to determine independent predictors of survival . Variables included in the regression model were age , sex , FEV(1 ) , PaO(2 ) , PaCO(2 ) , body mass index , long-term use of oral corticosteroids , comorbidity index , and hospital readmissions . The maintenance use of oral glucocorticosteroids ( relative risk [ RR ] , 5.07 ; 95 % confidence interval [ CI ] , 2.03 to 12.64 ) , PaCO(2 ) ( RR , 1.17 ; 95 % CI , 1.01 to 1.38 ) , and age ( RR , 1.07 ; 95 % CI , 1.01 to 1.12 ) were independently related to mortality . CONCLUSION We conclude that the prognosis for patients who have been admitted to the hospital for acute exacerbation of COPD is poor . Long-term use of oral corticosteroids , higher PaCO(2 ) , and older age could be identified as risk factors associated with higher mortality The American College of PhysiciansAmerican Society of Internal Medicine ( ACPASIM ) and the American College of Chest Physicians ( ACCP ) developed this evidence -based clinical practice guideline in collaboration . A joint expert panel examined the evidence and developed recommendations . The numbers in square brackets are cross-references to the numbered sections in the accompanying background paper , Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease : A Summary and Appraisal of Published Evidence , which is part 2 of this guideline ( see pages 600 - 620 ) . The guideline and background paper are based primarily on a systematic review compiled in an Agency for Healthcare Research and Policy evidence report prepared by the Evidence -Based Practice Center at Duke University ( 1 ) . Our target audience is primary care physicians and specialists who care for patients with chronic obstructive pulmonary disease ( COPD ) . Although most acute exacerbations of COPD take place and are treated on an outpatient basis , research studies focus on emergency department or inpatient setting s. As a result , this guideline applies to exacerbations treated in those setting s. The guideline presents the available evidence on risk stratification for relapse and 6-month mortality rates , diagnostic testing for acute exacerbations of COPD , and current treatment options for acute exacerbations of COPD . In the United States , 16 million adults have COPD , which accounts annually for 110 000 deaths , more than 16 million office visits , 500 000 hospitalizations , and $ 18 billion in direct health care costs . The disease is characterized by chronic airflow obstruction and episodic increases in dyspnea , cough , and sputum production that are commonly called exacerbations . After an acute exacerbation , most patients experience a transitory or permanent decrease in quality of life , and nearly 50 % of patients discharged from hospitals after acute exacerbations are readmitted more than once in the following 6 months . Therefore , one of the main treatment goals for patients with COPD is reducing the number and severity of annual exacerbations . There is no widely accepted definition of acute exacerbation of COPD , but most published definitions encompass some combination of three clinical findings : worsening dyspnea , increase in sputum purulence , and increase in sputum volume . A severity scale for acute exacerbations developed by Anthonisen and colleagues ( 2 ) is based on these findings as well as others . Type 1 exacerbations ( severe ) have all three clinical findings , and type 2 exacerbations ( moderate ) exhibit two . Type 3 exacerbations ( mild ) have one of these clinical findings plus at least one of the following : an upper respiratory tract infection in the past 5 days , fever without other apparent cause , increased wheezing , increased cough , or a 20 % increase in respiratory rate or heart rate above baseline . We use this scale when referring to severity in this guideline . Acute exacerbations can be triggered by tracheobronchial infections or environmental exposures , and patients often have associated clinical conditions , such as heart failure , extrapulmonary infections , and pulmonary embolism . Therefore , acute exacerbation is mainly a clinical diagnosis . Despite the importance of this disease , the review of the evidence brings to light the paucity of high- quality studies on this subject . Nevertheless , recommendations in this guideline are based on the highest- quality evidence currently available . While the studies of highest quality were often r and omized , controlled clinical trials , these were few in number and tended to enroll small numbers of patients . The clinician must consider this fact when basing management decisions on the guideline recommendations . Current practice s for the diagnosis and management of acute exacerbations of COPD are varied . Some commonly used tests and therapies are not supported by evidence , while others are . The Panel found enough evidence to make recommendations about the use of the following diagnostic and therapeutic methods in acute exacerbations of COPD : chest radiography , acute spirometry , bronchodilators , corticosteroids , antibiotics , oxygen , mucolytic agents , mucus-clearing strategies , and noninvasive positive-pressure ventilation ( NPPV ) . Indirect evidence shows that arterial blood gases are helpful for determining the present need for oxygen therapy and the potential need for mechanical ventilatory support . We did not find enough evidence to make recommendations regarding the use of pulse oximetry , sputum smear , and culture . Risk Stratification Prediction of Outpatient Relapse All of the studies included for analysis were performed in the emergency department . Relapse was defined as a return visit to the emergency department within 14 days of initial presentation . Identifying patients at high risk for relapse should help guide decisions about hospital admission and follow-up appointments . Several studies have confirmed what most clinicians intuitively know : Patients who have lower baseline FEV1 , low Po 2 , high Pco 2 , and low pH and who receive more bronchodilator treatments while in the emergency department are more likely to relapse within 14 days of initial presentation . Unfortunately , none of the predictive models perform well enough to justify their uniform use in clinical practice [ 2.1.1 ] . Prediction of 6-Month Mortality The Study to Underst and Prognoses and Preferences for Outcomes and Risks of Treatments ( SUPPORT ) found a 180-day mortality rate of 33 % in its cohort . Significant predictors of 180-day mortality were worse Acute Physiology and Chronic Health Evaluation ( APACHE ) III score , lower body mass index , older age , worse functional status 2 weeks before admission , lower ratio of Po 2 to fraction of inspired oxygen , history of congestive heart failure , lower serum albumin level , and presence of cor pulmonale . Other studies reported similar associations . Although these studies suggest that certain physiologic characteristics are associated with a higher likelihood of inpatient mortality , we conclude that there is currently no reliable method for identifying patients at high risk ( > 90 % ) for inpatient or 6-month mortality . Therefore , these measures should not influence decisions about instituting , continuing , or withdrawing life-sustaining therapies but should prompt a discussion regarding patient preferences for end-of-life care [ 2.1.2 ] . Diagnostic Testing : Chest Radiography and Spirometry Three observational studies showed substantial rates of abnormalities in chest radiography among patients admitted for acute exacerbation of COPD . In one prospect i ve study , which included patients with asthma , chest radiography results prompted change in management in 23.5 % of patients , mostly because of new infiltrates . Observational studies showed that spirometric assessment at presentation or during treatment is not useful in judging severity or guiding management of patients with acute exacerbations of COPD . When measured at the time of an exacerbation , FEV1 showed no significant correlation with Po 2 and only a weak ( although statistically significant ) correlation with Pco 2 . Peak expiratory flow rate is often used in the clinic to approximate FEV1 . One study found a correlation between peak expiratory flow rate and FEV1 . The clinical implication of this finding is not clear , however , because FEV1 is a poor predictor . Despite this fact , many studies use changes in FEV1 as the primary outcome rather than other , more clinical ly pertinent measures ( such as degree of dyspnea or sputum production and quality ) , probably because the latter are much more difficult to quantify and evaluate [ 2.2.2 , 2.2.3 ] . Therapeutic Interventions Bronchodilators Fourteen r and omized trials show that inhaled short-acting 2 agonists , such as albuterol , and anticholinergic bronchodilators , such as ipratropium , are equally efficacious in patients with acute exacerbations of COPD . They are also superior to all parenterally administered bronchodilators , including methylxanthines and sympathomimetic agents . Furthermore , some patients may experience additional benefit when a second inhaled bronchodilating agent is administered after the maximal dose of the initial agent is reached . Several studies examined patients receiving a short-acting 2 agonist plus an anticholinergic bronchodilator . In general , patients in these studies had marginally shorter lengths of stay and proportionally larger increases in FEV1 , but hospital admission rates were similar to those of patients receiving one bronchodilator . Since anticholinergic bronchodilators are associated with fewer and milder side effects , it is advisable to start with them and then add a short-acting 2 agonist . Studies are equivocal on the addition of a methylxanthine , such as aminophylline , to inhaled bronchodilators . More important , the potentially serious side effects of the methylxanthines make their use more problematic . In addition , some evidence shows that the efficacy of wet nebulization and dry aerosol delivery systems ( metered-dose inhaler plus a spacer ) are clinical ly equivalent . Therefore , the choice of a specific delivery method should be determined on an individual basis , depending on each patient 's ability to use the different methods ( 3 ) [ 2.3.1 ] . Corticosteroids Six r and omized , placebo-controlled trials showed that for patients hospitalized with acute exacerbation of COPD , systemic corticosteroids given for up to 2 weeks are helpful . Dosage , length of treatment , administration , and setting varied greatly among the studies evaluated . In the largest trial ( Systemic Corticosteroids in Chronic Obstructive Pulmonary Disease Exacerbations ) , patients received a 2-week or 8-week course . The 2-week course consisted of 3 days of intravenous methylprednisolone , 125 mg every 6 hours , followed by oral prednisone for 2 weeks ( 60 mg/d on days 4 to 7 , 40 mg/d on days 8 to 11 , and 20 mg/d on days 12 to Background There have been no r and omised controlled trials that specifically evaluate the effect of a comprehensive programme with multidisciplinary input on patients who have just been discharged from hospital after treatment of acute exacerbation of COPD ( AE COPD ) . The aim of this study was to assess whether a comprehensive care programme would decrease hospital readmissions and length of hospital stay ( LOS ) for patients with COPD . Methods Patients discharged from hospital after an episode of AE COPD were r and omised to an intervention group ( IG ) or usual care group ( UG ) . The IG received a comprehensive , individualised care plan which included education from a respiratory nurse , physiotherapist support for pulmonary rehabilitation , 3-monthly telephone calls by a respiratory nurse over 1 year , and follow-up at a respiratory clinic with a respiratory specialist once every 3 months for 1 year . The UG were managed according to st and ard practice . The primary outcome was hospital readmission rate at 12 months . Results 180 patients were recruited ( IG , N=90 ; UG , N=90 ; mean±SD age 74.7±8.2 years , 172 ( 95.6 % ) men ; mean±SD FEV1 45.4±16.6 % predicted ) . At 12 months , the adjusted relative risk of readmission was 0.668 ( 95 % CI 0.449 to 0.995 , p=0.047 ) for the IG compared with the UG . At 12 months , the IG had a shorter LOS ( 4.59±7.16 vs 8.86±10.24 days , p≤0.001 ) , greater improvement in mean Modified Medical Research Council Dyspnoea Scale ( −0.1±0.6 vs 0.2±0.6 , p=0.003 ) and St George 's Respiratory Question naire score ( −6.9±15.3 vs −0.1±13.8 , p=0.003 ) compared with the UG . Conclusions A comprehensive COPD programme can reduce hospital readmissions for COPD and LOS , in addition to improving symptoms and quality of life of the patients . Trial registration number NCT 01108835 , Results

Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third . In those who are treated there is a small increased risk of bleeding . In recent years CDT is the most studied route of administration , and results appear to be similar to systemic administration

BACKGROUND St and ard treatment for deep vein thrombosis aims to reduce immediate complications . Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome ( PTS ) ( pain , swelling , skin discolouration , or venous ulceration ) in the affected leg . This is the second up date of a review first published in 2004 . OBJECTIVES To assess the effects of thrombolytic therapy and anticoagulation versus anticoagulation in the management of people with acute deep vein thrombosis ( DVT ) of the lower limb as determined by the effects on pulmonary embolism , recurrent venous thromboembolism , major bleeding , post-thrombotic complications , venous patency and venous function . Systemic thrombolysis is now not commonly used and catheter-directed thrombolysis ( CDT ) is the more favoured means of administration .

Sequential ascending venographic studies were used to assess the healing of deep venous thrombosis in 50 patients r and omly assigned to streptokinase or heparin therapy . Various degrees of thrombolysis and /or recanalization were demonstrated by venograms performed on the fourth and tenth days of treatment . Late follow-up studies ( mean , 7 months after treatment ) showed three basic patterns of resolution : ( 1 ) return to normal , ( 2 ) complete recanalization , and ( 3 ) incomplete recanalization and /or collateralization . Loss of valves or their function was associated with recanalization . The character , speed , and outcome of healing reflected the nature and extent of thrombosis , prior thrombotic disease in the extremity , and the type and timing of treatment . Streptokinase was highly effective and preferable to heparin in patients with deep vein thrombosis when therapy was begun within 4 days of onset of symptoms . In later stages of acute or recurrent deep vein thrombosis , the effectiveness of both drugs was significantly reduced Objectives . We compared the efficacy and safety of percutaneous endovenous intervention ( PEVI ) plus anticoagulation with anticoagulation alone in the reduction of venous thromboembolism ( VTE ) and post‐thrombotic syndrome ( PTS ) in acute proximal deep venous thrombosis ( DVT ) . Background . Recurrent VTE and PTS are common complications of DVT . There are no r and omized trials investigating the efficacy of PEVI in the reduction of the above complications . Methods . Patients with symptomatic proximal DVT were r and omized to receive PEVI plus anticoagulation or anticoagulation alone . Anticoagulation consisted of intravenous unfractionated heparin or subcutaneous low‐molecular weight heparin plus warfarin . PEVI consisted of one or more of a combination of thrombectomy , balloon venoplasty , stenting , or local low‐dose thrombolytic therapy . Results . At 6 months follow‐up , recurrent VTE developed in 2 of 88 patients of the PEVI plus anticoagulation group versus 12 of 81of the anticoagulation‐alone group ( 2.3 % vs. 14.8 % , P = 0.003 ) . PTS developed in 3 of 88 patients of the PEVI plus anticoagulation Group and 22 of 81 of the anticoagulation‐alone group ( 3.4 % vs. 27.2 % , P < 0.001 ) . Conclusions . In patients with symptomatic proximal DVT , PEVI plus anticoagulation may be superior to anticoagulation — alone in the reduction of VTE and PTS at 6 months . © 2010 Wiley‐Liss , Heparin or streptokinase was administered in a prospect i ve r and omized fashion to 50 patients with phlebographically confirmed venous thrombosis of the extremities of 14 days or less duration . A total of 49 patients completed the investigative protocol with 26 receiving heparin and 23 receiving streptokinase . All patients were evaluated with sequential phlebograms . Complete thrombolysis with restoration of venous valve function occurred in one of 26 patients receiving heparin and in six of 23 patients receiving streptokinase . Fifty per cent of the patients treated with streptokinase with a total duration of symptoms of three days or less achieved complete lysis . The total incidence of therapeutic complications was similar in the two groups , but was more severe in the streptokinase treated patients Twenty-two patients who had an acute episode of thrombosis in the deep veins of the legs were studied by a new technique of ascending functional cinephlebography 6 to 12 months after the episode of thrombosis . If the condition was diagnosed within 36 hours and the thrombus was dissolved rapidly valve function was preserved . When diagnosis was delayed there was a very great risk of permanent damage to the valves Patients with symptoms of deep vein thrombosis for less than 10 days were treated with a st and ard dose of heparin . In the open label phase of the trial , 11 patients received 100 mg rt-PA on the first day and 50 mg on the subsequent day in an 8 hour infusion . In the double-blind phase , 8 patients were r and omized to the same rt-PA regimen , 6 patients to an infusion of 50 mg rt-PA over 8 hours on days 1 and 2 , and 7 patients to placebo infusions . The mean change in venographic score in all patients treated with rt-PA plus heparin is -3.8 units compared to -0.6 units in patients treated with heparin alone ( p = 0.06 ) . Bleeding complications classified as major were noted in 8/25 patients receiving the combined treatment The management of acute deep vein thrombosis ( DVT ) by medical therapy with anticoagulation has long been supported by evidence -based clinical practice guidelines outlined in the American College of Chest Physicians supplement . Early thrombus removal in patients with iliofemoral DVT has been reported to lead to improved venous valve function , improved quality of life , and decreased incidence of postthrombotic syndrome over anticoagulation alone . The ATTRACT trial will r and omize patients to medical management with st and ard anticoagulation versus catheter-directed thrombolysis in addition to st and ard anticoagulation after stratification to iliofemoral versus femoropopliteal DVT in order to determine the primary outcome of postthrombotic syndrome over a 24-month follow-up Treatment with streptokinase ( ' Kabikinase ' ) was given to 26 patients with venographically confirmed deep vein thrombosis extending into the popliteal vein or above . Treatment was continued for 4 days and the patients were allocated r and omly to oral anticoagulant therapy or a course of treatment with ancrod ( ' Arvin ' ) for 6 days followed by oral anticoagulant therapy . The degree of thrombolysis as judged by further venographic examination at 10 days was not significantly different between the 2 groups . The majority of patients showed clinical improvement but there was no appreciable difference between the groups at 3 and 6 months . Haemorrhagic complications were a more serious problem during the period of treatment with ancrod than during the equivalent period in the control group

The low- quality evidence from three small trials with 147 participants does not allow any firm conclusions to be drawn regarding the effectiveness of DMT for depression .

BACKGROUND Depression is a debilitating condition affecting more than 350 million people worldwide ( WHO 2012 ) with a limited number of evidence -based treatments . Drug treatments may be inappropriate due to side effects and cost , and not everyone can use talking therapies . There is a need for evidence -based treatments that can be applied across cultures and with people who find it difficult to verbally articulate thoughts and feelings . Dance movement therapy ( DMT ) is used with people from a range of cultural and intellectual background s , but effectiveness remains unclear . OBJECTIVES To examine the effects of DMT for depression with or without st and ard care , compared to no treatment or st and ard care alone , psychological therapies , drug treatment , or other physical interventions . Also , to compare the effectiveness of different DMT approaches . In the UK , the therapist would either be in training with , or accredited by , the Association for Dance Movement Psychotherapy ( ADMP , UK ) . Similar professional bodies exist in Europe , but in some countries ( e.g. China ) where the profession is in development , a lower level of qualification would mirror the situation some decades previously in the USA or UK .

Dance and movement therapy are consisted of music , easy exercises and sensorial stimulus and provide drugless treatment for the depression on low rates . In this study , it has been aim ed to examine the effect of dance over the depression . A total of 120 healthy male and female conservatory students ranged from 20 and 24 ages volunteered to participate in this study . They were divided r and omly into 1 of 2 groups : dance training group ( DTG ; N = 60 ) and control group ( CG ; N = 60 ) . A dance training program was applied to the subjects three days a week ( Tuesday , Thursday , and Saturday ) during 12 weeks . The subjects in the control group did not participate in the training and participated only in the pre and post test measurements . Beck Depression Scale was used for the pre and post test measurements of subjects . 12 weeks of dance training has been found to be effective on the depression levels of the subjects participating in the research as the training group ( p < 0.05 ) . The depression level of males and females before training has meaningfully decreased after 12 weeks of dance training ( p < 0.05 ) . When the depression levels of the subjects participated in research as the control group were separately evaluated for males and females , no meaningful change has been found in the depression levels during 12 weeks ( p > 0.05 ) . In conclusion , it has been seen that dance affects the depression levels of university students positively and decreases their depression levels The relative lack of research on movement therapy in inpatient versus outpatient setting s stems from the difficulty of conducting an interpretable study in clinical situations where multiple treatments exist . To control for the multiple treatment confound , this study used a r and omized single-case experimental design with 12 replications . Results indicated that the movement therapy , which was design ed to target the syndrome of a major depressive episode had a positive effect on mood across experiments ( p < .001 ) . From a clinical perspective , these results support the use of a movement program as adjunctive treatment , and challenge the view that movement is recreation but not therapy The purpose of this pilot study was to compare the effectiveness of conservative therapy involving medical exercise therapy ( MET ) versus arthroscopic surgery in patients with knee pain , with MRI-verified degenerative meniscus . The patients were r and omly assigned either to MET ( n = 9 ) or to arthroscopic surgery ( n = 8) . Patients receiving MET had 3 treatments a week for 3 months , a total of 36 treatments . The arthroscopy consisted of meniscectomy with no structured conservative therapy after surgery . Assessment of pain , function , anxiety and depression were performed at inclusion and after 3 months . At the end of treatment , which was 3 months after inclusion , there were no statistical differences between the two groups regarding pain and function . However , anxiety and depression were significantly reduced in the MET group compared with the patients receiving arthroscopic surgery . Bearing in mind the low number of included patients in this pilot study , arthroscopy was found to be no better than MET regarding knee pain and overall daily function . The results from this pilot study are similar to other clinical studies , thereby demonstrating that conservative therapy is just as effective as surgery OBJECTIVE The primary goal of the study was to assess the efficacy of mindfulness-based meditation therapy on anxiety , depression , and spiritual well-being of Japanese patients undergoing anticancer treatment . A secondary goal was to assess the relationships among anxiety , depression , spiritual well-being , growth , appreciation , pain , and symptoms . METHODS The subjects were 28 patients who were receiving anticancer treatment . The subjects participated in two sessions of mindfulness-based meditation therapy , including breathing , yoga movement and meditation . Each patient was taught the program in the first session , then exercised at home with a CD , and subsequently met the interviewer in a second session after 2 weeks . Primary physicians recruited the patients and interviews were conducted individually by nurses or psychologists with training in the program . Patients completed preintervention and postintervention question naires on anxiety and depression ( Hospital Anxiety and Depression Scale [ HADS ] ) , spiritual well-being ( Functional Assessment of Chronic Illness Therapy-Spiritual [ FACIT-Sp ] ) , and appreciation , growth , pain , and symptoms . RESULTS HADS scores significantly decreased from 12 + /- 5.3 to 8.6 + /- 6.3 ( p = 0.004 ) after the intervention , and FACIT-Sp increased from 32 + /- 6.5 to 33 + /- 6.9 ( p = 0.69 ) , but the change was not significant . There were significant associations between FACIT-Sp and HADS ( r = -0.78 , p = 000 ) , FACIT-Sp and growth ( r = -0.35 , p = 0.04 ) , FACIT-Sp and pain ( r = -0.41 , p = 0.02 ) , and growth and appreciation ( r = 0.45 , p = 0.009 ) . CONCLUSIONS Mindfulness-based meditation therapy may be effective for anxiety and depression in Japanese cancer patients , and spiritual well-being is related to anxiety and depression , growth , and pain . The negative correlation of spirituality with growth differs from the results of previous studies and the mechanism of this effect needs to be investigated further Background The increasing prevalence of psychological health problems among adolescent girls is alarming . Knowledge of beneficial effects of physical activity on psychological health is widespread . Dance is a popular form of exercise that could be a protective factor in preventing and treating symptoms of depression . The aim of this study was to assess the cost-effectiveness of a dance intervention in addition to usual school health services for adolescent girls with internalizing problems , compared with usual school health services alone . Methods A cost-utility analysis from a societal perspective based on a r and omized controlled intervention trial was performed . The setting was a city in central Sweden with a population of 130 000 . A total of 112 adolescent girls , 13–18 years old , with internalizing problems participated in the study . They were r and omly assigned to intervention ( n = 59 ) or control ( n = 53 ) group . The intervention comprised dance twice weekly during eight months in addition to usual school health services . Costs for the stakeholder of the intervention , treatment effect and healthcare costs were considered . Gained quality -adjusted life-years ( QALYs ) were used to measure the effects . Quality of life was measured with the Health Utility Index Mark 3 . Cost-effectiveness ratios were based on the changes in QALYs and net costs for the intervention group compared with the control group . Likelihood of cost-effectiveness was calculated . Results At 20 months , quality of life had increased by 0.08 units more in the intervention group than in the control group ( P = .04 ) , translating to 0.10 gained QALYs . The incremental cost-effectiveness ratio was USD $ 3,830 per QALY and the likelihood of cost-effectiveness was 95 % . Conclusions Intervention with dance twice weekly in addition to usual school health services may be considered cost-effective compared with usual school health services alone , for adolescent girls with internalizing problems . Trial registration Name of the trial registry : “ Influencing Adolescent Girls ’ With Creative Dance Twice Weekly”Trial registration number : Background : The Social Functioning Question naire ( SFQ ) , an eight-item selfreport scale ( score range 0–24 ) , was developed from the Social Functioning Schedule ( SFS ) , a semi-structured interview which has been used primarily with non-psychotic patients and has good test-retest and inter-rater reliability as well as construct validity . The SFQ was developed following the need for a quick assessment of perceived social function . Aims : To give further details of old and new data sets from studies involving over 4000 subjects assessed with the SFQ illustrating its epidemiological and clinical associations . Method : New data were analysed from a national epidemiological study , a comparison of key-worker and subject versions of the SFQ , and re analysis of data from three earlier clinical studies , of psychiatric emergencies , general practice psychiatric patients and those with recurrent psychotic illnesses . These data were examined further to determine their range , their relationship to other clinical measures , and change over time in clinical trials . Results : The population mean score in 4164 subjects was 4.6 and the data from all studies suggested that a score of 10 or more indicated poor social functioning . Those presenting as psychiatric emergencies had the poorest social function ( mean 11.4 ) and psychiatric patients from general practice the best function ( mean 7.7 ) of the clinical population s. The eight item scores had a normal distribution in psychiatric population s and a skewed one in a normal population ; scores were relatively stable over the short ( weeks ) and long-term ( months ) , and were high in the presence of acute mental health disturbance and personality disorder , giving support to the validity of the scale . The results from a UK sample of a r and omly selected population specifically weighted for ethnic minorities showed similar social function across groups OBJECTIVE In 2006 the psychosomatic day hospital for the treatment of acute mental illness of elderly people opened as the first clinic of its kind in Germany . The aim of this study was to determine treatment effectiveness and identify possible effects on health care utilization . METHODS Design ed as a naturalistic study with waiting time before admission as a control condition , the primary outcome was the level of depressive symptoms as measured by the hospital anxiety and depression scale . Secondary outcomes were depressive and somatoform symptoms and syndromes as measured with the patient health question naire , patient perception of interpersonal problems and health care use before and after treatment . RESULTS After treatment significant improvement ( p<0.01 ) with moderate effect sizes ( ES ) was found in all variables from admission to discharge ( ES from 0.3 to 0.8 ) and also to follow-up ( ES from 0.2 to 0.6 ) . Improvement remained stable at follow-up . Furthermore , after psychosomatic treatment a reduction in medical service usage was visible . Number of consultations ( pre : 13 , post : 9 ) , number and length of hospital stays ( pre : 1 , 7 weeks , post : 0 , 3 weeks ) were both significantly ( p<0.001 ) reduced six months after treatment as compared to the period six months prior to treatment . CONCLUSION Results indicate that the psychosomatic day hospital treatment of the elderly is successful . Reduced usage of health care and the lower costs for day hospital treatment compared to inpatient treatment point to a positive cost-effect-ratio . Exp and ing this psychosomatic intervention would be useful in reducing the current gap in mental health care for the elderly BACKGROUND Depressive symptoms are common among older adults , particularly those living in long-term care facilities . However , little is known about factors associated with depressive symptoms among long-term care residents in the Czech Republic and in other Eastern European countries . Moreover , the role of mobility and pain in depressive symptoms among long-term care residents is relatively understudied . OBJECTIVE We examined the relationship between functional status and depressive symptoms in 308 older adults from residential care facilities ( RCFs ) in the Czech Republic . METHOD We used baseline data from two r and omized controlled trials testing the effects of dance and reminiscence therapies on quality of life in older RCF residents . Functional status was measured as cognitive function , general ability to perform basic Activities of Daily Living ( ADLs ) , mobility , and functional limitation by pain . Depressive symptoms were measured using the 15-item Geriatric Depression Scale . RESULTS In multiple regression analyses adjusted for sociodemographic factors and taking antidepressants , we found that cognitive function and functional limitation by pain were most strongly associated with depressive symptoms . The ability to perform basic ADLs and mobility were also related to depressive symptoms . CONCLUSION Our findings suggest factors that may be important in efforts to improve psychological well-being in this population The present study has been carried out to investigate the effects of group-based Turkish folkloric dances on physical performance , balance , depression and quality of life ( QoL ) in 40 healthy adult elderly females over the age of 65 years . Subjects were r and omly allocated into Group 1 ( folkloric dance-based exercise ) and Group 2 ( control ) . A 8-week dance-based exercise program was performed . Outcome measures included a 20-m walk test , a 6-min walk test , stair climbing and chair rise time , Berg balance scale ( BBS ) , the Medical Outcomes Study ( MOS ) 36-item short form health survey ( SF-36 ) , and geriatric depression scale ( GDS ) question naires . In Group 1 statistically significant improvements were found in most of the physical performance tests , BBS and some SF-36 subscales after the exercise ( p<0.05 ) . In the Group 2 there was no clinical ly significant change in the variables . Comparing the groups , significant improvements in favor of Group 1 have emerged in most of the functional performance tests , in some of the SF-36 subscales and BBS score ( p<0.05 ) . We achieved improvements in physical performance , balance and QoL in elderly females . Application of folkloric dance specific to countries as an exercise program for elderly people may be helpful BACKGROUND In order to improve the treatment of medication-resistant negative symptoms in schizophrenia , new interventions are needed . Neuropsychological considerations and older reports in the literature point towards a potential benefit of body-oriented psychological therapy ( BPT ) . This is the first r and omized controlled trial specifically design ed to test the effectiveness of manualized BPT on negative symptoms in chronic schizophrenia . METHOD Out- patients with DSM-IV continuous schizophrenia were r and omly allocated to either BPT ( n=24 ) or supportive counseling ( SC , n=21 ) . Both therapies were administered in small groups in addition to treatment as usual ( 20 sessions over 10 weeks ) . Changes in negative symptom scores on the Positive and Negative Symptom Scale ( PANSS ) between baseline , post-treatment and 4-month follow-up were taken as primary outcome criteria in an intention-to-treat analysis . RESULTS Patients receiving BPT attended more sessions and had significantly lower negative symptom scores after treatment ( PANSS negative , blunted affect , motor retardation ) . The differences held true at 4-month follow-up . Other aspects of psychopathology and subjective quality of life did not change significantly in either group . Treatment satisfaction and ratings of the therapeutic relationship were similar in both groups . CONCLUSIONS BPT may be an effective treatment for negative symptoms in patients with chronic schizophrenia . The findings should merit further trials with larger sample sizes and detailed studies to explore the therapeutic mechanisms involved Background Based on experiences and empirical evidence gained in studies using the Lancashire Quality of Life Profile ( LQLP ) , the Manchester Short Assessment of Quality of Life ( MANSA ) has been developed as a condensed and slightly modified instrument for assessing quality of life . Its properties have been tested in a sample of community care patients . Method Fifty-five r and omly selected patients on the Care Programme Approach were interviewed using the LQLP , the MANSA and the Brief Psychiatric Rating Scale . Results Correlations between subjective quality of life scores on MANSA and LQLP were all 0.83 or higher ( 0.94 for the satisfaction mean score ) . Cronbach 's alpha for satisfaction ratings was 0.74 , and association with psychopathology was in line with results for LQLP as reported in the literature . Conclusions The MANSA is a brief instrument for assessing quality of life focusing on satisfaction with life as a whole and with life domains . Its psychometric properties appear satisfactory OBJECTIVE To test the short and longterm benefits of an 8 week mind-body intervention that combined training in mindfulness meditation with Qigong movement therapy for individuals with fibromyalgia syndrome ( FM ) . METHODS A total of 128 individuals with FM were r and omly assigned to the mind-body training program or an education support group that served as the control . Outcome measures were pain , disability ( Fibromyalgia Impact Question naire ) , depression , myalgic score ( number and severity of tender points ) , 6 minute walk time , and coping strategies , which were assessed at baseline and at 8 , 16 , and 24 weeks . RESULTS Both groups registered statistically significant improvements across time for the Fibromyalgia Impact Question naire , Total Myalgic Score , Pain , and Depression , and no improvement in the number of feet traversed in the 6 minute walk . However , there was no difference in either the rate or magnitude of these changes between the mind-body training group and the education control group . Salutary changes occurring by the eighth week ( which corresponded to the end of the mind-body and education control group sessions ) were largely maintained by both groups throughout the 6 month followup period . CONCLUSION While both groups showed improvement on a number of outcome variables , there was no evidence that the multimodal mind-body intervention for FM was superior to education and support as a treatment option . Additional r and omized controlled trials are needed before interventions of this kind can be recommended for treatment of FM This study assessed the profiles of psychological health and changes in neurohormones of adolescents with mild depression after 12 weeks of dance movement therapy ( DMT ) . Forty middle school seniors ( mean age : 16 years old ) volunteered to participate in this study and were r and omly assigned into either a dance movement group ( n = 20 ) or a control group ( n = 20 ) . All subscale scores of psychological distress and global scores decreased significantly after the 12 weeks in the DMT group . Plasma serotonin concentration increased and dopamine concentration decreased in the DMT group . These results suggest that DMT may stabilize the sympathetic nervous system . In conclusion , DMT may be effective in beneficially modulating concentrations of serotonin and dopamine , and in improving psychological distress in adolescents with mild depression A myriad of previous studies from a variety of disciplines has shown several effects of music on mind and body . This study investigated the relationship between different categories of contemporary music ( n = 6 ) and the mood states of a group of students ( n = 12 ) , using the Profile of Mood States ( POMS ) , to measure mood before and after exposure to these different pieces of music . When analysed together , all six pieces of music produced an overall change in mood ( P = 0.008 ) as measured by 2-way repeated measures analysis of variance ( ANOVA ) . When each category was examined individually , four categories of music produced highly significant changes in mood : the tense category ( score -4.0 + /- 1.8 POMS Units ; P < 0.001 ) ; depressed category ( + 0.5 + /- 0.2 ; P < 0.001 ) ; angry category ( + 0.9 + /- 1.6 ; P < 0.03 ) ; and the all moods category ( 1.6 + /- 0.3 ; P < 0.04 ) . One piece of dance music produced changes in all mood categories , giving the largest positive mean mood change . By contrast , the popular/independent music , associated with the tense category , produced the largest negative mean mood change . The five POMS mood states were analysed separately for each piece of music . These findings are consistent with previous work . In addition , the finding of the effects of specific music categories on mood may have important implication s for therapy in mental health and mental health nursing The aims of the present study were : a ) to examine associations between pre-treatment BMI , body dissatisfaction , perfectionism , alexithymia , and restraint , emotional and external eating behaviour in obese patients ; b ) to analyze the impact of the pre-treatment measures in psychological variables on the outcome of cognitive-behavioral therapy ( CBT ) program ; c ) to test the effectiveness of rhythmic movement therapy ( RMT ) in the treatment of disordered eating behaviors and obesity with the CBT non-responders . At the first stage of treatment a total of 104 patients ( 32 males and 72 females , mean age was 37.6 + /- 6.7 years ) self-referred or referred by professionals to CBT weight management program were selected at r and om . At the second stage 58 obese CBT-non-responders were r and omly divided among the continuing CBT individual treatment group and RMT group . Control group was included . Results revealed that : a ) significant associations existed between pre-treatment BMI , external eating and two dimensions of perfectionism , as well as between emotional and external eating and all dimensions of perfectionism , alexithymia and body image dissatisfaction ; b ) pre-treatment means of psychological variables significantly impacted the CBT program outcome ; c ) . the efficacy of RMT approach for weight reduction as well as for the improvement of psychological status for CBT-non-responders was confirmed Objective : To investigate the feasibility , acceptability and potential efficacy of group exercise for residents in care homes . Design : Exploratory cluster r and omized controlled trial . Setting : Five r and omly selected care homes in South Birmingham , UK . Participants : Fifty-six care home residents ( mean age 84.5 , 71 % female ) , 39 ( 70 % ) with cognitive impairments . Intervention : Two homes ( n = 28 ) were r and omized to group exercise held twice weekly for five weeks . The remaining three homes ( n = 28 ) formed the control group and received usual care , with no person specifically responsible for exercise training . Outcome measures : Assessment s were conducted at zero ( pre-intervention ) , three ( post-intervention ) and six months ( follow-up ) using the Rivermead Mobility Index and Hospital Anxiety and Depression Scale or Stroke Aphasic Depression Question naire ( depending on cognitive impairment ) . Adherence to group exercise and retention to the study were also documented . Results : No statistically significant improvements in mobility or depression were found in favour of group exercise . Retention to the study was high with 46 ( 82 % ) participants completing all assessment s. Adherence to group exercise was somewhat lower with participants attending a mean of 3.61 out of 8.5 prescribed sessions ( 42.5 % ) . Conclusions : Group exercise can be delivered to care home residents with reduced mobility but it is not suitable for residents with severe cognitive impairment . An estimated sample size of 240 participants would be required to detect a clinical ly significant difference in the Rivermead Mobility Index with 90 % power OBJECTIVES To determine whether tango dancing is as effective as mindfulness meditation in reducing symptoms of psychological stress , anxiety and depression , and in promoting well-being . DESIGN This study employed analysis of covariance ( ANCOVA ) and multiple regression analysis . PARTICIPANTS Ninety-seven people with self-declared depression were r and omised into tango dance or mindfulness meditation classes , or to control/waiting-list . SETTING classes were conducted in a venue suitable for both activities in the metropolitan area of Sydney , Australia . INTERVENTIONS Participants completed six-week programmes ( 1½h/week of tango or meditation ) . The outcome measures were assessed at pre-test and post-test . MAIN OUTCOME MEASURES Depression , Anxiety and Stress Scale ; The Self Esteem Scale ; Satisfaction with Life Scale , and Mindful Attention Awareness Scale . RESULTS Sixty-six participants completed the program and were included in the statistical analysis . Depression levels were significantly reduced in the tango ( effect size d=0.50 , p=.010 ) , and meditation groups ( effect size d=0.54 , p=.025 ) , relative to waiting-list controls . Stress levels were significantly reduced only in the tango group ( effect size d=0.45 , p=.022 ) . Attending tango classes was a significant predictor for the increased levels of mindfulness R(2)=.10 , adjusted R(2)=.07 , F (2,59)=3.42 , p=.039 . CONCLUSION Mindfulness-meditation and tango dance could be effective complementary adjuncts for the treatment of depression and /or inclusion in stress management programmes . Subsequent trials are called to explore the therapeutic mechanisms involved OBJECTIVE To investigate whether dance intervention influenced self-rated health for adolescent girls with internalizing problems . DESIGN R and omized controlled intervention trial with follow-up measures at 8 , 12 , and 20 months after baseline . SETTING A Swedish city with a population of 130 000 . PARTICIPANTS Girls aged 13 to 18 years with internalizing problems , ie , stress and psychosomatic symptoms . A total of 59 girls were r and omized to the intervention group and 53 were r and omized to the control group . INTERVENTION The intervention comprised dance classes twice weekly during 8 months . Each dance class lasted 75 minutes and the focus was on the joy of movement , not on performance . MAIN OUTCOME MEASURES Self-rated health was the primary outcome ; secondary outcomes were adherence to and experience of the intervention . RESULTS The dance intervention group improved their self-rated health more than the control group at all follow-ups . At baseline , the mean score on a 5-point scale was 3.32 for the dance intervention group and 3.75 for the control group . The difference in mean change was 0.30 ( 95 % CI , -0.01 to 0.61 ) at 8 months , 0.62 ( 95 % CI , 0.25 to 0.99 ) at 12 months , and 0.40 ( 95 % CI , 0.04 to 0.77 ) at 20 months . Among the girls in the intervention group , 67 % had an attendance rate of 50 % to 100 % . A total of 91 % of the girls rated the dance intervention as a positive experience . CONCLUSIONS An 8-month dance intervention can improve self-rated health for adolescent girls with internalizing problems . The improvement remained a year after the intervention BACKGROUND Chronic major depressive disorder and dysthymia are associated with a high burden and substantial care costs . New and more effective treatments are required . This is the first r and omized controlled trial design ed to evaluate the effectiveness of Body Psychotherapy ( BPT ) in patients with chronic depression . METHODS Patients with chronic depressive syndromes ( more than 2 years symptomatic ) and a total score of ≥ 20 on the Hamilton Rating Scale for Depression ( HAMD ) were r and omly allocated to either immediate BPT or a waiting group which received BPT 12 weeks later . BPT was manualized , delivered in small groups in 20 sessions over a 10 weeks period , and provided in addition to treatment as usual . In an intention to treat analysis , primary outcome were depressive symptoms at the end of treatment adjusted for baseline symptom levels . Secondary outcomes were self-esteem and subjective quality of life . RESULTS Thirty-one patients were included and twenty-one received the intervention . At the end of treatment patients in the immediate BPT group had significantly lower depressive symptom scores than the waiting group ( mean difference 8.7 , 95 % confidence interval 1.0 - 16.7 ) . Secondary outcomes did not show statistically significant differences . When the scores of the waiting group before and after BPT ( as offered after the waiting period ) were also considered in the analysis , the differences with the initial waiting group remained significant . CONCLUSIONS The results suggest that BPT may be an effective treatment option for patients with chronic depression . Difficulty recruiting and subsequent attrition was one of the limitations , but the findings merit further trials with larger sample s and process studies to identify the precise therapeutic mechanisms The present study examined the changes of depressive symptoms and salivary cortisol responses in 36 out patients with major depression . These patients were r and omly assigned to receive combination therapy ( CT ) , consisting of antidepressants and body-mind-spirit group psychotherapy , or monotherapy ( MT ) , consisting of antidepressants only . The results indicated that CT and MT had similar effects on reducing depressive symptoms . Nevertheless , the results revealed that cortisol levels at night appeared to have a greater reduction in CT than in MT , indicating a downward trend in CT but an upward trend in MT . Moreover , a steeper diurnal pattern of cortisol — a larger deviation in cortisol levels between 30 and 45 minutes postwaking and evening — was more likely associated with CT than MT . The findings suggest that CT produced a protective effect on out patients with major depression , preventing the increased night salivary cortisol levels and the flatter diurnal cortisol pattern that tended to occur in MT

The established endothelial-erectile dysfunction connection was thoroughly revised , from basic mechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vascular disease .

INTRODUCTION The endothelial monolayer plays a crucial role in the vasodilation and hemodynamic events involved in erection physiology . Due to its relevant functions , a close link has been established between endothelial integrity and erectile dysfunction ( ED ) . Endothelial dysfunction is induced by the detrimental actions of vascular risk factors ( VRFs ) , identified as common correlates for the development of cardiovascular disease and ED . It is currently recognized that ED is the early harbinger of a more generalized vascular systemic disorder , and , therefore , an evaluation of endothelial health in ED patients should be of prime relevance . Several noninvasive methods for endothelial function assessment have been proposed , including the Penile Nitric Oxide Release Test ( PNORT ) . AIM To highlight the most recent gathered knowledge on basic and clinical mechanisms underlying loss of cavernosal endothelial function promoted by VRFs and to discuss local and systemic methods for endothelial function assessment in ED individuals , focusing on the PNORT . MAIN OUTCOME MEASURES A complete revision on the novel basic and clinical links between endothelial and ED . RESULTS Risk factor-associated cavernosal endothelial dysfunction is mostly induced by unifying mechanisms , including oxidative stress and impaired endothelial nitric oxide functional activities , which present clinical ly as ED .

Men with erectile dysfunction ( ED ) frequently have a disproportionate burden of comorbid vascular disorders including atherosclerotic disease . We investigated whether scheduled tadalafil is better than on-dem and ( OD ) in improving endothelium-dependent vasodilatation of cavernous arteries in men with ED and whether this effect is also exerted on markers of endothelial function . We did an open-label , r and omized , crossover study including 20 male outclinic patients aged 18 years or older ( mean age 54 years ) who had at least a 3-month history of ED of any severity or etiology . Tadalafil ( 20 mg ) on alternate days ( ADs ) or OD was administered for 4 weeks . Primary end points were variations of basal inflow ( peak systolic velocity ( PSV ) ) and flow-mediated dilatation ( FMD ) of cavernous arteries compared with baseline at penile Duplex ultrasound . Secondary end points were variations of Q13-SIEDY scores regarding morning erections and of markers of endothelial function , that is , vascular cell adhesion molecule ( VCAM ) , intercellular cell adhesion molecule , endothelin-1 ( ET-1 ) , insulin and C-reactive protein ( CRP ) . PSVs and FMD were higher after AD treatment when compared with OD and baseline , respectively ( P=0.0001 ) , and improvements were maintained from 2 weeks after discontinuation ( P<0.005 ) . Patients receiving tadalafil AD experienced a significant improvement of morning erections as compared to AD treatment ( P<0.0001 ) ; ET1 , VCAM and CRP showed a robust decrease after chronic vs OD regimes ( P<0.05 ) , with concomitant increase in insulin levels ( P<0.05 ) , without any variation in blood pressure and other laboratory parameters . Chronic but not OD tadalafil improves endothelial function with sustained effects from its discontinuation . Chronic treatment also produces a dramatic increase in morning erections , which determines better oxygenation to the penis , thus providing a rationale for vascular rehabilitation PURPOSE We determined the effects of intracavernosal injection ( ICI ) of recombinant basic fibroblast growth factor ( rbFGF ) on corporal tissue in hypercholesterolemic rabbits . METHODS Twenty New Zeal and White rabbits were fed a 1 % cholesterol diet for 6 weeks and were r and omly divided into four groups . Group 1 ( N = 5 ) received an ICI of phosphate buffered saline solution ( PBS ) once and again 3 weeks later . Group 2 ( N = 4 ) received an ICI of 2.5 microg rbFGF once and PBS 3 weeks later . Group 3 ( N = 6 ) received an ICI of 2.5 microg rbFGF once and again 3 weeks later . Group 4 ( N = 5 ) received an ICI of 2.5 microg rbFGF once . All animals were maintained on the high cholesterol diet until sacrifice , 3 weeks after last injection . Strips of corporal tissue were submaximally contracted with norepinephrine , and dose-response curves were generated to evaluate endothelial-dependent ( acetylcholine , ACH ) and endothelial-independent ( sodium nitroprusside , SNP ) vasoreactivity . Protein levels of bFGF and vascular endothelial growth factor ( VEGF ) were assessed by enzyme-linked immunosorbent assay . Neuronal nitric oxide synthase ( nNOS ) protein and mRNA were detected by Western blot and semi-quantitative polymerase chain reaction , respectively . RESULTS Vasoreactivity was improved by bFGF treatment as shown by higher ED50[-log(M ) ] of ACH and SNP in Groups 2 , 3 , and 4 . The expression of bFGF protein , VEGF protein , nNOS protein , and mRNA were all increased after bFGF treatment . CONCLUSIONS ICI of bFGF improved vasoreactivity in hypercholesterolemic rabbit corporal tissue , offering a new direction to explore for the treatment of erectile dysfunction Penile NO release test ( PNORT ) has been design ed to try to evaluate clinical ly the penile endothelial function ( PEF ) . The shear-stress flow-mediated vasodilation ( FMD ) of the cavernous arteries is evaluated in two groups of patients with neurogenic ( n=23 ) and vasculogenic ( n=23 ) erectile dysfunction ( ED ) by measuring their percent of increase after a 5 min occlusion of the flow . Both groups show an important FMD decrease ( 17.78±11.78 and 17.82±13 % ) as compared to the age-matched control group ( n=12 ) ( 65.14±30.5 % , P<0.001 ) . In the vasculogenic and control groups , mean FMD is lower in patients with one or more arterial risk factors(41 vs 67 % , P=0.025 ) , and show a positive correlation with the plasmatic levels of bioavailable testosterone ( r=0.37 , P=0.03 ) and of DHEA-S ( r=0.46 , P=0.014 ) . Patients achieving full erection at pharmacological test with visual sexual stimulation have a higher FMD ( 43.8±38 % ) than those who did not ( 18.52±14.37 % , P=0.008 ) . We confirm clinical ly that PEF is strongly impaired in organic ED linked to neurological , vascular and endocrine factors Circulating angiogenic cells ( CACs ) contribute to repair of the vessel wall and dysfunctional CACs are associated to endothelial dysfunction in men with vascular risk factors ( VRFs ) . We investigated whether inhibition of phosphodiesterase type 5 ( PDE5 ) in men with erectile dysfunction ( ED ) and VRFs is accompanied to changes of CACs and to changes of endothelial function . Thirty-six men with ED and VRFs were r and omised to 4 weeks of tadalafil ( 20mg/other day ) or placebo treatment . The number of ex vivo exp and ed functional CAC 's , identified by uptake of 1,1'-dioctadecyl-3 , 3,3 ' , 3'-tetramethylindocarbocyanine-labelled acetylated low-density lipoprotein ( DiLDL ) and concomitant Ulex europaeus agglutinin I ( UEA-1 ) binding , was determined at baseline and after treatment . The number of cells double positive for DiLDL and for UEA-1 , per high-power field fluorescence microscopy was significantly reduced in patients compared to 10 controls ( 26.88+/-6.3 and 74.41+/-17.1 , respectively ; P<0.0001 ) and was markedly increased after tadalafil treatment ( 40.69+/-13.07 versus 25.82+/-6.49 ; P<0.0001 ) . The percentage variation of CACs number and of flow-mediated dilation in the brachial artery by ultrasound after treatment was significantly associated to the presence of endothelial dysfunction at baseline . In conclusion , the increased number of functional CACs after tadalafil treatment suggests a beneficial effect of prolonged PDE5 inhibition on vascular homeostasis BACKGROUND The aim of this study was first to compare the widely used flow mediated dilation ( FMD ) method with the iontophoretically induced acetylcholine vasodilation ( IAV ) procedure . The ultimate goal was to examine the endothelial activity ( EA ) in patients with various cardiovascular risk factors compared with control subjects . PATIENTS AND METHODS In the upper extremities of 27 subjects , comparisons of EA by FMD and IAV measured with laser Doppler flux method ( LDF ) were conducted . IAV-EA was then measured using LDF in an additional 93 subjects with various cardiovascular ( CVD ) risk factors and /or a diagnosis of coronary heart disease ( CHD ) . RESULTS The mean age of the subjects was 56.2 years and 54 % were male . There was a robust and significant correlation between FMD vs IAV endothelial activity ( r = 0.87 , p = 0.025 ) . After adjustment for age , there were significant differences in LDF-measured , acetylcholine-induced EA by diagnosis of CHD ( p = 0.02 ) , hyperlipidemia ( p = 0.03 ) and diabetes ( p < 0.01 ) , as well as by sex ( p < 0.01 ) . The difference by hypertension status was of borderline significance ( p = 0.07 ) . LDF EA was higher in non-smokers compared to smokers but this difference was not statistically significant ( p = 0.3 ) . After adjustment for age and gender , a 10-unit increase in LDF-measured EA was associated with a 12 % lower odds for a diagnosis of CHD ( p = 0.07 ) . CONCLUSIONS Measurement of IAV-EA by LDF is a simple , noninvasive methodology which is highly correlated with post-occlusive FMD EA and is also significantly associated with a diagnosis of CHD INTRODUCTION There is considerable clinical and scientific evidence that endothelial dysfunction may be an important clinical link connecting erectile dysfunction ( ED ) with cardiovascular diseases . AIMS To modify the method of assessment of endothelial function of cavernosal arteries , to develop a new algorithm for evaluating its results , and to investigate the relationship between postocclusive changes in the diameter of brachial and cavernous arteries . METHODS The study participants were 212 patients presenting to our department complaining of ED and 40 healthy volunteers without sexual problems , which formed the control group . All patients with ED underwent complex evaluation and ultrasound assessment of postocclusive changes in the diameter of cavernosal arteries modified by us and st and ard ultrasound assessment of endothelium-dependent flow-mediated dilation of the brachial artery . MAIN OUTCOME MEASURES As the main outcome measure , the percent of increase of the cavernosal arteries diameter ( PICAD ) was recorded . RESULTS In the patients with arteriogenic ED , PICAD values were significantly less than in other groups ( P < 0.001 for pairs of comparison ) . At the same time there were no differences between the control group and groups of patients with psychogenic and organic nonarterial ED . The sensitivity and specificity of a PICAD value of 50 % in diagnosis of arteriogenic ED were 100 % and 98.2 % , respectively . In all groups and in the entire sample of patients studied we did not find a correlation between PICAD and postocclusive changes in the diameter of brachial arteries . CONCLUSION The method of ultrasound assessment of postocclusive changes in the diameter of cavernosal arteries is reliable and a highly informative tool for diagnosis of arteriogenic ED . It can not be substituted by technically simpler method of ultrasound examination of brachial arteries , while results of the latter could help to define the necessity of performing an examination of cavernous arteries INTRODUCTION Human postocclusive forearm skin reactive hyperemia is not only a potential means of identifying early signs of cardiovascular diseases , it can also be used in the assessment of local microvascular response to topically applied compounds on skin . The method is not fully characterized . In this study , we investigated the influence of occlusion time on postocclusive forearm skin reactive hyperemia using laser Doppler fluximetry ( LDF ) . METHODS Twenty healthy male volunteers were studied on three separate days ( at least 24 h apart ) via a r and omized design . Volunteers were studied in a supine position while fasted . Laser Doppler probes were placed on the volar surface of the antebrachium . In preliminary studies , 3 min of upper arm blood flow occlusion at suprasystolic pressure was found to be the upper limit of tolerability . Subsequently , volunteers were r and omized to receive 1 , 2 , or 3 min occlusion on 3 different days . Skin blood flux was measured before , during , and after occlusion using LDF . The primary outcome calculated was maximal change in skin blood flux before and after occlusion , expressed in arbitrary units ( AU ) . RESULTS Skin blood flux changes ( mean+/-S.E.M. ) after 1 , 2 , and 3 min occlusion period were 15.39+/-1.27 AU , 24.84+/-1.62 AU , and 32.14+/-1.73 AU , respectively . Using repeated- measures analysis of variance ( ANOVA ) , significant difference ( P<.05 ) in skin blood flux changes were revealed between these three occlusion duration s , where 3 min occlusion produced significantly greater in skin blood flux occlusion change compared to 1 and 2 min occlusion . DISCUSSION Three minutes of occlusion produces the greater postocclusive reactive hyperemia . It is recommended that studies using postocclusive forearm skin reactive hyperemia should occlude the forearm for at least 3 min PURPOSE We investigated changes in serum biomarkers of vascular function after short-term , continuous sildenafil dosing in men with type 2 diabetes with erectile dysfunction . MATERIAL S AND METHODS Men with erectile dysfunction associated with type 2 diabetes mellitus were r and omized to receive continuous , daily sildenafil ( 50 mg for 1 week run-in and 100 mg for 3 weeks ) ( 148 ) , or placebo ( 144 ) for 4 weeks ( phase I ) and then sildenafil ( 25 , 50 or 100 mg ) on dem and for 12 weeks ( phase II ) . Blood draws at baseline and after phases I and II were analyzed for cyclic guanosine monophosphate ( endothelial function marker ) , 8-isoprostane ( oxidative stress marker ) , and interleukin-6 and interleukin-8 ( inflammatory cytokines ) . Primary and secondary erectile function outcome variables were affirmative responses on Sexual Encounter Profile question 3 ( ability to maintain erection sufficient for sexual intercourse ) and Erection Hardness Score , respectively . RESULTS Serum cyclic guanosine monophosphate levels were increased in the sildenafil group relative to the placebo group at 4 ( p < 0.01 ) and 16 ( p < 0.05 ) weeks , correlating with affirmative responses to Sexual Encounter Profile question 3 at the 4-week interval only ( p < 0.05 ) . Serum 8-isoprostane levels were decreased to a nonsignificant degree in the sildenafil group at 4 weeks with no further change at 16 weeks , whereas interleukin-6 and interleukin-8 levels were unchanged at either interval , and these levels were unassociated with erectile function outcomes . CONCLUSIONS These data suggest that short-term , continuous sildenafil treatment causes systemic endothelial function to be enhanced and remain so for a duration after its discontinuation . However , they do not indicate any influence of this treatment on systemic oxidative stress or inflammation , or an effect on long-term erectile function improvement

The average HBV-DNA level before treatment was approximately 8 log10 copies/mL. Compared to the onset of antiviral intervention in the third trimester , the beginning of treatment in the second trimester distinctly reduced maternal predelivery HBV-DNA levels . However , no significant difference in HBV MTCT was found between the second and third trimester groups . Furthermore , the subgroup analysis showed that there were no significant differences between groups beginning treatment at different times ( second or third trimester ) with regard to HBV MTCT or other evaluated endpoints . For pregnant women with HBV-DNA levels less than or equal to 8 log10 copies/mL , the beginning of antiviral treatment can be delayed until the third trimester

For pregnant women with high viral load , antiviral therapy has been administered in addition to active and passive immune prophylaxis as a crucial adjunctive therapy to interrupt mother-to-child hepatitis B virus ( HBV ) transmission ( MTCT ) . However , the time of antiviral therapy onset remains controversial . A systematic review and meta- analysis was conducted to compare the efficacy of antiviral therapy during the second or the third trimester for prevention of HBV vertical transmission .

Background To evaluate the efficacy and safety of treating HBV-positive mothers with telbivudine in early and middle pregnancy to prevent mother-to-infant HBV transmission . Methods The subject population comprised pregnant women with chronic hepatitis B ( CHB ; n = 188 ) from January 2013 to June 2015 , with HBV DNA ≥1.0 × 107copies/mL and increased alanine aminotransferase levels . Groups A ( n = 62 ) and B ( n = 61 ) were treated with telbivudine starting at 12 weeks or 20–28 weeks after gestation , respectively . Telbivudine was discontinued at postpartum 12 weeks . Group C ( n = 65 ) received no antiviral . All infants were vaccinated with hepatitis B immunoglobulin ( 200 IU ) and HBV vaccine ( 20 with hepatitis B The maternal HBV DNA levels of the groups were compared . Mother-to-infant transmission of HBV was indicated by the presence of HBsAg in infants 7 months after birth . Results Before treatment , the HBV DNA levels of the 3 groups were similar . Before delivery and 12 weeks after delivery , the HBV DNA levels of groups A and B were similar , but both were significantly lower than that of group C ( P < 0.01 , all ) . No infants in groups A and B were HBsAg-positive , but the infection rate of group C was 18.4 % ( P < 0.01 ) . The HBV infection rate of infants was positively associated with the HBV DNA levels of the pregnant mothers . Conclusion Administration of telbivudine to HBV-infected mothers , started during early and middle pregnancy , completely blocked mother-to-infant HBV transmission . Trial registration The study was registered retrospectively on Janurary 25 in 2016 at Chinese Clinical Trial Registry ( ChiCTR-OPC-16007899 ) Infection of hepatitis B virus ( HBV ) occurs in ~10 % of infants of HBV-infected mothers with positive hepatitis B e antigen ( HBeAg ) after immunoprophylaxis . We aim ed to evaluate the safety and efficacy of telbivudine used during late pregnancy for preventing mother-to-child transmission of HBV . We conducted a multicenter prospect i ve cohort study in 5 hospitals from 2012 to 2014 , which enrolled HBV-infected singleton pregnant women with positive HBeAg . By their choice , women were divided into therapy ( telbivudine 600 mg/day , from gestation 28 - 32 weeks to 3 - 4 weeks postpartum ) and control ( no antiviral agent ) groups . Infants received passive-active immunoprophylaxis and follow-up at the age of 7 - 14 months . Totally , 328 pregnant women were included : 149 in the telbivudine group and 179 in the control group . Baseline HBV DNA levels were similar in the 2 groups ( 7.43 vs 7.37 log10 IU/mL , P = .711 ) . At delivery , HBV DNA levels in the telbivudine and control groups were 3.80 and 7.26 log10 IU/mL , respectively ( P < .0001 ) . Of the infants , 128 ( 85.9 % ) in the telbivudine group and 156 ( 87.2 % ) in the control group were followed up . No infant in the telbivudine group had chronic infection , while 2 ( 1.28 % ) infants in the control group did ( P = .503 ) . Three ( 2.34 % ) infants in the telbivudine group , but none in the control group , had severe congenital or developmental abnormalities ( P = .090 ) . The data indicate that telbivudine may block perinatal HBV transmission . However , larger studies are required to clarify whether anti-HBV therapy in pregnancy is associated with severe adverse effects in the foetuses and infants Telbivudine , an FDA pregnancy category B drug , has been found to reduce hepatitis B virus ( HBV ) perinatal transmission with no safety concerns in infants aged up to 1 year . This study evaluated the long-term efficacy and safety of telbivudine in 214 infants born to 210 pregnant women with chronic hepatitis B infection who were treated with telbivudine during pregnancy ( weeks 20 - 32 of gestation ) . The infants were followed for up to 5 years after birth . The efficacy endpoint was the rate of perinatal transmission , which was established by HBsAg and HBV DNA levels at 7 and 12 months . Safety endpoints included head circumference , weight , height , congenital abnormality and hospitalization rates . In addition , the Denver Developmental Screening Test was performed in 92 r and omly selected infants . None of the 214 infants born to these women were infected with HBV , and all had effective serum hepatitis B surface antibody ( HBsAb ) levels . Compared with Chinese st and ard values , there were few differences in the infants ' mean head circumference , weight , and height values . No birth defects were diagnosed , and the congenital abnormality rate was 0.934 % . Serious adverse events requiring hospitalization occurred in 20 infants ( 9.35 % ) . The qualified Denver Developmental Screening Test rate in 92 infants was 97.82 % , which was comparable to a rate of 92 % in normal Chinese children . Thus , treatment with telbivudine during the second or third trimesters of pregnancy safely blocked perinatal transmission of HBV . Infants born to telbivudine-treated mothers showed normal growth and development during long-term follow-up of up to 5 years BACKGROUND Few data are available regarding the use of tenofovir disoproxil fumarate ( TDF ) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus ( HBV ) . METHODS In this trial , we included 200 mothers who were positive for hepatitis B e antigen ( HBeAg ) and who had an HBV DNA level higher than 200,000 IU per milliliter . Participants were r and omly assigned , in a 1:1 ratio , to receive usual care without antiviral therapy or to receive TDF ( at an oral dose of 300 mg per day ) from 30 to 32 weeks of gestation until postpartum week 4 ; the participants were followed until postpartum week 28 . All the infants received immunoprophylaxis . The primary outcomes were the rates of mother-to-child transmission and birth defects . The secondary outcomes were the safety of TDF , the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery , and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28 . RESULTS At delivery , 68 % of the mothers in the TDF group ( 66 of 97 women ) , as compared with 2 % in the control group ( 2 of 100 ) , had an HBV DNA level of less than 200,000 IU per milliliter ( P<0.001 ) . At postpartum week 28 , the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group , both in the intention-to-treat analysis ( with transmission of virus to 5 % of the infants [ 5 of 97 ] vs. 18 % [ 18 of 100 ] , P=0.007 ) and the per- protocol analysis ( with transmission of virus to 0 vs. 7 % [ 6 of 88 ] , P=0.01 ) . The maternal and infant safety profiles were similar in the TDF group and the control group , including birth-defect rates ( 2 % [ 2 of 95 infants ] and 1 % [ 1 of 88 ] , respectively ; P=1.00 ) , although more mothers in the TDF group had an increase in the creatine kinase level . After the discontinuation of TDF , alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group ( 45 % [ 44 of 97 women ] vs. 30 % [ 30 of 100 ] , P=0.03 ) . The maternal HBV serologic outcomes did not differ significantly between the groups . CONCLUSIONS In a cohort of HBeAg-positive mothers with an HBV DNA level of more than 200,000 IU per milliliter during the third trimester , the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy . ( Funded by Gilead Sciences ; Clinical Trials.gov number , NCT01488526 . ) Women with chronic hepatitis B should maintain nucleotide analogue treatment to prevent disease progression during pregnancy . The aim of this study was to prospect ively evaluate the efficacy and safety of telbivudine used throughout pregnancy for preventing hepatitis B virus ( HBV ) mother-to-child transmission ( MTCT ) . From January 2012 to June 2014 , women who were receiving telbivudine therapy and became pregnant were enrolled in group A at 28 weeks of gestation . Pregnant women with an HBV DNA level > 106 IU/mL were enrolled in either group B ( telbivudine started at 28 weeks of gestation ) or group C ( control group without treatment ) . MTCT was defined as infants who were positive for serum hepatitis B surface antigen at 7 months after birth . There were 41 , 179 and 177 pregnant women ( 397 infants ) enrolled in groups A , B and C , respectively . The HBV DNA load at 28 weeks of gestation and delivery was 1.50 ± 0.62 vs 1.45 ± 0.61 , 8.05 ± 0.37 vs 4.24 ± 0.89 and 7.94 ± 0.62 vs 7.86 ± 0.73 log10 IU/mL in groups A , B and C , respectively . The rate of MTCT in group C was 4.60 % , which was significantly higher than the rates in groups A and B ( 0 % and 0.6 % , respectively ) ( P = .043 ) . The difference between group A and group B was not significant . The rates of neonatal congenital abnormalities were 2.4 % , 0.6 % and 2.3 % in groups A , B and C , respectively , and there were no significant differences ( P = .140 ) . Telbivudine used throughout pregnancy may be safe and effective for mothers and infants , but it may not enhance the efficacy of an HBV MTCT block compared with treatment starting at 28 weeks of gestation ( NCT02253485 ) BACKGROUND In China , women with chronic HBV infection and who are of childbearing age receive lamivudine at an early age . Thus , viral resistance becomes a challenge for intervention to prevent mother-to-infant transmission . We prospect ively assessed the efficacy of tenofovir in pregnant women with lamivudine-resistant HBV . METHODS Chronic HBV-infected mothers resistant to lamivudine were enrolled . Tenofovir was administrated at gestation weeks 24 or 28 . Virological and biochemical parameters were assessed . All infants received combined immunoprophylaxis and were followed for 1 year . RESULTS Of the 48 mothers enrolled , 21 started tenofovir therapy at gestation week 24 and 27 started at week 28 . Tenofovir result ed in an HBV DNA decline of 5.23 ± 1.68 log10 IU/ml at delivery . The group starting therapy at week 24 exhibited a more rapid viral inhibition ( P<0.001 ) and more significant HBV DNA load decline ( 5.89 ± 1.66 versus 4.72 ± 1.55 ; P=0.019 ) than the group starting at week 28 . At delivery , all mothers had a viral titre < 10(6 ) IU/ml , 76.2 % from the week 24 starting group displayed virus < 10(4 ) IU/ml , and 52.4 % showed undetectable virus at delivery , much higher than the week 28 starting group ( 29.6 % ) , although there was no statistically significant difference in viral levels at delivery between the two groups . Congenital abnormalities and neonatal growth were comparable to the normal population . No case of perinatal transmission was diagnosed . CONCLUSIONS This investigation clarifies the efficacy of tenofovir for reducing vertical transmission of HBV in mothers with lamivudine-resistant HBV and demonstrates that tenofovir is well-tolerated in the second and third trimesters This study sought to assess the antiviral efficacy of lamivudine ( LMV ) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance . A prospect i ve observational analysis was performed on 26 mothers with high viral load ( > 10⁷ IU/mL ) . Twenty-one women received LMV ( treated group ) for an average of 53 days ( range 22 - 88 days ) , and the remaining five formed the untreated control group . Serum sample s from two time points were used to measure HBV DNA levels and antiviral drug resistance . The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment ( EOT ) HBV DNA in four ( 18 % ) LMV-treated women remained at > 10(7 ) IU/mL ( ± 0.5 log IU/mL ) , no mother-to-baby transmission was observed . In contrast , a baby from the untreated mother was HBsAg positive at 9 months postpartum . Four technologies were used for drug resistance testing . Only ultra-deep pyrosequencing ( UDPS ) was sufficiently sensitive to detect minor viral variants down to < 1 % . UDPS showed that LMV therapy result ed in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance ( rtM204I/V and rtA181 T ) in four ( 19 % ) women . These viral variants were detected mostly at low frequencies ( 0.63 - 5.92 % ) at EOT , but one LMV-treated mother had an rtA181 T variant that increased from 2.2 % pretherapy to 25.59 % at EOT . This mother was also infected with the vaccine escape variant ( sG145R ) , which was inhibited by LMV treatment . LMV therapy during late pregnancy only reduced maternal viraemia moderately , and drug-resistant viral variants emerged We evaluated the efficacy and safety of telbivudine ( LdT , 600 mg/day ) vs control patients ( no treatment ) in decreasing vertical transmission of HBV , in HBeAg-positive mothers ( HBVDNA > 6log(10 ) copies/mL ) . HBeAg-positive pregnant women either in the second or third trimester were recruited in a prospect i ve , case-control , open-label study , at the Second Affiliated Hospital of the Southeast University , China ( February 2008-December 2010 ) . Efficacy ( month 7 : HBVDNA ( + ) , HBsAg ( + ) infants ) in either the overall group or the treated group and control group was analysed using student 's t-test . Infants were followed for at least 1 year . 362 women received LdT ( second trimester n = 257 ; third trimester n = 105 ) and 92 were untreated . Before delivery , the mean maternal HBVDNA was 2.73 , 2.47 , 3.34 and 7.94 log10 copies/mL in the overall , second and third trimester treated and control groups , respectively ( P < 0.001 ) . At birth , 11.8 % of babies overall ( 43/365 ) , 13.5 % ( 35/259 ) of those treated in the second trimester , 7.5 % of those treated in the third trimester ( 8/106 ) and 20.7 % ( 19/92 ) of untreated infants were HBsAg positive . At month 7 , none of the LdT-treated infant had detectable HBVDNA , while eight infants from control mothers were HBsAg positive . Vertical transmission was 0 % in LdT treated and 9.3 % ( 8/86 ) in the control groups ( P < 0.001 ) . No difference in the vertical transmission rate was found in mothers treated in the second or third trimester . LdT treatment was safe for mothers and infants , and no congenital deformities were reported Hepatitis B immunoprophylaxis failure is linked to high maternal viraemia . There is limited North American data on hepatitis B outcomes in pregnancy . Pregnant hepatitis B carriers were enrolled January 2011-December 2014 and offered tenofovir in the 3rd trimester if hepatitis B virus (HBV)-DNA was > 7-log IU/mL. Outcomes were determined in treated vs untreated patients . In total , 161 women with 169 pregnancies ( one twin , 170 infants ; median age 32 years ) , 18 % ( 29/161 ) HBeAg+ and median HBV-DNA 2.51 log IU/mL ( IQR 1.66 - 3.65 ; range 0.8 - 8.1 ) were studied . 14.3 % ( 23/161 ) received tenofovir due to high viral load ( 16/23 , median 74 days , IQR 59 - 110 ) or due to liver disease ( 7/23 ) . In 10/16 treated due to high viraemia , with confirmed adherence , follow-up HBV-DNA showed a 5.49 log decline ( P = 0.003 ) . In treatment naïve mothers , median alanine aminotransferase ( ALT ) increased from 17 IU/L ( IQR 12 - 24 ) to 29 ( IQR 18 - 36 ) post-partum ( P = 1.5e-7 ) . In seven highly viraemic mothers who declined therapy ( HBV-DNA > 8-log IU/mL ) ; median ALT increased ~3X from baseline ( P < 0.01 ) . 26 % ( 44/169 ) had Caesarean section with no difference in treated vs untreated subjects . No tenofovir-treated mothers had renal dysfunction . Data were available on 167/170 infants ; in 50.8 % ( 85/167 ) who completed immunoprophylaxis , 98.8 % ( 84/85 , including 12 exposed to tenofovir in utero ) were HBV immune . One infant born to an HBeAg+ mother with HBV-DNA > 8-log IU/mL failed immunoprophylaxis . In this prospect i ve Canadian cohort study , most untreated mothers experienced mild HBV flares . Tenofovir in pregnancy is well tolerated and reduces viral load prior to parturition The efficacy and safety of maternal tenofovir disoproxil fumarate ( TDF ) in reducing mother‐to‐infant hepatitis B virus ( HBV ) transmissions is not clearly understood . We conducted a prospect i ve , multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen – positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication ( control group , n = 56 , HBV DNA 8.22 ± 0.39 log10 IU/mL ) or TDF 300 mg daily ( TDF group , n = 62 , HBV DNA 8.18 ± 0.47 log10 IU/mL ) from 30‐32 weeks of gestation until 1 month postpartum . Primary outcome was infant HBsAg at 6 months old . At delivery , the TDF group had lower maternal HBV DNA levels ( 4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL , P < 0.0001 ) . Of the 121/123 newborns , the TDF group had lower rates of HBV DNA positivity at birth ( 6.15 % versus 31.48 % , P = 0.0003 ) and HBsAg positivity at 6 months old ( 1.54 % versus 10.71 % , P = 0.0481 ) . Multivariate analysis revealed that the TDF group had lower risk ( odds ratio = 0.10 , P = 0.0434 ) and amniocentesis was associated with higher risk ( odds ratio 6.82 , P = 0.0220 ) of infant HBsAg positivity . The TDF group had less incidence of maternal alanine aminotransferase ( ALT ) levels above two times the upper limit of normal for ≥3 months ( 3.23 % versus 14.29 % , P = 0.0455 ) , a lesser extent of postpartum elevations of ALT ( P = 0.007 ) , and a lower rate of ALT over five times the upper limit of normal ( 1.64 % versus 14.29 % , P = 0.0135 ) at 2 months postpartum . Maternal creatinine and creatinine kinase levels , rates of congenital anomaly , premature birth , and growth parameters in infants were comparable in both groups . At 12 months , one TDF‐group child newly developed HBsAg positivity , presumably due to postnatal infection and inefficient humoral responses to vaccines . Conclusions : Treatment with TDF for highly viremic mothers decreased infant HBV DNA at birth and infant HBsAg positivity at 6 months and ameliorated maternal ALT elevations . ( Hepatology BACKGROUND & AIMS Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9 % of children from highly viraemic mothers . Antiviral therapy in this setting has been suggested , however with limited evidence to direct agent choice . METHODS We conducted a multi-centre , prospect i ve , opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load ( > 7 log IU/ml ) ; lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate ( TDF ) from late 2010 . Outcomes of treated and untreated cohorts were compared . RESULTS 120 women with 130 pregnancies used TDF ( 58 ) , lamivudine ( 52 including four who switched due to TDF intolerance ) and no therapy ( 20 ) . 96 % were HBeAg positive , with baseline viral load mean 7.8 log IU/ml ( ±0.72 ) and ALT median 25 U/L ( 18.75 - 33 ) . Duration of antiviral theraphy before birth was mean 58 days ( ±19 ) TDF and 53 ( ±14 ) lamivudine . Viral load declined by 3.64 log IU/ml ( ±0.9 ) TDF and 2.81 log IU/ml ( ±1.33 ) lamivudine . Virologic failure ( birth viral load > 7 IU/ml ) occurred in 3 % and 18 % respectively . Congenital abnormality rate and neonatal growth centiles were similar across cohorts . Perinatal transmission reduced significantly to 2 % and 0 % in TDF and lamivudine cohorts , compared with 20 % in untreated . CONCLUSIONS TDF in this setting is safe , effective and more potent than lamivudine . Antiviral therapy did not adversely impact obstetric or infant parameters . More TDF intolerance occurred than expected . Perinatal transmission was significantly reduced in antiviral therapy cohorts

There were mixed results for dietary interventions affecting growth and diarrhea outcomes in the post-acute period .

Background Although acute diarrhea often leads to acute dehydration and electrolyte imbalance , children with diarrhea also suffer long term morbidity , including recurrent or prolonged diarrhea , loss of weight , and linear growth faltering . They are also at increased risk of post-acute mortality . The objective of this systematic review was to identify interventions that address these longer term consequences of diarrhea . Conclusion Despite the significant post-acute mortality and morbidity associated with diarrheal episodes , there is sparse evidence evaluating the effects of interventions to decrease these sequelae .

Glutamine has been demonstrated to be an important source of fuel for the gut . The purpose of this study was to evaluate the effect of glutamine-supplemented hyperalimentation on gut immune function . Thirty-six female Fischer rats were r and omized into three groups : group 1 ( chow ) was fed rat chow and water ad libitum , group 2 ( total parenteral nutrition ) received a st and ard hyperalimentation formula , and group 3 ( total parenteral nutrition-glutamine ) received a hyperalimentation solution that contained 2 % glutamine . Animals were maintained on their respective diets for 2 weeks and then killed . Mesenteric lymph nodes were harvested for culture , bile was assayed for secretory IgA , and bowel was excised to assay bacterial adherence . Results indicated that glutamine-supplemented total parenteral nutrition protects against bacterial translocation from the gut seen with st and ard formulas . This effect may be mediated by the secretory IgA immune system A r and omized clinical trial was carried out to compare a packaged ready‐to‐mix rice oral rehydration solution ( ORS ) to the st and ard glucose ORS for the treatment of childhood diarrhoea . Children were of either gender , aged 3–35 months , presenting with a history of watery diarrhoea for 72 h or less . The main outcomes examined were stool output , ORS intake , duration of diarrhoea and nutritional recovery during follow‐up at 16 d of illness . Stool output in the first 24 h ( 106 vs 107 g kg‐1 ) , ORS intake in clinic ( 93 vs 102 ml per motion ) and duration of diarrhoea ( 88 h vs 81 h ) were similar in the two treatment groups . The few episodes that became persistent were similar ( 2 % ) in the two groups . The weight gain during follow‐up was similar in the two ORS groups Twenty male infants less than 1 year of age with acute diarrhea and dehydration were r and omly assigned to a study group and studied in blind fashion in a metabolic unit to assess the efficacy of the addition of 30 mmol/L alanine to the st and ard World Health Organization ( WHO ) oral rehydration solution ( ORS ) . Patients were exclusively rehydrated with one of two types of ORS during the first 24 hours of treatment . On the second day , oral feedings were started with a lactose-free formula , and ORS was given to replace stool losses . Body weight , ORS , food intake , vomitus , stool , and urine output were recorded at 6-hour intervals . Blood was drawn at the time of admission , after rehydration , and at 24 and 48 hours of hospitalization to monitor blood gases and electrolytes . Rehydration was satisfactory in both groups of patients . ORS that contained alanine did not reduce the purging rates of the infants compared with those who received st and ard ORS . Clinical ly no adverse effect of the alanine-based ORS was observed during hospitalization . None of the patients had significant hypernatremia or hyponatremia , and serum amino acid levels were not altered . These data show that the addition of 30 mmol/L alanine to the st and ard WHO-ORS produces no further improvement in the outcome of the infants with acute diarrhea compared with those fed the st and ard WHO-ORS In a double‐blind r and omized controlled clinical trial , moderately malnourished Bangladeshi children ( 61–75 % of the median weight/age ) were studied for the effect of zinc and /or vitamin A supplementation on the clinical outcome of persistent diarrhea . Children 6 mo to 2 y of age with diarrhea for more than 14 d were r and omly allocated into 4 groups of 24 receiving a multivitamin syrup and ( i ) zinc ( 20 mg elemental ) , ( ii ) vitamin A , ( iii ) both zinc and vitamin A , or ( iv ) neither , in 2 doses daily for 7 d. Clinical data on recovery and on stool output , consistency and frequency were recorded for 7 d , and weight change from day 1 to day 7 was assessed . The baseline characteristics of the four study groups were comparable . The mean daily stool outputs from days 2 to 7 of therapy were significantly less in the zinc and zinc plus vitamin A groups , but not in the vitamin A group , in comparison with the control group . In children receiving zinc , the cumulative stool weight in the 7 d was 39 % less than in the control group ( p < 0.001 ) and 32 % less than in the vitamin A group ( p= 0.006 ) . The cumulative stool weight in the zinc plus vitamin A group was 24 % less than in the control group ( p < 0.001 ) , but the 14 % lower output than in the vitamin A group was not statistically different The change in body weight over the 7d study period was significantly different between the group receiving zinc and the control group ( + 111 g vs –90 g , p = 0.045 ) . The rate of clinical recovery of children within 7 d was significantly greater in the zinc group ( 88 % ) compared with the control group ( 46 % , p= 0.002 ) or vitamin A group ( 50 % , p= 0 005 ) , but not statistically different from the zinc plus vitamin A group ( 67 % , p= 0.086 ) BACKGROUND Probiotics have a possible role in the treatment of pediatric acute gastroenteritis . We report the effect of the probiotic Lactobacillus rhamnosus GG ( LGG ) on intestinal function , immune response , and clinical outcomes in Indian children with cryptosporidial or rotavirus diarrhea . METHODS Children with gastroenteritis aged 6 months to 5 years , testing positive for either rotavirus or Cryptosporidium species in stool ( coinfections were excluded ) , were r and omized to LGG ( ATCC 53103 ) or placebo , once daily for 4 weeks . Baseline demographic and clinical details were obtained . Sera were tested for immunoglobulin G ( IgG ) and immunoglobulin A ( IgA ) antibodies to Cryptosporidium and rotavirus , and the lactulose to mannitol ratio for intestinal permeability was determined at baseline and at the end of follow-up . RESULTS Of the 124 children enrolled , 82 and 42 had rotavirus and cryptosporidial diarrhea , respectively . Median diarrheal duration was 4 days ; one-third of the children had severe diarrhea . Baseline and clinical parameters were comparable between children receiving LGG and placebo . At the end of follow-up , fewer children with rotavirus diarrhea on LGG had repeated diarrheal episodes ( 25 % vs 46 % ; P = .048 ) and impaired intestinal function ( 48 % vs 72 % ; P = .027 ) . Significant increase in IgG levels postintervention ( 456 vs 2215 EU ; P = .003 ) was observed in children with rotavirus diarrhea receiving LGG . Among children with cryptosporidial diarrhea , those receiving LGG showed significant improvement in intestinal permeability . CONCLUSIONS LGG has a positive immunomodulatory effect and may be useful in decreasing repeated episodes of rotavirus diarrhea . Improvement in intestinal function in children with rotavirus and cryptosporidial gastroenteritis emphasizes the role of probiotics in treating intestinal impairment after infection . CLINICAL TRIALS REGISTRATION CTRI/2010/091/000339 Introduction Diarrhoeal disease is the second-leading cause of death in young children . Current guidelines recommend treating children with acute non-bloody diarrhea with oral rehydration solutions and zinc , but not antimicrobials . However , in many re source -limited setting s , infections with treatable enteric bacterial and protozoan pathogens are common . Probiotics have shown promise as an adjunct treatment for diarrhoea but have not been studied in sub-Saharan Africa . Methods We conducted a pilot , factorial , r and omized , placebo-controlled trial of children aged 2–60 months hospitalized in Botswana for acute non-bloody diarrhoea . A rapid test- and -treat intervention , consisting of multiplex PCR testing of rectal swabs taken at enrolment , accompanied by targeted antimicrobial therapy if treatable pathogens were detected , was compared to the reference st and ard of no stool testing . Additionally , Lactobacillus reuteri DSM 17938 x 60 days was compared to placebo treatment . The main objective of this pilot study was to assess feasibility . The primary clinical outcome was the increase in age-st and ardized height ( HAZ ) at 60 days adjusted for baseline HAZ . Results Seventy-six patients were enrolled over a seven-month study period . We judged that the recruitment rate , lab processing times , communication protocol s , provision of specific antimicrobials , and follow-up rates were acceptable . Compared to the reference arm ( no stool testing and placebo treatment ) , the combination of the rapid test- and -treat strategy plus L. reuteri DSM 17938 was associated with an increase of 0.61 HAZ ( 95 % CI 0.09–1.13 ) and 93 % lower odds of recurrent diarrhoea ( OR 0.07 , 95%CI 0.01–0.61 ) at 60 days . Discussion We demonstrated that it was feasible to evaluate the study interventions in Botswana . Despite the small sample size , we observed a statistically significant increase in HAZ at 60 days and significantly lower odds of recurrent diarrhoea in children receiving both rapid test- and -treat and L. reuteri . There is sufficient evidence to warrant proceeding with a larger follow-up trial in a similar setting BACKGROUND Uncontrolled hospital-based studies in developing countries have reported promising results of dietary rehabilitation of children with persistent diarrhea . OBJECTIVE The objective was to determine the immediate and long-term effects of a dietary supplement and micronutrients given to children with persistent diarrhea during the episode and for 1 wk during convalescence . DESIGN The study was open , controlled , and community-based and was conducted in a periurban area in Guinea-BISSAU : Children <3 y of age with persistent diarrhea were identified during weekly household visits . The children r and omly assigned to the treatment and control groups were examined by a physician and all medical conditions were treated . The children in the treatment group were offered home-based dietary treatment consisting of locally available foods and micronutrient supplements . RESULTS There were 141 episodes of persistent diarrhea during the study : 70 in the treatment group ( in 58 children ) and 71 in the control group ( in 62 children ) . During the intervention period ( median : 17 d ) , weight gain in the treatment group exceeded that of the control group by 61.5 g/wk ( 95 % CI : 49.2 , 73.8 ) , whereas there was no significant difference in linear growth on the basis of knee-heel length . At a median follow-up period of 6.6 mo after the intervention was stopped , weight gain in the treatment group exceeded that of the control group by 12.5 g/wk ( 95 % CI : 7.7 , 17.3 ) ; knee-heel length was 7.5 mm/y ( 4.8 , 10.2 ) greater and total length was 0.65 cm/y ( 0.11 , 1.19 ) greater in the treatment group . CONCLUSION Therapeutic feeding and micronutrient supplementation had an immediate and sustained beneficial effect on growth in children with persistent diarrhea In a controlled clinical trial , we examined the effect of the short-term feeding of an energy-dense milk cereal formula in malnourished children with clinical ly severe dysentery due to acute shigellosis . Seventy-five malnourished children , aged 12 - 48 mo , passing blood or blood with mucous in the stool for < or = 96 h , were offered a hospital diet . In addition , study children ( n = 36 ) were offered a milk-cereal formula with an energy of 5 kJ/g ( an 11 % protein diet ) ; similarly , control children ( n = 39 ) were offered a milk-cereal formula with an energy content of 2.5 kJ/g ( an 11 % protein diet ) . Patients were admitted to the metabolic ward of the Clinical Research and Service Centre , Dhaka , at the International Centre for Diarrhoeal Disease Research , Bangladesh . Patients were studied for 10 hospital days and were then followed up at home after 30 d. After 10 d of dietary intervention , children in the study group had a significantly greater increase vs. controls in weight-for-age ( 6 vs. 3 % , P < 0.001 ) and in weight-for-height ( 7 vs. 3 % , P < 0.001 ) . Serum prealbumin concentrations were significantly higher ( study vs. control ) after 5 d ( 0.214 vs. 0.170 g/L , P = 0.01 ) and after 10 d ( 0.244 vs. 0.193 g/L , P = 0.006 ) of the study . Greater weight-for-age was sustained at home 1 mo after discharge ( 8 vs. 5 % , P = 0.005 ) from the hospital . Similarly , higher weight-for-height was sustained 1 mo after discharge ( 8 vs. 5 % , P = 0.01 ) . During their stay at home , there was no dietary intervention . The results of this study suggest that short-term feeding of an energy-dense diet enhances growth in malnourished children with acute dysentery due to shigellosis Research has shown that the positive effect of nutritional supplementation on child growth in malnourished population s is small relative to the large negative effect of diarrheal disease . To test the hypothesis that the effects of supplementation and diarrhea are synergistic in that supplementation modifies the negative effect of diarrhea on linear growth , length and diarrheal morbidity were compared at 36 mo of age for two cohorts of Colombian children : supplemented from birth and unsupplemented . Among unsupplemented children diarrhea was negatively associated with length . Among supplemented children diarrhea had no effect on length and differed from that of unsupplemented children . Thus , supplementation completely offset the negative effect of diarrheal disease on length . Targeting supplementation programs to the critical period of high diarrheal prevalence among infants and young children should increase the effectiveness of such programs in preventing growth retardation associated with diarrhea The impact of dietary supplementation on catch-up growth was evaluated in 69 malnourished children ages 24 - 60 mo after recovery from shigellosis . They were fed either a high-protein ( HP ) diet with 15 % of energy as protein , or a st and ard-protein ( SP ) diet with 7.5 % energy as protein , for 3 wk in a metabolic study ward . Children were followed up bi-weekly for 6 mo by trained health assistants when anthropometric measurements and information of any illness were collected . Thirty-one children in the HP group and 28 children in the SP group completed 6-mo follow-up . The increase in height ( mean + /- SD ) was 5.3 + /- 1.0 cm vs. 4.1 + /- 1.1 cm for HP and SP groups , respectively ( P < 0.001 ) , whereas increase in body weight was 1.39 + /- 0.58 and 1.29 + /- 0.72 kg for children fed HP and SP , respectively ( P = 0.59 ) . The proportion of children who were severely stunted ( < -2 SD height-for-age ) decreased from 45 to 29 % in the HP group compared to 50 to 46 % in the SP group ( P < 0.05 ) at 6-mo follow-up . The number of diarrheal episodes per child tended to be lower in the HP vs. SP than in the SP group ( 1.9 vs. 2.3 , P = 0.41 ) . These results demonstrate that feeding an HP diet to the malnourished children during recovery from shigellosis enhanced linear growth with a modest reduction in diarrheal morbidity during the 6-mo follow-up period BACKGROUND Preventing illness and improving growth in the first 6 mo of life is critical to reducing infant mortality . Zinc given for 14 d at the start of diarrhea has been shown to decrease the incidence and prevalence of diarrhea and pneumonia and improve growth in the 2 - 3 mo after , but no trial has been done in infants < 6 mo of age . OBJECTIVE This study sought to assess the effect of 14 d of zinc supplementation on subsequent morbidity and growth among infants 1 - 5 mo of age living in Pakistan , India , and Ethiopia . DESIGN Infants with acute diarrhea were r and omly assigned to receive zinc ( 10 mg/d ; n = 538 ) or placebo ( n = 536 ) for 2 wk . Weekly follow-up visits were conducted for 8 wk after the diarrhea episode . Incidence and prevalence of diarrhea and prevalence of respiratory infections including pneumonia were compared between the groups . Changes in weight , length , and corresponding z scores during the 8 wk of follow-up were also compared . RESULTS One thous and seventy-four infants were enrolled at the start of follow-up . The groups did not differ significantly in the proportion of infants with at least one episode of diarrhea or respiratory infections . Infants who received zinc had more days of diarrhea ( rate ratio = 1.20 ) than did the infants who received placebo . The groups had similar prevalences of pneumonia and overall respiratory infections . No significant differences in the mean changes in weight-for-age , length-for-age , and weight-for-length z scores were observed between the groups overall or in stratified analyses . CONCLUSION Young infants do not appear to benefit from 2 wk of zinc , unlike what has been observed among older children In a r and omized , double-blind , placebo-controlled trial , 229 infants hospitalized for acute diarrhea in rural India were given a 10-day course of Lactobacillus rhammosus GG ( minimum dose , 10 degrees bacteria ) or placebo . There was no difference in groups in the duration of diarrhea or numbers of stool on days 3 , 6 , or 10 of treatment A r and omized double-blind placebo-controlled study was conducted in children admitted to hospital with gastroenteritis ( ≥3 loose stools per day ) . All were treated for 5 days following admission with either zinc ( Zn , 3 mg ) or without Zn-fortified rice-based oral rehydration solution ( ORS ) . 13C-sucrose breath test ( SBT ) and intestinal permeability ( lactulose/rhamnose or L/R ratio ) were performed concurrently prior to commencement of ORS with or without Zn and at day 5 post-admission . There was a significant improvement in the SBT results in both the Zn-fortified group , median ( 5th-95th percentile ) 2.1 % ( 0.4 % to 8.3 % ) versus 4.4 % ( 0.4 % to 10.4 % ) , P < .05 , and control group , 1.4 % ( 0.1 % to 5.4 % ) versus 4.3 % ( 0.4 % to 11.4 % ) , P < .05 , between the day of admission and day 5 post-admission . In the Zn-fortified group , there was also a significant improvement in L/R ratio between the day of admission and day 5 post-admission , 53.0 ( 19.5 - 90.6 ) versus 17.7 ( 13.4 - 83.2 ) , P < .05 . Low levels of Zn improved intestinal permeability but did not enhance short-term recovery following diarrheal illness Recent studies have indicated that enteral diets can play an important role in the treatment of persistent diarrhea . Khitchri , a local weaning food in Pakistan , is composed of rice and lentils , which have previously been shown to be well tolerated in many children with acute diarrhea . The effectiveness of a khitchri and yogurt ( KY ) diet , which is inexpensive and widely available in Pakistan , was studied . One hundred two weaned boys ( 6 to 36 months old ) with persistent diarrhea were r and omly assigned to receive either soy formula ( group A ) or the KY diet ( group B ) for 14 days . Group A also received the KY diet in addition to formula for days 8 through 14 . Twenty-nine children did not complete the study because of severe infection ( 13 ) or their family 's decision to leave the study early ( 9 in group A and 7 in group B ) . Sixty-six children successfully completed the study protocol ; there were five clinical failures in group A and two in group B. On a comparable caloric intake , there was a significantly lower stool volume ( group B : 38 + /- 16 [ mean + /- SD ] vs group A : 64 + /- 75 g/kg per day , P less than .05 ) and frequency ( B : 4.4 + /- 2.0 vs. A : 6.6 + /- 4.2 stools per day , P less than .005 ) in children fed KY during the first week of therapy . Group B children also had a significantly greater weight gain than children in group A during the first week ( B : 468 + /- 373 g/wk vs A : 68 + /- 286 g/wk , P less than .005 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The effect of zinc supplementation on intestinal permeability changes and protein loss was studied in 32 children aged between 1 and 12 years during bouts of acute shigellosis and after recovery . An intestinal permeability test and then a 48 hour balance study were performed on all patients . They were then blindly assigned to receive vitamin B syrup either with or without zinc acetate ( 15 mg/kg per day ) for a month . All patients received a five day course of nalidixic acid . The balance study was repeated during convalescence and follow up , but a permeability test was done only at follow up after one month . Intestinal permeability , expressed as a urinary lactulose : mannitol excretion ratio , improved significantly ( p = 0.001 ) along with a significant increase ( p = 0.005 ) in mannitol excretion in the zinc supplemented children , suggesting a resolution of small bowel mucosal damage . The latter was associated with a higher coefficient of nitrogen absorption ( p = 0.03 ) , suggesting a possible role of zinc in the treatment of shigellosis . Enteric protein loss , as assessed by faecal alpha 1 antitrypsin clearance , was not influenced by zinc supplementation Objective : Glutamine is an important fuel for rapidly dividing cells such as enterocytes and lymphocytes . Exogenous glutamine supplementation in catabolic states preserves intestinal mucosal structure and function , decreases bacterial translocation , and supports normal immunologic responses . This study was planned to assess the effect of glutamine supplementation on duration and severity of diarrhea and to assess its immunomodulatory effect by measuring serum interleukin-8 ( IL-8 ) and salivary immunoglobulin A ( sIgA ) in children with acute diarrhea . Methods : In this placebo-controlled , double-blind and r and omized trial , 6- to 24-month-old otherwise healthy children admitted to the Diarrheal Diseases Training and Treatment Center with acute diarrhea received either 0.3 g/kg/day of glutamine ( n = 63 ) or placebo ( n = 65 ) for 7 days . Serum IL-8 and sIgA levels were determined on admission and 7 days later . All cases were followed until the diarrheal episode ended . Anthropometric measurements and history of subsequent infectious diseases were monitored monthly for 3 months after treatment . Results : Mean duration of diarrhea in the glutamine treated group was significantly shorter than that of the placebo group ( 3.40 ± 1.96 days , 4.57 ± 2.48 days , respectively ; P = 0.004 ) . No differences in serum IL-8 and sIgA were found between groups on admission or 1 week later . During 3 month follow-up , mean weight gain and incidence of infectious diseases were similar in both groups . Conclusion : Duration of diarrhea was shorter in children supplemented with glutamine . The beneficial impact of glutamine supplementation seems to be through effects on gastrointestinal mucosa rather than the host immune response Background Globally , Médecins Sans Frontières ( MSF ) treats more than 300,000 severely malnourished children annually . Malnutrition is not only caused by lack of food but also by illnesses and by poor infant and child feeding practice s. Breaking the vicious cycle of illness and malnutrition by providing ill children with nutritional supplementation is a potentially powerful strategy for preventing malnutrition that has not been adequately investigated . Therefore , MSF investigated whether incidence of malnutrition among ill children < 5 y old could be reduced by providing a fortified food product or micronutrients during their 2-wk convalescence period . Two trials , one in Nigeria and one in Ug and a , were conducted ; here , we report on the trial that took place in Kaabong , a poor agropastoral region of Karamoja , in east Ug and a. While the region of Karamoja shows an acute malnutrition rate between 8.4 % and 11.5 % of which 2 % to 3 % severe malnutrition , more than half ( 58 % ) of the population in the district of Kaabong is considered food insecure . Methods and Findings We investigated the effect of two types of nutritional supplementation on the incidence of malnutrition in ill children presenting at outpatient clinics during March 2011 to April 2012 in Kaabong , Karamoja region , Ug and a , a re source -poor region where malnutrition is a chronic problem for its seminomadic population . A three-armed , partially-blinded , r and omised controlled trial was conducted in children diagnosed with malaria , diarrhoea , or lower respiratory tract infection . Non-malnourished children aged 6 to 59 mo were r and omised to one of three arms : one sachet/d of ready-to-use therapeutic food ( RUTF ) , two sachets/d of micronutrient powder ( MNP ) , or no supplement ( control ) for 14 d for each illness over 6 mo . The primary outcome was the incidence of first negative nutritional outcome ( NNO ) during the 6 mo follow-up . NNO was a study -specific measure used to indicate progression to moderate or severe acute malnutrition ; it was defined as weight-for-height z-score < −2 , mid-upper arm circumference ( MUAC ) < 115 mm , or oedema , whichever came first . Of the 2,202 r and omised participants , 51.2 % were girls , and the mean age was 25.2 ( ±13.8 ) mo ; 148 ( 6.7 % ) participants were lost to follow-up , 9 ( 0.4 % ) died , and 14 ( 0.6 % ) were admitted to hospital . The incidence rates of NNO ( first event/year ) for the RUTF , MNP , and control groups were 0.143 ( 95 % confidence interval [ CI ] , 0.107–0.191 ) , 0.185 ( 0.141–0.239 ) , and 0.213 ( 0.167–0.272 ) , respectively . The incidence rate ratio was 0.67 ( 95 % CI , 0.46–0.98 ; p = 0.037 ) for RUTF versus control ; a reduction of 33.3 % . The incidence rate ratio was 0.86 ( 0.61–1.23 ; p = 0.413 ) for MNP versus control and 0.77 for RUTF versus MNP ( 95 % CI 0.52–1.15 ; p = 0.200 ) . The average numbers of study illnesses for the RUTF , MNP , and control groups were 2.3 ( 95 % CI , 2.2–2.4 ) , 2.1 ( 2.0–2.3 ) , and 2.3 ( 2.2–2.5 ) . The proportions of children who died in the RUTF , MNP , and control groups were 0 % , 0.8 % , and 0.4 % . The findings apply to ill but not malnourished children and can not be generalised to a general population including children who are not necessarily ill or who are already malnourished . Conclusions A 2-wk nutrition supplementation programme with RUTF as part of routine primary medical care to non-malnourished children with malaria , LRTI , or diarrhoea proved effective in preventing malnutrition in eastern Ug and a. The low incidence of malnutrition in this population may warrant a more targeted intervention to improve cost effectiveness . Trial Registration clinical trials.gov Prolonged parenteral feeding with st and ard nutrient solutions results in significant alteration in the structural , hormonal , and immunological composition of the intestinal tract . The purpose of the following study was to evaluate the effect of glutamine-supplemented parenteral nutrition on the immune cellularity of the gut . Twenty-one Fischer rats were r and omized to three groups of seven animals each . Group I was fed rat chow and water ad lib , Group II was fed a st and ard solution of total parenteral nutrition ( TPN ) ( D25/4.25 % amino acids ) via a central venous catheter , and Group III was fed the st and ard solution of TPN with 2 % glutamine which was isonitrogenous and isocaloric to Group II . Animals were fed their respective diets for 1 week and bile was collected and assayed for secretory IgA ( s-IgA ) and IgM. The terminal ileum was stained and assayed for IgA+ , IgM+ , IgG+ , CD4 + , and CD8 + plasma cells and lymphocytes . Results indicate that the feeding of a st and ard parenteral diet results in a significant decrease in biliary s-IgA and IgA+ plasma cells in the gut lamina propria compared to chow-fed animals ( S-IgA : chow , 858 + /- 23 micrograms/ml ; TPN , 494 + /- 41 micrograms/ml ; IgA cells : chow , 35.7 + /- 1.8 ; TPN , 8.6 + /- 0.9 cells/hpf ) . In addition a marked depletion of CD4 + and CD8 + lymphocytes was observed with st and ard solutions of parenteral nutrition compared to chow ( CD4 + : chow , 36.8 + /- 6.6 ; TPN , 14.9 + /- 6.0 ; CD8 + : chow , 18.8 + /- 5.6 ; TPN , 5.7 + /- 2.7 cells/hpf ) . The addition of glutamine to the st and ard TPN solution maintained both B and T cell population s at levels similar to chow-fed animals . ( ABSTRACT TRUNCATED AT 250 WORDS ABSTRACT : Shigellosis in children can cause growth retardation , worsening of malnutrition , and hypoproteinemia . To assess the effects of ingestion of a protein-rich diet during convalescence , 22 children aged 2 to 4 y with culture-proven shigellosis were r and omly assigned after 5 d of antibiotic treatment to 21-d feeding regimens of either a 150 kcal/kg/d high-protein diet with 15 % of calories as protein or an isocaloric control diet with 6 % of calories as protein . At the start and end of dietary treatment , weight , height , mid-arm circumference , skinfold thickness , serum protein concentrations , and serum IGF-I were measured . Means of weight gain and increases in mid-arm circumference were greater in children fed high-protein diets than those fed control diets ( 1.23 versus 0.76 kg ; 1.40 versus 0.96 cm ; p < 0.05 ) . Mean increase in height in children fed high-protein diets ( 0.83 cm ) was not significantly greater than with control diets ( 0.74 cm ) . Mean increases in serum concentrations of total protein , prealbumin , and retinol-binding protein were greater in the high-protein group than in controls ( p < 0.05 ) . Mean serum concentrations of IGF-I were low in both groups before treatment [ 4.2 ± 2.6 nmol/L ( 31.9 ± 19.6 ng/mL ) in controls ; 3.1 ± 3.4 nmol/L ( 24.0 ± 26.3 ng/mL ) in the high-protein group ] but increased more in the high-protein group [ 39.0 ± 16.2 nmol/L ( 298 ± 124 ng/mL ) ] than in the control group [ 16.7 ± 9.2 nmol/L ( 128 ± 70 ng/mL ) , p < 0.01 ] . These results suggest that high dietary protein is more effective than a normal protein intake in repleting body proteins and in stimulating growth after shigellosis in children . A possible mechanism for this stimulatory effect on growth may be through the restoration of OBJECTIVE Previous studies have shown increased stool output when children with persistent diarrhea ( PD ) received milk as the predominant source of nutrition . METHODS We evaluated the efficacy of milk given in modest amounts as a part of a mixed diet in children with PD . One hundred sixteen children 3 to 24 months of age with diarrhea for between 14 days and 12 weeks were allocated to milk-based ( n = 60 ) or milk-free ( n = 56 ) cereal dietary regimens . The two diets were isocaloric ( 86.9 calories/100 g for < or = 9 months ; 95.6 cal/100 g for > 9 months ) consisting of puffed rice cereal , sugar , and oil differing in only their source of protein , which was either milk or egg white , respectively . An average of 30 % of the calories were constituted by milk in the milk-cereal diet . Both diets were offered at the rate of 150 kcal/kg per day . Children receiving milk-cereal consumed an average of 1.9 g/kg lactose per day . RESULTS The baseline characteristics in the two groups were similar . Comparable amounts of diet were consumed in both groups . The milk-cereal group did not have higher median ( range ) stool output ( g/kg/h ) compared with the milk-free group during a 0- to 48-hour ( milk-cereal , 1.7 [ 0.2 to 8.7 ] ; milk-free , 1.5 [ 0.1 to 6.6 ] ) or 0- to 120-hour ( milk-cereal , 1.6 [ 0.4 to 7.2 ] ; milk-free , 1.3 [ 0.1 to 7.6 ] ) period . The percentage of weight gain was similar in the two groups , and there were no significant differences in the duration of diarrhea . Overall , 23 children had treatment failures , 10 ( 17 % ) in the milk-cereal and 13 ( 23.6 % ) in the milk-free groups . CONCLUSIONS Our findings suggest that modest intakes of milk are well tolerated as a part of mixed diet during PD Abstract Objective : To evaluate the effect on morbidity and mortality of providing daily zinc for 14 days to children with diarrhoea . Design : Cluster r and omised comparison . Setting : Matlab field site of International Center for Diarrhoeal Disease Research , Bangladesh . Participants : 8070 children aged 3 - 59 months contributed 11 881 child years of observation during a two year period . Intervention : Children with diarrhoea in the intervention clusters were treated with zinc ( 20 mg per day for 14 days ) ; all children with diarrhoea were treated with oral rehydration therapy . Main outcome measures : Duration of episode of diarrhoea , incidence of diarrhoea and acute lower respiratory infections , admission to hospital for diarrhoea or acute lower respiratory infections , and child mortality . Results : About 40 % ( 399/1007 ) of diarrhoeal episodes were treated with zinc in the first four months of the trial ; the rate rose to 67 % ( 350/526 ) in month 5 and to > 80 % ( 364/434 ) in month 7 and was sustained at that level . Children from the intervention cluster received zinc for about seven days on average during each episode of diarrhoea . They had a shorter duration ( hazard ratio 0.76 , 95 % confidence interval 0.65 to 0.90 ) and lower incidence of diarrhoea ( rate ratio 0.85 , 0.76 to 0.96 ) than children in the comparison group . Incidence of acute lower respiratory infection was reduced in the intervention group but not in the comparison group . Admission to hospital of children with diarrhoea was lower in the intervention group than in the comparison group ( 0.76 , 0.59 to 0.98 ) . Admission for acute lower respiratory infection was lower in the intervention group , but this was not statistically significant ( 0.81 , 0.53 to 1.23 ) . The rate of non-injury deaths in the intervention clusters was considerably lower ( 0.49 , 0.25 to 0.94 ) . Conclusions : The lower rates of child morbidity and mortality with zinc treatment represent substantial benefits from a simple and inexpensive intervention that can be incorporated in existing efforts to control diarrhoeal disease . What is already known on this topic Zinc deficiency is highly prevalent in children in developing countries Zinc supplements given during diarrhoea reduce the duration and severity of treated episodes If given for 14 days during and after diarrhoea , zinc reduces the incidence of diarrhoea and pneumonia in the subsequent two to three months What this study adds Zinc used as a treatment for diarrhoea reduces mortality in children Zinc reduces admissions to hospital for diarrhoea The impact of zinc on mortality and morbidity can be achieved in a realistic large scale public health Objective . To evaluate the potential benefit of dietary supplementation of a rice-lentil ( Khitchri ) and yogurt diet with 3 mg/kg/d of elemental zinc ( as zinc sulfate ) in hospitalized malnourished children ( age 6–36 months ) with persistent diarrhea for 14 days . Methodology . R and omized , double-blind placebo-controlled trial . Setting . Nutrition Research Ward at the National Institute of Child Health , Karachi , Pakistan , where children were admitted for 14 days of inpatient supervised rehabilitation . Main Outcome Measures . Primary outcome : overall weight gain by day 14 . Secondary outcomes : overall energy intake , stool output , time to diarrheal recovery and weight gain ( ≥3 days ) , plasma zinc , copper , prealbumin , and insulin-like growth factor-1 . Results . Of 87 children r and omized for supplementation with either zinc or placebo , the two groups were comparable at admission in terms of severity and duration of diarrhea , as well as nutritional and anthropometric parameters . The overall weight gain , stool volume , stool frequency , as well as the time taken for diarrheal recovery or steady weight gain , were comparable for both supplemented children and controls . Supplemented children had a significant improvement in plasma zinc levels and serum alkaline phosphatase by day 14 of therapy in comparison with controls . Plasma copper levels were low in both groups at admission and although an increase was seen in control children , levels decreased further after zinc supplementation . There was no significant difference between the two groups for hemoglobin , serum albumin , prealbumin , and plasma insulin-like growth factor-1 increments during the course of therapy . Evaluation of primary and secondary outcome criteria among the subset of children with plasma zinc levels < 60 μg/d at admission did not reveal any significant differences . Conclusions . Although there was satisfactory recovery in malnourished children with persistent diarrhea receiving the Khitchri-yogurt diet , there was no evidence of improved weight gain or acceleration of recovery from diarrhea with zinc supplementation . In contrast , the reduction in plasma copper levels in zinc-supplemented malnourished children suggests that caution should be exercised in supplementing severely malnourished children with zinc alone Abstract Objective To investigate the clinical characteristics of children who died from diarrhoea in low- and middle-income countries , such as the duration of diarrhoea , comorbid conditions , care-seeking behaviour and oral rehydration therapy use . Methods The study included verbal autopsy data on children who died from diarrhoea between 2000 and 2012 at seven sites in Bangladesh , Ethiopia , Ghana , India , Pakistan , Ug and a and the United Republic of Tanzania , respectively . Data came from demographic surveillance sites , r and omized trials and an extended Demographic and Health Survey . The type of diarrhoea was classified as acute watery , acute bloody or persistent and risk factors were identified . Deaths in children aged 1 to 11 months and 1 to 4 years were analysed separately . Findings The proportion of childhood deaths due to diarrhoea varied considerably across the seven sites from less than 3 % to 30 % . Among children aged 1–4 years , acute watery diarrhoea accounted for 31–69 % of diarrhoeal deaths , acute bloody diarrhoea for 12–28 % , and persistent diarrhoea for 12–56 % . Among infants aged 1–11 months , persistent diarrhoea accounted for over 30 % of diarrhoeal deaths in Ethiopia , India , Pakistan , Ug and a and the United Republic of Tanzania . At most sites , more than 40 % of children who died from persistent diarrhoea were malnourished . Conclusion Persistent diarrhoea remains an important cause of diarrhoeal death in young children in low- and middle-income countries . Research is needed on the public health burden of persistent diarrhoea and current treatment practice s to underst and why children are still dying from the condition Objectives : Assess the safety of rapid intravenous rehydration of severely malnourished children and compare the efficacy of 3 formulations of oral rehydration salts solutions . Patients and Methods : A group of 175 severely malnourished children of either sex ( weight/length < 70 % of National Center for Health Statistics median ) , ages 6 to 36 months with cholera , were r and omly assigned to receive 1 of 3 oral rehydration solutions ( ORSs ) : glucose-ORS ( n = 58 ) , glucose-ORS plus 50 g/L of amylase-resistant starch ( n = 59 ) , or rice-ORS ( n = 58 ) . Severely dehydrated children at enrollment were administered 100 mL/kg of an intravenous solution for 4 to 6 hours before r and omisation , and those with some dehydration were r and omised on enrollment . The electrolytes of the 3 ORSs were identical . In acute and convalescence phases , treatment was similar other than the nature of the ORSs . Results : Intravenous fluid ( mean ) administered to 149 study children was 103 mL/kg ( 95 % confidence interval [ CI ] 96–109 ) , and all were rehydrated within 6 hours . None of them developed overhydration or heart failure . During the first 24 hours , stool output ( 31 % ; 95 % CI 14%–42 % ; P = 0.004 ) and the ORS intake ( 26 % ; 95 % CI 12%–37 % ; P = 0.002 ) of children receiving rice-ORS were significantly less compared with children receiving glucose-ORS . The mean duration of diarrhoea in all children ( 66 hours ; 95 % CI 62–71 ) , and time to attain 80 % of median weight/length ( 7.15 ± 2.81 days ) were not different . Conclusions : Dehydration in severely malnourished children can safely be corrected within 6 hours . All study ORSs were equally efficient in correcting dehydration . Rice-ORS significantly reduced the stool output and ORS intake , confirming previous reports Thirty-eight moderately to severely malnourished children with severe acute or subacute diarrhea were treated according to two different feeding schemes , divided at r and om half of the children received semi-elemental diet ( SED ) with an osmolarity of 302 milliosmol per liter , a low lactose content and a relatively high content of lactalbumine hydrolysate ( 1 g/100 ml ) . The other half of the patients received available proprietory formulas or diluted cow 's milk with added carbohydrates . The results obtained showed that the children who were fed the SED had a better average weight gain during the first three weeks of hospitalization compared to the control group . The children receiving the SED also required a smaller number or rehydrations BACKGROUND Cryptosporidiosis in children in developing countries causes persistent diarrhoea and malnutrition and is associated with increased mortality , but there is no effective treatment . We aim ed to assess the effect of nitazoxanide-a new broad-spectrum antiparasitic drug-on morbidity and mortality in Zambian children with diarrhoea due to Cryptosporidium parvum . METHODS Children with cryptosporidial diarrhoea who were admitted to the University Teaching Hospital , Lusaka , Zambia , between November , 2000 , and July , 2001 , and whose parents consented to their having an HIV test were r and omly assigned nitazoxanide ( 100 mg twice daily orally for 3 days ) or placebo . The primary endpoint was clinical response on day 7 after the start of treatment . Secondary endpoints included parasitological response by day 10 and mortality at day 8 . Analysis was by intention to treat , with exclusion of patients subsequently found to be negative for C parvum or co-infected at baseline . The trial was stratified by HIV serology . FINDINGS 50 HIV-seropositive and 50 HIV-seronegative children were recruited for the study , four of whom were subsequently excluded . In HIV-seronegative children , diarrhoea resolved in 14 ( 56 % ) of 25 receiving nitazoxanide and 5 ( 23 % ) of 22 receiving placebo ( difference 33 % , 95 % CI 7 - 59 ; p=0.037 ) . C parvum was eradicated from stool in 13 ( 52 % ) of 25 receiving nitazoxanide and three ( 14 % ) of 22 receiving placebo ( 38 % , 95 % CI 14 - 63 ; p=0.007 ) . Four children ( 18 % ) of 22 in the placebo group had died by day 8 , compared with none of 25 in the nitazoxanide group ( -18 % , -34 to 2 ; p=0.041 ) . HIV-seropositive children did not benefit from nitazoxanide . Nitazoxanide was not significantly associated with adverse events in either stratum . INTERPRETATION A 3-day course of nitazoxanide significantly improved the resolution of diarrhoea , parasitological eradication , and mortality in HIV-seronegative , but not HIV-seropositive , children We examined whether malnutrition ( underweight [ WAZ ] < -2 ) increased the risk of diarrhea equally for all enteropathogens . The study was conducted prospect ively between January 1999 and July 2002 in Mirpur , an urban slum in Dhaka . Two hundred eighty-nine Bangladeshi children ( 147 male and 142 female ) 2 - 5 years of age were included in the study . Malnutrition was present in 39 % of the children at the time of enrollment . The parents and children were visited and interviewed every other day by health care workers for details about any diarrheal episodes . Stool sample s were successfully collected from 62 % of episodes of diarrhea . Of the identified enteropathogens , only enterotoxigenic Escherichia coli ( ETEC ) , Cryptosporidium sp. , and Entamoeba histolytica were significantly more prevalent in malnourished children . We concluded that the malnutrition attributed risk is not equal for enteric pathogens associated with diarrheal illness OBJECTIVE To determine whether the routine use of a lactose free formula ( AL-110 , Nestle Labs . ) in hospitalized children aged one to 24 months reduces the duration of acute diarrhea ( AD ) . METHODS After being stratified according to age and nutritional state , 28 and 24 patients were r and omly allocated to receive AL-110 or lactose formula , respectively . The main outcome was the duration of diarrhoea after refeeding , both in hours and days . Secondary outcomes were evaluated by blind observers . Results were compared using t test , the Mann-Whitney test and Chi square . RESULTS No differences were found between the diets without and with lactose regarding duration of diarrhoea in hours ( mean , 41.9 h vs 54.4 h ; p = 0.247 ) or days ( median , 0 d vs 0 d ; p = 0.717 ) , the percentage of failures ( 3.6 % vs 8.3 ; p = 0.2 ) , and the mean weight increment ( 0.78 kg vs. 0.82 kg ; p = 0.788 ) . The study power to find a 50 % ( 27h ) reduction of AD duration was 71 % . CONCLUSION Although the power of this trial was slightly below that previously fixed ( 80 % ) , the results suggest that routine use of lactose free formula does not reduce the duration of AD in hospitalized children Goals To determine fecal protein loss in children with acute and persistent diarrhea . Background In children with diarrhea , ongoing losses of endogenous proteins have been suggested as contributing to impairment of nutritional and immunologic status . However , there is a paucity of information and inconclusive data in the literature . Study Fecal protein loss was assessed prospect ively in children ( <3 years of age ) with acute diarrhea ( < 7 days ' duration ) or persistent diarrhea ( > 14 days ) and in controls using alpha-1-antitrypsin determination ; fecal protein loss then was correlated with age , duration of diarrhea , nutritional status , plasma proteins , and stool pathogens . Results Children with acute diarrhea ( n = 43 ) and those with persistent diarrhea ( n = 41 ) had significantly higher fecal alpha-1-antitrypsin levels compared with controls ( n = 14 ) ( 2.26 ± 1.71 and 2.25 ± 1.51 , respectively , vs. 1.02 ± 0.73 mg/g stools;p = 0.002 ) . However , there was no significant decrease of plasma albumin , globulin , or immunoglobulins . Fecal protein loss did not differ significantly among stool pathogens ( bacterial , viral , and parasitic ) and demonstrated no significant correlation with age , duration of diarrhea , or nutritional status ( mild malnutrition ) . Conclusions Enhanced fecal protein loss was observed in more than 50 % of children with acute and persistent diarrhea caused by various pathogens . This did not correlate with age , duration of diarrhea , or nutritional status and did not result in significant decrease of plasma proteins or immunoglobulins . This protein-losing enteropathy does not appear to have a causal role in perpetuation of diarrheal episodes in children with mild malnutrition Objective : To assess the impact of zinc supplementation on clinical recovery , weight gain and subsequent growth and morbidity in moderately malnourished children with shigellosis . Design : A r and omized , double-blind , controlled trial . Setting : Dhaka hospital of ICDDR , B : Centre for Health and Population Research , Dhaka , Bangladesh . Subjects : Fifty-six moderately malnourished children , aged 12–59 months with culture-proven shigellosis . Methods : Subjects were r and omly allocated to receive zinc ( 20 mg/day elemental ) in multivitamin syrup ( intervention ) or multivitamin syrup without zinc ( control ) in two equally divided doses daily for 2 weeks . All children received pivmecillinam in a dose of 15 mg/kg every 6 h for 5 days . After supplementation , children were followed in their respective homes every 2 weeks for 6 months . Results : Children receiving zinc recovered from acute illness significantly faster than the control children ( P<0.05 ) . The medians time ( days ) to recovery and disappearances of blood and mucous were significantly 50 % shorter in the zinc-supplemented group compared to the control group . The mean body weight of zinc supplemented children increased significantly from 8.8 kg on admission to 9.2 kg ( P<0.01 ) at recovery , which was not observed in the control children ( from 9.3 to 9.6 kg ; P=0.12 ) . During the 6-month follow-up period , zinc-supplemented children had significantly fewer mean episodes of diarrhoea compared to the control children ( 2.2 vs 3.3 ; P=0.03 ) . Conclusion : Zinc supplementation significantly shortens the duration of acute shigellosis , promotes better weight gain during recovery and reduces diarrhoeal morbidity during the subsequent 6 months BACKGROUND In developing countries the duration and severity of diarrheal illnesses are greatest among infants and young children with malnutrition and impaired immune status , both factors that may be associated with zinc deficiency . In children with severe zinc deficiency , diarrhea is common and responds quickly to zinc supplementation . METHODS To evaluate the effects of daily supplementation with 20 mg of elemental zinc on the duration and severity of acute diarrhea , we conducted a double-blind , r and omized , controlled trial involving 937 children , 6 to 35 months of age , in New Delhi , India . All the children also received oral rehydration therapy and vitamin supplements . RESULTS Among the children who received zinc supplementation , there was a 23 percent reduction ( 95 percent confidence interval , 12 percent to 32 percent ) in the risk of continued diarrhea . Estimates of the likelihood of recovery according to the day of zinc supplementation revealed a reduction of 7 percent ( 95 percent confidence interval , -9 percent to + 22 percent ) in the risk of continued diarrhea during days 1 through 3 and a reduction of 38 percent ( 95 percent confidence interval , 27 percent to 48 percent ) after day 3 . When zinc supplementation was initiated within three days of the onset of diarrhea , there was a 39 percent reduction ( 95 percent confidence interval , 7 percent to 61 percent ) in the proportion of episodes lasting more than seven days . In the zinc-supplementation group there was a decrease of 39 percent ( 95 percent confidence interval , 6 percent to 70 percent ) in the mean number of watery stools per day ( P = 0.02 ) and a decrease of 21 percent ( 95 percent confidence interval , 10 percent to 31 percent ) in the number of days with watery diarrhea . The reductions in the duration and severity of diarrhea were greater in children with stunted growth than in those with normal growth . CONCLUSION For infants and young children with acute diarrhea , zinc supplementation results in clinical ly important reductions in the duration and severity of diarrhea Background The aim of this study was to compare the effect of infant formula and the same formula subjected to microbial fermentation ( yogurt ) on the duration of diarrhea in young children with acute watery diarrhea , with or without reducing substances in stools . Methods One hundred twelve well-nourished children , aged 3 to 24 months , who were admitted to the hospital with acute watery diarrhea were included in a r and omized trial . After appropriate rehydration , they were fed either an infant formula ( group M , n = 56 ) or the same formula fermented with Lactobacillus bulgaricus and Streptococcus thermophilus ( group Y , n = 56 ) . The two feedings were comparable in lactose concentration ( 40 to 42 g/L ) , pH 4.5 , flavor , and texture . The groups were subdivided into those with or without reducing sugars in stools at presentation . The presence of reducing sugars in stool was used as a marker of carbohydrate malabsorption . Results Group M and group Y had comparable clinical characteristics at admission , including the number of patients with reducing sugars in stools ( n = 31 in group M and 27 in group Y ) . The success rate ( cessation of diarrhea and appropriate weight gain 7 days after enrollment into the study ) was similar in both groups ( 82 % in group M vs. 84 % group Y ) . Clinical failure was 3.6 % in both groups . The percentage of patients withdrawn from the study for medical reasons ( 5.4 % in group M vs. 7.1 % in group Y ) or withdrawn at the parents ’ request ( 8.9 % in group M vs. 5.4 % in group Y ) was similar . Duration of diarrhea and number of stools were significantly less in group Y compared with group M. Forty-eight hours after inclusion , diarrhea was still present in 62 % of group M versus in 35 % of group Y ( P < 0.002 ) . In children with reducing sugars in stools , the rate of success ( 82 % ) was similar in groups M and Y , but the duration of diarrhea and number of stools per day were significantly decreased in group Y. Forty-height hours after inclusion , diarrhea was still present in 75 % of group M patients and in 20 % of group Y patients who had reducing substances in the stool . Conclusion Young children with acute watery diarrhea , without malnutrition or associated disease , can be equally well treated with feeding of either infant formula or yogurt . Yogurt feeding is associated with a clinical ly relevant decrease in stool frequency and duration of diarrhea in children who have reducing sugars in stools OBJECTIVES To determine whether continuing with zinc supplementation after zinc treatment ( ZT ) of an acute diarrhoea episode will result in additional clinical benefits beyond ZT alone . METHODS Children 6 - 23 months of age , living in an urban slum in Dhaka , Bangladesh with acute childhood diarrhoea ( ACD ) , were enrolled in a r and omized , double-blind field trial . All children received 10 days of ZT ( 20 mg/day ) and were then r and omized to zinc ( 10 mg/day ) or placebo supplementation for 3 months . Weekly follow-up of all children occurred over a period of 9 months . RESULTS A total of 353 subjects were enrolled , with 93 % of the zinc supplemented and 96 % of the placebo children followed for 9 months . The incidence density of ACD among those receiving zinc supplementation compared to those receiving placebo was reduced by 28 % ( 2.64 vs.3.66 episodes/p-y follow-up ) over the 3 months while on supplementation and by 21 % ( 2.05 vs.2.59 episodes/p-y follow-up ) over the 9 months of follow-up . There was no observed effect on the incidence of acute respiratory infections ( ARIs ) or on growth . CONCLUSIONS Zinc supplementation after treatment provides additional preventive ACD benefits to children in early childhood . Larger , effectiveness trials of this strategy are warranted Summary Zinc has been shown to enhance intestinal mucosal repair in patients suffering from acrodermatitis enteropathica ; but the impact on mucosal integrity during acute ( AD ) or persistent ( PD ) diarrhoea is unknown . One hundred eleven children with AD and 190 with PD aged between 3 and 24 months received , r and omly and blind to the investigators , either an elemental zinc supplement of 5 mg/kg body wt/day or placebo in multivitamin syrup for 2 weeks while intestinal permeability and , biochemical and anthropometric markers were serially monitored . The permeability test was administered as an oral dose of 5 g lactulose/1 g mannitol in a 20-ml solution followed by a 5-h urine collection . The ratio of the urinary probe sugars was correlated to clinical , biochemical , and microbiological parameters . At presentation , lactulose excretion was increased and mannitol excretion decreased in both AD and PD as compared with age-matched asymptomatic children . The lactulose/mannitol ratio ( L/M ) was higher in subjects with mucosal invasive pathogens ( rotavirus and enteropathogenic Escherichia coli ) compared with children excreting Vibrio cholera and enterotoxigenic . coli . Two-week zinc supplementation significantly reduced lactulose excretion in both AD and PD , whereas the change in mannitol excretion and L/M was similar between study groups in both studies . Changes in lactulose excretion were significantly influenced by zinc supplementation in children with E. coli , Shigella sp. , and Campylobacter jejuni stool isolates . The greatest reduction in total lactulose excretion was seen in supplemented children who on presentation were lighter ( wt/age < 80 % ) , thinner ( wt/ht < 85 % ) , and undernourished [ middle upper arm circumference ( MUAC ) < 12.5 cm ] or with hypozincaemia ( < 14 μmlmol/L ) . The results suggest zinc supplementation improves intestinal permeability in certain groups of children with AD or PD syndrome and contributes to their recovery . This effect may indirectly reflect enhanced mucosal recovery . Further studies on the mechanisms of mucosal repair following zinc supplementation are recommended To date there have been few reports on the impact of dietary intervention on the clinical course of acute shigellosis . Current management of acute shigellosis is primarily focused on antibiotic therapy with less emphasis on nutritional management . In a r and omised clinical trial , we examined the role of an energy-dense diet on the clinical outcome in malnourished children with acute dysentery due to shigellosis . Seventy-five children aged 12 - -48 months with acute dysentery r and omly received either a milk -- cereal formula with an energy density of 4960 kJ/l ( test group ) or a milk-cereal formula with energy of 2480 kJ/l ( control group ) for 10 d in hospital . In both milk-cereal formulas , protein provided 11 % energy . In addition , the st and ard hospital diet was offered to all children and all children received an appropriate antibiotic for 5 d. The mean food intakes ( g/kg per d ) in the test and control groups were : 112 ( SE 2.28 ) and 116 ( SE 3.48 ) on day 1 ; 118 ( SE 2.72 ) and 107 ( SE 3.13 ) on day 5 ; 120 ( SE 2.25 ) and 100 ( SE 3.83 ) on day 10 . The mean energy intakes ( kJ/kg per d ) in the test and control groups respectively were : 622 ( SE 13.2 ) and 315 ( SE 11.3 ) on day 1 ; 655 ( SE 15.1 ) and 311 ( SE 7.98 ) on day 5 ; 672 ( SE 14.7 ) and 294 ( SE 11.1 ) on day 10 . The food and energy intakes were mostly from the milk-cereal diet . There was no difference between two groups in resolution of fever , dysenteric ( bloody and or mucoid ) stools , stool frequency and tenesmus . However , vomiting was more frequently observed among the test-group children during the first 5 d of intervention ( 67 % v. 41 % , There was an increase in the mean weight-for-age ( % ) in the test group compared with the control group after the 10 d of dietary intervention ( 6.2 ( SE 0.6 ) v. 2.7 ( SE 0.4 ) , In addition , resolution of rectal prolapse was better ( 26 % v. 8 % , in the test group v. control group after 5 d , and 13 % v. 6 % , after 10 d of dietary intervention . Supplementation with a high-energy diet does not have any adverse effect on clinical course of acute shigellosis and reduces the incidence of rectal prolapse in malnourished children To evaluate the impact of zinc supplementation on the clinical recovery and body weight of children with persistent diarrhoea , a r and omized , double‐blind , controlled trial was conducted in 190 children with persistent diarrhoea aged between 3 and 24 months . Children were r and omly allocated to receive either zinc ( 20 mg d−1 ) syrup with multivitamin ( 2 × RDA ) or multivitamin alone in three divided daily doses for 2 weeks . The trial was conducted in a diarrhoeal disease hospital in Dhaka , Bangladesh . Duration until clinical recovery ( d ) , impact on body weight and serum zinc level after 2 weeks of zinc supplementation were recorded . The duration of illness was significantly reduced ( 33 % ) with zinc supplementation among children who were underweight ( ≤70 % wt/age , p= 0:03 ) . Supplemented male children also had a significant reduction ( 27 % ) in duration for recovery compared with unsupplemented children ( p= 0:05 ) . From baseline to convalescence , zinc‐supplemented children maintained their serum zinc concentration ( 13.4 vs 13.6/μmol l−1 ) , whereas unsupplemented children had a decrease in serum zinc after the 2 weeks of diarrhoea ( 13.6 vs 11.8 μmol l−1 , p < 0:03 ) . The mean body weight of the children in the supplemented group was maintained ( 5.72 vs 5.70 kg , p= 0:62 ) during hospitalization , unlike that of the control group , in which there was a reduction in body weight ( 5.75 vs 5.67 kg , p= 0:05 ) . Five children in the unsupplemented group and one child in the zinc‐supplemented group died during the 2 weeks of supplementation ( p= 0:06 ) . Zinc supplementation in persistent diarrhoea significantly reduced the length of the recovery period in malnourished children and prevented a fall in body weight and serum zinc concentration , indicating that zinc is a beneficial therapeutic strategy in this high‐risk childhood illness Background Globally , Médecins Sans Frontières ( MSF ) treats more than 300,000 severely malnourished children annually . Malnutrition is not only caused by lack of food and poor infant and child feeding practice s but also by illnesses . Breaking the vicious cycle of illness and malnutrition by providing ill children with nutritional supplementation is a potentially powerful strategy for preventing malnutrition that has not been adequately investigated . Therefore , MSF investigated whether incidence of malnutrition among ill children < 5 y old could be reduced by providing a fortified food product or micronutrients during their 2-wk convalescence period . Two trials , one in Nigeria and one in Ug and a , were conducted ; here we report on the trial that took place in Goronyo , a rural region of northwest Nigeria with high morbidity and malnutrition rates . Methods and Findings We investigated the effect of supplementation with ready-to-use therapeutic food ( RUTF ) and a micronutrient powder ( MNP ) on the incidence of malnutrition in ill children presenting at an outpatient clinic in Goronyo during February to September 2012 . A three-armed , partially-blinded , r and omised controlled trial was conducted in children diagnosed as having malaria , diarrhoea , or lower respiratory tract infection . Children aged 6 to 59 mo were r and omised to one of three arms : one sachet/d of RUTF ; two sachets/d of micronutrients or no supplement ( control ) for 14 d for each illness over 6 mo . The primary outcome was the incidence of first negative nutritional outcome ( NNO ) during the 6 mo follow-up . NNO was a study -specific measure used to indicate occurrence of malnutrition ; it was defined as low weight-for-height z-score ( < −2 for non-malnourished and < −3 for moderately malnourished children ) , mid-upper arm circumference < 115 mm , or oedema , whichever came first . Of the 2,213 r and omised participants , 50.0 % were female and the mean age was 20.2 ( st and ard deviation 11.2 ) months ; 160 ( 7.2 % ) were lost to follow-up , 54 ( 2.4 % ) were admitted to hospital , and 29 ( 1.3 % ) died . The incidence rates of NNO for the RUTF , MNP , and control groups were 0.522 ( 95 % confidence interval ( 95 % CI ) , 0.442–0.617 ) , 0.495 ( 0.415–0.589 ) , and 0.566 ( 0.479–0.668 ) first events/y , respectively . The incidence rate ratio was 0.92 ( 95 % CI , 0.74–1.15 ; p = 0.471 ) for RUTF versus control ; 0.87 ( 0.70–1.10 ; p = 0.242 ) for MNP versus control and 1.06 ( 0.84–1.33 , p = 0.642 ) for RUTF versus MNP . A subgroup analysis showed no interaction nor confounding , nor a different effectiveness of supplementation , among children who were moderately malnourished compared with non-malnourished at enrollment . The average number of study illnesses for the RUTF , MNP , and control groups were 4.2 ( 95 % CI , 4.0–4.3 ) , 3.4 ( 3.2–3.6 ) , and 3.6 ( 3.4–3.7 ) . The proportion of children who died in the RUTF , MNP , and control groups were 0.8 % ( 95 % CI , 0.3–1.8 ) , 1.8 % ( 1.0–3.3 ) , and 1.4 % ( 0.7–2.8 ) . Conclusions A 2-wk supplementation with RUTF or MNP to ill children as part of routine primary medical care did not reduce the incidence of malnutrition . The lack of effect in Goronyo may be due to a high frequency of morbidity , which probably further affects a child ’s nutritional status and children ’s ability to escape from the illness – malnutrition cycle . The duration of the supplementation may have been too short or the doses of the supplements may have been too low to mitigate the effects of high morbidity and pre-existing malnutrition . An integrated approach combining prevention and treatment of diseases and treatment of moderate malnutrition , rather than prevention of malnutrition by nutritional supplementation alone , might be more effective in reducing the incidence of acute malnutrition in ill children . Trial Registration clinical trials.gov OBJECTIVE To evaluate the efficacy of a chicken-based diet for the treatment of persistent diarrhea in severely malnourished children . STUDY DESIGN Prospect i ve , r and omized , double-blind study that compared a chicken-based diet with elemental ( Vivonex ) and soy ( Nursoy ) diets . Hospitalized children with third-degree malnutrition and persistent diarrhea , aged 3 to 36 months , were included . Diets were isocaloric and given nasogastrically at 150 ml/kg per day in progressively increasing concentrations . RESULTS Fifty-six children were included ( 18 received Vivonex , 19 Nursoy , 19 chicken ) . They had a mean age of 6.4 + /- 4.4 months , a mean weight of 3604 + /- 1232 gm , and a mean weight-for-age percentage of 51.4 % + /- 7.2 % . Sixty-four percent had associated conditions on admission to the hospital . Forty-one children ( 73.2 % ) were successfully treated ( 13 Vivonex , 13 Nursoy , 15 chicken ) . There were no differences in diarrheal outcomes , and all groups had significant weight gain . Failure was independent of the diet and was associated with the presence of infection on admission . There was a significantly higher nitrogen balance in the children from the chicken group ( 358.2 + /- 13 mg/kg per day ) than in those receiving Vivonex ( 226.6 + /- 61 ) or Nursoy ( 291 - 4 + /- 111.6 ; p < 0.05 ) groups . CONCLUSIONS The chicken-based diet was as effective as Vivonex or Nursoy . It is well tolerated , inexpensive , and widely available and thus represents an effective and inexpensive alternative to the treatment of severely malnourished children with persistent diarrhea In a double‐blind , controlled trial with a factorial design , 684 patients ( aged 6 months to 2 y ; excludes 6 early dropouts ) with acute watery diarrhoea of 3 d or less and some dehydration , who were attending a hospital , were r and omly assigned to 4 groups to receive : ( a ) vitamin A 4500 μg retinol equivalent daily for 15 d ; ( b ) 14.2 mg elemental zinc as acetate for the first 417 patients and 40 mg of the remaining 273 patients r and omized to this group for 15 d ; ( c ) both vitamin A 4500 μg retinol equivalent and zinc at the above doses daily for 15 d ; or ( d ) placebo mixtures for 15 d. Patients were observed in the hospital for 24 h and followed up at home for 15 d. All received ascorbic acid 30 mg with each dose of medicine or placebo . Zinc supplementation was associated with a reduced duration of diarrhoea ( 13 % , p= 0.03 ) and markedly reduced rate ( 43 % , p= 0.017 ) of prolonged diarrhoea ( < 7 d ) . Vitamin A supplementation was associated with a nonsignificant trend for reduced rate of prolonged diarrhoea ( p= 0.089 ) . In conclusion , zinc supplementation as adjunct therapy had a substantial impact on the rate of prolonged diarrhoea and some impact on duration and may be beneficial in children with diarrhoea in developing countries Objective : To assess the impact of zinc supplementation during acute diarrhoea on subsequent growth and morbidity in malnourished young children . Design : Double blind r and omized controlled clinical trial Setting : International Centre for Diarrhoeal Disease Research , Bangladesh . Subjects : Sixty-five children aged 3–24 months with acute diarrhoea for less than 3 d . Intervention : Either elemental zinc ( 20 mg/d ) in a multivitamin syrup or multivitamin syrup alone divided in three divided daily doses for a period of two weeks . Children were followed up weekly at home to assess subsequent growth and morbidity for a period of eight weeks . Main outcome measures : Gain in length and body weight and reduction in diarrhoea and respiratory tract infection . Results : During the follow-up , zinc supplemented children showed significantly greater cumulative length gain ( 18.9 mm vs 14.5 mm , P<0.03 ) and comparable body weight gain than the children of the control group . Subsequent length gain was not correlated with initial height in the zinc-supplemented group ( r=−0.13 ) , P=0.5 ) , but was significantly correlated in the control group ( r=-0.6 , P<0.0007 ) . Zinc-supplemented and stunted children ( ≤ 90 % length for age n=18 ) experienced significantly fewer episodes of diarrhoea ( 0.07 vs 0.6 , P 0.05 ) and respiratory illness ( 1.0 vs 2.4 , P<0.01 ) compared to the control group . The underweight children ( ≤ 71 % weight/age n=38 ) receiving zinc-supplementation also had fewer episodes of diarrhoea ( 0.4 vs 1.0 , P<0.04 ) and shorter duration of diarrhoeal episodes ( 1.0 vs 3.0 d , P<0.04 ) compared to their counterparts in the control group . Conclusion : These results suggest that a short course of zinc supplementation to malnourished children during acute diarrhoea reduces growth-faltering and diarrhoeal and respiratory morbidity during subsequent two months . Sponsorship : Wellcome Trust Sixty children less than 2 years of age suffering from mild acute gastroenteritis with less than 5 % dehydration were r and omly assigned to two different isocaloric feeding regimens , viz . , a locally prepared milk-free formulation ( group A ) of rice , lentil , sugar , and coconut oil and a spray dried commercial cow 's milk formula ( group B ) . There were two treatment failures in group A and one in group B. The postintervention duration of diarrhea ( days ) in group A ( 11.0 + /- 10.0 ) was higher than in group B ( 7.6 + /- 10.8 ) , but these differences were not significant ( p greater than 0.05 ) . The energy intake ( kcal/kg/24 h ) on postintervention day 4 was 78.7 + /- 31.7 in group A and 101.3 + /- 41.1 in group B ( p greater than 0.05 ) . The corresponding values for day 7 were 74.2 + /- 29.1 and 110.0 + /- 41.1 , respectively ( p less than 0.05 ) . The mean weight gain ( g/kg/24 h ) between admission and the day of recovery in group A ( 2.0 + /- 4.2 ) was significantly lower ( p less than 0.05 ) than in group B ( 5.8 + /- 7.8 ) . Similar trends in weight gain were observed at days 4 and 7 . These findings suggest that a cow 's milk-based formula is well tolerated by majority of the infants with mild acute gastroenteritis after initial rehydration with ORS . The infants who were fed the milk-free cereal-based diet showed significantly less energy intake and gained weight less rapidly than those who were fed the cow 's milk-based formula To establish optimal therapy for severe dysentery due to Shigella dysenteriae type 1 and Shigella flexneri , we compared in a prospect i ve r and omized trial two oral ampicillin doses ( 50 and 150 mg/kg per day ) in 57 children and 39 adults in Dacca , Bangladesh . Clinical failure did not occur in either group , indicating that conventional doses need not be increased even in severe disease . Among children 3 years of age or under , bacteriological relapses tended to be more frequent in the low-dose group and were not related to serum levels of ampicillin , nutritional status , or the severity of colitis on admission . Therefore , we recommend that younger children be treated with 100 mg/kg per day of oral ampicillin Background Partially hydrolyzed guar gum ( Benefiber ; Novartis Nutrition , Minneapolis , MN , U.S.A. ) is fermented by colonic bacteria liberating short-chain fatty acids ( SCFAs ) , which accelerate colonic absorption of salt and water . The purpose of this study was to evaluate the effect of Benefiber (BF)-supplemented World Health Organization Oral Rehydration Solution ( WHO ORS ) in the treatment of acute noncholera diarrhea in children . Methods A double-blind , r and omized , controlled clinical trial was performed at ICDDR , B in 150 male children aged 4 to 18 months who had watery diarrhea of less than 48 hours ' duration . After admission , children were assigned to receive either WHO ORS or BF-supplemented WHO ORS until recovery . Major outcome measures , such as duration of diarrhea and amount of stool output , were compared between the treatment groups . Results Patients receiving BF-supplemented WHO ORS had significantly reduced duration of diarrhea compared with the control group ( mean ± SD , 74 ± 37 vs. 90 ± 50 hours , P = 0.03 ) . Survival analysis for duration of diarrhea also showed a reduction the BF-supplemented WHO ORS – treated group ( P = 0.025 , log rank test ) . There was also less stool output daily from days 2 through 7 in the patients treated with BF-supplemented WHO ORS compared with that in the children treated with WHO ORS ; the reduction was significant on day 7 only . Conclusion Benefiber added to st and ard WHO ORS substantially reduces the duration of diarrhea and modestly reduced stool output in acute noncholera diarrhea in young children , indicating its potential as a new antidiarrheal therapy for acute diarrhea in children Objective : This r and omized , placebo controlled trial was design ed to assess the safety and efficacy of 10-mg zinc supplementation for the treatment of acute diarrhea in infants . Methods : A total of 1110 infants aged 28 days to 5 months with acute diarrhea were enrolled and r and omized to receive either zinc ( n = 554 ) or placebo ( n = 556 ) for 14 days . Diarrhea history , anthropometric status , breast-feeding status and socioeconomic indicators were assessed at baseline . The homes of all infants were visited every 3 days until the diarrhea episode was over . The number of stools , presence of blood and additional illnesses were recorded daily . Results : The geometric mean duration of the diarrhea episode was 0.21 days longer among infants receiving zinc versus those receiving placebo , but this was not statistically significant and no difference was observed after controlling for sex , exclusive breast-feeding and length for age Z score . There were no differences in any subgroup ( ie , sex , baseline length for age Z score , exclusive breast-feeding or site after controlling for the remaining subgroup variables ) . There were no differences in reported stool frequency or among the proportion of episodes lasting longer than 7 days . Rates of vomiting were similar in the zinc and placebo groups . Conclusions : Young infants do not appear to benefit from zinc supplementation for the treatment of diarrhea Ninety six children upto the age of five years suffering from uncomplicated acute dysentery of less than 3 days ' duration were studied to find out the impact of feeding of extra-protein rich diet during their acute phase of illness . These children were r and omly allocated to either control group ( receiving only hospital diet ) and study group ( receiving hospital diet and extra milk which constituted 30 % of ideal total calorie requirement of patients . Patients in the two groups were comparable on admission . Forty percent reduced food intake was observed among the children of both the groups due to severe anorexia which was reflected by no significant differences in clinical outcome , anthropometrical measurements and haematological parameters between the two groups on day 7 of hospitalisation and on day 15 after discharge Oral rehydration solutions ( ORS ) containing 90 mmol/liter or 50 mmol/liter of sodium have been successfully used in the treatment of hospitalized well-nourished and undernourished children ; however , few data are available on the use of these ORS in well-nourished ambulatory children with minimal dehydration . We therefore compared the safety and efficacy of both ORS with st and ard outpatient management in a controlled , r and omized study among 93 well-nourished children aged 3 months to 2 years , with minimal dehydration secondary to acute diarrhea at an outpatient clinic in Panama . Patients in all three groups were hydrated successfully . However , patients in both ORS groups gained significantly ( P less than 0.05 ) more weight at the 2-week follow-up compared to the control group . There were no complications due to the use of either ORS . No child developed hypernatremia nor hyponatremia during therapy . These studies indicate that both ORS ( containing 90 or 50 mmol/liter of sodium ) are effective and safe in hydrating well-nourished ambulatory children with minimal dehydration BACKGROUND & AIMS Because of the beneficial intestinal effects of dietary fibers , we have evaluated the therapeutic effects of green banana or pectin in children with persistent diarrhea . METHODS In a double-blind trial , 62 boys , age 5 - 12 months , were r and omly given a rice-based diet containing either 250 g/L of cooked green banana ( n = 22 ) or 4 g/kg pectin ( n = 19 ) or the rice-diet alone ( control , n = 21 ) , providing 54 kcal/dL daily for 7 days . Stool weight and consistency , frequency of vomiting and purging , and duration of illness were measured . RESULTS Most children ( 60 % ) had no pathogens isolated from stools , 17 % had rotavirus , 5 % Vibrio cholerae , 4 % Salmonella group B , and 11 % had enterotoxigenic Escherichia coli infections . By day 3 posttreatment , significantly ( P < 0.001 ) more children recovered from diarrhea receiving pectin or banana than controls ( 59 % , 55 % , and 15 % , respectively ) . By day 4 , these proportions correspondingly increased to 82 % , 78 % , and 23 % , respectively , the study diet groups being significantly ( P < 0.001 ) different than controls . Green banana and pectin significantly ( P < 0.05 ) reduced amounts of stool , oral rehydration solution , intravenous fluid , and numbers of vomiting , and diarrheal duration . CONCLUSIONS Green banana and pectin are useful in the dietary management of persistent diarrhea in hospitalized children and may also be useful to treat children at home BACKGROUND In Nigeria , diarrhoeal disease is second only to malaria as a cause of death the under 5 age group . This study was aim ed at assessing the benefit or otherwise of zinc supplement in acute diarrhoea . SUBJECTS AND METHODS This was a multi-centred r and omized double blind controlled study . Children with acute diarrhoea aged between 6 and 24 months were r and omized into zinc supplemented and placebo groups . Plasma zinc levels were analyzed at enrollment and at the end of the study . The children were review ed for the next three months from the time of enrollment . RESULTS The mean plasma zinc levels at baseline and at the end of the study were 0.06 + /- 0.04 and 0.067 + /- 0.03 ppm in the zinc supplemented group and 0.11 + /- 0.02 and 0.05 + /- 0.03 ppm in the control group . The differences were not statistically significant . The zinc supplemented group had an average weight gain of 1.1 kg as against 0.73 kg ( p = 0.00 ) for the control group in the study period . No adverse effect was reported on account of zinc supplementation . CONCLUSION Zinc supplementation is beneficial in acute diarrhoea as observed in this study Our objective was to evaluate the effect of zinc and copper supplementation in acute diarrhea on morbidity and growth during 12 weeks of follow-up . In a double-blind r and omized controlled clinical trial of 724 children aged 6–59 months , none of the 11 evaluated outcomes showed significant association with zinc or zinc and copper supplementation . Thus , therapeutic zinc supplementation may not always yield short-term benefits BACKGROUND Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries . We design ed the Global Enteric Multicenter Study ( GEMS ) to identify the aetiology and population -based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia . METHODS The GEMS is a 3-year , prospect i ve , age-stratified , matched case-control study of moderate-to-severe diarrhoea in children aged 0 - 59 months residing in censused population s at four sites in Africa and three in Asia . We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three r and omly selected matched community control children without diarrhoea . From patients with moderate-to-severe diarrhoea and controls , we obtained clinical and epidemiological data , anthropometric measurements , and a faecal sample to identify enteropathogens at enrolment ; one follow-up home visit was made about 60 days later to ascertain vital status , clinical outcome , and interval growth . FINDINGS We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea . By analysing adjusted population attributable fractions , most attributable cases of moderate-to-severe diarrhoea were due to four pathogens : rotavirus , Cryptosporidium , enterotoxigenic Escherichia coli producing heat-stable toxin ( ST-ETEC ; with or without co-expression of heat-labile enterotoxin ) , and Shigella . Other pathogens were important in selected sites ( eg , Aeromonas , Vibrio cholerae O1 , Campylobacter jejuni ) . Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls ( odd ratio 8·5 , 95 % CI 5·8 - 12·5 , p<0·0001 ) ; most deaths ( 167 [ 87·9 % ] ) occurred during the first 2 years of life . Pathogens associated with increased risk of case death were ST-ETEC ( hazard ratio [ HR ] 1·9 ; 0·99 - 3·5 ) and typical enteropathogenic E coli ( HR 2·6 ; 1·6 - 4·1 ) in infants aged 0 - 11 months , and Cryptosporidium ( HR 2·3 ; 1·3 - 4·3 ) in toddlers aged 12 - 23 months . INTERPRETATION Interventions targeting five pathogens ( rotavirus , Shigella , ST-ETEC , Cryptosporidium , typical enteropathogenic E coli ) can substantially reduce the burden of moderate-to-severe diarrhoea . New methods and accelerated implementation of existing interventions ( rotavirus vaccine and zinc ) are needed to prevent disease and improve outcomes . FUNDING The Bill & Melinda Gates Foundation Although previous studies have shown successful treatment of persistent diarrhea ( PD ) with the use of yogurt-based diets , some recent ones speculate the need of special formulas for the nutritional management of PD complicated cases . In the present study , we tested the hypothesis that the consumption of 3 lactose-free diets , with different degrees of complexity , is associated with lower stool output and shorter duration of diarrhea when compared with the use of a yogurt-based one on the nutritional management of PD . A total of 154 male infants , aged between 1 and 30 months , with PD and with or without dehydration , were r and omly assigned to 1 of 4 treatment groups . Throughout the study , the patients were placed in a metabolic unit ; their body weights and intakes of oral rehydration solution , water , and formula diets , in addition to outputs of stool , urine , and vomit , were measured and recorded at 24-hour intervals . Four different diets were used in this study : diet 1 , yogurt-based formula ; diet 2 , soy-based formula ; diet 3 , hydrolyzed protein-based formula ; and diet 4 , amino acid-based formula . Throughout the study , only these formula diets were fed to the children . The data showed that children fed the yogurt-based diet ( diet 1 ) or the amino acid-based diet ( diet 4 ) had a significant reduction in stool output and in the duration of diarrhea . The use of an inexpensive and worldwide-available yogurt-based diet is recommended as the first choice for the nutritional management of mild to moderate PD . For the few complicated PD cases , when available , a more complex amino acid-based diet should be reserved for the nutritional management of these unresponsive and severe presentations . Soy-based or casein-based diets do not offer any specific advantage or benefits and do not seem to have a place in the management of PD We conducted a r and omized , double-blind placebo controlled , community trial in rural Bangladesh in children 4 - 59 mo of age to compare the efficacy of a 5- and 10-d course of zinc therapy on the incidence and duration of diarrhea over the subsequent 90-d follow-up after initial treatment for an acute childhood diarrheal ( ACD ) episode . Children ( n = 1622 ) with ACD were r and omly allocated to either 5 or 10 d of zinc treatment . Female field workers visited each child daily , supervised the administration of zinc , recorded the duration of current episode , and the occurrence and duration of diarrhea over the subsequent 3 mo . The incidence of diarrhea over the 90 d of follow-up did not differ between the 5-d ( 1.08 ± 1.38 episodes ) and 10-d ( 1.02 ± 1.35 episodes ) groups ( P = 0.35 ) . Children in both groups experienced a comparable duration of diarrheal episodes ( 3.1 ± 5.6 d vs. 2.9 ± 5.6 d , 5-d vs. 10-d , respectively ; P = 0.64 ) with a mean difference between groups within the defined range of equivalence . Time to onset of the first episode and the proportion children experiencing diarrhea during the 90-d follow-up also did not differ between groups . These findings suggest that among Bangladeshi children , a 5-d zinc treatment for ACD is as efficacious as 10 d in preventing diarrhea in the subsequent 3 mo

A systematic review of topic-specific faith-based health programs determined that health outcomes can be improved though faith-based health interventions .

A university research team , in partnership with the Kansas United Method ist Church and a United Method ist philanthropy , facilitated planning and development of a statewide initiative to increase the capacity of laity-led health ministry teams . The purpose of this paper is to describe the processes utilized to design and implement an initiative to increase capacity for laity-led comprehensive health ministry among Kansas United Method ist Church congregations and to share the key elements of the initiative

Background Community-based approaches have been increasing in the effort to raise awareness and early detection for cancer and other chronic disease . However , many times , such interventions are tested in r and omized trials , become evidence -based , and then fail to reach further use in the community . Project HEAL ( Health through Early Awareness and Learning ) is an implementation trial that aims to compare two strategies of implementing evidence -based cancer communication interventions in African American faith-based organizations . Method This article describes the community-engaged process of transforming three evidence -based cancer communication interventions into a coherent , br and ed strategy for training community health advisors with two delivery mechanisms . Peer community health advisors receive training through either a traditional classroom approach ( with high technical assistance/support ) or a web-based training portal ( with low technical assistance/support ) . Results We describe the process , outline the intervention components , report on the pilot test , and conclude with lessons learned from each of these phases . Though the pilot phase showed feasibility , it result ed in modifications to data collection protocol s and team and community member roles and expectations . Conclusions Project HEAL offers a promising strategy to implement evidence -based interventions in community setting s through the use of technology . There could be wider implication s for chronic disease prevention and control Colorectal cancer screening has clear benefits in terms of mortality reduction ; however , it is still underutilized and especially among medically underserved population s , including African Americans , who also suffer a disproportionate colorectal cancer burden . This study consisted of a theory-driven ( health belief model ) spiritually based intervention aim ed at increasing screening among African Americans through a community health advisor-led educational series in 16 churches . Using a r and omized design , churches were assigned to receive either the spiritually based intervention or a nonspiritual comparison , which was the same in every way except that it did not contain spiritual/religious content and themes . Trained and certified peer community health advisors in each church led a series of two group educational sessions on colorectal cancer and screening . Study enrollees completed a baseline , 1-month , and 12-month follow-up survey at their churches . The interventions had significant pre – post impact on awareness of all four screening modalities , and self-report receipt of fecal occult blood test , flexible sigmoidoscopy , and colonoscopy . There were no significant study group differences in study outcomes , with the exception of fecal occult blood test utilization , whereas those in the nonspiritual intervention reported significantly greater pre – post change . Both of these community-engaged , theory-driven , culturally relevant approaches to increasing colorectal cancer awareness and screening appeared to have an impact on study outcomes . Although adding spiritual/religious themes to the intervention was appealing to the audience , it may not result in increased intervention efficacy OBJECTIVES Body and Soul was a collaborative effort among two research universities , a national voluntary agency ( American Cancer Society ) , and the National Institutes of Health to disseminate and evaluate under real-world conditions the impact of previously developed dietary interventions for African Americans . METHODS Body and Soul was constructed from two successful research -based interventions conducted in African-American churches . Components deemed essential from the prior interventions were combined , and then tested in a cluster r and omized-effectiveness trial . The primary outcome was fruit and vegetable intake measured with two types of food frequency question naires at baseline and 6-month follow-up . RESULTS At the 6-month follow-up , intervention participants showed significantly greater fruit and vegetable ( F&V ) intake relative to controls . Post-test differences were 0.7 and 1.4 servings for the 2-item and 17-item F&V frequency measures , respectively . Statistically significant positive changes in fat intake , motivation to eat F&V , social support , and efficacy to eat F&V were also observed . CONCLUSIONS The results suggest that research -based interventions , delivered collaboratively by community volunteers and a health-related voluntary agency , can be effectively implemented under real-world conditions BACKGROUND Using community-based participatory research ( CBPR ) as a guiding framework , a faith-based diet , nutrition and physical activity intervention for African Americans was implemented and evaluated as a small-scale r and omized trial . METHODS Five churches were recruited ( intervention=3 , control=2 ) , result ing in an enrolled sample of 106 adults ( intervention=74 , control=32 ) . The control group received a minimal intervention consisting of one educational workshop . The Living Well By Faith intervention group received a more intensive 8-week program . Classes were held twice a week and included educational workshops and exercise sessions . Both interventions were delivered at participating churches . Assessment s for program evaluation occurred at baseline and 2-month follow-up . These included weight , blood pressure , percent body fat , and physical fitness using the step test . RESULTS The sample was predominantly African American , female and well educated . At baseline , no significant differences between intervention and control groups were found for any of the primary endpoints . At 2-months follow up , the intervention group , compared to the control group , showed significant decreases in weight ( P<.02 ) , BMI ( P<.05 ) , and % body fat ( P<.03 ) , with a significant increase in physical fitness ( P<.02 ) . Systolic blood pressure also showed group differences in the predicted direction ( P=.10 ) . CONCLUSION This study provides an exemplar of CBPR . The results obtained are sufficiently promising to support more research involving similar interventions of longer duration and with longer-term follow-up for evaluation Objective . The authors tested the impact on cardiovascular risk profiles of African American women ages 40 years and older after one year of participation in one of three church-based nutrition and physical activity strategies : a st and ard behavioral group intervention , the st and ard intervention supplemented with spiritual strategies , or self-help strategies . Methods . Women were screened at baseline and after one year of participation . The authors analyzed intention-to-treat within group and between groups using a generalized estimating equations adjustment for intra-church clustering . Because spiritual strategies were added to the st and ard intervention by participants themselves , the results from both active groups were similar and , thus , combined for comparisons with the self-help group . Results . A total of 529 women from 16 churches enrolled . Intervention participants exhibited significant improvements in body weight ( −1.1 lbs ) , waist circumference ( −0.66 inches ) , systolic blood pressure ( −1.6 mmHg ) , dietary energy ( −117 kcal ) , dietary total fat ( −8 g ) , and sodium intake ( −145 mg ) . The self-help group did not . In the active intervention group , women in the top decile for weight loss at one year had even larger , clinical ly meaningful changes in risk outcomes ( −19.8 lbs ) . Conclusions . Intervention participants achieved clinical ly important improvements in cardiovascular disease risk profiles one year after program initiation , which did not occur in the self-help group . Church-based interventions can significantly benefit the cardiovascular health of African American women Physical activity ( PA ) is low among African American women despite awareness of its positive impact on health . Learning and Developing Individual Exercise Skills for a Better Life ( L.A.D.I.E.S. ) compares three strategies for increasing PA among African American women using a cluster r and omized , controlled trial . Underactive adult women from 30 churches ( n=15 participants /church ) were recruited . Churches were r and omized to a faith-based intervention , a non-faith based intervention , or an information only control group . Intervention groups will meet 25 times in group sessions with other women from their church over a 10-month period . Control group participants will receive st and ard educational material promoting PA . All participants will be followed for an additional 12 months to assess PA maintenance . Data will be collected at baseline , 10 , and 22 months . The primary outcome is PA ( steps/day , daily moderate-to-vigorous PA ) . We expect treatment effects indicating that assignment to either of the active interventions is associated with greater magnitude of change in PA compared to the control group . In exploratory analyses , we will test whether changes in the faith-based intervention group are greater than changes in the non-faith-based intervention group . L.A.D.I.E.S. focuses on a significant issue-increasing PA levels-in a segment of the population most in need of successful strategies for improving health . If successful , L.A.D.I.E.S. will advance the field by providing an approach that is successful for initiating and sustaining change in physical activity , which has been shown to be a primary risk factor for a variety of health outcomes , using churches as the point of delivery BACKGROUND Faith-based interventions using a community-based participatory approach hold promise for eliminating ethnic health disparities . This study evaluated the effects of a volunteer-led statewide program to increase physical activity among members of African-American churches . METHODS African Method ist Episcopal churches within six regions ( Conferences ) were r and omly assigned to receive training in the program immediately or 1 year later . A cohort of 20 r and omly selected churches and 571 members within them took part in telephone surveys at baseline ( May-September 2003 ) and 1 year ( May-August 2004 ) and 2 years later ( June-September 2005 ) . Primary outcomes were physical activity participation , meeting physical activity recommendations , and stage of readiness for physical activity change . Statistical analyses were completed in April 2006 . RESULTS Volunteers ( N=889 ) from 303 churches were trained . Among survey respondents , physical activity did not increase significantly over time , although 67 % were aware of the program . Program awareness was significantly related to all three physical activity outcomes and to fruit and vegetable consumption . Pastoral support was significantly associated with physical activity . CONCLUSIONS Although this intervention reached a large number of churches and created awareness of intervention components , no effects on physical activity behaviors were found . Potential reasons for the lack of significant effects are discussed Despite multidisciplinary efforts to control the nation 's obesity epidemic , obesity has persisted as one of the U.S. 's top public health problems , particularly among African Americans . Innovative approaches to address obesity that are sensitive to the unique issues of African Americans are needed . Thus , a faith-based weight-loss intervention using a community-based participatory research approach was developed , implemented , and evaluated with a rural African American faith community . A two-group , quasi-experimental , delayed intervention design was used , with church as the unit of assignment ( treatment n = 2 , control n = 2 ) and individual as the unit of observation ( treatment n = 36 , control n = 37 ) . Weekly small groups led by trained community members met for 8 weeks and emphasized healthy nutrition , physical activity , and faith 's connection with health . The mean weight loss of the treatment group was 3.60 ± 0.64 lbs . compared to the 0.59 ± 0.59-lb loss of the control group OBJECTIVE To examine the extent to which participants in a combined physical activity ( PA ) and dietary intervention achieved changes in multiple health behaviors . DESIGN Group r and omized trial ; includes only participants assigned to the intervention group only . SETTING Thirty-six churches in South Carolina . PARTICIPANTS Three hundred sixty African American church members . INTERVENTION A 15-month PA and dietary intervention , guided by the structural ecological model , targeting environmental ( i.e. , social , cultural , physical ) and organizational ( ie , policies , practice s ) changes within the church . MAIN OUTCOME MEASURES Self-reported PA , fruit and vegetable consumption , fat- , and fiber-related behaviors . ANALYSIS Change in each behavior was defined as unadjusted pretest-posttest improvement ≥ 0.20 of the baseline st and ard deviation . The total number and each combination of behaviors changed were calculated . RESULTS Up to 19 % changed no health behaviors as defined above , 31 % changed 1 health behavior , 31 % changed 2 health behaviors , 13 % changed 3 health behaviors , and 5 % changed all 4 of the targeted health behaviors . Combinations of multiple behavior change included PA and dietary behaviors , which suggests that both behaviors can be changed simultaneously . CONCLUSIONS AND IMPLICATION S Nearly half of participants changed at least 2 health behaviors . Faith-based interventions targeting environmental and organizational change can successfully change multiple behaviors , potentially leading to greater improvements in public health BACKGROUND African Americans are at increased risk for cardiovascular disease and cancer morbidity and mortality . Physical activity and healthy dietary practice s can reduce this risk . The church is a promising setting to address health disparities , and community-based participatory research is a preferred approach . OBJECTIVES Using a community-based participatory approach and the social ecologic model , the FAN trial aims to increase self-reported moderate-intensity physical activity and fruit and vegetable consumption and reduce blood pressure in African American church members . Secondary aims are to increase objective ly measured moderate-intensity physical activity and fiber/whole grain consumption and reduce fat consumption . DESIGN FAN is a group r and omized trial ( GRT ) with two levels of clustering : participants ( N=1279 ; n=316 accelerometer subgroup ) within church and church within church cluster . In the first wave , seven clusters including 23 churches were r and omized to an immediate intervention or delayed intervention . In subsequent waves , 51 churches were r and omized to an immediate or delayed intervention . METHODS Church committee members , pastors , and cooks participate in full-day trainings to learn how to implement physical activity and dietary changes in the church . Monthly mailings and technical assistance calls are delivered over the 15-month intervention . Members complete measurements at baseline and 15 months . A detailed process evaluation is included . SUMMARY FAN focuses on modifying the social , cultural , and policy environment in a faith-based setting . The use of a community-based participatory research approach , engagement of church leaders , inclusion of a detailed process evaluation , and a formal plan for sustainability and dissemination make FAN unique BACKGROUND Faith-based interventions hold promise for promoting health in ethnic minority population s. To date , however , few of these interventions have used a community-based participatory research ( CBPR ) approach , have targeted both physical activity and healthy eating , and have focused on structural changes in the church . PURPOSE To report the results of a group r and omized CBPR intervention targeting physical activity and healthy eating in African-American churches . DESIGN Group RCT . Data were collected from 2007 to 2011 . Statistical analyses were conducted in 2012 . SETTING / PARTICIPANTS Seventy-four African Method ist Episcopal ( AME ) churches in South Carolina and 1257 members within them participated in the study . INTERVENTION Churches were r and omized to an immediate ( intervention ) or delayed ( control ) 15-month intervention that targeted organizational and environmental changes consistent with the structural ecologic model . A CBPR approach guided intervention development . Intervention churches attended a full-day committee training and a full-day cook training . They also received a stipend and 15 months of mailings and technical assistance calls to support intervention implementation . MAIN OUTCOME MEASURES Primary outcomes were self-reported moderate- to vigorous-intensity physical activity ( MVPA ) , self-reported fruit and vegetable consumption , and measured blood pressure . Secondary outcomes were self-reported fat- and fiber-related behaviors . Measurements were taken at baseline and 15 months . Intent-to-treat repeated measures ANOVA tested group X time interactions , controlling for church clustering , wave , and size , and participant age , gender , and education . Post hoc ANCOVAs were conducted with measurement completers . RESULTS There was a significant effect favoring the intervention group in self-reported leisure-time MVPA ( d=0.18 , p=0.02 ) , but no effect for other outcomes . ANCOVA analyses showed an intervention effect for self-reported leisure-time MVPA ( d=0.17 , p=0.03 ) and self-reported fruit and vegetable consumption ( d=0.17 , p=0.03 ) . Trainings were evaluated very positively ( training evaluation item means of 4.2 - 4.8 on a 5-point scale ) . CONCLUSIONS This faith-based structural intervention using a CBPR framework showed small but significant increases in self-reported leisure-time MVPA . This program has potential for broad-based dissemination and reach . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT00379925 INTRODUCTION Although cardiovascular diseases ( CVD ) are the leading cause of death among Americans , significant disparities persist in CVD prevalence , morbidity , and mortality based on race and ethnicity . However , few studies have examined risk factor reduction among the poor and ethnic minorities . METHODS Community-based participatory research ( CBPR ) study using a cluster r and omized design --African-American church congregations are the units of r and omization and individuals within the congregations are the units of analysis . Outcome variables include dietary change ( Diet History Question naire ) , level of physical activity ( 7-Day Physical Activity Recall ) , lipoprotein levels , blood pressure , fasting glucose , and hemoglobin A1c . RESULTS Eighteen ( 18 ) church congregations were r and omized to either a health maintenance intervention or a control condition . Complete data were obtained on 392 African-American individuals , 18 to 70 years of age , predominantly employed women with more than a high school diploma . Treatment and intervention groups were similar at baseline on saturated fat intake , metabolic equivalent of tasks ( METS ) per day , and other risk factors for CVD . CONCLUSIONS The GoodNEWS trial successfully recruited and evaluated CVD-related risk among African-American participants using a CBPR approach . Several logistical challenges result ed in extending the recruitment , preliminary training , and measurement periods . The challenges were overcome with the assistance of a local community consultant and a professional event planner . Our experience supports the need for incorporating non-traditional community-based staff into the design and operational plan of CBPR trials Purpose . To examine associations among psychosocial constructs of behavior change and postintervention changes in diet and physical activity ( PA ) . Design . Quasi-experimental with cluster ( church ) treatment assignment . Setting . Churches ( n = 8) in a rural , southern region of the United States . Subjects . A total of 403 African-American adults participating in the Delta Body and Soul study . Intervention . Six-month diet and PA intervention consisting of monthly didactic educational sessions with specific emphasis on increasing consumption of fruits , vegetables , and whole grains , and decreasing consumption of added sugars . Self-directed PA was promoted throughout the intervention . Measures . Vali date d surveys for all dietary , PA , and psychosocial measures . Analysis . Secondary analysis using generalized linear mixed models to test for significant intervention effects on psychosocial constructs and for significant associations between changes in psychosocial constructs and changes in diet and PA outcomes after controlling for covariates . Results . Intervention effects were apparent for several dietary psychosocial constructs ( improvements ranging from .5 to 2.0 points ) , but only one PA construct ( decisional balance for exercise ) . Changes in psychosocial constructs , including self-efficacy , social support , and decisional balance , were significant predictors of dietary outcome changes ( model coefficients ranging from .03 to .42 ) , but not PA changes . Conclusion . Underst and ing which psychosocial constructs predict improvements in dietary and PA behaviors helps inform theoretical mechanisms of action and identify social and behavioral processes to target in faith-based interventions

Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group . No significant differences were found in the remaining comparisons with regard to lung function . Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate , but pooled estimates of the level of benefit were very limited . The best evidence is for inhaled tobramycin .

BACKGROUND Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis . Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older . The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function . This is an up date of a previously published review . OBJECTIVES To evaluate the effects long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes ( lung function , frequency of exacerbations and nutrition ) , quality of life and adverse events ( including drug sensitivity reactions and survival ) .

RATIONALE Inhaled tobramycin has been shown to transiently clear Pseudomonas from lower airways in early cystic fibrosis ( CF ) , but does not markedly reduce lung inflammation , a key factor in disease progression . OBJECTIVE Test the hypothesis that systemic antibiotics are more effective than inhaled antibiotics for reducing lower airways inflammation . METHODS Clinical ly stable CF children with recent Pseudomonas were r and omized to receive 4 weeks of inhaled tobramycin or 2 weeks of systemic antibiotics ( intravenous ceftazidime and tobramycin ) . Bronchoalveolar lavage fluid was obtained just before and 4 - 6 weeks after treatment . The primary outcome was change in % neutrophils in lavage fluid . RESULTS Fifteen subjects ( inhaled = 6 , systemic = 9 ) completed the protocol . Three Systemic Group subjects could not have central venous access established and were treated with oral ciprofloxacin ( plus inhaled tobramycin ) for 2 weeks as an alternative " systemic " regimen , per protocol . Groups were well matched in age , markers of disease severity , and initial % neutrophils . The Systemic Group showed a modest median change in percent neutrophils ( -7 % ) which was not statistically significant compared to inhaled ( + 5.4 % , P = 0.07 ) . However , the Systemic Group had significantly greater reductions in total cells ( -50 % vs. -3 % , P < 0.01 ) and neutrophils ( -74 % vs. -10 % , P = 0.02 ) per ml lavage fluid . Both groups had reduced bacterial quantity after treatment , but there was no significant difference between groups . CONCLUSIONS In clinical ly stable children with CF , systemic antibiotics result in greater short-term reduction in lower airways inflammation than inhaled antibiotics Purpose To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis ( CF ) aged ≥6 years with chronic Pseudomonas aeruginosa lung infection . Study design and methods A prospect i ve , central ly r and omised , phase III , open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection . Patients were r and omised to Colobreathe dry powder for inhalation ( CDPI , one capsule containing colistimethate sodium 1 662 500 IU , twice daily ) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution ( TIS ) . Study duration was 24 weeks . Results 380 patients were r and omised . After logarithmic transformation of data due to a non-normal distribution , adjusted mean difference between treatment groups ( CDPI vs TIS ) in change in forced expiratory volume in 1 s ( FEV1 % predicted ) at week 24 was −0.98 % ( 95 % CI −2.74 % to 0.86 % ) in the intention-to-treat population ( n=373 ) and −0.56 % ( 95 % CI −2.71 % to 1.70 % ) in the per protocol population ( n=261 ) . The proportion of colistin-resistant isolates in both groups was ≤1.1 % . The number of adverse events was similar in both groups . Significantly more patients receiving CDPI rated their device as ‘ very easy or easy to use ’ ( 90.7 % vs 53.9 % respectively ; p<0.001 ) . Conclusion CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment . There was no emergence of resistance of P aeruginosa to colistin . Overall , CDPI was well tolerated . Trial Reg No EudraCT 2004 - 003675 - 36 OBJECTIVES To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis ( CF ) , rather than st and ard therapy , was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions . STUDY DESIGN Costs were assessed in a r and omized controlled trial conducted in Australia and New Zeal and on infants diagnosed with CF after newborn screening and assigned to receive either BAL-directed or st and ard therapy until they reached 5 years of age . A health care funder perspective was adopted . Re source use measurement was based on st and ardized data collection forms administered for patients across all sites . Unit costs were obtained primarily from government schedules . RESULTS Mean costs per child during the study period were Australian dollars (AUD)92 860 in BAL-directed therapy group and AUD90 958 in st and ard therapy group ( mean difference AUD1902 , 95 % CI AUD-27 782 to 31 586 , P = .90 ) . Mean hospital costs per child during the study period were AUD57 302 in the BAL-directed therapy group and AUD66 590 in the st and ard therapy group ( mean difference AUD-9288 ; 95 % CI AUD-35 252 to 16 676 , P = .48 ) . CONCLUSIONS BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a st and ard protocol based upon clinical features and oropharyngeal culture results alone . Following on our previous findings that BAL-directed treatment offers no clinical advantage over st and ard therapy at age 5 years , flexible bronchoscopy with BAL can not be recommended for the routine management of preschool children with CF on the basis of overall cost savings Six children with cystic fibrosis who had persistently had Pseudomonas aeruginosa isolated from their respiratory tract , completed a double-blind cross-over comparison of oral flucloxacillin and nebulized aminoglycoside versus double placebo . The patients had higher FEV1 results at the end of the month of active treatment than after the month of placebo Background Initial pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis ( CF ) is currently treated with intensive antibiotic therapy . At this stage , inflammation and tissue injury might have already occurred . Moreover , bacterial eradication is not always achieved . Prophylactic treatment against P aeruginosa seemed to have a preventive effect in retrospective studies . A study was undertaken to establish prospect ively the effect of cycled prophylactic treatment on prevention of initial P aeruginosa infection in children with CF . Methods This 3-year triple-blind r and omised controlled trial included 65 children with CF without P aeruginosa infection . Intervention existed of 3-monthly 3-week treatments with oral ciprofloxacin and inhaled colistin or both placebo controls . The primary outcome was P aeruginosa infection . Secondary outcomes were serum anti-Pseudomonas antibodies , pulmonary function , exacerbations , chest x-ray scores , inflammation parameters , respiratory pathogens and antimicrobial resistance . Results There was no difference in acquisition of P aeruginosa infection between the control and treatment groups ( annual incidence 14 % vs 11 % ; HR 0.738 , 95 % CI 0.299 to 1.822 ) . Anti-Pseudomonas antibodies emerged earlier in the control group , but this difference had disappeared after 3 years . Chronic infection was observed in 19 % of controls and 12 % of treated patients . Decline in pulmonary function and other clinical outcomes did not differ between the two groups . In the treatment group , significantly fewer Gram-positive bacteria and Enterobacteriaceae were observed but there were more non-P aeruginosa non-fermentative Gram-negative bacteria . Conclusions Three-monthly cycled anti-P aeruginosa prophylaxis does not reduce the risk of initial and chronic infection in P aeruginosa-negative children with CF of all ages . Shifts in bacterial colonisation dem and caution . Trial Registration Number IS RCT N 11604593 Rationale In cystic fibrosis ( CF ) , the paranasal sinuses are sites of first and persistent colonization by pathogens such as Pseudomonas aeruginosa . Pathogens subsequently descend to the lower airways , with P. aeruginosa remaining the primary cause of premature death in patients with the inherited disease . Unlike conventional aerosols , vibrating aerosols applied with the PARI Sinus ™ nebulizer deposit drugs into the paranasal sinuses . This trial assessed the effects of vibrating sinonasal inhalation of the antibiotic tobramycin in CF patients positive for P. aeruginosa in nasal lavage . Objectives To evaluate the effects of sinonasal inhalation of tobramycin on P. aeruginosa quantification in nasal lavage ; and on patient quality of life , measured with the Sino-Nasal Outcome Test ( SNOT-20 ) , and otologic and renal safety and tolerability . Methods Patients were r and omized to inhalation of tobramycin ( 80 mg/2 mL ) or placebo ( 2 mL isotonic saline ) once daily ( 4 minutes/nostril ) with the PARI Sinus ™ nebulizer over 28 days , with all patients eligible for a subsequent course of open-label inhalation of tobramycin for 28 days . Nasal lavage was obtained before starting and 2 days after the end of each treatment period by rinsing each nostril with 10 mL of isotonic saline . Results Nine patients participated , six initially receiving tobramycin and three placebo . Sinonasal inhalation was well tolerated , with serum tobramycin < 0.5 mg/L and stable creatinine . P. aeruginosa quantity decreased in four of six ( 67 % ) patients given tobramycin , compared with zero of three given placebo ( non-significant ) . SNOT-20 scores were significantly lower in the tobramycin than in the placebo group ( P=0.033 ) . Conclusion Sinonasal inhalation of vibrating antibiotic aerosols appears promising for reducing pathogen colonization of paranasal sinuses and for control of symptoms in patients with CF BACKGROUND Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis ( CF ) patients chronically infected with Pseudomonas aeruginosa . Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin . However , nebulized colistin can cause bronchoconstriction in CF patients . Therefore , in the progress of developing a dry powder formula , the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects . To investigate the side effects , a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF- patients . METHODS Nine CF- patients chronically infected with P. aeruginosa participated in a double blind , r and omized cross over study . On two visits to the outpatient clinic , patients were su bmi tted to either nebulized colistin sulphate or colistin sulphomethate solution . Lung function tests were performed immediately before and 15 and 30 min after nebulization . RESULTS Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate . A significant decrease in mean changes ( SD ) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of -7.3 % ( 8.6 % ) , -5.7 % ( 7.3 % ) and -8.4 % ( 7.5 % ) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate ( P < 0.05 ) . Seven patients were not able to complete the nebulization of colistin sulphate because of throat irritation and severe cough . CONCLUSION Based on these results it was concluded that inhalation with nebulized colistin sulphate is not suitable for treatment of CF patients chronically infected with P. aeruginosa . Colistin sulphomethate is the drug of choice for pulmonary administration of colistin BACKGROUND A light-porous-particle , dry-powder formulation of tobramycin was developed , using PulmoSphere ® technology , to improve airway delivery efficiency , substantially reduce delivery time , and improve patient convenience and satisfaction . We evaluated the safety , efficacy and convenience of tobramycin inhalation powder ( TIP ™ ) versus tobramycin inhalation solution ( TIS , TOBI ® ) for treating Pseudomonas aeruginosa infection in cystic fibrosis ( CF ) patients aged ≥6 years . METHODS In this open-label study , 553 patients were r and omized 3:2 to TIP ( total 112 mg tobramycin ) via the Novartis T-326 Inhaler or TIS 300mg/5mL via PARI LC ® PLUS nebulizer twice daily for three treatment cycles ( 28 days on-drug , 28 days off-drug ) . Safety , efficacy , and treatment satisfaction outcomes were evaluated . RESULTS TIP was generally well-tolerated ; adverse events were similar in both groups . The rate of cough suspected to be study drug related was higher in TIP-treated patients ( TIP : 25.3 % ; TIS : 4.3 % ) , as was the overall discontinuation rate ( TIP : 26.9 % ; TIS : 18.2 % ) . Increases in FEV(1)% predicted from baseline to Day 28 of Cycle 3 were similar between groups ; the mean reduction in sputum P. aeruginosa density ( log(10 ) CFU/g ) on Day 28 of Cycle 3 was also comparable between groups . Administration time was significantly less for TIP ( mean : 5.6 versus 19.7min , p<0.0001 ) . Treatment satisfaction was significantly higher for TIP for effectiveness , convenience , and global satisfaction . CONCLUSIONS TIP has a safety and efficacy profile comparable with TIS , and offers a far more convenient treatment option for pseudomonas lung infection in CF A r and omized cross-over study was undertaken to compare nebulized ( 1 ) ceftazidime with ( 2 ) a combination of gentamicin and carbenicillin , and ( 3 ) saline , each given for 4 months , in patients with cystic fibrosis infected with Pseudomonas aeruginosa . Mean peak expiratory flow on ceftazidime , 299 litres/min , and on gentamicin and carbenicillin , 297 litres/min , were greater than on saline , 278 litres/min ( P less than 0.02 and P less than 0.05 respectively ) . Similarly mean forced expiratory volume in 1 second on ceftazidime , 1.70 litres , and on gentamicin and carbenicillin , 1.70 litres , were greater than on saline , 1.48 litres ( P less than 0.02 and P less than 0.01 respectively ) . Mean forced vital capacity on gentamicin and carbenicillin , 2.93 litres , was also greater than on saline ( P less than 0.05 ) . We were unable to demonstrate any difference in efficacy between the antibiotic regimens . The patients were admitted to hospital less frequently during the study year compared with the previous year ( P less than 0.05 ) . Sixty-nine per cent of patients had a clinical ly significant ( 20 % ) increase in forced expiratory volume in 1 second on an antibiotic regimen compared with that on entry to study , but a minority of patients appear not to respond to this form of treatment INTRODUCTION Aerosolized tobramycin is a st and ard of care for chronic Pseudomonas aeruginosa ( Pa ) infection in patients with cystic fibrosis ( CF ) . OBJECTIVES The long-term safety and efficacy of intermittent ( 28-day " on"/"off " cycles ) inhaled tobramycin nebulization solution 300 mg/4 ml ( TNS4 , Bramitob( ® )/Bethkis ( ® ) ) was assessed over 56 weeks in CF patients aged ≥6 years having baseline 1 sec forced expiratory volume ( FEV(1 ) ) 40 - 80 % predicted . METHODS Patients were initially r and omized in an 8-week open-label trial ( core phase ) to compare TNS4 ( N = 159 ) and tobramycin 300 mg/5 ml ( TNS5 , TOBI ( ® ) ) ( N = 165 ) . A subset of patients continued in a 48-week , single-arm extension receiving TNS4 only . The primary endpoint of the core phase was to demonstrate the non-inferiority of TNS4 compared to TNS5 in terms of absolute change from baseline to week 4 in FEV(1 ) % predicted . The assessment of long-term safety was the primary purpose of the extension phase . Throughout all phases of the study , microbiological assessment s , adverse events , and audiometry findings were also evaluated . RESULTS In the core phase ( N = 321 ) , FEV(1 ) ( % predicted ) increased from baseline ( absolute change ) following a single on-treatment cycle for both TNS4 ( 7.0 % ) and TNS5 ( 7.5 % ) and the non-inferiority between treatments was met [ difference between treatments of -0.5 ( 95 % CI : -2.6 ; 1.6 ) ] . These improvements were maintained throughout the extension phase ( N = 209 ) , ranging throughout the study between 5.1 % ( 95 % CI : 3.2 ; 6.9 ) and 8.1 % ( 95 % CI : 6.8 ; 9.4 ) compared to baseline . Pa sputum count reductions ranged between 0.6 ( 95 % CI : 0.2 ; 0.9 ) to 2.3 ( 95 % CI : 2.0 ; 2.6 ) log10 CFU/g throughout the 56 weeks . No remarkable safety issues were identified throughout both study phases , with similar percentages of patients reporting adverse events in the two treatment groups during the 8-week core phase [ TNS4 ( 31.4 % ) ; TNS5 ( 28.0 % ) ] . CONCLUSIONS Overall , TNS4 demonstrated short-term clinical benefits similar to TNS5 which were maintained during the long-term use of TNS4 and was also associated with a favorable tolerability profile BACKGROUND Aztreonam lysine for inhalation ( AZLI ) is being developed for treatment of CF patients with Pseudomonas aeruginosa airway infection . METHODS This double-blind , r and omized , placebo-controlled Phase 2 study evaluated the safety , tolerability and efficacy of 75 and 225 mg AZLI administered BID for 14 days using the eFlow Electronic Nebulizer ( Pari Innovative Manufacturers , Inc. , Midlothian , VA ) . Patients were 13 years and older with FEV1>or=40 % predicted , chronic P. aeruginosa infection , and had used no anti-pseudomonal antibiotics for 56 days . RESULTS Of 131 patients screened , 105 received AZLI or placebo . Mean age was 26 years and mean FEV1 percent predicted was 77 % at baseline . There was a statistically significant reduction , compared to placebo , in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 ( P<0.001 ) . The planned primary analysis , percent change in FEV1 at Day 14 , demonstrated no statistically significant difference . Post hoc analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75 % predicted in the 225 mg AZLI group . Bronchodilator use was associated with greater improvement in FEV1 , as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group . Adverse events were similar between placebo and AZLI although there was a trend toward increased respiratory symptoms in the 225 mg AZLI group . CONCLUSION These data support the further development of AZLI and provide information for the design of subsequent studies Aminoglycoside-resistance mechanisms were characterized in Pseudomonas aeruginosa isolates from cystic fibrosis ( CF ) patients during a recent clinical trial of inhaled tobramycin . Impermeability , in which bacteria have reduced susceptibility to all aminoglycosides , was the predominant mode of resistance in isolates obtained both before and after 6 months of cyclic treatment with tobramycin or placebo administered by aerosol . Enzymatic resistance mechanisms were found in fewer than 10 % of resistant isolates . P. aeruginosa from individual patients could be grouped on the basis of genetic relatedness . When enzymatic resistance was involved , all isolates in a group had elevated tobramycin MICs . When impermeability occurred , MICs of a genotypic group varied from susceptible to resistant . These findings suggest that impermeability resistance occurs in only a fraction of the P. aeruginosa population in lungs of persons with CF and that this form of resistance arises by a process involving multiple small changes in MIC Rationale Antibiotic therapy for early Pseudomonas aeruginosa infection in patients with cystic fibrosis ( CF ) is effective , but the optimal therapeutic regimen and duration for early treatment remains unclear . The EarLy Inhaled Tobramycin for Eradication ( ELITE ) study was design ed to assess the efficacy and safety of two regimens ( 28 and 56 days ) of tobramycin inhalation solution ( TIS ) 300 mg/5 ml twice daily for the treatment of early onset P aeruginosa infection in patients with CF . Methods In this open-label r and omised multicentre study , patients with CF ( aged ≥6 months ) with early P aeruginosa infection were treated for 28 days with TIS twice daily administered by the PARI LC PLUS ( PARI GmbH , Starnberg , Germany ) jet nebuliser . After 28 days , patients were r and omised 1:1 to either stop TIS ( n=45 ) or to receive a further 28 days of TIS ( n=43 ) . The primary endpoint was the median time to recurrence of P aeruginosa ( any strain ) . Secondary endpoints included the proportion of patients free of P aeruginosa infection 1 month after cessation of therapy and safety assessment s. Results The median time to recurrence of P aeruginosa ( any strain ) was similar between the two groups . In total , 93 % and 92 % of the patients were free of P aeruginosa infection 1 month after the end of treatment and 66 % and 69 % remained free at the final visit in the 28-day and 56-day groups , respectively . TIS was well tolerated . Conclusions Treatment with TIS for 28 days is an effective and well tolerated therapy for early P aeruginosa infection in patients with CF . Trial registration number NCT00391976 Background Newborn screening allows novel treatments for cystic fibrosis ( CF ) to be trialled in early childhood before irreversible lung injury occurs . As respiratory exacerbations are a potential trial outcome variable , we determined their rate , duration and clinical features in preschool children with CF ; and whether they were associated with growth , lung structure and function at age 5 years . Methods Respiratory exacerbations were recorded prospect ively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years , when all participants underwent clinical assessment , chest CT scans and spirometry . Results 168 children ( 88 boys ) experienced 2080 exacerbations , at an average rate of 3.66 exacerbations per person-year ; 80.1 % were community managed and 19.9 % required hospital admission . There was an average increase in exacerbation rate of 9 % ( 95 % CI 4 % to 14 % ; p<0.001 ) per year of age . Exacerbation rate differed by site ( p<0.001 ) and was 26 % lower ( 95 % CI 12 % to 38 % ) in children receiving 12 months of prophylactic antibiotics . The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores . Ever having a hospital-managed exacerbation was associated with bronchiectasis ( OR 2.67 , 95 % CI 1.13 to 6.31 ) in chest CT scans , and lower weight z scores at 5 years of age ( coefficient −0.39 , 95 % CI −0.74 to −0.05 ) . Conclusions Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group OBJECTIVE The paranasal sinuses are almost always involved in cystic fibrosis , and chronic rhinosinusitis and nasal polyps are very frequent in the disease . Hereby , the patients ' quality of life and their overall health are relevantly impaired . Although dornase alfa , a mucolytic agent , may also be effective in the upper airways , deposition of inhaled drugs into paranasal sinuses is substantially limited . The novel PARI SINUS ™ nebuliser has been shown in deposition studies to deliver aerosol into paranasal sinuses but has not yet been clinical ly tested . This DBPC pilot-trial applying dornase alfa aims to evaluate outcome parameters and sample sizes for a subsequent efficacy trial . METHODS Primary outcome parameters assessed were the Sino-Nasal Outcome Test ( SNOT-20 , a disease-specific quality of life assessment tool ) and ventilated volume as measured by magnetic resonance imaging . Five CF patients were r and omised to inhale either dornase alfa or 0.9 % NaCl for 28 days and , after a wash-out period of 28 days , crossed over to the alternative treatment . RESULTS Whereas normal saline was not associated with relevant changes in SNOT-20 scores , dornase alfa improved quality of life ( p=0.043 ) . MRI results showed no definite trend . CONCLUSION This first clinical study with the novel device gives promising results for the new therapeutic concept of sinonasal inhalation with vibrating aerosols in regard to further analysis involving larger collectives BACKGROUND Previous aztreonam for inhalation solution ( AZLI ) studies included patients with cystic fibrosis , Pseudomonas aeruginosa ( PA ) airway infection , and forced expiratory volume in 1s ( FEV(1 ) ) 25 % to 75 % predicted . This double-blind , multicenter , r and omized , placebo-controlled trial enrolled patients ( ≥6 years ) with FEV(1)>75 % predicted . METHODS AZLI 75 mg ( n=76 ) or placebo ( n=81 ) was administered 3-times daily for 28days with a 14-day follow-up . RESULTS Day 28 treatment effects were 1.8points for CFQ-R-Respiratory Symptoms Scale ( 95%CI : -2.8 , 6.4 ; p=0.443 ; primary endpoint ) ; -1.2 for log(10 ) sputum PA colony-forming units ( p=0.016 ; favoring AZLI ) , and 2.7 % for relative FEV(1)% predicted ( p=0.021 ; favoring AZLI ) . Treatment effects favoring AZLI were larger for patients with baseline FEV(1 ) < 90 % predicted compared to ≥90 % predicted . AZLI was well-tolerated . CONCLUSIONS Effects on respiratory symptoms were modest ; however , FEV(1 ) improvements and bacterial density reductions support a possible role for AZLI in these relatively healthy patients Rationale Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition . Objectives To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis ( CF ) patients chronically infected with P aeruginosa . Methods 105 subjects were evaluated in double-blind , placebo-controlled studies . Subjects were r and omised to once-daily Arikace ( 70 , 140 , 280 and 560 mg ; n=7 , 5 , 21 and 36 subjects ) or placebo ( n=36 ) for 28 days . Primary outcomes included safety and tolerability . Secondary outcomes included lung function ( forced expiratory volume at one second ( FEV1 ) ) , P aeruginosa density in sputum , and the Cystic Fibrosis Quality of Life Question naire — Revised ( CFQ-R ) . Results The adverse event profile was similar among Arikace and placebo subjects . The relative change in FEV1 was higher in the 560 mg dose group at day 28 ( p=0.033 ) and at day 56 ( 28 days post-treatment , 0.093L±0.203 vs −0.032L±0.119 ; p=0.003 ) versus placebo . Sputum P aeruginosa density decreased > 1 log in the 560 mg group versus placebo ( days 14 , 28 and 35 ; p=0.021 ) . The Respiratory Domain of the CFQ-R increased by the Minimal Clinical ly Important Difference ( MCID ) in 67 % of Arikace subjects ( 560 mg ) versus 36 % of placebo ( p=0.006 ) , and correlated with FEV1 improvements at days 14 , 28 and 42 ( p<0.05 ) . An open-label extension ( 560 mg Arikace ) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density ( n=49 ) . Conclusions Once-daily Arikace demonstrated acute tolerability , safety , biologic activity and efficacy in patients with CF with P aeruginosa infection STUDY OBJECTIVE To determine the effect of long-term suppression of Pseudomonas aeruginosa on lung function and other clinical end points in adolescent patients with cystic fibrosis ( CF ) . DESIGN Two identical , r and omized , placebo-controlled trials followed by three open-label follow-on trials . SETTING Sixty-nine CF study centers in the United States . INTERVENTIONS Active drug consisting of a 300-mg tobramycin solution for inhalation ( TSI ) . PATIENTS One hundred twenty-eight adolescent CF patients ( aged 13 to 17 years ) with P aeruginosa and mild-to-moderate lung disease ( FEV(1 ) percent predicted > or = 25 % and < or = 75 % ) . MEASUREMENTS Pulmonary function , P aeruginosa colony forming unit density , incidence of hospitalization and IV antibiotic use , weight gain , and aminoglycoside toxicity were monitored . RESULTS At the end of the first three 28-day cycles of TSI treatment , patients originally r and omized to TSI and placebo treatments exhibited improvements in FEV(1 ) percent predicted of 13.5 % and 9.4 % , respectively . FEV(1 ) percent predicted was maintained above the value at initiation of TSI treatment in both groups . At the end of the last " on-drug " period ( 92 weeks ) , patients originally r and omized to TSI and placebo treatments showed improvements of 14.3 % and 1.8 % , respectively . Improvement in pulmonary function was significantly correlated with reduction in P aeruginosa colony forming unit density ( p = 0.0001 ) . The average number of hospitalizations and IV antibiotic courses did not increase over time . TSI treatment was associated with increased weight gain and body mass index . P aeruginosa susceptibility to tobramycin decreased slightly over time , but this was not correlated with clinical response . CONCLUSIONS TSI treatment improved pulmonary function and weight gain in adolescent patients with CF over a 2-year period of long-term , intermittent use The major cause of morbidity and mortality in patients with cystic fibrosis ( CF ) is respiratory disease ( Penketh et al. , Thorax 1987 ; 42 : 526 - 532 ) . Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa ( Ramsey et al. , N Engl J Med 1999 ; 340 : 23 - 30 ; Ramsey et al. , Proceedings of the 12th Annual North American Cystic Fibrosis Conference , 1998 , Montreal , Canada ; Ramsey et al. , Abstract from 23rd European Cystic Fibrosis Conference , 1999 , the Hague , Netherl and s ) . In Europe , the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread . A recently published study compared the efficacy and safety of tobramycin nebuliser solution ( TNS ) and nebulised colistin in CF patients . One hundred and fifteen patients were r and omised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV(1 ) and sputum P. aeruginosa density . TNS produced a mean 6.7 % improvement in lung function ( P=0.006 ) , whilst there was no significant improvement in the colistin-treated patients . The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin ( P=0.008 ) . The safety profile of both treatments was good . We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin CONTEXT Early pulmonary infection in children with cystic fibrosis leads to increased morbidity and mortality . Despite wide use of oropharyngeal cultures to identify pulmonary infection , concerns remain over their diagnostic accuracy . While bronchoalveolar lavage ( BAL ) is an alternative diagnostic tool , evidence for its clinical benefit is lacking . OBJECTIVE To determine if BAL-directed therapy for pulmonary exacerbations during the first 5 years of life provides better outcomes than current st and ard practice relying on clinical features and oropharyngeal cultures . DESIGN , SETTING , AND PARTICIPANTS The Australasian Cystic Fibrosis Bronchoalveolar Lavage ( ACFBAL ) r and omized controlled trial , recruiting infants diagnosed with cystic fibrosis through newborn screening programs in 8 Australasian cystic fibrosis centers . Recruitment occurred between June 1 , 1999 , and April 30 , 2005 , with the study ending on December 31 , 2009 . INTERVENTIONS BAL-directed ( n = 84 ) or st and ard ( n = 86 ) therapy until age 5 years . The BAL-directed therapy group underwent BAL before age 6 months when well , when hospitalized for pulmonary exacerbations , if Pseudomonas aeruginosa was detected in oropharyngeal specimens , and after P. aeruginosa eradication therapy . Treatment was prescribed according to BAL or oropharyngeal culture results . MAIN OUTCOME MEASURES Primary outcomes at age 5 years were prevalence of P. aeruginosa on BAL cultures and total cystic fibrosis computed tomography ( CF-CT ) score ( as a percentage of the maximum score ) on high-resolution chest CT scan . RESULTS Of 267 infants diagnosed with cystic fibrosis following newborn screening , 170 were enrolled and r and omized , and 157 completed the study . At age 5 years , 8 of 79 children ( 10 % ) in the BAL-directed therapy group and 9 of 76 ( 12 % ) in the st and ard therapy group had P. aeruginosa in final BAL cultures ( risk difference , -1.7 % [ 95 % confidence interval , -11.6 % to 8.1 % ] ; P = .73 ) . Mean total CF-CT scores for the BAL-directed therapy and st and ard therapy groups were 3.0 % and 2.8 % , respectively ( mean difference , 0.19 % [ 95 % confidence interval , -0.94 % to 1.33 % ] ; P = .74 ) . CONCLUSION Among infants diagnosed with cystic fibrosis , BAL-directed therapy did not result in a lower prevalence of P. aeruginosa infection or lower total CF-CT score when compared with st and ard therapy at age 5 years . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12605000665639 Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis ( CF ) patients . The purpose of this trial was to assess the efficacy and safety of tobramycin nebuliser solution ( TNS ) and nebulised colistin in CF patients chronically infected with P. aeruginosa . One-hundred and fifteen patients , aged ≥6 yrs , were r and omised to receive either TNS or colistin , twice daily for 4 weeks . The primary end point was an evaluation of the relative change in lung function from baseline , as measured by forced expiratory volume in one second % predicted . Secondary end points included changes in sputum P. aeruginosa density , tobramycin/colistin minimum inhibitory concentrations and safety assessment s. TNS produced a mean 6.7 % improvement in lung function ( p=0.006 ) , whilst there was no significant improvement in the colistin-treated patients ( mean change 0.37 % ) . Both nebulised antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density , and there was no development of highly resistant strains over the course of the study . The safety profile for both nebulised antibiotics was good . Tobramycin nebuliser solution significantly improved lung function of patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa , but colistin did not , in this study of 1-month 's duration . Both treatments reduced the bacterial load Background Treatment of infective bronchitis involving Pseudomonas aeruginosa is a cornerstone of care in patients with cystic fibrosis ( CF ) . This phase IIb , r and omised , double-blind , placebo-controlled study assessed the efficacy and safety of ciprofloxacin dry powder for inhalation ( DPI ) in this population . Methods Patients with CF , ≥12 years of age ( N=286 ) , were r and omised to ciprofloxacin DPI ( 32.5 mg ( n=93 ) or 48.75 mg ( n=93 ) ) , or corresponding placebo ( 32.5 mg , n=65 ; 48.75 mg , n=35 ) twice daily for 28 days . The primary objective was the change in forced expiratory volume in 1 s ( FEV1 ) from baseline ( day 0 ) to end of treatment ( day 29 ) in the intent-to-treat population for ciprofloxacin DPI compared with the corresponding placebo group . Results The primary effectiveness objective was not met ; there were no significant differences in change in FEV1 between ciprofloxacin DPI and the corresponding placebo group for either dose ( p=0.154 ) . However , in pooled analyses , FEV1 decline from baseline to treatment end was significantly lower with ciprofloxacin DPI than with placebo ( pooled data ; p=0.02 ) . Ciprofloxacin DPI showed positive effects on sputum bacterial load and quality of life , but these effects were not maintained at the 4-week follow-up . Ciprofloxacin DPI was well tolerated and there were no significant differences in type/incidence of treatment-emergent adverse events by treatment group ( p=0.115 ) . Conclusions Further investigations are needed to determine the full scope of the beneficial effects of ciprofloxacin DPI for patients with CF . Trial registration number Clinical trials.gov NCT00645788 ; EudraCT 2008 - 008314 - 40 BACKGROUND : Tobramycin powder for inhalation ( TIP ) is a drug-device combination design ed to reduce treatment time and improve ease of use compared with tobramycin inhalation solution ( TIS ) in cystic fibrosis ( CF ) patients . However , the ability of patients to use dry powder inhalers , and the efficacy of the treatments , may vary by age . METHODS : The “ Establish a New Gold St and ard for Efficacy and Safety With Tobramycin in Cystic Fibrosis ” ( EAGER ) trial was a r and omized , 24-week , multicenter , open-label , parallel-group study design ed to evaluate the safety of TIP versus TIS in 553 subjects , ages ≥ 6 years , with CF and P. aeruginosa infection . The main efficacy end point was percent-of-predicted FEV1 at week 20 ( end of third cycle of treatment ) . A post hoc analysis was undertaken in 517 subjects who took ≥ 1 dose of study medication , to evaluate the relative efficacy and safety of TIP and TIS by age group : ≥ 6 to < 13 y ( children , n = 46 ) ; ≥ 13 to < 20 y ( adolescents , n = 114 ) ; and ≥ 20 y ( adults , n = 357 ) . RESULTS : Improvements in percent-of-predicted FEV1 from baseline to end of cycle 3 were greatest in the children for both TIP and TIS . The treatment differences ( TIP − TIS ) were 4.7 % ( 85 % CI −1.2 to 10.6 ) , 3.7 % ( 85 % CI −0.1 to 7.5 ) , and −0.8 % ( 85 % CI −3.1 to 1.5 ) in children , adolescents , and adults , respectively . Sputum P. aeruginosa density decreased from baseline with both treatments , with comparable treatment differences across the age groups after 3 cycles : children −0.93 ( 85 % CI −2.4 to 0.5 ) , adolescents −0.17 ( 85 % CI −1.2 to 0.8 ) , and adults −0.89 ( 85 % CI −1.3 to −0.4 ) . Overall , subject satisfaction scores were greater in all subjects with TIP , irrespective of age group . With the exception of cough and dysphonia , the safety profile of TIP was comparable to TIS , irrespective of age . CONCLUSIONS : TIP is comparable to TIS in efficacy outcomes and safety profile but had greater patient satisfaction in all the age groups OBJECTIVES This r and omized , double-blind , cross-over study evaluated the risk of bronchoconstriction with two preparations of inhaled tobramycin in children with cystic fibrosis ( CF ) infected with Pseudomonas aeruginosa with and without airway hyperreactivity . DESIGN Of 19 children with CF ( age range , 7 to 16 years ) with mild-to-moderate pulmonary disease , 10 children were at high risk ( HR ) for bronchospasm ( family history of asthma and previous response to bronchodilators ) and 9 children were at low risk ( LR ) for bronchospasm ( no family history of asthma or previous response to bronchodilators ) . Two solutions of tobramycin were administered : ( 1 ) 80 mg in a 2-mL vial diluted with 2 mL of saline solution containing the preservatives phenol and bisulfites ( IV preparation ) ; and ( 2 ) 300 mg in a preservative-free preparation in a 5-mL solution . Following a bronchodilator-free period of 12 h , the patients inhaled either one or the other preparation in r and om order on two different occasions , 2 weeks apart . RESULTS Prechallenge and postchallenge results for the LR group showed a percentage of fall in FEV(1 ) ( DeltaFEV(1 ) ) of 12 + /- 9 % ( mean + /- SD ) for the IV preparation , compared to 4 + /- 5 % for the preservative-free preparation ( p = 0.046 ) . An DeltaFEV(1 ) of > 10 % was seen in six of nine patients for the IV preparation and in one of nine patients for preservative-free preparation . For the HR group , the DeltaFEV(1 ) was 17 + /- 13 % for the IV-preparation group , compared to 16 + /- 12 % for the preservative-free group ( p = 0.4 ) . In this group , equal numbers of patients ( 8 of 10 patients ) had an DeltaFEV(1 ) > 10 % after inhaling each preparation . The largest DeltaFEV(1 ) was 44 % ( HR group with the preservative-free preparation that forced the early termination of inhalation ) . CONCLUSIONS Both preparations caused significant bronchoconstriction in the HR group , and the preservative-containing IV preparation caused more bronchospasm in LR group than the preservative-free solution . Heightened airway reactivity in children with CF places them at risk of bronchospasm from inhalation therapy In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis ( CF ) , antibiotic therapy generally fails to eradicate the bacterial pathogen . The mucoid bacterial phenotype , high sputum production by the host , and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy . We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection . In a prospect i ve placebo-controlled , double-blind , r and omized multicenter study , 22 CF patients received either 80 mg b.i.d . of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization . Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period . Using life table analysis , the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group ( P < 0.05 , log rank test ) . Lung function parameters and markers of inflammation did not change in either group during treatment . The results of this study suggest that early tobramycin inhalation may prevent and /or delay P. aeruginosa pulmonary infection in CF patients BACKGROUND Inhalation of hypertonic nebulised colistin causes chest tightness and is a reason for discontinuing the treatment . This study examines the relationship of chest tightness and change in lung function in response to the inhalation of a range of tonicities of nebulised colistin and their influence on patients ' preference . METHODS Twenty seven adult patients with cystic fibrosis and a mean forced expiratory volume in one second ( FEV1 ) of 54 % predicted ( range 24 - 98 ) were studied . They inhaled a nebulised solution of hypertonic , isotonic , and hypotonic colistin over three consecutive days in r and om order in a double blind fashion . Measurements of chest tightness , using a visual analogue scale ( VAS ) , and FEV1 were recorded before and 0 , 15 , 30 , 60 , and 90 minutes following inhalation . The solution preferred by each patient was determined at the end of the three days . RESULTS All tonicities caused a significant fall in FEV1 % predicted and an increase in chest tightness , with no differences between the solutions . However , the mean ( SE ) time to the maximum fall in FEV1 % predicted was significantly different between the solutions ( hypertonic 7.8 ( 2.1 ) min , isotonic 19.2 ( 5.5 ) min , and hypotonic 34.2 ( 5.9 ) min ) with a mean difference ( 95 % CI ) between hypotonic and hypertonic solutions of 28.04 ( 14.6 to 41.5 ) min , between isotonic and hypertonic solutions of 12.0 ( -0.1 to 24.1 ) min , and between hypotonic and isotonic solutions of 15.6 ( 1.8 to 29.4 ) min . Positive correlations existed for the maximum fall in FEV1 % predicted between the hypertonic and isotonic solutions ( r = 0.62 , p < 0.001 ) and between the hypotonic and isotonic solutions ( r = 0.64 , p < 0.001 ) . There was no correlation between the objective and subjective measurements for any solution . The patients ' preference varied . CONCLUSIONS All tonicities of colistin caused equal symptoms of chest tightness and reduction in pulmonary function . It is recommended that the patient is challenged with nebulised colistin before prescription of the drug and that the challenge is preceded by an inhaled bronchodilator . Most of the patients preferred the isotonic or hypotonic solutions . The isotonic solution reflects a fall in FEV1 representative of all the solutions . The fall in FEV1 to the hypotonic solution occurred over a longer period and may be better tolerated by some patients Abstract Background and aim Progressive respiratory failure due to Pseudomonas aeruginosa colonization is the most significant morbidity in patients with cystic fibrosis ( CF ) . This trial was design ed to investigate the efficacy and safety of a highly concentrated ( 300mg/4mL ) tobramycin solution for inhalation ( TSI ) [ Bramitob ® ] in patients with CF and P. aeruginosa infection . Methods Fifty-nine patients were r and omized to receive a 4-week treatment with tobramycin or placebo administered twice daily via the Pari LC Plus ® nebulizer and Pari TurboBoy ™ compressor , followed by a 4-week run-out phase . Pulmonary function ( forced expiratory volume in 1 second [ FEV1 ] , forced vital capacity [ FVC ] , and forced expiratory flow at the midportion of vital capacity [ FEF25–75 % ] ) , P. aeruginosa susceptibility , microbiologic results , and in vitro minimum inhibitory concentration for 90 % of strains ( MIC90 ) were the efficacy outcome measures , while safety was monitored by the recording of adverse events , audiometry ( bone conduction at 250–8000Hz frequency ) , laboratory tests , physical examination and general health condition . The concentration of tobramycin attained in sputum was measured in a cohort of 21 patients . Results FEV1 significantly increased from baseline in the tobramycin group compared with no change in the placebo group : the absolute difference between groups ( intent-to-treat population ) of predicted normal was 13.2 % at week 2 ( p = 0.002 ) and 13.3 % at week 4 ( p = 0.003 ) . Significant differences in favor of the tobramycin group were also observed for FVC and FEF25–75 % . The microbiologic results at the end of the treatment period ( P. aeruginosa-negative culture , persistence , superinfection ) showed a significantly better outcome in the tobramycin group compared with placebo ( p = 0.033 ) . The effects of tobramycin on pulmonary function and microbiology were not maintained at the end of the run-out phase . Mean sputum concentrations of tobramycin after the first dose ( 695.6 ± 817.0 µg/mL ) were similar to those measured after the last dose ( 716.9 ± 799 µg/mL ) and were superior to the detected specific MIC90.The proportion of patients with drug-related adverse events was lower in the tobramycin group and no signs of renal or auditory toxicity were observed . Conclusions The 4-week administration of a highly concentrated TSI significantly improved pulmonary function and microbiologic outcome compared with placebo and was well tolerated . The results of this study should be confirmed in further long-term trials in larger population BACKGROUND AND METHODS We conducted two multicenter , double-blind , placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection . A total of 520 patients ( mean age , 21 years ) were r and omly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks , followed by four weeks with no study drug . Patients received treatment or placebo in three on-off cycles for a total of 24 weeks . The end points included pulmonary function , the density of P. aeruginosa in sputum , and hospitalization . RESULTS The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second ( FEV1 ) of 10 percent at week 20 as compared with week 0 , whereas the patients receiving placebo had a 2 percent decline in FEV1 ( P<0.001 ) . In the tobramycin group , the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units ( CFU ) per gram of expectorated sputum from week 0 to week 20 , as compared with an increase of 0.3 log10 CFU per gram in the placebo group ( P<0.001 ) . The patients in the tobramycin group were 26 percent ( 95 percent confidence interval , 2 to 43 percent ) less likely to be hospitalized than those in the placebo group . Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum . The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group , as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group . CONCLUSIONS In a 24-week study of patients with cystic fibrosis , intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function , decreased the density of P. aeruginosa in sputum , and decreased the risk of hospitalization UNLABELLED In patients with cystic fibrosis ( CF ) , treatment of new Pseudomonas aeruginosa ( Pa ) infection postpones the occurrence of chronic infection , but the best eradication regimen is unknown . AIM OF THE STUDY Compare 2 Pa eradication regimens in children with new Pa infection . METHODS Children with CF ( 0 - 18 years ) and a new isolation of Pa from sputum , cough swab or BAL were r and omized to treatment with tobramycin inhalation solution for 28 days ( TIS ) or inhaled sodiumcolistimethate ( 2 × 2millU/day ) plus oral ciprofloxacin ( 30 mg/kg/day ) for 3 months ( CC ) . Airway cultures were taken for 6 consecutive months , then every 3 months . The primary outcome was Pa eradication at the end of treatment . Secondary outcome parameters were : time to Pa relapse from end of treatment , total and Pa specific IgG , FEV(1 ) , BMI and Pa status at 2year follow-up . RESULTS 58 patients with new Pa isolation were r and omized . Their median age was 9 years ( IQR 4.7 - 13.1 ) and their median FEV(1 ) 98 % predicted ( IQR 87 - 107 ) . Eighteen treatments concerned the first Pa isolation ' ever ' ( TIS : 8 ; CC : 10 ) . For the remaining , median time since previous Pa was 19 months ( IQR 9 - 41 ) . Eradication at end of treatment was similar for both treatments : 26/29 CC and 23/29 in TOBI treated patients ( p=0.47 ) . Median time to recurrence of Pa was 9 months ( 95 % CI 0.0 - 19.0 ) for CC and 5 months ( 95 % CI 1.7 - 8.3 ) for TIS ( p=0.608 ) . After 1 year , the 2 groups did not differ in change in total and Pa specific IgG , FEV(1 ) and BMI . After 2 years , 10 % of patients had chronic Pa infection . CONCLUSION In children with CF and new Pa infection , inhalation of TIS ( 28 days ) or CC ( 3 months ) result ed in similar eradication success at the end of treatment ( 80 and 90 % respectively ) and similar clinical evolution during the first 2 years of follow-up Forty patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection entered a prospect i ve double-blind placebo-controlled study of colistin inhalation . Active treatment consisted of inhalation of colistin one million units twice daily for three months and was compared to placebo inhalations of isotonic saline . Significantly more patients in the colistin inhalation group completed the study as compared to the placebo group ( 18 versus 11 ) . Colistin treatment was superior to placebo treatment in terms of a significantly better clinical symptom score , maintenance of pulmonary function and inflammatory parameters . We recommend colistin inhalation therapy for cystic fibrosis patients with chronic P. aeruginosa lung infection as a supplementary treatment to frequent courses of intravenous anti-pseudomonas chemotherapy BACKGROUND Dry powder inhalation ( DPI ) may be an alternative to nebulisation of drugs in the treatment of chest infections in cystic fibrosis ( CF ) patients . In a pilot study the feasibility of a colistin dry powder inhaler ( prototype Twincer ) by a single dose in CF- patients was assessed and compared to nebulised colistin . METHODS Ten CF- patients , chronically infected with P. aeruginosa , participated in a r and omised cross over study . On two visits to the outpatient clinic , patients inhaled colistin sulphomethate as 25 mg dry powder ( Twincer ) or as 158 mg nebulised solution ( Ventstream nebuliser , PortaNeb compressor ) . Pulmonary function tests were performed before , 5 and 30 min after inhalation . Serum sample s were drawn prior to each dose and at 15 , 45 min , 1.5 ; 2.5 ; 3.5 and 5.5 h after inhalation . RESULTS The DPI was well tolerated by the patients : no significant reduction in FEV1 was observed . Relative bioavailability of DPI to nebulisation was approx . 140 % based on actual dose and approx . 270 % based on drug dose label cl aim . CONCLUSIONS The colistin DPI ( Twincer inhaler ) is well tolerated and appreciated by CF- patients . Optimisation with respect to particle size and internal resistance of the inhaler is necessary to attain equivalent pulmonary deposition to liquid nebulisation OBJECTIVE The efficacy and safety of oral ciprofloxacin as a maintenance antipseudomonal therapy were evaluated in 44 patients with cystic fibrosis who had completed a 14-day regimen of intensive hospital therapy with intravenous ceftazidime and amikacin , supplemented by amikacin inhalation therapy . METHODS Twenty-one patients were r and omly assigned to oral ciprofloxacin alone ( Group I ) and 23 received ciprofloxacin plus inhaled amikacin ( Group II ) . RESULTS Negative sputum cultures were achieved in 34 patients ( 77 % ) at the end of intensive therapy ( 19 Group I and 15 Group II ) and were sustained after 3 months of maintenance therapy in 5 of the 19 responders in Group I ( 26 % ) and in 8 of the 15 responders in Group II ( 53 % ) . Resistance to ciprofloxacin was found in 7 of 31 ( 23 % ) sputum isolates at the end of ciprofloxacin therapy . During maintenance therapy , continued improvement in clinical symptoms was observed in 14 patients in both treatment groups ; 6 in each group had further improvements whereas only 4 patients were clinical failures . There was no correlation between clinical outcome and either elimination of Pseudomonas aeruginosa from sputum culture or development of ciprofloxacin resistance . Both maintenance regimens were well-tolerated by this population of patients which included 28 children younger than 15 years of age . There were no severe or serious adverse events , no signs of quinolone-related arthropathy and no growth impairment . CONCLUSION Ciprofloxacin was efficacious , safe and well-tolerated as maintenance antipseudomonal therapy in cystic fibrosis patients . These results suggest further evaluation of ciprofloxacin as an oral maintenance therapy is warranted The effect of prophylactic antibiotics on bacterial colonization of the respiratory tract and on general progression of cystic fibrosis was studied in a two-year prospect i ve study of 47 mildly to moderately affected patients . One group of patients received inhaled cephaloridine and the other received no inhaled antibiotic ; both groups received cloxacillin orally . Carriage of Haemophilus influenzae was greater in the group not receiving inhaled antibiotic ( 55 % vs 20 % ) . Rates of carriage of Staphylococcus aureus ( 23 % ) . Pseudomonas aeruginosa ( greater than 90 % ) . Pseudomonas cepacia ( 45 % ) , and other organisms were similar in both groups . There were no significant differences between the two groups in incidence of respiratory tract infections or hospital admissions , clinical scores , radiologic scores , or rate of change of pulmonary function . Although continuous antistaphylococcal antibiotic prophylaxis may be successful in suppressing colonization with S. aureus , it may also contribute to the high rates of carriage of Ps . aeruginosa and Ps . cepacia observed in patients with cystic fibrosis Burkholderia cepacia is an aggressive pathogen that colonizes cystic fibrosis ( CF ) patients , causing greatly increased morbidity and mortality . It is resistant to most antibiotics , but sensitive in vitro to a novel agent , taurolidine . This has not previously been used against B. cepacia , nor given in nebulized form . We assessed the effect of nebulized taurolidine on United Kingdom epidemic ( ET12 ) B. cepacia infection in 20 adult CF patients attending our regional adult cystic fibrosis outpatient clinic using a prospect i ve , r and omized , double-blinded placebo-controlled crossover trial . Nebulized taurolidine ( 4 mL 2 % solution ) or saline ( 4 mL 0.9 % solution ) was given twice daily . Each arm lasted 4 weeks , with a 2-week intervening washout period . Sputum B. cepacia colony counts ( primary outcome measure ) , spirometry , and symptoms ( secondary outcome measures ) were assessed . Eighteen patients completed the study . There was no change in B. cepacia colony counts or spirometry , nor symptom scores . We conclude that , although taurolidine is well tolerated in nebulized form , in this study it had no in vivo anti-B. cepacia activity OBJECTIVE Two identical 24-week , double-blind , placebo-controlled trials of tobramycin solution for inhalation ( TOBI [ PathoGenesis Corporation , Seattle , Washington ] ) in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection were conducted in the United States . The aim of the present study was to extrapolate the US trial data to a Canadian setting , using Canadian costs to estimate the savings in direct medical costs that might result from use of a similar 24-week TOBI regimen versus usual care in 2 Canadian provinces . BACKGROUND Cystic fibrosis is a genetic disease in which persistent respiratory infection , usually due to P. aeruginosa infection , is the major cause of morbidity and mortality . METHODS The US trials demonstrated that TOBI produced significant improvements in pulmonary function test results , reduced sputum levels of P. aeruginosa , and result ed in a 26 % reduction in the probability of hospitalization ( 95 % CI , 2%-43 % vs placebo in the clinical trials ) . Individual patient data from the US trials were used to calculate the mean number of days in hospital as well as the mean number of days of home intravenous or oral antibiotic therapy . To adjust for Canadian pricing , pertinent economic data were obtained from Statistics Canada and the Ontario and Quebec health ministries . Demographic and baseline data were obtained from health surveys conducted by the Canadian Cystic Fibrosis Foundation . RESULTS Economic analysis showed that the use of TOBI for 24 weeks would result in estimated mean per-patient savings in direct medical costs ( in Canadian dollars ) of $ 4055 in Ontario and $ 4916 in Quebec , which would substantially offset the Canadian acquisition price of $ 8602 for the same 24-week period . CONCLUSIONS Assuming that the percentage of reduction in hospital days observed in the US trials would also occur in the Canadian clinical setting , use of TOBI would reduce the use of health care services , particularly hospital days , and lead to substantial savings in direct medical costs that would offset its acquisition price . Whether this reduction actually occurs after TOBI enters the Canadian market is a subject for future investigation Abstract Background and objectives To compare in vitro characteristics and pharmacokinetics of Bramitob ® , a preservative-free tobramycin solution for nebulization , and Tobi ® in patients with cystic fibrosis ( CF ) and Pseudomonas aeruginosa infection . Methods In vitro characteristics of Bramitob ® and Tobi ® were evaluated using Pari TurboBoy ™ /LC Plus ® and the Systam 290 LS ™ nebulizers . In the r and omized , double-blind , two-way crossover pharmacokinetic study , 11 patients with CF received a single nebulized dose ( 300 mg ) of Bramitob ® or Tobi ® , separated by a 7-day washout period . Plasma and sputum tobramycin concentrations were measured immediately before and over 24 hours after administration . Results Bramitob ® and Tobi ® performed alike during nebulization . The fine particle fraction was 33–37 % and the mass median aerodynamic diameter was < 5 µm . Nine patients completed the pharmacokinetic study . Tobramycin plasma profiles after administration of Bramitob ® or Tobi ® were similar , with a peak at 90 and 72 minutes after inhalation of Bramitob ® and Tobi ® , respectively . The elimination half-life was ∼5 hours for both products . The relative bioavailability of Bramitob ® to Tobi ® was 1.01 , indicating comparable systemic exposure . Peak sputum concentration of tobramycin was 816 ± 681 µg/g for Tobi ® and 1289 ± 851 µg/g for Bramitob ® and was > 400 µg/g ( threshold sufficient for an antibacterial effect against P. aeruginosa ) in 5 out of 9 patients receiving Tobi ® and 8 out of 9 patients receiving Bramitob ® . All adverse events were considered mild and judged not related to the study drugs . Conclusions In vitro performance of Bramitob ® was similar when nebulized with Pari TurboBoy ™ /LC Plus ® and Systam 290 LS ™ nebulizers and comparable to that of Tobi ® . The systemic bioavailability of tobramycin was similar after administration of either Bramitob ® or Tobi ® ; however , in sputum sample s the tobramycin peak concentration was slightly greater after administration of Bramitob ® than after Tobi ® BACKGROUND Direct aerosol delivery of aminoglycosides such as tobramycin to the lower airways of patients with cystic fibrosis may control infection with Pseudomonas aeruginosa and improve pulmonary function , with low systemic toxicity . We conducted a r and omized crossover study to evaluate the safety and efficacy of aerosolized tobramycin in patients with cystic fibrosis and P. aeruginosa infections . METHODS Seventy-one patients with stable pulmonary status were recruited from seven U.S. centers for the treatment of cystic fibrosis and r and omly assigned to one of two crossover regimens . Group 1 received 600 mg of aerosolized tobramycin for 28 days , followed by half-strength physiologic saline ( placebo ) for two 28-day period . Group 2 received placebo for 28 days , followed by tobramycin for two 28-day periods . Pulmonary function , the density of P. aeruginosa in sputum , ototoxicity , nephrotoxicity , and the emergence of tobramycin-resistant P. aeruginosa were monitored . RESULTS In the first 28-day period , treatment with tobramycin was associated with an increase in the percentage of the value predicted for forced expiratory volume in one second ( 9.7 percentage points higher than the value for placebo ; P < 0.001 ) , forced vital capacity ( 6.2 percentage points higher than the value for placebo ; P = 0.014 ) , and forced expiratory flow at the midportion of the vital capacity ( 13.0 percentage points higher than the value for placebo ; P < 0.001 ) . A decrease in the density of P. aeruginosa in sputum by a factor of 100 ( P < 0.001 ) was found during all periods of tobramycin administration . Neither ototoxicity nor nephrotoxicity was detected . The frequency of the emergence of tobramycin-resistant bacteria was similar during both tobramycin and placebo administration . CONCLUSIONS The short-term aerosol administration of a high dose of tobramycin in patients with clinical ly stable cystic fibrosis is an efficacious and safe treatment for endobronchial infection with P. aeruginosa STUDY OBJECTIVE Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis ( CF ) patients despite reports of chest tightness and bronchospasm . The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity . DESIGN AND METHODS A prospect i ve placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration . Subjects were recruited as follows : high risk ( HR ) for bronchospasm due to a personal history of recurrent wheezing , a family history of asthma and /or atopy , or bronchial lability , as demonstrated in pulmonary function tests ; or low risk ( LR ) without these characteristics . RESULTS The mean FEV(1 ) ( expressed as the mean [ + /- SD ] fall from baseline ) of the HR group ( n = 12 ) fell 12 + /- 9 % after placebo was administered , and fell 17 + /- 10 % after colistin was administered . For the LR group ( n = 8) , the mean FEV(1 ) fell 9 + /- 4 % following placebo administration and 13 + /- 8 % following colistin administration . There was a greater number of subjects in the HR group compared to the LR group , which had a mean fall in FEV(1 ) of > /= 15 % ( p < 0.01 ) after inhaling colistin . The differences between placebo and colistin therapy in the LR group were not significant . CONCLUSION The results demonstrated that colistin can cause bronchospasm , particularly in those patients with coexisting CF and asthma BACKGROUND The primary cause of morbidity and mortality in patients with cystic fibrosis ( CF ) is progressive obstructive pulmonary disease due to chronic endobronchial infection , particularly with Pseudomonas aeruginosa ( Pa ) . Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood . PURPOSE The present studies are design ed to evaluate risk factors and outcomes associated with early Pa acquisition , and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture . METHODS The Early Pseudomonas Infection Control ( EPIC ) program consists of two studies , a r and omized multicenter trial in CF patients ages 1 - 12 years at first isolation of Pa from a respiratory culture , and a longitudinal cohort study enrolling Pa-negative patients . Using a factorial design , trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis ( cycled therapy ) or based on recovery of Pa from quarterly respiratory cultures ( culture-based therapy ) . The study drugs include inhaled tobramycin ( 300 mg BID ) for 28 days , combined with either oral ciprofloxacin ( 15 - 20 mg/kg BID ) or oral placebo for 14 days . The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms , and the proportion of patients with new Pa-positive respiratory cultures during the study . The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were r and omized in the clinical trial and 1787 were enrolled in the cohort study . CONCLUSIONS These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition , and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF Nebulized antibiotics are being used increasingly in children with cystic fibrosis . We assessed the effect of nebulized antibiotic solutions of varying tonicity on lung function in 12 children aged 5 - 15 yrs with cystic fibrosis . Baseline forced expiratory volume in one second and ( FEV1 ) was measured , followed by a single nebulization of normal saline ( 272 mosmol.kg-1 ) , tobramycin ( 248 mosmol.kg-1 ) , or ticarcillin ( 3,080 mosmol.kg-1 ) . All children received each of these , administered r and omly , one per day . FEV1 was remeasured 5 , 15 and 30 min after completion of the nebulization . Ticarcillin ( mean fall 10.7 % ( SD 8.9 ) ) caused a larger fall in FEV1 than normal saline ( 4.8 % ( 4.3 ) , p less than 0.05 ) . The fall in FEV1 for ticarcillin was greater than for tobramycin ( 1.2 % ( 2.0 ) , p less than 0.05 ) . Normal saline did not result in a significantly larger fall in FEV1 than tobramycin ( p greater than 0.05 ) . Bronchoconstriction to ticarcillin persisted at 30 min . We conclude that nebulized antibiotics can affect lung function in children with cystic fibrosis if the solutions are hypertonic RATIONALE Lower respiratory tract infection with Pseudomonas aeruginosa ( PA ) is associated with increased morbidity in patients with cystic fibrosis ( CF ) . Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy , increasing resistance , drug intolerance , and high treatment burden with current aerosol antibiotics . New treatment options for CF pulmonary infections are needed . OBJECTIVES This study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin ( MP-376 , Aeroquin ) in a heavily treated CF population with PA infection . METHODS This study r and omized 151 patients with CF with chronic PA infection to one of three doses of MP-376 ( 120 mg every day , 240 mg every day , 240 mg twice a day ) or placebo for 28 days . The primary efficacy endpoint was the change in sputum PA density . Secondary endpoints included changes in pulmonary function , the need for other anti-PA antimicrobials , changes in patient-reported symptom scores , and safety monitoring . MEASUREMENTS AND MAIN RESULTS All doses of MP-376 result ed in reduced sputum PA density at Day 28 , with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo ( P = 0.001 ) . There was a dose-dependent increase in FEV(1 ) for MP-376 , with a difference of 8.7 % in FEV(1 ) between the 240 mg twice a day group and placebo ( P = 0.003 ) . Significant reductions ( 61 - 79 % ) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo . MP-376 was generally well tolerated relative to placebo . CONCLUSIONS Nebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection . Clinical trial registered with www . clinical trials.gov ( NCT00677365 ) Our objective was to study the effect of tobramycin solution for inhalation ( TSI ; TOBI , Chiron Corp. ) on lung function decline rate in 400 young persons with cystic fibrosis ( CF ) and mild lung disease . Effects on hospitalization , antibiotic use , school days missed , and nutritional status also were determined . This was an open-label , r and omized ( stratified by sex and age group , i.e. , 6 - 10 and 11 - 15 years ) , parallel-group , multicenter study . Routine subject management ( control group ) was compared to routine management plus 28 days of twice-daily TSI inhalation , followed by 28 days off the drug ( TSI group ) for 56 weeks . Primary efficacy endpoints included rate of lung function decline ( as measured by forced expiratory volume in 1 sec ; FEV(1 ) ) , hospitalization , and concomitant antibiotic use . Safety was assessed by analysis of treatment-emergent adverse events . Only 184 of 400 planned subjects were recruited and r and omized ( 93 to the TSI group , and 91 to the control group ) . Enrollment was ended after 2 years because of difficult recruitment . An interim safety review showed a 2.42-fold risk of respiratory hospitalization for control group subjects ( P = 0.020 ) , and the study was terminated . Sixty-three subjects ( 34.2 % ) completed the entire study ( 30 in the TSI group , or 32.3 % ; and 33 in the control group , or 36.3 % ) . Significantly fewer TSI subjects were hospitalized for worsening of respiratory symptoms ( 11.0 % vs. 25.6 % ; P = 0.011 ) , and fewer TSI subjects were hospitalized overall ( 16.5 % vs. 27.8 % ; P = 0.065 ) . Fewer TSI subjects received antibiotics other than the study drug ( 78.0 % vs. 95.6 % ) , and significantly fewer received oral antibiotics ( 76.9 % vs. 91.1 % ; P = 0.009 ) . No other safety or adverse event differences were observed . In conclusion , significant reductions in respiratory hospitalizations , concomitant antibiotic use , and a trend towards improvement in percent predicted forced expiratory flow ( FEF(25 - 75 ) ) provide evidence of a clinical benefit of TSI use in young persons with CF and mild lung disease . An effect on lung function decline rate could not be evaluated as planned , due to inadequate enrollment and early study termination BACKGROUND We assessed the short-term efficacy and safety of aztreonam lysine for inhalation ( AZLI [ an aerosolized monobactam antibiotic ] ) in patients with cystic fibrosis ( CF ) and Pseudomonas aeruginosa ( PA ) airway infection . METHODS In this r and omized , double-blind , placebo-controlled , international study ( AIR-CF1 trial ; June 2005 to April 2007 ) , patients ( n = 164 ; > or= 6 years of age ) with FEV(1 ) > or= 25 % and < or= 75 % predicted values , and no recent use of antipseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI ( three times daily for 28 days ) or placebo ( 1:1 r and omization ) , then were monitored for 14 days after study drug completion . The primary efficacy end point was change in patient-reported respiratory symptoms ( CF- Question naire-Revised [ CFQ-R ] Respiratory Scale ) . Secondary end points included changes in pulmonary function ( FEV(1 ) ) , sputum PA density , and nonrespiratory CFQ-R scales . Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored . RESULTS After 28 days of treatment , AZLI improved the mean CFQ-R respiratory score ( 9.7 points ; p < 0.001 ) , FEV(1 ) ( 10.3 % predicted ; p < 0.001 ) , and sputum PA density ( - 1.453 log(10 ) cfu/g ; p < 0.001 ) , compared with placebo . Significant improvements in Eating , Emotional Functioning , Health Perceptions , Physical Functioning , Role Limitation/School Performance , and Vitality CFQ-R scales were observed . Adverse events were consistent with symptoms of CF lung disease and were comparable for AZLI and placebo except the incidence of " productive cough " was reduced by half in AZLI-treated patients . PA aztreonam susceptibility at baseline and end of therapy were similar . CONCLUSIONS In patients with CF , PA airway infection , moderate-to-severe lung disease , and no recent use of antipseudomonal antibiotics or azithromycin , 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function , and was well tolerated . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00112359 OBJECTIVES We evaluated the pharmacokinetics , safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution ( TIS ) in 29 cystic fibrosis ( CF ) patients chronically infected with Pseudomonas aeruginosa . PATIENTS AND METHODS In this r and omized , multicentre , open-label , two-period crossover study , TIS ( 300 mg/5 mL ) was administered via PARI eFlow ( ® ) rapid once daily and twice daily each for 8 weeks . Serum pharmacokinetics of these two regimens was analysed . Tobramycin levels were determined before the morning dose and at 30 , 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle . At these timepoints , trough and peak serum tobramycin concentrations ( Cmax , mg/L ) as well as the area under the curve for 0 - 90 min of tobramycin ( AUC0 - 90min ) were assessed in order to evaluate the risk of systemic toxicity . Safety parameters and forced expiratory volume in 1 s ( FEV1 ) were assessed . RESULTS For once-daily treatment , tobramycin levels were 10 % higher after 8 weeks compared with 4 weeks ( AUC0 - 90min ratio = 1.096 , 90 % CI = 0.860 - 1.396 , P = 0.5237 ) . For twice-daily treatment , tobramycin levels after 8 weeks showed a 40 % decrease compared with 4 weeks ( AUC0 - 90min ratio = 0.608 , 90 % CI = 0.461 - 0.802 , P = 0.0055 ) . The AUC0 - 90min ratio at 8 weeks ( once daily versus twice daily ) did not differ significantly ( AUC0 - 90min ratio = 0.749 , 90 % CI = 0.514 - 1.092 , P = 0.2009 ) . The mean FEV1 did not differ markedly compared between treatment periods or with baseline . No audiological or nephrotoxic side effects were noted . CONCLUSIONS Continuous treatment with TIS ( once daily or twice daily ) over 8 weeks appears to be safe and tolerable RATIONALE The Early Pseudomonal Infection Control ( EPIC ) r and omized trial rigorously evaluated the efficacy of different antibiotic regimens for eradication of newly identified Pseudomonas ( Pa ) in children with cystic fibrosis ( CF ) . Protocol based therapy in the trial was provided based on culture positivity independent of symptoms . It is unclear whether outcomes observed in the clinical trial were different than those that would have been observed with historical st and ard of care driven more heavily by respiratory symptoms than culture positivity alone . We hypothesized that the incidence of Pa recurrence and hospitalizations would be significantly reduced among trial participants as compared to historical controls whose st and ard of care preceded the widespread adoption of tobramycin inhalation solution ( TIS ) as initial eradication therapy at the time of new isolation of Pa. METHODS Eligibility criteria from the trial were used to derive historical controls from the Epidemiologic Study of CF ( ESCF ) who received st and ard of care treatment from 1995 to 1998 , before widespread availability of TIS . Pa recurrence and hospitalization outcomes were assessed over a 15-month time period . RESULTS As compared to 100 % of the 304 trial participants , only 296/608 ( 49 % ) historical controls received antibiotics within an average of 20 weeks after new onset Pa. Pa recurrence occurred among 104/298 ( 35 % ) of the trial participants as compared to 295/549 ( 54 % ) of historical controls ( 19 % difference , 95 % CI : 12 % , 26 % , P < 0.001 ) . No significant differences in the incidence of hospitalization were observed between cohorts . CONCLUSIONS Protocol -based antimicrobial therapy for newly acquired Pa result ed in a lower rate of Pa recurrence but comparable hospitalization rates as compared to a historical control cohort less aggressively treated with antibiotics for new onset To evaluate the sensitivity of high-resolution computerized tomography ( H RCT ) of the chest compared to spirometry measures in evaluating the effects of tobramycin solution for inhalation ( TSI ) in cystic fibrosis ( CF ) patients .Thirty-two subjects > /=6 years old with mild to moderate CF lung disease were enrolled in a r and omized , double-blind , placebo-controlled pilot study . Duration was 28 days ; 31 subjects completed the study .H RCT scores decreased 4.06 + /- 3.20 ( mean + /- SD ) for TSI and decreased 0.17 + /- 1.78 for placebo subjects ( P = 0.13 ) . Mean forced expiratory flow during middle half of forced vital capacity ( FEF(25%-75 % ) ) predicted increased 6.08 + /- 4.86 for TSI and decreased 0.60 + /- 2.34 for placebo ( P = 0.23 ) . Percentage forced expiratory volume in 1 s ( FEV(1 ) ) predicted increased slightly for both TSI and placebo ( 1.29 + /- 3.33 for TSI and 1.17 + /- 1.4 for placebo ) ( P = 0.97 ) . Two of eight H RCT component scores ( atelectasis and inhomogeneity ) were observed to be highly discordant with observed H RCT global total score and other H RCT component scores . A modified total score was calculated by dropping them from the global total score . The modified H RCT total scores decreased 6.68 + /- 3.09 for TSI subjects and increased 0.02 + /- 2.0 for the placebo subjects ( P = 0.07 ) . Sample sizes were calculated to show statistical significance by differences in modified total H RCT scores , global total H RCT scores , FEF(25%-75 % ) predicted or FEV(1 ) % predicted . A total of 60 , 100 , 200 , and over 800 patients would be necessary respectively . H RCT can be a useful measure of change in CF pulmonary disease , requiring a smaller sample size than that required to show treatment effect by pulmonary function testing ( PFT ) alone We conducted a double-blind , placebo-controlled , multicenter , r and omized trial to test the hypothesis that 300 mg of tobramycin solution for inhalation administered twice daily for 28 days would be safe and result in a profound decrease in Pseudomonas aeruginosa ( Pa ) density from the lower airway of young children with cystic fibrosis . Ninety-eight subjects were to be r and omized ; however , the trial was stopped early because of evidence of a significant microbiological treatment effect . Twenty-one children under age 6 years were r and omized ( 8 active ; 13 placebo ) and underwent bronchoalveolar lavage at baseline and on Day 28 . There was a significant difference between treatment groups in the reduction in Pa density ; no Pa was detected on Day 28 in 8 of 8 active group patients compared with 1 of 13 placebo group patients . We observed no differences between treatment groups for clinical indices , markers of inflammation , or incidence of adverse events . No abnormalities in serum creatinine or audiometry and no episodes of significant bronchospasm were observed in association with active treatment . We conclude that 28 days of tobramycin solution for inhalation of 300 mg twice daily is safe and effective for significant reduction of lower airway Pa density in young children with cystic fibrosis RATIONALE Recent studies of inhaled tobramycin in subjects with cystic fibrosis ( CF ) find less clinical improvement than previously observed . Nonhuman data suggest that in some strains of Pseudomonas aeruginosa , azithromycin can antagonize tobramycin . OBJECTIVES We tested the hypothesis that concomitant azithromycin use correlates with less improvement in key outcome measures in subjects receiving inhaled tobramycin while not affecting those receiving a comparative , nonaminoglycoside inhaled antibiotic . METHODS We studied a cohort of 263 subjects with CF enrolled in a recent clinical trial comparing inhaled tobramycin with aztreonam lysine . We performed a secondary analysis to examine key clinical and microbiologic outcomes based on concomitant , chronic azithromycin use at enrollment . MEASUREMENTS AND MAIN RESULTS The cohort r and omized to inhaled tobramycin and reporting azithromycin use showed a significant decrease in the percent predicted FEV1 after one and three courses of inhaled tobramycin when compared with those not reporting azithromycin use ( 28 d : -0.51 vs. 3.43 % , P < 0.01 ; 140 d : -1.87 vs. 6.07 % , P < 0.01 ) . Combined azithromycin and inhaled tobramycin use was also associated with earlier need for additional antibiotics , lesser improvement in disease-related quality of life , and a trend toward less reduction in sputum P. aeruginosa density . Subjects r and omized to inhaled aztreonam lysine had significantly greater improvement in these outcome measures , which were unaffected by concomitant azithromycin use . Outcomes in those not using azithromycin who received inhaled tobramycin were not significantly different from subjects receiving aztreonam lysine . Azithromycin also antagonized tobramycin but not aztreonam lysine in 40 % of P. aeruginosa clinical isolates tested in vitro . CONCLUSIONS Oral azithromycin may antagonize the therapeutic benefits of inhaled tobramycin in subjects with CF with P. aeruginosa airway infection The development of drug resistance is a major theoretical concern with the long-term delivery of aerosolized antibiotics via inhalation . A r and omized , placebo-controlled , double-blind study , which compared inhaled tobramycin plus st and ard cystic fibrosis ( CF ) care to placebo plus st and ard CF care , examined the following microbiological parameters : percentage of patients with at least one Pseudomonas aeruginosa ( PA ) strain with a minimal inhibitory concentration ( MIC ) > 16 microg/mL ( ie , the breakpoint for tobramycin resistance delivered by the parenteral route ) ; changes in the levels of the lowest concentration required to inhibit the growth of 50 % of strains tested ( MIC(50 ) ) and 90 % of strains tested ( MIC(90 ) ) ; the percentage of patients with an increase , decrease , or change in the MIC of the most resistant and most prevalent PA strains ; and the percentage of patients in whom the PA strain with the highest MIC also was the most prevalent . During the first 6 months , which included three on-drug and off-drug cycles of 4 weeks ' duration each , the percentage of tobramycin-treated patients with at least one PA isolate and with an MIC > 16 microg/mL was 13 % at baseline , 26 % at 20 weeks , and 23 % at 24 weeks vs 10 % , 17 % , and 8 % , respectively , for placebo-treated patients . No significant change was observed in MIC(50 ) at 20 and 24 weeks . The increase in MIC(90 ) was not statistically significant . At 24 weeks , there was no increase in the percentage of patients in either group in whom the PA strain with the highest MIC became most the prevalent strain . After the third on-drug cycle , 33 % of the tobramycin group showed an increase in the MIC of the strain with the highest MIC . This decreased to 26 % after 1 month off drug therapy . A preliminary analysis of the 12-month and 18-month data showed a decrease in the proportion of resistant PA isolates after each off-drug cycle . This return to susceptibility following an off-drug cycle was not observed at 24 months . The mechanism of resistance in this setting is believed to be increased impermeability to drug . At all time points , pulmonary function improved even in patients with MICs of > or = 128 microg/mL. At 6 months , no increase was seen in the rates of superinfection with tobramycin-resistant , Gram-negative pathogens . Increases in Stenotrophomonas maltophilia were detected in patients after 18 and 24 months of tobramycin therapy and were similar to those rates in patients receiving placebo . These rates may be independent of inhalation therapy BACKGROUND Open-label , parallel-group , international trial comparing aztreonam for inhalation solution ( AZLI ) and tobramycin nebulizer solution ( TNS ) for cystic fibrosis patients with airway Pseudomonas aeruginosa . METHODS 273 patients ( ≥ 6 years ) ; r and omized to three 28-day courses ( AZLI 75 mg [ three-times/day ] or TNS 300 mg [ twice/day ] ) ; 28 off-days separated each course . RESULTS 268 patients were treated ( AZLI/TNS : 136/132 ) . Mean baseline FEV1 was 52 % predicted . Mean relative changes after 1 course ( AZLI : 8.35 % ; TNS : 0.55 % ; p<0.001 ) and mean actual changes across 3 courses ( AZLI : 2.05 % ; TNS : -0.66 % ; p=0.002 ) indicated AZLI statistical superiority vs. TNS . AZLI-treated patients had fewer respiratory hospitalizations ( p=0.044 ) and respiratory events requiring additional antipseudomonal antibiotics ( p=0.004 ) ; both treatments were well tolerated . 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period ( 28-day courses separated by 28 days off-treatment ) ; lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period . CONCLUSIONS AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses ( Clinical Trials.gov : NCT00757237 ) Twenty-seven patients with cystic fibrosis and endobronchial colonization with Pseudomonas aeruginosa were r and omly assigned to inhale either 2 mL saline ( 12 patients ) or 80 mg tobramycin solution ( 15 patients ) 3 times daily . One control patient died ; all others completed the study ( mean duration 32 months ) . No significant differences were found between the two groups at enrollment . The treatment group showed no change , while the control group had a significant decline in both pulmonary function and clinical status over the study period . Individually , 11 of 12 patients in the control group showed deterioration , while 9 of 15 in the treatment group with susceptible P. aeruginosa at enrollment acquired resistant organisms . There was no evidence of significant nephro- or ototoxicity . Although inhaled tobramycin appeared to arrest the decline in pulmonary status , further work is required to identify patients most likely to respond Abstract Background : Tobramycin inhalation powder ( TIP ) was reported to be effective in two Phase III studies in patients with cystic fibrosis ( CF ) chronically infected with Pseudomonas aeruginosa ( Pa ) . The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6–21 years . Methods : CF patients with a forced expiratory volume in 1 second ( FEV1 ) ≥25 % to ≤80 % predicted , positive Pa cultures and inhaled antipseudomonal therapy naïve ( or at least for past 4 months ) were enrolled into this double-blind , multicenter trial . Patients were r and omized to receive TIP or placebo ( 1:1 ) twice daily for one treatment cycle ( 28.5 days on drug , 28 days off drug ) . The primary endpoint was relative change in FEV1 percentage predicted from baseline to day 29 . A pre-specified sensitivity analysis evaluated absolute change in FEV1 % predicted . Other endpoints included Pa sputum density and safety . Results : A total of 62 patients out of a target of 100 ( mean age 12.9 years , baseline FEV1 59.2 % predicted , Pa sputum density 7.4 log10 colony forming units [ CFU ] per gram ) were r and omized . Mean treatment differences ( TIP - placebo ) were 5.9 % ( p = 0.148 ) and 4.4 % ( p < 0.05 ) for relative and absolute change in FEV1 % predicted respectively . TIP significantly reduced Pa sputum density by −1.2 log10 CFU ( p = 0.002 ) . Treatment with TIP was well tolerated . Conclusions : Relative change in FEV1 % predicted with TIP treatment was in the expected range based on the literature , but did not reach statistical significance versus placebo . Placebo control and use of treatment naïve patients led to significant recruitment challenges and an underpowered study with consequent impact on the generated data . However , significant improvements in other outcomes including absolute change in FEV1 % predicted and reduction in Pa sputum density indicate that TIP is efficacious and well tolerated in CF patients . Clinical Trials.gov identifier : Clinical Trials.gov identifier : NCT00918957 RATIONALE Fosfomycin/tobramycin for inhalation ( FTI ) , a unique , broad-spectrum antibiotic combination , may have therapeutic potential for patients with cystic fibrosis ( CF ) . OBJECTIVES To evaluate safety and efficacy of FTI ( 160/40 mg or 80/20 mg ) , administered twice daily for 28 days versus placebo , in patients greater than or equal to 18 years of age , with CF , chronic Pseudomonas aeruginosa ( PA ) airway infection , and FEV(1 ) greater than or equal to 25 % and less than or equal to 75 % predicted . METHODS This double-blind , placebo-controlled , multicenter study assessed whether FTI/placebo maintained FEV(1 ) % predicted improvements achieved following a 28-day , open-label , run-in course of aztreonam for inhalation solution ( AZLI ) . MEASUREMENTS AND MAIN RESULTS A total of 119 patients were r and omized to FTI ( 160/40 mg : n = 41 ; 80/20 mg : n = 38 ) or placebo ( n = 40 ) . Mean age was 32 years and mean FEV(1 ) was 49 % predicted at screening . Relative improvements in FEV(1 ) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo ( 160/40 mg vs. placebo : 6.2 % treatment difference favoring FTI , P = 0.002 [ primary endpoint ] ; 80/20 mg vs. placebo : 7.5 % treatment difference favoring FTI , P < 0.001 ) . The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo ( -1.04 log(10 ) PA colony-forming units/g sputum difference , favoring FTI ; P = 0.01 ) . Adverse events , primarily cough , were consistent with CF disease . Respiratory events , including dyspnea and wheezing , were less common with FTI 80/20 mg than FTI 160/40 mg . No clinical ly significant differences between groups were reported for laboratory values . CONCLUSIONS FTI maintained the substantial improvements in FEV(1 ) % predicted achieved during the AZLI run-in and was well tolerated . FTI is a promising antipseudomonal therapy for patients with CF STUDY OBJECTIVE To determine whether adequate concentrations of a new formulation of tobramycin could be delivered to the lower respiratory tract of patients with cystic fibrosis ( CF ) using a jet nebulizer delivery system . DESIGN A multicenter , open-label , r and omized , crossover study . SETTING Ten tertiary care , university-affiliated , teaching hospitals in the United States . PATIENTS AND CONTROL SUBJECTS Sixty-eight patients recruited from 10 CF Foundation centers and who were at least 8 years of age , had a diagnosis of CF , and expectorated daily sputum . No control subjects enrolled . INTERVENTIONS Each patient received one administration of aerosolized tobramycin from each of the three nebulizer systems in r and om order . Each administration was separated by a minimum of 48 h. The two jet nebulizer systems tested were the Sidestream ( Medic-Aid ; Sussex , UK ) , and the Pari LC ( Pari Respiratory Equipment ; Richmond , Va ) , with a DeVilbiss Pulmoaide compressor ( DeVilbiss Health Care ; Somerset , Pa ) , both administering 300 mg tobramycin in 5 mL of 1/4 normal saline solution ( NS ) . Patients were also administered 600 mg tobramycin in 30 mL of 1/2 NS with the UltraNeb 99/100 ( DeVilbiss ) . MEASUREMENTS Sputum and serum tobramycin concentration and pulmonary function were monitored . An adequate peak sputum tobramycin concentration was defined as > 128 microg/g sputum at any of three time points ( 10 , 60 , or 120 min ) after completion of treatments . RESULTS The peak tobramycin concentrations in expectorated sputum were 687+/-663 microg/g ( mean+/-SD ) with the Pari LC and 489+/-402 microg/g with the Sidestream . Adequate peak sputum tobramycin concentration was achieved in 93 % of the patients with the Sidestream , and in 87 % of the patients with the Pari LC . Peak sputum concentrations were found to be substantially higher when patients received tobramycin administered with the UltraNeb 99/100 , 1,498+/-1,331 microg/g with 30 % of patients having levels exceeding 2,000 microg/g . Serum tobramycin concentrations were < or = 4 microg/mL for all patients following administration with each nebulizer . CONCLUSIONS Adequately high sputum tobramycin concentrations were documented in sputum in > 85 % of patients following the administration of 300 mg/5 mL formulation of tobramycin aerosolized by the two jet nebulizer delivery systems , Sidestream and Pari LC . The single tobramycin administration delivered by these two systems is well-tolerated Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy . We evaluated the pharmacokinetics ( PK ) and safety of tobramycin inhalation powder ( TIP ) , a novel dry-powder formulation design ed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections . This was a multi-center , open-label , sequential-cohort , single-dose , dose-escalation study using the st and ard 300 mg dose of tobramycin solution for inhalation ( TSI ) as an active control . Subjects were r and omized to TIP or TSI in a 3:1 ratio in each of five cohorts . Measurements included serum and sputum tobramycin concentrations , administration time , serum chemistries , acute change in lung function , and adverse events ( AEs ) . Out of 90 r and omized subjects , 86 had data for safety analysis ; and 84 had data for PK analysis . Serum tobramycin PK profiles were similar for TIP and TSI . Four capsules of 28 mg TIP ( total tobramycin dose 112 mg ) produced comparable systemic exposure to 300 mg TSI , in less than one-third the administration time . The most common AEs associated with TIP were cough ( 20 % ) and dysgeusia ( 17 % ) . TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation . The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation . The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections OBJECTIVE To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection . DESIGN R and omized controlled trial . SETTING Multicenter trial in the United States . PARTICIPANTS Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection . INTERVENTIONS Participants were r and omized to 1 of 4 antibiotic regimens for 18 months ( six 12-week quarters ) between December 2004 and June 2009 . Participants r and omized to cycled therapy received tobramycin inhalation solution ( 300 mg twice a day ) for 28 days , with oral ciprofloxacin ( 15 - 20 mg/kg twice a day ) or oral placebo for 14 days every quarter , while participants r and omized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures . MAIN OUTCOME MEASURES The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures . RESULTS The intention-to-treat analysis included 304 participants . There was no interaction between treatments . There were no statistically significant differences in exacerbation rates between cycled and culture-based groups ( hazard ratio , 0.95 ; 95 % confidence interval [ CI ] , 0.54 - 1.66 ) or ciprofloxacin and placebo ( hazard ratio , 1.45 ; 95 % CI , 0.82 - 2.54 ) . The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 ( 95 % CI , 0.49 - 1.23 ) and 1.10 ( 95 % CI , 0.71 - 1.71 ) comparing ciprofloxacin vs placebo . Adverse events were similar across groups . CONCLUSIONS No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies . Adding ciprofloxacin produced no benefits . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00097773 BACKGROUND Inhaled tobramycin has been shown to improve lung function in cystic fibrosis ( CF ) patients chronically infected with Pseudomonas aeruginosa . However , to date no comparative data are available for different dose regimens used in clinical practice . OBJECTIVES To compare the clinical efficacy of the two most commonly used treatment regimens of inhaled tobramycin in patients with CF . METHODS In an open crossover study of CF patients , subjects were r and omly allocated to receive either 80 mg tobramycin twice-daily continuous treatment or 300 mg tobramycin twice daily in cycles of 28 days on and 28 days off treatment . After three months , patients were switched to the alternative treatment regimen . RESULTS A total of 32 patients with a mean ( + /- SD ) age of 18.5+/-8.6 years were included in the study . Compared with the treatment period using colistin , forced expiratory volume in 1 s decreased by -2.1+/-13.8 % in the 80 mg tobramycin group and increased by + 2.3+/-13.0 % in the 300 mg group . Similar changes were observed in forced vital capacity ( -2.5+/-12.9 % in the 80 mg tobramycin group versus + 2.5+/-9.6 % in the 300 mg tobramycin group ) . Variability in responses was large but the differences were not statistically significant . Personal preference indicated that the majority of patients preferred the high-dose cycle compared with the lower dose continuous inhalation , but this was not linked to objective data on efficacy . CONCLUSIONS The present trial fails to provide convincing evidence for superiority in efficacy of either of the two treatment regimens of inhaled tobramycin in CF patients To assess whether chronic pulmonary colonisation with Pseudomonas aeruginosa in cystic fibrosis is preventable , 26 patients who had never received anti-pseudomonas chemotherapy were r and omly allocated to groups receiving either no anti-pseudomonas chemotherapy or oral ciprofloxacin and aerosol inhalations of colistin twice daily for 3 weeks , whenever Ps aeruginosa was isolated from routine sputum cultures . During the 27 months of the trial , infection with Ps aeruginosa became chronic in significantly fewer treated than untreated subjects ( 2 [ 14 % ] vs 7 [ 58 % ] ; p less than 0.05 ) and there were significantly fewer Ps aeruginosa isolates in routine sputum cultures in the treated group ( 49/214 [ 23 % ] vs 64/158 [ 41 % ] ; p = 0.0006 ) . Thus , chronic colonisation with Ps aeruginosa can be prevented in cystic fibrosis by early institution of anti-pseudomonas chemotherapy Tobramycin inhalation solution is used to treat chronic Pseudomonas aeruginosa lung infection in cystic fibrosis ( CF ) patients . We evaluated the efficacy and safety of a novel , light-porous particle , dry-powder formulation of tobramycin , which was developed to improve delivery efficiency to the airways and substantially reduce the delivery time . In this r and omized , double-blind study , patients with CF ( age 6 - 21 years ) received tobramycin inhalation powder ( 112 mg tobramycin ) twice daily ( n = 46 ) or placebo ( n = 49 ) via the T-326 Inhaler for one cycle , followed by two open-label cycles ( all patients ) . Cycles were 28 days on , 28 days off treatment . The primary endpoint was change in forced expiratory volume in 1 sec ( FEV1 ) % predicted from baseline to Day 28 of Cycle 1 . The study was terminated early based on positive results in the interim analysis . Tobramycin inhalation powder significantly improved FEV1 % predicted versus placebo at Day 28 ( difference 13.3 , 95 % CI : 5.31 - 21.28 ; P = 0.0016 ) . Similar changes in FEV1 were seen in patients switching from placebo to tobramycin inhalation powder in Cycle 2 ; improvements were maintained over time . Tobramycin inhalation powder also reduced sputum P. aeruginosa density , respiratory-related hospitalization and antipseudomonal antibiotic use versus placebo . The most common adverse event was cough ; the frequency of cough was higher in patients receiving placebo ( 26.5 % ) versus tobramycin inhalation powder ( 13.0 % ) in Cycle 1 . Tobramycin inhalation powder was not associated with ototoxicity or nephrotoxicity . Administration time was between 4 and 6 min . In conclusion , tobramycin inhalation powder was effective and well tolerated in CF patients , and may offer an important treatment option to decrease the treatment burden of CF pseudomonas lung infections Pseudomonas aeruginosa endobronchial infection causes significant morbidity and mortality among cystic fibrosis patients . Microbiology results from two multicenter , double-blind , placebo-controlled trials of inhaled tobramycin in cystic fibrosis were monitored for longitudinal changes in sputum microbial flora , antibiotic susceptibility , and selection of P. aeruginosa isolates with decreased tobramycin susceptibility . Clinical response was examined to determine whether current susceptibility st and ards are applicable to aerosolized administration . Treatment with inhaled tobramycin did not increase isolation of Burkholderia cepacia , Stenotrophomonas maltophilia , or Alcaligenes xylosoxidans ; however , isolation of C and ida albicans and Aspergillus species did increase . Although P. aeruginosa tobramycin susceptibility decreased in the tobramycin group compared with that in the placebo group , there was no evidence of selection for the most resistant isolates to become most prevalent . The definition of resistance for parenteral administration does not apply to inhaled tobramycin : too few patients had P. aeruginosa with a tobramycin MIC > /=16 microgram/mL to define a new break point on the basis of clinical response BACKGROUND Tobramycin inhalation is an accepted treatment of chronic pseudomonal infection in cystic fibrosis ( CF ) patients . Twice daily inhalation is efficacious , but time-consuming . METHODS In this r and omized , open-label , multicentre , two-period , crossover study , 58 patients with CF and chronic Pseudomonas aeruginosa ( PA ) infection received two tobramycin nebuliser solutions : T100/eFlow or TNS/PARI LC PLUS . The primary objective was to demonstrate the equivalence of both treatments with respect to pharmacokinetics ( area under the concentration-time curve and maximum concentration in plasma ) . Secondary endpoints were tobramycin sputum pharmacokinetics , reduction in PA colony forming units , improvement of lung function , incidence of adverse drug reactions and reduction of inhalation times . RESULTS Tobramycin plasma AUC and Cmax were lower after administration of T100 than after TNS . The study failed to demonstrate systemic bioequivalence of the two treatments . After T100 administration , tobramycin sputum AUC and Cmax achieved higher values than after TNS . Changes in efficacy parameters from baseline were similar . Safety profiles were not different or unexpected . Inhalation time per inhalation was shorter during treatment with T100 . CONCLUSION The lower systemic drug burden and the higher local drug deposition together with a comparable efficacy/safety profile and a shorter inhalation time render T100/eFlow an attractive treatment option for CF patients . ( www.controlled-trials.com/IS RCT N85410458 ) OBJECTIVES Despite the central importance of pulmonary exacerbations ( PExs ) as an outcome measure in cystic fibrosis clinical trials , no st and ardized definition of PEx exists . We conducted a prospect i ve , multicenter study to establish a st and ardized PEx definition and score for use in clinical trials , based on clinical status rather than on treatment decisions . STUDY DESIGN Subjects were 246 patients enrolled in the placebo arm of a r and omized , controlled trial of tobramycin for inhalation . Physician-investigators completed PEx question naires on all subjects at scheduled intervals during the 6-month study , indicating new or worsening symptoms , physical examination findings , and impression of PEx status ( presence or absence and severity ) . Logistic regression was used to assess the relative importance of each of the characteristics in predicting a PEx . RESULTS We developed 2 PEx scores that use easily ascertained symptoms and chest examination findings ; one also includes change in forced expiratory volume in 1 second over the preceding month . Both scores were sensitive and specific for predicting the presence of a PEx ( sensitivity , 86 % ; specificity , 86 % ) . The scores were vali date d in subjects in the intervention arm of the trial . CONCLUSION We hope that the proposed PEx score might serve as a st and ardized outcome measure for future clinical trials in cystic fibrosis , allowing meaningful comparisons of study results To determine the potential toxicity of prolonged aerosol tobramycin administration , 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks . Prior to , four times during administration and approximately 6 weeks after discontinuation of treatment , we assessed pulmonary function , weight , height , body temperature , eighth cranial nerve function , serum creatinine , blood urea nitrogen , urinary creatinine clearance , plasma iothalamate clearance , urinary beta-2 microglobulin concentration , and Pseudomonas aeruginosa density in sputum . There was no detectable laboratory evidence of nephrotoxicity . Neither a decrease in auditory acuity ( range 250 - 20,000 Hz ) nor vestibular dysfunction was detected . Pulmonary function tests significantly improved during the first month in all subjects ( P less than 0.05 ) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol . Sputum P. aeruginosa density initially decreased from a mean of 10(7 ) cfu/gm to a mean of 10(4 ) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout . Coincident with the reduced bacterial density , a reduction in cough frequency and sputum production , as well as a weight gain was observed . Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration . However , 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin . We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity . Transient emergence of tobramycin resistant P. aeruginosa may occur RATIONALE The effectiveness and safety of aztreonam lysine for inhalation ( AZLI ) in patients with cystic fibrosis ( CF ) on maintenance treatment for Pseudomonas aeruginosa ( PA ) airway infection was evaluated in this r and omized , double-blind , placebo-controlled study . OBJECTIVES To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF . METHODS After r and omization and a 28-day course of tobramycin inhalation solution ( TIS ) , patients ( n = 211 ; > or = 6 yr ; > or =3 TIS courses within previous year ; FEV(1 ) > or = 25 % and < or = 75 % predicted values ) were treated with 75 mg AZLI or placebo , twice or three times daily for 28 days , then monitored for 56 days . The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics . Secondary endpoints included changes in respiratory symptoms ( CF Question naire-Revised [ CFQ-R ] Respiratory Scale ) , pulmonary function ( FEV(1 ) ) , and sputum PA density . Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored . MEASUREMENTS AND MAIN RESULTS AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days , compared with placebo ( AZLI , 92 d ; placebo , 71 d ; P = 0.007 ) . AZLI improved mean CFQ-R respiratory scores ( 5.01 points , P = 0.02 ) , FEV(1 ) ( 6.3 % , P = 0.001 ) , and sputum PA density ( -0.66 log(10 ) cfu/g , P = 0.006 ) compared with placebo ; no AZLI dose-response was observed . Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease . Susceptibility of PA to aztreonam at baseline and end of therapy were similar . CONCLUSIONS AZLI was effective in patients with CF using frequent TIS therapy . AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics , improved respiratory symptoms and pulmonary function , and was well tolerated . Clinical trial registered with www . clinical trials.gov ( NCT 00104520 ) Abstract Background and aim Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis ( CF ) causes progressive deterioration in lung function . The purpose of this trial was to assess the efficacy and tolerability of a tobramycin highly concentrated solution for inhalation ( TSI ) [ 300mg/4mL ; Bramitob ® ] when added to other antipseudomonal therapies in CF patients with chronic P. aeruginosa infection . Methods In a multinational , double-blind , multicenter study , CF patients with chronic P. aeruginosa infection were r and omized to receive nebulized tobramycin or placebo over a 24-week study period in which 4-week treatment periods ( ‘ on ’ cycles ) were followed by 4-week periods without treatment ( ‘ off ’ cycles ) . Forced expiratory volume in 1 second ( FEV1 ) percentage of predicted normal was used as the primary efficacy outcome parameter . Forced vital capacity ( FVC ) , forced expiratory flow at 25–75 % of FVC ( FEF25–75 % ) , P. aeruginosa susceptibility , minimum concentration required to inhibit 90 % of strains ( MIC90 ) , rates of P. aeruginosa-negative culture , P. aeruginosa persistence and superinfection , need for hospitalization and parenteral antipseudomonal antibiotics , loss of school/working days due to the disease , and nutritional status ( bodyweight and body mass index ) were considered as secondary efficacy outcome parameters . Adverse events reporting , audiometry , and renal function were monitored to evaluate the tolerability and safety of TSI . Results A total of 247 patients were r and omized in the study . At endpoint time assessment ( week 20 ) , FEV1 was significantly increased in the tobramycin group and the adjusted mean difference between groups ( intention-to-treat population ) was statistically significant ( p < 0.001 ) . At the same time , clinical ly relevant improvements in FVC and FEF25–75 % were detected in the TSI group ( p = 0.022 and p = 0.001 , respectively ) . The microbiologic outcomes at the end of the last ‘ on ’ cycle period were significantly better in the TSI group than the placebo group ( p = 0.024 ) , although there was a concomitant trend toward an increase in the MIC of isolated P. aeruginosa strains . The percentage of patients hospitalized as well as the need for parenteral antipseudomonal antibiotics was significantly lower in the TSI group ( p = 0.002 and p = 0.009 , respectively ) . Patients treated with TSI had fewer lost school/working days due to the disease ( p < 0.001 ) . A favorable effect of tobramycin in terms of an increase in bodyweight and body mass index was also noted , when compared with placebo , at all timepoints ( p < 0.01 and p < 0.001 , respectively ) . No significant changes in serum creatinine and auditory function were detected . The proportion of patients with drug-related adverse events was 15 % in both treatment groups . Conclusions Long-term , intermittent administration of this aerosolized tobramycin formulation ( 300mg/4mL ) in CF patients with P. aeruginosa chronic infection significantly improved pulmonary function and microbiologic outcome , decreased hospitalizations , increased nutritional status , and was well tolerated In a previously published placebo-controlled trial , tobramycin solution for inhalation ( TSI ) was shown to improve lung function and other outcomes in patients with cystic fibrosis ( CF ) . The objectives of the current study were to examine the effects of TSI on global ratings of health-related quality of life ( HRQOL ) by patients ( or their parents ) and physicians blind to group assignment , and to determine whether any perceived benefits persisted over time . The global ratings of HRQOL in 520 patients with CF and chronic Pseudomonas aeruginosa infection were analyzed retrospectively . Patients were r and omly assigned to receive 24 weeks of placebo or treatment with TSI 300 mg b.i.d . , both administered in cycles of 28 days on drug ( or placebo ) followed by 28 days off , for a total of three cycles . After each on-drug cycle , patients or parents , and physicians , were asked to rate whether the patient 's condition was better , unchanged , or worse . There was strong agreement between the paired patient/parent and physician global HRQOL ratings across the three cycles . Regression analyses demonstrated that patients in the TSI group were significantly more likely to report improvements in HRQOL than were patients in the placebo group . This effect was found to be both immediate ( end of on-drug cycle 1 ) and delayed ( end of subsequent on-drug cycles 2 and 3 ) ( P < 0.05 ) . In addition , change in forced expired volume in 1 sec ( FEV(1 ) ) % predicted values was a significant predictor of improvement in HRQOL ratings by patients and parents . After controlling for change in FEV(1 ) % predicted , physician ratings showed significant improvement only at the end of cycle 1 . Finally , controlling for initial lung disease severity , longitudinal growth models revealed that patients on TSI and their physicians reported higher HRQOL ratings than did placebo patients and their physicians across the three cycles ; however , the magnitude of this effect decreased over time . Results of this study provided consistent evidence that TSI was associated with improved global ratings of HRQOL completed by both patients or parents , and physicians . Although these results are promising , they are limited by the use of a single-item rating of health . Future studies of the effects of TSI should utilize a well-vali date d , disease-specific measure of HRQOL BACKGROUND Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis ( CF ) and non-CF bronchiectasis . However , established nebulized preparations impose a substantial time burden on patients . A dry powder formulation of ciprofloxacin for inhalation ( ciprofloxacin DPI ) has been developed using PulmoSphere ™ ( Novartis , Pharma AG , Basel , Switzerl and ) technology ( administered using a T-326 inhaler ) to maximize antibacterial activity and convenience . OBJECTIVE This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF . METHODS A Phase I , r and omized , single-blind , placebo-controlled , dose-escalation study in patients with CF ( median age 29.0 years [ 19 - 40 ] ) , stable pulmonary status , and chronic Pseudomonas aeruginosa colonization . Sequential cohorts received ciprofloxacin DPI 32.5 mg qd ( 1 capsule for inhalation ; n = 6 ) , 65 mg qd ( 2 capsules for inhalation ; n = 6 ) , or 32.5 mg ( n = 6 ) bid for 7 days . Each group was placebo controlled . RESULTS Twenty-five patients were enrolled ( 12 men ; median age , 29.0 years [ range , 19 - 40 years ] ; 6 , 6 , 6 , and 7 patients in the ciprofloxacin DPI 32.5 mg qd , 65 mg qd , and 32.5 mg bid and placebo groups , respectively ) . No serious treatment-emergent adverse events or clinical ly relevant changes in tolerability parameters , including lung function measurements , were reported . Twenty-one patients ( ciprofloxacin , n = 17 ; placebo , n = 4 ) experienced 29 mild drug-related treatment-emergent adverse events , including bitter taste ( ciprofloxacin , 17 patients ; placebo , 2 ) and bronchospasm ( ciprofloxacin , 3 ; placebo , 2 ) . Ciprofloxacin DPI was absorbed rapidly after inhalation . Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups , suggesting an absence of substantial drug accumulation . The geometric mean AUCs after the last dose were 0.383 , 1.472 , and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd , 65 mg qd , and 32.5 mg bid , respectively . The range of geometric mean t(½ ) in plasma was 3.4 to 9.5 hours . Sputum concentrations of ciprofloxacin were high , with substantial variability . Geometric mean ciprofloxacin concentrations ( % CV ) in induced sputum were 57.7 ( 118.2 ) , 177.5 ( 53.4 ) , and 149.7 ( 249.7 ) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd , 65 mg qd , and 32.5 mg bid , respectively . CONCLUSIONS Ciprofloxacin DPI was well tolerated , especially with respect to lung function , with minimal systemic exposure compared with data from previous studies of oral and intravenous administration , and with no apparent accumulation at steady state . Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected . Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities . Eudra clinical trial identifier : 2006 - 003690 - 26 Tobramycin nebuliser solution ( TNS ) has been investigated in several clinical trials , including a large , placebo-controlled study that demonstrated efficacy over a 24-week period . The open-label extension phase of this trial enabled observations to be conducted for an additional period of almost 18 months . Patients from both treatment arms ( n=396 ) entered the open-label phase and received up to nine 28-day on , 28-day off cycles of TNS 300 mg by aerosol twice daily ( b.i.d . ) . Mean lung function in patients who had received placebo during the double-blind phase improved during the first three cycles of the open-label treatment . However , lung function in these patients did not recover to the levels seen in those patients who had received TNS throughout the double-blind and open-label phases . In both groups of patients , improvement was maintained during the study . Greater improvements were seen in adolescents compared with older patients . Adverse events were generally uncommon , with a notably lower incidence of fever , anorexia , abdominal pain and vomiting than was observed in the double-blind phase among patients who received placebo , and a generally low incidence of tinnitus . We conclude that long-term TNS administration is safe and effective Eighty-seven patients with cystic fibrosis were admitted to hospital with an acute exacerbation of pulmonary symptoms associated with isolation of Pseudomonas aeruginosa from sputum . The patients were r and omly allocated to receive intravenously administered ceftazidime ( 250 mg/kg/day ) and amikacin ( 33 mg/kg/day ) alone or with inhaled amikacin ( 100 mg twice a day ) . Other aspects of the 2-week treatment were constant . The two therapy groups were comparable in all aspects . At the completion of therapy , the addition of aerosolized amikacin produced temporary eradication of P. aeruginosa in 70 % of the patients , compared with 41 % in the intravenous therapy only group ( P less than 0.02 ) . Suppression of P. aeruginosa in sputum cultures was correlated with the amikacin sputum concentrations . However , both regimens result ed in similar improvements in clinical , radiologic , laboratory , and pulmonary function measurements , and within 4 to 6 weeks most patients were recolonized with P. aeruginosa . There was no serious toxicity or adverse effect . In patients with cystic fibrosis , the addition of aerosol aminoglycoside to systemic antipseudomonal combination therapy is not clinical ly beneficial BACKGROUND Inhaled antibiotics are st and ard of care for persons with cystic fibrosis ( CF ) and chronic Pseudomonas aeruginosa airway infection . APT-1026 ( levofloxacin inhalation solution , LIS ) is fluoroquinolone in development . We compared the safety and efficacy of LIS to tobramycin inhalation solution ( TIS ) in persons ≥12 years old with CF and chronic P. aeruginosa infection . METHODS This multinational , r and omized ( 2:1 ) , non-inferiority study compared LIS and TIS over three 28-day on/off cycles . Day 28 FEV(1 ) % predicted relative change was the primary endpoint . Time to exacerbation and patient-reported quality of life were among secondary endpoints . RESULTS Baseline demographics for 282 subjects were comparable . Non-inferiority was demonstrated ( 1.86 % predicted mean FEV(1 ) difference [ 95 % CI -0.66 to 4.39 % ] ) . LIS was well-tolerated , with dysgeusia ( taste distortion ) as the most frequent adverse event . CONCLUSIONS LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection RATIONALE For patients with cystic fibrosis ( CF ) , the use of inhaled antibiotics has become st and ard of care to suppress chronic Pseudomonas airways infection . There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time , making additional inhaled antibiotic classes desirable . APT-1026 ( levofloxacin inhalation solution , LIS ) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF . OBJECTIVES To compare the safety and efficacy of a 28-day course of treatment with LIS 240 mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection . METHODS A multinational , r and omized ( 2:1 ) , double-blinded study of LIS and placebo over 28days in CF patients ≥12years with chronic P. aeruginosa infection . Time to exacerbation was the primary endpoint . FEV1 ( % predicted ) and patient-reported quality of life were among secondary endpoints . MAIN RESULTS Baseline demographics for 330 subjects ( LIS=220 ) were similar although significantly more patients r and omized to LIS had experienced multiple exacerbations in the year prior to study entry . There was no statistically significant difference in protocol -defined pulmonary exacerbations between treatment arms . Relative change in FEV1 % predicted from baseline was significantly greater for patients r and omized to LIS compared to those r and omized to placebo ( mean difference 1.31 % , p=0.01 [ 95 % CI 0.27 , 2.34 % ] ) . LIS was well-tolerated , with dysguesia the most frequent adverse event . CONCLUSIONS LIS did not demonstrate a difference in time to next exacerbation when compared to placebo . Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups . An improvement in FEV1 ( % predicted ) at 28days was observed and LIS was well tolerated . LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa BACKGROUND Levofloxacin inhalation solution ( LIS ) is the first aerosolized fluoroquinolone licensed for treatment of patients with cystic fibrosis ( CF ) and chronic Pseudomonas aeruginosa lung infection . This study evaluated the safety and efficacy of extended LIS treatment . METHODS Patients completing a multinational , r and omized study comparing LIS and tobramycin inhalation solution ( TIS ) were enrolled in an open-label extension in which all patients received three additional cycles of 28days of LIS 240 mg twice daily followed by 28days off drug . Endpoints included mean relative change in percent predicted forced expiratory volume in 1s ( FEV1 ) , time to pulmonary exacerbation , and patient-reported quality of life . RESULTS Extended treatment with LIS in 88 patients was well tolerated with no new safety signals and evidence of positive effects on FEV1 and quality of life . CONCLUSION Patients receiving extended LIS treatment continued to show favorable efficacy with no additional safety concerns BACKGROUND Inhaled antibiotics are st and ard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients , initially approved for intermittent administration . However , use of continuous inhaled antibiotic regimens of differing combinations is growing . METHODS This double-blind trial compared continuous alternating therapy ( CAT ) to an intermittent treatment regimen . Subjects were treated with 3cycles of 28-days inhaled aztreonam ( AZLI ) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution ( TIS ) . RESULTS 90 subjects were r and omized over 18months . Study enrollment was limited , in part because of evolving practice s by clinicians of adopting a CAT regimen in clinical practice ; consequently the study was underpowered . AZLI/TIS treatment reduced exacerbation rates by 25.7 % ( p=0.25 ; primary endpoint ) and rates of respiratory hospitalizations by 35.8 % compared with placebo/TIS ( p=0.14 ) . AZLI/TIS CAT therapy was well tolerated . CONCLUSIONS This trial illustrates challenges with study ing treatment regimens in a constantly evolving CF care environment . Nonetheless , the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone . Clinical trials.gov : NCT01641822

There is no evidence for managing adults , or children who do not have HbSS sickle cell disease . In children who are at higher risk of stroke and have not had previous long-term transfusions , there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke , and low quality evidence they also reduce the risk of other sickle cell disease-related complications . In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration . In secondary prevention of stroke there is low- quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events .

BACKROUND Sickle cell disease is one of the commonest severe monogenic disorders in the world , due to the inheritance of two abnormal haemoglobin ( beta globin ) genes . Sickle cell disease can cause severe pain , significant end-organ damage , pulmonary complications , and premature death . Stroke affects around 10 % of children with sickle cell anaemia ( HbSS ) . Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation . This is an up date of a Cochrane Review first published in 2002 , and last up date d in 2013 . OBJECTIVES To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention ( excluding silent cerebral infa rcts ) .

Noninvasive , quantitative , and accurate assessment of liver iron concentration ( LIC ) by MRI is useful for patients receiving transfusions , but R2 and R2 * MRI techniques have not been systematic ally compared in sickle cell anemia ( SCA ) . We report baseline LIC results from the TWiTCH trial , which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients . Liver R2 was collected and processed using a FDA ‐approved commercial process ( FerriScan ® ) , while liver R2 * quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data . Baseline LIC studies using both MRI techniques were available for 120 participants . LICR2 * and LICR2 results were highly correlated ( r2 = 0.93 ) . A proportional bias of LIC(R2*)/LIC(R2 ) , decreasing with average LIC , was observed . Systematic differences between LICR2 * and LICR2 were also observed by MRI manufacturer . Importantly , LICR2 * and LICR2 estimates had broad 95 % limits of agreement with respect to each other . We recommend LICR2 and LICR2 * not be used interchangeably in SCA patients to follow individual patient trends in iron burden . Am . J. Hematol . 90:806–810 , 2015 . © 2015 Wiley Periodicals , Hydroxyurea has hematologic and clinical efficacy in sickle cell anemia ( SCA ) , but its effects on transcranial Doppler ( TCD ) flow velocities remain undefined . Fifty-nine children initiating hydroxyurea therapy for clinical severity had pretreatment baseline TCD measurements ; 37 with increased flow velocities ( > or = 140 cm/s ) were then enrolled in an institutional review board (IRB)-approved prospect i ve phase 2 trial with TCD velocities measured at maximum tolerated dose ( MTD ) and one year later . At hydroxyurea MTD ( mean + /- 1 SD = 27.9 + /- 2.7 mg/kg per day ) , significant decreases were observed in the right middle cerebral artery ( MCA ) ( 166 + /- 27 cm/s to 135 + /- 27 cm/s , P < .001 ) and left ( MCA ) ( 168 + /- 26 cm/s to 142 + /- 27 cm/s , P < .001 ) velocities . The magnitude of TCD velocity decline was significantly correlated with the maximal baseline TCD value . At hydroxyurea MTD , 14 of 15 children with conditional baseline TCD values improved , while 5 of 6 with abnormal TCD velocities whose families refused transfusions became less than 200 cm/s . TCD changes were sustained at follow-up . These prospect i ve data indicate that hydroxyurea can significantly decrease elevated TCD flow velocities , often into the normal range . A multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values , and ultimately for primary stroke prevention in children with SCA The Stroke With Transfusions Changing to Hydroxyurea ( SWiTCH ) trial compared st and ard ( transfusions/chelation ) to alternative ( hydroxyurea/phlebotomy ) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment . St and ardized brain magnetic resonance imaging/magnetic resonance angiography ( MRA ) and transcranial Doppler ( TCD ) exams were performed at entry and exit , with a central blinded review . A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis ( 53%/41 % ≥ Grade 4 ) ; 31 % had no vessel stenosis on either side . Baseline parenchymal injury was prevalent ( 85%/79 % subcortical , 53%/37 % cortical , 50%/35 % subcortical and cortical ) . Most children had low or uninterpretable baseline middle cerebral artery TCD velocities , which were associated with worse stenoses ( incidence risk ratio [ IRR ] = 5.1 , P ≤ .0001 and IRR = 4.1 , P < .0001 ) than normal velocities ; only 2 % to 12 % had any conditional/abnormal velocity . Patients with adjudicated stroke ( 7 ) and transient ischemic attacks ( 19 in 11 st and ard/8 alternative arm subjects ) had substantial parenchymal injury/vessel stenosis . At exit , 1 child ( alternative arm ) had a new silent infa rct , and another had worse stenosis . SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury . The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials . This trial was registered at www . clinical trials.gov as # NCT00122980 The Stroke Prevention Trial in Sickle Cell Anemia ( STOP ) was a r and omized multicenter controlled trial comparing prophylactic blood transfusion with st and ard care in sickle cell anemia ( SCA ) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler ( TCD ) . More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the r and omized trial . A total of 5613 TCD studies from 2324 children were evaluated . We also collected information on stroke . We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort . Risk of stroke was higher with abnormal TCD than with normal or conditional TCD ( P < .001 ) or inadequate TCD ( P = .002 ) , and risk with conditional TCD was higher than with normal TCD ( P < .001 ) . Repeated TCD in 1215 children showed that the condition of 9.4 % of children became abnormal during observation . Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs . Screening in STOP confirmed the predictive value of TCD for stroke . Substantial differences in the probability of conversion to abnormal TCD were observed , with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening BACKGROUND A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infa rct ion as seen on magnetic resonance imaging ( MRI ) . OBJECTIVES To determine if transfusion therapy affects the rate at which silent infa rcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler ( TCD ) ultrasonography . STUDY DESIGN Children with elevated TCD ultrasonographic velocity were r and omized to receive long-term transfusion therapy or st and ard care . Magnetic resonance imaging of the brain was obtained at r and omization , annually , and with clinical neurologic events . The risk for new silent lesions and /or stroke was compared for each treatment arm . RESULTS Among the 37 % of subjects with silent infa rcts , those receiving st and ard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy . For subjects receiving st and ard care , those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality . CONCLUSIONS Transfusion therapy lowers the risk for new silent infa rct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infa rct . However , those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infa rct or stroke than are those whose initial MRI showed no abnormality . The finding of a silent infa rct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen . Similarly , elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infa rct or stroke The Stroke Prevention Trial in Sickle Cell Anemia ( STOP ) was a r and omized trial to evaluate whether chronic transfusion could prevent initial stroke in children with sickle-cell anemia at high risk as determined by transcranial Doppler ( TCD ) . The trial demonstrated a large benefit of transfusion and was halted early . After termination of the trial , patients participated in a post-trial follow-up study . More patients in the transfusion group ( 70 % ) elected transfusion for primary stroke prevention compared with those on st and ard care ( 45 % ) . Six patients with persistently abnormal TCD results developed stroke . A minority with initially abnormal TCD results remained stroke-free without transfusion . Except for lower baseline and follow-up TCD velocities compared with those with stroke , no predictive features of this apparent lower-risk subgroup could be determined . TCD results at last testing in 108 patients that did not have stroke were : normal ( 44.4 % ) , conditional ( 26.9 % ) , abnormal ( 22.2 % ) , and inadequate ( 6.5 % ) . Patients on transfusion were more likely to have normal TCD results . Transfusion result ed in iron overload and alloimmunization , but no infection . The study provides new information on acceptance rates and long-term effects of transfusion . Persistent TCD elevation signals ongoing stroke risk . Reduction in TCD results over time without transfusion is observed in some patients and requires further study Background : Silent cerebral infa rct ( SCI ) is the most common cause of serious neurological disease in sickle cell anemia ( SCA ) , affecting approximately 22 % of children . The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI , and if so , the magnitude of this benefit . Procedure : The Silent Cerebral Infa rct Transfusion ( SIT ) Trial includes 29 clinical sites and 3 subsites , a Clinical Coordinating Center , and a Statistical and Data Coordinating Center , to test the following hypothesis : prophylactic blood transfusion therapy in children with SCI will result in at least an 86 % reduction in the rate of subsequent overt strokes or new or progressive cerebral infa rcts as defined by magnetic resonance imaging ( MRI ) of the brain . The intervention is blood transfusion versus observation . Two hundred and four participants ( 102 in each treatment assignment ) will ensure 85 % power to detect the effect necessary to recommend transfusion therapy ( 86 % reduction ) , after accounting for 10 % drop out and 19 % crossover rates . MRI examination of the brain is done at screening , immediately before r and omization and study exit . Each r and omly assigned participant receives a cognitive test battery at study entry , 12–18 months later , and study exit and an annual neurological examination . Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA . Conclusion : The SIT Trial could lead to a change in st and ard care practice s for children affected with SCA and SCI , with a consequent reduction in neurological morbidity The Silent Cerebral Infa rct Multicenter Transfusion ( SIT ) Trial is a multi-institutional intervention trial in which children with silent cerebral infa rcts are r and omized to receive either blood transfusion therapy or observation ( st and ard care ) for 36 months . The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States , Canada , UK , and France . Each child undergoes a screening magnetic resonance imaging ( MRI ) of the brain to detect the presence of silent cerebral infa rct -like lesions , a pre-r and omization ( baseline ) MRI and exit MRI to determine if there are new or enlarged cerebral infa rcts , using a design ated , prospect i ve imaging protocol . The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging . Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers . Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infa rct -like lesions . Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center . The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days . This novel strategy was design ed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures . The technology , process , and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements BACKGROUND Prophylactic transfusion prevents strokes in children with sickle cell anemia who have abnormalities on transcranial Doppler ultrasonographic examination . However , it is not known how long transfusion should be continued in these children . METHODS We studied children with sickle cell disease who had a high risk of stroke on the basis of a transcranial Doppler screening examination and who had received transfusions for 30 months or longer , during which time the Doppler readings became normal . The children were r and omly assigned to continued transfusion or no continued transfusion . Children with severe stenotic lesions on cerebral magnetic resonance angiography were excluded . The composite primary end point was stroke or reversion to a result on Doppler examination indicative of a high risk of stroke . RESULTS The study was stopped after 79 children of a planned enrollment of 100 underwent r and omization . Among the 41 children in the transfusion-halted group , high-risk Doppler results developed in 14 and stroke in 2 others within a mean ( + /-SD ) of 4.5+/-2.6 months ( range , 2.1 to 10.1 ) of the last transfusion . Neither of these events of the composite end point occurred in the 38 children who continued to receive transfusions . The average of the last two transcranial Doppler results before transfusion was started was the only predictor of the composite end point ( P=0.05 ) . CONCLUSIONS Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease results in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke . ( Clinical Trials.gov number , NCT00006182 . Transcranial Doppler ( TCD ) With Transfusions Changing to Hydroxyurea ( TWiTCH ) trial is a r and omized , open‐label comparison of hydroxycarbamide ( also termed hydroxyurea ) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia ( SCA ) and abnormal TCD . Severity and location of iron overload is an important secondary outcome measure . We report the baseline findings of abdominal organ iron burden in 121 participants . At enrollment , patients were young ( 9·8 ± 2·9 years ) , predominantly female ( 60:40 ) , and previously treated with transfusions ( 4·1 ± 2·4 years ) and iron chelation ( 3·1 ± 2·1 years ) . Liver iron concentration ( LIC ; 9·0 ± 6·6 mg/g dry weight ) and serum ferritin were moderately elevated ( 2696 ± 1678 μg/l ) , but transferrin was incompletely saturated ( 47·2 ± 23·6 % ) . Spleen R2 * was 509 ± 399 Hz ( splenic iron ~13·9 mg/g ) and correlated with LIC ( r2 = 0·14 , P = 0·0008 ) . Pancreas R2 * was increased in 38·3 % of patients but not to levels associated with endocrine toxicity . Kidney R2 * was increased in 80·7 % of patients ; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin‐creatinine ratios . Extra‐hepatic iron deposition is common among children with SCA who receive chronic transfusions , and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin The completion of the Multicenter Silent Infa rct Transfusion Trial demonstrated that children with pre‐existing silent cerebral infa rct and sickle cell anemia ( SCA ) who received regular blood transfusion therapy had a 58 % relative risk reduction of infa rct recurrence when compared to observation . However , the total benefit of blood transfusion therapy , as assessed by the parents , was not measured against the burden of monthly blood transfusion therapy . In this planned ancillary study , we tested the hypothesis that a patient centered outcome , health‐related quality of life ( HRQL ) , would be greater in participants r and omly assigned to the blood transfusion therapy group than the observation group . A total of 89 % ( 175 of 196 ) of the r and omly allocated participants had evaluable entry and exit HRQL evaluations . The increase in Change in Health , measured as the child 's health being better , was significantly greater for the transfusion group than the observation group ( difference estimate = −0.54 , P ≤ 0.001 ) . This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy . Am . J. Hematol . 90:139–143 , 2015 . © 2014 Wiley Periodicals , Although long-term transfusion therapy is at least 90 % effective in preventing recurrent strokes after an initial cerebrovascular accident in patients with sickle cell disease , it is unknown how long transfusion therapy should be continued . To address this question , we prospect ively discontinued transfusions in 10 patients with sickle cell disease whose median duration of transfusion therapy after an initial stroke was 9 1/2 years ( range 5 to 12 years ) . Before the transfusions were discontinued , patients were examined by cerebral angiography , magnetic resonance imaging of the head , neuropsychologic testing , electroencephalography , and a complete neurologic examination . Within 12 months after transfusion therapy was stopped , 5 of 10 patients had had an ischemic event . Three events caused relatively mild deficits in the same areas as those originally affected . Two were associated with massive intracranial hemorrhage , including one on the contralateral side of original involvement . An additional patient died suddenly of unknown causes . Of the four remaining patients , three declined to resume transfusion and are relatively well at greater than or equal to 18 months after therapy was stopped . The studies performed before transfusions were stopped were not predictive of recurrent stroke . The risk of recurrent cerebrovascular accident in this group was significantly greater than the estimated risk of 10 % in patients who are receiving long-term transfusion therapy ( p = 0.002 ) . This adverse outcome suggests that patients with sickle cell disease who have had a stroke must receive long-term transfusion indefinitely or a suitable therapeutic alternative must be devised BACKGROUND Stroke occurs in 5 - 10 % of children with sickle cell anemia ( SCA ) and has a high ( > 50 % ) risk of recurrence without therapy . Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke , but their long-term use is limited by serious side effects , including iron overload . An alternative to transfusion for secondary stroke prevention in SCA is needed , especially one that also improves the management of iron overload . METHODS Stroke With Transfusions Changing to Hydroxyurea ( SWiTCH ) is an NHLBI-sponsored Phase III multicenter r and omized controlled clinical trial for children with SCA , stroke , and iron overload ( NCT00122980 ) . The primary goal of SWiTCH is to compare 30 months of alternative therapy ( hydroxyurea and phlebotomy ) with st and ard therapy ( transfusions and chelation ) for the prevention of secondary stroke and reduction of transfusional iron overload . DISCUSSION SWiTCH has several distinctive study features including novel method ological and design components : ( 1 ) composite primary endpoint including both stroke recurrence rate and iron burden ; ( 2 ) non-inferiority design with an " acceptable " increased stroke risk ; ( 3 ) transfusion goals based on current academic community practice s ; ( 4 ) special oversight for the enrollment and r and omization process ; ( 5 ) overlap treatment period within the alternative treatment arm ; ( 6 ) masking of the overall trial Principal Investigator to treatment results ; ( 7 ) inclusive independent stroke adjudication process for all suspected new neurological events ; and ( 8) periodic therapeutic phlebotomy program to alleviate iron overload . CONCLUSION Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA , stroke , and iron overload OBJECTIVE Transfusions prevent secondary stroke in children with sickle cell anemia ( SCA ) but also cause iron overload . Alternatives for stroke prophylaxis with effective therapy to reduce iron burden are needed . STUDY DESIGN For 35 children with SCA and stroke , transfusions were prospect ively discontinued . Hydroxyurea was prescribed for stroke prophylaxis , and phlebotomy removed excess iron . Initial patients discontinued transfusions before hydroxyurea therapy , but later patients overlapped transfusions with hydroxyurea until tolerating full-dose therapy . RESULTS Children received hydroxyurea for 42 + /- 30 months ( range , 3 - 104 months ) . Hydroxyurea ( 26.7 + /- 4.8 mg/kg per day ) led to mild neutropenia ( 3.9 + /- 2.3 x 10(9)/L ) with significant increases in hemoglobin concentration , mean corpuscular volume , and fetal hemoglobin . Stroke recurrence rate was 5.7 events per 100 patient-years , but children receiving overlapping hydroxyurea therapy had only 3.6 events per 100 patient-years . For 26 children with > 6 months of phlebotomy , 14,311 + /- 12,459 mL blood ( 315 + /- 214 mL/kg ) was removed , with serum ferritin decreasing from a median of 2722 to 298 ng/mL. Among patients completing phlebotomy , liver biopsy documented normal histology and no excess iron deposition . CONCLUSIONS For children with SCA and stroke , hydroxyurea effectively prevents secondary stroke and serial phlebotomy leads to complete resolution of transfusional iron overload OBJECTIVE The Stroke Prevention Trial ( STOP ) demonstrated that chronic transfusion is highly effective in reducing the risk of stroke in children with sickle-cell disease and an abnormal transcranial Doppler ultrasonography examination result . Our objective was to determine whether chronic transfusion therapy reduces the incidence of pain and acute chest syndrome . METHODS During STOP , 130 children with sickle-cell anemia or sickle beta(0)-thalassemia and abnormal transcranial Doppler ultrasonography examination result were r and omly assigned to chronic transfusion ( n = 63 ) or observation ( n = 67 ) . In addition to monitoring for stroke , nonneurologic sickle-cell complications were identified and recorded . RESULTS Mean age at STOP study entry was 8.3 + /- 3.3 years , and mean follow-up was 19.6 + /- 6.5 months . Hospitalization rates ( based on intent-to-treat analysis ) for acute chest syndrome were 4.8 and 15.3 per 100 patient-years ( P = .0027 ) and for pain were 16.2 and 27.6 per 100 patient-years ( P = .13 ) in the chronic transfusion and observed groups , respectively . If analyzed according to treatment actually received , the difference in pain rate becomes significant ( 9.7 vs 27.1 events per 100 patient-years , P = .014 ) , and transfusion remains protective from acute chest syndrome ( 2.2 vs 15.7 events per 100 patient-years , P = .0001 ) . CONCLUSIONS Compliance with aggressive chronic transfusion reduces the frequency of acute chest syndrome and pain episodes Background and Purpose — Intravascular hemolysis releases large amounts of free hemoglobin ( PFH ) in plasma of sickle- cell disease ( SCD ) patients . PFH has been associated with harmful endothelial actions including scavenging nitric oxide ( NO ) . Whether PFH plays a role in stroke in SCD has not been examined . Methods — Serum levels of PFH , lactate dehydrogenase , and total bilirubin were measured in stored sera from children at risk for stroke treated in a r and omized controlled trial of regular red cell transfusion ( STOP study ) . Baseline and post-treatment ( ≈1 year of transfusion ) were compared to determine whether treatment ( which reduces stroke risk by 90 % ) was associated with reduction in markers of hemolysis . Results — Baseline serum PFH values did not differ between treatment groups . PFH declined with repeated transfusion from 78.7±8.2 mg/dL to 34.4±3.4 mg/dL ( P<0.001 ) . With only episodic or no transfusion the drop was smaller : 80.9±7.5 to 62.8±5.0 ( P=0.019 ) . The decrease was larger in those with regular transfusion ( 56 % versus 22 % ; P<0.001 ) . Reduction of lactate dehydrogenase and total bilirubin was observed only in those on regular transfusion . Conclusions — Regular transfusion which lowers stroke risk is associated with a significant reduction in PFH . A role for PFH in promoting stroke in SCD should be investigated BACKGROUND Blood transfusions prevent recurrent stroke in children with sickle cell anemia , but the value of transfusions in preventing a first stroke is unknown . We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then r and omly assigned them to receive st and ard care or transfusions to prevent a first stroke . METHODS To enter the study , children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher . The patients were r and omly assigned to receive st and ard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration . The incidence of stroke ( cerebral infa rct ion or intracranial hemorrhage ) was compared between the two groups . RESULTS A total of 130 children ( mean [ + /-SD ] age , 8.3+/-3.3 years ) were enrolled ; 63 were r and omly assigned to receive transfusions and 67 to receive st and ard care . At base line , the transfusion group had a slightly lower mean hemoglobin concentration ( 7.2 vs. 7.6 g per deciliter , P=0.001 ) and hematocrit ( 20.4 vs. 21.7 percent , P=0.002 ) . Ten patients dropped out of the transfusion group , and two patients crossed over from the st and ard-care group to the transfusion group . There were 10 cerebral infa rct ions and 1 intracerebral hematoma in the st and ard-care group , as compared with 1 infa rct ion in the transfusion group -- a 92 percent difference in the risk of stroke ( P<0.001 ) . This result led to the early termination of the trial . CONCLUSIONS Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography OBJECTIVE To determine the effect of a transfusion program on risk of stroke recurrence in children with sickle cell disease . DESIGN The clinical course and experience with transfusion therapy at eight centers were review ed for subjects whose initial stroke occurred after January 1988 . RESULTS Sixty subjects were observed for 191.7 patient-years . Eight had a single recurrent stroke ( two intracranial hemorrhages and six infa rct ions ) for a prevalence of 13.3 % , or one recurrence for each 24 patient-years of observation . Thirteen subjects had 15 transient neurologic events ; two of these had subsequent strokes , but the overall risk was similar for those who did and those did not have transient events . Hemoglobin S levels were greater than the desired maximum of 30 % at the time of 7 of 16 transient events and five of six recurrent infa rct ions . The stroke recurrence rate was similar to those in previous reports of children receiving long-term transfusion therapy but significantly less than that reported for children who did not receive transfusions ( p < 0.001 ) . CONCLUSIONS We conclude that maintenance of hemoglobin S at a level less than 30 % appears to be effective in reducing the rate of recurrent infa rct ion but does not prevent transient neurologic events . Transient neurologic events are common but do not appear to be related to recurrent stroke The stroke prevention study in sickle cell disease ( STOP ) demonstrated a 90 % reduction in stroke risk with transfusion among patients with time-averaged mean cerebral blood velocity ( TAMV ) of 200 cm/s or more as measured by transcranial Doppler ( TCD ) . In STOP , 232 brain magnetic resonance angiograms ( MRAs ) were performed on 100 patients , 47 in the transfusion arm and 53 in the st and ard care arm . Baseline MRA findings were interpreted as normal in 75 patients and as indicating mild stenosis in 4 patients and severe stenosis in 21 patients . Among 35 patients who underwent magnetic resonance angiography within 30 days of r and om assignment , the TAMV was significantly higher in 7 patients with severe stenosis compared with 28 patients with normal MRA findings or mild stenosis ( 276.7 + /- 34 vs 215 + /- 15.6 cm/s ; P<.001 ) . In the st and ard care arm , 4 of 13 patients with abnormal MRA findings had strokes compared with 5 of 40 patients with normal MRA findings ( P=.03 ) . In this arm , TAMV became normal ( less than 170 cm/s ) or conditional ( 170 - 199 cm/s ) in 26 of 38 patients with normal or mildly abnormal baseline MRA but remained abnormal in 8 of 10 patients with severely abnormal baseline MRA . These results suggest that TCD often detects flow abnormalities indicative of stroke risk before MRA lesions become evident . Furthermore , patients with abnormal MRA findings and higher TCD velocities are at higher risk for stroke , and their cerebral TAMVs are unlikely to decrease without transfusion Chronic transfusion reduces the risk of recurrent stroke in children with sickle cell anemia ( SCA ) but leads to iron loading . Management of transfusional iron overload in SCA has been reported as suboptimal [ 1 ] , but studies characterizing monitoring and treatment practice s for iron overload in children with SCA , particularly in recent years with the expansion of chelator options , are lacking . We investigated the degree of iron loading and treatment practice s of 161 children with SCA receiving transfusions for a history of stroke who participated in the Stroke with Transfusions Changing to Hydroxyurea ( SWiTCH ) trial . Data obtained during screening , including past and entry liver iron concentration ( LIC ) measurements , ferritin values , and chelation were analyzed . The mean age at enrollment was 12.9 ± 4 years and the mean duration of transfusion was 7 ± 3.8 years . Baseline LIC ( median 12.94 mg/g dw ) and serum ferritin ( median 3,164 ng/mL ) were elevated . Chelation therapy was initiated after a mean of 2.6 years of transfusions . At study entry , 137 were receiving chelation , most of whom ( 90 % ) were receiving deferasirox . This study underscores the need for better monitoring of iron burden with timely treatment adjustments in chronically transfused children with SCA BACKGROUND For children with sickle cell anaemia and high transcranial doppler ( TCD ) flow velocities , regular blood transfusions can effectively prevent primary stroke , but must be continued indefinitely . The efficacy of hydroxycarbamide ( hydroxyurea ) in this setting is unknown ; we performed the TWiTCH trial to compare hydroxyurea with st and ard transfusions . METHODS TWiTCH was a multicentre , phase 3 , r and omised , open-label , non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada . We enrolled children with sickle cell anaemia who were aged 4 - 16 years and had abnormal TCD flow velocities ( ≥ 200 cm/s ) but no severe vasculopathy . After screening , eligible participants were r and omly assigned 1:1 to continue st and ard transfusions ( st and ard group ) or hydroxycarbamide ( alternative group ) . R and omisation was done at a central site , stratified by site with a block size of four , and an adaptive r and omisation scheme was used to balance the covariates of baseline age and TCD velocity . The study was open-label , but TCD examinations were read central ly by observers masked to treatment assignment and previous TCD results . Participants assigned to st and ard treatment continued to receive monthly transfusions to maintain 30 % sickle haemoglobin or lower , while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day , which was escalated to each participant 's maximum tolerated dose . The treatment period lasted 24 months from r and omisation . The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model , with the non-inferiority margin set at 15 cm/s . The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment . This study is registered with Clinical Trials.gov , number NCT01425307 . FINDINGS Between Sept 20 , 2011 , and April 17 , 2013 , 159 patients consented and enrolled in TWiTCH . 121 participants passed screening and were then r and omly assigned to treatment ( 61 to transfusions and 60 to hydroxycarbamide ) . At the first scheduled interim analysis , non-inferiority was shown and the sponsor terminated the study . Final model-based TCD velocities were 143 cm/s ( 95 % CI 140 - 146 ) in children who received st and ard transfusions and 138 cm/s ( 135 - 142 ) in those who received hydroxycarbamide , with a difference of 4·54 ( 0·10 - 8·98 ) . Non-inferiority ( p=8·82 × 10(-16 ) ) and post-hoc superiority ( p=0·023 ) were met . Of 29 new neurological events adjudicated central ly by masked review ers , no strokes were identified , but three transient ischaemic attacks occurred in each group . Magnetic resonance brain imaging and angiography ( MRI and MRA ) at exit showed no new cerebral infa rcts in either treatment group , but worsened vasculopathy in one participant who received st and ard transfusions . 23 severe adverse events in nine ( 15 % ) patients were reported for hydroxycarbamide and ten serious adverse events in six ( 10 % ) patients were reported for st and ard transfusions . The most common serious adverse event in both groups was vaso-occlusive pain ( 11 events in five [ 8 % ] patients with hydroxycarbamide and three events in one [ 2 % ] patient for transfusions ) . INTERPRETATION For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions , and have no MRA-defined severe vasculopathy , hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke . FUNDING National Heart , Lung , and Blood Institute , National Institutes of Health OBJECTIVE To determine whether long-term transfusion improves growth in children with sickle cell anemia . STUDY DESIGN In the Stroke Prevention Trial for Sickle Cell Anemia Study , patients were r and omized to receive long-term transfusion ( CTX ) or st and ard care ( STC ) . Transfusions were administered every 3 to 5 weeks , and hemoglobin S levels were maintained at 30 % pretransfusion for an average of 2 years . Serial height and weight measurements ( obtained every 3 months ) , body mass index ( BMI ) values , and growth z-scores were analyzed . RESULTS Children in the CTX ( n=53 ) and STC ( n=41 ) groups were similar at baseline . After 24 months , the z-scores for height , weight , and BMI of those receiving CTX had improved significantly , whereas no changes occurred in the STC group . Patients in the CTX group approached normal height-for-age and weight-for-age z-scores . Patients from a large historical control group had significantly lower weight and height growth velocities than patients in the CTX group . CONCLUSIONS Patients in the Stroke Prevention Trial for Sickle Cell Anemia Study who received CTX had improved height and weight and BMI over a 2-year period . Higher hemoglobin levels result ing from transfusion may improve growth by lowering energy expenditure . In addition to the prevention of vasoocclusive events , CTX results in significant improvement in the growth of children with sickle cell disease Stroke occurs in 7 - 8 % of children with Sickle Cell Disease ( Hb SS ) and is a major cause of morbidity . Rates of recurrence have been reduced from 46 - 90 % to less than 10 % through chronic blood transfusions . Prevention of first stroke , however , would be preferable because even one stroke can cause irreversible brain injury . Transcranial Doppler ( TCD ) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk . By combining TCD screening and a potentially effective treatment , first stroke may be prevented . The Stroke Prevention Trial in Sickle Cell Anemia ( STOP ) is the first stroke prevention trial in Hb SS and the first r and omized , controlled use of transfusion in Hb SS . This multi-center trial is design ed to test whether reducing sickle hemoglobin to 30 % or less with periodic blood transfusions will reduce first-time stroke by at least 70 % compared to st and ard care . Primary endpoints will be clinical ly evident symptoms of cerebral infa rct ion with consistent findings on Magnetic Resonance Imaging and Angiography ( MRI/MRA ) or symptomatic intracranial hemorrhage . Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints . The design calls for a 6-month start-up interval , 18 months of TCD screening and r and omization , and observation for stroke from entry through month 54 . Key features of the trial are st and ardized TCD and MRI/MRA protocol s interpreted blindly , and blinded adjudication of endpoints . The sample size ( 60 per treatment group ) is based on prospect i ve data relating TCD velocity to risk of stroke . A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46 % risk of cerebral infa rct ion over 39 months . The sample size is sufficient to detect 70 % reduction in the primary endpoint at 90 % power . This trial will determine if transfusion is effective in the primary prevention of stroke . Secondary aims may further the underst and ing of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS Purpose Chronic red cell transfusion has been used for prevention of recurrent stroke in patients with sickle cell disease for three decades , and its effectiveness in primary prevention was recently shown . Iron overload , the inevitable result of chronic transfusion , is commonly monitored with serum ferritin concentration . Patients and Methods Sixty-one patients at high risk for stroke received chronic transfusion in a clinical trial of stroke prevention . A serum ferritin level of less than 500 ng/mL was required for study entry . Ferritin levels were obtained quarterly . Fifty patients who had four or more ferritin measurements were included in this analysis . Transfusions were administered as exchange or simple , with washed , reconstituted , or packed red blood cells , at the discretion of the site investigator . Results Serum ferritin levels increased linearly with cumulative transfusion volume during the first four ferritin measurements , but the rate of increase varied widely among patients . Rates of increase varied similarly among 23 patients who received exclusively simple transfusion with packed red cells and in five patients who received exchange transfusions . Thirty-two patients received a total transfusion volume of more than 250 mL/kg . Ferritin continued to increase linearly after the first four measurements in 14 , but the remaining 18 experienced a plateau before the level reached 3,000 ng/mL. Six of those with a linear increase never reached a ferritin level of 3,000 ng/dL. Conclusions There was strong intrapatient correlation between serum ferritin levels and volume transfused but wide interpatient variability early during chronic transfusion therapy . Intrapatient correlation declined at transfusion volumes of more than 250 mL/kg . Direct iron store assessment is needed to determine the clinical significance of serum ferritin variability The Stroke Prevention in Sickle Cell Disease ( STOP ) trial used transcranial Doppler ( TCD ) to screen children with sickle cell disease with no history of stroke . Children ( who consented ) who had time-averaged mean of the maximum ( TAMM ) velocities in the middle cerebral artery and /or distal internal carotid artery were r and omized to transfusion or st and ard . Over a slightly more than 20-month average follow-up , there were 11 strokes in the st and ard care arm and 1 stroke in the transfusion arm . This study has caused a great deal of interest in using TCD to screen children with sickle cell disease . For the STOP TCD data to be applied appropriately , it is necessary for users of TCD to underst and how the STOP TCD examinations were performed , how the TCD velocities were measured , and which velocities were used . This article will review the STOP TCD scanning protocol and the reading protocol and review the TAMM velocity and how it differs from other velocity measurements BACKGROUND Most sickle cell anemia patients undergo transfusion therapy to prevent complications . The Stroke Prevention Trial in Sickle Cell Anemia showed that transfusion therapy is effective in the primary prevention of stroke . Despite its efficacy , transfusion therapy is limited by alloimmunization . The purpose of this study was to determine if a multicenter trial could implement a transfusion program utilizing phenotypically matched blood to reduce alloimmunization . STUDY DESIGN AND METHODS One hundred thirty children underwent RBC phenotyping and antibody screening with review of blood bank records . The protocol required use of WBC-reduced RBCs , which were matched for E , C , and Kell . Monthly alloantibody testing and review of transfusion forms were performed to determine compliance and the occurrence of any adverse events . RESULTS Patient RBCs expressed a low frequency of Kell ( 2 % ) , E ( 20 % ) , and C ( 25 % ) antigens . Sixty-one patients received 1830 units . Ninety-seven percent of all units were WBC reduced . Only 29 units were inadvertently not matched for E , C , and Kell . Five patients ( 8 % ) developed a clinical ly significant alloantibody . Four developed a single antibody to E or Kell . Three patients ( 5 % ) developed a warm autoantibody . There were 11 transfusion reactions and 8 transfusion-associated events . Transfusion reactions included 6 febrile reactions ( 0.33%/unit ) , 3 allergic ( 0.16%/unit ) , and 2 hemolytic ( 0.11%/unit ) . Associated events included 4 episodes of hypertension ( 0.22%/unit ) , 3 crises ( 0.16%/unit ) , and 1 transient ischemic attack ( 0.05%/unit ) . CONCLUSION This is the first multicenter study to show that extended RBC phenotyping can be implemented nationwide . Compared to studies , the alloimmunization rate dropped from 3 percent to 0.5 percent per unit , and hemolytic transfusion reactions dropped by 90 percent . It is recommended that all transfused sickle cell anemia patients be antigen matched for E , C , and Kell . Patients should be closely monitored during transfusions to avoid preventable risks The efficacy of a long-term transfusion regimen in preventing sickle cell disease complications is unknown . We examined 17 patients before , during , and after transfusion for cerebral vascular accident and vaso-occlusive crisis . Total hospitalization rate , as well as admissions for vaso-occlusive crisis , cases of acute chest syndrome , and bacterial infections decreased while patients were on a transfusion regimen BACKGROUND Silent cerebral infa rcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infa rct ( stroke or silent cerebral infa rct ) . We tested the hypothesis that the incidence of the recurrence of an infa rct would be lower among children who underwent regular blood-transfusion therapy than among those who received st and ard care . METHODS In this r and omized , single-blind clinical trial , we r and omly assigned children with sickle cell anemia to receive regular blood transfusions ( transfusion group ) or st and ard care ( observation group ) . Participants were between 5 and 15 years of age , with no history of stroke and with one or more silent cerebral infa rcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions . The primary end point was the recurrence of an infa rct , defined as a stroke or a new or enlarged silent cerebral infa rct . RESULTS A total of 196 children ( mean age , 10 years ) were r and omly assigned to the observation or transfusion group and were followed for a median of 3 years . In the transfusion group , 6 of 99 children ( 6 % ) had an end-point event ( 1 had a stroke , and 5 had new or enlarged silent cerebral infa rcts ) . In the observation group , 14 of 97 children ( 14 % ) had an end-point event ( 7 had strokes , and 7 had new or enlarged silent cerebral infa rcts ) . The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events , respectively , per 100 years at risk , corresponding to an incidence rate ratio of 0.41 ( 95 % confidence interval , 0.12 to 0.99 ; P=0.04 ) . CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infa rct in children with sickle cell anemia . ( Funded by the National Institute of Neurological Disorders and Stroke and others ; Silent Cerebral Infa rct Multi-Center Clinical Trial Clinical Trials.gov number , NCT00072761 , and Current Controlled Trials number , IS RCT N52713285 . ) To compare the non‐neurological events in children with sickle cell anemia ( SCA ) and previous stroke enrolled in SWiTCH . The NHLBI‐sponsored Phase III multicenter r and omized clinical trial stroke with transfusions changing to hydroxyurea ( SWiTCH ) ( Clinical Trials.gov NCT00122980 ) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload . All r and omized children were included in the analysis ( intention to treat ) . The Fisher 's Exact test was used to compare the frequency of subjects who experienced at least one SCA‐related adverse event ( AE ) or serious adverse event ( SAE ) in each arm and to compare event rates . One hundred and thirty three subjects , mean age 13 ± 3.9 years ( range 5.2–19.0 years ) and mean time of 7 years on chronic transfusion at study entry , were r and omized and treated . Numbers of subjects experiencing non‐neurological AEs were similar in the two treatment arms , including SCA‐related events , SCA pain events , and low rates of acute chest syndrome and infection . However , fewer children continuing transfusion/chelation experienced SAEs ( P = 0.012 ) , SCA‐related SAEs ( P = 0.003 ) , and SCA pain SAEs ( P = 0.016 ) as compared to children on the hydroxyurea/phlebotomy arm . The timing of phlebotomy did not influence SAEs . Older age at baseline predicted having at least 1 SCA pain event . Patients with recurrent neurological events during SWiTCH were not more likely to experience pain . In children with SCA and prior stroke , monthly transfusions and daily iron chelation provided superior protection against acute vaso‐occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy . Am . J. Heamtol . 88:932–938 , 2013 . © 2013 Wiley Periodicals , Children with sickle cell anemia ( SCA ) and conditional transcranial Doppler ( TCD ) ultrasound velocities ( 170–199 cm/sec ) may develop stroke . However , with limited available clinical data , the current st and ard of care for conditional TCD velocities is observation . The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD ( ≥200 cm/sec ) , which confers a higher stroke risk , has not been studied prospect ively in a r and omized trial . Sparing Conversion to Abnormal TCD Elevation ( SCATE # NCT01531387 ) was a National Heart , Lung , and Blood Institute‐funded Phase III multicenter international clinical trial comparing alternative therapy ( hydroxyurea ) to st and ard care ( observation ) to prevent conversion from conditional to abnormal TCD velocity in children with SCA . SCATE enrolled 38 children from the United States , Jamaica , and Brazil [ HbSS ( 36 ) , HbSβ0‐thalassemia ( 1 ) , and HbSD ( 1 ) , median age = 5.4 years ( range , 2.7–9.8 ) ] . Because of the slow patient accrual and administrative delays , SCATE was terminated early . In an intention‐to‐treat analysis , the cumulative incidence of abnormal conversion was 9 % ( 95 % CI = 0–35 % ) in the hydroxyurea arm and 47 % ( 95 % CI = 6–81 % ) in observation arm at 15 months ( P = 0.16 ) . In post hoc analysis according to treatment received , significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation ( 0 % vs. 50 % , P = 0.02 ) . After a mean of 10.1 months , a significant change in mean TCD velocity was observed with hydroxyurea treatment ( −15.5 vs. + 10.2 cm/sec , P = 0.02 ) . No stroke events occurred in either arm . Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities . Am . J. Hematol . 90:1099–1105 , 2015 . © 2015 Wiley Periodicals , Children with sickle cell disease ( SCD ) and strokes receive blood transfusion therapy for secondary stroke prevention ; despite this , approximately 20 % experience second overt strokes . Given this rate of second overt strokes and the clinical significance of silent cerebral infa rcts , we tested the hypothesis that silent cerebral infa rcts occur among children with SCD being transfused for secondary stroke prevention . A prospect i ve cohort enrolled children with SCD and overt strokes at 7 academic centers . Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years ; studies were review ed by a panel of neuroradiologists . Eligibility criteria included regularly scheduled blood transfusion therapy . Forty children were included ; mean pretransfusion hemoglobin S concentration was 29 % . Progressive cerebral infa rcts occurred in 45 % ( 18 of 40 children ) while receiving chronic blood transfusion therapy ; 7 had second overt strokes and 11 had new silent cerebral infa rcts . Worsening cerebral vasculopathy was associated with new cerebral infa rct ion ( overt or silent ; relative risk = 12.7 ; 95 % confidence interval , 2.65 - 60.5 , P = .001 ) . Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infa rcts at a higher rate than previously recognized . Additional therapies are needed for secondary stroke prevention in children with SCD The most common form of neurologic injury in sickle cell anemia ( SCA ) is silent cerebral infa rct ion ( SCI ) . In the Silent Cerebral Infa rct Multi-Center Clinical Trial , we sought to identify risk factors associated with SCI . In this cross-sectional study , we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA ( HbSS or HbSβ ° thalassemia ) between the ages of 5 and 15 years with no history of overt stroke or seizures . Neuroradiology and neurology committees adjudicated the presence of SCI . SCIs were diagnosed in 30.8 % ( 251 of 814 ) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates . The mean age of the participants was 9.1 years , with 413 males ( 50.7 % ) . In a multivariable logistic regression analysis , lower baseline hemoglobin concentration ( P < .001 ) , higher baseline systolic blood pressure ( P = .018 ) , and male sex ( P = .030 ) were statistically significantly associated with an increased risk of an SCI . Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI . This study is registered at www . clinical trials.gov as # NCT00072761 Stroke is a devastating complication of sickle cell anemia ( SCA ) with high recurrence if untreated . Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload . Stroke With Transfusions Changing to Hydroxyurea ( SWiTCH ) was a multicenter phase 3 r and omized trial comparing st and ard treatment ( transfusions/chelation ) to alternative treatment ( hydroxyurea/phlebotomy ) for children with SCA , stroke , and iron overload . SWiTCH was a noninferiority trial with a composite primary end point , allowing an increased stroke risk but requiring superiority for removing iron . Subjects on st and ard treatment received monthly transfusions plus daily deferasirox iron chelation . Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose ( MTD ) , followed by monthly phlebotomy . Subjects on st and ard treatment ( N = 66 ) maintained 30 % sickle hemoglobin ( HbS ) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d . Subjects on alternative treatment ( N = 67 ) initiated hydroxyurea and 60 ( 90 % ) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1 % ± 6.7 % fetal hemoglobin ( HbF ) . Adjudication documented no strokes on transfusions/chelation but 7 ( 10 % ) on hydroxyurea/phlebotomy , still within the noninferiority stroke margin . The National Heart , Lung , and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content , indicating futility for the composite primary end point . Transfusions and chelation remain a better way to manage children with SCA , stroke , and iron overload

Sivelestat was not associated with decreased mortality , even when including studies published in Japanese language

INTRODUCTION Sivelestat is neutrophil elastase inhibitor , which is widely used in Japan for the treatment of acute lung injury . However , the clinical efficacy of the medication has not been convincingly demonstrated .

Overwhelming evidence shows the quality of reporting of r and omised controlled trials ( RCTs ) is not optimal . Without transparent reporting , readers can not judge the reliability and validity of trial findings nor extract information for systematic review s. Recent method ological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects . Such systematic error is seriously damaging to RCTs , which are considered the gold st and ard for evaluating interventions because of their ability to minimise or avoid bias . A group of scientists and editors developed the CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to improve the quality of reporting of RCTs . It was first published in 1996 and up date d in 2001 . The statement consists of a checklist and flow diagram that authors can use for reporting an RCT . Many leading medical journals and major international editorial groups have endorsed the CONSORT statement . The statement facilitates critical appraisal and interpretation of RCTs . During the 2001 CONSORT revision , it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports . A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement . After an expert meeting in January 2007 , the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement . This up date improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition , such as selective outcome reporting bias . This explanatory and elaboration document-intended to enhance the use , underst and ing , and dissemination of the CONSORT statement-has also been extensively revised . It presents the meaning and rationale for each new and up date d checklist item providing examples of good reporting and , where possible , references to relevant empirical studies . Several examples of flow diagrams are included . The CONSORT 2010 Statement , this revised explanatory and elaboration document , and the associated website ( www.consort-statement.org ) should be helpful re sources to improve reporting of r and omised trials BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use RATIONALE In a clinical trial by the Acute Respiratory Distress Syndrome Network ( ARDSNet ) , mechanical ventilation with tidal volumes of 6 ml/kg decreased mortality from acute lung injury . However , interpretations of these results generated controversy and it was unclear if this trial would change usual-care practice s. OBJECTIVES First , to determine if clinical practice s at ARDSNet hospitals changed after the tidal volume trial . Second , to determine if tidal volume and plateau pressure ( Pplat ) within 48 hours before r and omization affected hospital mortality in patients subsequently managed with 6 ml/kg predicted body weight ( PBW ) . METHODS We used preenrollment data from 2,451 patients enrolled in six trials ( 1996 - 2005 ) to describe changes in tidal volume over time . We used logistic regression to determine if preenrollment tidal volume or Pplat affected mortality . MEASUREMENTS AND MAIN RESULTS Median preenrollment tidal volume decreased from 10.3 ml/kg PBW ( range , 4.3 - 17.1 ) during the tidal volume trial ( 1996 - 1999 ) to 7.3 ml/kg PBW ( range , 3.9 - 16.2 ) after its completion ( P < 0.001 ) . Preenrollment tidal volume was not associated with mortality ( P = 0.566 ) . The odds of death increased multiplicatively with each cm H(2)O of preenrollment Pplat ( P < 0.001 ) ( e.g. , the odds of death was 1.37 times greater when preenrollment Pplat increased by 10 cm H(2)O ) . CONCLUSIONS Physicians used lower tidal volumes after publication of the tidal volume trial . Preenrollment Pplat was strongly associated with mortality , and may reflect disease severity independent of tidal volume . Pplat measured early in the course of acute lung injury , after accounting for tidal volume , is a respiratory system-specific value with strong prognostic significance We conducted clinical trials in patients with acute lung injury ( ALI ) associated with systemic inflammatory response syndrome using a selective neutrophil elastase inhibitor , sivelestat sodium hydrate ( Sivelestat ) , to investigate the involvement of neutrophil elastase in ALI . In the phase III double-blind study ( Study 1 ) in 230 patients , the efficacy of Sivelestat was evaluated with the pulmonary function improvement ( PFI ) rating as the primary endpoint , and the weaning rate from mechanical ventilator , the discharge rate from intensive care unit ( ICU ) , and the survival rate as secondary endpoints . Afterwards , an unblinded study ( Study 2 ) in 20 patients was conducted using procedures for weaning from mechanical ventilation to reevaluate its efficacy with ventilator-free days ( VFD ) value , the primary endpoint , and to compare with that of Study 1 subgroup , which met the selection criteria used in Study 2 . Sivelestat increased PFI rating , reduced duration of mechanical ventilation , and shortened stay in ICU in Study 1 , although there was no significant efficacy on the survival rate . VFD value in Study 2 was comparable to that in the optimal-dose group of Study 1 subgroup , and increase in VFD value correlated with PFI rating and increase in ICU free days . It was concluded that neutrophil elastase may be involved in the pathogenesis of ALI in humans Sivelestat sodium hydrate ( sivelestat ) is a selective inhibitor of polymorphonuclear leukocyte elastase ( PMN-E ) . We administered sivelestat to patients with septic acute lung injury ( ALI ) to examine its usefulness . The primary endpoints in the study were the duration of artificial ventilation and pulmonary oxygenation ability , and the secondary endpoints were mortality and the concentrations of PMN-E , SP-D , TNF-alpha and IL-8 in blood . In the sivelestat group , the duration of artificial ventilation , pulmonary oxygenation ability , and the blood PMN-E , SP-D , TNF-alpha and IL-8 concentrations decreased significantly . Administration of sivelestat was found to reduce alveolar dysfunction and improve respiratory function , and it was suggested that early administration might be useful Objective To assess multicentre , r and omised , controlled trials ( MC- RCTs ) of systemic inflammatory response syndrome ( SIRS ) and sepsis conducted in Japan , published in Japanese and not available to English- language medical data bases . Design Method ological review .SubjectsAll Japanese RCTs relevant to SIRS and sepsis . Intervention Identification of manuscripts using a Japanese electronic library . Critical analysis of methodology and reporting quality using a modified Method ological Quality Assessment Score and the CONSORT group check list . Measurements and results Three MC- RCTs were identified . In the first , 147 patients with septic shock were r and omised to methylprednisolone ( 1000 mg i.v . ) or placebo . In the second , 221 patients were r and omised to 0.20 mg/kg per h or 0.004 mg/kg per h of sivelestat for acute lung injury with SIRS . In the third , 504 patients were r and omised to immunoglobulin ( 5 g for 3 days ) or to a control group . The average method ological quality score was higher than that of equivalent Western trials . The reporting quality ( CONSORT checklist ) was comparable to Western studies published during the same period . Conclusions Despite sound methodology and quality , the information obtained from relatively large Japanese critical care trials is not widely available to English-speaking investigators and therefore might be ignored in meta-analyses Evidence has linked neutrophil elastase to acute respiratory distress syndrome ( ARDS ) , suggesting that inhibiting the activity of this enzyme could prevent the development and progression of ARDS . However , few clinical trials have examined this notion . We therefore examined the effects of ONO-5046 ( sivelestat , a specific inhibitor of neutrophil elastase ; sodium N-[2-[4-(2,2-dimethylpropionyloxy ) phenylsulfonylaminobenzoyl]amino-acetate tetrahydrate ] ) in a r and omized , double-blinded trial in patients with ARDS . We r and omly assigned 24 patients with ARDS to groups that received conventional therapy without or with sivelestat ( 0.2 mg·kg−1·h−1 ) for 14 days . The variables of interest associated with clinical outcome were the duration of mechanical ventilation ; changes in oxygenation from baseline ; changes in cytokine levels from baseline ; number of patients alive at 30 days who did not need mechanical ventilation ; and mortality rate . The length of intensive care unit stay , number of ventilation days , and mortality rates did not statistically differ between groups . ARDS was more persistent in the control than in the sivelestat group ( control , 19.5 ± 7.4 days ; sivelestat , 13.5 ± 5.9 days ; P = 0.039 ) . Neutrophil elastase activity significantly differed between groups at 72 h after treatment . Levels of interleukin-6 were lower in the sivelestat group than in the controls at 24 , 48 , and 72 h after treatment . ONO-5046 apparently did not affect survival or the duration of mechanical ventilation Objective : Neutrophil elastase is believed to be an important mediator of acute lung injury . Sivelestat ( ONO-5046 , Elaspol ) is a small molecular weight inhibitor of neutrophil elastase . The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days ( days alive and free from mechanical ventilation from day 1 to day 28 ) compared with placebo in mechanically ventilated patients with acute lung injury . Design : Multiple-center , double-blind , placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg·kg−1·hr−1 . Setting : One hundred and five institutions in the United States , Canada , Belgium , Spain , Australia , and New Zeal and . Patients : A total of 492 mechanically ventilated patients with acute lung injury . Interventions : Patients were r and omized in a 1:1 fashion to sivelestat or placebo . Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days . All patients were managed using low tidal volume mechanical ventilation . Measurements and Main Results : The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board , which noted a negative trend in long-term mortality rate . Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days ( day 1–day 28 ) or 28-day all-cause mortality . There were 64 deaths in each treatment group within the 28-day study period , and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups , respectively ( p = .536 ) . There was no evidence of effect on measures of pulmonary function , including Pao2/Fio2 , static lung compliance , and time to meeting weaning criteria . There was no difference in adverse events or serious adverse events between treatment groups . A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups ( p = .102 ) , but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group ( p = .006 ) . Conclusions : Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation

Conclusion Country specific pharmacoeconomic analyses are too scarce and inconsistently used to have had a significant influence on the selection of essential medicines in Tanzania .

Background Due to escalating treatment costs , pharmacoeconomic analysis has been assigned a key role in the quest for increased efficiency in re source allocation for drug therapies in high-income countries . The extent to which pharmacoeconomic analysis is employed in the same role in low-income countries is less well established . This systematic review identifies and briefly describes pharmacoeconomic studies which have been conducted in Tanzania and further assesses their influence in the selection of essential medicines .

Background Intermittent preventive treatment in infants ( IPTi ) is a new malaria control tool . However , it is uncertain whether IPTi works mainly through chemoprophylaxis or treatment of existing infections . Underst and ing the mechanism is essential for development of replacements for sulfadoxine-pyrimethamine ( SP ) where it is no longer effective . This study investigated how protection against malaria given by SP , chlorproguanil-dapsone ( CD ) and mefloquine ( MQ ) , varied with time since administration of IPTi . Methods and Findings A secondary analysis of data from a r and omised , placebo-controlled trial in an area of high antifolate resistance in Tanzania was conducted . IPTi using SP , CD , MQ or placebo was given to 1280 infants at 2 , 3 and 9 months of age . Poisson regression with r and om effects to adjust for potential clustering of malaria episodes within children was used to calculate incidence rate ratios for clinical malaria in defined time strata following IPTi . The short-acting antimalarial CD gave no protection against clinical malaria , whereas long-acting MQ gave two months of substantial protection ( protective efficacy ( PE ) 73.1 % ( 95 % CI : 23.9 , 90.5 ) and 73.3 % ( 95 % CI : 0 , 92.9 ) in the first and second month respectively ) . SP gave some protection in the first month after treatment ( PE 64.5 % ( 95 % CI : 10.6 , 85.9 ) ) although it did not reduce the incidence of malaria up to 12 months of age . There was no evidence of either long-term protection or increased risk of malaria for any of the regimens . Conclusion Post-treatment chemoprophylaxis appears to be the main mechanism by which IPTi protects children against malaria . Long-acting antimalarials are therefore likely to be the most effective drugs for IPTi , but as monotherapies could be vulnerable to development of drug resistance . Due to concerns about tolerability , the mefloquine formulation used in this study is not suitable for IPTi . Further investigation of combinations of long-acting antimalarials for IPTi is needed . Trial Registration Clinical trials.gov Background Intermittent Preventive Treatment for malaria control in infants ( IPTi ) consists of the administration of a treatment dose of an anti-malarial drug , usually sulphadoxine-pyrimethamine , at scheduled intervals , regardless of the presence of Plasmodium falciparum infection . A pooled analysis of individually r and omized trials reported that IPTi reduced clinical episodes by 30 % . This study evaluated the effect of IPTi on child survival in the context of a five-district implementation project in southern Tanzania . [ Trial registration : clinical trials.gov NCT00152204 ] . Methods After baseline household and health facility surveys in 2004 , five districts comprising 24 divisions were r and omly assigned either to receive IPTi ( n = 12 ) or not ( n = 12 ) . Implementation started in March 2005 , led by routine health services with support from the research team . In 2007 , a large household survey was undertaken to assess the impact of IPTi on survival in infants aged two-11 months through birth history interviews with all women aged 13 - 49 years . The analysis is based on an " intention-to-treat " ecological design , with survival outcomes analysed according to the cluster in which the mothers lived . Results Survival in infants aged two-11 months was comparable in IPTi and comparison areas at baseline . In intervention areas in 2007 , 48 % of children aged 12 - 23 months had documented evidence of receiving three doses of IPTi , compared to 2 % in comparison areas ( P < 0.0001 ) . Over the three years of the study there was a marked improvement in survival in both groups . Between 2001 - 4 and 2005 - 7 , mortality rates in two-11 month olds fell from 34.1 to 23.6 per 1,000 person-years in intervention areas and from 32.3 to 20.7 in comparison areas . In 2007 , divisions implementing IPTi had a 14 % ( 95 % CI -12 % , 49 % ) higher mortality rate in two-11 month olds in comparison with non-implementing divisions ( P = 0.31 ) . Conclusion The lack of evidence of an effect of IPTi on survival could be a false negative result due to a lack of power or imbalance of unmeasured confounders . Alternatively , there could be no mortality impact of IPTi due to low coverage , late administration , drug resistance , decreased malaria transmission or improvements in vector control and case management . This study raises important questions for programme evaluation design Background As a result of rising levels of drug resistance to conventional monotherapy , the World Health Organization ( WHO ) and other international organisations have recommended that malaria endemic countries move to combination therapy , ideally with artemisinin-based combinations ( ACTs ) . Cost is a major barrier to deployment . There is little evidence from field trials on the cost-effectiveness of these new combinations . Methods and Findings An economic evaluation of drug combinations was design ed around a r and omised effectiveness trial of combinations recommended by the WHO , used to treat Tanzanian children with non-severe slide-proven malaria . Drug combinations were : amodiaquine ( AQ ) , AQ with sulfadoxine-pyrimethamine ( AQ+SP ) , AQ with artesunate ( AQ+AS ) , and artemether-lumefantrine ( AL ) in a six-dose regimen . Effectiveness was measured in terms of re source savings and cases of malaria averted ( based on parasitological failure rates at days 14 and 28 ) . All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis . Incremental analysis comparing each combination to monotherapy ( AQ ) revealed that from a societal perspective AL was most cost-effective at day 14 . At day 28 the difference between AL and AQ+AS was negligible ; both result ed in a gross savings of approximately US$ 1.70 or a net saving of US$ 22.40 per case averted . Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs , respectively , but this did not change the finding that AL and AQ+AS dominate monotherapy . Conclusions In an area of high drug resistance , there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive , because they are significantly more effective than other options and therefore reduce the need for further treatment . This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment ( and their combination ) is lower so that the relative advantage of ACTs is smaller , or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria The aim of this study is to compare the safety efficacy and cost effectiveness of vaginal misoprostol and intravenous oxytocin in induction of labor . A r and omized trial was performed in 142 women requiring labor induction in Muhimbili National Hospital Dar es Salaam Tanzania from June to December 2004 . Inclusion criteria were singleton vertex presentation ; gestational age > 36 weeks . Exclusion criteria were previous myomectomy uteroplasty or cesarean section . Sequential sealed envelopes generated by computer were used . Patients were assigned to receive either oxytocin or 25 mcg 4-hourly vaginal misoprostol ( Continental pharma Inc Belgium ; maximum dose 100 mcg ) . If contractions were not established 4 h after the insertion of the fourth misoprostol induction was considered a failure and the patient was managed according to hospital protocol s. In the oxytocin group infusion of 5 I in 500 ml of 5 % dextrose ( 10 mU/ ml ) was started ( maximum dosage 40 mU/min ) . If labor was not established within 12 h induction was regarded as a failure and the patient was managed according to hospital protocol s. ( excerpt BACKGROUND The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death , vascular occlusive events , and blood transfusion in trauma patients with significant haemorrhage . Tranexamic acid significantly reduced all-cause mortality . Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis , we undertook exploratory analyses of its effect on death due to bleeding . METHODS The CRASH-2 trial was undertaken in 274 hospitals in 40 countries . 20,211 adult trauma patients with , or at risk of , significant bleeding were r and omly assigned within 8 h of injury to either tranexamic acid ( loading dose 1 g over 10 min followed by infusion of 1 g over 8 h ) or placebo . Patients were r and omly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number . Both participants and study staff ( site investigators and trial coordinating centre staff ) were masked to treatment allocation . We examined the effect of tranexamic acid on death due to bleeding according to time to treatment , severity of haemorrhage as assessed by systolic blood pressure , Glasgow coma score ( GCS ) , and type of injury . All analyses were by intention to treat . The trial is registered as IS RCT N86750102 , Clinical Trials.gov NCT00375258 , and South African Clinical Trial Register/Department of Health DOH-27 - 0607 - 1919 . FINDINGS 10,096 patients were allocated to tranexamic acid and 10,115 to placebo , of whom 10,060 and 10,067 , respectively , were analysed . 1063 deaths ( 35 % ) were due to bleeding . We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment ( test for interaction p<0.0001 ) . Early treatment ( ≤1 h from injury ) significantly reduced the risk of death due to bleeding ( 198/3747 [ 5.3 % ] events in tranexamic acid group vs 286/3704 [ 7.7 % ] in placebo group ; relative risk [ RR ] 0.68 , 95 % CI 0.57 - 0.82 ; p<0.0001 ) . Treatment given between 1 and 3 h also reduced the risk of death due to bleeding ( 147/3037 [ 4.8 % ] vs 184/2996 [ 6.1 % ] ; RR 0.79 , 0.64 - 0.97 ; p=0.03 ) . Treatment given after 3 h seemed to increase the risk of death due to bleeding ( 144/3272 [ 4.4 % ] vs 103/3362 [ 3.1 % ] ; RR 1.44 , 1.12 - 1.84 ; p=0.004 ) . We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure , Glasgow coma score , or type of injury . INTERPRETATION Tranexamic acid should be given as early as possible to bleeding trauma patients . For trauma patients admitted late after injury , tranexamic acid is less effective and could be harmful . FUNDING UK NIHR Health Technology Assessment programme , Pfizer , BUPA Foundation , and J P Moulton Charitable Foundation

However , the trend was for sclerotherapy to be evaluated as significantly better than surgery at one year ; after one year ( sclerotherapy result ed in worse outcomes ) the benefits with sclerotherapy were less , and by three to five years surgery had better outcomes . REVIEW ERS ' CONCLUSIONS There was insufficient evidence to preferentially recommend the use of sclerotherapy or surgery .

BACKGROUND Varicose veins are a relatively common condition and account for around 54,000 in-patient hospital episodes per year . The two most common interventions for varicose veins are surgery and sclerotherapy . However , there is little comparative data regarding their effectiveness . OBJECTIVES To identify whether the use of surgery or sclerotherapy should be recommended for the management of primary varicose veins .

PURPOSE Surgical treatment of varicose veins with preservation of the greater saphenous vein ( GSV ) was studied . METHODS Patients with reflux at the saphenofemoral junction and grossly normal GSV were treated with two different surgical techniques : perivalvular b and ing valvuloplasty ( PVBV-A ) of the saphenous valve , wherein the diameter of the uppermost saphenous valve was narrowed by Dacron-reinforced silicone b and ( 12 patients , 15 extremities ) ; and high ligation ( HL-A ) of the saphenous vein , wherein the GSV was ligated flush with the femoral vein ( 14 patients , 16 extremities ) . Both groups also had varicose tributaries of GSV avulsed through multiple stab incisions . RESULTS In the HL-A group two GSV ( 13 % ) remained completely patent , 10 GSV ( 62.5 % ) thrombosed partially , and the remaining four GSV ( 25 % ) had complete thrombosis . In the PVBV-A group 12 GSV ( 80 % ) remained completely patent and without reflux , one GSV ( 7 % ) remained patent but showing reflux . Two GSV ( 13 % ) thrombosed completely . There were no surgical complications or recurrences ( mean follow-up was 9.4 months for PVBV-A and 9.5 months for HL-A ) , and the postoperative recovery time was similar for both groups . CONCLUSIONS Both techniques are equally effective in the early elimination of varicosities . Preservation of the saphenous vein is significantly better after PVBV-A ( p < 0.01 ) . A prospect i ve r and omized trial with long-term follow-up is required Three techniques for treatment of chronic venous incompetence on an out patients basis were compared in a r and omised study . One hundred thirty eight limbs ( 107 patients ) with superficial venous incompetence were r and omly treated with the dentist 's technique ( DT ) [ Group A , 44 limbs ] , compression sclerotherapy ( CS ) [ Group B , 45 limbs ] or the SAVAS ( section en Ambulatoire des Varices avec Sclérothérapie ) technique [ Group C , 49 limbs ] . Patients were evaluated and followed up ( every year for 4 years ) with ambulatory venous pressure ( AVP ) measurements and Quantum angiodynography ( colour duplex scanning ) . DT consisted in the section under local anesthesia of incompetent veins . CS was done injecting polidocanol 3 % with compression applied for 4 weeks . The SAVAS was done with a combination of DT and CS with section of the incompetent veins under local anesthesia and retro grade injection in the distal vein of polidocanol 3 % . With this type of injection only incompetent veins were perfused . After 4 years there was a significantly lower refilling time ( RT ) with AVP in the SAVAS group ( 21 sec ) . RT was 13 sec in group B and 16 in A. The number of significantly incompetent residual veins was in average 0.5 in the SAVAS group , significantly lower than in the other two groups . Also the average cost per treated limb was significantly lower in the SAVAS group ( 917 francs in comparison with 1100 in group A and 1211 in group B ) . In conclusion considering the four year follow up , the SAVAS technique is a more effective treatment of superficial venous incompetence , its hemodynamic value is superior to sclerotherapy alone and its costs are lower The influence of compression sclerotherapy upon hemostasis activation was investigated in 41 consecutive patients with lower extremity varices by serial measurement of thrombin-antithrombin III complexes ( TAT ) , D-dimer , fibrinogen and C-reactive protein ( CRP ) . Blood sampling was carried out before operation and on the 7th and 28th post-operative day in patients r and omly assigned to either the control group ( n = 18 ) , in which high ligation of sapheno-femoral junction and local excision of varices were performed , or the sclerotherapy group ( n = 23 ) in which the comparable surgical intervention and compression sclerotherapy using hypertonic saline were performed simultaneously . In both groups , the TAT , D-dimer and fibrinogen concentrations at day 7 were significantly elevated compared to the value before operation while CRP showed no significant change during the observation period . In the sclerotherapy group , higher incidence of superficial thrombosis was observed and the TAT concentration at day 7 was significantly higher than that in the control group ( p < 0.01 ) , and the TAT at day 28 was still significantly elevated compared to the pre-operative level ( p < 0.05 ) . However , no relationship between TAT and D-dimer concentrations and the extent of superficial thrombosis was observed . We conclude that compression sclerotherapy for lower extremity varices causes latent activation of coagulation system and can be a risk factor for venous thromboembolism A prospect i ve observational study of 63 legs in 49 patients was undertaken to evaluate the adequacy of primary varicose vein surgery performed by surgical trainees . Appropriate surgery was carried out by a surgical senior house officer ( SHO ) under direct consultant supervision . All patients underwent pre- and postoperative duplex scanning . The preoperative duplex scan demonstrated incompetence of the saphenofemoral junction ( SFJ ) or long saphenous vein ( LSV ) in 59 limbs , a mid-thigh perforator ( MTP ) in 11 limbs , and saphenopopliteal junction ( SPJ ) in 5 limbs . Surgery successfully abolished all sites of pre-existing reflux . The postoperative duplex scan revealed that 17 new sites of reflux , not identified preoperatively , had developed in 12 limbs . With a consultant-led service and accurate preoperative identification of sites of reflux , the surgical trainee can adequately perform varicose vein surgery . This would seem a reasonable approach to training and eliminating recurrence owing to inadequate surgery . The development of new sites of reflux within 6 months of varicose vein surgery may be owing to altered venous haemodynamics consequent upon this surgery OBJECTIVE The aim of this r and omized study was to compare a new method of endovenous saphenous vein obliteration ( Closure System , VNUS Medical Technologies , Inc , Sunnyvale , Calif ) with the conventional stripping operation in terms of short-term recovery and costs . METHODS Twenty-eight selected patients for operative treatment of primary greater saphenous vein tributary varicose veins were r and omly assigned to endovenous obliteration ( n = 15 ) or stripping operation ( n = 13 ) . Postoperative pain was daily assessed during the 1st week and on the 14th postoperative day . The length of sick leave was determined . The R AND -36 health survey was used to assess the patient health-related quality of life . The patient conditions were controlled 7 to 8 weeks after surgery , and patients underwent examination with duplex ultrasonography . The comparison of costs included both direct medical costs and costs result ing from lost of productivity of the patients . Costs that were similar in the study groups were not considered in the analysis . RESULTS All operations were successful , and the complication rates were similar in the two groups . Postoperative average pain was significantly less severe in the endovenous obliteration group as compared with the stripping group ( at rest : 0.7 , st and ard deviation [ SD ] 0.5 , versus 1.7 , SD 1.3 , P = .017 ; on st and ing : 1.3 , SD 0.7 , versus 2.6 , SD 1.9 , P = .026 ; on walking : 1.8 , SD 0.8 , versus 3.0 , SD 1.8 , P = .036 ; with t test ) . The sick leaves were significantly shorter in the endovenous obliteration group ( 6.5 days , SD 3.3 days , versus 15.6 days , SD 6.0 days ; 95 % CI , 5.4 to 12.9 ; P < .001 , with t test ) . Physical function was also restored faster in the endovenous obliteration group . The estimated annual investment costs of the closure operation were US $ 3360 . The other direct medical costs of the Closure operation were about $ 850 , and those of the conventional treatment were $ 360 . With inclusion of the value of the lost working days , the Closure treatment was cost-saving for society , and when 40 % of the patients are retired ( or 60 % of the productivity loss was included ) , the Closure procedure became cost-saving at a level of 43 operations per year . CONCLUSION Endovenous obliteration may offer advantages over the conventional stripping operation in terms of reduced postoperative pain , shorter sick leaves , and faster return to normal activities , and it appears to be cost-saving for society , especially among employed patients . Because the procedure is also associated with shorter convalescence , this new method may potentially replace conventional varicose vein surgery OBJECTIVE AND DESIGN in 1978 Sheppard described using a flap of pectineus fascia in an attempt to reduce the further development of neovascularised veins at the saphenofemoral junction . The perceived benefits of this manoeuvre have not been tested by a prospect i ve r and omised trial . MATERIAL S AND METHODS consecutive patients with symptomatic recurrent varicose veins referred to a single consultant were examined for evidence of further reflux from the saphenofemoral junction . This was subsequently confirmed in forty limbs ( thirty-seven patients ) by descending venography . All had features of a neovascularised segment . These patients were treated by complete exposure and ligation of the recurrences arising from the common femoral vein , with or without the placement of a flap of pectineus fascia ( prospect ively r and omised ) . The patients were assessed a minimum of eighteen months later by both clinical examination and duplex ultrasound scanning . RESULTS six patients were lost to follow-up . This left seventeen limbs remaining in each half of the study . The characteristics in each group were broadly matched . CONCLUSIONS this study failed to demonstrate any apparent benefit from the application of a flap of pectineus fascia . Most patients showed evidence of re-recurrence arising from the common femoral vein In a prospect i ve study of 100 sequential varicose patients treated with sclerotherapy , 15 had some light brown pigmentations at the end of the treatment . One year later , 1 patient still had some linear pigmentations , while 4 other patients had a single , macular , barely visible pigmentation of no cosmetic significance BACKGROUND Although no r and omized controlled trial has assessed the effects of either compression sclerotherapy or ambulatory phlebectomy , both techniques are used to treat varicose veins worldwide . We performed a r and omized controlled trial to compare recurrence rates of varicose veins and complications after compression sclerotherapy and ambulatory phlebectomy . METHODS From September 1996 to October 1998 , we r and omly allocated 49 legs to compression sclerotherapy and 49 legs to ambulatory phlebectomy . Our primary outcome parameters were as follows : recurrence rates at 1 and 2 years and complications related to therapy . Eighty-two patients were included , of whom 16 were included with both of their legs . The number of treated legs was therefore 98 , but two patients were lost to follow-up . RESULTS One year recurrence amounted to 1 out of 48 for phlebectomy and 12 out of 48 for compression sclerotherapy ( P < 0.001 ) ; at 2 years , six additional recurrences were found , but then solely for compression sclerotherapy ( P < 0.001 ) . Significant differences in complications occurring more in phlebectomy than in compression sclerotherapy therapy were blisters , teleangiectatic matting , scar formation , and bruising from b and aging . CONCLUSION Our results show that ambulatory phlebectomy is an effective therapy for varicose veins of the leg . Recurrence rates are significantly lower than for compression sclerotherapy therapy . If varicose veins persist 4 weeks after compression sclerotherapy , it can be argued that to reduce the risk of future recurrence ambulatory phlebectomy should be considered as the better treatment option The study was planned to evaluate efficacy and costs of endovascular sclerotherapy ( ES ) in comparison with surgery and surgery associated with sclerotherapy in a prospect i ve ( 10-year follow-up ) , good- clinical - practice study . Patients with varicose veins and pure , superficial venous incompetence were included . Of the patients r and omized into the three groups 39 ( group A ) were treated with ES , 40 ( B ) with surgery + sclerotherapy , and 42 with surgery only ( C ) . Surgery consisted of ligation of the SFJ ( saphenofemoral junction ) and of incompetent veins detected with color duplex . Of the preselected 150 patients , 121 subjects entered the study ; 96 completed the 10-year follow-up ( mean age 52.6 ±6 years ; 51 men , 45 women ) . Dropouts were due to nonmedical problems . At 10 years no incompetence was observed in subjects treated with SPJ ligation ( B and C ) . In the ES group 18.8 % of the SFJs were patent and incompetent and in 43.8 % of limbs the distal ( below-knee ) venous system was still incompetent [ 16.1 % in the surgery + scle rotherapy group ( p < 0.05 ) and 36 % in the group treated with surgery only ( p < 0.05 vs B and 0.05 vs A ) ] . Color duplex of the long saphenous vein indicated atrophy or obstruc tion of a segment ( average 6.7 cm ) after SFJ ligation ( 4.2 cm after ES ) . The cost of ES was 68 % of surgery while the cost of surgery and sclerotherapy was 122 % of surgery only . Endovascular sclerotherapy is an effective , cheaper treatment option , but surgery after 10 years is superior OBJECTIVE To compare the long-term value of different forms of treatment for primary varicose veins with saphenous vein insufficiency . EXPERIMENTAL DESIGN A prospect i ve , partially r and omized study with 5-year follow-up . SETTING Ambulatory day-case care . PATIENTS AND INTERVENTIONS The study includes 211 patients ( 214 lower limbs ) , who received compression sclerotherapy ( CST ; n = 78 ) , radical operation ( OP ; n = 74 ) or CST combined with high tie under local anesthesia ( HT + CST ; n = 63 ) . MEASURES The patient 's subjective opinion , objective finding by the surgeon and functional ( foot-volumetric ) assessment were obtained just after treatment and 6 months , 1 , 3 and 5 years later . RESULTS Subjectively the result started to deteriorate in both the CST and HT + CST groups after one year . The patient satisfaction was greatest in the OP group throughout the study period . Objective ly the CST group cure rate fell markedly after 6 months and at 5 year follow-up the failure rate reached 51 % , while the OP group still had a high rate of cured ( 60 % ) and improved ( 35 % ) patients . The HT + CST treatment seemed to hold well for three years followed by increasing failure rate with only 16 % objective ly cured after 5 years . The foot-volumetric parameters expelled volume (= calf pump function ) and refilling flow ratio (= venous reflux ) increased 51 - 79 % respectively decreased 8 - 29 % post-treatment in all groups . After 5 years these parameters had returned to pre-treatment levels in the CST and HT + CST groups , while the OP group was still significantly improved . CONCLUSIONS Radical surgery is superior to compression sclerotherapy alone or in combination with high tie in the treatment of varicose veins with saphenous vein incompetence . The foot-volumetric assessment correlated well with and supported objective findings as a whole but could not replace the clinical examination of each individual patient OBJECTIVE A prospect i ve study was performed in order to compare results obtained in the treatment of early and /or limited primary varicose veins of the lower limbs using two different procedures : external valvuloplasty and high ligation or disconnection of the sapheno-femoral junction . MATERIAL S AND METHODS 116 limbs ( 113 patients ) were selected . 57 with normal cusps in dilated valves were subjected to external valvuloplasty with Silicone prosthesis under Doppler control ( intraoperative angioscopy in 16 cases ) ; 59 limbs were subjected to high ligation or disconnection of the junction ; 57 limbs out of 116 were subjected to complementary procedures . Duplex and photoplethysmographic examinations were performed before and after the surgical procedures in all patients . Doppler venous pressures were measured in 36 limbs and invasive pressures in 40 limbs . Patients were postoperatively followed up every 4 months until the 12th month . RESULTS Indications for valvuloplasty were found in 8.2 % of cases and in 66.3 % of the early varices . Clinical results were slightly superior in the reparative surgery group . Thrombotic occlusion of the proximal long saphenous vein was significantly higher in the ligation-disconnection group . Results from photoplethysmography and venous pressure measurements indicated that both operations are equally effective in the elimination of reflux in the junction background The 3S technique enables treatment of large incontinent greater saphenous veins in patients who , for medical or social reasons , refuse traditional surgical methods . It associates phlebectomy with section‐ligation and injection of a sclerosing solution in the proximal and distal segments . The 3S technique is merely one stage in the treatment of the saphenous vein , aim ed at suppressing reflux , and associated with sclerosis of the junction . It must always be combined with later sclerotherapy sessions . methods One hundred and eight patients were operated on by the 3S technique , of which 100 had 1‐year follow‐up . Each patient was checked by duplex scan examination before treatment , and 1 month and 1 year after . results We obtained good results without reflux in 96 % at the sapheno‐femoral junction at 1 year . conclusions Superficial venous insufficiency is a chronic disease with evolution or recurrences . To appreciate the efficiency of 3S technique , it will be better to have 5 years worth of follow‐up . This is a preliminary study with a short follow‐up The study compared , by a prospect i ve , r and omized method , 6 treatment options : A : Sclero therapy ; B : High-dose sclerotherapy ; C : Multiple ligations ; D : Stab avulsion ; E : Foam-sclero therapy ; F : Surgery ( ligation ) followed by sclerotherapy . Results were analyzed 10 years after inclusion and initial treatment . Endpoints of the study were variations in ambulatory venous pressure ( AVP ) , refilling time ( RT ) , presence of duplex-reflux , and number of recurrent or new incompetent venous sites . The number of patients , limbs , and treated venous segments were comparable in the 6 treatment groups , also comparable for age and sex distribution . The occur rence of new varicose veins at 5 years varied from 34 % for group F ( surgery + sclero ) and ligation ( C ) to 44 % for the foam + sclero group ( E ) and 48 % for group A ( dose 1 sclero ) . At 10 years the occurrence of new veins varied from 37 % in F to 56 % in A. At inclusion AVP was comparable in the different groups . At 10 years the decrease in AVP and the increase in RT ( indicating decrease in reflux ) , was generally comparable in the different groups . Also at 10 years the number of new points of major incompetence was comparable in all treatment groups . These results indicate that , when correctly performed , all treatments may be similarly effective . " St and ard , " low-dose sclerotherapy appears to be less effective than high-dose sclero and foam-sclerotherapy which may obtain , in selected subjects , results comparable to surgery Graduated compression stockings are used in both surgical and non-surgical treatment of varicose veins . In a trial of high versus low compression stockings ( 40 mmHg vs 15 mmHg at ankle ) after varicose vein surgery , both were equally effective in controlling bruising and thrombophlebitis , but low compression stockings proved to be more comfortable . In a further trial after sclerotherapy , high compression stockings alone produced comparable results to Elastocrepe b and ages with stockings . It is concluded that after varicose vein surgery low compression stockings provide adequate support for the leg and that after sclerotherapy , b and aging is not required if a high compression stocking is used Abstract Objective : To define the relations between age , sex , lower limb symptoms , and the presence of trunk varicose veins on clinical examination . Design : Cross sectional population study . Setting : 12 general practice s with catchment areas geographically and socioeconomically distributed throughout Edinburgh . Participants : An age stratified r and om sample of 1566 people ( 699 men and 867 women ) aged 18 - 64 selected from the computerised age-sex registers of participating practice s. Main outcome measures : Self administered question naire on the presence of lower limb symptoms and physical examination to determine the presence and severity of varicose veins . Results : Women were significantly more likely than men to report lower limb symptoms such as heaviness or tension , swelling , aching , restless legs , cramps , and itching . The prevalence of symptoms tended to increase with age in both sexes . In men , only itching was significantly related to the presence and severity of trunk varices ( linear test for trend , P=0.011 ) . In women there was a significant relation between trunk varices and the symptoms of heaviness or tension ( P 0.001 ) , aching ( P 0.001 ) , and itching ( P 0.005 ) . However , the level of agreement between the presence of symptoms and trunk varices was too low to be of clinical value , especially in men . Conclusions : Even in the presence of trunk varices , most lower limb symptoms probably have a non-venous cause . Surgical extirpation of trunk varices is unlikely to ameliorate such symptoms in most patients In a controlled clinical investigation 516 patients with previously untreated saphenous varices were divided into three treatment groups according to a stratified group comparative design . The patients in treatment group 1 underwent a radical operation under full anaesthesia ; the patients in group 2 were treated by means of minor operations followed by injection/compression therapy ; the patients in group 3 were treated by means of injection/compression therapy alone . The results were evaluated both objective ly and subjectively 3 months and 3 years after treatment , the follow‐up being 100 per cent and 98.1 per cent complete at those times . With regard to the period of disability among those patients with jobs outside the home ( 63.8 per cent ) , there was a statistically significant difference between the three groups , the median period of disability being 14.2 , 7.6 and 0 days respectively . In all three treatment groups the results were worse after 3 years than after 3 months , but the difference was significantly less following radical operation than after combined treatment , and significantly less following combined treatment than after injection/compression therapy alone . The patients were r and omized and treated by the author and the results of treatment were evaluated by the author and partly controlled by another investigator This prospect i ve r and omized study compared the treatment of greater saphenous vein insufficiency by stripping and local avulsions of varicose veins with high ligation of the saphenofemoral junction ( crossectomy ) combined with sclerocompression therapy . Of 156 consecutive patients , 89 legs were r and omly allocated to stripping and 92 to high ligation . At follow-up of 3 months and 1 , 2 , and 3 years after treatment , clinical and Doppler ultrasound results , and complaints and cosmetic results , as judged by the patient and the surgeon , were scored . At 3 years , 69 limbs in the stripping group ( 78 % ) and 73 limbs in the ligation group ( 79 % ) were available to follow-up . The cosmetic results , both judged by the patient and the surgeon , were significantly better ( P < 0.05 ) in the stripped limbs than in the limbs with high ligation and sclerotherapy . Clinical and Doppler ultrasound evidence of reverse flow in the saphenous vein was significantly less ( P < 0.001 ) after the stripping operation . The results of treatment of isolated saphenous vein insufficiency by stripping operation , therefore , were superior to those obtained by high ligation combined with sclerotherapy A r and omised controlled trial was carried out to compare the clinical outcome 5 years after inpatient surgery and outpatient injection/compression sclerotherapy . 91.3 % of those originally treated by injection/compression sclerotherapy and 93.9 % of those originally treated surgically were seen at follow-up . 40 % of patients treated initially by injection/compression sclerotherapy and 24.2 % of those treated surgically were given further treatment . The probability of having no further treatment is significantly greater for those treated surgically . The improved outcome after surgery increased with age , being most striking in those aged over 45 . The implication s of the 5-year follow-up findings for the long-term cost of treatment are discussed Varicose veins are a common problem , and yet there is divergent opinion as to whether surgery or sclerotherapy is the preferred method of treatment . After establishing a reliable injection technique , the method was compared with st and ard surgical procedures in a r and om trial . The results showed that after one year 82 % of unselected patients were cured by injection , but after six years the cure rate was only 7 % . The surgical result was not as good at one year , but much better than injection after six years . When the results were considered for three distinct clinical groups , the analysis showed that the best primary treatment for dilated superficial veins and for incompetent perforating veins in the lower part of the legs was injection-compression . However , surgery was much more successful and long-lasting when there was involvement of the saphenous systems with proximal incompetence Abstract A r and omised controlled trial has been carried out to compare the clinical outcome in patients treated for varicose veins by routine surgery and injection/compression sclerotherapy . 115 patients were treated with injection/ compression sclerotherapy and 100 were treated surgically . 93 % of those treated have been seen three years after treatment , by then 14 % in the surgical group and 22 % in the injection/compression group had been given further treatment ; there is no significant difference between the results of the two forms of treatment . The patients preferred injection/ compression sclerotherapy , and fewer failed to attend for this treatment than for surgery A clinical trial was carried out to compare the effectiveness of compressive sclerotherapy with that of the traditional operative procedures in the treatment of varicose veins . One hundred and ten patients were treated by compression sclerotherapy and 91 patients by operation 1 . The current practice of operating upon patients with varicose veins as the treatment of choice costs more than £ 15 millions a year AIM This study was undertaken to determine the haemodynamic effect of incompetent calf perforating veins in patients with uncomplicated varicose veins and long saphenous incompetence . METHODS Thirty-eight limbs from 35 patients were studied . All patients had uncomplicated varicose veins with both long saphenous and calf perforator incompetence on duplex ultrasonography . Patients were r and omized to have incompetent calf perforators ligated or left intact , in addition to saphenofemoral junction ligation , strip of long saphenous vein to knee and stab avulsion of any visible varicosities in the leg . Patients were assessed with air plethysmography pre-operatively and 3 months postoperatively . RESULTS Superficial venous surgery improved venous volume , venous filling index and ejection fraction in the patient cohort . No significant haemodynamic difference was demonstrated between the two groups of patients who were r and omized . CONCLUSIONS At present , the results of this study do not support the use of routine perforator ligation during superficial surgery for uncomplicated varicose veins This study compares a st and ard method of care for patients following excision and ligation of varicose veins with a new regimen which involves intermittent compression dressings . In a fully r and omized between‐patient prospect i ve trial it has been found that the use of such dressings results in a significant reduction in postoperative pain and in the length of hospitalization and indicates that such dressings may improve the healing of surgical wounds The risk of thrombosis after lower-extremity sclerotherapy is still an unresolved issue . This study was conducted to investigate the influence of sclerotherapy on coagulation and fibrinolysis by examining 20 patients who underwent surgical procedures , 10 of whom were treated by surgery alone ( control group ) , while the other 10 were given sclerotherapy using 1 % hydroxypolyaetoxydodecan as polidocanol ( sclerotherapy group ) . Sex , age , and severity of disease was comparable between the two groups . No significant difference was found in the transient elevation of acute phase proteins , C-reactive protein ( CRP ) , or fibrinogen . Thrombin antithrombin III complex ( TAT ) , a marker of coagulation , transiently increased following treatment . In the control group , TAT peaked 3 days after treatment , whereas in the sclerotherapy group the elevation was prolonged , peaking 7 days after treatment . Elevation of the markers of fibrinolysis , plasmin plasmin inhibitor complex ( PIC ) and fibrin degradation products ( FDP ) , was slower than that of TAT , peaking 7 days after treatment in both groups , the plasma PIC being significantly enhanced 7 days after treatment in the sclerotherapy group . A significant decrease in the platelet count was observed 3 days after treatment in the sclerotherapy group . These results suggest that sclerotherapy may enhance coagulation or fibrinolysis after surgical procedures

Community paramedicine research to date is lacking , but programs in the United Kingdom , Australia , and Canada are perceived to be promising , and one RCT shows that paramedics can safely practice with an exp and ed scope and improve system performance and patient outcomes .

BACKGROUND Paramedics are an important health human re source and are uniquely mobile in most communities across Canada . In the last dozen years , challenges in the delivery of health care have prompted governments from around the globe to consider exp and ing the role paramedics play in health systems . Utilizing paramedics for the management of urgent , low-acuity illnesses and injuries has been coined " community paramedicine , " but the role , safety , and effectiveness of this concept are poorly understood . OBJECTIVE We undertook a systematic review of the international literature to describe existing community paramedic programs .

Objective To evaluate the benefits of paramedic practitioners assessing and , when possible , treating older people in the community after minor injury or illness . Paramedic practitioners have been trained with extended skills to assess , treat , and discharge older patients with minor acute conditions in the community . Design Cluster r and omised controlled trial involving 56 clusters . Weeks were r and omised to the paramedic practitioner service being active ( intervention ) or inactive ( control ) when the st and ard 999 service was available . Setting A large urban area in Engl and . Participants 3018 patients aged over 60 who called the emergency services ( n=1549 intervention , n=1469 control ) . Main outcome measures Emergency department attendance or hospital admission between 0 and 28 days ; interval from time of call to time of discharge ; patients ' satisfaction with the service received . Results Overall , patients in the intervention group were less likely to attend an emergency department ( relative risk 0.72 , 95 % confidence interval 0.68 to 0.75 ) or require hospital admission within 28 days ( 0.87 , 0.81 to 0.94 ) and experienced a shorter total episode time ( 235 v 278 minutes , 95 % confidence interval for difference −60 minutes to −25 minutes ) . Patients in the intervention group were more likely to report being highly satisfied with their healthcare episode ( relative risk 1.16 , 1.09 to 1.23 ) . There was no significant difference in 28 day mortality ( 0.87 , 0.63 to 1.21 ) . Conclusions Paramedics with extended skills can provide a clinical ly effective alternative to st and ard ambulance transfer and treatment in an emergency department for elderly patients with acute minor conditions . Trial registration IS RCT N27796329 Over a 2-week period a prospect i ve study was undertaken of patients brought to an inner city accident and emergency department by the emergency ambulance service . Criteria for assessing the appropriateness of use of the emergency ambulance service are not well defined and at worst entirely subjective . The author 's finding that , of patients attending after a ‘ 999 ’ call , 49.8 % were discharged with no follow-up suggests that many of these journeys represented inappropriate use of the emergency ambulance service . Close liaison between senior medical staff and the emergency ambulance service may allow more appropriate and effective use of the service , improving patient care in the pre-hospital setting Background : A scheme to train paramedics to undertake a greater role in the care of older people following a call for an emergency ambulance was developed in a large city in the UK . Objectives : To assess the cost effectiveness of the paramedic practitioner ( PP ) scheme compared with usual emergency care . Methods : A cluster r and omised controlled trial was undertaken of PP compared with usual care . Weeks were allocated to the study group at r and om to the PP scheme either being active ( intervention ) or inactive ( control ) . Re source use data were collected from routine sources , and from patient-completed question naires for events up to 28 days . EQ-5D data were also collected at 28 days . Results : Whereas the intervention group received more PP contact time , it reduced the proportion of emergency department ( ED ) attendances ( 53.3 % vs 84.0 % ) and time in the ED ( 126.6 vs 211.3 minutes ) . There was also some evidence of increased use of health services in the days following the incident for patients in the intervention group . Overall , total costs in the intervention group were £ 140 lower when routine data were considered ( p = 0.63 ) . When the costs and QALY were considered simultaneously , PP had a greater than 95 % chance of being cost effective at £ 20 000 per QALY . Conclusion : Several changes in re source use are associated with the use of PP . Given these economic results in t and em with the clinical , operational and patient-related benefits , the wider implementation and evaluation of similar schemes should be considered Introduction : The Department of Health document Reforming emergency care stated that new initiatives need to be developed to improve the care and assessment of patients . The Audit Commission has suggested that ambulance services should be allowed to decide who should be sent to each type of emergency and treat some patients at home . Aims : This scheme explores a new way of providing clinical assessment of older patients in their homes or in care homes within Sheffield . It sets out to provide a very patient centred model of care by providing community based clinical assessment for patients presenting to the emergency services with minor acute conditions . Scope , development , and structure of scheme : The scheme trains paramedic practitioners in the assessment and treatment of minor conditions to emergency nurse practitioner level . It consists of a three week full time theory based course and a 45 day period of supervised clinical practice based in the emergency department , minor injury unit , care of the elderly falls clinic , and with community services . Subsequently , the competence of the practitioners is assessed . Service delivery : The service will be activated by a 999 call between 0800 to 2000 each day . It is anticipated that between 25 % to 50 % of patients eligible to receive the service will be assessed and treated within the home . This approach to providing emergency care is untested and the frequency of use , patient acceptability , safety , and cost effectiveness are unknown , therefore rigorous assessment is essential through a r and omised controlled trial To determine whether paramedics can safely treat and discharge insulin-dependent diabetic patients experiencing uncomplicated hypoglycemic events , we conducted a prospect i ve , observational study with a convenience sample of diabetic patients whose hypoglycemia resolved after intravenous administration of dextrose and before they were transported by paramedics . On-line medical control was contacted to obtain approval and informed consent for participation from interested patients who met all eligibility criteria for the study . Participating patients were given instructions upon discharge from the study and were contacted by telephone 24 hours later to ascertain their medical outcomes and their opinions of the study protocol . We enrolled a total of 36 patients with 38 incidents of hypoglycemia . Of these , 91 % reported no complications after discharge . Two patients developed recurrent hypoglycemia but treated themselves and did not require further emergency care . One further patient was found unresponsive on the morning following discharge and was subsequently admitted to a long-term care facility with hypoglycemic encephalopathy . Of the study participants , 85 % were very satisfied with not being transported to an emergency department ( ED ) and 91 % were very satisfied with the care they had received . All ( 100 % ) of the patients surveyed favored a permanent protocol allowing discharge of hypoglycemic patients without admission to an ED . We conclude that paramedics successfully treated , without complication , most of the patients with uncomplicated hypoglycemic events who were examined in our study . These patients generally preferred discharge without transportation to an ED BACKGROUND The role of paramedics with extended skills is evolving , enabling them to assess and treat patients in the community . A United Kingdom service led by extended-role paramedic practitioners ( PPs ) is aim ed at managing minor acute illness and injury among older people in the home when appropriate , avoiding unnecessary transfer to the emergency department ( ED ) . OBJECTIVES The objectives were to evaluate the safety of clinical decisions made by PPs operating within the new service . METHODS As part of a cluster-r and omized controlled trial , patients aged > 60 years contacting the emergency medical services ( EMS ) with a minor injury or illness were included in the study . The safety of the new PP intervention was compared with st and ard practice of EMS transfer and ED treatment . Outcomes included unplanned ED attendance within 7 days of the index episode . Clinical records were rated independently by two senior ED clinicians to identify related episodes , avoidable subsequent episodes , and suboptimal care . RESULTS Of the 2,025 patients included in this analysis , 219 ( 10.9 % ) went on to have an unplanned ED attendance within 7 days . Of these , 162 ( 74.0 % ) re-presented with a condition related to their index episode . The independent raters agreed on suboptimal care 83.4 % of the time . There were 16 agreed upon episodes related to suboptimal care ( 0.80 % ) . No significant differences were found between intervention and control groups in relation to re-presentation at hospital within 7 days for a related condition or rates of assessed suboptimal care . CONCLUSIONS This study suggests that appropriately trained paramedics with extended skills treating older people with minor acute conditions in the community are as safe as st and ard EMS transfer and treatment within the ED Objective To evaluate the impact of emergency care practitioners ( ECPs ) on the patient care pathway for children presenting with minor conditions in unscheduled care setting s. Design A pragmatic quasi-experimental multi-site community intervention trial comparing ECPs with usual care providers . Setting Three pairs of emergency and urgent care services in the UK : minor injury unit ( MIU ) , urgent care centre ( UCC ) and general practitioner out of hours . Patients Paediatric acute episodes ( n=415 intervention and n=748 control ) in participating services presenting with minor conditions . Main outcome measures Percentage of patients discharged following care episode and percentage of patients referred to hospital and primary care services . Interventions ECPs operational in emergency and unscheduled care setting s. Results ECPs discharged significantly fewer patients than usual care providers ( percentage difference 7.3 % , 95 % CI 13.6 % to 0.9 % ) . ECPs discharged fewer patients within all three pairs of services ( out of hours percentage difference 6.33 % , 95 % CI 15.17 % to 2.51 % ; UCC percentage difference 8.73 % , 95 % CI 19.22 % to 1.76 % ; MIU percentage difference 6.80 % , 95 % CI 24.36 % to 10.75 % ) . ECPs also referred more patients to hospital ( percentage difference 4.6 % , 95 % CI –2.9 % to 12.0 % ) and primary care providers ( percentage difference 3.0 % , 95 % CI 3.7 % to 9.7 % ) . Conclusions ECPs are not as effective as usual health providers in discharging children after assessment of urgent healthcare problems . This has implication s for the workload of other paediatric providers such as the emergency department . ECPs may be better targeted to setting s and patients groups in which there is more evidence of their effectiveness in patient care pathways

Five studies including a total of 403 participants provided no evidence that fluid optimization strategies improve outcomes for participants undergoing surgery for PFF .

BACKGROUND Proximal femoral fracture ( PFF ) is a common orthopaedic emergency that affects mainly elderly people at high risk of complications . Advanced methods for managing fluid therapy during treatment for PFF are available , but their role in reducing risk is unclear . OBJECTIVES To compare the safety and effectiveness of the following methods of perioperative fluid optimization in adult participants undergoing surgical repair of hip fracture : advanced invasive haemodynamic monitoring , such as transoesophageal Doppler and pulse contour analysis ; a protocol using st and ard measures , such as blood pressure , urine output and central venous pressure ; and usual care .

BACKGROUND Some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality . METHODS We performed a r and omized trial comparing goal -directed therapy guided by a pulmonary-artery catheter with st and ard care without the use of a pulmonary-artery catheter . The subjects were high-risk patients 60 years of age or older , with American Society of Anesthesiologists ( ASA ) class III or IV risk , who were scheduled for urgent or elective major surgery , followed by a stay in an intensive care unit . Outcomes were adjudicated by observers who were unaware of the treatment-group assignments . The primary outcome was in-hospital mortality from any cause . RESULTS Of 3803 eligible patients , 1994 ( 52.4 percent ) underwent r and omization . The base-line characteristics of the two treatment groups were similar . A total of 77 of 997 patients who underwent surgery without the use of a pulmonary-artery catheter ( 7.7 percent ) died in the hospital , as compared with 78 of 997 patients in whom a pulmonary-artery catheter was used ( 7.8 percent)--a difference of 0.1 percentage point ( 95 percent confidence interval , -2.3 to 2.5 ) . There was a higher rate of pulmonary embolism in the catheter group than in the st and ard-care group ( 8 events vs. 0 events , P=0.004 ) . The survival rates at 6 months among patients in the st and ard-care and catheter groups were 88.1 and 87.4 percent , respectively ( difference , -0.7 percentage point [ 95 percent confidence interval , -3.6 to 2.2 ] ; negative survival differences favor st and ard care ) ; at 12 months , the rates were 83.9 and 83.0 percent , respectively ( difference , -0.9 percentage point [ 95 percent confidence interval , -4.3 to 2.4 ] ) . The median hospital stay was 10 days in each group . CONCLUSIONS We found no benefit to therapy directed by pulmonary-artery catheter over st and ard care in elderly , high-risk surgical patients requiring intensive care Abstract Objectives To evaluate postoperative medical complications and the association between these complications and mortality at 30 days and one year after surgery for hip fracture and to examine the association between preoperative comorbidity and the risk of postoperative complications and mortality . Design Prospect i ve observational cohort study . Setting University teaching hospital . Participants 2448 consecutive patients admitted with an acute hip fracture over a four year period . We excluded 358 patients : all those aged < 60 ; those with periprosthetic fractures , pathological fractures , and fractures treated without surgery ; and patients who died before surgery . Interventions Routine care for hip fractures . Main outcome measures Postoperative complications and mortality at 30 days and one year . Results Mortality was 9.6 % at 30 days and 33 % at one year . The most common postoperative complications were chest infection ( 9 % ) and heart failure ( 5 % ) . In patients who developed postoperative heart failure mortality was 65 % at 30 days ( hazard ratio 16.1 , 95 % confidence interval 12.2 to 21.3 ) . Of these patients , 92 % were dead by one year ( 11.3 , 9.1 to 14.0 ) . In patients who developed a postoperative chest infection mortality at 30 days was 43 % ( 8.5 , 6.6 to 11.1 ) . Significant preoperative variables for increased mortality at 30 days included the presence of three or more comorbidities ( 2.5 , 1.6 to 3.9 ) , respiratory disease ( 1.8 , 1.3 to 2.5 ) , and malignancy ( 1.5 , 1.01 to 2.3 ) . Conclusions In elderly people with hip fracture , the presence of three or more comorbidities is the strongest preoperative risk factor . Chest infection and heart failure are the most common postoperative complications and lead to increased mortality . These groups offer a clear target for specialist medical assessment BACKGROUND Patients with proximal femoral fracture ( PFF ) are at high risk of postoperative complications . Goal -directed haemodynamic treatment ( GDHT ) in other high-risk surgical patients reduces postoperative complications . We aim ed to compare effects of GDHT and routine fluid treatment ( RFT ) on postoperative outcomes after PFF surgery . METHODS PFF patients ( ≥70 yr ) were enrolled in this single-centre , open , r and omized , controlled , parallel-group superiority trial with concealed allocation using computer-generated r and omization . TREATMENTS ( i ) GDHT to attain oxygen delivery index > 600 ml min(-1 ) m(-2 ) using fluids and dobutamine and ( ii ) a protocol -guided RFT . After 150 enrolled patients , the trial was stopped due to slow recruitment . The short-term primary outcome measure was the relative risk ( RR ) of postoperative complications ; secondary measures were ( i ) administered fluid levels , ( ii ) vasopressor requirements , and ( iii ) haemodynamic responses . RESULTS For the GDHT group , 74 and for the RFT group 75 patients were design ated . The RR of postoperative complications ( GDHT vs RFT ) was 0.79 ( 95 % confidence interval 0.54 - 1.16 ) ; the volumes of i.v . fluids decreased ( 1078 vs 1440 ml , P=0.01 ) ; fewer patients required treatment of hypotension ( 18.5 % vs 75 % , P<0.005 ) ; there were more patients with increased oxygen delivery at the end of operation ( 28 % vs 8 % , P=0.04 ) , but the haemodynamic goal was achieved in only 27 % of patients in the GDHT group . CONCLUSIONS The magnitude of risk reduction of postoperative complications is clinical ly relevant , but the trial was underpowered and the null hypothesis can not be rejected BACKGROUND A prospect i ve , r and omized controlled trial comparing conventional intraoperative fluid management with two differing methods of invasive haemodynamic monitoring to optimize intraoperative fluid therapy , in patients undergoing proximal femoral fracture repair under general anaesthesia . METHODS Ninety patients r and omized to three groups ; conventional intraoperative fluid management ( Gp CON , n=29 ) , and two groups receiving additional repeated colloid fluid challenges guided by central venous pressure ( Gp CVP , n=31 ) or oesophageal Doppler ultrasonography ( Gp DOP , n=30 ) . Primary outcome measures were time to medical fitness to discharge , hospital stay and postoperative morbidity . RESULTS The fluid challenge result ed in significantly greater perioperative changes in central venous pressure between Gp CVP and Gp CON ( mean 5 ( 95 % confidence interval 3 - 7 ) mm Hg ) ( P<0.0001 ) . Important perioperative changes were also shown in Gp DOP with increases of 49.4 ms ( 19.7 - 79.1 ms ) in the corrected flow time , 13.5 ml ( 7.4 - 19.6 ml ) in stroke volume , and 0.9 ( 0.49 - 1.39 ) litre min(-1 ) in cardiac output . As a result , fewer patients in Gp CVP and Gp DOP experienced severe intraoperative hypotension ( Gp CON 28 % ( 8/29 ) , Gp CVP 9 % ( 3/31 ) , Gp DOP 7 % ( 2/30 ) , P=0.048 ( chi-squared , 2 degrees of freedom ( df ) . No differences were seen between the three groups when major morbidity and mortality were combined , P=0.24 ( chi-squared , 2 df ) . Postoperative recovery for survivors , as defined by time to be deemed medically fit for discharge , was significantly faster , in comparison with Gp CON , in both the Gp CVP ( 10 vs 14 ( 95 % confidence interval 8 - 12 vs 12 - 17 ) days , P=0.008 ( t-test ) ) , and Gp DOP ( 8 vs 14 ( 95 % confidence interval 6 - 12 vs 12 - 17 ) days , P=0.023 ( t-test ) . There were no significant differences between groups , for survivors , with respect to acute orthopaedic hospital and total hospital stay . CONCLUSIONS Invasive intraoperative haemodynamic monitoring with fluid challenges during repair of femoral fracture under general anaesthetic shortens time to being medically fit for discharge Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Approximately 70,000 patients /year undergo surgery for repair of a fractured hip in the United Kingdom . This is associated with 30-day mortality of 9 % and survivors have a considerable length of acute hospital stay postoperatively ( median 26 days ) . Use of oesophageal Doppler monitoring to guide intra-operative fluid administration in hip fracture repair has previously been associated with a reduction in hospital stay of 4 - 5 days . Most hip fracture surgery is now performed under spinal anaesthesia . Oesophageal Doppler monitoring may be unreliable in the presence of spinal anaesthesia and most patients would not tolerate the probes . An alternative method of guiding fluid administration ( minimally-invasive arterial pulse contour analysis ) has been shown to reduce length of stay in high-risk surgical patients but has never been studied in hip fracture surgery . Methods Single-centre r and omised controlled parallel group trial . R and omisation by website using computer generated concealed tables . Setting : University hospital in UK . Participants : 128 patients with acute primary hip fracture listed for operative repair under spinal anaesthesia and aged > 65 years . Intervention : Stroke volume guided intra-operative fluid management . Continuous measurement of SV recorded by a calibrated cardiac output monitor ( LiDCOplus ) . Maintenance fluid and 250 ml colloid boluses given to achieve sustained 10 % increases in stroke volume . Control group : fluid administration at the responsible ( blinded ) anaesthetist 's discretion . The intervention terminates at the end of the surgical procedure and post-operative fluid management is at the responsible anaesthetist 's discretion . Primary outcome : length of acute hospital stay is determined by a blinded team of clinicians . Secondary outcomes include number of complications and total cost of care . Funding NIHR/RfPB : PB-PG-0407 - 13073.Trial registration numberTrial registration : Current Controlled Trials IS RCT N88284896 Background Intraoperative hypovolemia is common and is a potential cause of organ dysfunction , increased postoperative morbidity , length of hospital stay , and death . The objective of this prospect i ve , r and omized study was to assess the effect of goal -directed intraoperative fluid administration on length of postoperative hospital stay . Methods One hundred patients who were to undergo major elective surgery with an anticipated blood loss greater than 500 ml were r and omly assigned to a control group ( n = 50 ) that received st and ard intraoperative care or to a protocol group ( n = 50 ) that , in addition , received intraoperative plasma volume expansion guided by the esophageal Doppler monitor to maintain maximal stroke volume . Length of postoperative hospital stay and postoperative surgical morbidity were assessed . Results Groups were similar with respect to demographics , surgical procedures , and baseline hemodynamic variables . The protocol group had a significantly higher stroke volume and cardiac output at the end of surgery compared with the control group . Patients in the protocol group had a shorter duration of hospital stay compared with the control group : 5 ± 3 versus 7 ± 3 days ( mean ± SD ) , with a median of 6 versus 7 days , respectively ( P = 0.03 ) . These patients also tolerated oral intake of solid food earlier than the control group : 3 ± 0.5 versus 4.7 ± 0.5 days ( mean ± SD ) , with a median of 3 versus 5 days , respectively ( P = 0.01 ) . Conclusions Goal -directed intraoperative fluid administration results in earlier return to bowel function , lower incidence of postoperative nausea and vomiting , and decrease in length of postoperative hospital stay Background A r and omized , controlled trial , intended to include 460 patients , is currently study ing peroperative goal -directed hemodynamic treatment ( GDHT ) of aged hip-fracture patients . Interim efficacy analysis performed on the first 100 patients was statistically uncertain ; thus , the trial is continuing in accordance with the trial protocol . This raised the present investigation ’s main question : Is it reasonable to continue to fund the trial to decrease uncertainty ? To answer this question , a previously developed probabilistic cost-effectiveness model was used . That model depicts ( 1 ) a choice between routine fluid treatment and GDHT , given uncertainty of current evidence and ( 2 ) the monetary value of further data collection to decrease uncertainty . This monetary value , that is , the expected value of perfect information ( EVPI ) , could be used to compare future research costs . Thus , the primary aim of the present investigation was to analyze EVPI of an ongoing trial with interim efficacy observed . Methods A previously developed probabilistic decision analytic cost-effectiveness model was employed to compare the routine fluid treatment to GDHT . Results from the interim analysis , published trials , the meta- analysis , and the registry data were used as model inputs . EVPI was predicted using ( 1 ) combined uncertainty of model inputs ; ( 2 ) threshold value of society ’s willingness to pay for one , quality -adjusted life-year ; and ( 3 ) estimated number of future patients exposed to choice between GDHT and routine fluid treatment during the expected lifetime of GDHT . Results If a decision to use GDHT were based on cost-effectiveness , then the decision would have a substantial degree of uncertainty . Assuming a 5-year lifetime of GDHT in clinical practice , the number of patients who would be subject to future decisions was 30,400 . EVPI per patient would be € 204 at a € 20,000 threshold value of society ’s willingness to pay for one quality -adjusted life-year . Given a future population of 30,400 individuals , total EVPI would be € 6.19 million . Conclusions If future trial costs are below EVPI , further data collection is potentially cost-effective . When applying a cost-effectiveness model , statements such as ‘ further research is needed ’ are replaced with ‘ further research is cost-effective and ‘ further funding of a trial is justified’.Trial registration Clinical Trials.gov Introduction Several studies have shown that maximizing stroke volume ( or increasing it until a plateau is reached ) by volume loading during high-risk surgery may improve post-operative outcome . This goal could be achieved simply by minimizing the variation in arterial pulse pressure ( ΔPP ) induced by mechanical ventilation . We tested this hypothesis in a prospect i ve , r and omized , single-centre study . The primary endpoint was the length of postoperative stay in hospital . Methods Thirty-three patients undergoing high-risk surgery were r and omized either to a control group ( group C , n = 16 ) or to an intervention group ( group I , n = 17 ) . In group I , ΔPP was continuously monitored during surgery by a multiparameter bedside monitor and minimized to 10 % or less by volume loading . Results Both groups were comparable in terms of demographic data , American Society of Anesthesiology score , type , and duration of surgery . During surgery , group I received more fluid than group C ( 4,618 ± 1,557 versus 1,694 ± 705 ml ( mean ± SD ) , P < 0.0001 ) , and ΔPP decreased from 22 ± 75 to 9 ± 1 % ( P < 0.05 ) in group I. The median duration of postoperative stay in hospital ( 7 versus 17 days , P < 0.01 ) was lower in group I than in group C. The number of postoperative complications per patient ( 1.4 ± 2.1 versus 3.9 ± 2.8 , P < 0.05 ) , as well as the median duration of mechanical ventilation ( 1 versus 5 days , P < 0.05 ) and stay in the intensive care unit ( 3 versus 9 days , P < 0.01 ) was also lower in group I. Conclusion Monitoring and minimizing ΔPP by volume loading during high-risk surgery improves postoperative outcome and decreases the length of stay in hospital . Trial registration Abstract Objectives : To determine whether preoperative optimisation of oxygen delivery improves outcome after major elective surgery , and to determine whether the inotropes , adrenaline and dopexamine , used to enhance oxygen delivery influence outcome . Design : R and omised controlled trial with double blinding between inotrope groups . Setting : York District Hospital , Engl and . Subjects:138 patients undergoing major elective surgery who were at risk of developing postoperative complications either because of the surgery or the presence of coexistent medical conditions . Interventions : Patients were r and omised into three groups . Two groups received invasive haemodynamic monitoring , fluid and either adrenaline or dopexamine to increase oxygen delivery . Inotropic support was continued during surgery and for at least12 hours afterwards . The third group ( control ) received routine perioperative care . Main outcome measures : Hospital mortality and morbidity . Results : Overall , 3/92 ( 3 % ) preoptimised patients died compared with 8/46 controls ( 17 % ) ( P=0.007 ) . There were no differences in mortality between the treatment groups , but 14/46 ( 30 % ) patients in the dopexamine group developed complications compared with 24/46 ( 52 % ) patients in the adrenaline group ( difference 22 % , 95%confidence interval 2 % to 41 % ) and 28 patients ( 61 % ) in the control group ( 31 % , 11 % to 50 % ) . The use of dopexamine was associated with a decreased length of stay in hospital . Conclusion : Routine preoperative optimisation of patients undergoing major elective surgery would be a significant and cost effective improvement in perioperative care Background Anaemia following hip fracture is common . Approximately 30 to 45 % of patients have haemoglobin concentrations below population norms on admission , and around 10 % are severely anaemic . Anaemia on admission , and in the postoperative period , is associated with poor outcomes with regard to mobility , postoperative mortality and readmission . There is currently no clear consensus on the optimal method of managing perioperative anaemia in this group of frail patients with frequent comorbidity . Liberal red cell transfusion in the postoperative period does not appear to improve outcome , whereas tranexamic acid appears to reduce transfusion rate at the expense of increased cardiovascular morbidity . There are encouraging results from one centre with the use of agents to stimulate red cell production , including intravenous iron and erythropoietin . UK practice differs significantly from these patients and these studies , and it is not clear whether these promising results will translate to the UK population . Methods / Design This is a single-centre r and omized controlled parallel group trial , in a British university hospital . R and omization is achieved using a website and computer-generated concealed tables . Participants are 80 patients 70 years or over with acute hip fracture undergoing operative repair . The intervention group receive three daily infusions of 200 mg iron sucrose , starting within 24 hours of admission . The control group receive st and ard hospital care at the discretion of the clinical team . Red cell transfusions for each group are given in accordance with st and ard clinical triggers . The primary outcome is an increase in mean reticulocyte count in the intervention group at day 7 . Secondary outcome measures include haemoglobin concentrations , early and late transfusion rates , infectious and cardiovascular complications , mobility and 30-day mortality . Discussion This is a pilot study to demonstrate haematopoietic efficacy of intravenous iron in this setting . Hence , we have chosen to measure change in reticulocyte count rather than the more clinical ly relevant differences in haemoglobin concentration or transfusion rate . If our results are positive , the study will provide the necessary information for development of a full-scale trial of intravenous iron . Trial registration Current Controlled Trials IS RCT N76424792 ; UK Medicines and Healthcare products Regulatory Authority ( EuDRACT : 2011 - 003233 - 34 ) OBJECTIVE To assess outcomes of using a clinical pathway for managing patients with fractured neck of femur . DESIGN Prospect i ve , pseudor and omised , controlled trial . SETTING St Vincent 's Hospital , Melbourne , Victoria ( a tertiary referral , university teaching hospital ) , 1 October 1997 to 30 November 1998 . PARTICIPANTS 111 patients ( 80 women and 31 men ; mean age , 81 years ) admitted via the emergency department with a primary diagnosis of fractured neck of femur . INTERVENTIONS Management guided by a clinical pathway ( 55 patients ) or established st and ard of care ( control group , 56 patients ) . MAIN OUTCOME MEASURES Timing of referrals and discharge planning ; total length of stay ; and complication and readmission rates within 28 days of discharge . RESULTS Patients managed according to the clinical pathway had a shorter total stay ( 6.6 versus 8.0 days ; P = 0.03 ) , even if assessment for placement by the Aged Care Assessment Service was required ( 9.5 versus 13.6 days ; P = 0.03 ) . There were no significant differences in complication and readmission rates between pathway and control patients ( complication rates , 24 % versus 36 % ; P = 0.40 ; readmission rates , 4 % versus 11 % ; P = 0.28 ) . CONCLUSION Coordinated multidisciplinary care of patients with fractured neck of femur reduces length of stay without increasing complications AIMS Evaluate nutritional status and fluid and energy intake during the first ten days of hospitalisation in a selection of otherwise healthy patients with a hip fracture . METHODS A prospect i ve r and omised controlled study of 80 patients . Nutritional status was assessed at inclusion . The energy and fluid intake was recorded and calculated daily whilst hospitalised . All patients were given ordinary hospital food and beverage . In the treatment group ( n = 40 ) patients also received intraveneous supplementary nutrition ( 1000 kcal/day ) for three days followed by oral supplementary nutrition ( 400 kcal/day ) for seven days or until discharge . RESULTS One third of patients were classified as malnourished in both groups . The average daily fluid intake/patient was 1300 ml in the control group compared to 1856 ml in the treatment group ( P<0.0001 ) . The average daily energy intake/patient was 916 kcal in the control group compared to 1296 kcal in the treatment group ( P = 0.003 ) . The mean difference between actual and needed daily fluid intake was -739 ml in the control group and + 27 ml in the treatment group ( P<0.0001 ) . Corresponding numbers for energy intake was -783 kcal/day in the control group and -228 kcal/day in the treatment group ( P = 0.0003 ) . CONCLUSIONS Malnutrition is common even in a selection of healthy patients with hip fractures . During hospital stay the fluid and energy intake was considerably lower than that needed in the control group . Supplementary nutritional intake for ten days increased the total fluid and energy intake in the treatment group to near needed levels BACKGROUND Hip fracture is a condition with high mortality and morbidity in elderly frail patients . Intraoperative fluid optimization may be associated with benefit in this population . We investigated whether intraoperative fluid management using pulse-contour analysis cardiac monitoring , compared with st and ard care in patients undergoing spinal anaesthesia , would provide benefits in terms of reduced time until medically fit for discharge and postoperative complications . METHODS Patients undergoing surgical repair of fractured neck of femur , aged > 60 yr , receiving spinal anaesthesia were enrolled in this single-centre , blinded , r and omized , parallel group trial . Patients were allocated to either anaesthetist-directed fluid therapy or a pulse-contour-guided fluid optimization strategy using colloid ( Gelofusine ) boluses to optimize stroke volume . The primary outcome was time until medically fit for discharge . Secondary outcomes included postoperative complications , mobility , and mortality . We up date d a systematic review to include relevant trials to 2014 . RESULTS We recruited 130 patients . Time until medically fit for discharge was similar in both groups , mean [ 95 % confidence interval ( CI ) ] 12.2 ( 11.1 - 13.5 ) vs 13.1 ( 11.9 - 14.5 ) days ( P=0.31 ) , as was total length of stay 14.2 ( 12.9 - 15.8 ) vs 15.3 ( 13.8 - 17.2 ) days ( P=0.32 ) . There were no significant differences in complications , function , or mortality . An up date d meta- analysis ( four studies , 355 patients ) found non-significant reduction in early mortality [ relative risk 0.66 ( 0.24 - 1.79 ) ] and in-hospital complications [ relative risk 0.80 ( 0.61 - 1.05 ) ] . CONCLUSIONS Goal -directed fluid therapy during hip fracture repair under spinal anaesthesia does not result in a significant reduction in length of stay or postoperative complications . There is insufficient evidence to either support or discount its routine use . CLINICAL TRIAL REGISTRATION IS RCT N88284896 BACKGROUND The indications for transfusion have never been evaluated in an adequately sized clinical trial . A pilot study was conducted to plan larger clinical trials . STUDY DESIGN AND METHODS Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were r and omly assigned to receive 1 ) symptomatic transfusion : that is , transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2 ) threshold transfusion : that is , patients receive 1 unit of packed RBCs at the time of r and om assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality , morbidity , functional status , and place of residence . RESULTS Among 84 eligible patients enrolled , mean ( + /- SD ) prer and omization hemoglobin was 9.1 ( + /- 0.6 ) g/ dL. The median number of units transfused in the threshold transfusion group was 2 ( interquartile range , = 1 - 2 ) , and that in the symptomatic transfusion group was 0 ( 6 ; interquartile range , = 0 - 2 ) ( p < 0.001 ) . Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group : for example , on Day 2 , 10.3 ( + /- 0.9 ) g per dL versus 9.3 ( + /- 1.2 ) g per dL , respectively ( p < 0.001 ) . At 60 days , death or inability to walk across the room without assistance occurred in 16 ( 39.0 % ) of the symptomatic transfusion group and 19 ( 45.2 % ) of the threshold transfusion group . Death occurred by 60 days in 5 ( 11.9 % ) of the symptomatic transfusion group and 2 ( 4.8 % ) in the threshold transfusion group ( relative risk = 2.5 ; 95 % CI , 0.5 - 12.2 ) . Other outcomes were similar for the two groups . CONCLUSIONS Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy . However , it is unknown whether these two clinical strategies have comparable mortality , morbidity , or functional status . A definitive trial is needed Background Hypotension during spinal anesthesia is common and can lead to severe injuries and even death . Administration of crystalloid fluids is advised to prevent occurrence of hypotension ; however its effectiveness is still the matter of arguments . Objectives This study was design ed to compare the effects of Ringer`s lactate and hydroxyethyl starch 6 % on hemodynamic parameters after spinal anesthesia in patients undergoing orthopedic surgeries on lower limbs . Patients and Methods This r and omized clinical trial was performed in Rasoul Akram Hospital , Tehran , Iran . 60 patients undergoing elective femoral fracture surgeries with spinal anesthesia were included in this study . Fitted patients were r and omly divided into two equal groups . After entrance to the operation room and before spinal anesthesia , patients ' hemodynamic parameters including systolic blood pressure ( SBP ) , cardiac output ( CO ) , and cardiac index ( CI ) were evaluated using monitoring electro-velocimetry set . In both groups , spinal anesthesia was performed using needle no. 25 and 3 mL of marcaine 0.5 % in the sterile situation . None of the treatment group was aware of investigated group during the study . Results The baseline values of mentioned variables did not show a significant difference between two groups using t-test ( P > 0.05 ) . Also SBP , CI , and CO after intervention was not significantly different between two groups using t-test ( P > 0.05 ) . Conclusions The result of present study on patients undergoing femoral fracture surgeries who received Hetastarch or Ringer`s lactate solutions showed that Hetastarch was not significantly more effective in compensation of hypotension induced by spinal anesthesia OBJECTIVE To determine the effect of an early intervention program in an acute care setting on the length of stay in hospital of elderly patients with proximal femoral fractures . SETTING Acute orthopaedic ward of a large teaching hospital . DESIGN AND PARTICIPANTS A r and omised controlled trial comparing 38 Intervention patients with 33 St and ard Care patients . INTERVENTION Early surgery , minimal narcotic analgesia , intense daily therapy and close monitoring of patient needs via a multidisciplinary approach versus routine hospital management . MAIN OUTCOME MEASURES Length of stay ( LOS ) ; deaths ; level of independent functioning . RESULTS Mean LOS was shorter in the Intervention group than in the St and ard Care group ( 21 days v. 32.5 days ; P < 0.01 ) . After adjusting for other factors that could affect LOS ( eg , age , sex , pre-trauma functional levels , pre-trauma comorbidity and postsurgical complications ) , the Intervention program was significantly predictive of shorter LOS ( P = 0.01 ) . The Intervention group did not experience greater numbers of deaths , deterioration in function or need for social support than the St and ard Care group . CONCLUSION This early intervention program in an acute care setting results in significantly shorter length of hospital stay for elderly patients with femoral fractures BACKGROUND Patients affected by hip fracture ( HF ) have high risk of perioperative complications . Despite regional anesthesia is widely used , hypotension is common and increases the risk of myocardial ischemia . The aim of this work was to study hemodynamic changes following spinal ( SA ) and general ( GA ) anesthesia in this selected population of patients . METHODS Twenty patients over 70 years , ASA III , scheduled for HF repair were r and omized to receive SA or general anesthesia GA . Hemodynamic responses to SA and GA were analyzed trough LiDCO ™ plus monitor ( LiDCO Ltd. , Cambridge , UK ) . RESULTS SA provided a more stable hemodynamic profile . SA group received less interventions to keep mean arterial pressure ( MAP ) within limits . GA group had intraoperative cardiac index ( CI ) , stroke volume index ( SVI ) and MAP significantly lower than baseline . Despite both groups experienced hypotension after the induction , MAP reduction in SA group was primarily due to systemic vascular resistance index ( SVRI ) decline , whereas hypotension in GA group was primarily due to a reduction in SVI and CI . The coefficient of variation ( CV ) was significantly higher in GA group for CI , SVI , MAP and heart rate ( HR ) within one hour analysis comparing to SA group . SA group had an higher CV for SVRI . CONCLUSION SA in the elderly population with hip fracture provides a more stable hemodynamic profile requiring less intervention to keep MAP close to baseline value . Hypotension was common in SA and GA after induction and within intraoperative period . A larger r and omized clinical study should be performed to confirm these preliminary data BACKGROUND : The intrathoracic blood volume index ( ITBVI ) and central venous pressure ( CVP ) are routinely used to predict fluid responsiveness in critically ill patients with acute circulatory failure ( systolic blood pressure < 90 mm Hg or vasopressor requirement ) . However , they have never been compared . METHODS : In this prospect i ve interventional study , we included 35 ( 21 men ) mechanically ventilated and se date d patients with acute cardiovascular failure requiring cardiac output measurement ( transpulmonary thermodilution technique ) . Fluid responsiveness was defined as an increase in stroke index ( cardiac output/heart rate/body surface area ) ≥15 % . Receiver operating characteristic curves were generated for ITBVI and CVP . RESULTS : Fluid challenge induced a stroke index increase ≥15 % in 18 ( 51 % ) patients ( responders ) . At baseline , no studied hemodynamic variables were different between responders and nonresponders . The areas under the receiver operating characteristic curves were 0.64 [ 95 % CI : 0.46–0.80 ] for ITBVI and 0.68 [ 95 % CI : 0.50–0.83 ] for CVP , without any statistical difference ( P = 0.73 ) . The best cut-off values for CVP and ITBVI were 9 mm Hg ( sensitivity = 61 % ; specificity = 82 % ) and 928 mL · m−2 ( sensitivity = 78 % ; specificity = 53 % ) . CONCLUSION : ITBVI is similar to CVP in its ability to predict fluid responsiveness in critically ill patients with acute circulatory failure Abstract Objectives : To assess whether intraoperative intravascular volume optimisation improves outcome and shortens hospital stay after repair of proximal femoral fracture . Design : Prospect i ve , r and omised controlled trial comparing conventional intraoperative fluid management with repeated colloid fluid challenges monitored by oesophageal Doppler ultrasonography to maintain maximal stroke volume throughout the operative period . Setting : Teaching hospital , London . Subjects : 40 patients undergoing repair of proximal femoral fracture under general anaesthesia . Interventions : Patients were r and omly assigned to receive either conventional intraoperative fluid management ( control patients ) or additional repeated colloid fluid challenges with oesophageal Doppler ultrasonography used to maintain maximal stroke volume throughout the operative period ( protocol patients ) . Main outcome measures : Time declared medically fit for hospital discharge , duration of hospital stay ( in acute bed ; in acute plus long stay bed ) , mortality , perioperative haemodynamic changes . Results : Intraoperative intravascular fluid loading produced significantly greater changes in stroke volume ( median 15 ml ( 95 % confidence interval 10 to 21 ml ) ) and cardiac output ( 1.2 l/min ( 0.1 to 2.3 l/min ) ) than in the conventionally managed group ( −5 ml ( −10 to 1 ml ) and −0.4 l/min ( −1.0 to 0.2 l/min ) ) ( P<0.001 and P<0.05 , respectively ) . One protocol patient and two control patients died in hospital . In the survivors , postoperative recovery was significantly faster in the protocol patients , with shorter times to being declared medically fit for discharge ( median 10 ( 9 to 15 ) days v 15 ( 11 to 40 ) days , P<0.05 ) and a 39 % reduction in hospital stay ( 12 ( 8 to 13 ) days v 20 ( 10 to 61 ) days , P<0.05 ) . Conclusions : Proximal femoral fracture repair constitutes surgery in a high risk population . Intraoperative intravascular volume loading to optimal stroke volume result ed in a more rapid postoperative recovery and a significantly reduced hospital stay . Key messages Patients undergoing hip fracture repair constitute a high risk group with considerable mortality and morbidity and an often protracted postoperative hospital stay These patients often have depleted intravascular volume in the perioperative period and rarely receive either invasive haemodynamic monitoring or high dependency care Haemodynamic optimisation guided by pulmonary artery catheter in the perioperative period has been shown to improve outcome in high risk patients undergoing major surgery , but this is not considered routinely practicable for hip fracture repair Intravascular volume optimisation directed by minimally invasive oesophageal Doppler monitoring in the intraoperative period significantly reduces hospital BACKGROUND The Nottingham Hip Fracture Score ( NHFS ) was developed and vali date d in a single centre in 2007 as a predictor of 30 day mortality . It has subsequently been shown to predict longer term and functional outcomes . We wished to assess the ability of NHFS to predict outcomes in other centres and to investigate the change in outcome after hip fracture over time . METHODS The NHFS was calculated for all patients with data from three UK hip fracture units : Peterborough ( 1992 - 2009 ) , Brighton ( 2008 - 9 ) , and Nottingham ( 2000 - 9 ) including 4804 , 585 , and 1901 patients , respectively . The logistic regression was used to recalibrate the NHFS to 30 day mortality across the three units using a r and om selection of 50 % of the data set . Calibration was assessed using the Hosmer-Lemeshow goodness of fit . RESULTS The median ( inter-quartile range ) NHFS values were Peterborough [ 4.0 ( 1 - 6 ) ] , Brighton [ 5.0 ( 3 - 7 ) ] , and Nottingham [ 5.0 ( 3 - 7 ) ] . There was no correlation between 30 day mortality and time ( R(2)=0.05 , P=0.115 ) . The proportion of patients with NHFS ≥ 4 showed a weak correlation with time ( R(2)=0.2 , P=0.003 ) . The original NHFS equation overestimates mortality in the higher-risk groups . A modified equation shows good calibration for all three centres { 30 day mortality (%)=100/1+e([(5.012 × ( NHFS × 0.481)])}. The hospital was not a predictor of 30 day mortality . CONCLUSIONS The NHFS , with an up date d equation , is a robust predictor of 30 day mortality after hip fracture repair in geographically distinct UK centres

Although the data are limited , radioisotopes seem to reduce pain with a rapid onset of action and duration of response of 1 to 3 months . The evidence that bisphosphonates or denosumab reduce or prevent pain in patients with NSCLC and bone metastases or that they have an influence on QoL is very weak . Radioisotopes can be used to reduce diffuse pain , although there is no high-level evidence supporting such use

Bone metastases are common in patients with non-small cell lung cancer ( NSCLC ) , often causing pain and a decrease in quality of life ( QoL ) . The effect of bone-targeted agents is evaluated by reduction in skeletal-related events in which neither pain nor QoL are included . Radioisotopes can be administered for more diffuse bone pain that is not eligible for palliative radiotherapy . The evidence that bone-targeted agents relieve pain or improve QoL is not solid . We performed a systematic review of the effect of bone-targeted agents on pain and QoL in patients with NSCLC .

OBJECTIVE To evaluate the measurement of Samarium-153 ethylenediaminetetramethylene phosphonic acid ( (153)Sm-EDTMP ) bone uptake rate using whole-body scintigraphy and analyze the relationship between bone uptake rate and therapeutic effect . METHODS Sixty-six patients with painful bony metastases from prostate ( n = 15 ) , lung ( n = 20 ) , breast ( n= 18 ) , nasopharyngeal carcinoma ( NPC ) ( n=5 ) , colon ( n=2 ) , kidney ( n=2 ) and unknown cause ( n=4 ) carcinoma were examined with whole-body scintigraphy 10 min and 5 h post administration of (153)Sm-EDTMP . Bone uptake rate was then calculated . ( 1 ) Complete response ( CR ) : disappearance of > 2 metastases , Karnofsky Performance Score ( KPS ) increase > 20 , moderate or complete remission of bone pain 7 d post injection of (153)Sm-EDTMP . ( 2 ) Partial response ( PR ) : disappearance of 1 - 2 metastases , KPS increase 10 - 20 , moderate remission of bone pain in 3 wk . ( 3 ) Non-response ( NR ) : no disappearance or shrinkage of metastases , KPS increase < 10 , no or slight remission of bone pain . RESULTS The range of bone uptake rate in 66 patients was 31 .9 % - 86.6 % ( mean = 56 . 0 % ) . The bone uptake rate in the CR group ( 17 cases , 25.7 % ) , PR group ( 24 cases , 36.4 % ) , and NR group ( 25 cases , 37.9 % ) was 52.4 % - 86.6 % ( mean = 68.7 % ) , 43.7 % - 70.4 % ( mean = 58.3 % ) , and 31.9%- 51 .5 % ( mean = 41 . 0 % ) respectively . Statistical analysis showed that there was a significant difference between the CR and PR groups ( t = 4.258 , P = 0.001 ) as well as between PR and NR groups ( t = 8.48,P = 0.001 ) . CONCLUSIONS Using a simple and reliable whole-body scintigraphic technique to calculate prospect ively the bone uptake rate , we have , for the first time in China , reported the relationship between bone uptake rate and therapeutic effect . This allows nuclear medicine physicians to calculate a safe and effective dose of (153)Sm-EDTMPin individual patients to palliate bone cancer pain without myelotoxicity

Intervention strength was positively correlated with reporting of positive anthropometric outcomes for physical activity , diet , and combined interventions , and parent engagement components increased the strength of these relationships . Study quality was modestly related to percent successful healthy eating outcomes . Relationships between intervention strength and behavioral outcomes demonstrated negative relationships for all behavioral outcomes . Specific components of intervention strength ( number of intervention strategies , potential impact of strategies , frequency of use , and duration of intervention ) were correlated with some of the anthropometric and parent engagement outcomes . The review provided tentative evidence that multi-component , multi-level ECE interventions with parental engagement are most likely to be effective with anthropometric outcomes

TIME AND PLACE OF STUDY 2010 - 2015 ; INTERNATIONAL : Given the high levels of obesity in young children , numbers of children in out-of-home care , and data suggesting a link between early care and education ( ECE ) participation and overweight/obesity , obesity prevention in ECE setting s is critical . As the field has progressed , a number of interventions have been review ed yet there is a need to summarize the data using more sophisticated analyses to answer questions on the effectiveness of interventions . We conducted a systematic review of obesity prevention interventions in center-based ECE setting s published between 2010 and 2015 . Our goal was to identify promising intervention characteristics associated with successful behavioral and anthropometric outcomes .

Background Many unhealthy dietary and physical activity habits that foster the development of obesity are established by the age of five . Presently , approximately 70 percent of children in the United States are currently enrolled in early childcare facilities , making this an ideal setting to implement and evaluate childhood obesity prevention efforts . We describe here the methods for conducting an obesity prevention r and omized trial in the child care setting . Methods / design A r and omized , controlled obesity prevention trial is currently being conducted over a three year period ( 2010-present ) . The sample consists of 28 low-income , ethnically diverse child care centers with 1105 children ( sample is 60 % Hispanic , 15 % Haitian , 12 % Black , 2 % non-Hispanic White and 71 % of caregivers were born outside of the US ) . The purpose is to test the efficacy of a parent and teacher role-modeling intervention on children ’s nutrition and physical activity behaviors . . The Healthy Caregivers-Healthy Children ( HC2 ) intervention arm schools received a combination of ( 1 ) implementing a daily curricula for teachers/parents ( the nutritional gatekeepers ) ; ( 2 ) implementing a daily curricula for children ; ( 3 ) technical assistance with meal and snack menu modifications such as including more fresh and less canned produce ; and ( 4 ) creation of a center policy for dietary requirements for meals and snacks , physical activity and screen time . Control arm schools received an attention control safety curriculum . Major outcome measures include pre-post changes in child body mass index percentile and z score , fruit and vegetable and other nutritious food intake , amount of physical activity , and parental nutrition and physical activity knowledge , attitudes , and beliefs , defined by intentions and behaviors . All measures were administered at the beginning and end of the school year for year one and year two of the study for a total of 4 longitudinal time points for assessment . Discussion Although few attempts have been made to prevent obesity during the first years of life , this period may represent the best opportunity for obesity prevention . Findings from this investigation will inform both the fields of childhood obesity prevention and early childhood research about the effects of an obesity prevention program housed in the childcare setting .Trial registration Trial registration number : This pilot study examined the effects of a teacher-taught , locomotor skill (LMS)-based physical activity ( PA ) program on the LMS and PA levels of minority preschooler-aged children . Eight low-socioeconomic status preschool classrooms were r and omized into LMS-PA ( LMS-oriented lesson plans ) or control group ( supervised free playtime ) . Interventions were delivered for 30 min/day , five days/week for six months . Changes in PA ( accelerometer ) and LMS variables were assessed with MANCOVA . LMS-PA group exhibited a significant reduction in during-preschool ( F ( 1,16 ) = 6.34 , p = .02 , d = 0.02 ) and total daily ( F ( 1,16 ) = 9.78 , p = .01 , d = 0.30 ) percent time spent in sedentary activity . LMS-PA group also exhibited significant improvement in leaping skills , F ( 1 , 51 ) = 7.18 , p = .01 , d = 0.80 ) . No other , significant changes were observed . The implementation of a teacher-taught , LMS-based PA program could potentially improve LMS and reduce sedentary time of minority preschoolers INTRODUCTION A pilot intervention was conducted to promote physical activity and nutrition in public preschool education ( near half a million children in Chile ) , in order to prevent obesity . OBJECTIVE To assess the primary ( body fat ) and secondary outcomes ( physical activity and energy intake ) of a nutrition and physical activity pilot intervention for preschool children , attending day care centres . METHODS A pilot intervention in six day care centres selected at r and om ( n = 530 ) , in 4 - 5 years old preschool children , Santiago , Chile intending to : provide nutritional and physical activity education to educators and health promotion activities for the family , which in turn , will affect the primary ( body fat ) , and secondary outcomes ( physical activity pattern and energy food intake ) were measured in a representative sub sample of 120 intervened and 145 controls children . RESULTS In relation to secondary outcomes monitoring , moderate-vigorous activity was duplicated in the intervention group ( + 5.4 % and + 4.7 % , respectively ) , in both obese and eutrophic children . Energy intake decreased in 11.7 % in obese and 7.5 % in eutrophic children . Dietary fat intake was reduced ( -11 g in obese and -8.4 g in eutrophic children ) . Intervened obese children reduced body fat in 1.5 % , meanwhile in control obese children , body fat increased 1.3 % ( p < 0.01 ) . CONCLUSIONS The pilot intervention demonstrated the feasibility to influence dietary risk factors and physical activity at the day care centres and families . Therefore , the implementation of the vali date d intervention program will be tested in different weather conditions , to prevent unhealthy habits in preschool children and their families Objective To assess the effect of a governmentally-led center based child care physical activity program ( Youp’là Bouge ) on child motor skills . Patients and methods We conducted a single blinded cluster r and omized controlled trial in 58 Swiss child care centers . Centers were r and omly selected and 1:1 assigned to a control or intervention group . The intervention lasted from September 2009 to June 2010 and included training of the educators , adaptation of the child care built environment , parental involvement and daily physical activity . Motor skill was the primary outcome and body mass index ( BMI ) , physical activity and quality of life secondary outcomes . The intervention implementation was also assessed . Results At baseline , 648 children present on the motor test day were included ( age 3.3 ± 0.6 , BMI 16.3 ± 1.3 kg/m2 , 13.2 % overweight , 49 % girls ) and 313 received the intervention . Relative to children in the control group ( n = 201 ) , children in the intervention group ( n = 187 ) showed no significant increase in motor skills ( delta of mean change ( 95 % confidence interval : -0.2 ( −0.8 to 0.3 ) , p = 0.43 ) or in any of the secondary outcomes . Not all child care centers implemented all the intervention components . Within the intervention group , several predictors were positively associated with trial outcomes : 1 ) free-access to a movement space and parental information session for motor skills 2 ) highly motivated and trained educators for BMI 3 ) free-access to a movement space and purchase of mobile equipment for physical activity ( all p < 0.05 ) . Conclusion This “ real-life ” physical activity program in child care centers confirms the complexity of implementing an intervention outside a study setting and identified potentially relevant predictors that could improve future programs . Trial registration Clinical trials.gov OBJECTIVE The purpose of the present study was to evaluate the effects of a school-based , 2-year , multi-component intervention on BMI , eating and physical activity behaviour in Fl and ers , Belgium , targeting children aged 3 - 6 years in communities of high and low socio-economic status ( SES ) . DESIGN Cluster-r and omized controlled trial . SETTING Thirty-one pre- primary and primary schools in three different intervention communities and three paired-matched ( on SES profile ) control communities in Fl and ers , Belgium . SUBJECTS BMI Z-scores at baseline and follow-up were calculated for 1102 children . Question naires with sociodemographic data and FFQ were available from 694 of these 1102 children . RESULTS No significant effects were found on BMI Z-scores for the total sample . However , there was a significant decrease in BMI Z-score of 0·11 in the low-SES intervention community compared with the low-SES control community , where the BMI Z-score increased by 0·04 ( F = 6·26 , P = 0·01 ) . No significant intervention effects could be found for eating behaviour , physical activity or screen-time . There were no significant interaction effects of age and gender of the children on the outcome variables . CONCLUSIONS Although no significant effects were found for BMI Z-scores in the total sample , this intervention had a promising effect in the low-SES community of reducing excess weight gain among young children This pilot aims to better underst and the market for childcare in Saudi Arabia – both the supply and dem and sides – and to design a r and omized controlled experiment to test whether access to affordable day care ( in the form of subsidies , for example ) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired . In addition , the study seeks to underst and the degree to which employment early on in one ’s life impacts employment in later stages . The pilot will provide information on the groups of women the experiment should target , appropriate levels for the childcare subsidy , and the quality and current geographic locations of daycare sites . Expected Impact Determine the effects of facilitating childcare access on Saudi women ’s employment . PRINCIPAL INVESTIGATORS  Boston University Patricia Cortes  Harvard University Claudia Goldin  Swarthmore College Jennifer OBJECTIVE Determine whether Color Me Healthy ( CMH ) , an interactive nutrition and physical activity program for preschool children , increases fruit and vegetable consumption . DESIGN Intervention study . Data were collected at baseline , 1 week post-intervention , and 3 months post-intervention . SETTING Child care centers . PARTICIPANTS Preschool children ( n = 263 ) in 17 child care centers . INTERVENTION Child care centers were r and omly assigned to 1 of 2 conditions ; children ( n = 165 ) in 10 centers received the CMH curriculum , and children ( n = 98 ) in 7 centers acted as comparisons and did not receive the curriculum . MAIN OUTCOME MEASURES Process and outcome evaluation . Consumption of fruit and vegetable snacks . ANALYSIS Data were analyzed using repeated- measures analysis of variance and hierarchical linear modeling . RESULTS Children who received CMH significantly increased their consumption of fruit snacks by approximately 20.8 % and vegetable snacks by approximately 33.1 % between baseline assessment and the assessment conducted 3 months after the completion of the CMH program . Hierarchical linear modeling determined that group assignment ( ie , CMH or control ) was the only significant predictor of fruit and vegetable consumption . CONCLUSIONS AND IMPLICATION S Findings suggest that CMH may be used in child care setting s for developing healthful eating habits Early childhood is a critical time for promoting physical activity . Few studies have investigated the effect of interventions in this population . The aim of this study was to investigate the effect of a school-based active play intervention on preschool children 's sedentary time and physical activity . Preschool children were recruited from r and omly selected preschools . Schools were r and omly assigned to an intervention or comparison group . One teacher per intervention school received training from active play professionals in the delivery of a 6-week active play programme . Comparison schools continued their usual practice . Children wore a uni-axial accelerometer for 7 days at baseline , immediately after and at 6-month post-intervention . No significant intervention effects were observed for sedentary time or physical activity . However , sex and hours spent at school were significant predictors of physical activity . Children who spent fewer hours ( half-day children ) at school were significantly more active than their full-day counterparts . Physical activity during the intervention classes was high even though neither daily physical activity nor sedentary time changed . Notably children who spent more time at preschool were less active suggesting that preschool was not as conducive to physical activity engagement as other environments Background To address the public health crisis of overweight and obese preschool-age children , the Nutrition And Physical Activity Self Assessment for Child Care ( NAP SACC ) intervention was delivered by nurse child care health consultants with the objective of improving child care provider and parent nutrition and physical activity knowledge , center-level nutrition and physical activity policies and practice s , and children ’s body mass index ( BMI ) . Methods A seven-month r and omized control trial was conducted in 17 licensed child care centers serving predominantly low income families in California , Connecticut , and North Carolina , including 137 child care providers and 552 families with racially and ethnically diverse children three to five years old . The NAP SACC intervention included educational workshops for child care providers and parents on nutrition and physical activity and consultation visits provided by trained nurse child care health consultants . Demographic characteristics and pre - and post-workshop knowledge surveys were completed by providers and parents . Blinded research assistants review ed each center ’s written health and safety policies , observed nutrition and physical activity practice s , and measured r and omly selected children ’s nutritional intake , physical activity , and height and weight pre- and post-intervention . Results Hierarchical linear models and multiple regression models assessed individual- and center-level changes in knowledge , policies , practice s and age- and sex-specific st and ardized body mass index ( z BMI ) , controlling for state , parent education , and poverty level . Results showed significant increases in providers ’ and parents ’ knowledge of nutrition and physical activity , center-level improvements in policies , and child-level changes in children ’s z BMI based on 209 children in the intervention and control centers at both pre- and post-intervention time points . Conclusions The NAP SACC intervention , as delivered by trained child health professionals such as child care health consultants , increases provider knowledge , improves center policies , and lowers BMI for children in child care centers . More health professionals specifically trained in a nutrition and physical activity intervention in child care are needed to help reverse the obesity epidemic . Trial registration National Clinical Trials Number This study examined the effect of an early childhood obesity prevention program on changes in Body Mass Index ( BMI ) z-score and nutrition practice s. Eight child care centers were r and omly assigned to an intervention or attention control arm . Participants were a multiethnic sample of children aged 2 to 5 years old ( N = 307 ) . Intervention centers received healthy menu changes and family-based education focused on increased physical activity and fresh produce intake , decreased intake of simple carbohydrate snacks , and decreased screen time . Control centers received an attention control program . Height , weight , and nutrition data were collected at baseline and at 3 , 6 , and 12 months . Analysis examined height , weight , and BMI z-score change by intervention condition ( at baseline and at 3 , 6 , and 12 months ) . Pearson correlation analysis examined relationships among BMI z-scores and home activities and nutrition patterns in the intervention group . Child BMI z-score was significantly negatively correlated with the number of home activities completed at 6-month post intervention among intervention participants . Similarly , intervention children consumed less junk food , ate more fresh fruits and vegetables , drank less juice , and drank more 1 % milk compared to children at control sites at 6 months post baseline . Ninety-seven percent of those children who were normal weight at baseline were still normal weight 12 months later . Findings support child care centers as a promising setting to implement childhood obesity prevention programs in this age group OBJECTIVE A multidimensional lifestyle intervention performed in 652 preschoolers ( 72 % of migrant , 38 % of low educational level ( EL ) parents ) reduced body fat , but not BMI and improved fitness . The objective of this study is to examine whether the intervention was equally effective in children of migrant and /or low EL parents . METHODS Cluster-r and omized controlled single blinded trial , conducted in 2008/09 in 40 r and omly selected preschools in Switzerl and . The culturally tailored intervention consisted of a physical activity program and lessons on nutrition , media use and sleep . Primary outcomes included BMI and aerobic fitness . Secondary outcomes included % body fat , waist circumference and motor agility . RESULTS Children of migrant parents benefitted similarly from the intervention compared to their counterparts ( p for interaction≥ 0.09 ) . However , children of low EL parents benefitted less , although these differences did not reach statistical significance ( p for interaction≥ 0.06 ) . Average intervention effect sizes for BMI were -0.10 , -0.05 , -0.11 and 0.04 kg/m(2 ) and for aerobic fitness were 0.55 , 0.20 , 0.37 and -0.05 stages for children of non-migrant , migrant , middle/high EL and low EL parents , respectively . CONCLUSIONS This intervention was similarly effective among preschoolers of migrant parents compared to their counterparts , while children of low EL parents benefitted less Purpose . Examine the effectiveness of the “ Eat Healthy , Stay Active ! ” pilot program , a multisite , 6-month educational intervention to promote healthy nutrition and physical activity among Head Start staff , parents , and children . Design . Comparison of within-group preintervention and postintervention knowledge and behavior , along with anthropomorphic measurements . Setting . The study was conducted in a convenience sample of six large Head Start agencies in five states . Subjects . Participants included 496 staff , 438 parents , and 112 preschool children . Intervention . The 6-month intervention consisted of core trainings and reinforcing activities for staff and parents that aligned with children 's curricula . Measures . Pre-post question naires and anthropometric measurements examined changes in body mass index ( BMI ) , knowledge , and behaviors related to nutrition and physical activity . Analysis . Paired t-tests to compare preintervention and postintervention weights and BMI ; multiple regression analyses to examine associations between weight changes and other covariates , including knowledge and behavior changes , controlling for sociodemographic variables . Results . Each group of participants demonstrated significant reductions in BMI ( mean = 30.1 to 29.2 ; p < .001 in adults and 17.0 to 16.6 ; p < 0.001 in children ) and in the proportion of obese children ( 30 % to 21 % ; p < .001 ) and adults ( 45 % to 40 % ; p < .001 ) . Child weight changes correlated with parent weight changes . Conclusion . This intervention showed promising initial results , with potential effectiveness as an intervention to promote healthier behaviors among adults and children in Head Start setting The aim of this study was to assess the feasibility , acceptability and potential efficacy of a physical activity program for preschool children . A 20-week , 2-arm parallel cluster r and omized controlled pilot trial was conducted . The intervention comprised structured activities for children and professional development for staff . The control group participated in usual care activities , which included design ated inside and outside playtime . Primary outcomes were movement skill development and objective ly measured physical activity . At follow-up , compared with children in the control group , children in the intervention group showed greater improvements in movement skill proficiency , with this improvement statically significant for overall movement skill development ( adjust diff . = 2.08 , 95 % CI 0.76 , 3.40 ; Cohen 's d = 0.47 ) and significantly greater increases in objective ly measured physical activity ( counts per minute ) during the preschool day ( adjust diff . = 110.5 , 95 % CI 33.6 , 187.3 ; Cohen 's d = 0.46 ) . This study demonstrates that a physical activity program implemented by staff within a preschool setting is feasible , acceptable and potentially efficacious Background Early childhood services have been identified as a key setting for promoting healthy eating and physical activity as a means of preventing overweight and obesity . However , there is limited evidence on effective nutrition and physical activity programs in this setting . The purpose of this study was to evaluate Munch and Move , a low-intensity , state-wide , professional development program design ed to support early childhood professionals to promote healthy eating and physical activity among children in their care . Methods The evaluation involved 15 intervention and 14 control preschools ( n = 430 ; mean age 4.4 years ) in Sydney , New South Wales , Australia and was based on a r and omised-control design with pre and post evaluation of children 's lunchbox contents , fundamental movement skills ( FMS ) , preschool policies and practice s and staff attitudes , knowledge and confidence related to physical activity , healthy eating and recreational screen time . Results At follow up , FMS scores for locomotor , object control and total FMS score significantly improved by 3.4 , 2.1 and 5.5 points more ( respectively ) in the intervention group compared with the control group ( P < 0.001 ) and the number of FMS sessions per week increased by 1.5 ( P = 0.05 ) . The lunchbox audit showed that children in the intervention group significantly reduced sweetened drinks by 0.13 serves ( i.e. , 46 ml ) ( P = 0.05 ) . Conclusion The findings suggest that a low intensity preschool healthy weight intervention program can improve certain weight related behaviours . The findings also suggest that change to food policies are difficult to initiate mid-year and potentially a longer implementation period may be required to determine the efficacy of food policies to influence the contents of preschoolers lunchboxes BACKGROUND School programs can be effective in modifying knowledge , attitudes , and habits relevant to long-term risk of chronic diseases associated with sedentary lifestyles . As part of a long-term research strategy , we conducted an educational intervention in preschool facilities to assess changes in preschoolers ' knowledge , attitudes , and habits toward healthy eating and living an active lifestyle . METHODS Using a cluster design , we r and omly assigned 14 preschool facilities in Bogotá , Colombia to a 5-month educational and playful intervention ( 7 preschool facilities ) or to usual curriculum ( 7 preschool facilities ) . A total of 1216 children aged 3 - 5 years , 928 parents , and 120 teachers participated . A structured survey was used at baseline , at the end of the study , and 12 months later to evaluate changes in knowledge , attitudes , and habits . RESULTS Children in the intervention group showed a 10.9 % increase in weighted score , compared with 5.3 % in controls . The absolute adjusted difference was 3.90 units ( 95 % confidence interval [ CI ] , 1.64 - 6.16 ; P < .001 ) . Among parents , the equivalent statistics were 8.9 % and 3.1 % , respectively ( absolute difference 4.08 units ; 95 % CI , 2.03 to 6.12 ; P < .001 ) , and among teachers , 9.4 % and 2.5 % , respectively ( absolute difference 5.36 units ; 95 % CI , -0.29 - 11.01 ; P = .06 ) . In the intervened cohort 1 year after the intervention , children still showed a significant increase in weighted score ( absolute difference of 6.38 units ; P < .001 ) . CONCLUSIONS A preschool-based intervention aim ed at improving knowledge , attitudes , and habits related to healthy diet and active lifestyle is feasible , efficacious , and sustainable in very young children Background The onset of inadequate behaviors leading to the development of risk factors for chronic diseases is known to occur early in life . An effective program for health promotion should therefore focus on children and their environment , as the starting point for behavior development . The overarching objective of the Program SI ! ( Salud Integral - Comprehensive Health ) is to intervene at the school level , to establish and develop life-lasting habits that will help preserving health during adulthood . The Program SI ! comprises five consecutive subprograms according to the five stages of education in Spain , the first being in preschoolers . This study aims to evaluate the efficacy of Program SI ! to establish and improve lifestyle behaviors in children ( preschoolers aged 3–5 years ) , their parents , and teachers , and also improving the school environment . A secondary objective is to evaluate improvements in cardiovascular health-related markers ( anthropometric parameters , blood pressure , and dietary and physical activity patterns ) in these same children . Methods / design 24 public schools from the city of Madrid ( Spain ) were allocated through stratified r and omization to intervention or control . The intervention schools follow the Program SI ! , which provides didactic units , emotions cards , healthy tips , and online re sources . The intervention schools integrate the Program SI ! into their scholar curriculum organized in four complete weeks during each academic year during the 3 years of preschool education . Control schools follow their normal curriculum . Primary outcomes are 1-year , and 3-year changes from baseline of scores for knowledge , attitudes , and habits ( KAH ) of children , their parents and teachers in regards to a healthy lifestyle . Secondary outcomes are 1-year , and 3-year changes from baseline in clinical and anthropometric parameters of children . Discussion The Program SI ! is a long-term health promotion program starting in 3 years old . It incorporates the traditional areas of intervention ( diet and physical activity ) , introducing additional components such as knowledge of the human body and management of emotions to achieve a comprehensive intervention . The Program SI ! is design ed to be an effective , sustainable health promotion program for the adoption of healthy behaviors from early in life . Trial registration Trial registration number : Background Physical activity and motor skills acquisition are of high importance for health-related prevention and a normal development in childhood . However , few intervention studies exist in preschool children focussing on an increase in physical activity and motor skills . Proof of positive effects is available but not consistent . Methods / Design The design , curriculum , and evaluation strategy of a cluster r and omised intervention study in preschool children are described in this manuscript . In the Prevention through Activity in Kindergarten Trial ( PAKT ) , 41 of 131 kindergartens of Wuerzburg and Kitzingen , Germany , were r and omised into an intervention and a control group by a r and om number table stratified for the location of the kindergarten in an urban ( more than 20.000 inhabitants ) or rural area . The aims of the intervention were to increase physical activity and motor skills in the participating children , and to reduce health risk factors as well as media use . The intervention was design ed to involve children , parents and teachers , and lasted one academic year . It contained daily 30-min sessions of physical education in kindergarten based on a holistic pedagogic approach termed the " early psychomotor education " . The sessions were instructed by kindergarten teachers under regular supervision by the research team . Parents were actively involved by physical activity homework cards . The kindergarten teachers were trained in workshops and during the supervision . Assessment s were performed at baseline , 3 - 5 months into the intervention , at the end of the intervention and 2 - 4 months after the intervention . The primary outcomes of the study are increases in physical activity ( accelerometry ) and in motor skills performance ( composite score of obstacle course , st and ing long jump , balancing on one foot , jumping sidewise to and fro ) between baseline and the two assessment s during the intervention . Secondary outcomes include decreases in body adiposity ( BMI , skin folds ) , media use ( question naire ) , blood pressure , number of accidents and infections ( question naire ) , increases in specific motor skills ( throwing , balancing , complex motor performance , jumping ) and in flexibility . Discussion If this trial proofs the effectiveness of the multilevel kindergarten based physical activity intervention on preschooler 's activity levels and motor skills , the programme will be distributed nationwide in Germany . Trial Registration Clinical Trials.gov Identifier : Background Strategies to increase fruit and vegetable consumption of preschool aged children are needed . Objectives Evaluate the independent effects of the following meal service strategies on intake of fruits and vegetables of preschool children : 1 . ) Serving fruits and vegetables in advance of other menu items as part of traditional family style meal service ; and 2 . ) Serving meals portioned and plated by providers . Methods Fifty-three preschool aged children completed a r and omized crossover experiment conducted at a Head Start center in Minneapolis , MN . Over a six week trial period each of the experimental meal service strategies ( serving fruits and vegetable first and serving meals portioned by providers ) was implemented during lunch service for two one-week periods . Two one-week control periods ( traditional family style meal service with all menu items served at once ) were also included over the six week trial period . Childrens lunch intake was observed as a measure of food and nutrient intake during each experimental condition . Results Fruit intake was significantly higher ( p<0.01 ) when fruits and vegetables were served in advance of other meal items ( 0.40 servings/meal ) compared to the traditional family style meal service control condition when they were served in t and em with other menu items ( 0.32 servings/meal ) . Intakes of some nutrients found in fruits ( vitamin A and folate ) were concomitantly higher . In contrast , fruit and vegetable intakes were significantly lower and energy intake significantly higher during the provider portioned compared with control condition . Conclusions Serving fruits in advance of other meal items may be a low cost easy to implement strategy for increasing fruit intake in young children . However , serving vegetables first does not appear to increase vegetable intake . Results provide support for current recommendations for traditional family style meal service in preschool setting Objective To test the effect of a multidimensional lifestyle intervention on aerobic fitness and adiposity in predominantly migrant preschool children . Design Cluster r and omised controlled single blinded trial ( Ballabeina study ) over one school year ; r and omisation was performed after stratification for linguistic region . Setting 40 preschool classes in areas with a high migrant population in the German and French speaking regions of Switzerl and . Participants 652 of the 727 preschool children had informed consent and were present for baseline measures ( mean age 5.1 years ( SD 0.7 ) , 72 % migrants of multicultural origins ) . No children withdrew , but 26 moved away . Intervention The multidimensional culturally tailored lifestyle intervention included a physical activity programme , lessons on nutrition , media use ( use of television and computers ) , and sleep and adaptation of the built environment of the preschool class . It lasted from August 2008 to June 2009 . Main outcome measures Primary outcomes were aerobic fitness ( 20 m shuttle run test ) and body mass index ( BMI ) . Secondary outcomes included motor agility , balance , percentage body fat , waist circumference , physical activity , eating habits , media use , sleep , psychological health , and cognitive abilities . Results Compared with controls , children in the intervention group had an increase in aerobic fitness at the end of the intervention ( adjusted mean difference : 0.32 stages ( 95 % confidence interval 0.07 to 0.57 ; P=0.01 ) but no difference in BMI ( −0.07 kg/m2 , −0.19 to 0.06 ; P=0.31 ) . Relative to controls , children in the intervention group had beneficial effects in motor agility ( −0.54 s , −0.90 to −0.17 ; P=0.004 ) , percentage body fat ( −1.1 % , −2.0 to −0.2 ; P=0.02 ) , and waist circumference ( −1.0 cm , −1.6 to −0.4 ; P=0.001 ) . There were also significant benefits in the intervention group in reported physical activity , media use , and eating habits , but not in the remaining secondary outcomes . Conclusions A multidimensional intervention increased aerobic fitness and reduced body fat but not BMI in predominantly migrant preschool children . Trial registration Clinical Trials NCT00674544 Background Unhealthy lifestyles contribute to the development of cardiovascular risk factors , whose incidence is increasing among children and adolescents . The Program SI ! is a long-term , multi-target behavioral intervention to promote healthy lifestyle habits in children through the school environment . The objective of the study is to evaluate the efficacy of this intervention in its first phase , preschoolers . Methods Cluster-r and omized controlled trial in public schools in the city of Madrid , Spain . A total 24 schools , including 2062 children ( 3–5 years ) , 1949 families , and 125 teachers participated in the study . Schools were assigned to their usual school curriculum or to engage in an additional multi-component intervention ( Program SI ! ) . The primary outcome of this trial is 1-school year changes from baseline in scores for children ’s knowledge , attitudes and habits ( KAH ) . Secondary outcomes are 1-school year changes from baseline in scores for knowledge , attitudes , and habits among parents , teachers , and the school environment . Results After 1-school year , our results indicate that the Program SI ! intervention increases children ’s KAH scores , both overall ( 3.45 , 95 % CI , 1.84 - 5.05 ) and component-specific ( Diet : 0.93 , 95 % CI , 0.12 - 1.75 ; Physical activity : 1.93 , 95 % CI , 1.17 - 2.69 ; Human body : 0.65 , 95 % CI , 0.07 - 1.24 ) score . Conclusions The Program SI ! is demonstrated as an effective and feasible strategy for increasing knowledge and improving lifestyle attitudes and habits among very young children . Trial registration NCT01579708 , Evaluation of the Program SI ! for Preschool Education : A School-Based R and omized Controlled Trial ( Preschool-SI ! ) Background Young children are not participating in recommended levels of physical activity and exhibit high levels of sedentary behaviour . Childcare services provide access to large numbers of young children for prolonged periods , yet there is limited experimental evidence regarding the effectiveness of physical activity interventions implemented in this setting . The aim of this study is to assess the effectiveness and acceptability of a multi-component physical activity intervention , delivered by childcare service staff , in increasing the physical activity levels of children attending long day care services . Methods / Design The study will employ a cluster r and omised controlled trial design . Three hundred children aged between 3 - 5 years from twenty r and omly selected long day care services in the Hunter Region of New South Wales , Australia will be invited to participate in the trial . Ten of the 20 long day care services will be r and omly allocated to deliver the intervention with the remaining ten services allocated to a wait list control group . The physical activity intervention will consist of a number of strategies including : delivering structured fundamental movement skill activities , increasing physical activity opportunities , increasing staff role modelling , providing children with a physical activity promoting indoor and outdoor environment and limiting children 's small screen recreation and sedentary behaviours . Intervention effectiveness will be measured via child physical activity levels during attendance at long day care . The study also seeks to determine the acceptability and extent of implementation of the intervention by services and their staff participating in the study . Discussion The trial will address current gaps in the research evidence base and contribute to the design and delivery of future interventions promoting physical activity for young children in long day care setting s . Trial registration Australian New Zeal and Clinical Trials Registry The purpose of this repeated exposure , r and omized , cross-over quasi-experimental study was to determine the individual and combined impact of ( a ) the timing of serving dessert and ( b ) portion size of main course in 2 - 5 year old children ( n=23 ) on energy intake at lunch in a childcare setting . Children were served two study lunches ( fish or pasta , each with dessert ) twice a week for 12 weeks that differed in the timing of dessert ( served with or after the main course ) and portion size of the main course ( reference portion or 50 % larger portion ) . Analyses of variance revealed that serving dessert after the meal result ed in higher energy intakes from both the main course and from dessert , and therefore greater total intake at the meal . Portion size of the main course did not influence total energy intake at the meal . Results indicate that the timing of serving dessert affects children 's energy intake regardless of the portion size of the main course . Specifically , serving dessert with the meal reduces total energy intake regardless of the main course portion size . This suggests that offering dessert with the main course may be an effective strategy for decreasing total energy intake at meals in preschool-aged children The preschool years offer an opportunity to interrupt the trajectory toward obesity in black children . The Hip-Hop to Health Jr. Obesity Prevention Effectiveness Trial was a group-r and omized controlled trial assessing the feasibility and effectiveness of a teacher-delivered weight control intervention for black preschool children . The 618 participating children were enrolled in 18 schools administered by the Chicago Public Schools . Children enrolled in the nine schools r and omized to the intervention group received a 14-week weight control intervention delivered by their classroom teachers . Children in the nine control schools received a general health intervention . Height and weight , physical activity , screen time , and diet data were collected at baseline and postintervention . At postintervention , children in the intervention schools engaged in more moderate-to-vigorous physical activity ( MVPA ) than children in the control schools ( difference between adjusted group means = 7.46 min/day , P = 0.02 ) . Also , children in the intervention group had less total screen time ( -27.8 min/day , P = 0.05 ) . There were no significant differences in BMI , BMI Z score , or dietary intake . It is feasible to adapt an obesity prevention program to be taught by classroom teachers . The intervention showed positive influences on physical activity and screen time , but not on diet . Measuring diet and physical activity in preschool children remains a challenge , and interventions delivered by classroom teachers require both intensive initial training and ongoing individualized supervision BACKGROUND Previous studies on physical activity interventions in preschools have reported limited effectiveness . Participatory community-based approaches hold promise for increasing intervention effectiveness and involving parents as key stakeholders in a sustainable way . PURPOSE To assess whether a participatory parent-focused approach using parents as agents of behavioral change enhances the efficacy of a preschool physical activity ( PA ) intervention . DESIGN Two-armed , cluster- RCT with preschool as unit of r and omization and children as unit of analysis . SETTING / PARTICIPANTS 39 South German preschools applying for an existing state-sponsored PA program with 826 children ( 52 % boys , aged 5.0±0.2 years ) , with 441 allocated to the intervention arm . INTERVENTION Control preschools received a state-sponsored program consisting of twice-weekly gym classes over 6 months . In intervention preschools , this program was augmented by motivating parents to develop and implement their own project ideas for promoting children 's PA . MAIN OUTCOME MEASURES Primary outcomes included mean accelerometry counts and time spent in moderate- to vigorous-intensity PA or sedentary behavior . Secondary outcomes were BMI , percentage body fat , quality of life , sleep quality , and general health . Outcomes were measured at baseline and at 6 and 12 months in both study arms ( time period : 2008 - 2010 ) . Using an intention-to-treat- analysis , linear multilevel regression models assessed change over time and across study arms , adjusted for age , gender , season , and preschool location . Analysis was conducted in 2011 . RESULTS In 15 intervention preschools , parents implemented 25 PA projects . Compared with controls , intervention arm children were 11 minutes less sedentary per day ( 95 % CI=5.39 , 17.01 , p=0.014 ) ; had significantly more mean accelerometry counts ( 1.4 counts/15 seconds [ 95 % CI=0.22 , 2.54 ] , p=0.019 ) ; and showed benefits in perceived general health and quality of life . All other outcomes showed no difference between study arms . CONCLUSIONS A participatory preschool intervention focusing on parents as agents of behavioral change may be able to promote PA and reduce sedentary behavior in preschoolers . These benefits may go beyond the effects of existing nonparticipatory interventions . TRIAL REGISTRATION This study is registered at clinical trials.gov NCT00987532 OBJECTIVE The role of diet quality and nutrient adequacy in the etiology of childhood obesity is poorly understood . The specific aims of these analyses were to assess overall diet quality and nutrient adequacy , and test for association between weight status and diet in children from low socioeconomic status ( SES ) Hispanic families at high risk for obesity . DESIGN A cross-sectional study design was used to assess dietary intake in low-SES Hispanic children with and without overweight who were enrolled in the Viva la Familia Study . Multiple-pass 24-hour dietary recalls were recorded on two r and om , weekday occasions . Diet quality was evaluated according to the Dietary Guidelines for Americans . Nutrient adequacy was assessed using z scores based on estimated average requirement or adequate intake . SUBJECTS/ SETTING The study included 1,030 Hispanic children and adolescents , aged 4 to 19 years , in Houston , TX , who participated between November 2000 and August 2004 . STATISTICAL ANALYSIS STATA software ( version 9.1 , 2006 , STATA Corp , College Station , TX ) was used for generalized estimating equations and r and om effects regression . RESULTS Diet quality did not adhere to the Dietary Guidelines for Americans for fat , cholesterol , saturated fatty acids , fiber , added sugar , and sodium . Although energy intake was significantly higher in children with overweight , food sources , diet quality , macro- and micronutrient composition were similar between non-overweight and overweight children . Relative to estimated average requirements or adequate intake levels , mean nutrient intakes were adequate ( 70 % to 98 % probability ) in the children without and with overweight , except for vitamins D and E , pantothenic acid , calcium , and potassium , for which z scores can not be interpreted given the uncertainty of their adequate intake levels . CONCLUSIONS Whereas the diets of low-SES Hispanic children with and without overweight were adequate in most essential nutrients , other components of a healthful diet , which promote long-term health , were suboptimal . Knowledge of the diets of high-risk Hispanic children will inform nutritional interventions and policy OBJECTIVE To assess the short-term impact of a nutritional intervention aim ed at reducing childhood overweight in German pre-school children . DESIGN Using a cluster-r and omized study design with waiting-list controls , we tested a 6-month intervention administered once weekly by a nutrition expert consisting of joint meal preparation and activities for children and parents such as tasting and preparing nutritious , fresh foods . At baseline , 6 and 12 months , a parent-completed question naire assessed fruit and vegetable intakes ( primary outcomes ) and water and sugared drinks consumption ( secondary outcomes ) . Direct measurement assessed BMI , skinfold thickness and waist-to-height-ratio . An intention-to-treat analysis used r and om-effects panel regression models to assess the intervention effect , adjusted for each child 's age , gender , immigrant background and maternal education . SETTING Eighteen pre-schools from three south German regions . SUBJECTS Healthy children aged 3 - 6 years . RESULTS Three hundred and seventy-seven ( 80 % ) eligible pre-school children participated in the study . Of these , 348 provided sufficient data for analysis . The sample mean age was 4·26 ( sd 0·78 ) years ; the majority ( 53·2 % ) were boys . Children 's fruit and vegetable intakes increased significantly ( P < 0·001 and P < 0·05 , respectively ) ; no significant changes in the consumption of water , sugared drinks or anthropometric measurements were noted . CONCLUSIONS Nutritional interventions in pre-schools have the potential to change eating behaviours in young children , which in the long term might reduce risk for developing overweight BACKGROUND The preschool years offer a unique window of opportunity to instill healthy life-style behaviors and promote cardiovascular health . OBJECTIVES This study sought to evaluate the effect of a 3-year multidimensional school-based intervention to improve life-style-related behaviors . METHODS We performed a cluster-r and omized controlled intervention trial involving 24 public schools in Madrid , Spain , that were assigned to either the SI ! Program intervention or the usual curriculum and followed for 3 years . The SI ! Program aim ed to instill and develop healthy behaviors in relation to diet , physical activity , and underst and ing how the human body and heart work . The primary outcome was change in the overall knowledge , attitudes , and habits ( KAH ) score ( range 0 to 80 ) . The intervention 's effect on adiposity markers was also evaluated . RESULTS A total of 2,062 children from 3 to 5 years of age were r and omized . After 3 years of follow-up , the overall KAH score was 4.9 % higher in children in the intervention group compared with the control group ( 21.7 vs. 16.4 ; p < 0.001 ) . A peak effect was observed at the second year ( improvement 7.1 % higher than in the control group ; p < 0.001 ) . Physical activity was the main driver of the change in KAH at all evaluation times . Children in the intervention group for 2 years and 1 year showed greater improvement than control subjects ( 5.9 % ; p < 0.001 and 2.9 % ; p = 0.002 , respectively ) . After 3 years , the intervention group showed a higher probability than the control group of reducing the triceps skinfold z-score by at least 0.1 ( hazard ratio : 1.40 , 95 % confidence interval : 1.04 to 1.89 ; p = 0.027 ) . CONCLUSIONS The SI ! Program is an effective strategy for instilling healthy habits among preschoolers , translating into a beneficial effect on adiposity , with maximal effect when started at the earliest age and maintained over 3 years . Wider adoption may have a meaningful effect on cardiovascular health promotion . ( Evaluation of the Program SI ! for Preschool Education : A School-Based R and omized Controlled Trial [ Preschool_PSI ! ] ; NCT01579708 ) BACKGROUND With evidence of increased levels of obesity in younger children , the child-care setting is an important intervention target . Few environmental interventions exist , and none target both diet and physical activity . The Nutrition and Physical Activity Self- Assessment for Child Care ( NAP SACC ) intervention was developed to fill this research and practice gap . DESIGN R and omized controlled . SETTING / PARTICIPANTS Health professionals ( child-care health consultants ) serving child-care centers in North Carolina were recruited ( n=30 ) , r and omly assigned into intervention or delayed-intervention control groups , and trained to implement the NAP SACC program . Up to three child-care centers were recruited ( n=84 ) from each consultant 's existing caseload . INTERVENTION Implemented in 2005 , the NAP SACC intervention includes an environmental self- assessment , selection of areas for change , continuing education workshops , targeted technical assistance , and re-evaluation . Implementation occurred over a 6-month period . MAIN OUTCOME MEASURES An observational instrument , Environment and Policy Assessment and Observation ( EPAO ) , provided objective evidence of intervention impact and was completed by trained research staff blinded to study assignment . Data were collected in 2005 and 2006 . Statistical analyses were conducted in 2006 . RESULTS Intention-to-treat analysis results were nonsignificant . Exploratory analyses using only centers that completed most of the NAP SACC program suggest an intervention effect . CONCLUSIONS Factors in the intervention design , the fidelity of implementation , the selection of outcome measure , or a combination of these may have contributed to the lack of intervention effect observed . Because of this study 's use of existing public health infrastructure and its potential for implementation , future studies should address strategies for improving effectiveness BACKGROUND The aim of the study was to objective ly determine whether the Nutrition and Physical Activity Self- Assessment for Child Care ( NAP SACC ) program improved physical activity levels during the school day . METHODS The study compared the physical activity levels of subjects from 26 daycare centers , r and omized into treatment ( N=13 ) and control ( N=13 ) groups . The subjects were 3 to 5 year olds ( N=209 , 104 males and 105 females ; age [years]=3.85±0.8 [ mean±st and ard deviation ] ) , and accelerometry was used to determine the subjects ' physical activity levels . Accelerometers were attached to each subject for 2 days before and immediately after a 6-month intervention . Height , mass , and waist were also measured . RESULTS Regression analyses indicated that the treatment group demonstrated significant increases in moderate and vigorous physical activity , as compared to the control group ( F(1 , 207)=6.3 , p<0.05 , Cohen 's d=0.30 ; F(1 , 207)=4.7 , p<0.05 , Cohen 's d=0.25 , respectively ) . The treatment group also showed significant increases in total physical activity ( F(1 , 218)=12.4 ; p<0.05 ) from pre- to post-test with significant increases in moderate and vigorous intensity physical activity ( F(1 , 218)=18.6 , p<0.05 ; F(1 , 218)=23.3 , p<0.05 , respectively ) . Regression analyses revealed significant increases in height for both groups from pre- to post-tests , but no differences were noted between groups . CONCLUSIONS Implementation of the NAP SACC program in treatment daycare facilities result ed in significant increases in objective ly measured physical activity levels , compared to the control group , demonstrating physical activity improvement in the treatment daycare centers OBJECTIVE This study evaluated whether a nutrition-education program in child-care centers improved children 's at-home daily consumption of fruits and vegetables , at-home use of low-fat/fat-free milk , and other at-home dietary behaviors . MATERIAL S AND METHODS Twenty-four child-care centers serving low-income families were matched by region , type , and size , and then r and omly assigned to either an intervention or control condition . In the 12 intervention centers , registered dietitian nutritionists provided nutrition education to children and parents separately during a 6- to 10-week period . They also held two training sessions for center staff , to educate them on healthy eating and physical activity policies at the centers , and distributed weekly parent newsletters that included activities and recipes . Parents ( n=1,143 ) completed a mail or telephone survey at baseline and follow-up to report information on their child 's fruit , vegetable , and milk consumption and other dietary behaviors at home . This study used general and generalized linear mixed models to evaluate program impacts , while accounting for the clustering of children within centers . This study included child age , child sex , household size , respondent race/ethnicity , respondent age , and respondent sex as covariates . RESULTS The program had a substantial impact on children 's at-home daily consumption of vegetables and use of low-fat/fat-free milk . This study also found a significant increase in the frequency of child-initiated vegetable snacking , which might have contributed to the significant increase in vegetable consumption . The program did not have a significant impact on fruit consumption or parental offerings of fruits and vegetables , child-initiated fruit snacking , or child fruit consumption . CONCLUSIONS This intervention in child-care setting s that emphasized children , parents , and teachers significantly increased at-home vegetable and low-fat/fat-free milk consumption among low-income preschoolers INTRODUCTION The preschool years provide a unique window of opportunity to intervene on obesity-related lifestyle risk factors during the formative years of a child 's life . The purpose of this study was to assess the impact of a preschool-based obesity prevention effectiveness trial at 1-year follow-up . DESIGN RCT . SETTING S/ PARTICIPANTS Primarily African American children ( aged 3 - 5 years , N=618 ) attending Head Start preschool programs administered by Chicago Public Schools . METHODS Eighteen preschools were r and omly assigned in 2007 - 2008 to receive either ( 1 ) a 14-week teacher-delivered intervention focused on healthy lifestyle behaviors or ( 2 ) a 14-week teacher-delivered general health curriculum ( control group ) . MAIN OUTCOME MEASURES The primary outcome , BMI , was measured at baseline , postintervention , and 1-year follow-up . Diet and screen time behaviors were also assessed at these time points . Multilevel mixed effects models were used to test for between-group differences . Data were analyzed in 2014 . RESULTS Significant between-group differences were observed in diet , but not in BMI z-score or screen time at 1-year follow-up . Diet differences favored the intervention arm over controls in overall diet quality ( p=0.02 ) and in subcomponents of diet quality , as measured by the Healthy Eating Index-2005 , and in fruit intake ( servings/day , excludes juice ) ( p=0.02 ) . Diet quality worsened more among controls than the intervention group at 1-year follow-up . CONCLUSIONS The adaptation of Hip-Hop to Health Jr. produced modest benefits in diet quality but did not significantly impact weight gain trajectory . Not unlike other effectiveness trials , this real-world version delivered by Head Start teachers produced fewer benefits than the more rigorous efficacy trial . It is important to underst and and build upon the lessons learned from these types of trials so that we can design , implement , and disseminate successful evidence -based programs more widely and effectively . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT00241878 ISSUES ADDRESSED This paper presents the findings from a cluster r and omised controlled evaluation of a preschool-based intervention ( children aged 3 - 6 years ) , on the North Coast of NSW , which aim ed to decrease overweight and obesity prevalence among children by improving fundamental movement skills ( FMS ) , increasing fruit and vegetable intake and decreasing unhealthy food consumption . METHODS The Tooty Fruity Vegie in Preschools program was implemented in 18 preschools for 10 months during 2006 and 2007 . It included nutrition and physical activity strategies . Pre and post intervention evaluation compared intervention and control children and was conducted at the beginning and end of each year . It included FMS testing , lunch box audits and anthropometric measures of children as well as parents ' surveys regarding children 's food intake , physical activity and sedentary behaviours . RESULTS In comparison to controls , children in intervention preschools significantly improved movement skills ( 14.79 units , p<0.001 ) , had more fruit and vegetable serves ( 0.63 serves , p=0.001 ) and were less likely to have unhealthy food items ( p<0.001 ) in their lunch boxes following the intervention . There was also a significant difference in waist circumference growth ( -0.80 cm , p=0.002 ) and a reduction of BMI Z scores ( -0.15 , p=0.022 ) . CONCLUSIONS The 10-month intervention in preschools produced significant changes in children 's food intake , movement skills and indicators of weight status BACKGROUND Obesity prevention research is sparse in young children at risk for obesity . This study tested the effectiveness of a culturally tailored , multicomponent prevention intervention to promote healthy weight gain and gross motor development in low-income preschool age children . METHODS Study participants were predominantly Mexican-American children ( n = 423 ; mean age = 4.1 ; 62 % in normal weight range ) enrolled in Head Start . The study was conducted using a quasi-experimental pretest/posttest design with two treatment groups and a comparison group . A center-based intervention included an age-appropriate gross motor program with structured outdoor play , supplemental classroom activities , and staff development . A combined center- and home-based intervention added peer-led parent education to create a broad supportive environment in the center and at home . Primary outcomes were weight-based z-scores and raw scores of gross motor skills of the Learning Achievement Profile Version 3 . RESULTS Favorable changes occurred in z-scores for weight ( one-tailed p < 0.04 ) for age and gender among children in the combined center- and home-based intervention compared to comparison children at posttest . Higher gains of gross motor skills were found in children in the combined center- and home-based ( p < 0.001 ) and the center-based intervention ( p < 0.01 ) . Children in both intervention groups showed increases in outdoor physical activity and consumption of healthy food . Process evaluation data showed high levels of protocol implementation fidelity and program participation of children , Head Start staff , and parents . CONCLUSION The study demonstrated great promise in creating a health-conducive environment that positively impacts weight and gross motor skill development in children at risk for obesity . Program efficacy should be tested in a r and omized trial This study examined the feasibility , acceptability , and potential efficacy of a gross motor skill program for toddlers . An 8-wk . skills program in which children practice d three skills was implemented for 10min . daily in two r and omly design ated childcare centers . Two other centers served as the control group . Recruitment and retention rates were collected for feasibility . Data on professional development , children 's participation , program duration , and appropriateness of the lessons were collected for acceptability , and the Test of Gross Motor Development–2 and Get Skilled , Get Active ( total of 28 points ) were used to look at the potential efficacy . The participants were 60 toddlers ( M age = 2.5 yr . , SD = 0.4 ; n = 29 boys ) , and the retention rate was 95 % . Overall participation was 76 % , and educators rated 98 % of the lessons as appropriate . Compared with the control group , the intervention group showed significantly greater improvements in motor skills ( p < .05 , Cohen 's d = 1.13 ) . This study shows that a brief intervention , which is easy to integrate on a daily basis in childcare setting s , can improve motor skills among toddlers

The most common measures for motor performances were the maximum strength of the trunk flexors and extensors and the endurance and fatigability of the trunk extensors . The meta-analyses demonstrated no negative effect by the continuous use of an LSO for 1 - 6 months . However , the quality of evidence ranged from low to very low , and more high- quality trials are required to draw a definitive conclusion on the impact of the continuous use of an LSO on trunk motor performances

BACKGROUND CONTEXT Lumbosacral orthosis ( LSO ) is prescribed by general practitioners for the management of low back pain . It may be speculated that continuous use of an LSO for a prolonged period reduces mechanical loading to the trunk muscle in daily living and results in impairments of the trunk muscle . PURPOSE This study aims to investigate whether trunk motor performances are impaired by the continuous use of an LSO .

BACKGROUND AND PURPOSE An active strategy was developed for the implementation of the clinical guidelines on physical therapy for patients with low back pain . The effect of this strategy on patients ' physical functioning , coping strategy , and beliefs regarding their low back pain was studied . SUBJECTS One hundred thirteen primary care physical therapists treated a total of 500 patients . METHODS The physical therapists were r and omly assigned to 1 of 2 groups . The control group received the guidelines by mail ( st and ard passive method of dissemination ) . The intervention group , in contrast , received an additional active training strategy consisting of 2 sessions with education , group discussion , role playing , feedback , and reminders . Patients with low back pain , treated by the participating therapists , completed question naires on physical functioning , pain , sick leave , coping , and beliefs . RESULTS Physical functioning and pain in the 2 groups improved substantially in the first 12 weeks . Multilevel longitudinal analysis showed no differences between the 2 groups on any outcome measure during follow-up . DISCUSSION AND CONCLUSION The authors found no additional benefit to applying an active strategy to implement the physical therapy guidelines for patients with low back pain . Active implementation strategies are not recommended if patient outcomes are to be improved Background The effects of lumbosacral orthoses ( LSOs ) on neuromuscular control of the trunk are not known . There is a concern that wearing LSOs for a long period may adversely alter muscle control , making individuals more susceptible to injury if they discontinue wearing the LSOs . The purpose of this study was to document neuromuscular changes in healthy subjects during a 3-week period while they regularly wore a LSO . Methods Fourteen subjects wore LSOs 3 hrs a day for 3 weeks . Trunk muscle activity prior to and following a quick force release ( trunk perturbation ) was measured with EMG in 3 sessions on days 0 , 7 , and 21 . A longitudinal , repeated- measures , factorial design was used . Muscle reflex response to trunk perturbations , spine compression force , as well as effective trunk stiffness and damping were dependent variables . The LSO , direction of perturbation , and testing session were the independent variables . Results The LSO significantly ( P < 0.001 ) increased the effective trunk stiffness by 160 Nm/rad ( 27 % ) across all directions and testing sessions . The number of antagonist muscles that responded with an onset activity was significantly reduced after 7 days of wearing the LSO , but this difference disappeared on day 21 and is likely not clinical ly relevant . The average number of agonist muscles switching off following the quick force release was significantly greater with the LSO , compared to without the LSO ( P = 0.003 ) . Conclusions The LSO increased trunk stiffness and result ed in a greater number of agonist muscles shutting-off in response to a quick force release . However , these effects did not result in detrimental changes to the neuromuscular function of trunk muscles after 3 weeks of wearing a LSO 3 hours a day by healthy subjects BACKGROUND CONTEXT Although previous studies suggest braces/corsets can reduce acute pain , no prior study has assessed back function after bracing with both self-reported and objective measures . Use of both self-reported and objective measures of spine function together may be important given evidence they assess unique aspects of function . PURPOSE The aim was to assess both self-reported and objective measures of spinal function before , and after , use of a nonrigid , inelastic lumbar brace . STUDY DESIGN / SETTING This was a non-r and omized clinical trial . PATIENT SAMPLE The sample included acute low back pain ( LBP ) participants and asymptomatic controls . OUTCOME MEASURES Oswestry Disability Index ( ODI ) , spinal stiffness , and muscle endurance were the outcome measures . METHODS Three groups were studied : -LBP/-Brace ( n=19 ) , -LBP/+Brace ( n=18 ) , and + LBP/+Brace ( n=17 ) . Both groups of braced participants were instructed to wear the brace continually for 2 weeks with the exception of bedroom and bathroom activities . Before and after the 2-week period , three measures of spinal function were performed : spinal stiffness via motorized indentation of the L3 spinous process , a modified Sorensen test ( timed lumbar extension against gravity ) , and the ODI . Repeated measures analyses of variance were conducted for all three outcomes . RESULTS Among the groups , ODI scores decreased significantly for the + LBP/+Brace group ( p<.001 ) compared with the other two groups . The + LBP/+Brace mean ODI score decreased 3.71 points ( 95 % confidence interval [ CI ] 2.01 - 5.40 ) compared with the -LBP/-Brace group and decreased 3.48 points ( 95 % CI 1.77 - 5.20 ) compared with the -LBP/+Brace group . Change scores for the Sorensen test were significantly increased in the + LBP/+Brace group ( p=.037 ) compared with the -LBP/-Brace group ( 22.47s 95 % CI 8.14 - 36.80 ) . Spinal stiffness did not change significantly between groups . CONCLUSIONS This study demonstrates that lumbar function assessed by self-reported and objective measures does not worsen when nonrigid , inelastic bracing is used for short periods of time for those with , or without , back pain . These data add to the existing literature that suggests short-term use of nonrigid , inelastic bracing for acute LBP does not decrease spinal function when measured separately with subjective or objective tools Study Design . Multicentric , r and omized , and controlled study of clinical evaluation of medical device in subacute low back pain . Objective . To evaluate the effects of an elastic lumbar belt on functional capacity , pain intensity in low back pain treatment , and the benefice on medical cost . Summary of Background Data . There is limited evidence of efficiency of lumbar supports for treatment of low back pain . There is also a lack of the methodology in the studies reported on the efficiency of this device . Methods . This study is r and omized , multicentric , and controlled with 2 groups : a patient group treated with a lumbar belt ( BWG ) and a control group ( CG ) . The main criteria of clinical evaluation were the physical restoration assessed with the EIFEL scale , the pain assessed by a visual analogic scale , the main economical criteria was the overall cost of associated medical treatments . Results . One hundred ninety-seven patients have participated . The results show a higher decrease in EIFEL score in BWG than CG between days 0 and 90 ( 7.6 ± 4.4 vs. de 6.1 ± 4.7;P = 0.023 ) . Respectively significant reduction in visual analogic scale was also noticed ( 41.5 ± 21.4 vs. 32.0 ± 20 ; P = 0.002 ) . Pharmacologic consumption decreased at D90 ( the proportion of patients who did not take any medication in BWG is 60.8 % vs. 40 % in CG;P = 0.029 ) . Conclusion . Lumbar belt wearing is consequent in subacute low back pain to improve significantly the functional status , the pain level , and the pharmacologic consumption . This study may be useful to underline the interest of lumbar support as a complementary and nonpharmacologic treatment beside the classic medication use in low back pain treatment OBJECTIVES To evaluate the effect of lumbopelvic belts on the thickness of lateral abdominal muscles and the cross-sectional area ( CSA ) of lumbar multifidus ( LM ) muscles . DESIGN A single-blinded r and omized controlled trial . SETTING An academic and tertiary care referral spine and sports medicine center . PARTICIPANTS Sixty healthy volunteers with no history of low back pain in the previous year . METHODS The subjects were allocated into belt and control groups . Lumbar belts were given to the subjects in the belt group , and they were asked to use the belts during the study period except during sleeping hours . The subjects were assessed at baseline and at 4 and 8 weeks . MAIN OUTCOME MEASURES The thickness of lateral abdominal muscles and the CSA of the LM muscles were measured by ultrasound with the patient in the hook-lying position on an examination table . RESULTS The thickness of lateral abdominal muscles and the CSA of LM muscles on both sides decreased significantly among healthy subjects in the belt group after 8 weeks . CONCLUSION The results of this study show that lumbopelvic belts might influence the ultrasonographic measurements of lateral abdominal and LM muscles and thereby spine stability One of the major challenges for general practitioners is to manage individuals with acute low back pain appropriately to reduce the risk of chronicity . A prospect i ve study was design ed to assess the actual management of acute low back pain in one primary care setting and to determine whether existing practice patterns conform to published guidelines . Twenty-four family physicians from public primary care centers of the Basque Health Service in Bizkaia , Basque Country ( Spain ) , participated in the study . A total of 105 patients aged 18–65 years presenting with acute low back pain over a 6-month period were included . Immediately after consultation , a research assistant performed a structured clinical interview . The patients ’ care provided by the general practitioner was compared with the Agency for Health Care Policy and Research ( AHCPR ) guidelines and guidelines issued by the Royal College of General Practitioners . The diagnostic process showed a low rate of appropriate use of history ( 27 % ) , physical examination ( 32 % ) , lumbar radiographs ( 31 % ) , and referral to specialized care ( 33 % ) . Although the therapeutic process showed a relatively high rate of appropriateness in earlier mobilization ( 77 % ) and educational advice ( 65 % ) , only 23 % of patients were taught about the benign course of back pain . The study revealed that management of acute low back pain in the primary care setting is far from being in conformance with published clinical guidelines Study Design . Prospect i ve cohort study . Objective . To quantify which 3 common lumbar orthoses of varying rigidity restrict both full , active range of motion ( ROM ) and functional ROM required for activities of daily living ( ADL ) . Summary of Background Data . Spinal orthoses are implemented to restrict lumbar motion . Despite widespread prevalence of lumbar bracing , the efficacy of these appliances for immobilizing the spine has not been definitively established . Methods . The full , active ROM of 10 asymptomatic individuals was quantified using an electrogoniometer that registered maximum rotation in all planes . Subjects subsequently completed 15 simulated ADLs during which time their functional ROM was measured ; performed without a brace and while wearing a corset , semirigid lumbosacral orthosis ( LSO ) , and rigid custom-molded LSO . Results . For flexion/extension , the mean percentage decreases ( with SDs ) in full , active ROM that were recorded with corset , semirigid , and a custom orthosis were 24.1 ± 7.9 % , 46.8 ± 7.1 % , and 64.7 ± 8 % , respectively ( P < 0.001 relative to no brace ) . In the coronal plane , motion was restricted by 33.9 ± 8.8 % , 51.9 ± 9.4 % , and 49.1 ± 11.8 % , respectively ( P < 0.001 ) . Finally , rotation was limited by 39.6 ± 8.8 % , 59.2 ± 10.2 % , and 70.6 ± 5.4 % , respectively ( P < 0.001 ) . There were no significant discrepancies between the ROM recorded in the semirigid and custom LSOs for the ADLs . Likewise , functional ROM associated with corset and semirigid LSOs were only different for 2 ADLs whereas significant disparities between values with corset and custom LSOs were observed for 4 simulations . Conclusion . The full , active ROM allowed by lumbar braces evaluated was greater than employed during ADLs in absence of any brace . The motion decrease beyond actual restriction of the braces suggests they will act primarily as proprioceptive guides to regulate movement This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence Study Design . Cluster r and omized controlled trial for a multifaceted implementation strategy . Objectives . To assess the effectiveness of tailored interventions ( multifaceted implementation strategy ) to implement the Dutch low back pain guideline for general practitioners with regard to adherence to guideline recommendations . Summary of Background Data . Guidelines for the management of low back pain in primary care have been developed in various countries , but little is known about the optimal implementation strategy . A multifaceted implementation strategy was developed to overcome identified barriers to the implementation of the Dutch low back pain guideline for general practitioners . Methods . General practitioners were r and omized to an intervention or a control group . The general practitioners in the intervention group ( n = 21 ) received tailored interventions consisting of the Dutch low back pain guideline for general practitioners , a 2-hour educational and clinical practice workshop ; two scientific articles on low back pain management ; the guideline for occupational physicians ; a tool for patient education ; and a tool for reaching agreement on low back care with physical , exercise , and manual therapists . The control group ( n = 20 ) received no intervention . The participating general practitioners were asked to recruit consecutive patients with a new episode of low back pain as the main reason for consultation . General practitioners completed registration forms of each individual consultation with regard to the main outcome measures : advice and information , referral to other health-care providers , and prescription of medication . Results . Forty-one of the 67 r and omized general practitioners reported on a total of 616 consultations for 531 patients with nonspecific low back pain . The advice and explanation provided by the general practitioners , the prescription of paracetamol or nonsteroidal anti-inflammatory drugs , and prescription of pain medication on atime contingent or a pain contingent basis showed no statistically significant differences between the intervention and control groups . There were also no differences in overall referral rate . However , in follow-up consultations fewer patients were referred to a physical or exercise therapist by the general practitioners in the intervention group than in the control group . Conclusions . The multifaceted intervention strategy modestly improved implementation ( for parts of the recommendations in ) the Dutch low back pain guideline by general practitioners and produced small concomitant changes in patient management . The implementation strategy produced fewer referrals to therapists during follow-up consultations Two hundred and one r and omly selected patients ( 109 women and 92 men ) fitted with their first lumbosacral corset because of low back pain were interviewed 3.5 - -4.5 years later . Two-thirds of the patients were 41 - -70 years when fitted with the corset . Barely three-quarters of them wore the corset regularly immediately after prescription . One-fifth became symptom-free within the period covered by the study . Of those who still had symptoms at the time of the interview , two-thirds ( about half of the original material ) were still wearing a corset . Of these two-thirds , about half wore the corset at least once a week . The women doing heavy work and female pensioners tended to use their corsets more frequently . The frequency with which the corsets were used was not influenced by the clinical diagnosis or the type of corset used . As many as 89 per cent of the patients reported that they used the corset because it supported their back or because it not only gave such support , but also relief from the pain . Thirty-seven of 96 non-users reported that the corset did not fit well but only 7 that they did not benefit from the use of the corset . A better follow-up of users would surely increase the frequency with which such corsets are used to the advantage of the patients This study was design ed to determine the effect of multimodal intervention and the prevention of back injury , and to evaluate the adverse side effects of using a lumbosacral corset in the workplace . Subjects were 90 male warehouse workers r and omly selected from over 800 employees at a grocery distribution center . Subjects were assigned to three groups : true controls , no back school , no brace orthoses ; back school only ; and back school plus wearing a custom molded lumbosacral orthosis . Comparisons of pre-testing and 6-month follow-up posttesting for abdominal strength , cognitive data , work injury incidence and productivity and use of health care services were evaluated . Controls and training-only group showed no changes in strength productivity or lost time . Orthoses and training-group showed no changes in strength productivity or accident rate ; however , they showed substantially less lost time . This study supports the concept of using education and prophylactic bracing to prevent back injury and reduce time loss . It appears that the use of intermittent prophylactic bracing has no adverse affects on abdominal muscle strength and may contribute to decreased lost time from work injuries INTRODUCTION R and omized and controlled study of clinical evaluation of medical device in healthy subjects . OBJECTIVE To evaluate the effect of wearing an elastic lumbar support , frequently used in low-back pain prevention or treatment , on the trunk flexors and extensors muscle strength on healthy subjects . SUMMARY OF BACKGROUND DATA The long-term use of a lumbar orthosis is still suspected of weakening on the trunk muscles . The results in the existing literature are contradictory but do n't seem to confirm this . METHODS Trunk muscle isokinetic and isometric strength measured before and after the wearing of an elastic orthosis over a period of 21days by healthy subjects with a control group without orthosis . RESULTS There were 20 healthy subjects using orthosis and 9 controls . No changes in isokinetic and isometric strength were observed except for the endurance parameter on extensors : it was significantly more important before than after the lumbar support use ( p=0.033 ) . CONCLUSION These results disprove any negative effects on muscle strength and add to the existing literature which argues for a more customized prescription of lumbar orthosis depending on the potential muscle strength of the subject Study Design A r and omized prospect i ve trial of manipulation , massage , corset and transcutaneous muscle stimulation ( TMS ) was conducted in patients with subacute low back pain . Objectives The authors determined the relative efficacy of chiropractic treatment to massage , corset , and TMS . Summary of Background Data Although all of these treatments are used for subacute low back pain treatment , there have been few comparative trials using objective outcome criteria . Patients were enrolled for a period of 3 weeks . They were evaluated once a week by question naires , visual analog scale , range of motion , maximum voluntary extension effort , straight leg raising and Biering-Sorensen fatigue test . The dropout rate was highest in the muscle stimulation and corset groups and lowest in the manipulation group . Rates of full compliance did not differ significantly across treatments . A measure of patient confidence was greatest in the manipulation group . Results After 3 weeks , the manipulation group scored the greatest improvements in flexion and pain while the massage group had the best extension effort and fatigue time , and the muscle stimulation group the best extension . Conclusion None of the changes in physical outcome measures ( range of motion , fatigue , strength or pain ) were significantly different between any of the groups There are few studies of the therapeutic effects of long-term corset wearing in patients with chronic low back pain . The aim of this study was to evaluate the effects of long-term corset wearing on chronic low back pain and to examine the myoelectrical activities of the paravertebral muscles . Forty subjects with chronic low back pain were enrolled and r and omly divided into two groups : a group wearing corsets for 6 months ( CW ) group and a group not wearing corsets ( NW ) . The treatment effects were measured using the Japanese Orthopaedic Association ( JOA ) score . Muscle endurance was evaluated during the Biering-Sorensen test ( S-test ) , and the degree of muscle fatigue was evaluated by the change in percent mean power frequency ( % MPF ) of the paravertebral muscles . Corset treatment for chronic low back pain improved low back pain and increased muscle endurance for a short period of time . Paravertebral muscle fatigue was not increased by long-term corset wearing for chronic low back pain , and weakening of the paravertebral muscles was not observed up to 6 months after the start of corset wearing OBJECTIVES Mechanical low back pain ( LBP ) is a major public health problem . Today 's st and ard care strategy involves a combination of drug-based and non-drug therapies . The use of conservative orthopaedic brace treatment is subject to debate . The lack of data and consensus in the literature on the value of this treatment in chronic LBP prompted to us to seek to estimate the modalities and indications for brace use in France . MATERIAL S AND METHOD We performed a question naire-based survey of physician members of the French Society of Physical Medicine and Rehabilitation ( SOFMER ) . RESULTS We received 55 completed question naires . Although the indications for this treatment were very heterogeneous ( in both clinical and para clinical terms ) , the prescribing behaviour was rather uniform . The brace is worn during the day for less than 3 months ( with a progressive reduction in use over 1 to 2 months ) , together with physiotherapy before and after immobilization . The patient keeps the brace at the end of the treatment period . Orthopaedic treatment appears to be prescribed in many chronic LBP situations . Analysis of spinal posture and magnetic resonance imaging results ( and Modic changes in particular ) influence the therapeutic decisions . CONCLUSION Clinical and para clinical indications of this treatment must be precisely defined and evaluated in prospect i ve , multicenter studies with homogeneous cohorts In the GRADE approach , r and omized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted Study Design . R and omized prevention trial . Objective . To compare the long-term effect of strengthening versus flexibility exercises and to evaluate the additional effect of abdominal bracing in recurrent low back pain ( LBP ) . Summary of Background Data . No conclusions could be made regarding appropriate exercise types or parameters in recurrent LBP . Abdominal bracing increases trunk stiffness ; however , its long-term effect has not been evaluated in recurrent LBP yet . Methods . Six hundred patients with recurrent LBP participated . They were r and omized into 4 groups—150 patients ( age : 42.5 ± 12.7 ) performed strengthening exercises ; 150 patients ( age : 41.3 ± 11.5 ) performed flexibility exercises ; 150 patients ( age : 41.0 ± 13.2 ) performed strengthening exercises and used abdominal bracing in daily activities/exercises ; and 150 patients ( age : 40.6 ± 12.3 ) performed flexibility exercises and used abdominal bracing in daily activities/exercises . At the beginning of the study and at the end of 10 consecutive years were recorded 6 outcomes —frequency , intensity , and duration of pain , as well as frequency , intensity , and duration of exercises . Results . Regarding the first 4 outcomes —all groups showed improvement from the beginning to the second year , but worsening from the second to the 10th year ; there was no difference between strengthening and flexibility groups ; bracing groups showed better results versus nonbracing groups . Intensity , frequency , and duration of the pain correlated with each other and with frequency of the exercises , but not with exercise duration or intensity . Conclusion . The exercise frequency is more important than the type , duration , or intensity of the exercise . Abdominal bracing adds to the exercise effect . It could be considered as a “ preliminary muscle back belt on dem and ” increasing the trunk stiffness and the frequency of the trunk muscle contractions/cocontractions without interruption of daily activities , which may remind/convince the patients to exercise more frequently . Frequent exercising and bracing seems effective long-term prevention advices in recurrent LBP . Level of Evidence : Study Design . R and omized clinical trial . Objectives . To evaluate the effectiveness of a back support plus education versus education alone in promoting recovery from a work-related low back disorder ( WR-LBD ) while simultaneously considering personal , health , and occupational factors and the impact of occupational factors on recovery . Summary of Background Data . No r and omized studies of active industrial workers with low back disorders exist regarding the effectiveness of back supports plus education . Methods . A total of 433 actively employed hourly union workers who had a recent diagnosis of a WR-LBD : 1 ) those who wore a specially design ed back support plus received education on back health ; and 2 ) those who received education on back health only . Demographic , health , medical , and occupational factors were obtained through interview or abstract ion of computer files ; individual ergonomic exposures were measured with a lumbar motion monitor . Outcomes evaluated over a 12-month period included : self-reported measures of back pain , back pain disability level , physical health , mental health , and administrative measures of recurrence , lost work time , and medical care utilization . Results . There was no difference between the study groups with respect to mental or physical health , low back pain , back pain disability , neurogenic symptoms , lost work time , likelihood of recurrence of an episode of a back disorder , or other administrative measures of healthcare utilization or lost work time . However , significant decreases in low back pain , low back pain disability , neurogenic symptoms , and an increase in physical health were observed over the 12 months of observation in both study groups . The only occupational variable found to influence was plant group whereby service parts operations workers in the back support plus education group experienced a lower likelihood of WR-LBD recurrence . Conclusion . Although there was no overall effect on self-reported recovery or administrative measures or lost work time between the study groups , a back support plus health education may have some value in preventing recurrent WR-LBD in industrial workers who work in psychosocial environments and perform manual material h and ling tasks similar to those found in parts distribution centers

AUTHORS ' CONCLUSIONS There is limited evidence which supports the use of compensatory scanning training for patients with visual field defects ( and possibly co-existing visual neglect ) to improve scanning and reading outcomes . There is insufficient evidence to reach a conclusion about the impact of compensatory scanning training on functional activities of daily living . There is insufficient evidence to reach generalised conclusions about the benefits of visual restitution training ( VRT ) ( restitutive intervention ) or prisms ( substitutive intervention ) for patients with visual field defects after stroke

BACKGROUND Visual field defects are estimated to affect 20 % to 57 % of people who have had a stroke . Visual field defects can affect functional ability in activities of daily living ( commonly affecting mobility , reading and driving ) , quality of life , ability to participate in rehabilitation , and depression , anxiety and social isolation following stroke . There are many interventions for visual field defects , which are proposed to work by restoring the visual field ( restitution ) ; compensating for the visual field defect by changing behaviour or activity ( compensation ) ; substituting for the visual field defect by using a device or extraneous modification ( substitution ) ; or ensuring appropriate diagnosis , referral and treatment prescription through st and ardised assessment or screening , or both . OBJECTIVES To determine the effects of interventions for people with visual field defects after stroke .

BACKGROUND The objective of this study was to determine the effect of a visual rehabilitation intervention on visual field defects in a US cohort . Vision Restoration Therapy ( VRT ) consists of a specific pattern of stimulation that is directed at the border of the blind field . METHODS This retrospective study evaluated individuals with homonymous visual field defect from retrochiasmatic lesions treated with 6 modules of VRT . Suprathreshold visual field testing of the central 43x32 was obtained at baseline and after each module . The main outcome measures were the change in stimuli detection and the shift in the position of the border of the blind field . The impact of age , time from injury and type of visual field defect were analyzed . RESULTS Among 161 patients , the mean absolute improvement in stimuli detection was 12.8 % . The average border shift was 4.87 . Improvements of > or =3 % was noted in 76 % of patients . Absolute change in stimulus detection of > or =3 % at mid-therapy was associated with a greater final improvement . Age , time from lesion and type of visual field defect did not influence the degree of field expansion . CONCLUSIONS VRT improves stimulus detection and results in a shift of the position of the border of the blind field as measured on suprathreshold visual field testing . These results support prior reports and support VRT as a useful rehabilitative intervention for a proportion of patients with visual field defects from retrochiasmatic lesions Background : Neurologically impaired persons seem to benefit from driving-training programs , but there is no convincing evidence to support this notion . The authors therefore investigated the effect of simulator-based training on driving after stroke . Methods : Eighty-three first-ever subacute stroke patients entered a 5-week 15-hour training program in which they were r and omly allocated to either an experimental ( simulator-based training ) or control ( driving-related cognitive tasks ) group . Performance in off-road evaluations and an on-road test were used to assess the driving ability of subjects pre- and post-training . Outcome of an official predriving assessment administered 6 to 9 months poststroke was also considered . Results : Both groups significantly improved in a visual and many neuropsychological evaluations and in the on-road test after training . There were no significant differences between both groups in improvements from pre- to post-training except in the “ road sign recognition test ” in which the experimental subjects improved more . Significant improvements in the three-class decision ( “ fit to drive , ” “ temporarily unfit to drive , ” and “ unfit to drive ” ) were found in favor of the experimental group post-training . Academic qualification and overall disability together determined subjects that benefited most from the simulator-based driving training . Significantly more experimental subjects ( 73 % ) than control subjects ( 42 % ) passed the follow-up official predriving assessment and were legally allowed to resume driving . Conclusions : Simulator-based driving training improved driving ability , especially for well educated and less disabled stroke patients . However , the findings of the study may have been modified as a result of the large number of dropouts and the possibility of some neurologic recovery unrelated to training PURPOSE ( 1 ) To compare the outcomes of orientation and mobility and driving training with Fresnel prisms and the Gottlieb Visual Field Awareness System for patients with homonymous hemianopsia , and ( 2 ) To determine whether the patients continue to use the optical enhancement devices at a 2-year follow-up point . METHODS Patients with homonymous hemianopsia were provided with a rehabilitation program where they were fitted with prism lenses and trained to use them for navigation and driving . Telephone interviews were used to obtain information about device usage 2 years following the completion of the training program . RESULTS Patients ' performance was compared with a test-retest criterion in the visual skills areas of recognition , mobility , peripheral detection , scanning , tracking , and visual memory . Patients with hemianopic loss showed improvements in all of the visual skills categories , ranging from the highest improvements of 26 % of tasks improved in the mobility category to 13 % in the recognition category . The majority of the hemianopic patients reported using the devices at the 2-year follow-up interview . CONCLUSIONS The patients with homonymous hemianopsia showed improvements in visual functioning using prism lenses , although these improvements were smaller than those found in previous studies with central or bilateral peripheral vision loss groups who were trained to use other optical enhancement devices for navigation and driving using a similar curriculum . However , given the evidence of increased risk of accidents for patients with peripheral vision loss , the safety of peripheral enhancement devices for driving must be thoroughly evaluated before their impact on public safety is known This article reports on two studies that examine the relationship between measurements of activities of daily living ( ADL ) and cognitive skills performance . Study 1 is a post hoc analysis of ADL improvement scores collected on acute stroke patients who were either given or not given cognitive skills remediation . An examination of individual ADL scores showed significantly higher personal hygiene , bathing , and toilet activity improvement scores for patients receiving cognitive skills remediation . In Study 2 , cognitive skills and ADL pre- and posttest scores for stroke patients were measured by occupational therapists , who also implemented an ADL as well as a cognitive skills remediation program as part of the patient 's therapy . Some significant positive correlations between initial cognitive skills measurements and ADL outcome were found . The best correlate of patients ' ADL performance at discharge was performance on an auditory attention task . Verbal comprehension correlated with overall ADL improvement , and overall cognitive skills improvement correlated with overall ADL improvement . Implication s of these two studies are discussed BACKGROUND the types of visual impairment followings stroke are wide ranging and encompass low vision , eye movement and visual field abnormalities , and visual perceptual difficulties . OBJECTIVE the purpose of this paper is to present a 1-year data set and identify the types of visual impairment occurring following stroke and their prevalence . METHODS a multi-centre prospect i ve observation study was undertaken in 14 acute trust hospitals . Stroke survivors with a suspected visual difficulty were recruited . St and ardised screening/referral and investigation forms were employed to document data on visual impairment specifically assessment of visual acuity , ocular pathology , eye alignment and movement , visual perception ( including inattention ) and visual field defects . RESULTS three hundred and twenty-three patients were recruited with a mean age of 69 years [ st and ard deviation ( SD ) 15 ] . Sixty-eight per cent had eye alignment/movement impairment , 49 % had visual field impairment , 26.5 % had low vision and 20.5 % had perceptual difficulties . CONCLUSIONS of patients referred with a suspected visual difficulty , only 8 % had normal vision status confirmed on examination . Ninety-two per cent had visual impairment of some form confirmed which is considerably higher than previous publications and probably relates to the prospect i ve , st and ardised investigation offered by specialist orthoptists . However , under-ascertainment of visual problems can not be ruled out Objective : An acquired right-sided homonymous hemianopia can result in slowed left-to-right text reading , called hemianopic alexia ( HA ) . Patients with HA lack essential visual information to help guide ensuing reading fixations . We tested two hypotheses : first , that practice with a visual rehabilitation method that induced small-field optokinetic nystagmus ( OKN ) would improve reading speeds in patients with HA when compared to a sham visual rehabilitation therapy ; second , that this therapy would preferentially affect reading saccades into the blind field . Methods : Nineteen patients with HA were entered into a two-armed study with two therapy blocks in each arm : one group practice d reading moving text ( MT ) that scrolled from right to left daily for two 4-week blocks ( Group1 ) , while the other had sham therapy ( spot the difference ) for the first block and then crossed over to MT for the second . Results : Group 1 showed significant improvements in static text reading speed over both therapy blocks ( 18 % improvement ) , while Group 2 did not significantly improve over the first block ( 5 % improvement ) but did when they crossed over to the MT block ( 23 % improvement ) . MT therapy was associated with a direction-specific effect on saccadic amplitude for rightward but not leftward reading saccades . Conclusion : Optokinetic nystagmus inducing therapy preferentially affects reading saccades in the direction of the induced ( involuntary ) saccadic component . This is the first study to demonstrate the effectiveness of a specific eye movement based therapy in patients with hemianopic alexia ( HA ) in the context of a therapy-controlled trial . A free Web-based version of the therapy used in this study is available online to suitable patients with HA Background : In patients with postgenicular lesions of the visual system , areas of residual vision ( ARVs ) are the main predictor of recovery induced by vision restoration therapy ( VRT ) . In these partially defective regions , the elevated perceptual thresholds can be acutely reduced by attentional cueing . Objective : To examine whether directing attention to ARVs using a visuospatial cue also increases long-term neural plasticity and thus enhances permanent training outcome . Methods : In a prospect i ve , r and omized clinical trial , treatment outcome was compared in patients with postgenicular visual system lesions who received either st and ard VRT ( control group [ CG ] ; n = 10 ) or VRT with attentional cueing ( experimental group [ EG ] ; n = 9 ) . Visual field size was determined before and after a 6-month treatment period using Tübingen Automated Perimetry and computer-based high-resolution perimetry ( HRP ) and in regular intervals throughout this period by HRP and detection performance in VRT . Results : In the area of the cue , restoration of vision was significantly greater than during VRT without cueing : cued patients showed a much more pronounced shift of the visual field border toward the blind area than that observed in the CG or in uncued regions of the EG . Focusing attention at ARVs during treatment changed topographic and temporal patterns of recovery as compared with uncued regions of the visual field . Conclusions : Use of a visuospatial cue to focus attention at areas of residual vision amplifies long-term neuronal plasticity . The authors propose that top-down signals preactivate partially damaged areas of V1 , thus linking visual and attentional neuronal networks , with the effect of permanently increasing conscious visual perception Objective : Patients with homonymous hemianopia are disabled on everyday exploratory activities . We examined whether explorative saccade training ( EST ) , compared with flicker-stimulation training ( FT ) , would selectively improve saccadic behavior on the patients ’ blind side and benefit performance on natural exploratory tasks . Methods : Twenty-eight hemianopic patients were r and omly assigned to distinct groups performing for 6 weeks either EST ( a digit- search task ) or FT ( blind-hemifield stimulation by flickering letters ) . Outcome variables ( response times [ RTs ] during natural search , number of fixations during natural scene exploration , fixation stability , visual fields , and quality -of-life scores ) were collected before , directly after , and 6 weeks after training . Results : EST yielded a reduced ( post/pre , 47 % ) digit- search RT for the blind side . Natural search RT decreased ( post/pre , 23 % ) on the blind side but not on the seeing side . After FT , both sides ’ RT remained unchanged . Only with EST did the number of fixations during natural scene exploration increase toward the blind and decrease on the seeing side ( follow-up/pre difference , 238 % ) . Even with the target located on the seeing side , after EST more fixations occurred toward the blind side . The EST group showed decreased ( post/pre , 43 % ) fixation stability and increased ( post/pre , 482 % ) asymmetry of fixations toward the blind side . Visual field size remained constant after both treatments . EST patients reported improvements in social domain . Conclusions : Explorative saccade training selectively improves saccadic behavior , natural search , and scene exploration on the blind side . Flicker-stimulation training does not improve saccadic behavior or visual fields . The findings show substantial benefits of compensatory exploration training , including subjective improvements in mastering daily-life activities , in a r and omized controlled trial Partial blindness after brain injury has been considered non-treatable . To evaluate whether patients with visual-field defects can profit from computer-based visual restitution training ( VRT ) , two independent clinical trials were conducted using patients with optic nerve ( n = 19 ) or post-chiasmatic brain injury ( n = 19 ) . In post-chiasma patients , VRT led to a significant improvement ( 29.4 % ) over baseline in the ability to detect visual stimuli ; in optic nerve patients , the effects were even more pronounced ( 73.6 % improvement ) . Visual-field enlargements were confirmed by the observation of a visual-field expansion of 4.9 ° –5.8 ° of visual angle and improved acuity in optic nerve patients . Ninety five percent of the VRT-treated patients showed improvements , 72.2 % confirmed visual improvements subjectively . Patients receiving a placebo training did not show comparable improvements . In conclusion , VRT with a computer program improves vision in patients with visual-field defects and offers a new , cost-effective therapy for partial blindness Visual field deficits in patients have long been considered to be nontreatable , but in previous studies we have found an enlargement of the intact visual field following vision restoration therapy ( VRT ) . In the present pilot study , we wished to determine whether a double-stimulation approach would facilitate visual field enlargements beyond those achieved by the single-stimulus paradigm used in st and ard VRT . This was motivated by the findings that following visual cortex injury in animals , the size of receptive fields could be enlarged by systematic costimulation , where two stimuli were used to excite visual cortex neurons ( Eysel , Eyding , & Schweigart , 1998 ) . Patients ( n = 23 ) with stable homonymous field deficits after trauma , cerebral ischemia , or hemorrhage ( lesion age > 6 months ) carried out either ( a ) st and ard VRT with a single stimulation ( n = 9 ) , or vision therapy with ( b ) a parallel costimulation ( n = 7 ) or ( c ) a moving costimulation paradigm ( n = 7 ) . Training was carried out twice daily for 30 min over a 3-month period . Before and after therapy , visual fields were tested with 30 ° and 90 ° Tübinger automatic perimetry ( TAP ) and with high-resolution perimetry ( HRP ) . Eye movements were recorded with an eye tracking system . When data of all three types of visual field training were pooled , we found significant improvements of stimulus detection in HRP ( 4.2 % ) and fewer misses within the central 30 ° perimetrically ( −3.7 % right eye , OD , or −4.4 % left eye , OS ) . However , the type of training did not make any difference such that the three training groups profited equally . A more detailed analysis of trained versus untrained visual field areas in 16 patients revealed a superiority of the trained area of only 1.1 % in HRP and between 3.5 % ( OS ) and 4.4 % ( OD ) in TAP . Spatial attention and alertness improved significantly in all three groups and correlated significantly with visual field enlargements . While vision training had no influence on the patient 's testimonials concerning their visual abilities , the patients significantly improved in a practical paper- and -pencil number tracking task ( Zahlen-Verbindungs Test ; ZVT ) . Visual field enlargement does not benefit from a double-stimulation paradigm , but visual attention seems to play an important role in vision restoration . The improvements in trained as well as in untrained areas are explained by top-down attentional control mechanisms interacting with local visual cortex plasticity The purpose of this study was to determine whether a cognitive skills remediation program could help acute stroke patients regain important thinking skills . Patients in a community hospital stroke program were pre-tested in three skill areas --visual scanning , visual-spatial orientation , and time judgment-- and r and omly assigned to a treatment ( n = 16 ) or control ( n = 17 ) group . The treatment group received cognitive skill retraining on a one-to-one basis for 30 minutes per day , 3 days per week , for 3 weeks . The retraining involved the use of paper and pencil tasks , simple cuing procedures , positive reinforcement , and immediate feedback . Although the control group did not receive this treatment , conventional therapies continued for both groups . Patients receiving treatment had overall and separate skill improvement scores that were significantly higher than those for control patients . The implication s of this type of treatment program are discussed We r and omly assigned 39 patients with stroke and homonymous hemianopia or unilateral visual neglect to treatment with 15-diopter plastic press-on Fresnel prisms ( n = 18 ) or to serve as controls ( n = 21 ) . Baseline evaluations of visual perception and activities-of-daily-living ( ADL ) function were similar for both groups . After 4 weeks , the prism-treated group performed significantly better than controls on the following : ( 1 ) Motor Free Visual Perception Test ; ( 2 ) Line Bisection Task ; ( 3 ) Line Cancellation Task ; ( 4 ) Harrington Flocks Visual Field Screener ; and ( 5 ) Tangent Screen Examination . There was no significant difference in Barthel ADL assessment at 4 weeks . Thus , treatment with 15-diopter Fresnel prisms improves visual perception test scores but not ADL function in stroke patients with homonymous hemianopia or unilateral visual neglect In a previous r and omized placebo-controlled clinical trial , we observed significant visual field enlargements induced by computer-based restitution training in patients with cerebral lesions ( Kasten et al. , Nature med . , 4 , 1998 , 108387 ) . Now we asked the question whether this effect is stable after training was discontinued Here we report data of a follow-up study after a training-free interval ( mean 23.52.3 months after end of therapy ) . 16 patients of the original restitution group and 6 patients of the placebo group were re-examined . On average , in high resolution computer campimetry ( stimulus detection : PeriMa , form recognition : PeriForm , color perception : PeriColor ) as well as in conventional automatic perimetry ( TAP-2000 ) both groups showed no significant decline in the number of correctly detected stimuli after training was discontinued . However , cluster analysis revealed three different types of patients , who showed either increase ( Type-I ) , decrease ( Type-II ) or stability ( Type-III ) in performance . We propose that many patients learn to use the regained visual capacities not only in the setting of a computer training but also in every day life , while other patients do not use the areas of restored vision and show a decrease of visual functions after the end of training . The Type-I group does not need continuous training , while the Type-II group may benefit from phases of refreshment exercises This study presents a method for analyzing and remediating the visual perceptual deficits often found in persons with acquired right brain injury due to stroke . A total of 57 patients were r and omly assigned to experimental ( N=25 ) or control ( N=32 ) groups . All patients were administered the same test battery prior to assignment . Experimentals received the specific training program and the controls received st and ard rehabilitation . Both groups were retested after a period of one month . Analysis revealed the superior performance of the experimental group . The results suggest that the academic disorders found in right brain damage can be treated as secondary to a primary disturbance in visual scanning behavior

Store environment interventions showed mixed effects . Education-only interventions appeared effective in simulated environments but not in real stores . Available data suggested that effects of economic interventions did not differ by socioeconomic status , whereas for other interventions impact was variable . In our qualitative comparative analysis , economic interventions ( regardless of setting ) and environmental and swap interventions in real stores were associated with statistically significant changes in purchasing in the desired direction for ≥1 of the foods targeted by the intervention , whereas education-only interventions in real stores were not . Conclusions Findings suggest that interventions implemented in grocery stores-particularly ones that manipulate price , suggest swaps , and perhaps manipulate item availability-have an impact on purchasing and could play a role in public health strategies to improve health .

Background Diet is an important determinant of health , and food purchasing is a key antecedent to consumption . Objective We set out to evaluate the effectiveness of grocery store interventions to change food purchasing , and to examine whether effectiveness varied based on intervention components , setting , or socioeconomic status .

Objective Small food store interventions show promise to increase healthy food access in under-re source d areas . However , none have tested the impact of price discounts on healthy food supply and dem and . We tested the impact of store-directed price discounts and communications strategies , separately and combined , on the stocking , sales and prices of healthier foods and on storeowner psychosocial factors . Design Factorial design r and omized controlled trial . Setting Twenty-four corner stores in low-income neighbourhoods of Baltimore City , MD , USA . Subjects Stores were r and omized to pricing intervention , communications intervention , combined pricing and communications intervention , or control . Stores that received the pricing intervention were given a 10–30 % price discount by wholesalers on selected healthier food items during the 6-month trial . Communications stores received visual and interactive material s to promote healthy items , including signage , taste tests and refrigerators . Results All interventions showed significantly increased stock of promoted foods υ . control . There was a significant treatment effect for daily unit sales of healthy snacks ( β = 6·4 , 95 % CI 0·9 , 11·9 ) and prices of healthy staple foods ( β = −0·49 , 95 % CI −0·90 , −0·03 ) for the combined group υ . control , but not for other intervention groups . There were no significant intervention effects on storeowner psychosocial factors . Conclusions All interventions led to increased stock of healthier foods . The combined intervention was effective in increasing sales of healthier snacks , even though discounts on snacks were not passed to the consumer . Experimental research in small stores is needed to underst and the mechanisms by which store-directed price promotions can increase healthy food supply and dem and Background Lowering the price of fruit and vegetables is a promising strategy in stimulating the purchase of those foods . However , the true effects of this strategy are not well studied and it is unclear how the money saved is spent . The aim of this study is to examine the effects of a 25 % discount on fruits and vegetables on food purchases in a supermarket environment . Methods A r and omized controlled trial with two research conditions was conducted : a control condition with regular prices ( n = 52 ) and an experimental condition with a 25 % discount on fruits and vegetables ( n = 63 ) . The experiment was carried out using a three-dimensional web-based supermarket , which is a software application in the image of a real supermarket . Data were collected in 2010 in the Netherl and s. Participants received a fixed budget and were asked to buy weekly household groceries at the web-based supermarket . Differences in fruit and vegetable purchases , differences in expenditures in other food categories and differences in total calories were analyzed using independent sample s t-tests and multiple linear regression models accounting for potential effect modifiers and confounders . Results The purchased amount of fruit plus vegetables was significantly higher in the experimental condition compared to the control condition ( Δ984 g per household per week , p = .03 ) after appropriate adjustments . This corresponds to a 25 % difference compared to the control group . Both groups had similar expenditures in unhealthier food categories , including desserts , soda , crisps , c and y and chocolate . Furthermore , both groups purchased an equal number of food items and an equal amount of calories , indicating that participants in the discount condition did not spend the money they saved from the discounts on other foods than fruits and vegetables . Conclusion A 25 % discount on fruits and vegetables was effective in stimulating purchases of those products and did neither lead to higher expenditures in unhealthier food categories nor to higher total calories purchased . Future studies in real supermarkets need to confirm these findings Twenty-four-hour urine collection , as a gold st and ard method of measuring salt intake , is costly and re source consuming , which limits its use in monitoring population salt reduction programs . Our study aim ed to determine whether a salt sales survey could serve as an alternative method . This was a sub study of China Rural Health Initiative-Sodium Reduction Study ( CRHI-SRS ) , in which 120 villages were r and omly allocated ( 1:1:2 ) into a price subsidy+health education ( PS+HE ) group , a HE-only group or a control group . Salt substitutes ( SS ) were supplied to shops in the intervention groups ; 24-h urine was collected from 2567 r and omly selected adults at the end of the trial to evaluate the effects of the intervention . Ten villages were r and omly selected from each group ( that is , 30 villages in total ) , and 166 shops from these villages were invited to participate in the monthly salt sales survey . The results showed that during the intervention period , mean monthly sales of SS per shop were 38.0 kg for the PS+HE group , 19.2 kg for the HE only and 2.2 kg for the control group ( P<0.05 ) , which was consistent with the results from the 24-h urine sodium and potassium data . The intervention effects of CRHI-SRS on sodium and potassium intake estimated from SS sales were 101 % and 114 % , respectively , of those observed from the 24-h urine data . Furthermore , the salt sales survey cost only 14 % of the cost of the 24-h urine method and had greater statistical power . The results indicate that a salt sales survey could serve as a simple , sensitive and cost-effective method to evaluate community-based salt reduction programs in which salt is mainly added by the consumers OBJECTIVE Fiscal policies may form a solution in improving dietary intake . This study aim ed to examine the effectiveness of varying taxing and subsiding schemes to stimulate healthier food purchases . METHODS A r and omized controlled trial with three levels of price reduction on healthy foods ( no ; 25 % ; 50%) × three levels of price increase on unhealthy foods ( 5 % ; 10 % ; 25 % ) factorial design was used . 150 participants were r and omized into one of nine conditions and were asked to purchase groceries at a web-based supermarket . Data were collected in the Netherl and s in January-February 2010 and analyzed using analysis of covariance . RESULTS Subjects receiving 50 % discount purchased significantly more healthy foods than subjects receiving no ( mean difference=6.62 items , p<0.01 ) or 25 % discount ( mean difference=4.87 items , p<0.05 ) . Moreover , these subjects purchased more vegetables ( mean difference=821 g;p<0.05 compared to no discount ) . However , participants with the highest discount also purchased significantly more calories . No significant effects of the price increases on unhealthy foods were found . CONCLUSION Price decreases are effective in stimulating healthy food purchases , but the proportion of healthy foods remains unaffected . Price increases up to 25 % on unhealthier products do not significantly affect food purchases . Future studies are important to vali date these results in real supermarkets and across different countries Background Two strategies commonly recommended to improve population diets include food labels and food taxes/subsidies . The aim of this study was to examine the effects of both strategies separately and in combination . Findings An experiment with a 3x3 factorial design was conducted , including : three levels of price reduction ( 10 % ; 25 % ; and 50 % ) x three labels ( ‘ special offer ’ , ‘ healthy choice ’ and ‘ special offer & healthy choice ’ ) on healthy foods defined following the Choices front-of-pack nutrition label . N = 109 participants completed the experiment by conducting a typical weekly shop for their household at a three-dimensional web-based supermarket . Data were analysed using analysis of covariance . Participants receiving a 50 % price discount purchased significantly more healthy foods for their household in a typical weekly shop than the 10 % discount ( + 8.7 items ; 95%CI = 3.8 - 13.6 ) and the 25 % discount group ( + 7.7 items ; 95%CI = 2.74 – 12.6 ) . However , the proportion of healthy foods was not significantly higher and the discounts lead to an increased amount of energy purchased . No significant effects of the labels were found . Conclusion This study brings some relevant insights into the effects of price discounts on healthier foods coupled with different labels and shows that price effects over shadowed food labels . However , price discounts seem to have ambiguous effects ; they do encourage the purchase of healthy products , but also lead to increased energy purchases . More research is needed to examine how pricing strategies can work in directing consumers towards interchanging unhealthier options for healthier alternatives OBJECTIVE This study tested the efficacy of a multicomponent supermarket point-of-purchase intervention featuring in-person nutrition education on the nutrient composition of food purchases . DESIGN The design was a r and omized trial comparing the intervention with usual care ( no treatment ) . SETTING AND PARTICIPANTS A supermarket in a socioeconomically diverse region of Phoenix , AZ . One hundred fifty-three adult shoppers were recruited onsite . INTERVENTION The intervention consisted of brief shopping education by a nutrition educator and an explanation and promotion of a supermarket point-of-purchase healthful shopping program that included posted shelf signs identifying healthful foods , sample shopping lists , tips , and signage . MAIN OUTCOME MEASURES Outcomes included purchases of total , saturated , and trans fat ( grams/1,000 kcal ) , and fruits , vegetables , and dark-green/yellow vegetables ( servings/1,000 kcal ) derived through nutritional analysis of participant shopping baskets . ANALYSIS Analysis of covariance compared the intervention and control groups on food purchasing patterns while adjusting for household income . RESULTS The intervention result ed in greater purchasing of fruit and dark-green/yellow vegetables . No other group differences were observed . CONCLUSIONS AND IMPLICATION S Long-term evaluations of supermarket interventions should be conducted to improve the evidence base and to determine the potential for influence on food choices associated with decreased chronic disease incidence OBJECTIVES Financial constraint is the underpinning determinant of household food insecurity ; however , there has been little research examining the impact that increasing the ‘ money available ’ to food-insecure households could have on food purchasing . The main objective of the present study was to examine the effect of additional money ( in the form of supermarket vouchers ) on food expenditure in food-insecure households with children . DESIGN A parallel r and omized controlled trial with a 4-week baseline phase followed by a 4-week intervention phase . Households were r and omized to either receive vouchers ( coupons ) for 4 weeks or a control group that did not receive any vouchers . SETTING Dunedin , New Zeal and . SUBJECTS Low-income households with children ≥ 18 years ) reporting food insecurity ( n 214 ) . RESULTS The mean monetary value of the vouchers received by households was $ NZ 17?00 per week . The voucher group spent ≥ NZ 15.20 ( 95 % CI 1.46 , 28.94 ) more per week on food during the intervention phase compared with the control group ( P50.030 ) . There were no differences in expenditure between the voucher and the control group for the food groups ‘ fruit and vegetables ’ ( mean difference : ≥ NZ 0?46 ; 95 % CI 21.97 , 2.89 ; P50.709 ) , ‘ meat and poultry ’ ( mean difference : ≥ NZ 0.29 ; 95 % CI 23.07 , 3.64 ; P50.866 ) and ‘ dairy ’ ( mean difference : ≥ NZ 0.82 ; 95 % CI 20.75 , 2.42 ; P50.302 ) . CONCLUSIONS Providing money via supermarket vouchers to food-insecure result ed in an increase in overall expenditure on food Background : Nutrition labeling is a prominent policy to promote healthy eating . Objective : We aim ed to evaluate the effects of 2 interpretive nutrition labels compared with a noninterpretive label on consumer food purchases . Design : In this parallel-group r and omized controlled trial , we enrolled household shoppers across New Zeal and who owned smartphones and were aged ≥18 y. Eligible participants were r and omly assigned ( 1:1:1 ) to receive either traffic light labels ( TLLs ) , Health Star Rating labels ( HSRs ) , or a control [ nutrition information panel ( NIP ) ] . Smartphone technology allowed participants to scan barcodes of packaged foods and to receive allocated labels on their smartphone screens . The primary outcome was the mean healthiness of all packaged food purchases over the 4-wk intervention period , which was measured by using the Food St and ards Australia New Zeal and Nutrient Profiling Scoring Criterion ( NPSC ) . Results : Between October 2014 and November 2015 , 1357 eligible shoppers were r and omly assigned to TLL ( n = 459 ) , HSR ( n = 443 ) , or NIP ( n = 455 ) labels . Overall difference in the mean transformed NPSC score for the TLL group compared with the NIP group was -0.20 ( 95 % CI : -0.94 , 0.54 ; P = 0.60 ) . The corresponding difference for HSR compared with NIP was -0.60 ( 95 % CI : -1.35 , 0.15 ; P = 0.12 ) . In an exploratory per- protocol analysis of participants who used the labeling intervention more often than average ( n = 423 , 31 % ) , those who were assigned to TLL and HSR had significantly better NPSC scores [ TLL compared with NIP : -1.33 ( 95 % CI : -2.63 , -0.04 ; P = 0.04 ) ; HSR compared with NIP : -1.70 ( 95 % CI : -2.97 , -0.43 ; P = 0.01 ) ] . Shoppers who were r and omly assigned to HSR and TLL also found the labels significantly more useful and easy to underst and than the NIP ( all P values < 0.001 ) . Conclusions : At the relatively low level of use observed in this trial , interpretive nutrition labels had no significant effect on food purchases . However , shoppers who used interpretive labels found them to be significantly more useful and easy to underst and , and compared with frequent NIP users , frequent TLL and HSR users had significantly healthier food purchases . This trial was registered at the Australian New Zeal and Clinical Trials Registry ( https://www.anzctr.org.au/Trial/ Registration /Trial Review .aspx?id=366446&is Review = true ) as ACTRN12614000644662 Objectives : The supermarket industry now services many customers through online food shopping over the Internet . The Internet shopping process offers a novel opportunity for the modification of dietary patterns . The aim of this study was to evaluate the effects on consumers ' purchases of saturated fat of a fully automated computerised system that provided real-time advice tailored to the consumers ' specific purchases recommending foods lower in saturated fat . Design : This study was a blinded , r and omised controlled trial . Setting : The study was conducted in Sydney , New South Wales , Australia . Participants : The participants were consumers using a commercial online Internet shopping site between February and June 2004 . Interventions : Individuals assigned to intervention received fully automated advice that recommended specific switches from selected products higher in saturated fat to alternate similar products lower in saturated fat . Participants assigned to control received general non-specific advice about how to eat a diet lower in saturated fat . Outcome Measures : The outcome measure was the difference in saturated fat ( grams per 100 g of food ) in shopping baskets between the intervention and control groups . Results : There were 497 r and omised participants , mean age 40 y , each shopping for an average of about three people . The amount of saturated fat in the foods purchased by the intervention group was 0.66 % lower ( 95 % confidence interval 0.48–0.84 , p < 0.001 ) than in the control group . The effects of the intervention were sustained over consecutive shopping episodes , and there was no difference in the average cost of the food bought by each group . Conclusions : Fully automated , purchase-specific dietary advice offered to customers during Internet shopping can bring about changes in food purchasing habits that are likely to have significant public health implication s. Because implementation is simple to initiate and maintain , this strategy would likely be highly cost-effective Background Swaps are often used to encourage healthier food choices , but there is little evidence of their effectiveness . The current study assessed the impact of offering swaps on groceries purchased within a bespoke online supermarket ; specifically the objective was to measure the impact on energy density ( ED ) of food purchases following the offer of lower ED alternatives ( a ) at point of selection or at checkout , and ( b ) with or without explicit consent to receive swap prompts . Method Participants were asked to complete a 12-item shopping task within an online shopping platform , developed for study ing food purchasing . 1610 adults were r and omly assigned to a no swap control condition or to one of four interventions : consented swaps at selection ; consented swaps at checkout ; imposed swaps at selection ; or imposed swaps at checkout . Each swap presented two lower ED options from the same category as the participant ’s chosen food . Swap acceptance rate and purchased food ED were the primary outcomes . Results Of the mean 12.36 ( SD 1.26 ) foods purchased , intervention participants were offered a mean of 4.1 ( SD 1.68 ) swaps , with the potential to reduce the ED of purchased food ( effect ( 95 % CI ) : −83 kJ/100 g ( −110 – -56 ) , p = < 0.0001 ) . A median of one swap ( IQR 0 to 2 ) was accepted , not significantly reducing the purchased food ED ( effect ( 95 % CI ) : −24 kJ/100 g ( 4 – -52 ) , p = 0.094 ) . More swaps were accepted when offered at selection than at checkout ( OR ( 95 % CI ) = 1.224 ( 1.11 – 1.35 ) , p < 0.0001 ) , but no differences were seen with consent . Purchased food ED was unaffected by point of swap or consent , but reduced with number of swaps accepted ( effect per swap ( 95 % CI ) = −24 kJ/100 g ( −35 – -14 ) , p < 0.0001 ) . Conclusion Within category swaps did not reduce the ED of food purchases reflecting the observation that the use of swaps within an on-line shopping platform offered small potential gains in ED and a minority was accepted BACKGROUND Reducing fruit and vegetable ( F&V ) prices is a frequently considered policy to improve dietary habits in the context of health promotion . However , evidence on the effectiveness of this intervention is limited . OBJECTIVE The objective was to examine the effects of a 50 % price discount on F&Vs or nutrition education or a combination of both on supermarket purchases . DESIGN A 6-mo r and omized controlled trial within Dutch supermarkets was conducted . Regular supermarket shoppers were r and omly assigned to 1 of 4 conditions : 50 % price discounts on F&Vs , nutrition education , 50 % price discounts plus nutrition education , or no intervention . A total of 199 participants provided baseline data ; 151 ( 76 % ) were included in the final analysis . F&V purchases were measured by using supermarket register receipts at baseline , at 1 mo after the start of the intervention , at 3 mo , at 6 mo ( end of the intervention period ) , and 3 mo after the intervention ended ( 9 mo ) . RESULTS Adjusted multilevel models showed significantly higher F&V purchases ( per household/2 wk ) as a result of the price discount ( + 3.9 kg ; 95 % CI : 1.5 , 6.3 kg ) and the discount plus education intervention ( + 5.6 kg ; 95 % CI : 3.2 , 7.9 kg ) at 6 mo compared with control . Moreover , the percentage of participants who consumed recommended amounts of F&Vs ( ≥400 g/d ) increased from 42.5 % at baseline to 61.3 % at 6 mo in both discount groups ( P = 0.03 ) . Education alone had no significant effect . CONCLUSIONS Discounting F&Vs is a promising intervention strategy because it result ed in substantially higher F&V purchases , and no adverse effects were observed . Therefore , pricing strategies form an important focus for future interventions or policy . However , the long-term effects and the ultimate health outcomes require further investigation . This trial was registered at the IS RCT N Trial Register as number IS RCT N56596945 and at the Dutch Trial Register ( http://www.trialregister.nl/trialreg/index.asp ) as number NL22568.029.08 Objective Although many initiatives exist to improve the availability of healthy foods in corner stores , few r and omized trials have assessed their effects . This study evaluated , in a r and omized , controlled trial , the effects of a first-generation healthy corner store intervention on students ’ food and beverage purchases over a two-year period . Design and Methods Participants ( n=767 ) were 4th-6th grade students . Ten schools and their nearby corner stores ( n=24 ) were r and omly assigned to the healthy corner store intervention or an assessment -only control . Intercept surveys directly assessed the nutritional characteristics of students ’ corner store purchases at baseline , 1 and 2 years . Students ’ weight and heights were measured at baseline , 1 and 2 years . Results There were no differences in energy content per intercept purchased from control or intervention schools at year 1 ( p=0.12 ) or 2 ( p=0.58 ) . There were no differences between control and intervention students in BMI -z score ( year 1 , p=0.83 ; year 2 , p=0 . 98 ) or obesity prevalence ( year 1 , p=0.96 ; year 2 , p=0.58 ) . Conclusions A healthy corner store initiative did not result in significant changes in the energy content of corner store purchases or in continuous or categorical measures of obesity . These data will help to inform future interventions OBJECTIVE To assess the effects of a 50 % discount on low-energy density ( ED ) fruits and vegetables ( F&V ) , bottled water , and diet sodas on shoppers ' purchasing , food intake , and body weight . DESIGN AND METHODS A r and omized , controlled trial was conducted at two Manhattan supermarkets , in which a 4-week baseline period ( no discounts ) preceded an 8-week intervention period ( 50 % discount ) , and a 4-week follow-up period ( no discounts ) . Twenty-four hour dietary recall , as well as body weight and body composition measures were obtained every 4 weeks . Participants ( n = 47 , 33f ; 14 m ) were overweight and obese ( BMI ≥ 25 ) shoppers . RESULTS Purchasing of F&V during intervention was greater in the discount group than in the control group ( P < 0.0001 ) . Purchasing of these items by the discount group relative to the control group during follow-up was reduced from intervention ( P = 0.002 ) , but still remained higher than during baseline ( P = 0.01 ) , indicating a partially sustained effect . Intake of F&V increased from baseline to intervention in the discount group relative to the control group ( P = 0.037 ) and was sustained during follow-up . Body weight change did not differ significantly between groups , although post hoc analysis indicated a change within the discount group ( -1.1 kg , P = 0.006 ) but not within the control group . CONCLUSIONS Discounts of low-ED F&V led to increased purchasing and intake of those foods BACKGROUND The greater presence of supermarkets in low-income , high-minority neighborhoods has the potential to positively affect diet quality among those at greatest risk of obesity . In-store marketing strategies that draw attention to healthier products may be effective , sustainable , and scalable for improving diet quality and health . Few controlled studies of in-store marketing strategies to promote sales of healthier items in low-income , high-minority neighborhoods have been conducted . OBJECTIVE The objective of this study was to evaluate the effects of in-store marketing strategies to promote the purchase of specific healthier items in 5 product categories : milk , ready-to-eat cereal , frozen meals , in-aisle beverages , and checkout cooler beverages . DESIGN The design was a cluster-r and omized controlled trial conducted from 2011 to 2012 . Eight urban supermarkets in low-income , high-minority neighborhoods were the unit of r and omization , intervention , and analysis . Stores were matched on the percentage of sales from government food-assistance programs and store size and r and omly assigned to an intervention or control group . The 4 intervention stores received a 6-mo , in-store marketing intervention that promoted the sales of healthier products through placement , signage , and product availability strategies . The 4 control stores received no intervention and were assessment -only controls . The main outcome measure was weekly sales of the targeted products , which was assessed on the basis of the stores ' sales data . RESULTS Intervention stores showed significantly greater sales of skim and 1 % milk , water ( in aisle and at checkout ) , and 2 of 3 types of frozen meals compared with control store sales during the same time period . No differences were found between the stores in sales of cereal , whole or 2 % milk , beverages , or diet beverages . CONCLUSIONS These data indicate that straightforward placement strategies can significantly enhance the sales of healthier items in several food and beverage categories . Such strategies show promise for significant public health effects in communities with the greatest risk of obesity INTRODUCTION Despite growing evidence supporting the utility of front-of-pack nutrition labels in enabling consumer evaluation of food product healthiness , research on food choices is scarce . This study aims at comparing the impact of front-of-pack nutrition labels on consumers ' purchasing intentions . DESIGN Five-arm , open-label RCT . SETTING / PARTICIPANTS The study setting was a virtual web-based supermarket , with participants from the French NutriNet-Santé study . The eligibility requirement was grocery shopping involvement . INTERVENTION The intervention was to simulate one shopping situation with front-of-pack nutrition labels affixed on food products ( December 2014 to March 2015 ) . Participants were r and omly assigned to one of five exposure conditions using a central computer system : Guideline Daily Amounts , Multiple Traffic Lights , Five-Color Nutrition Label , Green Tick , or control ( no front-of-pack exposure ) . Given the nature of the intervention , masking of participants was not performed . MAIN OUTCOME MEASURES The primary outcome was the overall nutritional quality of the contents of the shopping cart , estimated using the United Kingdom Food St and ards Agency nutrient profiling system . Secondary outcomes included energy and nutrient content of the shopping cart . Impact of the front-of-pack labels was also evaluated across sociodemographic subgroups based on age , educational level , income , and nutrition knowledge . RESULTS A total of 11,981 participants were included in the analyses ( April 2015 ) . The Five-Color Nutrition Label significantly led to the highest overall nutritional quality of the shopping cart , as reflected by lower Food St and ards Agency scores ( M=8.72 ; SD=2.75 ) , followed by Multiple Traffic Lights ( M=8.97 ; SD=2.68 ) and Green Tick ( M=8.99 ; SD=2.71 ) , compared with the control ( M=9.34 ; SD=2.57 ) ( p<0.0001 ) . The Five-Color Nutrition Label was the only front-of-pack format that led to a lower content in lipids , saturated fatty acids , and sodium of the shopping cart ( all p<0.05 ) . The impact of the different front-of-pack labels was similar across sociodemographic subgroups . CONCLUSIONS The Five-Color Nutrition Label based on a color-coded and grade d scale indicating overall nutritional quality is effective in promoting overall healthier food choices in all population subgroups . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT02385838 Although much evidence links dietary patterns with coronary heart disease , effective and economical methods for inducing dietary change in non clinical population s are needed to influence public health . This study was design ed as a preliminary investigation of the feasibility of conducting effective nutrition education campaigns in supermarket setting s. Eight supermarkets from a supermarket chain in the Twin Cities area participated . Four were assigned to an experimental condition in which educational material s consisting of posters , recipes , and brochures were placed in the dairy section during a 6-month period . Four other stores were assigned to a control condition and received no educational material s. Shoppers in experimental and control stores completed a nutrition survey pre- and post-intervention . In addition , sales data for 25 dairy products were collected during a 10-month period . A significant increase in knowledge on the nutrition survey between pre- and posttests occurred among shoppers in all stores . There was no significant knowledge or product sales effect due to the education campaign . Study results suggest that , overall , shopper knowledge of food selection s for cardiovascular disease risk reduction is high and improving . Unfortunately , knowledge is often not reflected in food purchase patterns Objectives . We assessed the impact of a rewards-based incentive program on fruit and vegetable purchases by low-income families . Methods . We conducted a 4-phase prospect i ve cohort study with r and omized intervention and wait-listed control groups in Philadelphia , Pennsylvania , in December 2010 through October 2011 . The intervention provided a rebate of 50 % of the dollar amount spent on fresh or frozen fruit and vegetables , reduced to 25 % during a tapering phase , then eliminated . Primary outcome measures were number of servings of fruit and of vegetables purchased per week . Results . Households assigned to the intervention purchased an average of 8 ( 95 % confidence interval [ CI ] = 1.5 , 16.9 ) more servings of vegetables and 2.5 ( 95 % CI = 0.3 , 9.5 ) more servings of fruit per week than did control households . In longitudinal price-adjusted analyses , when the incentive was reduced and then discontinued , the amounts purchased were similar to baseline . Conclusions . Investigation of the financial costs and potential benefits of incentive programs to supermarkets , government agencies , and other stakeholders is needed to identify sustainable interventions We compared several procedures design ed to modify consumer food purchases with the objectives of reducing fat and increasing carbohydrate content , and reducing dollar expenditures on food . Participants were 126 volunteer community households which , after a 7-week baseline period , were r and omly assigned to video-modeling , video-modeling-feedback , video-lecture , video-lecture-feedback , participant-modeling , video-modeling- discussion , and control conditions . The main dependent measure was a weekly record of food purchases , convertible to percentages of nutrients and dollar expenditures . Results indicated that modeling-feedback and participant-modeling procedures were most effective ( e.g. , 6 % reduction of total fat consumption , 19 % dollar savings ) . Strategies to refine and automate modeling and feedback in supermarkets that may benefit consumers , corporations , and government are discussed BACKGROUND Behavioral interventions show potential for promoting increased fruit and vegetable consumption in the general population . However , little is known about their effectiveness or cost-effectiveness among socioeconomically disadvantaged groups , who are less likely to consume adequate fruit and vegetables . OBJECTIVE This study investigated the effects and costs of a behavior change intervention for increasing fruit and vegetable purchasing and consumption among socioeconomically disadvantaged women . DESIGN ShopSmart 4 Health was a r and omized controlled trial involving a 3-mo retrospective baseline data collection phase [ time ( T ) 0 ] , a 6-mo intervention ( T1-T2 ) , and a 6-mo no-intervention follow-up ( T3 ) . Socioeconomically disadvantaged women who were primary household shoppers in Melbourne , Australia , were r and omly assigned to either a behavior change intervention arm ( n = 124 ) or a control arm ( n = 124 ) . Supermarket transaction ( sales ) data and surveys measured the main outcomes : fruit and vegetable purchases and self-reported fruit and vegetable consumption . RESULTS An analysis of supermarket transaction data showed no significant intervention effects on vegetable or fruit purchasing at T2 or T3 . Participants in the behavior change intervention arm reported consumption of significantly more vegetables during the intervention ( T2 ) than did controls , with smaller intervention effects sustained at 6 mo postintervention ( T3 ) . Relative to controls , vegetable consumption increased by ∼0.5 serving · participant(-1 ) · d(-1 ) from baseline to T2 and remained 0.28 servings/d higher than baseline at T3 among those who received the intervention . There was no intervention effect on reported fruit consumption . The behavior change intervention cost A$ 3.10 ( in Australian dollars ) · increased serving of vegetables(-1 ) · d(-1 ) CONCLUSIONS : This behavioral intervention increased vegetable consumption among socioeconomically disadvantaged women . However , the lack of observed effects on fruit consumption and on both fruit and vegetable purchasing at intervention stores suggests that further investigation of effective nutrition promotion approaches for this key target group is required . The ShopSmart 4 Health trial was registered at www.is rct n.com as IS RCT N48771770 This study reports the results of one effort to help supermarket shoppers alter food purchases to make purchases ( and meals ) that are lower in fat and higher in fiber . A prototype interactive information system using instructional video programs , feedback on purchases with specific goals for change , weekly programs , and the ability to track user interactions and intended purchases was evaluated . The major dependent measure was users ' actual food purchases as derived from participants ' highly detailed supermarket receipts . After a 5- to 7-week baseline phase , participants were r and omly assigned to an experimental or control condition for the 7- to 8-week intervention phase . A follow-up phase began 5 to 8 weeks after participants completed the intervention and discontinued use of the system . The results indicated that experimental participants , when compared to control participants , decreased high fat purchases and increased high fiber purchases during intervention , with evidence for some maintenance of effect in follow-up . Plans for increasing the use and impact of the system are discussed A r and omized-control test of a multimedia nutrition intervention — the Nutrition for a Lifetime System (NLS © )— utilized supermarket receipts to examine effects of NLS treatment on the daily per person nutritional content of participants ' supermarket purchases . In regression analyses controlling for background variables , baseline purchases and trends toward increased purchasing , NLS treatment contributed to lower levels of total fat and to higher levels of total fiber and servings of fruits and vegetables at post-test . Redemption of NLS coupons contributed to greater decreases in fat and increases in servings of fruits and vegetables in users ' purchases . Implication s for future interventions promoting healthier food choices include tailoring program content and addressing broader lifestyle issues such as caloric intake and expenditure OBJECTIVE To report the design and baseline results of a rewards-based incentive to promote purchase of fruit and vegetables by lower-income households . DESIGN A four-phase r and omized trial with wait-listed controls . In a pilot study , despite inadequate study coupon use , purchases of fresh fruit ( but not vegetables ) increased , but with little maintenance . In the present study , credits on the study store gift card replace paper coupons and a tapering phase is added . The primary outcome is the number of servings of fresh and frozen fruit and vegetables purchased per week . SETTING A large full-service supermarket located in a predominantly minority community in Philadelphia , Pennsylvania , USA . SUBJECTS Fifty-eight households , with at least one child living in the home . RESULTS During the baseline period , households purchased an average of 3·7 servings of fresh vegetables and an average of less than 1 serving of frozen vegetables per week . Households purchased an average of 1·9 servings of fresh fruit per week , with little to no frozen fruit purchases . Overall , the range of fresh and frozen produce purchased during this pre-intervention period was limited . CONCLUSIONS At baseline , produce purchases were small and of limited variety . The study will contribute to underst and ing the impact of financial incentives on increasing the purchases of healthier foods by lower-income population Purpose . The purpose of this study was to evaluate whether a supermarket point-of-purchase intervention could increase shoppers ' consumption of fruits and vegetables . Methods . Eight supermarkets in rural Iowa were r and omized to receive either an 8-month intervention or no intervention . The intervention consisted of ( 1 ) one-page supermarket flyers that identified fruits and vegetables on sale , gave recipes and menu ideas for using sale foods , and gave a store coupon worth 50 cents toward the purchase of any fruit or vegetable ; ( 2 ) store signage to identify fruits and vegetables featured on the flyer ; and ( 3 ) consciousness raising activities such as food demonstrations and nutrition related signage . Evaluation was based on exit interviews and take-home surveys , completed by r and om sample s of 120 shoppers from each store at baseline and approximately 1-year post r and omization . Results . At follow-up , 42.9 % of intervention store shoppers and 6.5 % of control shoppers recalled seeing the intervention flyer . Thirty-six percent of intervention shoppers had used a 50-cent coupon and 18 % had used a recipe . Approximately 70 % of all shoppers had purchased fruits or vegetables on the day they were interviewed , which did not differ between intervention and control stores . Compared to change in control shoppers , there was a borderline statistically significant 8.4 percentage point increase ( p < .07 ) in the percentage of intervention store shoppers in the action or maintenance stages of dietary change , but there was no corresponding increase in fruit and vegetable consumption . Discussion . Studies to test point-of-purchase interventions are difficult to design , implement , and evaluate . More powerful interventions are probably necessary to induce shoppers to purchase and consume more fruits and vegetables BACKGROUND Evidence is mounting that price discounts can be effective in improving diet . This study examined the effectiveness of a 20 % price discount on food and drink purchases with and without consumer education in remote Indigenous Australia . METHODS A 20 % discount on fruit , vegetables , water , and artificially sweetened soft drinks was applied for 24 weeks in 20 communities in remote Indigenous Australia where the community store was managed by the Arnhem L and Progress Aboriginal Corporation ( ALPA ) or Outback Stores ( OBS ) in a stepped-wedge r and omised trial . Communities were r and omly allocated to a fixed framework of five sets of four stratified by store association ; ten stores ( two in each set ) were r and omly assigned to receive consumer education . A store from each of the ALPA and OBS store groups ( contained in separate opaque envelopes ) was selected , and stores in turn continued to be consecutively allocated to the fixed store set framework , starting with the first store slot in the first store set , until all stores had been allocated . The effect of the discount on the weight of fruit and vegetables purchased ( the primary endpoint ) was assessed using weekly store sales data and mixed models per protocol . We did sensitivity analyses by repeating the analyses with the outliers included and repeating the analyses for the primary outcome measure removing each store one at a time . This trial was registered with Australian New Zeal and Clinical Trials Registry , number ACTRN12613000694718 . FINDINGS Weekly store sales data on all food and drink products sold in 20 stores were collected from July 1 , 2012 , to Dec 28 , 2014 . Price discount alone was associated with a 12·7 % ( 95 % CI 4·1 - 22·1 ) increase in purchases in grams of fruit and vegetables combined ( primary outcome ) , and a 19·8 % ( 6·2 - 35·1 ) increase post discount ( after vs before ) ; an effect of 12 g and 18 g per capita per day . Sensitivity analyses did not modify the results for the primary outcome measure . INTERPRETATION A 20 % discount can only increase fruit and vegetable purchases to help protect against obesity and diet related disease to a certain extent . Large discounts might have a greater impact than small discounts . Creative merch and ising approaches to consumer education could also be considered alongside fiscal interventions to achieve marked improvements in diet . FUNDING Australian National Health and Medical Research Council Sugar sweetened beverage ( SSB ) taxes are receiving increased political interest . However , there have been no experimental studies of the effects of price increases on SSBs or the effects on close substitutes such as diet drinks , alcohol or sugary snacks . Therefore , the aim of this study was to examine the effects of a price increase on SSBs on beverage and snack purchases using a r and omized controlled design within a three-dimensional web-based supermarket . The trial contained two conditions : experimental condition with a 19 % tax on SSBs ( to reflect an increase in Dutch value added tax from 6 % to 19 % ) ; and a control condition with regular prices . N = 102 participants were r and omized and purchased groceries on a single occasion at a three-dimensional Virtual Supermarket . Data were analysed using independent t-tests and regression analysis . Results showed that participants in the price increase condition purchased significantly less SSBs than the control group ( B = -.90 ; 95 % CI = -1.70 to -.10 L per household per week ) . There were no significant effects on purchases in other beverage or snack food categories . This means that the higher VAT rate was effective in reducing SSB purchases and had no negative side-effects OBJECTIVE To conduct a pilot study to determine if improving the visibility and quality of fresh produce ( choice architecture ) in corner stores would increase fruit/vegetable purchases by families participating in the Special Supplemental Nutrition Program for Women , Infants , and Children ( WIC ) . DESIGN Six stores were r and omly assigned to choice architecture intervention or control . Store-level WIC sales data were provided by the state . Primary outcomes were WIC fruit/vegetable voucher and non-fruit/vegetable voucher sales , comparing trends from baseline ( December 2012-October 2013 ) with the five-month intervention period ( December 2013-April 2014 ) . Secondary outcomes were differences in customer self-reported fruit/vegetable purchases between baseline and end of the intervention . SETTING Chelsea , MA , USA , a low-income urban community . SUBJECTS Adult customers ( n 575 ) completing store exit interviews . RESULTS During baseline , WIC fruit/vegetable and non-fruit/vegetable sales decreased in both intervention and control stores by $ US 16/month . During the intervention period , WIC fruit/vegetable sales increased in intervention stores by $ US 40/month but decreased in control stores by $ US 23/month ( difference in trends : $ US 63/month ; 95 % CI 4 , 121 $ US/month ; P=0·036 ) ; WIC non-fruit/vegetable sales were not different ( P=0·45 ) . Comparing baseline and intervention-period exit interview responses by customers participating in WIC ( n 134 ) , intervention store customers reported increased fruit/vegetable purchases compared with control store customers ( 18 v. -2 % ) , but this did not achieve statistical significance ( P=0·11 ) . CONCLUSIONS Placement of fruits/vegetables near the front of corner stores increased purchase of produce by customers using WIC . New policies that incentivize stores to stock and prominently display good- quality produce could promote healthier food choices of low-income families BACKGROUND Traditional methods to improve population diets have largely relied on individual responsibility , but there is growing interest in structural interventions such as pricing policies . OBJECTIVE The aim was to evaluate the effect of price discounts and tailored nutrition education on supermarket food and nutrient purchases . DESIGN A 2 x 2 factorial r and omized controlled trial was conducted in 8 New Zeal and supermarkets . A total of 1104 shoppers were r and omly assigned to 1 of the following 4 interventions that were delivered over 6 mo : price discounts ( 12.5 % ) on healthier foods , tailored nutrition education , discounts plus education , or control ( no intervention ) . The primary outcome was change in saturated fat purchased at 6 mo . Secondary outcomes were changes in other nutrients and foods purchased at 6 and 12 mo . Outcomes were assessed by using electronic scanner sales data . RESULTS At 6 mo , the difference in saturated fat purchased for price discounts on healthier foods compared with that purchased for no discount on healthier foods was -0.02 % ( 95 % CI : -0.40 % , 0.36 % ; P = 0.91 ) . The corresponding difference for tailored nutrition education compared with that for no education was -0.09 % ( 95 % CI : -0.47 % , 0.30 % ; P = 0.66 ) . However , those subjects who were r and omly assigned to receive price discounts bought significantly more predefined healthier foods at 6 mo ( 11 % more ; mean difference : 0.79 kg/wk ; 95 % CI : 0.43 , 1.16 ; P < 0.001 ) and 12 mo ( 5 % more ; mean difference : 0.38 kg/wk ; 95 % CI : 0.01 , 0.76 ; P = 0.045 ) . Education had no effect on food purchases . CONCLUSIONS Neither price discounts nor tailored nutrition education had a significant effect on nutrients purchased . However , the significant and sustained effect of discounts on food purchases suggests that pricing strategies hold promise as a means to improve population diets

Conclusions : Despite a statistically significant reduction of myocardial damage in STEMI patients , the magnitude of the reduction was small and a significant impact on clinical events is unlikely . With respect to elective percutaneous coronary intervention , remote ischaemic conditioning had no influence on myocardial injury and its use is not supported by our analysis

Background : The efficacy of remote ischaemic conditioning in clinical trials of ST-segment elevation myocardial infa rct ion ( STEMI ) or elective percutaneous coronary intervention is controversial . We aim ed to systematic ally review and meta-analyse whether remote ischaemic conditioning reduces myocardial damage in those patients .

Remote ischemic preconditioning reduces myocardial infa rct ion ( MI ) in animal models . We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia ( PerC ) and before reperfusion and examined the role of the K(+)-dependent ATP ( K(ATP ) ) channel . Twenty 20-kg pigs were r and omized ( 10 in each group ) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion . PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion . Left ventricular ( LV ) function was assessed by a conductance catheter and extent of infa rct ion by tetrazolium staining . The extent of MI was significantly reduced by PerC ( 60.4 + /- 14.3 vs. 38.3 + /- 15.4 % , P = 0.004 ) and associated with improved functional indexes . The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion ( P = 0.01 and 0.04 , respectively ) . At 120 min of reperfusion , preload-recruitable stroke work declined 38 + /- 6 % and 3 + /- 5 % in control and PerC , respectively ( P = 0.001 ) . The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups , but optimal heart rate was significantly lower in the control group ( P = 0.04 ) . There were fewer malignant arrhythmias with PerC during reperfusion ( P = 0.02 ) . These protective effects of PerC were abolished by glibenclamide . Intermittent limb ischemia during myocardial ischemia reduces MI , preserves global systolic and diastolic function , and protects against arrhythmia during the reperfusion phase through a K(ATP ) channel-dependent mechanism . Underst and ing this process may have important therapeutic implication s for a range of ischemia-reperfusion syndromes BACKGROUND Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty . We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infa rct ion , and done before primary percutaneous coronary intervention , increases myocardial salvage . METHODS 333 consecutive adult patients with a suspected first acute myocardial infa rct ion were r and omly assigned in a 1:1 ratio by computerised block r and omisation to receive primary percutaneous coronary intervention with ( n=166 patients ) versus without ( n=167 ) remote conditioning ( intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff ) . Allocation was concealed with opaque sealed envelopes . Patients received remote conditioning during transport to hospital , and primary percutaneous coronary intervention in hospital . The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention , measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment ; analysis was per protocol . This study is registered with Clinical Trials.gov , number NCT00435266 . FINDINGS 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria , 32 were lost to follow-up , and 77 did not complete the follow-up with data for salvage index . Median salvage index was 0.75 ( IQR 0.50 - 0.93 , n=73 ) in the remote conditioning group versus 0.55 ( 0.35 - 0.88 , n=69 ) in the control group , with median difference of 0.10 ( 95 % CI 0.01 - 0.22 ; p=0.0333 ) ; mean salvage index was 0.69 ( SD 0.27 ) versus 0.57 ( 0.26 ) , with mean difference of 0.12 ( 95 % CI 0.01 - 0.21 ; p=0.0333 ) . Major adverse coronary events were death ( n=3 per group ) , reinfa rct ion ( n=1 per group ) , and heart failure ( n=3 per group ) . INTERPRETATION Remote ischaemic conditioning before hospital admission increases myocardial salvage , and has a favourable safety profile . Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes . FUNDING Fondation Leducq OBJECTIVES We sought to relate left ventricular ejection fraction ( EF ) , end-systolic volume index ( ESVI ) and infa rct size ( IS ) , as measured in a single r and omized trial , to six-month mortality after myocardial infa rct ion ( MI ) treated with thrombolysis . BACKGROUND These three prognostic indicators have never been compared in the same study group . METHODS Radionuclide angiographic and single-photon emission computed tomographic sestamibi measurements of IS were performed in 1,194 and 1,181 patients , respectively , of the 2,948 patients enrolled in the Collaborative Organization for RheothRx Evaluation ( CORE ) trial . Ejection fraction , ESVI and IS , as measured by central laboratories in these radionuclide sub studies , were tested for their association with six-month mortality . RESULTS Ejection fraction ( n = 1,137 ; p < 0.0001 ) , ESVI ( n = 945 ; p = 0.055 ) and IS ( n = 1,164 ; p = 0.03 ) were all associated with six-month mortality . Each of these measurements was significantly correlated with the other two , regardless of MI location . In an " overlap " group of 753 patients ( 25.5 % of the population ; 13 deaths ) in whom all three measurements were available , EF ( p = 0.001 ) was a stronger predictor than ESVI ( p = 0.005 ) or IS ( p = 0.01 ) . Neither of the other two measurements added independent prognostic information . The highest risk subgroup ( EF < 30 % ) had an 11 % six-month mortality , but comprised only 95 patients ( 8.3 % ) . CONCLUSIONS Ejection fraction , ESVI and IS measurements performed one to two weeks after MI can each predict six-month mortality . Ejection fraction was superior to the other two measurements . However , this study had limited power to detect independent significance of ESVI or IS BACKGROUND Contrast medium-induced acute kidney injury ( CI-AKI ) is a cardiovascular complication after myocardial infa rct ion treated with emergency percutaneous coronary intervention . The aim of this r and omized , sham-controlled trial was to evaluate the impact of remote ischemic preconditioning ( RIPC ) on CI-AKI in patients with ST-elevation myocardial infa rct ion who received emergency primary percutaneous coronary intervention . METHODS AND RESULTS Patients with a suspected ST-elevation myocardial infa rct ion were r and omly assigned at a 1:1 ratio to receive percutaneous coronary intervention either with ( n=63 ) or without ( n=62 ) RIPC ( intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a blood pressure cuff ) . A total of 47 RIPC patients and 47 control patients met all study criteria . The primary endpoint was the incidence of CI-AKI , which was defined as an increase in serum creatinine > 0.5mg/dL or > 25 % over the baseline value 48 - 72h after administration of contrast medium . The incidence of CI-AKI was 10 % ( n=5 ) in the RIPC group and 36 % ( n=17 ) in the control group ( p=0.003 ) . The odds ratio of CI-AKI in patients who received RIPC was 0.18 ( 95 % confidence interval : 0.05 - 0.64 ; p=0.008 ) . CONCLUSIONS In patients with ST-elevation myocardial infa rct ion , RIPC before percutaneous coronary intervention reduced the incidence of CI-AKI Introduction Myocardial injury after percutaneous coronary intervention ( PCI ) occurs in approximately 30 % of procedures , and is related to worse prognosis . Effects of remote ischemic preconditioning ( RIPC ) on reperfusion injury have been investigated before , yielding conflicting results . Aim To assess the impact of a single episode of RIPC on myocardial injury after elective PCI . Material and methods One hundred and four patients undergoing elective PCI , with normal baseline cardiac troponin-I ( cTn-I ) values , were r and omized to two groups . Two patients were excluded due to data loss , and 102 patients were analyzed . Five minutes of ischemic preconditioning was delivered just before the intervention to the preconditioning group , by inflating the blood pressure cuff up to 200 mm Hg on the non-dominant arm . Postprocedural 16th hour cTn-I , ΔcTn-I ( difference between the 16th h and baseline cTn-I values ) and the prevalence of type 4a myocardial infa rct ion were compared between the two groups . Results Median cTn-I values after the procedure were compared . 16th hour cTn-I was insignificantly lower in the preconditioning arm ( 0.026 μg/l vs. 0.045 μg/l , p = 0.186 ) . The incidence of cTn-I elevation 5-fold above the upper reference limit ( URL ) ( > 0.115 μg/l ) was lower in the preconditioning group , but it was also not significant ( 21.6 % vs. 11.8 % , p = 0.184 ) . Conclusions A single episode of RIPC before elective PCI demonstrated less troponin elevation but failed to show a significant effect Background Remote ischemic postconditioning ( RIPC ) is suggested to protect the myocardium against ischemia in various setting s. However , the effect of RIPC in patients with acute ST-elevation myocardial infa rct ion ( STEMI ) who undergo thrombolysis has yet to be examined . Patients and methods In this single-center , r and omized controlled trial , we examined the effect of RIPC on the resolution of ST-segment elevation ( STR ) in response to thrombolysis . Patients in the RIPC group had three cycles of 5‑min cuff inflation followed by 5‑min deflation to the upper arm . Results The study comprised 78 patients ( 15 women ) , of whom 41 were r and omized to the RIPC group and 37 to the control group . STR occurred in 61 % of the patients in the RIPC group , while it was detected only in 35 % of controls ( p = 0.026 ) . Although STR was more common in the RIPC group , there was no difference in the extent of ΣCK-48 h between the two groups . Furthermore , the length of hospital stay and the frequency of adverse events were similar between the RIPC and control groups . Conclusion RIPC during thrombolytic therapy in STEMI was associated with a higher frequency of STR . However , it did not affect enzymatic infa rct size or the frequency of adverse events . ( Clinical trial registration number : I RCT 2014011916229N2.)ZusammenfassungHintergrundDie indirekte ischämische Postkonditionierung ( „ remote ischemic postconditioning “ , RIPC ) soll das Myokard gegen Ischämie in verschiedenen Situationen schützen . Die Wirksamkeit der RIPC bei Patienten mit akutem ST-Strecken-Hebungs-Infarkt ( STEMI ) , bei denen eine Thrombolyse erfolgt , muss allerdings noch untersucht werden . Patienten und Method enIn der vorliegenden r and omisierten kontrollierten Einzelzentrumsstudie wurde die Wirksamkeit des RIPC auf die Rückbildung der ST-Strecken-Hebung ( STR ) als Reaktion auf die Thrombolyse untersucht . Patienten in der RIPC-Gruppe hatten 3 Zyklen mit 5‑minütigem Aufpumpen der Manschette und anschließendem 5‑minütigem Ablassen der Manschette am Oberarm . ErgebnisseAn der Studie nahmen 78 Patienten ( davon 15 Frauen ) teil , von denen 41 r and omisiert der RIPC-Gruppe und 37 der Kontrollgruppe zugeteilt wurden . Eine STR trat bei 61 % der Patienten in der RIPC-Gruppe auf , aber nur bei 35 % der Kontrollen ( p = 0,026 ) . Zwar gab es eine STR häufiger in der RIPC-Gruppe , aber es best and kein Unterschied i m Ausmaß von ΣCK-48 h zwischen den beiden Gruppen . Darüber hinaus waren die Verweildauer und die Häufigkeit unerwünschter Ereignisse zwischen der RIPC- und der Kontrollgruppe ähnlich . SchlussfolgerungEine RIPC während der Thromobolysetherapie bei STEMI ging mit größerer Häufigkeit einer STR einher . Sie hatte jedoch keine Auswirkung auf die enzymatische Infarktgröße oder die Häufigkeit unerwünschter Ereignisse . ( Nummer i m Register klinischer Studien , „ clinical trial registration number “ : I RCT 2014011916229N2 . Background — The effect of & bgr;-blockers on infa rct size when used in conjunction with primary percutaneous coronary intervention is unknown . We hypothesize that metoprolol reduces infa rct size when administered early ( intravenously before reperfusion ) . Methods and Results — Patients with Killip class II or less anterior ST-segment – elevation myocardial infa rct ion ( STEMI ) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were r and omized to receive intravenous metoprolol ( n=131 ) or not ( control , n=139 ) before reperfusion . All patients without contraindications received oral metoprolol within 24 hours . The predefined primary end point was infa rct size on magnetic resonance imaging performed 5 to 7 days after STEMI . Magnetic resonance imaging was performed in 220 patients ( 81 % ) . Mean±SD infa rct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control ( 25.6±15.3 versus 32.0±22.2 g ; adjusted difference , −6.52 ; 95 % confidence interval , −11.39 to −1.78 ; P=0.012 ) . In patients with pre – percutaneous coronary intervention Thrombolysis in Myocardial Infa rct ion grade 0 to 1 flow , the adjusted treatment difference in infa rct size was −8.13 ( 95 % confidence interval , −13.10 to −3.16 ; P=0.0024 ) . Infa rct size estimated by peak and area under the curve creatine kinase release was measured in all study population s and was significantly reduced by intravenous metoprolol . Left ventricular ejection fraction was higher in the intravenous metoprolol group ( adjusted difference , 2.67 % ; 95 % confidence interval , 0.09–5.21 ; P=0.045 ) . The composite of death , malignant ventricular arrhythmia , cardiogenic shock , atrioventricular block , and reinfa rct ion at 24 hours in the intravenous metoprolol and control groups was 7.1 % and 12.3 % , respectively ( P=0.21 ) . Conclusions — In patients with anterior Killip class II or less ST-segment – elevation myocardial infa rct ion undergoing primary percutaneous coronary intervention , early intravenous metoprolol before reperfusion reduced infa rct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01311700 . EUDRACT number : 2010 - 019939 - 35 Background — Myocyte necrosis as a result of elective percutaneous coronary intervention ( PCI ) occurs in approximately one third of cases and is associated with subsequent cardiovascular events . This study assessed the ability of remote ischemic preconditioning ( IPC ) to attenuate cardiac troponin I ( cTnI ) release after elective PCI . Methods and Results — Two hundred forty-two consecutive patients undergoing elective PCI with undetectable preprocedural cTnI were recruited . Subjects were r and omized to receive remote IPC ( induced by three 5-minute inflations of a blood pressure cuff to 200 mm Hg around the upper arm , followed by 5-minute intervals of reperfusion ) or control ( an uninflated cuff around the arm ) before arrival in the catheter laboratory . The primary outcome was cTnI at 24 hours after PCI . Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months . The median cTnI at 24 hours after PCI was lower in the remote IPC compared with the control group ( 0.06 versus 0.16 ng/mL ; P=0.040 ) . After remote IPC , cTnI was < 0.04 ng/mL in 44 patients ( 42 % ) compared with 24 in the control group ( 24 % ; P=0.01 ) . Subjects who received remote IPC experienced less chest discomfort ( P=0.0006 ) and ECG ST-segment deviation ( P=0.005 ) than control subjects . At 6 months , the major adverse cardiac and cerebral event rate was lower in the remote IPC group ( 4 versus 13 events ; P=0.018 ) . Conclusion — Remote IPC reduces ischemic chest discomfort during PCI , attenuates procedure-related cTnI release , and appears to reduce subsequent cardiovascular events Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more There is conflicting evidence regarding the effectiveness of remote ischemic preconditioning ( RIPC ) in patients undergoing elective percutaneous coronary intervention ( PCI ) . Therefore , we prospect ively enrolled elderly patients with coronary heart disease ( CHD ) with diabetes mellitus ( DM ) undergoing elective drug-eluting stent ( DES ) implantation . They were r and omized to receive RIPC within 2 hours before PCI ( n = 102 ) or not ( controls , n = 98 ) . Baseline clinical characteristics were similar between the 2 groups . Despite a trend toward decline , the median high-sensitivity cardiac troponin I ( hscTnI ) level ( P = .256 ) and the incidence of myocardial infa rct ion ( MI ) type 4a ( P = .106 ) in the RIPC group 16 hours after PCI procedure was not significantly different from the control group . The RIPC could attenuate the release of a myocardial biomarker but failed to show a significant effect on hscTnI level or MI type 4a incidence after PCI procedure in elderly patients with CHD having DM undergoing elective DES implantation OBJECTIVES This study aim ed to determine whether remote ischemic conditioning ( RIC ) initiated prior to primary percutaneous coronary intervention ( PPCI ) could reduce myocardial infa rct ( MI ) size in patients presenting with ST-segment elevation myocardial infa rct ion . BACKGROUND RIC , using transient limb ischemia and reperfusion , can protect the heart against acute ischemia-reperfusion injury . Whether RIC can reduce MI size , assessed by cardiac magnetic resonance ( CMR ) , is unknown . METHODS We r and omly assigned 197 ST-segment elevation myocardial infa rct ion patients with TIMI ( Thrombolysis In Myocardial Infa rct ion ) flow grade 0 to receive RIC ( four 5-min cycles of upper arm cuff inflation/deflation ) or control ( uninflated cuff placed on upper arm for 40 min ) protocol s prior to PPCI . The primary study endpoint was MI size , measured by CMR in 83 subjects on days 3 to 6 after admission . RESULTS RIC reduced MI size by 27 % , when compared with the MI size of control subjects ( 18.0 ± 10 % [ n = 40 ] vs. 24.5 ± 12.0 % [ n = 43 ] ; p = 0.009 ) . At 24 h , high-sensitivity troponin T was lower with RIC ( 2,296 ± 263 ng/l [ n = 89 ] vs. 2,736 ± 325 ng/l [ n = 84 ] ; p = 0.037 ) . RIC also reduced the extent of myocardial edema measured by T2-mapping CMR ( 28.5 ± 9.0 % vs. 35.1 ± 10.0 % ; p = 0.003 ) and lowered mean T2 values ( 68.7 ± 5.8 ms vs. 73.1 ± 6.1 ms ; p = 0.001 ) , precluding the use of CMR edema imaging to correctly estimate the area at risk . Using CMR-independent coronary angiography jeopardy scores to estimate the area at risk , RIC , when compared with the control protocol , was found to significantly improve the myocardial salvage index ( 0.42 ± 0.29 vs. 0.28 ± 0.29 ; p = 0.03 ) . CONCLUSIONS This r and omized study demonstrated that in ST-segment elevation myocardial infa rct ion patients treated by PPCI , RIC , initiated prior to PPCI , reduced MI size , increased myocardial salvage , and reduced myocardial edema To assess whether late remote ischemic preconditioning ( L-RIPC ) is effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention ( PCI ) . L-RIPC is exerted by newly synthesized cardioprotective proteins . The cardioprotective effects of L-RIPC are more durable . 200 consecutive patients undergoing elective PCI were r and omized to receive L-RIPC ( induced by three 5-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm , followed by 5-min intervals of reperfusion ) or control ( an uninflated cuff around the arm ) at 18 h before PCI . Creatine phosphokinase ( CK ) , its cardiac isoenzyme ( CK-MB ) , troponin I ( TNI ) , and high-sensitivity C-reactive protein ( hs-CRP ) levels were measured at 24 h after PCI . Adverse events ’ rates at 6 months were assessed . Compared with the control group , patients in L-RIPC group were observed with significantly lower incidences in Chest pain score > 1 and ECG ST deviation > 1 mm ( P < 0.05 ) . The median TNI , CK , and CK-MB concentrations at 24 h were lower in the L-RIPC group ( 0.009 vs. 0.036 ng/mL , 123 vs. 186 IU/L , 15 vs. 27 IU/L ; P < 0.05 ) . There was no statistical difference in hs-CRP between two groups . At 6 months , the adverse events ’ rate was lower in the L-RIPC group ( P = 0.036 ) . L-RIPC is effective in myocardial protection in patients undergoing elective PCI and reduces adverse events ’ rate at 6 months Background Third‐generation P2Y12 antagonists ( prasugrel and ticagrelor ) are recommended in guidelines on ST‐segment elevation myocardial infa rct ion . Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second‐generation P2Y12 antagonist clopidogrel are unclear . The aim of this post hoc analysis of the Complete Versus Lesion‐Only PRImary PCI Trial‐CMR ( CvLPRIT‐CMR ) sub study was to assess whether prasugrel and ticagrelor were associated with reduced infa rct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention . Methods and Results CvLPRIT‐CMR was a multicenter , prospect i ve , r and omized , open‐label , blinded end point trial in 203 ST‐segment elevation myocardial infa rct ion patients with multivessel disease undergoing primary percutaneous coronary intervention with either infa rct ‐related artery – only or complete revascularization . P2Y12 inhibitors were administered according to local guidelines . The primary end point of infa rct size on cardiovascular magnetic resonance was not significantly different between the r and omized groups . P2Y12 antagonist administration was not r and omized . Patients receiving clopidogrel ( n=70 ) compared with those treated with either prasugrel or ticagrelor ( n=133 ) were older ( 67.8±12 versus 61.5±10 years , P<0.001 ) , more frequently had hypertension ( 49 % versus 29 % , P=0.007 ) , and tended to have longer symptom‐to‐revascularization time ( 234 versus 177 minutes , P=0.05 ) . Infa rct size ( median 16.1 % [ quartiles 1–3 , 10.5–27.7 % ] versus 12.1 % [ quartiles 1–3 , 4.8–20.7 % ] of left ventricular mass , P=0.013 ) and microvascular obstruction incidence ( 65.7 % versus 48.9 % , P=0.022 ) were significantly greater in patients receiving clopidogrel . Infa rct size remained significantly different after adjustment for important covariates using both generalized linear models ( P=0.048 ) and propensity score matching ( P=0.025 ) . Conclusions In this analysis of CvLPRIT‐CMR , third‐generation P2Y12 antagonists were associated with smaller infa rct size and lower microvascular obstruction incidence versus the second‐generation P2Y12 antagonist clopidogrel for ST‐segment elevation myocardial infa rct ion . Clinical Trial Registration URL : http://www.is rct n.com/IS RCT N70913605 Local ischemic postconditioning ( IPost ) and remote ischemic perconditioning ( RIPer ) are promising cardioprotective therapies in ST-elevation myocardial infa rct ion ( STEMI ) . We aim ed : ( 1 ) to investigate whether RIPer initiated at the catheterization laboratory would reduce infa rct size , as measured using serum creatine kinase-MB isoenzyme ( CK-MB ) release as a surrogate marker ; ( 2 ) to assess if the combination of RIPer and IPost would provide an additional reduction . Patients ( n = 151 ) were r and omly allocated to one of the following groups : ( 1 ) control group , percutaneous transluminal coronary angioplasty ( PTCA ) alone ; ( 2 ) RIPer group , PTCA combined with RIPer , consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion ; ( 3 ) RIPer+IPost group , PTCA combined with RIPer and IPost , consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon . The CK-MB area under the curve ( AUC ) over 72 h was reduced in RIPer , and RIPer+IPost groups , by 31 and 29 % , respectively , compared to the Control group ; however , CK-MB AUC differences between the three groups were not statistically significant ( p = 0.06 ) . Peak CK-MB , CK-MB AUC to area at risk ( AAR ) ratio , and peak CK-MB level to AAR ratio were all significantly reduced in the RIPer and RIPer+IPost groups , compared to the Control group . On the contrary , none of these parameters was significantly different between RIPer+IPost and RIPer groups . To conclude , starting RIPer therapy immediately prior to revascularization was shown to reduce infa rct size in STEMI patients , yet combining this therapy with an IPost strategy did not lead to further decrease in infa rct size Abstract The role of remote ischemic postconditioning ( RIPostC ) in improving left ventricular ( LV ) remodeling after primary percutaneous coronary intervention ( PCI ) is not well established . To determine the efficacy and safety of RIPostC in improving LV remodeling and cardiovascular outcomes after primary PCI for anterior ST‐elevation myocardial infa rct ion ( STEMI ) . Seventy‐one patients with anterior STEMI were r and omized to primary PCI with RIPostC protocol ( n = 36 ) versus conventional primary PCI ( n = 35 ) . Primary outcomes included LV remodeling and LV ejection fraction ( LVEF ) at 6 month follow‐up using transthoracic echocardiography . Secondary outcomes included infa rct size , ST‐segment resolution ( STR ) ≥70 % , Thrombolysis in Myocardial Infa rct ion ( TIMI ) flow grade , and myocardial blush grade ( MBG ) . Major adverse cardiac events ( MACEs ) were also assessed at 6 months . Safety outcome included incidence of acute kidney injury ( AKI ) post primary PCI . Sixty patients completed the study . At 6 months , there was no significant decrease in the incidence of LV remodeling with RIPostC group ( p = 0.42 ) . Similarly , RIPostC failed to show significant improvement in LVEF . However , STR ≥ 70 % after primary PCI was achieved more in the RIPostC group ( p = 0.04 ) , with a trend toward less AKI in the RIPostC group ( p = 0.08 ) . All other secondary end points , including MACEs at 6 months , were similar in both groups . RIPostC might be associated with better STR after reperfusion as well as less incidence of AKI in patients undergoing primary PCI for anterior wall STEMI , indicating potential benefit in those patients . Whether this role can be translated to better outcomes after primary PCI warrants further investigation BACKGROUND The effect of remote ischemic preconditioning ( RIPC ) and nicor and il on periprocedural myocardial injury ( pMI ) in patients with planned percutaneous coronary intervention ( PCI ) remains controversial . The aim of this r and omized trial was to evaluate the effect of RIPC or nicor and il on pMI following PCI in patients with stable coronary artery disease ( CAD ) compared with a control group . METHODS Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control , RIPC , or intravenous nicor and il ( 6mg/h ) . Automated RIPC was performed by a device , which performs intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a pressure cuff . The primary outcome was the incidence of pMI , determined by an elevation in high-sensitive troponin T or creatine kinase myocardial b and at 12 or 24h after PCI . The secondary outcomes were ischemic events during PCI and adverse clinical events at 8months after PCI . RESULTS A total of 391 patients were enrolled . The incidence of pMI following PCI was not significantly different between the control group ( 48.9 % ) and RIPC group ( 39.5 % ; p=0.14 ) , or between the control group and nicor and il group ( 40.3 % ; p=0.17 ) . There were no significant differences in ischemic events during PCI or adverse clinical events within 8months after PCI among the three groups . CONCLUSIONS This study demonstrated moderate reductions in biomarker release and pMI by RIPC or intravenous nicor and il prior to the PCI consistently , but may have failed to achieve statistical significance because the study was underpowered AIMS Remote ischaemic conditioning ( RIC ) and postconditioning ( PostC ) are both potent activators of innate protection against ischaemia-reperfusion injury and have demonstrated cardioprotection in experimental and clinical ST-elevation myocardial infa rct ion ( STEMI ) trials . However , their combined effects have not been studied in detail . The aim of this study was to evaluate if the co-application of intrahospital RIC and PostC has a more powerful effect on myocardial salvage compared with either PostC alone or control . METHODS AND RESULTS This prospect i ve , controlled , single-centre study r and omized 696 STEMI patients to one of the following three groups : ( i ) combined intrahospital RIC + PostC in addition to primary percutaneous coronary intervention ( PCI ) ; ( ii ) PostC in addition to PCI ; and ( iii ) conventional PCI ( control ) . The primary endpoint myocardial salvage index was assessed by cardiac magnetic resonance ( CMR ) imaging within 3 days after infa rct ion . Secondary endpoints included infa rct size and microvascular obstruction ( MVO ) assessed by CMR . The combined clinical endpoint consisted of death , reinfa rct ion , and new congestive heart failure within 6 months . The primary endpoint myocardial salvage index was significantly greater in the combined RIC + PostC group when compared with the control group ( 49 [ interquartile range 30 - 72 ] vs. 40 [ interquartile range 16 - 68 ] , P = 0.02 ) . Postconditioning alone failed to improve myocardial salvage when compared with conventional PCI ( P = 0.39 ) . The secondary endpoints , including infa rct size and MVO , showed no significant differences between groups . Clinical follow-up at 6 months revealed no differences in the combined clinical endpoint between groups ( P = 0.44 ) . CONCLUSION Combined intrahospital RIC + PostC in conjunction with PCI in STEMI significantly improves myocardial salvage in comparison with control and PostC. CLINICAL TRIALSGOV NCT02158468 BACKGROUND Myocardial necrosis occurs frequently in elective percutaneous coronary intervention ( PCI ) and is associated with subsequent major adverse cardiovascular events ( MACEs ) . This study assessed the protective effect of remote ischemic preconditioning ( RIPC ) in patients undergoing successful drug-eluting stent implantation with normal baseline troponin values . METHODS We analyzed 205 participants with normal baseline troponin values undergoing successful coronary stent implantation . Subjects were r and omized to 2 groups : The RIPC group ( n = 101 ) , whose members received RIPC ( created by three 5-minute inflations of a pneumatic medical tourniquet cuff to 200 mm Hg around the upper arm , interspersed with 5-minute intervals of reperfusion ) < 2 hours before the PCI procedure , and the control group ( n = 104 ) . RESULTS The primary outcomes were high sensitive cardiac troponin I ( hscTnI ) levels and incidence of myocardial infa rct ion ( MI 4a , defined as hscTnI > 0.20 ng/mL ) at 16 hours after the PCI procedure . The median hscTnI at 16 hours after PCI was lower in the RIPC group compared with the unpreconditioned , control group ( 0.11 vs 0.21 ng/mL ; P < 0.01 ) . The incidence of MI 4a was lower in the RIPC group compared with the control group ( 39 % vs 54 % , P < 0.05 ) . Index of renal function showed no difference between the 2 groups at 16 hours after PCI ( P > 0.05 ) . CONCLUSION RIPC reduced post-PCI TnI release and incidence of MI 4a in patients undergoing elective coronary stent implantation Aims : Percutaneous coronary intervention ( PCI ) is frequently accompanied by myocardial injury . The present study was performed to determine whether remote ischemic preconditioning ( IP ) induces cardioprotection during PCI . Methods : We enrolled 95 patients requiring nonemergency PCI for stable disease or unstable angina into this prospect i ve clinical trial . Patients were r and omized to either remote IP ( induced by three 3‐min cycles of blood pressure cuff inflations to 200 mm Hg around the upper arm , followed by 3‐min of reperfusion n = 47 ) or sham control ( n = 48 ) immediately preceding PCI . The primary outcome measure was the frequency of post‐PCI myonecrosis , defined as a peak postprocedural cTnT T ≥0.03 ng/dL. Secondary outcome measures were the change in plasma high‐sensitivity C‐reactive protein ( hsCRP ) levels following PCI and in endothelial progenitor cells ( EPC ) counts following IP . Results : There was no difference in the primary endpoint of the frequency of PCI related myonecrosis which occurred in 22 ( 47 % ) and 19 ( 40 % ) patients in the remote IP and control groups , respectively , P = 0.42 . There was significant increase in hsCRP post‐PCI in both groups ( P < 0.001 ) , but there was no difference between the groups ( median % change in hsCRP 46 % vs. 54 % , P = 0.73 ) . There was no significant change in circulating early ( CD34 −/CD133+/KDR+ ) , intermediate ( CD34+/CD133+/KDR+ ) , or late ( CD34+/CD133−/KDR+ ) EPC in the two groups immediately following IP . The composite rate of death , myocardial infa rct ion , and target lesion revascularization at 1 year was 14.1 % versus 13.7 % ( P = 0.90 ) . Conclusions : Our study indicates that remote IP immediately before PCI does not induce cardioprotection in low to moderate risk patients . © 2012 Wiley Periodicals , Infa rct size after ST-segment elevation myocardial infa rct ion ( STEMI ) is associated with long-term clinical outcomes . However , there is insufficient information correlating creatine kinase-MB ( CK-MB ) or troponin levels to infa rct size and infa rct location in first-time occurrence of STEMI . We , therefore , assessed the utility of CK-MB measurements after primary percutaneous coronary intervention of a first anterior STEMI using bivalirudin anticoagulation in patients who were r and omized to intralesion abciximab versus no abciximab and to manual thrombus aspiration versus no aspiration . Infa rct size ( as a percentage of total left ventricular [ LV ] mass ) and LV ejection fraction ( LVEF ) were evaluated by cardiac magnetic resonance imaging at 30 days and correlated to peak CK-MB . Peak CK-MB ( median 240 IU/L ; interquartile range 126 to 414 ) was significantly associated with infa rct size and with LVEF ( r = 0.67 , p < 0.001 ; r = -0.56 , p < 0.001 , respectively ) . A large infa rct size ( greater than or equal the median , defined as 17 % of total LV mass ) and LVEF ≤40 % were more common in the highest peak CK-MB tertile group than in the other tertiles ( 87.6 % vs 49.5 % vs 9.1 % , p < 0.001 ; 43.2 % vs 14.0 % vs 4.6 % , p < 0.001 , respectively ) . Peak CK-MB of at least 300 IU/L predicted with moderate accuracy both a large infa rct size ( area under the curve 0.88 ) and an LVEF ≤40 % ( area under the curve 0.78 ) . Furthermore , CK-MB was an independent predictor of 1-year major adverse cardiac events ( hazard ratio 1.42 per each additional 100 IU/L [ 1.20 to 1.67 ] , p < 0.001 ) . In conclusion , CK-MB measurement is useful in estimating infa rct size and LVEF and in predicting 1-year clinical outcomes after primary percutaneous coronary intervention for first anterior STEMI OBJECTIVES We sought to determine the potential of remote ischemic periconditioning ( RIPC ) , and its combination with morphine , to reduce reperfusion injury in primary percutaneous coronary interventions . BACKGROUND Remote ischemic post-conditioning is implemented by applying cycles of ischemia and reperfusion on a remote organ , which result in release of circulating factors inducing the effects of post-conditioning on the myocardium . METHODS A total of 96 patients ( 59 men ) were enrolled . The patients were r and omized to groups as follows : 33 to each treatment group ( Group A : RIPC ; Group B : RIPC and morphine ) and 30 to the control group ( Group C ) . Measures of efficacy were achievement of full ST-segment resolution ( primary ) , and reduction of ST-segment deviation score and peak troponin I during hospitalization . RESULTS A higher proportion of patients in Groups A ( 73 % ) and B ( 82 % ) achieved full ST-segment resolution after percutaneous coronary intervention , compared with control patients ( 53 % ) ( p = 0.045 ) . Peak troponin I was lowest in Group B , 103.3 + /- 13.3 ng/ml , in comparison to peak levels in Group A , 166.0 + /- 28.0 ng/ml , and the control group , 255.5 + /- 35.5 ng/ml ( p = 0.0006 ) . ST-segment deviation resolution was 87.3 + /- 2.7 % in Group B , compared with 69.9 + /- 5.1 % in Group A and 53.2 + /- 6.4 % in the control group ( p = 0.00002 ) . In paired comparisons between groups , Group B did better than the control group in terms of both ST-segment reduction ( p = 0.0001 ) and peak troponin I ( p = 0.004 ) , whereas Group A differences from the control group did not achieve statistical significance ( p = 0.054 and p = 0.062 , respectively ) . CONCLUSIONS These findings demonstrate a cardioprotective effect of RIPC and morphine during primary percutaneous coronary intervention for the prevention of reperfusion injury . This is in agreement with observations that the beneficial effect of RIPC is inhibited by the opioid receptor blocker naloxone BACKGROUND Previous studies indicate that remote ischemic conditioning performed before percutaneous coronary intervention ( PCI ) reduces infa rct size in patients with ST-elevation myocardial infa rct ion ( STEMI ) . It remains unclear whether remote conditioning affords protection when performed in adjunct to primary PCI . We aim ed to study whether remote ischemic per-postconditioning ( RIperpostC ) initiated after admission to the catheterization laboratory attenuates myocardial infa rct size in patients with anterior STEMI . METHODS In this prospect i ve multicenter trial 93 patients with anterior STEMI were r and omized to RIperpostC or sham procedure as adjunct to primary PCI . RIperpostC was started on arrival in the catheterization laboratory by 5-minute cycles of inflation and deflation of a blood pressure cuff around the left thigh and continued throughout the PCI procedure . Infa rct size and myocardium at risk were determined by cardiac magnetic resonance at day 4 to 7 . The primary outcome was myocardial salvage index . RESULTS There was no significant difference in myocardial salvage index between the RIperpostC and control group ( median 48.5 % and interquartile range 30.9%-60.8 % vs 49.2 % [ 42.1%-58.8 % ] ) . Neither did absolute infa rct size in relation to left ventricular myocardial volume differ significantly ( RIperpostC 20.6 % [ 14.1%-31.7 % ] vs control 17.9 % [ 13.4%-25.0 % ] ) . The RIperpostC group had larger myocardial area at risk than the control group ( 43.1 % ( 35.4%-49.7 % ) vs 37.0 % ( 30.8%-44.1 % ) of the left ventricle , P=.03 ) . Peak value and area under the curve for troponin T did not differ significantly between the study groups . CONCLUSIONS RIperpostC initiated after admission to the catheterization laboratory in patients with anterior STEMI did not confer protection against reperfusion injury Background —Remote ischemic preconditioning may result in reduction in infa rct size during percutaneous coronary intervention ( PCI ) . It is unclear whether remote ischemic postconditioning ( RIPost ) will reduce the incidence of myocardial injury after PCI , and whether ischemic conditioning of a larger remote organ ( thigh versus arm ) would provide further myocardial protection . Methods and Results —We r and omized 360 patients presenting with stable or unstable angina ( 28 % of patients ) and negative Troponin T at baseline to 3 groups : 2 groups received RIPost ( induced by ischemia to upper or lower limb ) , and a third was the control group . RIPost was applied during PCI immediately after stent deployment , by three 5-minute cycles of blood pressure cuff inflation to > 200 mm Hg in the arm or thigh ( 20 mm Hg in the control ) with 5-minute breaks between each cycle . The primary end-point was the proportion of patients with Troponin T levels > 3 × ULN postprocedure ( at 6 or 18–24 hours ) , where ULN st and s for upper limit of normal . A total of 120 patients were r and omized to each group . There were no differences in baseline characteristics between the 3 groups . The primary outcome occurred in 30 % , 35 % , and 35 % of the arm , thigh , and control groups , respectively ( P=0.64 ) . There were no differences in creatine kinase or high sensitivity C-reactive protein levels after PCI or in the incidence of acute kidney injury between the groups . Conclusions —RIPost during PCI did not reduce the incidence of periprocedural myocardial injury . Similar effect was obtained when remote ischemia was induced to the upper or lower limb . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00970827 Objective Determine whether remote ischaemic postconditioning ( RIP ) protects against percutaneous coronary intervention-related myocardial infa rct ion ( PCI-MI ) . Design Single-centre , r and omised , blinded to the research ers , clinical trial . Clinical Trials.gov ( NCT 01113008 ) . Setting Tertiary hospital centre . Patients 232 patients underwent elective PCI for stable or unstable angina . Interventions Patients were r and omised to RIP ( induction of three 5-min cycles of ischaemia in the arm after the PCI ) versus placebo . Main outcome measures The primary outcome measure was the peak 24-h troponin I level . PCI-MI was defined by an elevation of troponin values > 3 or > 5 of the 99th percentile according to the classical or the new definition . The secondary outcome measure was hospital admission , PCI for stable angina or acute coronary syndrome and mortality after 1 year of follow-up . The use of RIP in diabetic patients was specifically studied . Results The mean age was 64.6 years , and 42 % were diabetic . The peak troponin in the RIP patients was 0.476 vs 0.478 ng/mL ( p=0.99 ) . PCI-MI occurred in 36 % of the RIP patients versus 30.8 % in the placebo group ( p=0.378 ) . Diabetic RIP patients had more PCI-MI ( new definition ) : OR 2.7 ; 95 % CI 1.10 to 6.92 ; p=0.027 . The secondary outcome measure was seen in 11.7 % of the RIP patients versus 10.8 % in the placebo group ( p=0.907 ) . Conclusions RIP did not reduce the damage associated with elective PCI or cardiovascular events during the follow-up . The diabetic population who underwent RIP had more PCI-MI

The incidence of some high grade ( ≥ 3 ) AEs increased , such as hemorrhage , hypertension and neutropenia . Conclusions : Our study demonstrated that regimens with VEGFR-TKIs combined with chemotherapy improved PFS , ORR and DCR in patients with advanced NSCLC , but had no impact on OS . VEGFR-TKIs induced more frequent and serious AEs compared with control therapies

Introduction : To estimate the efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors ( VEGFR-TKIs ) in combination with chemotherapy for patients with advanced non-small cell lung cancer ( NSCLC ) .

PURPOSE This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between February 2007 and March 2009 , 904 patients were r and omly assigned to daily sorafenib ( 400 mg twice a day ) or matching placebo plus gemcitabine ( 1,250 mg/m(2 ) per day on days 1 and 8) and cisplatin ( 75 mg/m(2 ) on day 1 ) for up to six 21-day cycles . Because of safety findings from the Evaluation of Sorafenib , Carboplatin and Paclitaxel Efficacy in NSCLC ( ESCAPE ) trial , patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis . The primary end point was overall survival ( OS ) , and secondary end points included progression-free survival ( PFS ) and time-to-progression ( TTP ) . RESULTS The primary analysis population consisted of 772 patients ( sorafenib , 385 ; placebo , 387 ) ; the two groups had similar demographic and baseline characteristics . Median OS was similar in the sorafenib and placebo groups ( 12.4 v 12.5 months ; hazard ratio [ HR ] , 0.98 ; P = .401 ) . By investigator assessment , sorafenib improved median PFS ( 6.0 v 5.5 months ; HR , 0.83 ; P = .008 ) and TTP ( 6.1 v 5.5 months ; HR , 0.73 ; P < .001 ) . Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included h and -foot skin reaction ( 8.6 % v 0.3 % ) , fatigue ( 7.3 % v 3.6 % ) , rash ( 5.7 % v 0.5 % ) , and hypertension ( 4.2 % v 1.8 % ) . No unexpected toxicities were observed . CONCLUSION This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC . Identification of predictive biomarkers is warranted in future trials of sorafenib Purpose : Hypertension is a commonly reported side effect in antiangiogenic therapy . We investigated the hypothesis that telatinib , a small molecule angiogenesis inhibitor , impairs vascular function , induces rarefaction , and causes hypertension . Experimental Design : A side- study was done in a phase I trial of telatinib , a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 2 and 3 , platelet-derived growth factor receptor , and c-KIT in patients with advanced solid tumors . Measurements of blood pressure , flow-mediated dilation , nitroglycerin-mediated dilation , aortic pulse wave velocity , skin blood flux with laser Doppler flow , and capillary density with sidestream dark field imaging were done at baseline and after 5 weeks of treatment . Blood pressure and proteinuria were measured weekly . Results : Mean systolic and diastolic blood pressure values increased significantly at + 6.6 mm Hg ( P = 0.009 ) and + 4.7 mm Hg ( P = 0.016 ) , respectively . Mean flow-mediated dilation and mean nitroglycerin-mediated dilation values significantly decreased by −2.1 % ( P = 0.003 ) and −5.1 % ( P = 0.001 ) , respectively . After 5 weeks of treatment , mean pulse wave velocity significantly increased by 1.2 m/s ( P = 0.001 ) . A statistically significant reduction of mean skin blood flux of 532.8 % arbitrary units was seen ( P = 0.015 ) . Capillary density statistically significantly decreased from 20.8 to 16.7 capillary loops ( P = 0.015 ) . Proteinuria developed or increased in six patients during telatinib treatment . Conclusion : The increase in blood pressure observed in the treatment with telatinib , an angiogenesis inhibitor , may be caused by functional or structural rarefaction BACKGROUND Hypertension ( HTN ) , a recognized adverse effect of angiogenesis inhibitors , may be a potential biomarker of activity of these agents . We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib , and the relationship of this adverse event with treatment outcomes . PATIENTS AND METHODS BR24 was a double-blind placebo-controlled phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo in patients ( n = 296 ) with advanced non-small-cell lung cancer ( NSCLC ) . Exploratory analyses characterized relationships between HTN , baseline variables , and efficacy outcomes . RESULTS New onset or worsening of preexisting HTN ( treatment-emergent HTN ) was more frequent in patients receiving cediranib ( 68 versus 45 % , P < 0.0001 ) . Factors associated with HTN in all r and omized patients were good performance status and treatment with cediranib . In both arms , treatment-emergent HTN was associated with improved efficacy outcomes , but there was no evidence of a differential treatment effect , with nonsignificant interaction P values . CONCLUSIONS In advanced NSCLC , HTN is frequent in patients receiving chemotherapy , with or without cediranib . The development of HTN was favorably prognostic in these patients , but not predictive of a differential outcome with cediranib Background : Anlotinib ( AL3818 ) is a novel multitarget tyrosine kinase inhibitor , inhibiting tumour angiogenesis and proliferative signalling . The objective of this study was to assess the safety and efficacy of third-line anlotinib for patients with refractory advanced non-small-cell lung cancer ( RA-NSCLC ) . Methods : Eligible patients were r and omised 1 : 1 to receive anlotinib ( 12 mg per day , per os ; days 1–14 ; 21 days per cycle ) or a placebo . The primary end point was progression-free survival ( PFS ) . Results : A total of 117 eligible patients enrolled from 13 clinical centres in China were analysed in the full analysis set . No patients received immune check-point inhibitors and epidermal growth factor receptor status was unknown in 60.7 % of the population . PFS was better with anlotinib compared with the placebo ( 4.8 vs 1.2 months ; hazard ratio (HR)=0.32 ; 95 % confidence interval ( CI ) , 0.20–0.51 ; P<0.0001 ) , as well as overall response rate ( ORR ) ( 10.0 % ; 95 % CI , 2.4–17.6 % vs 0 % ; 95 % CI , 0–6.27 % ; P=0.028 ) . The median overall survival ( OS ) was 9.3 months ( 95 % CI , 6.8–15.1 ) for the anlotinib group and 6.3 months ( 95 % CI , 4.3–10.5 ) for the placebo group ( HR=0.78 ; 95 % CI , 0.51–1.18 ; P=0.2316 ) . Adverse events were more frequent in the anlotinib than the placebo group . The percentage of grade 3–4 treatment-related adverse events was 21.67 % in the anlotinib group . Conclusions : Anlotinib as a third-line treatment provided significant PFS benefits to patients with RA-NSCLC when compared with the placebo , and the toxicity profiles showed good tolerance PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with st and ard chemotherapy as initial therapy for advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( area under the serum concentration-time curve 6 ) were given every 3 weeks , with daily oral cediranib or placebo at 30 mg ( first 45 patients received 45 mg ) . Progression-free survival ( PFS ) was the primary outcome of the phase II interim analysis ; phase III would proceed if the hazard ratio ( HR ) for PFS < or = 0.77 and toxicity were acceptable . Results A total of 296 patients were enrolled , 251 to the 30-mg cohort . The phase II interim analysis demonstrated a significantly higher response rate ( RR ) for cediranib than for placebo , HR of 0.77 for PFS , no excess hemoptysis , and a similar number of deaths in each arm . The study was halted to review imbalances in assigned causes of death . In the primary phase II analysis ( 30-mg cohort ) , the adjusted HR for PFS was 0.77 ( 95 % CI , 0.56 to 1.08 ) with a higher RR for cediranib than for placebo ( 38 % v 16 % ; P < .0001 ) . Cediranib patients had more hypertension , hypothyroidism , h and -foot syndrome , and GI toxicity . Hypoalbuminemia , age > or = 65 years , and female sex predicted increased toxicity . Survival up date ( N = 296 ) 10 months after study unblinding favored cediranib over placebo ( median of 10.5 months v 10.1 months ; HR , 0.78 ; 95 % CI , 0.57 to 1.06 ; P = .11 ) . Causes of death in the cediranib 30-mg cohort were NSCLC ( 81 % ) , protocol toxicity + /- NSCLC ( 13 % ) , and other ( 6 % ) ; for the placebo group , they were 98 % , 0 % , and 2 % , respectively . CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS , but does not appear tolerable at a 30-mg dose . Consequently , the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a r and omized , double-blind , placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC Using MRI techniques , we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset , is prolonged but reversible , and has the significant clinical benefit of alleviating edema . Reversal of normalization began by 28 days , though some features persisted for as long as four months . Basic FGF , SDF1alpha , and viable circulating endothelial cells ( CECs ) increased when tumors escaped treatment , and circulating progenitor cells ( CPCs ) increased when tumors progressed after drug interruption . Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor BACKGROUND V and etanib ( ZACTIMA ; ZD6474 ) is a once-daily , oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling . The safety and tolerability of v and etanib plus pemetrexed was assessed in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with previously treated NSCLC ( stage IIIB/IV ) received once-daily oral v and etanib ( 100 or 300 mg ) with pemetrexed ( 500 mg/m(2 ) i.v . infusion every 21 days ) . RESULTS Patients received v and etanib 100 mg + pemetrexed ( n=10 ) or v and etanib 300 mg + pemetrexed ( n=11 ) . The protocol definition of a tolerable dose [ v and etanib-related dose-limiting toxicity ( DLT ) in less than 2 patients ] was met in both dose cohorts , with one DLT reported in each : asymptomatic QTc prolongation ( > 100 ms increase from baseline , but absolute QTc<500 ms ) in the 100 mg cohort and interstitial lung disease , which resolved after steroid therapy , in the 300 mg cohort . The most common adverse events were rash , anorexia , fatigue and diarrhea ( all n=10 ) . CONCLUSION V and etanib and pemetrexed in combination were generally well tolerated in patients with advanced NSCLC Background The efficacy and safety of axitinib , a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1 , 2 , and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non – small-cell lung cancer ( NSCLC ) . Methods Overall , 170 patients were r and omly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of up to six 21-day cycles ( arm I ) ; axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin ( arm II ) ; or pemetrexed/cisplatin alone ( arm III ) . The primary endpoint was progression-free survival ( PFS ) . Results Median PFS was 8.0 , 7.9 , and 7.1 months in arms I , II , and III , respectively ( hazard ratio : arms I vs. III , 0.89 [ P = 0.36 ] and arms II vs. III , 1.02 [ P = 0.54 ] ) . Median overall survival was 17.0 months ( arm I ) , 14.7 months ( arm II ) , and 15.9 months ( arm III ) . Objective response rates ( ORRs ) for axitinib-containing arms were 45.5 % ( arm I ) and 39.7 % ( arm II ) compared with 26.3 % for pemetrexed/cisplatin alone ( arm III ) . Gastrointestinal disorders and fatigue were frequently reported across all treatment arms . The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms ( 20 % and 17 % , arms I and II , respectively ) and fatigue with pemetrexed/cisplatin alone ( 16 % ) . Conclusion Axitinib in combination with pemetrexed/cisplatin was generally well tolerated . Axitinib combinations result ed in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.Trial registration Clinical Trials.gov : NCT00768755 ( October 7 , 2008 ) BACKGROUND This preplanned subset analysis of the phase III MONET1 study aim ed to determine whether motesanib combined with carboplatin/paclitaxel ( C/P ) would result in improved overall survival ( OS ) versus chemotherapy alone , in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with nonsquamous NSCLC ( stage IIIB/IV or recurrent ) and no prior systemic therapy for advanced disease were r and omized to IV carboplatin ( AUC , 6 mg/ml min ) and paclitaxel ( 200 mg/m2 ) for up to six 3-week cycles , plus either oral motesanib 125 mg q.d . or placebo . Primary end point was OS ; secondary end points included progression-free survival ( PFS ) , objective response rate ( ORR ) , and safety . RESULTS Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis . Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm ( P=0.0223 ) ; median PFS was 7.0 and 5.3 months , respectively , ( P=0.0004 ) ; and ORR was 62 % and 27 % , respectively , ( P<0.0001 ) . Grade ≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P ( 79 % versus 61 % ) . CONCLUSION In this preplanned subset analysis of Asian patients with nonsquamous NSCLC , motesanib plus C/P significantly improved OS , PFS , and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER NCT00460317 Introduction : The aim of the present study was to evaluate the efficacy and tolerability of v and etanib plus gemcitabine ( V/G ) compared with gemcitabine alone in elderly patients with untreated advanced non – small-cell lung cancer . Methods : This was a phase II , r and omized , double-blind study . A total of 124 elderly patients ( mean age , 75 yr ; age range , 70–84 yr ; 73 % men ) received V/G ( n = 61 ) or placebo plus gemcitabine ( n = 63 ) . Progression-free survival ( PFS ) was the primary endpoint . Secondary endpoints were overall survival , objective response rate , duration of response , disease control rate , time to deterioration of performance status , and safety outcomes . Results : PFS was significantly prolonged with V/G ( median , 183 days ; 95 % confidence interval , 116–214 ) compared with placebo plus gemcitabine ( median , 169 days ; 95 % confidence interval , 95–194 ; p = 0.047 ) . No statistically significant differences between arms were observed in all secondary endpoints , including overall survival . The addition of v and etanib to gemcitabine was well tolerated . The rate of patients with ≥1 treatment-related adverse event was comparable in the two arms , pyrexia , dyspnea , and neutropenia being the most common adverse events . Conclusions : V/G combination was associated with a statistically significant prolongation of PFS compared with gemcitabine alone in untreated elderly patients with advanced non – small-cell lung cancer , with an acceptable safety profile BACKGROUND AND OBJECTIVE Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer ( NSCLC ) . This r and omized controlled study prospect ively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC . METHODS Thirty patients , which were confirmed advanced NSCLC histologically or cytologically , were r and omly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo . The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events . RESULTS Overall demographics were balanced between experimental group ( sorafenib+chemotherapy ) and controlled group ( chemotherapy only ) . Overall response ( OS ) rate was 55.6 % and 41.7 % in experimental arm and controlled arm , respectively ( P=0.905 ) . Median progressive-free survival ( PFS ) and median overall survival were similar ( 5 months vs 4 months , P=0.75 ; 18 months vs 18 months , P=0.68 ) . Adverse events were tolerable , though the risk of hypertension and diarrhea was increase in experimental arm . Since patients with ECOG PS 0 , stage IIIb , no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive , these factors seemed to be predictive factors favor of survival in Cox regression analyses . CONCLUSIONS No additional benefit of response rate , PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy . Selecting aproper patients is needed in further study Introduction : This r and omized open-label phase II study evaluated the efficacy , safety , and tolerability of pazopanib in combination with pemetrexed compared with the st and ard cisplatin/pemetrexed doublet in patients with previously untreated , advanced , nonsquamous non – small-cell lung cancer . Methods : Patients were r and omized ( 2:1 ratio ) to receive pemetrexed 500 mg/m2 intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m2 intravenously once every 3 weeks up to six cycles . All patients received folic acid , vitamin B12 , and steroid prophylaxis . The primary endpoint was progression-free survival ( PFS ) . Results : The study was terminated after 106 of 150 patients were r and omized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm . At the time enrolment was discontinued , there were three fatal adverse events in the pazopanib/pemetrexed arm , including ileus , tumor embolism , and bronchopneumonia/sepsis . Treatment with pazopanib/pemetrexed was discontinued result ing in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm . There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS ( median PFS , 25.0 versus 22.9 weeks , respectively ; hazard ratio = 0.75 ; 95 % confidence interval , 0.43%–1.28 % ; p = 0.26 ) or objective response rate ( 23 % versus 34 % , respectively ; 95 % confidence interval , –30.6 % to 7.2 % ; p = 0.21 ) . Conclusion : The combination of pazopanib/pemetrexed in first-line treatment of non – small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity Introduction : This study assessed activity and safety of linifanib ( ABT-869 ) , a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors , in patients with locally advanced or metastatic non-small cell lung cancer . Methods : In this open-label trial ( NCT00517790 ) , patients who received one to two prior lines of systemic therapy were r and omized to oral linifanib 0.10 mg/kg ( low dose ) or 0.25 mg/kg ( high dose ) once daily . Tumor responses were assessed by independent central imaging review every 8 weeks . The primary end point was progression-free rate at 16 weeks . Secondary end points included objective response rate , time to progression , progression-free survival , and overall survival . Safety was also assessed . Results : Between August 2007 and October 2008 , 139 patients were enrolled ; 60 % had two or more prior regimens , and 88 % had nonsquamous cell carcinoma . The objective response rate ( low dose and high dose ) was 5.0 % ( 3.1 and 6.8 % ) , progression-free rate at 16 weeks was 33.1 % ( 32.3 and 33.8 % ) , median time to progression was 3.6 months ( 3.6 and 3.7 months ) , median progression-free survival was 3.6 months ( 3.5 and 3.6 months ) , and median overall survival was 9.0 months ( 10.0 and 8.3 months ) . The most common linifanib-related adverse events were fatigue ( 42 % ) , decreased appetite ( 38 % ) , hypertension ( 37 % ) , diarrhea ( 32 % ) , nausea ( 27 % ) , palmar-plantar erythrodysesthesia ( 24 % ) , and proteinuria ( 22 % ) . These events were more common in the high-dose group . The most common linifanib-related grade 3 or 4 adverse event was hypertension ( 14 % ) . Conclusions : Linifanib is active in advanced non-small cell lung cancer as second- or third-line therapy . Increased adverse event rates were observed at the high dose of linifanib PURPOSE We evaluated whether motesanib ( a selective oral inhibitor of vascular endothelial growth factor receptors 1 , 2 , and 3 ; platelet-derived growth factor receptor ; and Kit ) combined with carboplatin/paclitaxel improved overall survival ( OS ) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer ( NSCLC ) and in the subset of patients with adenocarcinoma . PATIENTS AND METHODS Patients with stage IIIB/IV or recurrent nonsquamous NSCLC ( no prior systemic therapy for advanced disease ) were r and omly assigned 1:1 to carboplatin ( area under the curve , 6 mg/ml · min ) and paclitaxel ( 200 mg/m(2 ) ) intravenously for up to six 3-week cycles plus either motesanib 125 mg ( arm A ) or placebo ( arm B ) once daily orally . OS was the primary end point . Secondary end points included progression-free survival ( PFS ) , objective response rate ( ORR ) , adverse events ( AEs ) , and association between placental growth factor ( PLGF ) change and OS . RESULTS A total of 1,090 patients with nonsquamous NSCLC were r and omly assigned ( arms A/B , n = 541 of 549 ) ; of those , 890 had adenocarcinoma ( n = 448 of 442 ) . Median OS in arms A and B was 13.0 and 11.0 months , respectively ( hazard ratio [ HR ] , 0.90 ; 95 % CI , 0.78 to 1.04 ; P = .14 ) ; median OS for the adenocarcinoma subset was 13.5 and 11.0 months , respectively ( HR , 0.88 ; 95 % CI , 0.75 to 1.03 ; P = .11 ) . In descriptive analyses ( arms A v B ) , median PFS was 5.6 months versus 5.4 months ( P = < .001 ) ; ORR was 40 % versus 26 % ( P < .001 ) . There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs ( arms A and B , 73 % and 59 % , respectively ) and grade 5 AEs ( 14 % and 9 % , respectively ) was higher with motesanib treatment . CONCLUSION Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset PURPOSE V and etanib is a once-daily , oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling . The antitumor activity of v and etanib monotherapy or v and etanib with paclitaxel and carboplatin ( VPC ) was compared with paclitaxel and carboplatin ( PC ) in previously untreated patients with non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded , placebo-controlled , r and omized phase II study . Patients were r and omly assigned 2:1:1 to receive v and etanib , VPC , or PC . Progression-free survival ( PFS ) was the primary end point , and the study was powered to detect a reduced risk of progression with VPC versus PC ( hazard ratio = 0.70 ; one-sided P < .2 ) and to demonstrate noninferiority for v and etanib versus PC . Overall survival was a secondary assessment . RESULTS The risk of progression was reduced for patients receiving VPC ( n = 56 ) versus PC ( n = 52 ; hazard ratio = 0.76 , one-sided P = .098 ) ; median PFS was 24 weeks ( VPC ) and 23 weeks ( PC ) . The v and etanib monotherapy arm ( n = 73 ) was discontinued after a planned interim PFS analysis met the criterion for discontinuation ( hazard ratio > 1.33 v PC ) . Overall survival was not significantly different between patients receiving VPC or PC . Rash , diarrhea , and hypertension were common adverse events ; no pulmonary or CNS hemorrhage events required intervention . CONCLUSION VPC could be safely administered to patients with NSCLC , including those with squamous cell histology and treated brain metastases . Compared with the PC control arm , patients receiving VPC had longer PFS , meeting the prespecified study end point , whereas those receiving v and etanib monotherapy had shorter PFS BACKGROUND V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor ( VEGFR ) , epidermal growth factor receptor ( EGFR ) , and rearranged during transfection ( RET ) tyrosine kinases . In a r and omised phase 2 study in patients with previously treated non-small-cell lung cancer ( NSCLC ) , adding v and etanib 100 mg to docetaxel significantly improved progression-free survival ( PFS ) compared with docetaxel alone , including a longer PFS in women . These results supported investigation of the combination in this larger , definitive phase 3 trial ( ZODIAC ) . METHODS Between May , 2006 , and April , 2008 , patients with locally advanced or metastatic ( stage IIIB-IV ) NSCLC after progression following first-line chemotherapy were r and omly assigned 1:1 through a third-party interactive voice system to receive v and etanib ( 100 mg/day ) plus docetaxel ( 75 mg/m(2 ) intravenously every 21 days ; maximum six cycles ) or placebo plus docetaxel . The primary objective was comparison of PFS between the two groups in the intention-to-treat population . Women were a co primary analysis population . This study has been completed and is registered with Clinical Trials.gov , number NCT00312377 . FINDINGS 1391 patients received v and etanib plus docetaxel ( n=694 [ 197 women ] ) or placebo plus docetaxel ( n=697 [ 224 women ] ) . V and etanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel ( hazard ratio [ HR ] 0.79 , 97.58 % CI 0.70 - 0.90 ; p<0.0001 ) ; median PFS was 4.0 months in the v and etanib group versus 3.2 months in placebo group . A similar improvement in PFS with v and etanib plus docetaxel versus placebo plus docetaxel was seen in women ( HR 0.79 , 0.62 - 1.00 , p=0.024 ) ; median PFS was 4.6 months in the v and etanib group versus 4.2 months in the placebo group . Among grade 3 or higher adverse events , rash ( 63/689 [ 9 % ] vs 7/690 [ 1 % ] ) , neutropenia ( 199/689 [ 29 % ] vs 164/690 [ 24 % ] ) , leukopenia ( 99/689 [ 14 % ] vs 77/690 [ 11 % ] ) , and febrile neutropenia ( 61/689 [ 9 % ] vs 48/690 [ 7 % ] ) were more common with v and etanib plus docetaxel than with placebo plus docetaxel . The most common serious adverse event was febrile neutropenia ( 46/689 [ 7 % ] in the v and etanib group vs 38/690 [ 6 % ] in the placebo group ) . INTERPRETATION The addition of v and etanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy INTRODUCTION This r and omised double-blind placebo-controlled study evaluated the addition of cediranib , an inhibitor of vascular endothelial growth factor receptors 1 - 3 , to st and ard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer . METHODS Eligible patients received paclitaxel ( 200mg/m(2 ) ) and carboplatin ( area under the concentration time curve 6 ) intravenously every 3 weeks . Daily oral cediranib/placebo 20 mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4 - 6 cycles of chemotherapy . The primary end-point of the study was overall survival ( OS ) . The trial would continue to full accrual if an interim analysis ( IA ) for progression-free survival ( PFS ) , performed after 170 events of progression or death in the first 260 r and omised patients , revealed a hazard ratio ( HR ) for PFS of ⩽ 0.70 . RESULTS The trial was halted for futility at the IA ( HR for PFS 0.89 , 95 % confidence interval [ CI ] 0.66 - 1.20 , p = 0.45 ) . A final analysis was performed on all 306 enrolled patients . The addition of cediranib increased response rate ( [ RR ] 52 % versus 34 % , p = 0.001 ) but did not significantly improve PFS ( HR 0.91 , 95 % CI 0.71 - 1.18 , p = 0.49 ) or OS ( HR 0.94 , 95 % CI 0.69 - 1.30 , p=0.72 ) . Cediranib patients had more grade 3 hypertension , diarrhoea and anorexia . CONCLUSIONS The addition of cediranib 20 mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity , but not survival PURPOSE To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life ( QoL ) in advanced non-small-cell lung cancer ( NSCLC ) compared with vinorelbine plus cisplatin as first-line chemotherapy . PATIENTS AND METHODS Patients ( n = 1,218 ) with stage IIIB to IV NSCLC were r and omly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks ( DC ) ; docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks ( DCb ) ; or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks ( VC ) . RESULTS Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients ( P = .044 ; hazard ratio , 1.183 [ 97.2 % confidence interval , 0.989 to 1.416 ] ) . The 2-year survival rate was 21 % for DC-treated patients and 14 % for VC-treated patients . Overall response rate was 31.6 % for DC-treated patients v 24.5 % for VC-treated patients ( P = .029 ) . Median survival ( 9.4 v 9.9 months [ for VC ] ; P = .657 ; hazard ratio , 1.048 [ 97.2 confidence interval , 0.877 to 1.253 ] ) and response ( 23.9 % ) with DCb were similar to those results for VC . Neutropenia , thrombocytopenia , infection , and febrile neutropenia were similar with all three regimens . Grade 3 to 4 anemia , nausea , and vomiting were more common ( P < .01 ) with VC than with DC or DCb . Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients , who experienced deterioration in QoL. CONCLUSION DC result ed in a more favorable overall response and survival rate than VC . Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC . These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC PURPOSE This phase III , multicenter , r and omized , placebo-controlled trial assessed the efficacy and safety of sorafenib , an oral multikinase inhibitor , in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Nine hundred twenty-six patients were r and omly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2 ) ( CP ) on day 1 , followed by either sorafenib 400 mg twice a day ( n = 464 , arm A ) or placebo ( n = 462 , arm B ) on days 2 to 19 . The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day . The primary end point was overall survival ( OS ) ; secondary end points included progression-free survival and tumor response . RESULTS Overall demographics were balanced between arms ; 223 patients ( 24 % ) had squamous cell histology . On the basis of a planned interim analysis , median OS was 10.7 months in arm A and 10.6 months in arm B ( hazard ratio [ HR ] = 1.15 ; 95 % CI , 0.94 to 1.41 ; P = .915 ) . The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point . A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B ( HR = 1.85 ; 95 % CI , 1.22 to 2.81 ) . Main grade 3 or 4 sorafenib-related toxicities included rash ( 8.4 % ) , h and -foot skin reaction ( 7.8 % ) , and diarrhea ( 3.5 % ) . CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity . The activity of v and etanib plus docetaxel was assessed in patients with previously treated non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This two-part study comprised an open-label run-in phase and a double-blind r and omized phase . Eligible patients had locally advanced or metastatic ( stage IIIB/IV ) NSCLC after failure of first-line platinum-based chemotherapy . The primary objective of the r and omized phase was to prolong progression-free survival ( PFS ) in patients receiving v and etanib ( 100 or 300 mg/d ) plus docetaxel ( 75 mg/m2 intravenous infusion every 21 days ) versus placebo plus docetaxel . The study was design ed to have more than 75 % power to detect 50 % prolongation at a one-sided significance level of P < .20 . Secondary objectives included objective response rate , overall survival , safety and tolerability . RESULTS In the r and omized phase ( n = 127 ) , median PFS was 18.7 weeks for v and etanib 100 mg plus docetaxel ( n = 42 ; hazard ratio v docetaxel = 0.64 ; one-sided P = .037 ) ; 17.0 weeks for v and etanib 300 mg plus docetaxel ( n = 44 ; hazard ratio v docetaxel = 0.83 ; one-sided P = .231 ) ; and 12 weeks for docetaxel ( n = 41 ) . There was no statistically significant difference in overall survival among the three treatment arms . Common adverse events included diarrhea , rash , and asymptomatic prolongation of corrected QT ( QTC ) interval . CONCLUSION The primary objective was achieved , with v and etanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level . On the basis of these encouraging data , phase III evaluation of v and etanib 100 mg plus docetaxel in second-line NSCLC has been initiated BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer ( NSCLC ) . METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy , stratified by ECOG performance status , previous bevacizumab treatment , histology , and presence of brain metastases , were allocated ( by computer-generated sequence through an interactive third-party system , in 1:1 ratio ) , to receive docetaxel 75 mg/m(2 ) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2 - 21 , every 3 weeks until unacceptable adverse events or disease progression . Investigators and patients were masked to assignment . The primary endpoint was progression-free survival ( PFS ) by independent central review , analysed by intention to treat after 714 events in all patients . The key secondary endpoint was overall survival , analysed by intention to treat after 1121 events had occurred , in a prespecified stepwise order : first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy , then in all patients with adenocarcinoma , then in all patients . This trial is registered with Clinical Trials.gov , number NCT00805194 . FINDINGS Between Dec 23 , 2008 , and Feb 9 , 2011 , 655 patients were r and omly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo . The primary analysis was done after a median follow-up of 7·1 months ( IQR 3·8 - 11·0 ) . PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group ( median 3·4 months [ 95 % CI 2·9 - 3·9 ] vs 2·7 months [ 2·6 - 2·8 ] ; hazard ratio [ HR ] 0·79 [ 95 % CI 0·68 - 0·92 ] , p=0·0019 ) . After a median follow-up of 31·7 months ( IQR 27·8 - 36·1 ) , overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group ( 206 patients ) compared with those in the docetaxel plus placebo group ( 199 patients ; median 10·9 months [ 95 % CI 8·5 - 12·6 ] vs 7·9 months [ 6·7 - 9·1 ] ; HR 0·75 [ 95 % CI 0·60 - 0·92 ] , p=0·0073 ) . Similar results were noted for all patients with adenocarcinoma histology ( 322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group ; median overall survival 12·6 months [ 95 % CI 10·6 - 15·1 ] vs 10·3 months [ 95 % CI 8·6 - 12·2 ] ; HR 0·83 [ 95 % CI 0·70 - 0·99 ] , p=0·0359 ) , but not in the total study population ( median 10·1 months [ 95 % CI 8·8 - 11·2 ] vs 9·1 months [ 8·4 - 10·4 ] ; HR 0·94 , 95 % CI 0·83 - 1·05 , p=0·2720 ) . Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea ( 43 [ 6·6 % ] of 652 vs 17 [ 2·6 % ] of 655 ) , reversible increases in alanine aminotransferase ( 51 [ 7·8 % ] vs six [ 0·9 % ] ) , and reversible increases in aspartate aminotransferase ( 22 [ 3·4 % ] vs three [ 0·5 % ] ) . 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression ; the most common of these events were sepsis ( five with docetaxel plus nintedanib vs one with docetaxel plus placebo ) , pneumonia ( two vs seven ) , respiratory failure ( four vs none ) , and pulmonary embolism ( none vs three ) . INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy , especially for patients with adenocarcinoma . FUNDING Boehringer Ingelheim Purpose : This retrospective analysis sought to investigate the safety , feasibility , and outcomes of platinum doublet therapy in patients aged 70 years or older with advanced non-small cell lung cancer compared with patients younger than 70 years who participated in two r and omized phase III trials conducted by the Southwest Oncology Group . Patients and Methods : Outcomes and toxicity data from fit patients with stage IIIB or stage IV non-small cell lung cancer treated with cisplatin/vinorelbine and carboplatin/paclitaxel were pooled from Southwest Oncology Group trials 9308 ( S9308 ) and 9509 ( S9509 ) and compared with respect to age . Results : A total of 616 patients were available for efficacy analyses , of which 122 ( 20 % ) were aged 70 years or older . The median progression-free survival was 4 months in both age groups ( p = 0.71 ) , and response rates were similar . Overall survival was significantly higher in the younger patient cohort ( median 9 months versus 7 months , p = 0.04 ) . Individual parameters of toxicity were similar in both age groups . Conclusion : Although patients aged 70 years or older derived initial benefit from platinum-based therapy , survival was better in younger patients . Additional studies in this growing patient population are needed to develop treatment strategies that minimize toxicity and increase efficacy PURPOSE This phase II study evaluated efficacy and safety of single-agent axitinib , an oral , potent , selective inhibitor of vascular endothelial growth factor receptors ( VEGFR ) -1 , -2 , and -3 , in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This was an open-label , single-arm , multicenter , phase II study with a Simon two-stage minimax design . Patients received a starting dose of axitinib 5 mg orally BID . The primary end point was Response Evaluation Criteria in Solid Tumors ( RECIST ) -defined objective response rate . Secondary end points included safety and tolerability , overall survival ( OS ) , and progression-free survival ( PFS ) . RESULTS Thirty-two patients were enrolled , with a median age of 66.5 years . The majority of patients ( 75 % ) had adenocarcinoma . Nine patients ( 28 % ) had received no prior chemotherapy for metastatic disease , and 23 ( 72 % ) had received > or = one regimen . Three patients ( 9 % ) had a RECIST investigator-assessed , confirmed partial response ( PR ) ; disease control rate ( PR + stable disease ) was 41 % . Median PFS was 4.9 months overall ( 95 % CI , 3.6 to 7.0 months ) . Median OS was 14.8 months ( 95 % CI , 10.7 months to not estimable ) overall and 14.8 months ( 95 % CI , 12.5 months to not estimable ) in patients receiving first-line axitinib . One-year survival rates for patients with or without prior therapy for metastatic disease were 57 % and 78 % , respectively . Grade 3 treatment-related adverse events in > or = 5 % of patients comprised fatigue ( 22 % ) , hypertension ( 9 % ) , and hyponatremia ( 9 % ) . CONCLUSION Axitinib demonstrated single-agent activity in patients with advanced NSCLC . Therapy was well tolerated with manageable toxicities . Further investigation of this VEGFR inhibitor in NSCLC is of interest PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling . This r and omized , placebo-controlled phase III study assessed the efficacy of v and etanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer . PATIENTS AND METHODS Patients ( N = 534 ) were r and omly assigned to receive v and etanib 100 mg/d plus pemetrexed 500 mg/m(2 ) every 21 days ( n = 256 ) or placebo plus pemetrexed ( n = 278 ) . Progression-free survival ( PFS ) was the primary end point ; overall survival , objective response rate , disease control rate , time to deterioration of symptoms , and safety were secondary assessment s. RESULTS There was no significant difference in PFS between treatment arms ( hazard ratio [ HR ] , 0.86 ; 97.58 % CI , 0.69 to 1.06 ; P = .108 ) . Overall survival was also not significantly different ( HR , 0.86 ; 97.54 % CI , 0.65 to 1.13 ; P = .219 ) . Statistically significant improvements in objective response rate ( 19 % v 8 % ; P < .001 ) and time to deterioration of symptoms ( HR , 0.71 ; P = .0052 ; median , 18.1 weeks for v and etanib and 12.1 weeks for placebo ) were observed in patients receiving v and etanib . Adding v and etanib to pemetrexed increased the incidence of some adverse events , including rash , diarrhea , and hypertension , while showing a reduced incidence of nausea , vomiting , anemia , fatigue , and asthenia with no reduction in the dose intensity of pemetrexed . CONCLUSION This study did not meet the primary end point of statistically significant PFS prolongation with v and etanib plus pemetrexed versus placebo plus pemetrexed . The v and etanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population Importance Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling . A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival , leading to the phase 3 trial to confirm the drug ’s efficacy in advanced non – small cell lung cancer ( NSCLC ) . Objective To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment . Design , Setting , and Participants The ALTER 0303 trial was a multicenter , double-blind , phase 3 r and omized clinical trial design ed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC . Patients from 31 grade -A tertiary hospitals in China were enrolled between March 1 , 2015 , and August 31 , 2016 . Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible ( n = 606 ) , and those who had central ly located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded . Patients ( n = 440 ) were r and omly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo . All cases were treated with study drugs at least once in accordance with the intention-to-treat principle . Main Outcomes and Measures The primary end point was overall survival . The secondary end points were progression-free survival , objective response rate , disease control rate , quality of life , and safety . Results In total , 439 patients were r and omized , 296 to the anlotinib group ( 106 [ 36.1 % ] were female and 188 [ 64.0 % ] were male , with a mean [ SD ] age of 57.9 [ 9.1 ] years ) and 143 to the placebo group ( 46 [ 32.2 % ] were female and 97 [ 67.8 % ] were male , with a mean [ SD ] age of 56.8 [ 9.1 ] years ) . Overall survival was significantly longer in the anlotinib group ( median , 9.6 months ; 95 % CI , 8.2 - 10.6 ) than the placebo group ( median , 6.3 months ; 95 % CI , 5.0 - 8.1 ) , with a hazard ratio ( HR ) of 0.68 ( 95 % CI , 0.54 - 0.87 ; P = .002 ) . A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group ( median , 5.4 months [ 95 % CI , 4.4 - 5.6 ] vs 1.4 months [ 95 % CI , 1.1 - 1.5 ] ; HR , 0.25 [ 95 % CI , 0.19 - 0.31 ] ; P < .001 ) . Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group . The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia . Conclusions and Relevance Among the Chinese patients in this trial , anlotinib appears to lead to prolonged overall survival and progression-free survival . This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC . Trial Registration Clinical Trials.gov identifier : Objective : To evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer ( NSCLC ) . Methods : Patients with stage ⅢB/Ⅳ NSCLC who progressed after two lines or more regimens were r and omized into anlotinib group ( 12 mg daily from day 1 to 14 of a 21-day cycle ) or placebo group with ratio of 2∶1 . Study drugs or placebo were given until disease progression or intolerable toxicity . The primary endpoint was overall survival ( OS ) , and the second endpoints were progression free survival ( PFS ) , objective response rate , and disease control rate . Results : Between April 2015 and December 2015 , twenty-four patients were assigned at Peking Union Medical College Hospital . The baseline characteristics of the anlotinib group ( n=16 ) and placebo group ( n=8 ) were fairly comparable . The median OS was 12.7 months in anlotinib group and 11.1 months in placebo group (P=0.460).The median PFS was 4.0 months in anlotinib group and 1.4 months in placebo group (P=0.065).The common adverse events were manageable such as hypertension , h and -foot syndrome , thyroiddy sfunction . No drug-related mortality occurred . Conclusions : Anlotinib had a trend of improvement in OS and PFS as third-line treatment or beyond in advanced NSCLC compared with placebo with manageable toxicity . Clinical Trials : : NCT02388919 Background : Second-line chemotherapy for advanced non-small cell lung cancer ( NSCLC ) improves survival modestly but new strategies are needed . This trial was design ed to evaluate an antivascular endothelial growth factor strategy with or without st and ard chemotherapy in previously treated NSCLC . Methods : Patients with stage IIIB/IV NSCLC with performance status 0 to 1 progressive after first-line chemotherapy were eligible for r and omization to pemetrexed , sunitinib , or the combination . Patients were stratified by performance status , stage , and sex . Primary objective was 18-week progression-free survival ( PFS ) rate ; secondary objectives included response , overall survival ( OS ) , and toxicity . Target accrual was 225 . The study was terminated early because of decreasing accrual rates . Results : Between April 2008 and September 2011 , 130 patients were registered and r and omized ; of this , 125 patients were treated . Baseline characteristics in the three arms were well balanced . Toxicity was higher in the sunitinib-containing arms . The 18-week PFS rate in the pemetrexed , sunitinib , and combination arms was 54 % ( 95 % confidence interval [ CI ] , 40–71 ) , 37 % ( 95 % CI , 25–54 ) , and 48 % ( 95 % CI , 35–66 ) , respectively ( p = 0.25 ) . Median PFS in the pemetrexed , sunitinib , and combination arms in months was 4.9 ( 2.1–8.8 ) , 3.3 ( 2.3–4.2 ) , and 3.7 ( 2.5–5.8 ) , respectively ( p = 0.18 ) . There was an overall statistically significant difference in OS between the three arms : median OS in months was 10.5 ( 8.3–20.2 ) for pemetrexed , 8.0 ( 6.8–13.5 ) for sunitinib , and 6.7 ( 4.1–10.1 ) for the combination ( p = 0.03 ) . Conclusion : Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib . The 18-week PFS rate was not significantly different between the arms . OS was significantly better with pemetrexed alone compared with the two sunitinib-containing arms , with the doublet performing worst for OS Introduction : The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with ( arm A ) or without ( arm B ) daily oral cediranib as first-line therapy for advanced non – small-cell lung cancer . Methods : A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m2 on days 1 and 8 , and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 ( B ) r and omized phase II study . The primary end point was confirmed overall response rate ( ORR ) with 6-month progression-free survival ( PFS6 ) rate in arm A as secondary end point . Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome . Results : On the basis of the safety assessment , cediranib 30 mg daily was used in the phase II portion . A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3 + nonhematologic adverse events , 71 % versus 45 % ( p = 0.01 ) . The ORR was 19 % ( A ) versus 20 % ( B ) ( p = 1.0 ) . PFS6 in A was 48 % ( 95 % confidence interval : 35%–62 % ) , thus meeting the protocol -specified threshold of at least 40 % . The median overall survival was 12.0 versus 9.9 months ( p = 0.10 ) . FGFR1 rs7012413 , FGFR2 rs2912791 , and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival ( hazard ratio 2.78–5.01 , p = 0.0002–0.0095 ) . Conclusions : The trial did not meet its primary end point of ORR but met its secondary end point of PFS6 . The combination with cediranib 30 mg daily result ed in increased toxicity . Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival PURPOSE Patients with early-stage , resectable , non-small-cell lung cancer ( NSCLC ) are at risk for recurrent disease , and 5-year survival rates do not exceed 75 % . Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC , raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial . This proof-of-concept study examined safety and efficacy of short-term , preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC . PATIENTS AND METHODS Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively . Tumor response was measured by high-resolution computed tomography , permitting estimation of change in tumor volume and diameter . Gene-expression profiling was performed on 77 pre- and post-treatment lung sample s from 34 patients . RESULTS Of 35 patients enrolled , 33 ( 94 % ) had clinical stage I NSCLC and two ( 6 % ) had clinical stage II NSCLC . Median treatment duration was 16 days ( range , 3 to 29 days ) . Thirty patients ( 86 % ) achieved tumor-volume reduction after pazopanib treatment . Two patients achieved tumor-volume reduction > or = 50 % , and three patients had partial response according to Response Evaluation Criteria in Solid Tumors . Pazopanib was generally well tolerated . The most common adverse events included grade 2 hypertension , diarrhea , and fatigue . One patient developed pulmonary embolism 11 days after surgery . Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment . CONCLUSION Short- duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC . Several target genes were dysregulated after pazopanib treatment , validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue . Further clinical evaluation of pazopanib in NSCLC is planned PURPOSE Linifanib , a potent , selective inhibitor of vascular endothelial growth factor ( VEGF ) and platelet-derived growth factor ( PDGF ) receptors , has single-agent activity in non-small-cell lung cancer ( NSCLC ) . We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC . PATIENTS AND METHODS Patients with stage IIIB/IV nonsquamous NSCLC were r and omly assigned to 3-week cycles of carboplatin ( area under the curve 6 ) and paclitaxel ( 200 mg/m(2 ) ) with daily placebo ( arm A ) , linifanib 7.5 mg ( arm B ) , or linifanib 12.5 mg ( arm C ) . The primary end point was progression-free survival ( PFS ) ; secondary efficacy end points included overall survival ( OS ) and objective response rate . RESULTS One hundred thirty-eight patients were r and omly assigned ( median age , 61 years ; 57 % men ; 84 % smokers ) . Median PFS times were 5.4 months ( 95 % CI , 4.2 to 5.7 months ) in arm A ( n = 47 ) , 8.3 months ( 95 % CI , 4.2 to 10.8 months ) in arm B ( n = 44 ) , and 7.3 months ( 95 % CI , 4.6 to 10.8 months ) in arm C ( n = 47 ) . Hazard ratios ( HRs ) for PFS were 0.51 for arm B versus A ( P = .022 ) and 0.64 for arm C versus A ( P = .118 ) . Median OS times were 11.3 , 11.4 , and 13.0 months in arms A , B , and C , respectively . HRs for OS were 1.08 for arm B versus A ( P = .779 ) and 0.88 for arm C versus A ( P = .650 ) . Both linifanib doses were associated with increased toxicity , including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition . Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg . CONCLUSION Addition of linifanib to chemotherapy significantly improved PFS ( arm B ) , with a modest trend for survival benefit ( arm C ) and increased toxicity reflective of known VEGF/PDGF inhibitory effects

However , significant within-group effects for change from baseline were prevalent , suggesting that high inter-individual variability precluded significant treatment effects . Berry consumption in general appears to cause a fluctuation in the pools of small molecule metabolites already present at baseline , rather than the appearance of unique berry-derived metabolites , which likely reflects the ubiquitous nature of (poly)phenols in the background diet

Diets rich in berries provide health benefits , however , the contribution of berry phytochemicals to the human metabolome is largely unknown . The present study aim ed to establish the impact of berry phytochemicals on the human metabolome . A “ systematic review strategy ” was utilized to characterize the phytochemical composition of the berries most commonly consumed in the USA ; (poly)phenols , primarily anthocyanins , comprised the majority of reported plant secondary metabolites .

BACKGROUND There are very limited data regarding the effects of blueberry flavonoid intake on vascular function in healthy humans . OBJECTIVES We investigated the impact of blueberry flavonoid intake on endothelial function in healthy men and assessed potential mechanisms of action by the assessment of circulating metabolites and neutrophil NADPH oxidase activity . DESIGN Two r and omized , controlled , double-blind , crossover human-intervention trials were conducted with 21 healthy men . Initially , the impact of blueberry flavonoid intake on flow-mediated dilation ( FMD ) and polyphenol absorption and metabolism was assessed at baseline and 1 , 2 , 4 , and 6 h after consumption of blueberry containing 766 , 1278 , and 1791 mg total blueberry polyphenols or a macronutrient- and micronutrient-matched control drink ( 0 mg total blueberry polyphenols ) . Second , an intake-dependence study was conducted ( from baseline to 1 h ) with 319 , 637 , 766 , 1278 , and 1791 mg total blueberry polyphenols and a control . RESULTS We observed a biphasic time-dependent increase in FMD , with significant increases at 1 - 2 and 6 h after consumption of blueberry polyphenols . No significant intake-dependence was observed between 766 and 1791 mg . However , at 1 h after consumption , FMD increased dose dependently to ≤766 mg total blueberry polyphenol intake , after which FMD plateaued . Increases in FMD were closely linked to increases in circulating metabolites and by decreases in neutrophil NADPH oxidase activity at 1 - 2 and 6 h. CONCLUSIONS Blueberry intake acutely improves vascular function in healthy men in a time- and intake-dependent manner . These benefits may be mechanistically linked to the actions of circulating phenolic metabolites on neutrophil NADPH oxidase activity . This trial was registered at clinical trials.gov as NCT01292954 and NCT01829542 SCOPE Blueberries are a rich source of flavonoids and phenolic acids . Currently , little information is available regarding the impact of processing on the bioavailability and the bioactivity of blueberry (poly)phenols . METHODS AND RESULTS In a r and omized , controlled crossover trial , ten healthy volunteers consumed ( a ) blueberry-containing baked products , ( b ) an unprocessed blueberry drink containing the same amount of freeze-dried blueberry powder as used in the baked products , and ( c ) matched control baked products . Endothelial function was measured as flow-mediated dilation ( FMD ) and plasma sample s taken at baseline and at 1 , 2 , 4 , and 6 h postconsumption . Although processing did not significantly change the total (poly)phenolic amount , the processed products contained significantly less anthocyanins ( -42 % ) , more chlorogenic acid ( 23 % ) , no flavanol nonamers or decamers , and significantly more flavanol dimers and trimers ( 36 % and 28 % , respectively ) . FMD increased after 1 , 2 , and 6 h consumption of the baked products to a similar degree as the unprocessed blueberries , despite significant differences in the levels of individual plasma metabolites . No changes were observed after the consumption of the control product . CONCLUSION Careful processing can preserve important biological activities of blueberries despite changing the blueberry (poly)phenol composition and plasma metabolite profile SCOPE Underst and ing the metabolic fate of polyphenols from plant foods can aid in developing dietary recommendations that maximize their health benefits . Wild blueberries ( WBB ) provide a distinctive composition of dietary anthocyanins and chlorogenic acid ( CGA ) . METHODS AND RESULTS This is a single blind , r and omized , two-arm crossover controlled study . Human subjects ingested a WBB beverage ( 25 g freeze dried WBB powder ) or placebo beverage with a meal and plasma was collected over 24 h. Anthocyanins , CGA and their metabolites were characterized and quantified in beverages and in plasma using targeted and non-targeted mass analyses . Bioavailability of WBB anthocyanins and 3-CGA was 1.1 and 0.2 % , respectively . Parent anthocyanins and 3-CGA peaked ≈2 h post ingestion , while phase II metabolites , including glucuronide conjugates of peonidin , delphinidin , cyanidin and petunidin peaked ≈ 2.6 , 6.3 , 7 and 8.8 h , respectively . Phenolic acids ( metabolites ) peaked between 0.5 and 24 h. Biphasic responses were evident suggesting preferential enterohepatic recycling for some compounds . CONCLUSION The data indicate bioavailability of early and late phase WBB metabolites peaking at different times during the 24 h period , which may be important for maximizing their biological activity Using a r and omized , double-blinded , placebo-controlled , parallel group design , this investigation determined if the combination of two weeks of flavonoid supplementation ( 329 mg/day , quercetin , anthocyanins , flavan-3-ols mixture ) and a 45-minute walking bout ( 62.2 ± 0.9 % VO2max ( maximal oxygen consumption rate ) ) enhanced the translocation of gut-derived phenolics into circulation in a group of walkers ( n = 77 ) . The walkers ( flavonoid , placebo groups ) were r and omized to either sit or walk briskly on treadmills for 45 min ( thus , four groups : placebo – sit , placebo – walk , flavonoid – sit , flavonoid – walk ) . A comparator group of runners ( n = 19 ) ingested a double flavonoid dose for two weeks ( 658 mg/day ) and ran for 2.5 h ( 69.2 ± 1.2 % VO2max ) . Four blood sample s were collected ( pre- and post-supplementation , immediately post- and 24 h post-exercise/rest ) . Of the 76 metabolites detected in this targeted analysis , 15 increased after the 2.5 h run , and when grouped were also elevated post-exercise ( versus placebo – sit ) for the placebo– and flavonoid – walking groups ( p < 0.05 ) . A secondary analysis showed that pre- study plasma concentrations of gut-derived phenolics in the runners were 40 % higher compared to walkers ( p = 0.031 ) . These data indicate that acute exercise bouts ( brisk walking , intensive running ) are linked to an increased translocation of gut-derived phenolics into circulation , an effect that is amplified when combined with a two-week period of increased flavonoid intake or chronic training as a runner

Hepatic portal hemodynamic parameters were improved in statin users for a short-term response . Statin seemed not to decrease the risk of esophageal variceal bleeding and spontaneous bacterial peritonitis . However , statin was proved to decrease the risk of hepatic encephalopathy and ascites . Incidence of drug related adverse events did n’t increase in statin users . Dose-dependent effects of statin on hepatocellular carcinoma development , decompensated cirrhosis events occurrence , and liver cirrhosis progression . ConclusionS tatin influenced parameters of hepatic portal vessel pressure in short-term treatment . Prognosis of liver cirrhosis benefited from statin treatment in long term follow-up . The efficacy and safety of statin in liver cirrhosis treatment is confirmed .

Background Statin has been more and more widely used in chronic liver disease , however , existed studies have attained contradictory results . According to the present study , we aim ed to test the efficacy and safety of statin via a meta- analysis .

Background : Portal hypertension is one of the most frequent complications of cirrhosis . β-adrenergic blockers , with or without organic nitrates , are currently used as hypotensive agents . Statins such as simvastatin seem to be safe for patients with chronic liver diseases and exert multiple pleiotropic actions . This study aim ed to assess PTH using Doppler ultrasound in patients with cirrhosis before and after simvastatin administration . Methods : This r and omized controlled clinical trial was conducted on 40 patients with cirrhosis who were r and omized into 2 groups : group I included 20 patients with cirrhosis who were administered 20 mg of simvastatin daily for 2 weeks and then 40 mg daily for another 2 weeks , and group II included 20 patients with cirrhosis who did not receive simvastatin as a control group . All patients underwent full clinical examination , laboratory investigations , and abdominal Doppler ultrasound at baseline and after 30 days to evaluate portal vein diameter , blood flow volume , direction and velocity of portal vein blood flow , hepatic artery resistance and pulsatility indices , splenic artery resistance index , portal hypertension index ( PHI ) , liver vascular index , and modified liver vascular index ( MLVI ) . Results : There was a highly significant decrease in the hepatic artery resistance index in group I , from 0.785 ± 0.088 to 0.717 ± 0.086 ( P < 0.001 ) . There was a significant decrease in the PHI in group I , from 3.915 ± 0.973 m/sec to 3.605 ± 1.168 m/sec ( P = 0.024 ) . Additionally , there was a significant increase in the MLVI in group I from 11.540 ± 3.266 cm/sec to 13.305 ± 3.222 cm/sec , an increase of 15.3 % from baseline ( P = 0.009 ) . No significant adverse effects were detected . Conclusions : Simvastatin is safe and effective in lowering portal hypertension . [ Clinical Trials.gov Identifier : NCT02994485 BACKGROUND In r and omized clinical trials statins and placebo treated patients showed the same degree of coronary artery calcium ( CAC ) progression . We reanalyzed data from two clinical trials to further investigate the time and dose dependent effects of statins on CAC . Additionally , we investigated whether CAC progression was associated with incident cardiovascular events . METHODS AND RESULTS Data were pooled from two clinical trials : St. Francis Heart Study ( SFHS ) ( 419 and 432 patients treated with placebo and 20 mg atorvastatin daily , respectively ) and EBEAT Study ( 164 and 179 patients respectively treated with 10 mg and 80 mg atorvastatin daily ) . CAC scores were assessed at baseline , 2 years and 4 - 6 years in SFHS ; in EBEAT they were measured at baseline and 12 months . After a short-term follow-up ( 12 to 24 months ) placebo and low dose atorvastatin showed a similar CAC increase , although 80 mg/daily atorvastatin increased CAC an additional 12 - 14 % over placebo ( p<0.001 ) . In the long-term , atorvastatin caused a greater progression of CAC compared to placebo ( additional 1.1 % , p=0.04 ) . In SFHS 42 cardiovascular events occurred after the second CT scan . The baseline and progression of CAC were greater in patients with events . However , only baseline CAC and family history of premature cardiovascular disease but not CAC progression were independent predictors of events . CONCLUSIONS Despite a greater CAC increase with high dose and long-term statin therapy , events did not occur more frequently in statin treated patients . This suggests that CAC growth under treatment with statins represents plaque repair rather than continuing plaque expansion BACKGROUND & AIMS In cirrhosis , an insufficient release of nitric oxide contributes to increased hepatic resistance and portal pressure and enhances the postpr and ial increase in portal pressure . We hypothesized that simvastatin , which enhances Akt-dependent endothelial nitric oxide synthase phosphorylation , may increase hepatic nitric oxide release and decrease hepatic resistance in patients with cirrhosis and portal hypertension . METHODS In protocol 1 , 13 patients had measurements of the hepatic venous pressure gradient , hepatic blood flow , mean arterial pressure , cardiac output , and nitric oxide products before and 30 and 60 minutes after 40 mg of simvastatin . In protocol 2 , 17 patients were r and omized to receive placebo or simvastatin ( 40 mg ) 12 hours and 1 hour before the study . After baseline measurements of the hepatic venous pressure gradient , hepatic blood flow , and nitric oxide products , a st and ard liquid meal was given , and measurements were repeated at 15 , 30 , and 45 minutes . RESULTS In protocol 1 , acute simvastatin did not modify the hepatic venous pressure gradient but increased the hepatic blood flow ( 21 % + /- 13 % at 30 minutes ; P = 0.01 ) and decreased hepatic sinusoidal resistance by 14 % + /- 11 % ( P = 0.04 ) . Nitric oxide product levels significantly increased in hepatic venous blood ( from 31.4 + /- 12.3 nmol . mL(-1 ) to 35.8 + /- 10.7 nmol . mL(-1 ) ; P = 0.04 ) , but not in peripheral blood . Systemic hemodynamics were not modified . In protocol 2 , simvastatin pretreatment significantly attenuated the postpr and ial increase in hepatic venous pressure gradient ( mean peak increase , 10 % + /- 9 % vs. 21 % + /- 6 % in placebo ; P = 0.01 ) . Hepatic blood flow increased similarly in the 2 groups . Hepatic nitric oxide products increased in the simvastatin group but not in the placebo group . CONCLUSIONS Simvastatin administration increases the hepatosplanchnic output of nitric oxide products and decreases hepatic resistance in patients with cirrhosis BACKGROUND & AIMS Simvastatin improves liver generation of nitric oxide and hepatic endothelial dysfunction in patients with cirrhosis , so it could be an effective therapy for portal hypertension . This r and omized controlled trial evaluated the effects of continuous simvastatin administration on the hepatic venous pressure gradient ( HVPG ) and its safety in patients with cirrhosis and portal hypertension . METHODS Fifty-nine patients with cirrhosis and portal hypertension ( HVPG > or = 12 mm Hg ) were r and omized to groups that were given simvastatin 20 mg/day for 1 month ( increased to 40 mg/day at day 15 ) or placebo in a double-blind clinical trial . R and omization was stratified according to whether the patient was being treated with beta-adrenergic blockers . We studied splanchnic and systemic hemodynamics and variables of liver function and safety before and after 1 month of treatment . RESULTS Simvastatin significantly decreased HVPG ( -8.3 % ) without deleterious effects in systemic hemodynamics . HVPG decreases were observed in patients who were receiving beta-adrenergic blockers ( -11.0 % ; P = .033 ) and in those who were not ( -5.9 % ; P = .013 ) . Simvastatin improved hepatic , fractional , and intrinsic clearance of indocyanine green , showing an improvement in effective liver perfusion and function . No significant changes in HVPG and liver function were observed in patients receiving placebo . The number of patients with adverse events did not differ significantly between groups . No patient was withdrawn from the study based on adverse events . CONCLUSIONS Simvastatin decreased HVPG and improved liver perfusion in patients with cirrhosis . These effects were additive with those of beta-adrenergic blockers . The beneficial effects of simvastatin should be confirmed in long-term clinical trials for portal hypertension BACKGROUND Pleiotropic effects of statins decrease intrahepatic resistance and portal hypertension . AIM We evaluated the effects of simvastatin on hepatic venous pressure gradient ( HVPG ) and azygos vein blood flow in cirrhotic patients . METHODS A 3-month prospect i ve , r and omized , triple-blind trial with simvastatin ( 40 mg/day ) vs. placebo was conducted in patients with cirrhotic portal hypertension . HVPG and azygos blood flow , measured by colour Doppler endoscopic ultrasound , were assessed before and after treatment . The primary endpoint was a decrease in the HVPG of at least 20 % from baseline or to ≤12 mmHg after the treatment . RESULTS 34 patients were prospect ively enrolled , and 24 completed the protocol . In the simvastatin group 6/11 patients ( 55 % ) presented a clinical ly relevant decrease in the HVPG ; no decrease was observed in the placebo group ( p=0.036 ) . Patients with medium/large oesophageal varices and previous variceal bleeding had a higher response rate to simvastatin . HVPG and azygos blood flow values were not correlated . No significant adverse events occurred . CONCLUSION Simvastatin lowers portal pressure and may even improve liver function . The haemodynamic effect appears to be more evident in patients with severe portal hypertension Background and aim Statins can modulate portal microvascular dynamics in patients with cirrhosis . We present data from a proof-of-concept study aim ed at comparing combination of propranolol and atorvastatin versus propranolol alone in reducing portal pressure in patients with cirrhosis . Patients and methods In this open-label proof-of-concept study , 23 consecutive patients with cirrhosis were r and omized into group A ( incremental dose propranolol , n=12 ) or group B ( atorvastatin 20 mg daily with propranolol in incremental dose , n=11 ) . Hepatic venous pressure gradient ( HVPG ) was estimated at baseline , and after 30 days , clinical outcomes were evaluated after 1 year . Results The two groups were matched with respect to etiology of cirrhosis ; clinical , biochemical , and endoscopic parameters ; child status ; and baseline HVPG . Decreases of wedged hepatic venous pressure , free hepatic venous pressure , and HVPG in group A and group B after 30 days were 4.67±2.57 versus 6.09±3.56 ( P=0.290 ) , 1.83±2.62 versus 1.27±1.67 ( P=0.546 ) , and 2.58±1.88 versus 4.81±2.82 mmHg ( P=0.041 ) , respectively . The proportion of HVPG responders in group A and group B were 50.00 and 90.91 % , respectively . The two groups did not , however , differ significantly in terms of clinical outcomes ( variceal bleed , endoscopic variceal ligation sessions , hepatic encephalopathy , requirement of therapeutic paracentesis , spontaneous bacterial peritonitis , and death ) . Conclusion Decrease of HVPG in patients with cirrhosis treated with atorvastatin and propranolol is significantly more than those treated with only propranolol . Atorvastatin , with its pleiotropic effects , may be useful in portal hypertension in cirrhosis . Larger data sets are required for ratification BACKGROUND & AIMS Concerns related to hepatotoxicity frequently lead to discontinuation or non-initiation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase therapy in patients with cirrhosis despite data supporting statin use . We investigated the independent effects of hyperlipidemia and statin exposure on mortality , hepatic decompensation , and hepatocellular carcinoma development in a large national cohort of patients with cirrhosis . METHODS We performed a retrospective cohort study of patients with newly diagnosed cirrhosis from January 1 , 2008 through June 30 , 2016 in the Veterans Health Administration . Subjects were divided into 2 cohorts : 21,921 patients with prior statin exposure ( existing users ) and 51,023 statin-naïve individuals , of whom 8794 subsequently initiated statin therapy ( new initiators ) and 44,269 did not ( non-initiators ) . Multivariable Cox proportional hazard models with inverse probability weighting were constructed to assess the effects of time-updating lipid profiles and cumulative exposure to statins on survival and hepatic decompensation . Statin-naïve new initiators were propensity matched with non-initiators to simulate a r and omized controlled trial of statin use in cirrhosis . RESULTS In statin-naïve subjects , every 10-mg/dL increase in baseline total cholesterol was associated with a 3.6 % decrease in mortality . In existing users , each year of continued statin exposure was associated with a hazard ratio of 0.920 ( 95 % confidence interval 0.0.897 - 0.943 ) for mortality . After risk-set matching , each year of statin exposure among new initiators was associated with a hazard ratio of 0.913 ( 95 % confidence interval 0.890 - 0.937 ) for mortality . CONCLUSIONS In a retrospective cohort study of veterans with a new diagnosis of cirrhosis , we associated hypercholesterolemia with well-preserved hepatic function and decreased mortality . Nonetheless , each cumulative year of statin exposure was associated with an independent 8.0%-8.7 % decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and BACKGROUND & AIMS The combination of β-blockers and b and ligation is the st and ard approach to prevent variceal rebleeding , but bleeding recurs and mortality is high . The lipid-lowering drug simvastatin decreases portal pressure , improves hepatocellular function , and might reduce liver fibrosis . We assessed whether adding simvastatin to st and ard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis . METHODS We performed a multicenter , double-blind , parallel trial of 158 patients with cirrhosis receiving st and ard prophylaxis to prevent rebleeding ( a β-blocker and b and ligation ) in Spain from October 2010 through October 2013 . Within 10 days of bleeding , subjects were r and omly assigned , but stratified by Child-Pugh class of A or B vs C , to groups given simvastatin ( 20 mg/d the first 15 days , 40 mg/d thereafter ; n = 69 ) or placebo ( n = 78 ) . Patients were followed for as long as 24 months . The primary end point was a composite of rebleeding and death , and main secondary end points were the individual components of the composite ( death and rebleeding ) . RESULTS The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group ( P = .423 ) . Seventeen patients in the placebo group died ( 22 % ) vs 6 patients in the simvastatin group ( 9 % ) ( hazard ratio for adding simvastatin to therapy = 0.39 ; 95 % confidence interval : 0.15 - 0.99 ; P = .030 ) . Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis . Rebleeding occurred in 28 % of patients in the placebo group and 25 % in the simvastatin group ( P = .583 ) . Serious adverse events occurred in 53 % of patients in the placebo group and 49 % in the simvastatin group ( P = .752 ) ; the percentages of serious adverse events related to therapy were 11 % in the placebo group vs 8 % in the in the simvastatin group ( P = .599 ) . Two patients in the simvastatin group , each with advanced liver disease , developed rhabdomyolysis . CONCLUSIONS In a r and omized controlled trial , addition of simvastatin to st and ard therapy did not reduce rebleeding , but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis . Survival was not the primary end point of the study , so these results require validation . The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected . European Clinical Trial Data base ID : EUDRACT 2009 - 016500 - 24 ; Clinical Trials.gov ID : NCT01095185

Lifestyle interventions appear effective for treating overweight and obesity among people with serious mental illness . Interventions of ≥12-months duration compared to ≤6-months duration appear to achieve more consistent outcomes , though effect sizes are similar for both shorter and longer duration interventions

OBJECTIVE To conduct a systematic review and meta- analysis to estimate effects of lifestyle intervention participation on weight reduction among overweight and obese adults with serious mental illness .

Abstract Depressive symptoms have debilitating effects on the physical health and functioning of people with serious mental illness . We examined change in depressive symptoms among overweight and obese adults with serious mental illness ( n = 343 ) using data combined from two r and omized trials comparing the 12-month In SHAPE program to a gym membership control condition . In SHAPE consists of a gym membership , weekly individual meetings with a fitness trainer , and instruction on healthy eating and nutrition . Depressive symptoms were measured at baseline , 3 , 6 , and 12 months . Change in depressive symptoms did not differ between groups , but depressive symptoms decreased over time across the entire sample ( p = 0.045 ) . At 12 months , reduced depressive symptoms were associated with clinical ly significant improved cardiorespiratory fitness ( p = 0.030 ) , 10 % or more weight loss ( p = 0.044 ) , and cardiovascular risk reduction ( p = 0.028 ) across both groups . Our findings suggest that participation in health promotion programs result ing in cardiovascular risk reduction may be associated with reduced depressive symptoms Objective : Weight gain is common for individuals with serious mental illness ( SMI ) receiving antipsychotic drug therapy . Contingency management ( CM ) is a behavioral intervention that rewards positive performance and has demonstrated effectiveness in reducing drug use in SMI population s. This study evaluated the feasibility of using CM to promote weight loss in individuals with SMI over 8 weeks . Method : 30 individuals ( BMI ≥ 28 kg/m2 ) were r and omized to one of three conditions : i ) The combination of a st and ardized lifestyle modification ( LM ) program for individuals with SMI and payment for group attendance ( CMattendance ) , ii ) The combination of LM and payment for weight loss ( CMweight ) , and iii ) waitlist control ( CON ) . After the waitlist period , those participants joined a LM group and received payment for behavioral change ( CMbehavior ) . Results : Subjects in the CMattendance and in the CMweight group lost a mean of 1.16 kg and 1.23 kg , respectively , while subjects in the CON gained a mean of 0.68 kg . Subjects receiving CMbehavior , lost a mean of 2.54 kg , which was a significant weight loss compared to the control period . Conclusion : LM supplemented with CM may facilitate weight loss in patients taking antipsychotic medications ; financial reimbursement for behavioral change may be particularly effective in this population BACKGROUND Individuals with serious mental illness have high rates of obesity and a need for specialized weight loss intervention programs . This study examines the efficacy of the RENEW weight loss intervention and examines the impact of the intervention setting on outcomes . METHOD 136 individuals with serious mental illness from 4 different setting s were r and omly assigned to receive the RENEW weight loss intervention or a control condition of treatment as usual . The RENEW intervention is a one year program that includes an intensive , maintenance and intermittent supports phase . RESULTS The intervention group experienced a modest weight loss of 4.8 lbs at 3 months , 4.1 lbs at 6 months and a slight weight gain of 1.5 lbs at 12 months . The control group gained a total of 6.2 lbs at 12 months . However when setting s were examined separately the responder sites had a weight loss of 9.4 lbs at 3 months , 10.9 lbs at 6 months and 7 lbs at 12 months . DISCUSSION These results suggest that the setting s in which individuals receive services may act as a support or hindrance toward response to weight loss interventions . The concept of the obesogenic environment deserves further examination as a factor in the success of weight loss programs How should health care professionals choose among the many therapies cl aim ed to be efficacious for treating specific disorders ? The practice of evidence -based medicine provides an answer . Advocates of this approach urge health care professionals to base treatment choices on the best evidence from systematic research on both the efficacy and adverse effects of various therapeutic alternatives . Ideally , health care professionals would compare different treatments by referring to r and omized , double-blind , head-to-head trials that compared the treatment options . Although individual medications are typically well research ed when these placebo-controlled studies are performed , studies that directly compare treatments are rare . In the absence of direct head-to-head trials , other evidence comes from indirect comparisons of two or more therapies by examining individual studies involving each treatment . This article provides an introductory review of methods of such indirect comparisons of therapies across studies , provides examples of how these methods can be used to make treatment decisions , and presents a general overview of relevant issues and statistics for readers interested in underst and ing these methods more thoroughly Obesity and diabetes have caused problems for individuals with schizophrenia long before atypical antipsychotic agents . The prevalence of obesity , insulin resistance , impaired glucose tolerance , type 2 diabetes mellitus , dyslipidemia , and the Metabolic Syndrome has increased in people with schizophrenia as compared to the general population . Risk reduction studies for persons with obesity , diabetes , and cardiovascular disease indicate that cognitive/behavioral interventions that promote motivation and provide strategies to overcome the barriers in adherence to diet and activity modification are effective interventions for weight management and risk reduction . In the l and mark multi-center r and omized-controlled trial study , the Diabetes Prevention Project ( DPP ) , a cognitive/behavioral intervention , was more successful in producing weight loss and preventing diabetes than the drugs metformin , troglitazone or placebo . This pilot study examined the effectiveness of a cognitive/behavioral group intervention , modified after the DPP program , in individuals with schizophrenia or schizoaffective disorder taking atypical antipsychotics in a large urban public mental health system . Outcome measures included body weight , body mass index , waist-hip ratios , and fasting glucose levels . Both groups demonstrated elevated fasting glucose levels and were obese with a mean BMI of 33 . The group that received the cognitive/behavioral group intervention lost more weight than the treatment as usual group . The CB group participants lost an average of 5.4 lb or 2.9 % of body weight , and those in the control group lost 1.3 lb or 0.6 % body weight . The range of weight loss for the treatment group was from 1 to 20 lb . This pilot study has demonstrated that weight loss is possible with cognitive/behavioral interventions in a population with a psychotic disorder BACKGROUND Available data on atypical antipsychotic-induced weight gain are limited by a number of method ological factors . The objective of this report is to evaluate short-term ( N=1742 ) and long-term ( N=1649 ) weight effects in patients receiving st and ard doses of amisulpride , haloperidol , olanzapine , risperidone , ziprasidone , and placebo based on 21 r and omized , placebo-controlled , parallel-group studies from an integrated clinical trial data base . METHOD Analyses of the integrated ziprasidone schizophrenia trials data base were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain ( or weight loss ) across studies for each agent studied , based on fixed- and r and om-effects models . Duration s of treatment exposure in long-term trials were controlled by well-defined time windows ( 6 month : 150 to 210 days ; 1 year : 330 to 390 days ) . Weight gain or loss was defined using a 7 % change from baseline threshold . RESULTS During long-term therapy with 1-year treatment duration , incidence of weight gain for subjects treated with ziprasidone ( 17 % ) was not significantly different from the placebo ( 13 % ) or haloperidol ( 41 % ) groups based on 95 % confidence interval . In contrast , significantly greater weight gain incidence was observed for the olanzapine ( 57 % ) and risperidone ( 39 % ) groups compared to placebo . Median weight change of + 0.49 , -0.18 , + 1.50 and + 0.55 lb/month was observed for haloperidol , ziprasidone , olanzapine and risperidone subjects , respectively , indicating differential weight change patterns compared to placebo ( -0.32 ) . Similar results were observed for the short-term ( 4 - 12 weeks ) and 6-month treatment exposure cohorts . CONCLUSIONS Our results confirm significant differences in long-term weight effects among atypical antipsychotics , consistent with findings from prior meta- analysis of antipsychotic-induced weight gain [ Allison , D.B. , Mentore , J.L. , Heo , M. , Ch and ler , L.P. , Capelleri , J.C. , Infante , M.C. , Weiden , P.J. , 1999 . Antipsychotic induced weight gain : a comprehensive research synthesis . Am J Psychiatry 156 , 1686 - 1696 ] and the CATIE schizophrenia study [ Lieberman , J.A. , Stroup , T.S. , McEvoy , J.P. , et al. , 2005 . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia . N Engl J Med 353 , 1209 - 1223 ] Approximately one fourth of the U.S. adult population nearly 50 million peoplehas hypertension ( 1 , 2 ) . Taking a broader perspective , more than half of the adult population has higher than optimal blood pressure ( 1 ) , defined as systolic blood pressure greater than 120 mm Hg and diastolic blood pressure greater than 80 mm Hg ( 2 ) . These persons are at significantly increased risk for cardiovascular disease and stroke ( 3 ) . Although pharmacologic treatment for hypertension significantly reduces morbidity and mortality from cardiovascular diseases ( 4 , 5 ) , long-term pharmacologic therapy can have undesirable side effects and requires the expense of continuing medical supervision . Furthermore , pharmacologic therapy is not usually initiated when blood pressure is higher than optimal yet below diagnostic thresholds for hypertension . Thus , lifestyle interventions for primary prevention and initial treatment of high blood pressure remain a vital strategy for controlling this highly prevalent condition ( 2 ) . Weight loss has been shown to reduce blood pressure in overweight hypertensive patients ( 6 - 9 ) and in overweight persons with high-normal blood pressure ( 10 - 12 ) . Two review s of r and omized trials of weight reduction to reduce blood pressure examined the results of nine studies ( 13 , 14 ) . Most of these trials were small , only one had more than 500 participants ( 11 ) , and most had short-term follow-up ( 1 year or less ) . Only three studies had follow-up of 3 to 5 years ( 8 , 10 , 11 ) . Compared with controls , weight loss averaged nearly 7 kg in the short-term trials and approximately 3 kg in the three longer-term trials . In almost all trials , systolic blood pressure and diastolic blood pressure were reduced in the intervention groups . Since these review s were published , the Trials of Hypertension Prevention ( TOHP ) Phase I reported mean weight reduction of 3.9 kg at 18 months in 564 overweight participants with high-normal blood pressure , result ing in significant decreases in systolic blood pressure and diastolic blood pressure compared with a usual care control group ( 12 , 15 ) . To investigate whether nonpharmacologic interventions can prevent hypertension over the long term , TOHP II was initiated . This was a r and omized , controlled trial examining the effects of weight loss and dietary sodium reduction , alone and in combination , in reducing blood pressure in overweight adults with high-normal diastolic blood pressure ( 16 ) . This target population is at high risk for hypertension as they age . The primary outcome paper from this trial ( 17 ) provided only a brief overview of the effects of weight loss on blood pressure . Here , we provide more detailed analysis of weight loss and blood pressure in TOHP II . Of special interest are the long-term effects of weight loss on blood pressure , the magnitude of the doseresponse relationship at 36 months , the effect of patterns of weight loss on blood pressure , and the predictors of weight loss and blood pressure response . Methods Participants Participants in TOHP II were overweight adults with nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg . Other eligibility criteria included age 30 to 54 years and a body mass index of 26.1 to 37.4 kg/m2 for men and 24.4 to 37.4 kg/m2 for women , approximately 110 % to 165 % of ideal weight ( 18 ) . Principal exclusion criteria were current treatment with medications that might affect blood pressure , clinical or laboratory evidence of cardiovascular disease , diabetes mellitus , renal insufficiency ( serum creatinine concentration 150 mol/L [ 1.7 mg/dL ] for men and 132 mol/L [ 1.5 mg/dL ] for women ) , and current or planned pregnancy . Detailed descriptions of recruitment and participant characteristics have been published elsewhere ( 19 , 20 ) . The study was review ed and approved by the institutional review boards at all nine TOHP centers and the coordinating center , and all participants signed informed consent forms . Design Eligible participants were r and omly assigned with equal probability to one of four groups : weight loss only , sodium reduction only , combined weight loss and sodium reduction , or usual care ( controls ) . Measurements Age , sex , ethnicity , and years of education were obtained by question naire . Baseline blood pressure measurements were taken at three screening visits , each separated by 7 to 45 days . At each visit , three readings of systolic blood pressure and diastolic blood pressure were obtained and averaged . Certified staff obtained measurements in seated participants by using a Hawksley r and om-zero sphygmomanometer ( 21 ) . Body weight was measured to the nearest 0.2 kg ( 0.5 lb ) by using a calibrated balance-beam scale ; participants wore indoor clothing ( without shoes ) . Blood pressure and weight were measured every 6 months after r and omization to the end of follow-up at 36 , 42 , or 48 months , depending on r and omization date . Clinic staff who were blinded to study group assignment made these assessment s. Blood pressure measurements were obtained during a single visit at all follow-up points except for 18 and 36 months , when measurements were taken at a series of three visits approximately 1 week apart . Multiple measurements were taken at 18 and 36 months to provide a more precise assessment of average blood pressures at these primary outcome points . Dietary intake was assessed by 24-hour recall , and physical activity was assessed by question naire . Intervention Participants assigned to the weight loss intervention group sought to lose at least 4.5 kg ( 10 lb ) during the first 6 months of the intervention and to maintain their weight loss for the remainder of the trial . A brief description of the intervention methods is presented here ; a more detailed description has been published elsewhere ( 22 ) . The intervention started with an individual counseling session , followed by 14 weekly group meetings led by dietitians or health educators . After this 14-week intensive phase , participants attended six biweekly group meetings and then monthly group meetings . Beginning in the 18th month , participants were offered a variety of options to keep them involved in the intervention , including individual counseling sessions and special group sessions focused on selected weight loss topics . The intervention focused on self-directed behavior change ( behavioral self-management ) , nutrition education , information on physical activity , and social support for making and maintaining behavior changes . Specific behavior change techniques included self-monitoring ( food diaries and graphs of minutes of physical activity per day ) , setting explicit short-term goals and developing specific action plans to achieve those objectives , and developing alternative strategies for situations that trigger problem eating . The dietary intervention focused on reducing caloric intake by decreasing consumption of excess fat , sugar , and alcohol . Keeping daily food diaries was emphasized for monitoring intake and assessing progress . With experience , the participants determined the caloric intake that produced moderate weight loss for them . It was suggested that men not consume less than 1500 kcal/d and women not less than 1200 kcal/d . Weight loss of more than 0.9 kg ( 2 lb ) per week was discouraged . The physical activity goal was to gradually increase activity to 30 to 45 minutes per day , four to five days per week . Exercise intensity was moderate , approximately 40 % to 55 % of heart rate reserve , and consisted primarily of brisk walking . Statistical Analysis Baseline characteristics of the weight loss and usual care groups were compared overall and by sex by using t-tests for means and chi-square tests for proportions . Although weight and blood pressure data were collected every 6 months , special efforts were made to achieve high follow-up rates at 18 and 36 months ; at each of these two time points , nine blood pressure readings were collected over three visits and were averaged . For participants prescribed antihypertensive medication , follow-up blood pressure for all subsequent visits was taken to be the last study blood pressure before therapy was started . Participants receiving medications that affect blood pressure for reasons other than hypertension or who became pregnant were treated as missing at that visit . We used two- sample t-tests to compare changes in weight and blood pressure from baseline in the weight loss intervention and usual care groups overall , by sex , by ethnicity , and by sex and ethnicity . The effects of the intervention in terms of changes in weight and blood pressure were examined overall and in subgroups defined by sex , ethnicity , and sex and ethnicity . Subgroup differences were tested by using terms for the interaction of treatment group with sex and with ethnicity in multiple linear regression models . Regression analyses were also used to analyze the doseresponse relationship between change in weight and change in blood pressure , overall and within sex and ethnicity subgroups . Differences in dose response were tested by using interaction terms in linear regression models . All regressions were adjusted for age and baseline weight . We also adjusted for baseline blood pressure in the blood pressure regression models . Change in blood pressure was also examined in relation to quintile of weight loss . Quintiles were computed by using the distribution of weight change in the weight loss intervention group . Additional multiple regression analyses were performed in which weight loss participants were categorized according to patterns of weight loss at 6 and 36 months . The PROC MIXED function of SAS software ( SAS Institute , Inc. , Cary , North Carolina ) was used to perform repeated- measures analyses that tested differences over time by pattern of weight loss . Cox proportional-hazards models were used for survival analyses , with onset of hypertension as the outcome . Results Baseline Findings The baseline characteristics of participants assigned to BACKGROUND The aim of this r and omized clinical trial follow-up at three months was to evaluate the effectiveness of an educational intervention with a focus on diet and physical activity ( PA ) to change the amount of PA , body mass index ( BMI ) and the waist circumference ( WC ) in patients with severe mental illness . METHODS We recruited 332 out patients with severe mental disorders undergoing treatment with antipsychotic medication from Mental Healthcare Centers of Barcelona . They were r and omly assigned to an intervention or a control group . The patients in the intervention group participated in a group PA and diet educational program . The blinded measurements at 0 and 3 months were : the level of PA ( IPAQ question naire ) , BMI , WC , blood pressure , dietary habits ( PREDIMED question naire ) , quality of life ( SF-36 question naire ) and laboratory parameters ( cholesterol , triglycerides , glucose ) . RESULTS The average age was 46.7 years and 55 % were males . Schizophrenia had been diagnosed in 67.1 % of them . At 3 months , the average weekly walking METs rose significantly in the IG 266.05 METs ( 95%CI : 16.86 to 515.25 ; P=0.036 ) . The total MET average also rose although not significantly : 191.38 METs ( 95%CI : 1.38 to 381.38 ; P=0.086 ) . However , the BMI decreased significantly more in the CG , by 0.26kg/m(2 ) ( 95%CI : 0.02 to 0.51 ; P=0.038 ) , than in the IG . There were no significant differences in the WC . CONCLUSIONS The short-term results suggest that the intervention increases the level of PA , but does not improve physical or laboratory parameters . TRIAL REGISTRATION Clinical trials.gov NCT01729650 ( effectiveness of a physical activity and diet program in patients with psychotic disorder [ CAPiCOR ] ) BACKGROUND People with psychosis often experience weight gain , which places them at risk of cardiovascular disease , diabetes , and early death . OBJECTIVE To determine the uptake , adherence , and clinical effectiveness of a healthy living intervention design ed to reduce weight gain . METHOD An exploratory r and omized controlled trial , comparing the intervention with treatment as usual ( TAU ) in 2 early intervention services for psychosis in Engl and . DSM-IV classification was the diagnostic criteria used to assign the psychiatric diagnoses . The primary outcome was change in body mass index ( BMI ) from baseline to 12-month follow-up . The study was conducted between February 2009 and October 2012 . RESULTS 105 service users , with a BMI of ≥ 25 ( ≥ 24 in South Asians ) , were r and omized to intervention ( n = 54 ) or TAU ( n = 51 ) after stratification by recent commencement of antipsychotic medication . Ninety-three service users ( 89 % ) were followed up at 12 months . Between-group difference in change in BMI was not significant ( effect size = 0.11 ) . The effect of the intervention was larger ( effect size = 0.54 , not significant ) in 15 intervention ( 28 % ) and 10 TAU ( 20 % ) participants who were taking olanzapine or clozapine at r and omization . CONCLUSIONS The healthy living intervention did not show a significant difference in BMI reduction compared to the TAU group . TRIAL REGISTRATION www.is rct n.org identifier : IS RCT N22581937 Individuals with severe and persistent mental illness ( SPMI ) have a preponderance of weight problems , possibly even greater than the obesity epidemic in the general population . Although atypical antipsychotics cause weight gain , their contribution to obesity has not been characterized in a community setting where individuals may take multiple psychotropics associated with weight gain . Using survey information including measured height and weight from a r and om sample of Maryl and Medicaid recipients with SPMI , we compared obesity prevalence to the National Health and Nutrition Examination Survey ( NHANES III ) sample and a Maryl and sample ( Behavioral Risk Factor Surveillance System ) of the general population adjusted to SPMI demographic characteristics . We investigated correlates of obesity in the SPMI sample . The results indicate that both men and especially women with SPMI had a higher prevalence of obesity than the general population ; this portends substantial health implication s. A fourfold association between atypical antipsychotics and prevalent obesity was found in men but not in women ; further work should clarify mechanisms of obesity in the SPMI BACKGROUND Overweight and obesity are epidemic among persons with serious mental illness , yet weight-loss trials systematic ally exclude this vulnerable population . Lifestyle interventions require adaptation in this group because psychiatric symptoms and cognitive impairment are highly prevalent . Our objective was to determine the effectiveness of an 18-month tailored behavioral weight-loss intervention in adults with serious mental illness . METHODS We recruited overweight or obese adults from 10 community psychiatric rehabilitation outpatient programs and r and omly assigned them to an intervention or a control group . Participants in the intervention group received tailored group and individual weight-management sessions and group exercise sessions . Weight change was assessed at 6 , 12 , and 18 months . RESULTS Of 291 participants who underwent r and omization , 58.1 % had schizophrenia or a schizoaffective disorder , 22.0 % had bipolar disorder , and 12.0 % had major depression . At baseline , the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 36.3 , and the mean weight was 102.7 kg ( 225.9 lb ) . Data on weight at 18 months were obtained from 279 participants . Weight loss in the intervention group increased progressively over the 18-month study period and differed significantly from the control group at each follow-up visit . At 18 months , the mean between-group difference in weight ( change in intervention group minus change in control group ) was -3.2 kg ( -7.0 lb , P=0.002 ) ; 37.8 % of the participants in the intervention group lost 5 % or more of their initial weight , as compared with 22.7 % of those in the control group ( P=0.009 ) . There were no significant between-group differences in adverse events . CONCLUSIONS A behavioral weight-loss intervention significantly reduced weight over a period of 18 months in overweight and obese adults with serious mental illness . Given the epidemic of obesity and weight-related disease among persons with serious mental illness , our findings support implementation of targeted behavioral weight-loss interventions in this high-risk population . ( Funded by the National Institute of Mental Health ; ACHIEVE Clinical Trials.gov number , NCT00902694 . ) BACKGROUND Obesity is common in persons with schizophrenia . Besides its adverse health effects , obesity reduces quality of life and contributes to the social stigma of schizophrenia . METHOD This 14-week , multicenter , open-label , rater-blinded , r and omized study evaluated the effects of a group-based behavioral treatment ( BT ) for weight loss in overweight and obese stable patients with DSM-IV schizophrenia or schizoaffective disorder who had been switched from olanzapine to risperidone . Participants were r and omly assigned to receive BT or usual clinical care ( UC ) . BT included 20 sessions during which patients were taught to reduce caloric intake . In UC , patients were encouraged to lose weight but received no special advice about weight reduction . The primary outcome measure was change in body weight . RESULTS Seventy-two patients were enrolled . The mean + /- SD weight loss at endpoint was significant in both groups ( p < .05 ) and numerically greater in patients receiving BT than in those receiving UC ( -2.0 + /- 3.79 and -1.1 + /- 3.11 kg , respectively ) . More patients in the BT group than in the UC group had lost > or = 5 % of their body weight at endpoint ( 26.5 % [ 9/34 ] and 10.8 % [ 4/37 ] , respectively ; p = .082 ) . A post hoc analysis of patients attending at least 1 BT session showed that significantly more patients in the BT than the UC group had lost > or = 5 % of their body weight at endpoint ( 32.1 % [ 9/28 ] vs. 10.8 % [ 4/37 ] , respectively , p = .038 ) and at week 14 ( complete population ; 40.9 % [ 9/22 ] and 14.3 % [ 4/28 ] , respectively , p = .027 ) . CONCLUSION BT may be an effective method for weight reduction in patients with chronic psychotic illness People taking antipsychotic medications are at increased risk for obesity , diabetes , and early mortality . Few weight loss interventions have targeted this population . Thirty-six individuals were r and omized to an evidence -based 12-week weight loss intervention ( PREMIER with DASH diet , n = 18 ) or to usual care ( n = 18 ) in this feasibility trial . Average attendance was 8.6 of 12 sessions . Intent-to-treat analyses of covariance , adjusted for baseline weight , showed significant changes in weight : Mean weight in intervention participants declined from 213.3 to 206.6 pounds , while control participants ’ weight was unchanged . It is possible to recruit , assess , intervene with , and retain participants taking antipsychotic medications in a dietary and exercise lifestyle change trial . Participants reported high levels of satisfaction with the intervention OBJECTIVE Patients with schizophrenia treated with clozapine often gain weight . This study evaluated the effects of dietary control and physical activity among obese in patients with schizophrenia being treated with clozapine . METHODS Fifty-three clozapine-treated obese patients with schizophrenia in a veterans hospital in eastern Taiwan who had a body mass index greater than 27 ( weight divided by height in meters squared ) and who were taking clozapine were r and omly assigned to a study group of 28 or a control group of 25 . The study group was placed on a diet that reduced calorie intake by 200 to 300 kcal per day ( to 1,300 to 1,500 kcal per day for women and to 1,600 to 1,800 kcal per day for men ) and a six-month regimen of regular physical activity in which participants used approximately 600 to 750 kcal per week ( level walking and walking on stairs for 60 minutes three days per week ) . Anthropometric , metabolic , and hormonal parameters were measured after three and six months by using anthropometry , an enzyme autoanalyzer , immunoassay , and enzyme-linked immunosorbent assay . RESULTS Compared with the control group , the study group showed a significant decrease in body weight , body mass index ( 5.4 % reduction ) , waist circumference ( 3.3 cm ) , and hip circumference ( 3.3 cm ) after three months and after six months . Triglyceride and insulin-like growth factor-binding protein-3 ( IGFBP-3 ) decreased significantly only after six months . CONCLUSIONS A program of dietary control and regular physical activity can significantly reduce body weight and improve metabolic profiles of insulin , triglyceride , and IGFBP-3 among obese in patients taking clozapine for the treatment of schizophrenia OBJECTIVES The STRIDE study assessed whether a lifestyle intervention , tailored for individuals with serious mental illnesses , reduced weight and diabetes risk . The authors hypothesized that the STRIDE intervention would be more effective than usual care in reducing weight and improving glucose metabolism . METHOD The study design was a multisite , parallel two-arm r and omized controlled trial in community setting s and an integrated health plan . Participants who met inclusion criteria were ≥18 years old , were taking antipsychotic agents for ≥30 days , and had a body mass index ≥27 . Exclusions were significant cognitive impairment , pregnancy/breastfeeding , recent psychiatric hospitalization , bariatric surgery , cancer , heart attack , or stroke . The intervention emphasized moderate caloric reduction , the DASH ( Dietary Approaches to Stop Hypertension ) diet , and physical activity . Blinded staff collected data at baseline , 6 months , and 12 months . RESULTS Participants ( men , N=56 ; women , N=144 ; mean age=47.2 years [ SD=10.6 ] ) were r and omly assigned to usual care ( N=96 ) or a 6-month weekly group intervention plus six monthly maintenance sessions ( N=104 ) . A total of 181 participants ( 90.5 % ) completed 6-month assessment s , and 170 ( 85 % ) completed 12-month assessment s , without differential attrition . Participants attended 14.5 of 24 sessions over 6 months . Intent-to-treat analyses revealed that intervention participants lost 4.4 kg more than control participants from baseline to 6 months ( 95 % CI=-6.96 kg to -1.78 kg ) and 2.6 kg more than control participants from baseline to 12 months ( 95 % CI=-5.14 kg to -0.07 kg ) . At 12 months , fasting glucose levels in the control group had increased from 106.0 mg/dL to 109.5 mg/dL and decreased in the intervention group from 106.3 mg/dL to 100.4 mg/dL. No serious adverse events were study -related ; medical hospitalizations were reduced in the intervention group ( 6.7 % ) compared with the control group ( 18.8 % ) . CONCLUSIONS Individuals taking antipsychotic medications can lose weight and improve fasting glucose levels . Increasing reach of the intervention is an important future step OBJECTIVES Veterans with serious mental illness are at increased risk of obesity , sedentary lifestyle , and a host of related chronic diseases . Although evidence suggests that lifestyle interventions can help mental health consumers achieve modest weight loss , several studies have failed to show a benefit and most have concluded that significant challenges remain in delivering effective interventions . In 2006 , the Veterans Health Administration introduced MOVE ! , a weight management program that includes behaviorally based dietary and physical activity self-management support . This article describes modifications used to manualize MOVE ! for veterans with serious mental illness and reports findings from a r and omized controlled trial of the new intervention . METHODS Between January 2007 and June 2009 , overweight or obese veterans with serious mental illness were r and omly assigned to a six-month trial of MOVE ! ( N=53 ) , which includes both individual and group sessions , or to a control condition that offered basic information about diet and exercise every month ( N=56 ) . Weight and metabolic , attitudinal , behavioral , and functional variables were measured at baseline and six months , and weight was also measured monthly . RESULTS Thirty participants in MOVE ! and 41 participants in the control group completed the six-month assessment , and only seven lost 5 % of their baseline weight ; there was no effect of group assignment on weight loss . There were no significant group × time differences in any metabolic , dietary , physical activity , attitudinal , or functional measure . CONCLUSIONS Despite the negative findings of this study , research is crucial to identify lifestyle interventions and related supports and services to help veterans with mental illness reduce overweight and obesity AIM The aim of this study was to design and examine a program called the ' pedometer walking plus motivational interviewing ( PWMI ) program ' in schizophrenic patients who are obese or overweight . METHODS This was a 12-week , r and omized , parallel , open-label , controlled trial in mildly ill schizophrenic patients with a body mass index ( BMI ) of 23.0 kg/m(2 ) or more . Each participant in the intervention or control group was given a leaflet entitled ' What is a healthy lifestyle ? ' The 1-week , PWMI program consisted of five 1-h sessions of individual motivational interviewing , group education , goal - setting , and practising of pedometer walking . The pedometers were given to the intervention group only . Weight , height , BMI and waist circumference were assessed at baseline , week 4 , week 8 , and week 12 . The primary outcome of this trial was the changed bodyweight at week 4 , week 8 , and week 12 . RESULTS Of 64 participants , 32 each were r and omly allocated to intervention and control groups . All participants completed the study . Only the means of changed bodyweight at week 12 were significantly different between groups ( P = 0.03 ) . At this week , the bodyweight of the intervention group decreased significantly more than that of the control group with a mean difference of 2.21 kg ( 95 % confidence interval of 4.12 - 0.29 ) . CONCLUSION Increased physical activity by pedometer walking plus individual motivational interviewing may be an effective program for the reduction of bodyweight and BMI in Thai schizophrenic patients who are obese or overweight . Its efficacy may be comparable to other cognitive/behavioral programs . Further studies in larger sample sizes are warranted OBJECTIVE Few studies targeting obesity in serious mental illness have reported clinical ly significant risk reduction , and none have been replicated in community setting s or demonstrated sustained outcomes after intervention withdrawal . The authors sought to replicate positive health outcomes demonstrated in a previous r and omized effectiveness study of the In SHAPE program across urban community mental health organizations serving an ethnically diverse population . METHOD Persons with serious mental illness and a body mass index ( BMI ) > 25 receiving services in three community mental health organizations were recruited and r and omly assigned either to the 12-month In SHAPE program , which included membership in a public fitness club and weekly meetings with a health promotion coach , or to fitness club membership alone . The primary outcome measures were weight and cardiorespiratory fitness ( as measured with the 6-minute walk test ) , assessed at baseline and at 3 , 6 , 9 , 12 , and 18 months . RESULTS Participants ( N=210 ) were ethnically diverse ( 46 % were nonwhite ) , with a mean baseline BMI of 36.8 ( SD=8.2 ) . At 12 months , the In SHAPE group ( N=104 ) had greater reduction in weight and improved fitness compared with the fitness club membership only group ( N=106 ) . Primary outcomes were maintained at 18 months . Approximately half of the In SHAPE group ( 51 % at 12 months and 46 % at 18 months ) achieved clinical ly significant cardiovascular risk reduction ( a weight loss ≥5 % or an increase of > 50 meters on the 6-minute walk test ) . CONCLUSIONS This is the first replication study confirming the effectiveness of a health coaching intervention in achieving and sustaining clinical ly significant reductions in cardiovascular risk for overweight and obese persons with serious mental illness OBJECTIVE To demonstrate the effectiveness of a Diabetes Prevention Program-inspired 12-month behavioral intervention for patients with severe mental illness ( SMI ) and medication-associated obesity . METHOD This r and omized , controlled , parallel , superiority study screened 225 volunteers from November 2005 to August 2008 at the VA Greater Los Angeles Healthcare System . 122 out patients with DSM-IV-diagnosed SMI taking antipsychotic medications who had ≥ 7 % weight gain or body mass index ( BMI ) > 25 were r and omized by computer-generated number to Lifestyle Balance treatment intervention ( n = 60 ) or usual care control ( n = 62 ) groups . Clinical raters were masked to r and omization . Treatment intervention included weekly classes and individual counseling for 8 weeks , food and exercise diaries , rewards , caregiver consultations , and monthly booster classes and counseling for 1 year . Controls received self-help material s and visited at equivalent intervals without formal classes or counseling . Outcomes were changes in anthropometric measurements , psychiatric symptoms , health knowledge , and glucose , hemoglobin A1c , and lipid levels . RESULTS Our intention-to-treat analysis found significant differences in predicted trajectory of mean weight change between the groups over 12 months ( P < .01 ) , with treatment participants expected to lose an average 4.6 kg , while control participants would gain an average 0.6 kg . BMI and body fat percentage followed the same pattern . Both groups demonstrated statistically significant improvements in health knowledge quiz scores over time ( P = .006 ) , without significant difference between groups . CONCLUSIONS Treatment was more effective than usual care control in treating medication-associated obesity , independent of SMI diagnosis , antipsychotic medication , and knowledge gained , suggesting that behavioral interventions are effective in SMI patients . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00344500 OBJECTIVES There have been few comprehensive studies of nutrition and exercise behaviors among patients with bipolar disorder ( BPD ) . Based on a national sample of patients receiving care in the Veterans Affairs ( VA ) health care system , we compared nutrition and exercise behaviors among individuals diagnosed with BPD , others diagnosed with schizophrenia , and others who did not receive diagnoses of serious mental illness ( SMI ) . METHODS We conducted a cross-sectional study of patients who completed the VA 's Large Health Survey of Veteran Enrollees section on health and nutrition in fiscal year ( FY ) 1999 and who either received a diagnosis of BPD ( n = 2,032 ) or schizophrenia ( n = 1,895 ) , or were included in a r and om sample of non-SMI VA patients ( n = 3,065 ) . We compared nutrition and exercise behaviors using multivariable logistic regression , controlling for patient socio-economic and clinical factors , and adjusting for patients clustered by site using generalized estimating equations . RESULTS Patients with BPD were more likely to report poor exercise habits , including infrequent walking ( odds ratio , OR = 1.33 , p < 0.001 ) or strength exercises ( OR = 1.28 , p < 0.001 ) than those with no SMI . They were also more likely to self-report suboptimal eating behaviors , including having fewer than two daily meals ( OR = 1.32 , p < 0.001 ) and having difficulty obtaining or cooking food ( OR = 1.48 , p < 0.001 ) . Patients with BPD were also more likely to report having gained > or=10 pounds in the past 6 months ( OR = 1.59 , p < 0.001 ) and were the least likely to report that their health care provider discussed their eating habits ( OR = 0.84 , p < 0.05 ) or physical activity ( OR = 0.81 , p < 0.01 ) . CONCLUSIONS Greater efforts are needed to reduce the risk of poor nutrition and exercise habits among patients diagnosed with BPD OBJECTIVE The objective of this study was to evaluate the effectiveness of a fitness health mentor program ( In SHAPE ) in improving physical fitness and weight loss among overweight and obese adults with serious mental illness . METHODS A r and omized controlled trial was conducted with 133 persons with serious mental illness and a body mass index ( BMI ) > 25 who were assigned either to the In SHAPE program ( one year of weekly sessions with a fitness trainer plus a fitness club membership ) or to one year of fitness club membership and education . Assessment s were conducted at baseline and three , six , nine , and 12 months later . RESULTS Participants had a mean baseline weight of 231.8±54.8 pounds and a mean BMI of 37.6±8.2 . At 12-month follow-up , In SHAPE ( N=67 ) compared with fitness club membership and education ( N=66 ) was associated with three times greater fitness club attendance , twice as much participation in physical exercise , greater engagement in vigorous physical activity , and improvement in diet . Twice the proportion of participants ( 40 % versus 20 % ) achieved clinical ly significant improvement in cardiorespiratory fitness ( > 50 m on the six-minute walk test ) . Weight loss and BMI did not differ between groups . Among In SHAPE participants , 49 % achieved either clinical ly significant increased fitness or weight loss ( 5 % or greater ) , and 24 % achieved both clinical ly significant improved fitness and weight loss . CONCLUSIONS The In SHAPE program achieved clinical ly significant reduction in cardiovascular risk for almost one-half of participants at 12 months . Although the intervention showed promise in improving fitness , optimizing weight loss may require additional intensive , multicomponent dietary interventions

All antihypertensives were cost effective compared with no treatment . ARBs appeared to be more cost effective than CCBs , ACEIs , and β-blockers .

CONTEXT Hypertension affects one third of the U.S. adult population . Although cost-effectiveness analyses of antihypertensive medicines have been published , a comprehensive systematic review across medicine classes is not available .

Objective : To estimate and compare the cost-effectiveness and safety of nebivolol with sustained-release metoprolol in reducing blood pressure by 1 mm of Hg per day in hypertensive patients . Material s and Methods : This was a prospect i ve , r and omized , open label , observational analysis of cost-effectiveness , in a question naire-based fashion to compare the cost of nebivolol ( 2.5 mg , 5 mg , 10 mg ) and sustained released metoprolol succinate ( 25 mg , 50 mg , 100 mg ) in hypertensive patients using either of the two drugs . A total of 60 newly detected drug naïve hypertensive patients were considered for the comparison , of which 30 patients were prescribed nebivolol and the other 30 were prescribed metoprolol succinate as per the recommended dosage . Based on the data , statistical analysis was carried out using GraphPad Prism 5 and MS Excel Spreadsheet 2007 . Result : The cost of reducing 1 mm of Hg blood pressure per day with nebivolol was 0.60 , 0.70 , and 1.06 INR , whereas that of metoprolol succinate was 0.93 , 1.18 , and 1.25 INR at their respective equivalent doses , hence significantly lower with the nebivolol group as compared to the metoprolol group ( P < 0.05 ) . Conclusion : This pharmacoeconomic analysis shows that nebivolol is more cost-effective as compared to metoprolol when the cost per reduction in blood pressure per day is considered . This may affect the patients economically during their long-term use of these molecules for the treatment of hypertension In hypertensive patients with chronic renal disease , angiotensin receptor blockers ( ARBs ) are among the first-line drugs , and calcium channel blockers ( CCBs ) are recommended as a second line . We examined the effects of two therapeutic strategies using ARBs and benidipine , a CCB , on blood pressure ( BP ) , urinary albumin excretion ( UAE ) , and cost-effectiveness in hypertensive patients with albuminuria . Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned r and omly to two groups . In Group A ( n=14 ) , the ARB dose was maximized and then benidipine was added until BP targets were reached ( < 130/85 mmHg ) . In Group B ( n=18 ) , benidipine was administered first and then the ARB dose was increased until BP targets were reached . The BP targets were achieved by ARB alone in 36 % of Group A patients and by the addition of benidipine in 83 % of Group B patients . Finally , BP decreased in each group , reaching the targets in 93 % of Group A patients and 94 % of Group B patients after a 4-month therapeutic period . UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period ( −33±6 % in Group A , −31±6 % in Group B ; p<0.001 , respectively ) . The monthly drug cost was higher ( 11,426±880 vs. 8,955±410 yen , p=0.012 ) and the cost-effectiveness of antihypertensive treatment was lower ( p=0.003 ) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is , in light of the renal protection and the cost-effectiveness of this approach , a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria Abstract Background : In the Ramipril Efficacy In Nephropathy ( REIN ) trial , ramipril significantly lowered the rate of reaching the combined end-point of doubling of baseline serum creatinine levels or end-stage renal failure ( ESRF ) . Objective : To determine the additional cost per patient-year of chronic ( long term ) dialysis avoided ( PYCDA ) when the ACE inhibitor , ramipril , was added to conventional treatment of patients with non-diabetic nephropathy and hypertension . Study perspective : Statutory Health Insurance ( SHI ) provider in Germany . Design and setting : Data from the REIN Study were used in a cost-effectiveness analysis ( CEA ) . A modelling approach was used , which was based on secondary analysis of published data , and costs were those incurred by the SHI provider ( i.e. SHI expenses ) . In the base-case analysis , average case-related SHI expenses were applied and PYCDA were quantified using the cumulative incidence of ESRF as observed in the REIN trial . Main outcome measures and results : The incremental cost-effectiveness ratios ( ICERs ) of ramipril varied between about − 76 700 deutschmarks ( DM ) and -DM81 900 per PYCDA(DM1 ≈ 0.55 US dollars ; 1999 values ) , according to the treatment periods of 1 year and 3 years , respectively . In the sensitivity analysis , the robustness of the model and its results were shown when the extent of influence of different model variables on the base-case results was investigated . First , probabilities of ESRF and PYCDA were estimated according to the Weibull method . Second , the influence of the model variables on the target variable was quantified using a deterministic model . Third , the dependency of the target variable ( ICER ) on r and om variables was described in a simulation . The cost for chronic dialysis had by far the greatest impact on the target variable , which was 28 times greater than the impact of clinical effectiveness of ramipril , i.e. the number of PYCDA . There were net savings per PYCDA with ramipril treatment after 1 , 2 and 3 years : 95 % of the 10 000 simulation steps result ed in savings of between DM69 500 and DM94 600 per PYCDA after 3 years . Conclusions : Results from this evaluation show that ramipril offers enormous savings from the perspective of the SHI provider ( third-party payer ) in Germany when added to the conventional treatment of patients with non-diabetic nephropathy and hypertension Objective To evaluate the cost-effectiveness of first-line treatments for hypertension . Background The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint , so differences in costs may be critical for optimizing decision-making . Methods Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty . Results Over a patient ’s lifetime , chlorthalidone was always least expensive ( mean $ 4,802 less than amlodipine , $ 3,700 less than lisinopril ) . Amlodipine provided more life-years ( LYs ) than chlorthalidone in 84 % of bootstrap sample s ( mean 37 days ) at an incremental cost-effectiveness ratio of $ 48,400 per LY gained . Lisinopril provided fewer LYs than chlorthalidone in 55 % of bootstrap sample s ( mean 7-day loss ) despite a higher cost . At a threshold of $ 50,000 per LY gained , amlodipine was preferred in 50 % , chlorthalidone in 40 % , and lisinopril in 10 % of bootstrap sample s , but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen . Incorporating quality of life did not appreciably alter the results . Overall , no reasonable combination of assumptions led to 1 treatment being preferred in over 90 % of bootstrap sample s. Conclusions Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine , but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative . A r and omized trial with power to exclude “ clinical ly important ” differences in survival will often have inadequate power to determine the most cost-effective treatment Background Although angiotensin receptor blockers have different receptor binding properties , no comparative r and omized studies with cardiovascular event endpoints have been performed for this class of drugs . The aim of this study was to assess the long-term cost-effectiveness of c and esartan ( Atac and ® ) versus generic losartan in the primary preventive treatment of hypertension . Methods A decision-analytic model was developed to estimate costs and health outcomes over a patient ’s lifetime . Data from a clinical registry study were used to estimate event rates for cardiovascular complications , such as myocardial infa rct ion and heart failure . Costs and quality of life data were from published sources . Costs were in Swedish kronor and the outcome was quality -adjusted life-years ( QALYs ) . Results Due to reduced rates of cardiovascular complications , c and esartan was associated with a QALY gain and lower health care costs compared with generic losartan ( 0.053 QALYs gained and reduced costs of approximately 4700 Swedish kronor for women ; and 0.057 QALYs gained and reduced costs of approximately 4250 Swedish kronor for men ) . This result was robust in several sensitivity analyses . Conclusion When modeling costs and health outcomes based on event rates for cardiovascular complications from a real-world registry study , c and esartan appears to bring a QALY gain and a reduction in costs compared with generic losartan in the primary preventive treatment of hypertension in Sweden BACKGROUND The Losartan Intervention For Endpoint reduction ( LIFE ) study was a r and omized , doubleblind trial that compared the effects of losartan-based treatment with those of atenolol-based treatment on cardiovascular disease (CVD)-related morbidity and mortality in 9193 patients with hypertension and left-ventricular hypertrophy ( LVH ) . Compared with atenolol , losartan reduced the combined risk for CVD-related morbidity and mortality by 13 % ( P = 0.021 ) , and reduced the risk for stroke by 25 % ( P = 0.001 ) , with comparable blood pressure control in both trial arms . OBJECTIVE The aim of this study was to analyze the cost-effectiveness of losartan compared with atenolol in the treatment of stroke from the Dutch health care perspective . METHODS Utilization of losartan and atenolol within the trial period ( mean , 4.8 years ) and an estimation of direct medical costs of stroke for The Netherl and s were combined with estimates of reduction in life expectancy through stroke . Medication costs and stroke incidence during 5.5 years of patient follow-up were estimated separately , adjusted for the baseline degree of LVH and Framingham risk score . To estimate lifetime stroke costs , the cumulative incidence of stroke was multiplied by the lifetime direct medical costs attributable to stroke . All costs are in 2006 Dutch prices and discounted following the former ( 4 % costs and effects ) and new Dutch guideline ( 4 % costs , 1.5 % effects ) for conducting pharmacoeconomic analyses . RESULTS With 4 % discounting , prevention of stroke was associated with a gain of 3.7 life-years . As a consequence , losartan treatment was associated with 0.059 life-year gained ( LYG ) per patient treated with losartan . Losartan reduced stroke-related costs by 1,076 Euros ( US $ 1,349 ) per patient . After inclusion of study medication cost , net cost per patient was 51 Euros ( $ 64 ) higher for losartan than atenolol . The net cost per LYG was 864 Euros ( $ 1083 ) , which is below the Dutch pharmacoeconomic threshold of 20,000 Euros/LYG ( ~$25,000/LYG ) for accepting interventions . The corresponding probability of a cost-effectiveness ratio below this Dutch threshold was 0.95 . Discounting money and health following the new Dutch guideline result ed in an even more favorable cost-effectiveness for losartan . CONCLUSIONS Results from the present analysis suggest that , in The Netherl and s , treatment with losartan compared with atenolol may well be a cost-effective intervention based on the reduced risk for stroke observed in the LIFE trial Background Systemic hypertension often accompanies chronic renal failure and can accelerate its progression to end-stage renal disease ( ESRD ) . Adjunctive moxonidine appeared to have benefits versus adjunctive nitrendipine , in a r and omised double-blind six-month trial in hypertensive patients with advanced renal failure . To underst and the longer term effects and costs of moxonidine , a decision analytic model was developed and a cost-effectiveness analysis performed . Methods A Markov model was used to extrapolate results from the trial over three years . All patients started in a non-ESRD state . After each cycle , patients with a glomerular filtration rate below 15 ml/min had progressed to an ESRD state . The cost-effectiveness analysis was based on the Dutch healthcare perspective . The main outcome measure was incremental cost per life-year gained . The percentage of patients progressing to ESRD and cumulative costs were also compared after three years . In the base case analysis , all patients with ESRD received dialysis . Results The model predicted that after three years , 38.9 % ( 95%CI 31.8–45.8 ) of patients treated with nitrendipine progressed to ESRD compared to 7.5 % ( 95%CI 3.5–12.7 ) of patients treated with moxonidine . Treatment with st and ard antihypertensive therapy and adjunctive moxonidine was predicted to reduce the number of ESRD cases by 81 % over three years compared to adjunctive nitrendipine . The cumulative costs per patient were significantly lower in the moxonidine group € 9,858 ( 95 % CI 5,501–16,174 ) than in the nitrendipine group € 37,472 ( 95 % CI 27,957–49,478).The model showed moxonidine to be dominant compared to nitrendipine , increasing life-years lived by 0.044 ( 95%CI 0.020–0.070 ) years and at a cost-saving of € 27,615 ( 95%CI 16,894–39,583 ) per patient . Probabilistic analyses confirmed that the moxonidine strategy was dominant over nitrendipine in over 98.9 % of cases . The cumulative 3-year costs and LYL continued to favour the moxonidine strategy in all sensitivity analyses performed . Conclusion Treatment with st and ard antihypertensive therapy and adjunctive moxonidine in hypertensive patients with advanced renal failure was predicted to reduce the number of new ESRD cases over three years compared to adjunctive nitrendipine . The model showed that adjunctive moxonidine could increase life-years lived and provide long term cost savings As recommended by the guidelines such as JSH 2004 , combination therapy with multiple agents is now being applied to many patients with hypertension . However , a pharmacoeconomic analysis of each therapy has not been fully undertaken in Japan , despite increasing societal interest . In this study , the cost-effectiveness of two calcium channel blockers , each coadministered with an angiotensin receptor blockade , was compared using data from the ADVANCE-Combi study . The ADVANCE-Combi study was a 16-week doubleblind , r and omized clinical trial to compare the efficacy and safety of two combination therapies ( controlledrelease nifedipine [ nifedipine CR ] plus valsartan vs. amlodipine plus valsartan ) on blood pressure ( BP ) control in patients with moderate to severe essential hypertension . The incremental cost effectiveness of each cohort was compared from the perspective of insurers . The average total cost per patient was Japanese yen ( JPY ) 31,615 for the nifedipine CR treatment group and JPY 35,399 for the amlodipine treatment group ( p<0.001 ) . The achievement rate of the target BP ( SBP/DBP<130/85 mmHg for patients aged under 60 years ; SBP/DBP<140/90 mmHg for those aged 60 years and over ) was significantly higher in the nifedipine CR treatment group ( 61.2 % ) than in the amlodipine treatment group ( 34.6 % ) ( p<0.001 ) , with no difference in the incidence of drug-related adverse events . Accordingly , the base case economic analysis demonstrated that the nifedipine CR treatment group was dominant ( more efficacious and less costly ) to the amlodipine treatment group . This result was supported by univariate and probabilistic sensitivity analyses . These results indicate that nifedipine CR-based combination therapy is superior to amlodipine-based combination therapy for the management of essential hypertension in the Japanese population Abstract The objective of this study was to examine the cost-effectiveness of angiotensin-converting enzyme inhibitor (ACEI)-based treatment compared with thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as an outcome along with cardiovascular outcomes from the Australian government 's perspective . We used a cost – utility analysis to estimate the incremental cost-effectiveness ratio ( ICER ) per quality -adjusted life-year ( QALY ) gained . Data on cardiovascular events and new onset of diabetes were used from the Second Australian National Blood Pressure Study , a r and omized clinical trial comparing diuretic-based ( hydrochlorothiazide ) versus ACEI-based ( enalapril ) treatment in 6083 elderly ( age ≥65 years ) hypertensive patients over a median 4.1-year period . For this economic analysis , the total study population was stratified into 2 groups . Group A was restricted to participants diabetes free at baseline ( n = 5642 ) ; group B was restricted to participants with preexisting diabetes mellitus ( type 1 or type 2 ) at baseline ( n = 441 ) . Data on utility scores for different events were used from available published literature s ; whereas , treatment and adverse event management costs were calculated from direct health care costs available from Australian government reimbursement data . Costs and QALYs were discounted at 5 % per annum . One-way and probabilistic sensitivity analyses were performed to assess the uncertainty around utilities and cost data .After a treatment period of 5 years , for group A , the ICER was Australian dollars ( AUD ) 27,698 ( & OV0556 ; 18,004 ; AUD 1–&OV0556 ; 0.65 ) per QALY gained comparing ACEI-based treatment with diuretic-based treatment ( sensitive to the utility value for new-onset diabetes ) . In group B , ACEI-based treatment was a dominant strategy ( both more effective and cost-saving ) . On probabilistic sensitivity analysis , the ICERs per QALY gained were always below AUD 50,000 for group B ; whereas for group A , the probability of being below AUD 50,000 was 85%.Although the dispensed price of diuretic-based treatment of hypertension in the elderly is lower , upon considering the potential enhanced likelihood of the development of diabetes in addition to the costs of treating cardiovascular disease , ACEI-based treatment may be a more cost-effective strategy in this population BACKGROUND In the 2003 European Society of Hypertension-European Society of Cardiology ( ESH-ESC ) guidelines , it is concluded that the major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive therapy . The aim of this study was to compare the cost-effectiveness of each one of the major antihypertensive agents as monotherapy in the management of mild-to-moderate hypertension in Greece , when following the 2003 ESH-ESC guidelines . METHODS We performed a cost-effectiveness analysis based on numbers needed to treat . A decision analysis model was developed to compare chlorthalidone , propranolol , amlodipine , enalapril and losartan . Clinical inputs were derived from a meta- analysis and r and omized controlled trials and cost data from public sources . The evaluation of the cost of managing hypertension includes the cost of drug therapy , monitoring , treating side effects , poor compliance and switching . All costs were calculated from a public insurance system perspective , in 2004 Euros . Future costs and clinical benefits were discounted at 5 % . The time frame was 5 years . Extensive sensitivity analyses were also performed . RESULTS The cost ( in Euros ) of uncomplicated hypertension treatment for 5 years was 485.87 , 567.66 , 851.44 , 607.45 , and 1279.88 for chlorthalidone , propranolol , amlodipine , enalapril , and losartan , respectively . The estimated total cost ( in Euros ) to prevent one death was 60230.71 , 70369.96 , 105596.72 , 75301.40 , and 158659.35 , respectively . CONCLUSIONS In mild-to-moderate uncomplicated hypertension chlorthalidone is the most cost-effective agent . If it was the drug of choice to initiate treatment of uncomplicated hypertension , it would probably save the public insurance system organizations a great amount of expenses for benefit of the insured patients Background Elevated blood pressure ( BP ) levels are common following acute stroke . However , there is considerable uncertainty if and when antihypertensive therapy should be initiated . Method Economic evaluation alongside a double-blind r and omised placebo-controlled trial ( National Research Register Trial Number N0484128008 ) of 112 hypertensive patients receiving an antihypertensive regimen ( labetalol or lisinopril ) within 36 hours post stroke versus 59 receiving placebo . Outcomes were incremental cost per incremental : QALY , survivor , and patient free from death or severe disability ( modified Rankin scale score < 4 ) at three months and 14 days post stroke . Results Actively treated patients on average had superior outcomes and lower costs than controls at three months . From the perspective of the acute hospital setting , there was a 96.5 % probability that the incremental cost per QALY gained at three months is below £ 30,000 , although the probability may be overstated due to data limitations . Conclusion Antihypertensive therapy when indicated immediately post stroke may be cost-effective compared with placebo from the acute hospital perspective . Further research is required to confirm both efficacy and cost-effectiveness and establish whether benefits are maintained over a longer time horizon OBJECTIVE To estimate 8-year health and economic outcomes of the angiotensin II receptor blocker valsartan versus the calcium channel blocker amlodipine in therapy of patients with type 2 diabetes and microalbuminuria based on clinical endpoints from a 6-month r and omized controlled clinical trial , the MicroAlbuminuria Reduction With VALsartan ( MARVAL ) study . METHODS We developed a Markov model that utilized urinary albumin excretion rate data to project patient distributions to 7 possible health states over 8 years . For each health state , we identified quality -adjustment weights ( health utilities ) and medical care costs from public sources . The model then calculated mean quality -adjusted survival , medical care costs , and cost-effectiveness ratios for each treatment arm . Treatment arms were compared with the incremental cost-effectiveness ratio . RESULTS Patients treated with valsartan gained 7 months ( mean ) per patient of quality -adjusted survival relative to patients treated with amlodipine ( 77 versus 70 months ; P<0.01 ) ; valsartan patients also incurred 32,412 dollars ( mean ) per patient lower medical costs than amlodipine patients ( 92,058 dollars versus 124,470 dollars ; P<0.01 ) . Model results were consistent for each year of analysis and robust to changes in key model parameters . CONCLUSION This research ( 1 ) extends 6-month clinical trial outcomes to an 8-year period , ( 2 ) translates health outcomes from technical clinical endpoints to quality -adjusted survival , and ( 3 ) estimates economic consequences of therapeutic outcomes . The results quantify the favorable long-term health ( i.e. , quality -adjusted survival ) and economic benefits ( i.e. , lower total medical costs ) of therapy with valsartan , an angiotensin II receptor blocker , versus amlodipine , a calcium channel blocker , in the treatment of patients with type 2 diabetes and microalbuminuria based on an extension of the results of a short-term clinical ( MARVAL ) trial . These research findings are important to the extent patients with type 2 diabetes and microalbuminuria do not receive the recommended antihypertensive agents that block the renin-angiotensin system ( angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers ) AIMS To compare the net cost of a tight blood pressure control policy with an angiotensin converting enzyme inhibitor ( captopril ) or beta blocker ( atenolol ) in patients with Type 2 diabetes . DESIGN A cost-effectiveness analysis based on outcomes and re sources used in a r and omized controlled trial and assumptions regarding the use of these therapies in a general practice setting . SETTING Twenty United Kingdom Prospect i ve Diabetes Study Hospital-based clinics in Engl and , Scotl and and Northern Irel and . SUBJECTS Hypertensive patients ( n = 758 ) with Type 2 diabetes ( mean age 56 years , mean blood pressure 159/94 mmHg ) , 400 of whom were allocated to the angiotensin converting enzyme inhibitor captopril and 358 to the beta blocker atenolol . MAIN OUTCOME MEASURES Life expectancy and mean cost per patient . RESULTS There was no statistically significant difference in life expectancy between groups . The cost per patient over the trial period was 6485 UK pounds in the captopril group , compared with 5550 UK pounds in the atenolol group , an average cost difference of 935 UK pounds ( 95 % confidence interval 188 UK pounds , 1682 UK pounds ) . This 14 % reduction arose partly because of lower drug prices , and also because of significantly fewer and shorter hospitalizations in the atenolol group , and despite higher antidiabetic drug costs in the atenolol group . CONCLUSIONS Treatment of hypertensive patients with Type 2 diabetes using atenolol or captopril was equally effective . However , total costs were significantly lower in the atenolol group . Diabet . Med . 18 , 438 - 444 ( 2001 There are substantial healthcare costs associated with the provision of renal replacement therapy . Patients with diabetes mellitus are the largest and fastest growing group developing end-stage renal disease ( ESRD ) in the United Kingdom ( UK ) . Treatment leading to a slowing of progression to ESRD in diabetic patients could lead to considerable cost savings . Using treatment-specific probabilities derived from the Irbesartan in Diabetic Nephropathy Trial ( IDNT ) , the cost effectiveness of treating patients with hypertension , type II diabetes and nephropathy with irbesartan , amlodipine or control was calculated using a Markov model . UK-specific ESRD-related data were retrieved from published sources to reflect local management practice s , ESRD outcomes and costs . Mean 10-year costs and changes in life expectancy due to ESRD delayed or avoided were calculated . Future costs and clinical benefits were discounted at 6.0 and 1.5 % per annum and extensive sensitivity analyses were performed . Delay in the onset of ESRD with irbesartan led to cost savings of £ 5125 and £ 2919/patient and improvements in projected discounted life expectancy of 0.07 and 0.21 years over 10 years vs amlodipine and control , respectively . The costs of treatment of ESRD were the main contributor to the total costs . The cost of trial medications had only a minor impact . These results were robust in a wide range of plausible assumptions . Given that the IDNT efficacy results could be translated to a UK setting , treating patients with hypertension , type II diabetes and overt nephropathy with irbesartan was cost saving over a 10-year period compared to amlodipine and control BACKGROUND The prevalence and incidence of diabetic nephropathy with endstage renal disease ( ESRD ) have increased globally over recent decades . Diabetic nephropathy with ESRD for type 2 diabetes mellitus ( DM ) now has to be recognized as a growing public health problem . Several studies have found that angiotensin-II receptor antagonists have a renoprotective effect in type 2 diabetics with diabetic nephropathy , independently of their antihypertensive effects . These studies have shown a prevention of the progression of nephropathy to ESRD , or a slowing of that progression . The RENAAL study demonstrated the clinical benefits of losartan in patients with DM type 2 and advanced diabetic nephropathy . AIM The aim of this cost-effectiveness analysis of the RENAAL study was to evaluate the effect of losartan compared to a placebo from a Swiss third party payer perspective . METHODS Using a decision analytic model , we evaluated the cost-effectiveness for losartan on the basis of the RENAAL study . A follow-up period of 3.5 years was used . Effectiveness was defined as the number of ESRD days saved . We valued haemodialysis , peritoneal dialysis and kidney transplantation . A weighted mean value was calculated for the daily costs of an ESRD ( CHF 215.05 ) . In the case of renal transplantation follow-on costs , re source utilization was determined through a telephone-based interview with 5 of the 6 Swiss transplantation centres . Expert consensus methodology was used to determine the proportion of health care re source utilization in type 2 diabetics . The percentage of patients receiving each of the 3 treatment alternatives was derived from a cross-sectional national study conceived for this purpose . The daily costs for haemodialysis and peritoneal dialysis were derived from figures provided by insurers . The costs of treatment with losartan were calculated on the basis of an average daily dose of losartan over a period of 3.5 years . RESULTS Over a period of 3.5 years , losartan significantly reduced the number of ESRD days of type 2 diabetics with nephropathy by an average of 33.6 days ( 95 % CI : 10.9 , 56.3 ) compared to the placebo . This reduction in the number of ESRD days result ed in ESRD-associated cost savings of CHF 7,226 per patient over a period of 3.5 years ( the ESRD-associated costs savings increased to CHF 10,086 per patient after 4 years ) . If the average costs per patient for treatment with losartan for the same period ( CHF 3,142 ) are subtracted from the CHF 7,226 then the reduction in ESRD days yields net cost savings of CHF 4,084 per patient over 3.5 years . The univariate sensitivity analyses for the variables ESRD daily costs and percentage distribution of the 3 treatment modalities always yielded net cost savings . DISCUSSION This evaluation revealed net cost savings of CHF 4,084 ( F 2,687 ) for patients with diabetic nephropathy and type 2 diabetes when given 50 to 100 mg losartan once daily over a period of 3.5 years compared to placebo . The net cost savings that administration of losartan yielded are of considerable importance given that the annual costs of diabetic nephropathy with ESRD in type 2 diabetics in Switzerl and are approximately CHF 46 million . On the basis of the scientific evidence currently available , the use of losartan to prevent the advance of diabetic nephropathy is worthwhile from both a clinical and economic perspective Background Controlled clinical trials of health care interventions are either explanatory or pragmatic . Explanatory trials test whether an intervention is efficacious ; that is , whether it can have a beneficial effect in an ideal situation . Pragmatic trials measure effectiveness ; they measure the degree of beneficial effect in real clinical practice . In pragmatic trials , a balance between external validity ( generalizability of the results ) and internal validity ( reliability or accuracy of the results ) needs to be achieved . The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention . The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized . However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability . We are conducting two pragmatic r and omized controlled trials on interventions in the management of hypertension in primary care . We describe the design of the trials and the steps taken to deal with the competing dem and s of external and internal validity . Discussion External validity is maximized by having few exclusion criteria and by allowing flexibility in the interpretation of the intervention and in management decisions . Internal validity is maximized by decreasing contamination bias through cluster r and omization , and decreasing observer and assessment bias , in these non-blinded trials , through baseline data collection prior to r and omization , automating the outcomes assessment with 24 hour ambulatory blood pressure monitors , and blinding the data analysis . Summary Clinical trials conducted in community practice s present investigators with difficult method ological choices related to maintaining a balance between internal validity ( reliability of the results ) and external validity ( generalizability ) . The attempt to achieve method ological purity can result in clinical ly meaningless results , while attempting to achieve full generalizability can result in invalid and unreliable results . Achieving a creative tension between the two is crucial Societal interest in pharmaco-economic analysis is increasing in Japan . In this study , the cost-effectiveness of low-dose combination therapy with controlled release nifedipine plus c and esartan and up-titrated monotherapy with c and esartan was estimated , based on the results of the NICE-Combi study . The NICE-Combi study was a double-blind , parallel arm , r and omized clinical trial to compare the efficacy of low-dose combination therapy of controlled release nifedipine ( 20 mg/day ) plus c and esartan ( 8 mg/day ) vs. up-titrated monotherapy of c and esartan ( 12 mg/day ) on blood pressure control in Japanese patients with mild to severe essential hypertension who were not sufficiently controlled by the conventional dose of c and esartan ( 8 mg/day ) . The incremental cost effectiveness of each cohort during the 8-week r and omization period was compared , from the perspective of a third-party payer ( i.e. , insurers ) . The average total cost per patient was 29,943 Japanese yen for the combination therapy group and 33,182 Japanese yen for the c and esartan monotherapy group , while the rate of achievement of the target blood pressure was significantly higher in the combination therapy group than in the up-titrated monotherapy group . In the combination therapy group , higher efficacy and lower incremental treatment cost ( “ Dominance ” ) were observed when compared to the monotherapy group . The sensitivity analyses also supported the results . In conclusion , these results suggest that combination therapy with controlled release nifedipine and low-dose c and esartan ( 8 mg ) is “ dominant ” to up-titrated c and esartan monotherapy for the management of essential hypertension . This conclusion was robust to sensitivity analysis This study examined the effect of enalapril on survival , re source use , and cost of care in patients with left ventricular dysfunction and hypertension using a retrospective analysis of patients who participated in the Studies of Left Ventricular Dysfunction ( SOLVD ) . Among the 6797 SOLVD participants , 1917 patients had either elevated systolic ( > or = 140 mm Hg ) or diastolic ( > or = 90 mm Hg ) blood pressure . Therapy with enalapril was associated with a significant relative risk reduction for mortality ( RR = 0.819 , 95 % CI : 0.68 to 0.98 ; P = .03 ) . This result ed in a gain of 0.11 years ( 95 % CI : 0.00 to 0.20 years ) of survival during the average 2.8 year follow-up for this subgroup and was projected to result in a gain of 2.14 years ( 95 % CI : 0.05 to 4.21 years ) during the patient 's lifetime . Enalapril significantly reduced the risk of first hospitalization for heart failure by 37 % . For all types of hospitalizations , there was an average reduction of 32 hospitalizations per 100 patients treated with enalapril during the trial period ( 95 % CI : 11.8 to 52.2 hospitalizations avoided per 100 patients ) , result ing in an estimated net savings of $ 1656 per patient during the trial period ( 95 % CI : increased cost of $ 191 to savings of $ 3502 ) . Although the projected lifetime net savings of $ 1456 was not significant ( 95 % CI : increased cost of $ 9243 to saving of $ 12,527 ) , evaluation of the cost per life year saved indicated that enalapril represented a cost-effective strategy . The estimated clinical benefit of enalapril among the hypertensive subgroup in SOLVD supports the recommendation that angiotensin converting enzyme ( ACE ) inhibitors should be considered as first line pharmacologic therapy for hypertensive patients with left ventricular dysfunction . From both the clinical and economic viewpoints , ACE inhibitors provide important clinical benefits and are cost-effective A comparison of treatment costs and cost effectiveness was performed retrospectively by using patient-level data from a r and omized , controlled , one-year clinical trial of amlodipine and enalapril in the treatment of mild-to-moderate hypertension . Unit costs of amlodipine and enalapril were applied to the daily dosages of individual patients to calculate the total costs and average costs per patient in each treatment group in the clinical trial on an intent-to-treat basis . Efficacy rates were used to calculate the average treatment costs per success in blood pressure control . Although not statistically significant , amlodipine treatment result ed in a higher efficacy ( 89.5 % ) vs. enalapril ( 85.2 % ) . The average costs per amlodipine-treated patient were consistently lower ( -$112.30 ) than for the enalapril-treated patient by week 50 . Treatment with amlodipine result ed in an average cost per success of $ 609 per patient compared with $ 772 per enalapril-treated patient . A sensitivity analysis revealed that , in the treatment of mild-to-moderate hypertension over the 50-week treatment period , amlodipine would remain less costly than enalapril , with a decrease in the cost of enalapril of up to 17 % , and would remain more cost effective , with a 21 % decrease in the cost of enalapril BACKGROUND Economic analyses of r and omized clinical trials often focus only on the results that are observed during the study . However , for many preventive interventions , associated costs and benefits will accrue over a patient 's remaining lifetime . To determine the importance of the chosen time horizon , the cost-effectiveness ( C/E ) of ramipril therapy was calculated and compared in the Heart Outcomes Prevention Evaluation ( HOPE ) , the Microalbuminuria , Cardiovascular , and Renal Outcomes in HOPE ( MICRO-HOPE ) and the Acute Infa rct ion Ramipril Efficacy ( AIRE ) study versus the entire life expectancy ( L/E ) of potential patients . METHODS The Cardiovascular Disease Life Expectancy model , a vali date d Markov model , was calibrated to accurately forecast the results of each trial . These results were then extrapolated over the remaining L/E of hypothetical patients 55 to 75 years of age . The predicted change in L/E and associated direct health care costs for Canadians were calculated and discounted 3 % annually . RESULTS In HOPE , the forecasted increased L/E averaged 0.06 years during the five-year study versus 1.3 years over the remaining years of L/E. The associated C/E of ramipril was $ 15,000 per year of life saved ( YOLS ) over the study duration and $ 8,500/YOLS over the remaining lifetime . For hypothetical patients , the C/E of ramipril over 4.5 years ranged from $ 6,700/YOLS to more than $ 58,300/YOLS and was lowest among elderly men . When the remaining L/E was considered , the C/E of ramipril was similar for men and women of all ages , ranging from $ 8,100/YOLS to $ 10,200/YOLS . The analyses of MICRO-HOPE and AIRE provided similar results . CONCLUSION The estimated efficacy and associated C/E of ramipril in HOPE , MICRO-HOPE and the AIRE study is extremely sensitive to the selected time horizon . Economic analyses beyond the duration of r and omized clinical trials are required to fully evaluate the potential costs and benefits of long-term preventive therapies Summary Diabetic nephropathy is one of the major complications of insulin-dependent diabetes mellitus ( IDDM ) , with proteinuria being the main clinical manifestation of diabetic nephropathy . Most patients who develop overt proteinuria progress to end-stage renal disease ( ESRD ) , usually within 5 to 7 years ; ESRD necessitates dialysis or renal transplantation . Although a relationship between blood pressure reduction and delaying of ESRD has been assumed for a long time , only recently has a controlled r and omised clinical trial shown that the treatment of diabetic nephropathy with an ACE inhibitor can significantly delay the loss of renal function and , therefore , ESRD.Consistent with the clinical trial on which this economic evaluation was based , the costs and consequences of 2 alternatives were considered : ( i ) patients subject to blood pressure control with only antihypertensive medication , but without an ACE inhibitor ( placebo group ) and ( ii ) patients given ACE inhibitor therapy ( captopril group ) with similar blood pressure control to the placebo group . This cost-effectiveness analysis was performed from the perspective of the Italian National Health Service [ Servizio Sanitario Nazionale ( SSN ) ] . Accordingly , only direct costs related to publicly funded healthcare services were included . The number of dialysis-years avoided ( DYA ) was the clinical end-point . A 10-year time horizon was considered for the economic evaluation . Captopril therapy was dominant , being at the same time more effective and less costly . The total cost for the captopril alternative during the 10-year period was 21 901 625 Italian lire ( L ; 1993 values ) per patient , while total cost for the placebo alternative was L30 352 590 per patient . Compared with placebo , 20.01 DYA per 100 patients treated were estimated with captopril therapy during the trial period , equivalent to 2.4 months per patient . The robustness of this result was confirmed by sensitivity analysis : for both extremes , captopril remained dominant . This economic evaluation , requested by the Italian Ministry of Health , demonstrated savings in healthcare expenditure with the use of an ACE inhibitor in patients with proteinuria Background and Objective Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important . The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists ( angiotensin II receptor blockers [ ARBs ] ) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs . Methods Cost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan , losartan , valsartan , and irbesartan . BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years , using an international health economics model that was adapted to the Netherl and s. Dutch costs ( 2006 values ) and complications derived from the model were discounted at 4 % and 1.5 % , respectively , and cost effectiveness was expressed in net costs per cardiovascular complication averted . In a drug-utilization study , pharmacy dispensing records were used to evaluate differences between within-trial and daily- practice dosing and related costs for treatment in the Netherl and s. Results After 8 weeks , the trial-based analysis showed that treatment with olmesartan versus losartan , valsartan , and irbesartan result ed in a significantly larger decrease in BP ( 11.5 vs 8.2 , 7.9 and 9.9 mmHg [ p<0.05 ] , respectively ) and consequently more complications averted . Cost effectiveness for olmesartan , losartan , valsartan , and irbesartan was estimated at € 39 100 , € 77 100 , € 70 700 , and € 50 900 per cardiovascular complication averted , respectively . The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan , with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs . The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice . On average , losartan , valsartan , and irbesartan were administered at doses above those used in clinical trials , whereas olmesartan was dosed lower than in clinical trials , result ing in relatively lower costs . Conclusion Based on the exact trial data , olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting . However , for definite conclusions to be drawn , this hypothesis-generating study requires confirmation from further prospect i ve studies comparing ARBs based on comparable BP control and including hard endpoints OBJECTIVE To determine the cost-effectiveness of routine administration , irrespective of blood pressure ( BP ) , of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus . DESIGN , SETTING AND PARTICIPANTS Prospect i ve cost-effectiveness analysis within the Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation ( ADVANCE ) trial , an international , multicentre , r and omised controlled trial of 11,140 participants with type 2 diabetes r and omly allocated to receive perindopril plus indapamide ( 4 mg-1.25 mg/day ) or placebo . MAIN OUTCOME MEASURES Health-related quality -of-life measured by the EuroQol-5D , re source utilisation , and cost-effectiveness ( cost per death averted at 4.3 years ' average follow-up , and estimated cost per life-year gained , by extrapolation ) . RESULTS The mean health-related quality -of-life score of survivors was 0.80 ( on a 0 - 1 scale [ death to full health ] ) , with no difference between treatment groups . Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5 % . For the Australian participants , perindopril-indapamide cost A$ 1368 per patient during the trial period , but reduced total hospitalisation costs by A$ 410 and other medication costs ( mainly other BP-lowering drugs ) by A$ 332 . The absolute reduction in all-cause mortality for the active treatment group was 1.1 % , giving a cost per life saved of A$ 49,200 . Lifetime extrapolation gave an estimated cost per life-year saved of A$ 10,040 ( discounted at 5 % per year ) . CONCLUSION The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective . TRIAL REGISTRATION United States National Library of Medicine NCT00145925 Objective : To compare the cost effectiveness of an amlodipine-based strategy and an atenolol-based strategy in the treatment of hypertension in the UK and Sweden . Design : A prospect i ve , r and omised trial complemented with a Markov model to assess long-term costs and health effects . Setting : Primary care . Patients : Patients with moderate hypertension and three or more additional risk factors . Interventions : Amlodipine 5–10 mg with perindopril 4–8 mg added as needed or atenolol 50–100 mg with bendroflumethiazide 1.25–2.5 mg and potassium added as needed Main outcome measures : Cost per cardiovascular event and procedure avoided , and cost per quality -adjusted life-year gained . Results : In the UK , the cost to avoid one cardiovascular event or procedure would be € 18 965 , and the cost to gain one quality -adjusted life-year would be € 21 875 . The corresponding figures for Sweden were € 13 210 and € 16 856 . Conclusions : Compared with the thresholds applied by NICE and in the Swedish National Board of Health and Welfare ’s Guidelines for Cardiac Care , an amlodipine-based regimen is cost effective for the treatment of hypertension compared with an atenolol-based regimen in the population studied Abstract Background : Current hypertension guidelines differ in their recommendations for first-line antihypertensive therapy . Objective : To evaluate the cost effectiveness of ACE inhibitor therapy as antihypertensive first-line therapy as compared with conventional antihypertensive therapy with β-adrenoceptor antagonists or diuretics . Study design : Cost-effectiveness analysis based on data from r and omised trials and observational studies comparing the effectiveness of ACE inhibitor and conventional antihypertensive therapy , we constructed a Markov model to compare four strategies in the management of uncomplicated hypertension : ( i ) prescribing ACE inhibitor therapy to all patients ; ( ii ) prescribing conventional therapy to all patients ; ( iii ) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on electrocardiography ( ECG ) ; or ( iv ) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on echocardiography . Methods : Cost data were derived from the medical literature and focus groups , and utility values were derived from patients on antihypertensive monotherapy . All costs were calculated in 1999 Canadian dollars , but are reported in US dollars according to the 1999 purchasing power parity rate for medical and healthcare . The effectiveness of ACE inhibitor therapy in the presence of left ventricular hypertrophy was derived from observational studies . The time horizon was over a lifetime . Perspective : Third-party payer . Patients / participants : A cohort of men aged 40 years without cardiovascular comorbidity requiring antihypertensive drug therapy . Main outcome measures and results : In the baseline analysis , all four strategies result ed in expected discounted QALYs that differed from each other only at the third decimal point ( i.e. less than 0.003 ) . Given the uncertainties in the variable estimates and the small size of the differences , these differences are extremely small and unlikely to represent real differences . Even accepting the small gains as real , the result ing cost-effectiveness ratios are unattractively high : $ US200 000 per QALY gained for the echocardiography strategy ( compared with ECG ) , and $ US700 000 for the ‘ ACE inhibitor for all ’ strategy ( compared with ECG ) . The incremental cost effectiveness of prescribing ACE inhibitor therapy to everybody was never less than $ US100 000/QALY in the sensitivity analysis . Conclusions : Prescribing ACE inhibitors as antihypertensive first-line therapy in patients without cardiovascular morbidity can not be recommended at the present time unless the aquisition costs of ACE inhibitors become substantially more attractive The aim of the present analysis was to calculate the cost-effectiveness of metoprolol versus thiazide diuretics in middle-aged men with mild to moderate uncomplicated hypertension . The analysis was based on the Metoprolol Atherosclerosis Prevention in Hypertensives ( MAPHY ) study , a r and omised trial which showed a significantly lower risk for coronary events in patients taking metoprolol than in patients on thiazide diuretics . The main analysis was based on Swedish costs , but the costs were also varied in a special sensitivity analysis . Metoprolol was shown to be cost-saving compared with thiazide diuretics when both direct and indirect costs of morbidity were included . When only direct costs were included , the cost per life-year gained was $ US2400 . The result of the present analysis suggests that metoprolol is to be preferred to thiazide diuretics from a cost-effectiveness st and point in the treatment of mild to moderate hypertension in middle-aged men . These findings regarding cost-effectiveness should , however , not be extrapolated to patient groups not included in the MAPHY trial The objective of this analysis was to assess the cost-effectiveness of achieving ' tight control ' versus ' less tight control ' of blood pressure , as defined in the UK Prospect i ve Diabetics Study 38 , in type II diabetic patients in the UK and Italy . The effect of including doxazosin in a ' tight control ' combination therapy was analysed . Given doxazosin 's positive impact on lipid levels in addition to its antihypertensive effect , it is hypothesised that treatment including doxazosin will reduce the incidence of macrovascular complications . For each country , a Markov model was constructed to simulate macrovascular outcomes of patients on various drug combinations . Transitional probabilities were based on the risk rates presented in UKPDS 38 . Risk rates were adjusted for the ageing of the cohort and the lipid-lowering properties of doxazosin using Framingham risk equations . Incremental cost-effectiveness ratios ranged from 2224 Pounds to 4867 Pounds ( US$ 3225 - 7057 ) per life-year saved for the UK and from L1.8 - 9.3 million ( US$ 818 - 4159 ) per life-year saved for Italy . Doxazosin is a cost-effective agent when included in a combination therapy in the treatment of hypertension in the diabetic population s of the UK and Italy Abstract Objective : To conduct an economic analysis in the US of antihypertensive treatment with and without benazepril in patients with chronic renal insufficiency . Design : A four-state Markov model , using clinical data obtained from a 3-year r and omised clinical trial [ the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency ( AIPRI ) study ] plus its extension study ( median 3.6 years ) , and cost data obtained from published US sources . The period of analysis was 7 years following r and omisation . Perspective : Healthcare payer . Setting : Clinical data were obtained from multiple medical centres in three European countries as described in the published studies . Key economic data were obtained from the US Healthcare Financing Administration ’s End Stage Renal Disease programme . Patients and interventions : In the clinical studies on which this economic analysis was based , patients with chronic renal insufficiency of various aetiologies were r and omised to antihypertensive therapy with or without concomitant benazepril . Main outcome measures and results : Over 7 years of analysis , patients r and omised to antihypertensive treatment with concomitant benazepril therapy incurred on average $ US12 991 ( 1999 values ) lower medical costs than patients prescribed antihypertensive treatment without benazepril , and obtained an additional 0.091 quality -adjusted life years ( QALYs ) . Costs and QALYs were greater for the benazepril arm than the placebo arm for all years of analysis after the first . Rank order stability of results favouring the benazepril therapy arm was found in sensitivity analyses of changes in key model parameters . Additional economic and health benefits favouring patients receiving benazepril would be seen if underlying model rates of dialysis and transplantation were increased , as may be appropriate to reflect treatment practice differences in the US relative to European countries . Conclusions : Benazepril therapy as a component of antihypertensive treatment of persons with chronic renal insufficiency initially costs money , but investment costs are recouped quickly and return on investment continues to grow . The impact of end-stage renal disease on patient health and healthcare costs is great . Thus , the quality -adjusted survival benefits and overall cost savings seen in benazepril recipients over a prolonged period ( 2 to 7 years ) indicate that the strategy of prescribing benazepril to reduce progression of renal disease in patients with renal insufficiency is both clinical ly and economically beneficial compared with current antihypertensive regimens without ACE inhibition The objective of this study was to determine how effective angiotensin-converting enzymes ( ACEs ) must be in preventing diabetic nephropathy to warrant routine administration to insulin-dependent diabetic patients . A Markov model was used to compare three strategies design ed to prevent the development of end-stage renal disease in insulin-dependent diabetic patients . Strategy I , screening for microalbuminuria and treatment of incipient nephropathy as currently recommended , was compared with strategy II , a protocol in which patients were routinely administered an ACE inhibitor 5 years after diagnosis of diabetes , and strategy III , in which patients at high risk for nephropathy were routinely treated and low-risk patients followed a protocol in which patients were treated with an ACE inhibitor if they developed hypertension and /or macroproteinuria . The model predicted that strategy II would produce as many quality -adjusted life-years as strategy I at nearly the same cost if routine drug therapy reduced the rate of development of microalbuminuria by 26 % in all patients . Strategy III produced as many quality -adjusted life-years at less cost than strategy I if a high-risk cohort could be identified with a rate of developing microalbuminuria at four times the rate of low-risk patients and if drug therapy reduced the rate of developing microalbuminuria in this high-risk group by 20 % . In conclusion , routine ACE inhibitor therapy could prove to be cost-effective , especially if high-risk individuals could be identified . A prospect i ve trial examining this goal should be considered Objective Evaluate the cost effectiveness of losartan compared with atenolol from a Swedish national health system perspective . Design The Losartan Intervention For Endpoint reduction in hypertension study ( LIFE ) was a double-masked , r and omized trial of losartan versus atenolol in 9193 patients with essential hypertension and left ventricular hypertrophy ( LVH ) ascertained by electrocardiography . Losartan reduced the primary composite end point of cardiovascular death , myocardial infa rct ion ( MI ) , or stroke by 13 % ( P = 0.021 ) and reduced the risk of stroke by 25 % ( P = 0.001 ) , despite a comparable degree of blood pressure control . Methods Life years gained was estimated by combining the absolute risk reduction in stroke with the life years gained by preventing stroke . Quality -adjusted life years ( QALYs ) gained was estimated by combining the absolute risk reduction in stroke with the QALYs gained by preventing stroke . QALYs were estimated by weighting life years by health-related quality of life ( QoL ) , as measured with visual analogue scale ( VAS ) data collected in the trial . Net costs were defined as the total of study medication cost , stroke-related costs , and costs of increased survival . Costs are in 2003 Swedish prices . All costs and effects were discounted at a 3 % annual rate . Results Prevention of a stroke result ed in a gain of 5.7 life years and 4.3 QALYs . As a consequence , losartan treatment result ed in a per patient increase of 0.092 life years [ 95 % confidence interval ( CI ) : 0.038 , 0.146 ] and 0.069 QALYs ( 95 % CI : 0.028 , 0.109 ) as compared with atenolol treatment . Losartan reduced direct stroke-related cost per patient by 1141 due to a lower cumulative incidence of stroke for losartan at 5.5 years ( 4.9 % ) as compared with atenolol ( 6.5 % ) ( 95 % CI of difference : 0.7 , 2.5 ) . The reduction in stroke-related cost offset 80 % of the added cost of losartan drug therapy . After inclusion of study medication cost , net cost per patient was 289 higher for losartan than atenolol . The net cost per QALY gained for losartan was 4188 ( 37 813 SEK ) , which is well within common Swedish benchmark upper values ( 200–500 000 SEK ) for accepted cost-effective interventions . Conclusion Based on the results from the LIFE trial , treatment with losartan compared with atenolol , in hypertensive patients with LVH , is a cost-effective intervention

Implication s This systematic review summarizes existing tobacco-related curriculum components ( content , intensity , competency evaluation , and barriers ) and training interventions for health-care professionals worldwide and demonstrates that they are associated with positive health-care professional outcomes ( knowledge , attitudes , behaviors , and skills ) and client outcomes ( quit attempts and smoking abstinence )

Introduction The objective of this systematic review was to investigate what education and training characteristics prepares and supports health-care professionals ( HCPs ) in the delivery of competent and effective care to clients who use tobacco-nicotine .

INTRODUCTION Advice can have a small but clinical ly important effect in promoting smoking cessation . Where studied , the rate of delivery has been found to be low . Training has been found to increases this rates , but there is little research on effectiveness in terms of smoking cessation rates . This study aim ed to assess the effectiveness and cost-effectiveness of an health professionals educational program to increase long-term rates of nicotine abstinence in smoking out patients . METHODS We conducted a pragmatic cluster-r and omized , controlled trial in 35 primary health care centers in Spain . Participants were all 830 health professionals who attended 5,970 smokers during recruiting period . After that we measured continuous abstinence 6 months after the intervention and biochemically vali date d ( saliva cotinine test ) 1 year following intervention . Cost-effectiveness was measured in terms of cost per life year gained . RESULTS After 6 months , the rate of continuous abstinence was significantly higher in the intervention group ( 2.1 % vs. 0.3 % , p > .0001 ) with an odds ratio of 6.5 ( 95 % CI = 3.3 - 12.7 ) . After 1 year , biochemical validation was performed on 31 of the 67 patients previously registered as abstinent . All of them were abstinent and belonged to intervention group . The incremental cost per life year gained after 6 months was € 969 . CONCLUSIONS A primary care training program on smoking cessation based on scientific evidence , behavioral theory , and active learning methods increases long-term continuous nicotine abstinence rate among out patients in a significant way . These may be relevant for planning training of professionals , clinical assistance , and public health programs PURPOSE Dental hygienists report a lack of confidence in initiating Tobacco Dependence Counseling ( TDC ) with their patients who smoke . The purpose of this study was to determine if the confidence of dental hygiene students in providing TDC can be increased by St and ardized Patient ( SP ) training , and if that confidence can be sustained over time . METHODS This 2-parallel group r and omized design was used to compare the confidence of students receiving SP training to stu dents with no SP training . After a classroom lecture , all subjects ( n=27 ) received a baseline test of knowledge and confidence . Subjects were r and omly assigned to test and control groups with equivalent mean knowledge scores . The test group subjects participated in a SP TDC session . Both groups gained parallel experience to treating patients who were smokers and giving TDC in clinical scenarios during the 6 month time period . One week end-training and 6 month post-training assessment s were administered to both groups . ANCOVA compared mean confidence scores . RESULTS End-training scores at 1 week showed a statistically significant increase ( p=0.002 ) in overall mean confidence following SP training for individuals in the test group . The 6 month follow-up test results showed a slight decline in confidence scores among subjects in the test group and an overall gain in confidence for control group participants . However , overall confidence scores were comparable for the groups . CONCLUSION SP training improved dental hygiene students ' initial confidence in providing TDC and was sustained , but not to a significant degree . Clinical experience alone increased confidence . Further studies may help determine how the initial confidence gained by SP training can be sustained and what the role of clinical experience plays in overall confidence in providing TDC BACKGROUND An increase in the number of dentists conducting tobacco-use cessation treatment is needed . The authors assessed the effects of high-intensity training ( HIT ) or low-intensity training ( LIT ) and reimbursement on general dentists ' tobacco-use-related attitudes and treatment behaviors . METHODS The authors r and omly selected 265 dentists in three states and assigned them to one of five groups : HIT workshop groups with and without tobacco-use cessation counseling reimbursement , LIT mailed self- study groups with and without reimbursement or a control group . Outcomes at follow-up were dentists ' self-reported tobacco-use-related attitudes and behaviors and patients ' reports of dentists ' behaviors . RESULTS Significantly more dentists in the intervention groups reported having positive attitudes and behaviors at follow-up than did dentists in the control group . Dentists in the HIT groups , however , reported assessing patients ' willingness to quit and assisting them with the quitting process significantly more often than did dentists in the LIT groups . Significantly more patients of dentists in the intervention groups who used tobacco reported receiving advice and assistance from their dentists than did patients of dentists in the control group . Adding reimbursement to HIT or LIT conditions did not provide additional intervention effect . CONCLUSION Dentists trained by means of a workshop or self- study program used components of a recommended guideline more frequently and felt more positive toward tobacco-use cessation counseling than did dentists in the control group . CLINICAL IMPLICATION S Although the workshop training was more successful than the self- study training , the latter 's reach among dentists could have a more significant public health impact . The effect of reimbursement needs further study OBJECTIVE Family physicians ( FPs ) are cornerstone for tobacco control . It was aim ed to compare the effect of training on their smoking cessation practice , knowledge level and attitudes towards smoking and tobacco control . METHODS AND MATERIAL S The cross-sectional and multi-centered study was carried out using structured survey modified WHO based question naire . It was delivered to 1500 FPs r and omly selected among approximately 23000 family physicians across the country . The study survey was self-reported by FPs , assessing their knowledge , attitudes , status of post-graduate training , and practice about tobacco control . Participants were assigned into two groups as non-trainee groups ( Group 1 ) and post-graduate trainee ( Group 2 ) . RESULTS The mean age was 38.4 ± 7.1 years-old . The percentage of male and female FPs in the study was 53.1 % and 46.9 % . The ratio of family physicians who participated in training program Group 2 ) was 26.5 % ( n = 327 ) . The ratio of female FPs who participated the SCP training course was significantly higher than that of male FPs ( 27.3 % versus 22.5 % , p = 0.035 ) . There was no significant difference for smoking status between groups ( p = 0.686 ) . When the number FPs whose consulted by the smokers over ≥ 5 a week was compared , the ratio of FPs was significantly higher in group 2 than group 1 ( p < 0.001 ) , but overall ratio of FPs ( 2.8 % ) who consulted within a week smokers was considerably lower Statements of Competence and confidence items stated by all FPs were 24.2 % and 32.2 % , respectively . Physicians who had attended post-graduate training on SCP were more competent and confident , compared to non-trained FPs ( p = 0.002 and p = 0.001 ) . CONCLUSION Post-graduate training on tobacco control improved self-confidence and competence of FPs . With post-graduate training , significant improvement was seen in practical skills of physicians . A continuing training program should be introduced to FPs , to engage them for smoking cessation practice The use of st and ardized patients ( SPs ) shows promise in tobacco cessation treatment ( TCT ) training by providing a simulated clinical environment for dental students to practice counseling skills with individuals trained to portray patients . The purpose of this study was to determine if there was a difference in attitudes , perceptions , and knowledge between dental students who received a lecture and practice sessions with SPs and those who received a lecture only . Dental students in an introductory clinical course at one dental school were invited to participate in the study by completing a pre and post question naire . The pre question naire was administered to all students prior to a tobacco cessation lecture . Students were group-r and omized to either the intervention or control group . The intervention group completed the post question naire after the lecture and practice sessions with SPs , and the control group completed it after the lecture only . Of ninety-eight students who attended the lecture and were invited to participate in the study , a total of ninety-four from the two groups ( 96 percent ) provided two linkable question naires for analysis . In the results , training with lecture and SPs increased the students ' underst and ing of barriers , subjective norms , perceived skills , self-efficacy , and intentions to provide TCT more than those in the lecture only ; however , it did not significantly increase their attitudes and knowledge . These findings suggest that using SPs is a valuable educational method to promote the provision of TCT by dental students and graduates OBJECTIVE Few continuing education programs to train behavioral health professionals to deliver tobacco treatment services have been described and evaluated . METHODS The effectiveness of two-day training on changing practice was examined by review of clinical charts from 20 clinicians who attended in 2012 . Ten medical records were r and omly selected for review from each clinician 's outpatient practice at a large behavioral health system . Five charts from smokers seen within six months before and after training were review ed per clinician , for a total of 200 . Records were electronically search ed on " cigarette , " " nicotine , " " tobacco , " " quit , " " smoking , " and " smoke . " RESULTS were compared via chi square tests ( all p<.05 ) . RESULTS Almost half of the smokers indicated that they were interested in quitting , although baseline rates of tobacco use treatment were very low . Documentation of tobacco use significantly increased between baseline and posttraining , both on the problem list ( 35 % versus 74 % ) and treatment plan ( 20 % versus 60 % ) . Also posttraining , clinicians advised significantly more out patients to quit ( 9 % versus 36 % ) or referred them to individual or group counseling . Discussion of nicotine replacement was documented more frequently in charts ( 10 % versus 31 % ) , and prescriptions for tobacco treatment medications increased significantly in the posttraining period , although overall prescribing remained low . The proportion of patients making quit attempts also significantly increased in the posttraining period ( 10 % versus 39 % ) , suggesting that providers were delivering more tobacco treatment than was reflected in charts . CONCLUSIONS An intensive training program for behavioral health professionals increased tobacco treatment and patient quit attempts . Strategies beyond training may be needed to enhance prescribing by these practitioners BACKGROUND Health professionals have a proven , positive impact on patients ' ability to quit smoking , yet few integrate cessation counseling into routine practice .The aim of this study was to evaluate the impact of continuing education training on physicians ' and pharmacists ' cessation counseling . METHODS A group-r and omized trial of health care providers ( 87 physicians and 83 pharmacists ) from 16 Texas communities compared smoking cessation training ( intervention group ) with skin cancer prevention training ( control group ) . Pretraining , posttraining , and extended follow-up surveys were collected from providers . Perceived ability , confidence , and intention ( ACI ) to address smoking with patients were assessed with a composite ACI index . Patient exit interviews ( at baseline , 1452 patients completed interviews ; after 12 months , 1303 completed interviews ) assessed counseling practice s. RESULTS There was a significant increase in the percentage of physicians with a high ACI index in the intervention group from pretraining to posttraining ( 27 % to 73 % ; P < .001 ) vs the control group ( 27 % to 34 % ; P = .42 ) and for pharmacists ( 4 % to 60 % ; P < .001 ) vs the control group ( 10 % to 14 % ; P = .99 ) . Similar results were seen from pretraining to extended follow-up . At baseline , fewer pharmacy patients reported being asked about smoking compared with patients seen by physicians ( 7 % vs 33 % ; P = .001 ) . There was an increase in assisting patients to quit ( 6 % to 36 % ; P = .002 ) by physicians ( baseline vs 12 months ) in the intervention group , but not in the control group . CONCLUSIONS Training led to significant and lasting improvement in counseling among physicians . Low levels of counseling were seen among pharmacists OBJECTIVES Tobacco use adversely affects oral health . Clinical guidelines recommend that oral health professionals promote tobacco abstinence and provide patients who use tobacco with brief tobacco use cessation counselling . Research shows that these guidelines are seldom implemented successfully . This study aim ed to evaluate two interventions to enhance tobacco use prevention and cessation ( TUPAC ) counselling among oral health professionals in Finl and . METHODS We used a cluster-r and omized community trial to test educational and fee-for-service interventions in enhancing TUPAC counselling among a sample of dentists ( n=73 ) and dental hygienists ( n=22 ) in Finl and . Educational intervention consisted of 1 day of training , including lectures , interactive sessions , multimedia demonstrations and a role play session with st and ard patient cases . Fee-for-service intervention consisted of monetary compensation for providing tobacco use prevention or cessation counselling . TUPAC counselling procedures provided were reported and measured using an electronic dental records system . In data analysis , intent-to-treat principles were followed at both individual and cluster levels . Descriptive analysis included chi-square and t-tests . A general linear model for repeated measures was used to compare the outcome measures by intervention group . RESULTS Of 95 providers , 73 participated ( 76.8 % ) . In preventive counselling , there was no statistically significant time effect or group-by-time interaction . In cessation counselling , statistically significant group-by-time interaction was found after a 6-month follow-up ( F=2.31 ; P=0.007 ) , indicating that counselling activity increased significantly in intervention groups . On average , dental hygienists showed greater activity in tobacco prevention ( F=12.13 ; P=0.001 ) and cessation counselling ( F=30.19 ; P<0.001 ) than did dentists . In addition , cessation counselling showed a statistically significant provider-by-group-by-time interaction ( F=5.95 ; P<0.001 ) , indicating that interventions to enhance cessation counselling were more effective among dental hygienists . CONCLUSIONS Educational intervention yielded positive short-term effects on cessation counselling , but not on preventive counselling . Adding a fee-for-service to education failed to significantly improve TUPAC counselling performance . Other approaches than monetary incentives may be needed to enhance the effectiveness of educational intervention . Further studies with focus on how to achieve long-term changes in TUPAC counselling activity among oral health professionals are needed One fifth of Americans smoke ; many have no plans to quit . Motivational Interviewing ( MI ) is an effective approach to intervention with precontemplative smokers , yet a substantial number of healthcare practitioners lack training in this approach . Two interactive online tutorials were developed to teach practitioners to deliver brief tobacco cessation interventions grounded in the MI approach . The tutorials emphasized the unique aspects of working with precontemplative smokers , incorporating audio and video examples of best practice s , interactive exercises , targeted feedback , and practice opportunities . One hundred and fifty-two healthcare providers-in-training were r and omly assigned to use the online tutorials or to read training material that was matched for content . A virtual st and ardized patient evaluation was given before and after the training . Both groups improved their scores from pre- to posttest ; however , the tutorial group scored significantly better than the reading group at posttest . The results of this study demonstrate the promise of interactive online tutorials as an efficient and effective way to deliver clinical education PURPOSE To evaluate a brief educational program about smoking cessation on the frequency of nurses ' interventions with smokers , and impact of nurses ' smoking status on outcomes . DESIGN Prospect i ve , single group design with pre study and 3 months post- study data . METHODS Nurses in the Czech Republic attended hospital-based 1-hr educational programs about helping smokers quit . They completed surveys about the frequency ( i.e. , always , usually , sometimes , rarely , never ) of their smoking cessation interventions with patients using the five A 's framework ( i.e. , ask , advise , assess , assist , arrange ) , and their attitudes prior to and 3 months after the course . Demographic data included smoking status . FINDINGS Among the 98 nurses with pre study and post- study data , all were female , mean age was 43 years , 33 % were current smokers , and 64 % worked in a medical or surgical or oncology setting s. At 3 months , compared to baseline , significantly ( p < .05 ) more nurses assessed patients ' interest in quitting , assisted with quit attempts , and recommended the use of the quitline for cessation . At 3 months after the program , nurses who smoked were less likely to ask about smoking status ( odds ratio [ OR ] = 4.24 , 95 % confidence interval [ CI ; 1.71 , 10.53 ] ) , advise smokers to quit ( OR = 3.03 , 95 % CI [ 1.24,7.45 ] ) , and refer patients to a quitline ( OR = 2.92 , 95 % CI [ 0.99 , 8.63 ] ) compared to nonsmokers , despite no differences in delivery of interventions at baseline . CONCLUSIONS Three months after attendance at an educational program focused on the nurses ' role in supporting smoking cessation efforts , more nurses engaged in interventions to help smokers quit . However , the program was less effective for nurses who smoked . CLINICAL RELEVANCE This program demonstrated promise in building capacity among Czech nurses to assist with smoking cessation , but nurses ' smoking poses a challenge INTRODUCTION This study examined the effectiveness of low-intensity , practice -tailored training for general practitioners ( GPs ) aim ed at personal and organizational barriers that arise when routinely asking patients ' smoking status , advising to quit , and arranging follow-up . METHODS A cluster-r and omized controlled trial with 49 GPs and 3,401 patients ( 677 smokers ) . Two patient groups participated : 2,068 patients ( 433 smokers ) at baseline and 1,333 patients ( 244 smokers ) postintervention . At follow-up , 225 smokers of both groups participated . The primary outcome was GP smoking cessation counseling ( asking about smoking status , advising to quit , prescribing pharmacotherapy , and referring for behavioral support ) . Secondary outcomes were GPs ' attitudes toward smoking cessation care , patients ' intention to quit , and long-term quit rates . Outcomes were measured with GP self-report and patient report . RESULTS Patients of trained GPs reported more often being asked about smoking behavior compared with patients of untrained GPs ( OR = 1.94 , 95 % CI = 1.45 - 2.60 ) . According to GP self-report , the training increased the provision of quit-smoking advices ( difference 0.56 advice per day ; 95 % CI = 0.13 - 0.98 ) and the ability and intention of providing smoking cessation care . We found no effect on GPs ' arrangement of follow-up , smokers ' intention to quit , and long-term quit rates . CONCLUSIONS After 1 hour of training , we found significant differences between trained and untrained GPs on the frequency in which they asked about smoking ( patient reported ) and advised smokers to quit ( GP self-reported ) . The training did not increase prescriptions of pharmacotherapy , referrals to behavioral support , or quit rates . Future training methods should focus on the GPs ' ability , tools , and skills to arrange follow-up to ensure intensive smoking cessation support OBJECTIVES In France , hospitals have been smoke free since February 2007 . A period of hospitalization may be a good time to enhance a smoker 's motivation to quit . This study aim ed to assess whether training medical staff in smoking cessation management might improve the rate of smoking cessation during hospitalization . STUDY DESIGN Non-r and omized intervention study . METHODS Staff of the participating care units either received ( intervention group ) or did not receive ( control group ) training in smoking cessation management . The dependent variable was the proportion of in patients that continued to smoke before ( Period 1 ) and after ( Period 2 ) the training session . RESULTS In total , 358 patients were included . In Period 1 , 55.6 % and 50 % of the smokers from the intervention and control groups stopped smoking , respectively ; the corresponding rates in Period 2 were 64.3 % and 48.1 % . In Period 2 , 36.4 % and 31.8 % of the smokers from the intervention and control groups cl aim ed that they had received motivational counselling . In the intervention group , the request rate for nicotine replacement therapy ( NRT ) was higher ( 41.7 % ) compared with the control group ( 11.1 % ) . In both groups , patients asked for NRT more often ( P < 0.001 ) when they had received motivational counselling . CONCLUSIONS This study was not able to demonstrate that training medical staff in smoking cessation management has a significant impact on smoking cessation in hospitalized smokers . The delivery of medium-intensity support to all smokers appears to be out of reach of physician/nurse teams . New strategies are needed , including a team specifically dedicated to the problems of addiction Objective : To evaluate new strategies to enhance the promotion of smoking cessation in general practice . Design : Cluster r and omised trial , 2 × 2 factorial design . Setting : 82 medical practice s in Germany , including 94 general practitioners . Participants : 577 patients who smoked at least 10 cigarettes per day ( irrespective of their intention to stop smoking ) and were aged 36–75 years . Interventions : Provision of a 2-h physician group training in smoking cessation methods and direct physician payments for every participant not smoking 12 months after recruitment ( TI , training+incentive ) ; provision of the same training and direct participant reimbursements for pharmacy costs associated with nicotine replacement therapy or bupropion treatment ( TM , training+medication ) . Main outcome measure : Self-reported smoking abstinence obtained at 12 months follow-up and vali date d by serum cotinine . Results : In intention-to-treat analysis , smoking abstinence at 12 months follow-up was 3 % ( 2/74 ) , 3 % ( 5/144 ) , 12 % ( 17/140 ) and 15 % ( 32/219 ) in the usual care , and interventions TI , TM and TI+TM , respectively . Applying a mixed logistic regression model , no effect was identified for intervention TI ( odds ratio ( OR ) 1.26 , 95 % confidence interval ( CI ) 0.65 to 2.43 ) , but intervention TM strongly increased the odds of cessation ( OR 4.77 , 95 % CI 2.03 to 11.22 ) . Conclusion : Providing cost-free effective drugs to patients along with improved training opportunities for general practitioners could be an effective measure to achieve successful promotion of smoking cessation in general practice Background In the USA , new regulations require the collection of information on tobacco constituents by br and and variety and publication of this information in a way not likely to be misconstrued by consumers . Underst and ing of such information becomes increasingly important as new tobacco products are marketed and modifications are made to reduce the toxicity of some products . This pilot study assessed the current knowledge of tobacco control professionals regarding the relative harmfulness of several tobacco products , and evaluated an online educational intervention aim ed at improving underst and ing of variations in nicotine and tobacco-specific N-nitrosamines ( TSNAs ) . Methods Fifty-two tobacco control professionals participated in an online intervention which presented and discussed the results of constituent analyses of Camel Snus and Marlboro Snus compared to several conventional smokeless tobacco products . Comparisons with cigarettes were also discussed . Pre- and post-intervention questions assessed underst and ing of the concepts . Results Pre-intervention responses demonstrated that 31 % did not know that cigarettes are more harmful than smokeless tobacco , 67 % did not know that smokeless products higher in nicotine are likely to be more effective substitutes for cigarettes , 52 % did not know TSNAs are the major carcinogens in tobacco and 81 % did not know new snus products tend to be lower in TSNAs than conventional spit tobacco . After intervention participation , knowledge increased on all points except one where pretest results were 100 % correct . Conclusions Public education campaigns are urgently needed for tobacco control professionals and consumers to increase awareness and underst and ing of the continuum of risk among tobacco products INTRODUCTION In English National Health Service ( NHS ) stop smoking services , stop smoking practitioners ( SSPs ) provide behavioral support and medication to support smokers wanting to quit . This study aim ed to evaluate an evidence -based national online knowledge training program for SSPs developed by the NHS Centre for Smoking Cessation and Training ( NCSCT ) . METHODS Knowledge required to deliver effective stop smoking interventions was assessed using 25 multiple-choice questions drawn r and omly from a common larger pool at baseline and after use of the training program in 778 consecutive users . Change in knowledge and association of this change with time spent on the training were assessed . Baseline and change in knowledge of SSPs with different amounts of experience , prior training , and time dedicated to smoking cessation were compared . RESULTS Knowledge improved from 64.4 % correct to 77.7 % ( p < .001 ) . Time spent on the training predicted improvement . Pretraining knowledge scores differed with experience , prior training , and time practicing . Training improved even the highest performing SSPs and minimized differences between groups . CONCLUSIONS Knowledge required to deliver effective stop smoking intervention is improved efficiently by using the NCSCT online training program for English smoking cessation practitioners . SSPs with all levels of prior knowledge benefit OBJECTIVE We prospect ively examined whether training home health care nurses is associated with changes in attitudes towards smoking cessation counseling and counseling behaviors . METHODS We trained 98 home health care nurses to deliver cessation counseling to their patients . Measures were administered at pre-training , post-training , and 6 months later . This was part of a larger study conducted in Providence , RI , USA ( 1998 - 2002 ) . RESULTS Compared with pre-training , at post-training , nurses reported significantly higher levels of self-efficacy to counsel , positive outcome expectations , optimism that patients would follow their advice , perceived worth of smoking counseling , perceived importance of quitting smoking , and perceived organizational support . These training effects were maintained 6 months later . Between the end of training and the 6-month follow-up , nurses reported significant increases in their perceived effectiveness to counsel smokers and confidence to encourage behavior change . Compared with pre-training , at 6 months of follow-up , nurses were significantly more likely to ask about smoking status , assess readiness to quit , advise to quit , assist with quitting , and arrange follow-up . Nurses spent significantly more time counseling smokers at 6 months than at pre-training , and were less likely to selectively counsel . CONCLUSIONS Brief training facilitates both short- and long-term changes in nurse attitudes and behaviors regarding smoking cessation counseling Objectives : General practitioners ( GPs ) are the main source of referrals to specialist smoking cessation services ( SSCS ) , but the referral rates are low . We evaluated effects of a brief GP training session on the number of referrals received by their local SSCS . Methods : A cluster-r and omised controlled trial was undertaken across three East London primary care trusts . A total of 91 GPs were r and omly allocated to a training session or usual care . Participants in the intervention arm were offered a 40-min training session addressing the rationale and skills for referral of smokers for treatment . Participants in the usual care arm received referral guidance by post . The main outcome measure was the number of referrals recorded by the SSCS over 3 months after the intervention . Results : Over the 3-month baseline period the average number of referrals per GP was 1.0 and 0.6 in the intervention and usual care arms , respectively . During the post-intervention period the mean number of referrals was 6.4 and 1.8 per GP . When adjusting for baseline variables the incidence rate ratio for the referrals from the intervention arm compared to usual care was 4.9 ( p<0.001 ; 95 CI 1.7 to 14.7 ) . Conclusion : A brief training session can significantly increase GP referral to smoking cessation services . Trial registration : National Research Register , Department of Health , UK N0261148824 ( available online at : http://www.nrr.nhs.uk/ViewDocument.asp?ID N0261148824

Where data were available there was no evidence of a difference between alginate dressings and alternative treatments in terms of complete wound healing or adverse events . AUTHORS ' CONCLUSIONS The relative effects of alginate dressings compared with alternative treatments are unclear .

BACKGROUND Pressure ulcers , also known as bedsores , decubitus ulcers and pressure injuries , are localised areas of injury to the skin or the underlying tissue , or both . Dressings are widely used to treat pressure ulcers and there are many options to choose from including alginate dressings . A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use for the treatment of pressure ulcers . This review is part of a suite of Cochrane review s investigating the use of dressings in the treatment of pressure ulcers . Each review will focus on a particular dressing type . OBJECTIVES To assess the effects of alginate dressings for treating pressure ulcers in any care setting .

OBJECTIVE To compare the efficacy and tolerability of a new ionic silver alginate matrix ( Askina Calgitrol Ag ) with that of a st and ard silver-free alginate dressing ( Algosteril ) . METHOD Patients with locally infected chronic wounds ( pressure ulcers , venous or mixed aetiology leg ulcers , diabetic foot ulcers ) or acute wounds were eligible for this prospect i ve , open-label , controlled and r and omised trial . Patients were r and omised to receive one of the two dressings for a two-week period . Criteria of efficacy were based on the evolution , from day 1 to day 15 , of local signs of infection using a clinical score ranging from 0 to 18 , and the evolution of the bacteriological status for each wound . The latter was determined by ( blind ) bacteriological examinations of results obtained from two biopsies performed at days 1 and 15 . A three-point scale ( deterioration , unchanged , improvement ) was also used . Acceptability , usefulness and tolerance were also assessed . RESULTS Forty-two patients ( 20 women and 22 men , 68.9 + /- 18.8 and 66.5 + /- 15.7 years old respectively ) were r and omly assigned to receive either Askina Calgitrol Ag ( n=20 ) or Algosteril ( n=22 ) . Most had chronic wounds such as pressure ulcers ( 57 % ) or venous or mixed aetiology leg ulcers and diabetic foot ulcers ( 29 % ) ; few had acute wounds ( 14 % ) . Clinical scores of infection were comparable in both groups at inclusion , 8.9 + /- 2.4 and 8.6 + /- 3.2 in the Askina Calgitrol Ag group and the Algosteril group respectively ( not significant ) , but decreased significantly in both groups at day 15 , 3.8 + /- 2.9 in the Askina Calgitrol Ag group ( p=0.001 ) and 3.8 + /- 3.4 in the Algosteril group ( p=0.007 ) . There was no significant difference between the two groups at day 15 . Although there was also no significant difference in bacteriological status between the treatment groups , a trend in favour of Askina Calgitrol Ag was found for the relative risk of improvement , especially in patients who were not treated with antibiotics either at the beginning of the study or during it . No differences between groups were observed regarding local tolerance , acceptability and usefulness of the dressings . CONCLUSION The regression of local signs of infection , local tolerance , acceptability and usefulness were similar for the two dressings . However , Askina Calgitrol Ag improved the bacteriological status of the wounds . Further trials are required to show that it has a positive impact on the healing process Pressure ulcers are common among elderly nursing home residents . To be effective in managing these wounds , a dressing should maintain a moist environment , facilitate healing , absorb exu date , remain in place for a number of days , and prevent trauma to the surrounding skin . An 8-week , open , r and omized , multicenter , controlled study was conducted to compare the effects of a new self-adherent soft silicone dressing and a self-adherent hydropolymer dressing on Stage II pressure ulcers . Thirty-eight ( 38 ) residents participated in the study . Eighteen residents ( mean age 83.8 years , range 74.9 to 95.1 years ) were r and omized to wound management with a soft silicone dressing , and the ulcers of 20 residents ( mean age 82.5 years , range 66.4 to 91.9 years ) were managed with a hydropolymer dressing . Wound healing , wound and surrounding skin characteristics , and ease of dressing removal were measured and documented . During the study , eight ( 44 % ) ulcers in the soft silicone group and 10 ( 50 % ) in the hydropolymer dressing group healed . Both dressings were changed approximately once a week and no differences in signs of inflammation , amount of exu date and odor , or incidence of leakage were observed . Damage to the surrounding skin , maceration , and dressing removal difficulties were less common with the soft silicone dressing . Differences in tissue damage between the two dressings were significant during weeks 1 , 2 , and 3 ( P < 0.05 ) . Studies with a larger sample size are needed to confirm these findings Objectives To evaluate if ‘ wrap therapy ’ using food wraps , which is widely used in Japanese clinical sites , is not inferior when compared to guideline adhesion treatments . Design Multicentre , prospect i ve , r and omised , open , blinded endpoint clinical trial . Setting 15 hospitals in Japan . Patients 66 older patients with new National Pressure Ulcer Advisory Panel stage II or III pressure ulcers . Interventions Of these 66 patients , 31 were divided into the conventional treatment guidelines group and 35 into the wrap therapy group . Main outcome measures The primary end point was the period until the pressure ulcers were cured . The secondary end point was a comparison of the speed of change in the Pressure Ulcer Scale for Healing score . Results 64 of the 66 patients were analysed . The estimated mean period until healing was 57.5 days ( 95 % CI 45.2 to 69.8 ) in the control group as opposed to 59.8 days ( 95 % CI 49.7 to 69.9 ) in the wrap therapy group . By the extent of pressure ulcer infiltration , the mean period until healing was 16.0 days ( 95 % CI 8.1 to 23.9 ) in the control group as opposed to 18.8 days ( 95 % CI 10.3 to 27.2 ) in the wrap therapy group with National Pressure Ulcer Advisory Panel stage II ulcers , and 71.8 days ( 95 % CI 61.4 to 82.3 ) as opposed to 63.2 days ( 95 % CI 53.0 to 73.4 ) , respectively , with stage III ulcers . There is no statistical significance in difference in Pressure Ulcer Scale for Healing scores . Conclusions It might be possible to consider wrap therapy as an alternative choice in primary care setting s as a simple and inexpensive dressing care . Clinical Trial registration UMIN Clinical Trials Registry UMIN000002658 . Summary protocol is available on https://upload.umin.ac.jp/cgi-bin/ctr/ctr.cgi?function=brows&action=brows&type=detail&recptno=R000003235&admin=0 & language = Background The treatment of pressure ulcers is complicated , given the various wound dressing products available . The cost of different treatments varies and the cost-effectiveness of each product has not been thoroughly evaluated . We compare two wound dressing protocol s-alginate silver dressing ( AlSD ) and silver zinc sulfadiazine cream ( AgZnSD ) with regard to wound healing and cost-effectiveness . Methods Patients with grade III or IV sacral or trochanteric pressure ulcers were eligible for this prospect i ve , r and omized controlled trial . The patients were r and omized to receive one of the two dressings for an eight-week period . The criteria of efficacy were based on the Pressure Ulcer Scale for Healing ( PUSH ) scoring tool . The cost of treatment was also assessed . Results Twenty patients ( 12 women and 8 men ) were r and omly assigned to receive either AlSD ( n=10 ) or AgZnSD cream ( n=10 ) . The demographic data and wound characteristics were comparable in the two groups . The two groups showed no significant difference in the reduction of PUSH score , wound size , or volume of exu date . The tissue type score was significantly lower in the AlSD group ( 3.15±0.68 - 1.85±0.68 vs. 2.73±0.79 - 2.2±0.41 ; P=0.015 ) . The cost of treatment was significantly lower in the AlSD group ( 377.17 vs. 467.74 USD , respectively ; P<0.0001 ) . Conclusions Alginate silver dressing could be effectively used in the treatment of grade III and IV pressure ulcers . It can improve wound tissue characteristics and is cost-effective Background There are many barriers to patient participation in r and omised controlled trials of cancer treatments . To increase participation in trials , strategies need to be identified to overcome these barriers . Our aim was to assess the effectiveness of interventions to overcome barriers to patient participation in r and omised controlled trials ( RCTs ) of cancer treatments . Methods A systematic review was conducted . Published and unpublished studies in any language were search ed for in fifteen electronic data bases , including MEDLINE , EMBASE , CINAHL and PsycINFO , from inception to the end of 2004 . Studies of any interventions to improve cancer patient participation in RCTs , which reported the change in recruitment rates , were eligible for inclusion . RCTs and non-r and omised controlled trials as well as before and after studies reporting baseline rates specific to the population being investigated were included . Data were extracted by one review er into structured summary tables and checked for accuracy by a second review er . Each included study was assessed against a checklist for method ological quality by one review er and checked by a second review er . A narrative synthesis was conducted . Results Eight studies were identified that met the inclusion criteria : three RCTs , two non-r and omised controlled trials and three observational studies . Six of the studies had an intervention that had some relevance to the UK . There was no robust evidence that any of the interventions investigated led to an increase in cancer patient participation in RCTs , though one good quality RCT found that urologists and nurses were equally effective at recruiting participants to a treatment trial for prostate cancer . Although there was no evidence of an effect in any of the studies , the evidence was not of sufficient quality to be able to conclude that these interventions therefore do not work . Conclusion There is not a strong evidence -base for interventions that increase cancer patient participation in r and omised trials . Further research is required to evaluate the effectiveness of strategies to increase participation in cancer treatment trials In a prospect i ve , r and omised , controlled trial of 92 patients with full-thickness pressure ulcers , the efficacy of an alginate wound dressing was compared to that of an established local treatment with dextranomer paste . During treatment , a minimal 40 % reduction in wound area was obtained in 74 % of the patients in the alginate group and in 42 % of those in the dextranomer group . The median time taken to achieve this goal was four weeks with alginate and more than eight weeks in the control group . Mean surface area reduction per week was 2.39cm2 ( sd 3.54 ) and 0.27cm2 ( sd 3.21 ) in the alginate and dextranomer groups respectively ( p=0.0001 ) . This difference was still highly significant when the sub-groups of almost completely healed subjects at the end of the study were considered . This striking healing efficacy of an alginate dressing suggests it possesses pharmacological properties which require further investigation BACKGROUND There have been no studies that have tested the Braden Scale for predictive validity and established cutoff points for assessing risk specific to different setting s. OBJECTIVES To evaluate the predictive validity of the Braden Scale in a variety of setting s ( tertiary care hospitals , Veterans Administration Medical Centers [ VAMCs ] , and skilled nursing facilities [ SNFs ] ) . To determine the critical cutoff point for classifying risk in these setting s and whether this cutoff point differs between setting s. To determine the optimal timing for assessing risk across setting s. METHOD R and omly selected subjects ( N= 843 ) older than 19 years of age from a variety of care setting s who did not have pressure ulcers on admission were included . Subjects were 63 % men , 79 % Caucasian , and had a mean age of 63 ( + /-16 ) years . Subjects were assessed for pressure ulcers using the Braden Scale every 48 to 72 hours for 1 to 4 weeks . The Braden Scale score and skin assessment were independently rated , and the data collectors were blind to the findings of the other measures . RESULTS One hundred eight of 843 ( 12.8 % ) subjects developed pressure ulcers . The incidence was 8.5 % , 7.4 % , and 23.9 % in tertiary care hospitals , VAMCs , and SNFs , respectively . Subjects who developed pressure ulcers were older and more likely to be female than those who did not develop ulcers . Braden Scale scores were significantly ( p = .0001 ) lower in those who developed ulcers than in those who did not develop ulcers . Overall , the critical cutoff score for predicting risk was 18 . Risk assessment on admission is highly predictive of pressure ulcer development in all setting s but not as predictive as the assessment completed 48 to 72 hours after admission . CONCLUSIONS Risk assessment on admission is important for timely planning of preventive strategies . Ongoing assessment in SNFs and VAMCs improves prediction and permits fine-tuning of the risk-based prevention protocol s. In tertiary care the most accurate prediction occurs at 48 to 72 hours after admission and at this time the care plan can be refined Background Pressure ulcers ( PrUs ) are ischemic wounds in the skin and underlying tissues caused by long-st and ing pressure force over an external bone or cartilaginous surface . PrUs are an important challenge for the overall health system because can prolong patient hospitalization and reduce quality of life . Moreover , 95 % of PrUs are avoidable , suggesting they are caused by poor quality care assistance . PrUs are also costly , increasing national costs . For example , they represent about 5 % of overall annual health expenses in Spain . Stages I and II PrUs have a combined prevalence of 65 % . According main clinical guidelines , stage II PrUs ( PrU-IIs ) are usually treated by applying special dressings ( polyurethane or hydrocolloid ) . However , little scientific evidence regarding their efficacy has been identified in scientific literature . Our aim is to assess the comparative efficacy of adhesive polyurethane foam and hydrocolloid dressings in the treatment of PrU-IIs in terms of healed ulcer after 8 weeks of follow-up . Methods / design This paper describes the development and evaluation protocol of a r and omized clinical trial of two parallel treatment arms . A total of 820 patients with at least 1 PrU-II will be recruited from primary health care and home care centers . All patients will receive st and ardized healing procedures and preventive measures ( e.g. positional changes and pressure-relieving support surfaces ) , following st and ardized procedures . The main outcome will be the percentage of wounds healed after 8 weeks . Secondary outcomes will include cost-effectiveness , as evaluated by cost per healed ulcer and cost per treated patient and safety evaluated by adverse events . Discussion This trial will address the hypothesis that hydrocolloid dressings will heal at least 10 % more stage II PrUs and be more cost-effective than polyurethane foam dressings after 8 weeks . Trial registration This trial has been registered with controlled-trials number ISC RCT N57842461 and EudraCT 2012 - 003945 - 14 The use of heat in wound healing has been demonstrated to aid oxygen flow and hence healing in acute wounds . However , the situation in chronic wounds is less clear . This study was design ed to investigate the benefits of using a radiant heat therapy system in the treatment of Stage 3 and 4 pressure ulcers . Despite r and omisation , patients receiving radiant heat therapy were more infirm than those receiving st and ard treatment . This prospect i ve , single-centre , r and omised trial result ed in an accelerated rate of healing for those receiving heat therapy compared to a st and ard treatment : time difference to 75 % of original area = 6.4 days ( p = 0.057 ) , to 50 % of original area = 9.6 days ( p = 0.039 ) , time to 25 % = 7.2 days ( p = 0.01 ) . This new development warrants further investigation to fully assess the role of a thermoregulation system in chronic wound healing Considerable progress has been made in the prevention and treatment of pressure ulcers but they remain a significant healthcare problem , particularly among the elderly . Treatment may include the use of wound dressings such as hydrogels as well as debridement products that contain relatively high concentrations of various enzymes . Unlike enzymes found in debridement products , low concentrations of endopeptidase enzymes can cleave to denatured proteins . Many endopeptidases have been reported to enhance the healing process . To evaluate the effect of a hydrogel wound dressing containing a combination of endopeptidases on pressure ulcers , a 12-week prospect i ve preliminary study was conducted involving 10 nursing home patients with Stage II ( n = 3 ) or Stage III ( n = 7 ) ulcers that had failed to respond to previous treatments . Seven subjects ( three with Stage II ulcers and four with Stage III ulcers ) completed the study . Healing was based on wound closure by re-epithelialization as determined by area measurement and clinical assessment . All three Stage II ulcers and two of the Stage III ulcers healed completely ; four Stage III ulcers were categorized as healing ( > 60 % improvement ) after 12 weeks of care . No dressing-related adverse events occurred and subject acceptance of the product , including comfort , was high . These results suggest that additional studies design ed to define the possible contribution of endopeptidase enzymes in wound healing are warranted The purpose of this study was to identify prospect ively risk factors for pressure sores and to compare these results with a cross-sectional analysis in the same population . Medical records on all admissions to a chronic care hospital over a 13-month period were review ed . Data on potential risk factors were abstract ed from the initial history , physical examination , nursing assessment , and laboratory studies . Pressure sore status on admission and at three weeks was determined from a st and ardized from completed on all patients with a score . The cross-sectional analysis was performed by comparing patients with and without a pressure sore at the time of admission . The cohort analysis used patients initially without a pressure sore and monitored for a new sore at three weeks . Factors associated with pressure sores on univariate testing were entered into a stepwise logistic regression model . One hundred of the 301 admissions presented with a pressure sore . Factors significantly associated with the presence of a sore were altered level of consciousness ( OR = 4.1 ) , bed- or chair-bound ( OR = 2.4 ) , impaired nutritional intake ( OR = 1.9 ) , and hypoalbuminemia ( OR = 1.8 for 10 mg/mL decrease ) . Of the 185 patients without a pressure sore , 20 ( 10.8 % ) developed a sore . Factors significantly associated with the development of a new pressure sore were a history of cerebrovascular accident ( OR = 5.0 ) , bed- or chair-bound ( OR = 3.8 ) , and impaired nutritional intake ( OR = 2.8 ) . Neither urinary nor fecal incontinence , nor the presence of hypoalbuminemia , was associated with sore development . We have prospect ively identified risk factors for pressure sores . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To evaluate the clinical impact of using a silver-releasing hydroalginate dressing to minimise the risk of local infection in colonised chronic wounds . METHOD This was a r and omised ( stratification according to wound type ) open-label multicentre comparative two-arm parallel-group study . Thirteen centres recruited 99 patients with either a venous leg ulcer or a pressure ulcer . None of the wounds required systemic antibiotics or were associated with lymphangitis and /or fever , but at least two of the following criteria had to be present : continuous pain ; erythema ; oedema ; heat ; and moderate to high levels of serous exu date . Patients were allocated to receive either a silver-releasing hydroalginate dressing ( Silvercel , the test group ) or a pure calcium alginate dressing ( Algosteril , the control group ) . Wounds were assessed daily over 14 days to complete a modified ASEPSIS index to evaluate risk of infection , and then weekly for two additional weeks . A global wound severity score and area tracings were recorded weekly . RESULTS Fifty-one and 48 patients were r and omised in the test and control groups respectively : 28 pressure ulcers and 71 venous leg ulcers . The total mASEPSIS score over 14 days did not differ significantly between groups : 95.4 + /- 62.2 and 104.2 + /- 72.8 in control and test groups respectively ( p = 0.791 ) . Of the patients who completed the total four-week study duration , four out of 38 ( 10.5 % ) in the control group and none of the 40 in the test group were treated with systemic antibiotics at the final visit ( p = 0.053 ) . According to the investigators , fewer wounds developed a clinical infection over the four-week follow-up in the test group ( 33 % versus 46 % ; p = 0.223 ) . Overall , the four-week closure rate was statistically greater in the test group ( 0.32 + /- 0.57cm2/day versus 0.16 + /- 0.40cm2/day ; p = 0.024 ) . Compared with baseline , the absolute decrease in wound severity score at week four was higher in the test group ( -5.6 + /- 3.2 versus -4.1 + /- 4.3 ; p = 0.063 ) ; this was also true of the percentage reduction ( -32 + /- 17 % versus -23 + /- 25 % ; p = 0.034 ) . Poor dressing acceptability and /or tolerability was noted in five out of 48 patients ( 10.4 % ) in the control group and in five out of 51 ( 9.8 % ) in the test group . CONCLUSION This study suggests that the use of silver-releasing dressings in the management of wounds at high risk of infection may have a clinical ly favourable influence on wound prognosis ; the dressings also appeared to be well tolerated . However , the evaluation of these advantages in controlled clinical trials is complex and requires potent studies and the development of more specific endpoints than those currently used The objective of this study was to determine the impact of pressure ulceration on health-related quality of life ( HRQoL ) and to undertake a pilot study for a future larger study . The study comprised two parts . First , data from a large UK prospect i ve cohort study were analyzed and the HRQoL of 218 people with pressure ulcers was compared with that of 2,289 people without ulcers using the Short Form-36 ( SF-36 ) question naire . After adjusting for age , sex , and comorbidities , patients with pressure ulceration had significantly lower scores for both the physical ( coefficient=-3.12 , p<0.001 ) and mental ( coefficient=-1.50 , p=0.04 ) component summary scores of the SF-36 . Second , a small pilot study was conducted to explore use of other tools . HRQoL was assessed in six patients with and 16 patients without pressure ulcers using the SF-36 , the EQ-5D and a pain visual analog scale . SF-36 scores indicated that patients with pressure ulcers had significantly poorer physical functioning ( d=22.3 , p=0.001 ) , role limitations due to physical problems ( d=12.9 , p=0.02 ) , and vitality ( d=20.6 , p=0.04 ) than those without . EQ-5D scores were also poorer for patients with pressure ulceration , for both the visual analog scale ( d=19.2 , p=0.02 ) and the index ( d=0.29 , p=0.08 ) . Patients with pressure ulceration had more perceived pain than those without ; however , this difference was of borderline significance ( d=-23.9 , p=0.06 ) . Pressure ulceration therefore has an impact on HRQoL that is measurable and persists after adjusting for potential confounding This investigation was conducted to determine if a correlation exists between wound healing outcomes and serial debridement in chronic venous leg ulcers ( VLUs ) and diabetic foot ulcers ( DFUs ) . We retrospectively analyzed the results from two controlled , prospect i ve , r and omized pivotal trials of topical wound treatments on 366 VLUs and 310 DFUs over 12 weeks . Weekly wound surface area changes following debridement and 12-week wound closure rates between centers and patients were evaluated . VLUs had a significantly higher median wound surface area reduction following clinical visits with surgical debridement as compared with clinical visits with no surgical debridement ( 34 % , p=0.019 ) . Centers where patients were debrided more frequently were associated with higher rates of wound closure in both clinical studies ( p=0.007 VLU , p=0.015 DFU ) . Debridement frequency per patient was not statistically correlated to higher rates of wound closure ; however , there was some minor evidence of a positive benefit of serial debridement in DFUs ( odds ratio-2.35 , p=0.069 ) . Our results suggest that frequent debridement of DFUs and VLUs may increase wound healing rates and rates of closure , though there is not enough evidence to definitively conclude a significant effect . Future clinical research in wound care should focus on the relationship between serial surgical wound debridement and improved wound healing outcomes as demonstrated in this study OBJECTIVES To compare the efficacy of a sequential strategy combining calcium alginate and hydrocolloid dressings treatment of grade III or IV pressure ulcers ( PUs ) and the efficacy of nonsequential strategy with hydrocolloids alone . DESIGN An open , r and omized , multicenter parallel-group trial . SETTING Twenty geriatrics hospital wards . PARTICIPANTS One hundred ten older patients with grade III or IV PUs . INTERVENTION The control strategy consisted of applying hydrocolloid dressings ( DuodermE ) for 8 weeks ; the sequential strategy consisted of applying combined calcium alginate dressings ( UrgoSorb ) for the first 4 weeks and hydrocolloid dressings ( Algoplaque ) for the next 4 weeks . MEASUREMENTS PU surface areas were measured weekly by ulcer tracing . The endpoints were the mean absolute surface area reduction ( SAR ) during the 8-week study period and the number of patients achieving a 40 or more SAR ( SAR40 ) . RESULTS Fifty-seven and 53 patients were r and omly allocated to sequential and control strategies respectively . Baseline patient characteristics and PU ulcer features at inclusion were similar in the two groups . Mean + /- st and ard deviation SAR was significantly larger in the sequential treatment group ( 5.4 + /- 5.7 cm2 and 7.6 + /- 7.1 cm2 at 4 and 8 weeks ) than in the control group ( 1.6 + /- 4.9 cm2 and 3.1 + /- 7.2 cm2 , P < .001 ) . In the sequential treatment group , 68.4 of the patients reached SAR40 at 4 weeks and 75.4 at 8 weeks , proportions significantly larger than in the control group ( 22.6 and 58.5 , respectively , P < .0001 ) . Dressing tolerance was good in both strategies . CONCLUSIONS In grade III or IV PUs , treatment using first calcium alginate dressings and then hydrocolloid dressings promotes faster healing than treatment with hydrocolloid dressings alone OBJECTIVE To determine whether or not the development of a Stage II or greater pressure ulcer in-hospital is associated with increased hospital costs and length of stay after adjusting for admission severity of illness , comorbidities , nosocomial infections , and other hospital complications . DESIGN Prospect i ve , inception cohort study . SETTING Tertiary care , urban , university teaching hospital . PARTICIPANTS 286 patients identified within 3 days of admission to a tertiary care , urban teaching hospital were enrolled in a prospect i ve , inception cohort study . Patients were age 55 or greater ; expected to be confined to bed or chair or with a hip fracture ; and expected to remain in hospital at least 5 days . MEASUREMENTS Baseline data were collected within 3 days of admission . Weekly skin assessment s were performed by study nurses to document the development of pressure ulcers . Medical record review s , patient exams , and physician and nurse interviews were used to obtain baseline demographic , medical , functional , nutritional , and global measures of disease severity . The incidence of nosocomial infections and the number of other hospital complications were monitored by medical record review s. Hospital costs were estimated using category-specific cost-to-charge ratios . Diagnostic-related group ( DRG ) adjusted length of stay was calculated by subtracting the mean length of stay for assigned DRGs from actual stays . RESULTS Incident pressure ulcers were associated with significantly higher mean unadjusted hospital costs ( $ 37,288 vs $ 13,924 , P = 0.0001 ) and length of stay ( 30.4 vs 12.8 days , P = 0.0001 ) . In addition to pressure ulcers , other independent predictors of hospital costs and length of stay after multivariable analyses included : admission to an intensive care unit or surgical service , younger age , nosocomial infection , the physician assessment of disease severity , and the number of other hospital complications . Compared with those who did not develop pressure ulcers , patients who developed pressure ulcers also were more likely to develop nosocomial infections ( 45.9 % [ 17/37 ] vs 20.1 % [ 50/249 ] , P = 0.001 ) and other hospital complications ( 86.5 % [ 32/37 ] vs 43.0 % [ 107/249 ] , P < 0.001 ) . After adjusting for only the admission predictors of costs and length of stay by multivariable analyses , hospital costs , and length of stay for those who developed pressure ulcers remained significantly greater than for those who did not develop pressure ulcers ( $ 14,260 vs $ 12,382 , P = 0.03 , and 16.9 vs 12.9 days , P = 0.02 , respectively ) . The differences in costs and length of stay for those with and without incident pressure ulcers were even greater when adjusted for admission predictors and also the occurrence of nosocomial infections and other complications ( $ 29,048 vs $ 13,819 , P = 0.002 , and 20.9 vs 12.7 days , P = 0.0001 , respectively ) . CONCLUSION Incident pressure ulcers are associated with substantial and significant increases in hospital costs and length of stay . Nosocomial infections and other hospital complications are additional significant independent predictors of health care utilization among patients at risk for pressure ulcers The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials The aim of this study was to observe both the clinical signs and symptoms of wounds at risk of infection , that is critically colonised ( biofilm infected ) and antimicrobial-performance of an ionic silver alginate/carboxymethylcellulose ( SACMC ) dressing , in comparison with a non silver calcium alginate fibre ( AF ) dressing , on chronic venous leg and pressure ulcers . Thirty-six patients with venous or pressure ulcers , considered clinical ly to be critically colonised ( biofilm infected ) , were r and omly chosen to receive either an SACMC dressing or a non silver calcium AF dressing . The efficacy of each wound dressing was evaluated over a 4-week period . The primary study endpoints were prevention of infection and progression to wound healing . The SACMC group showed a statistically significant ( P = 0.017 ) improvement to healing as indicated by a reduction in the surface area of the wound , over the 4-week study period , compared with AF controls . In conclusion , the SACMC dressing showed a greater ability to prevent wounds progressing to infection when compared with the AF control dressing . In addition , the results of this study also showed an improvement in wound healing for SACMC when compared with a non silver dressing

There is evidence that the use of certain doses of xylitol may be effective in arresting dental caries in primary dentition . Chlorhexidine and CPP-ACP may be more effective than a placebo in managing caries in primary dentition , but their effectiveness is borderline when compared with fluoride . Arginine-containing mint confection and 0.3 % triclosan varnish were found to reduce caries development in primary teeth but the evidence was at high risk of bias .

OBJECTIVE To assess the effect of non-fluoride agents on the prevention of dental caries in primary dentition .

OBJECTIVE The aim of the present study was to determine if a sugarless mint containing CaviStat ( an arginine bicarbonate calcium carbonate complex ) is capable of preventing the development of dental caries in the primary molars and first permanent molars of 10 1/2- to 11-year-old Venezuelan children . METHODS Two-hundred children were entered into this one-year study who showed the following : ( i ) age between 10 1/2 and 11 years ; ( ii ) first and second primary molars still present ; ( iii ) sound primary molars or early caries lesions in any of these teeth ; and ( iv ) at least some caries in the primary or permanent teeth as evidence of caries activity . Out of the 200 children initially selected , 195 finished and provided complete data . Children entered into the study were examined and then r and omly divided into two groups ( A and B ) , with distribution performed on the basis of the DMFS levels of the first permanent molars . All subjects were examined visually by a single examiner using good artificial light , mirror , and probe . Group A received a sugarless confection containing CaviStat ( BasicMints ) ; Group B received a sugarless mint control that contained all ingredients except for the CaviStat . Packaging and appearance of both types of mints were identical , except for their A and B design ations . RESULTS Mean differences in DMFS , defs , and DMFS + defs scores between Groups A and B were determined . In the first permanent molars and some early erupting premolars and second molars , the data showed 75.6 % fewer caries in Group A than in Group B children after six months , and 50.7 % fewer after 12 months . Corresponding defs scores showed reduced development of dental caries in deciduous molars of 76.7 % after six months and 131.3 % after 12 months . Combined DMFS and defs scores showed 76.2 and 74.8 % fewer caries lesions at six and 12 months , respectively . As exfoliation of primary molars occurred during the study period ( approximately equal in the two groups ) , a proportion correction was made to allow for caries score reductions due to lesions lost because of such exfoliation . When this was done , the results at the end of the study still showed larger caries reductions in Group A than in the Group B subjects , and statistical analyses showed these differences were still highly significant ( p < 0.001 ) . Noncavitated caries lesions in the first permanent molars were also determined . These showed once again less caries development in Group A than in Group B subjects , and did so at both six and twelve months ( 57.0 and 52.4 % , respectively ) . Levels of statistical significance at these times were p = 0.013 and 0.005 . CONCLUSION It was evident from this clinical trial that mint confections containing CaviStat are able to inhibit both caries onset and caries progression . As a result , one can conclude that CaviStat mint confection technology is a simple and economical means for reducing substantially one of the most prevalent diseases in these children Objective : We aim ed to evaluate the efficacy of oral hygiene instruction , fluoride varnish and casein phosphopeptide-amorphous calcium phosphate ( CPP-ACP ) for remineralizing white spot lesions ( WSL ) , and the effect of these on the dmft index in primary teeth . Subjects and Methods : In this 1-year , r and omized clinical trial , 140 children aged 12 - 36 months with WSL in the anterior maxillary teeth were selected and r and omly divided into 4 groups of 35 children each . Group 1 ( control ) received no preventive intervention . In group 2 , there was oral hygiene and dietary counseling . In group 3 , there was oral hygiene and the application of fluoride varnish at 4 , 8 and 12 months after baseline . In group 4 , there was oral hygiene and tooth mousse was applied by the parents twice a day over a 12-month period . At baseline and 4 , 8 and 12 months after the intervention , the size of WSL in millimeters and the dmft index were recorded . One hundred and twenty-two children completed the study . Data were analyzed using the repeated- measures ANOVA test . Results : In group 1 , the mean percent WSL area and dmft index values had increased significantly at 12 months after baseline ( p < 0.001 ) . The interventions led to significant decreases in the size of the WSL ; the greatest reduction was in group 4 ( 63 % ) followed by group 3 ( 51 % ) and group 2 ( 10 % ) after 12 months . The smallest increase in the dmft index was in group 4 ( 0.17 ) , followed by groups 3 ( 0.3 ) and 2 ( 0.42 ) . However , there were no significant differences between the groups ( p < 0.001 ) . Conclusions : Oral hygiene along with four fluoride varnish applications or constant CPP-ACP during the 12- month period reduced the size of WSL in the anterior primary teeth and caused a small increase in dmft index values PURPOSE The purpose of this study was to compare twice daily tooth-brushing using 0.304 percent fluoride toothpaste alone with : ( 1 ) twice daily tooth-brushing plus once daily 10 % casein phosphopeptide-amorphous calcium phosphate ( CPP-ACP ) paste ; and ( 2 ) twice daily tooth-brushing plus once daily 0.12 % chlorhexidine gel ( CHX ) for reducing early childhood caries ( ECC ) and mutans streptococci ( MS ) colonization . METHODS Subjects ( n=622 ) recruited at birth were r and omized to receive either CPP-ACP or CHX or no product ( study control [ SC ] ) . All children were examined at 6 , 12 , and 18 months old in their homes , and at 24 months old in a community dental clinic . RESULTS At 24 months old , the caries incidence was 1 % ( 2/163 ) in CPP-ACP , 2 % ( 4/180 ) in CHX , and 2 % ( 3/188 ) in SC groups . In children who were previously MS colonized at 12 and 18 months old , 0 % ( 0/11 ) and 5 % ( 3/63 ) , respectively , of the CPP-ACP group remained MS-positive versus 22 % ( 2/9 ) and 72 % ( 18/25 ) in CHX and 16 % ( 4/25 ) and 50 % ( 7/14 ) in SC groups ( P<.001 ) . CONCLUSIONS There is insufficient evidence to justify the daily use of casein phosphopeptide-amorphous calcium phosphate or chlorhexidine gel to control early childhood caries OBJECTIVES . This r and omised , controlled trial compared the effectiveness of 0.12 % chlorhexidine ( CHX ) gel and 304 % fluoride toothpaste to prevent early childhood caries ( ECC ) in a birth cohort by 24 months . METHODS . The participants were r and omised to receive either ( i ) twice daily toothbrushing with toothpaste and once daily 0.12 % CHX gel ( n = 110 ) or ( ii ) twice daily toothbrushing with toothpaste only ( study controls ) ( n = 89 ) . The primary outcome measured was caries incidence and the secondary outcome was percentage of children with mutans streptococci ( MS ) . All mothers were contacted by telephone at 6 , 12 , and 18 months . At 24 months , all children were examined at a community dental clinic . RESULTS . At 24 months , the caries prevalence was 5 % ( 3/61 ) in the CHX and 7 % ( 4/58 ) in the controls ( P = 0.7 ) . There were no differences in percentages of MS-positive children between the CHX and control groups ( 54%vs 53 % ) . Only 20 % applied the CHX gel once daily and 80 % less than once daily . CONCLUSIONS . Toothbrushing using 304 % fluoride toothpaste with or without the application of chlorhexidine gel ( 0.12 % ) reduces ECC from 23 % found in the general community to 5 - 7 % . The lack of effect with chlorhexidine is likely to be due to low compliance All field studies have unequivocally reported significant reductions in dental caries occurrence associated with the use of chewing gum containing xylitol . No other xylitol products besides chewing gum have so far been tested in field trials . A 5-year follow-up study with 2- or 3-year xylitol consumption periods began in Estonia in 1994 with 740 10-year-old children in 12 schools at baseline examinations . For the study , 3 clusters each including 3 - 5 schools were formed on the basis of baseline caries experience . The products were used under the supervision of the teachers 3 times per day during school days but not during weekends or during the 3-month summer holiday . The daily dose of xylitol was 5 g in all groups . The children were examined every year in September by two experienced clinicians . Dental caries was recorded according to WHO criteria . After 3 years , all xylitol groups showed a highly significant 35%-60 % reduction in caries incident , compared with the corresponding control groups . The differences between c and ies , between c and ies and chewing gum , and between 2- and 3-year users in the xylitol groups were non- systematic , indicating no trends between the groups . The results suggest that not only xylitol chewing gum but also xylitol c and ies are effective in caries prevention , and that a school-based delivery system seems to offer a practical way to distribute and control the use of the xylitol products OBJECTIVE The aim of this study was to investigate the caries prevention efficacy of chlorhexidine-thymol ( CHX-T ) varnish on newly erupted permanent first molars . METHODS Fifty-seven six- to eight-year-old school children were included in a program of sequential CHX-T varnish application . For inclusion , they had to have at least two homologous , newly erupted first permanent molars with visually sound occlusal surfaces . A clinical examination was used to determine the molar eruption stage , biofilm presence , and whole caries status . There were 99 pairs of molars in the study population . A split-mouth design was used where each child r and omly had one first molar treated with six applications of CHX-T varnish , and the other with a placebo varnish , every 15 days for 75 days . The children were then revaluated for caries one year following the conclusion of treatment . RESULTS Fourteen pairs of teeth presented incipient enamel caries lesions in both molars ( one CHX-T and one placebo varnish ) , four developed lesions in the placebo-treated molars only , and eight developed lesions in CHX-T varnish-treated molar only . No significant statistical differences were found between the two groups with regard to caries increment ( p = 0.20 ) . CONCLUSION Six applications of CHX-T varnish had no protective effect against caries development Objective . The aim was to investigate the effect of high and low amounts of xylitol on the interdental plaque-pH , directly and after sucrose challenge , in schoolchildren with habitual consumption . Material and methods . The study group consisted of 11 healthy children ( 10–15 years ) with low caries risk and the experiment had a single-blind crossover ( Latin square ) design . After a 2-week run-in period with a daily 4.0 g xylitol intake , the children were subjected to single-dose exposures of chewing gums with ( i ) paraffin ( CTR ; no xylitol ) , ( ii ) low-dose xylitol ( LX ; 2.0 g xylitol ) , and ( iii ) high-dose xylitol ( HX ; 6.0 g xylitol ) in a r and omized order separated by a washout period of 1 week . Sample s of chewing-stimulated whole saliva were collected prior to and after the experimental period for determination of bacterial counts . The outcome measures were in situ plaque-pH ( micro-touch method ) and area under the pH curve ( AUC ) . Results . The AUC was significantly greater ( p<0.05 ) in the HX group compared to the LX and control groups during the first 5 min after chewing . After a 10 % sucrose rinse , the interdental plaque-pH dropped in all groups but the HX regimen displayed significantly less reduction 0–5 min after chewing ( p<0.05 ) . No significant alterations of the total viable counts or mutans streptococci levels in saliva were disclosed during the 4-week experimental period . Conclusions . The present results suggested that a high single dose of xylitol had a short and limited beneficial effect on interdental plaque-pH in habitual xylitol consumers , while a low single dose , resembling normal chewing gum use , did not differ from the control The aim was to evaluate the effect of chlorhexidine gel treatment on the incidence of approximal caries in preschool children . One hundred and seventeen 4-year-olds , divided into two groups , participated : ( 1 ) chlorhexidine gel group ( n = 59 ) , and ( 2 ) placebo gel group ( n = 58 ) . Group 1 was treated 4 times a year with a 1 % chlorhexdine gel and group 2 with a placebo gel . Approximately 0.7 ml of gel was applied interdentally by means of a flat dental floss . A control group ( group 3 ) , which did not receive any flossing or gel treatment , was also included in the study ( n = 116 ) . After 3 years , i.e. when the children were 7 years old , the mean incidence of caries on approximal surfaces ( defs ) , including both enamel and dentin lesions , was 2.59 in the chlorhexidine gel , 4.53 in the placebo gel and 4.20 in the control group ( group 1 vs. 2 and group 1 vs. 3 : p < 0.01 ) . Mean number of approximal fillings at the end of the study , i.e. when the children were 7 years old , was 0.33 in the chlorhexidine gel , 1.04 in the placebo gel and 0.80 in the control group ( group 1 vs. 2 : p < 0.01 ; group 1 vs. 3 : p < 0.05 ) . The progression of approximal caries lesions , diagnosed on bitewing radiographs from the age of 5 to 7 , was slower in the chlorhexidine than in the placebo gel group ( the control group was not evaluated in this respect ) . A cost analysis , based on the total treatment time in minutes , showed a small gain for the flossing program . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Plaque control and caries arrest still remain a challenge for dentists . OBJECTIVE This study was conducted to assess the effect of the combined use of chlorhexidine varnish and fluoride varnish on the visible plaque index ( VPI ) and white spot lesion ( WS ) remineralization in primary dentition . METHODS A total of 80 caries-active preschool children ( 3 - 5 years ) were r and omly divided into four groups . Group 1 received a chlorhexidine varnish application every week during 4 weeks . Group 2 received a fluoride varnish application every week during 4 weeks . Group 3 received alternated applications of chlorhexidine and fluoride varnish during 4 weeks . Group 4 served as control ( without any type of cariostatic agent ) . RESULTS There was no statistically significant difference in the VPI and WS remineralization among the groups after 1 month . However , 3 months follow-up demonstrated that group 3 ( chlorhexidine + fluoride ) showed significantly better results for both VPI and WS remineralization . CONCLUSION The combined application of chlorhexidine and fluoride varnishes is more effective on plaque and remineralization of incipient caries after 3 months than the same agents applied separately The objective of this study was to assess the effect of six-monthly professional applications of chlorhexidine varnish on the prevention of dental caries in primary molars in Chinese preschool children . In a double-blinded , r and omized , placebo-controlled clinical trial , 334 children aged 4–5 years were r and omly divided into two groups . Children in the test group received six-monthly applications of a 40 % chlorhexidine varnish , and the control children received a placebo varnish . Caries status of the children was assessed by two calibrated examiners at baseline and after 24 months , according to criteria recommended by the World Health Organization . The two-year mean caries increments in the test and the control group children were 1.0 and 1.6 decayed , missing , or filled molar surfaces ( dmfs-molar ) , respectively , a 37.3 % reduction ( t test , p = 0.036 ) . No side-effects were found . It was concluded that six-monthly applications of chlorhexidine varnish were effective in reducing the incidence of dental caries in primary molars Casein phosphopeptide ( CPP ) has the potential to be added to mouth rinses , gels , toothpastes , chewing gums and confectioneries . Until now CPP has been studied in vitro , in situ and in animals , but clinical trials are lacking . This study was conducted to evaluate the efficacy of CPP-containing toothpaste in preventing dental caries in schoolchildren . The study was conducted among 150 schoolchildren r and omly divided into three groups , each using one of three types of toothpastes : ( a ) containing 2 % w/w CPP ; ( b ) containing 1,190 mg/kg fluoride as 0.76 % sodium monofluorophosphate ( SMFP ) ; ( c ) placebo toothpaste without CPP or fluoride . Students brushed with the given toothpastes for 24 months . Oral hygiene and caries experience were assessed at baseline , 12 and 24 months . The increments in caries lesions were calculated and analyzed to assess the caries-preventive effect . A significant reduction in caries increment was observed among students using CPP toothpaste or SMFP toothpaste , compared with the group using the placebo toothpaste . The reduction in caries increment was not significantly different between the CPP and SMFP groups . Oral Hygiene Index score increased from the 12-month to the 24-month examination . It is concluded that CPP can be effectively incorporated into calcium carbonate-based toothpaste and that toothpaste containing CPP is effective in preventing caries . Toothpaste containing 2 % CPP seemed to have an efficacy similar to paste containing 1,190 mg/kg SMFP in the prevention of caries Xylitol is effective as a non-cariogenic sugar substitute . Habitual xylitol consumption appears to select for mutans streptococci ( MS ) with impaired adhesion properties , i.e. , they shed easily to saliva from plaque . One hundred sixty-nine mother-child pairs participated in a two-year study exploring whether the mothers ' xylitol consumption could be used to prevent mother-child transmission of mutans streptococci . All mothers showed high salivary levels of mutans streptococci during pregnancy . The mothers in the xylitol group ( n = 106 ) were requested to chew xylitol-sweetened gum ( 65 % w/w ) at least 2 or 3 times a day , starting three months after delivery . In the two control groups , the mothers received either chlorhexidine ( n = 30 ) or fluoride ( n = 33 ) varnish treatments at 6 , 12 , and 18 months after delivery . The children did not chew gum or receive varnish treatments . MS were assessed from the mothers ' saliva at half-year intervals and from the children 's plaque at the one- and two-year examinations . The MS were cultured on Mitis salivarius agars containing bacitracin . The salivary MS levels of the mothers remained high and not significantly different among the three study groups throughout the study . At two years of age , 9.7 % of the children in the xylitol , 28.6 % in the chlorhexidine , and 48.5 % in the fluoride varnish group showed a detectable level of MS . In conclusion , therefore , habitual xylitol consumption by mothers was associated with a statistically significant reduction of the probability of mother-child transmission of MS assessed at two years of age . The effect was superior to that obtained with either chlorhexidine or fluoride varnish treatments performed as single applications at six-month intervals PURPOSE To assess the clinical effect of the 0.3 % Triclosan varnish on caries prevention . METHODS Six hundreds and six children aged 2 to 5 years old , who came from 4 different kindergartens , took part in this study . Two kindergartens were chosen r and omly as the experimental group , and the other two kindergartens as the control group . The mean dmft of two groups were recorded . The Triclosan varnish groups used the 0.3 % Triclosan varnish and were spreaded the varnish every half year , twice a year . After one year , the mean dmfs of the two groups were examined again . The SPSS 9.0 software package was used . RESULTS The mean dmfs of the two groups had no significant difference for data analysis ( P>0.05 ) . After one year , the increment of the mean dmfs had significant difference between the experimental and the control groups(P<0.05 ) . CONCLUSION 0.3 % Triclosan varnish can prevent primary teeth from caries effectively The aim of this study was to determine the effect on the human dental plaque flora of a varnish containing chlorhexidine diacetate . The in vitro release of chlorhexidine acetate from the varnish preparation was relatively fast on the first day , followed by a substantial decline in the subsequent three days . In a clinical experiment , 26 volunteers were r and omly distributed over four experimental groups . After a dental prophylaxis , the subjects were treated with a single application of a placebo varnish ( group I ) , a fluoride varnish ( group II ) , a chlorhexidine varnish ( group III ) , or a fluoride-plus-chlorhexidine varnish ( group IV ) . Saliva and pooled plaque sample s from approximal surfaces were taken before ( baseline ) and one , two , three , four , and six weeks after the treatments . No suppression was found of total cultivable flora or S. sanguis after the experimental treatments . Application of the fluoride varnish did not suppress the A. viscosus/naeslundii or S. mutans levels in the dental plaque . Chlorhexidine suppressed A. viscosus/naeslundii until two weeks after the treatment . S. mutans was significantly suppressed until four weeks after a single chlorhexidine application . While in some subjects S. mutans was effectively suppressed over the whole experimental period , in others S. mutans recovered quickly . In five subjects in whom S. mutans recovered quickly , the dentition was treated twice with chlorhexidine varnish , with an interval of one week between the treatments . After two chlorhexidine treatments , S. mutans in saliva and on the teeth was suppressed more strongly than after a single treatment . However , the second chlorhexidine treatment could not prevent the return of S. mutans in the approximal areas to its original level A professionally applied two – stage chlorhexidine varnish , Chlorzoin ® , was developed to achieve sustained release and minimise the problems of staining and bad taste associated with chlorhexidine mouthrinses . The primary aim of this r and omised controlled clinical trial was to assess the efficacy of Chlorzoin in reducing the caries increment in high – caries – risk adolescents . Secondary aims included investigating the effect of compliance upon caries increment , the effect of Chlorzoin upon salivary mutans streptococci levels and assessing the benefit of individual dental health advice by dental auxiliaries in a community setting . 1,240 children , initially aged 11–13 years , assessed to be at high caries risk were recruited into the trial . The trial design involved four arms : an observational group , a control group , an active ( Chlorzoin ) varnish group and a placebo varnish group . All subjects were examined annually by a calibrated examiner who was blind to the group allocation . Three – year caries increments were calculated using clinical , clinical and fibre – optic transillumination , and clinical and bitewing data sets . The results indicated that the use of Chlorzoin had an initial effect on mutans streptococci levels but that no long – term reduction in caries increment or mutans streptococci infection could be detected . One reason for this lack of efficacy may have been the regimen of reduced frequency of varnish applications after the initial period . Children who followed the protocol and , therefore , were seen regularly by dental auxiliaries had a lower caries increment than those who did not . This finding was independent of varnish allocation . In summary , under this regimen , Chlorzoin has been found to be effective in decreasing salivary mutans streptococci but ineffective as a caries – preventive agent in high – risk Scottish children when applied pragmatically in a community setting AIM The aim of the present study was to investigate the ability of operators using The Canary System and DIAGNOdent to detect natural pit and fissure caries under four commonly-used opaque dental sealants . METHODS Mixed sound and carious pits/fissures ( N = 105 ) selected from 40 human teeth were r and omly assigned ( 10 teeth/group ) to one of four opaque sealant groups ( Delton , Embrace WetBond , Helioseal F , UltraSeal XT Plus ) . Selected pits/fissures sites on occlusal surfaces were scanned with The Canary System and DIAGNOdent , sealed , re-scanned , and subjected to polarized light microscopy to confirm whether the scanned regions were sound or carious . Sensitivities and specificities for each detection method before and after sealant placement were calculated . RESULTS The Canary System and DIAGNOdent were able to distinguish between sound and carious tissue beneath opaque sealants with an accuracy of 76 % and 59 % , respectively . CONCLUSIONS The Canary System can serve as a clinical tool to aid dental professionals to detect and monitor the status of caries lesions and tooth structure underneath sealant . The increased likelihood of false-positive diagnoses with DIAGNOdent due to intrinsic auto-fluorescence of sealant filler and opacifying agents might limit its usefulness as an aid to detect caries underneath opaque sealants PURPOSE The objective of this study was to evaluate the effect of chlorhexidine-thymol varnish on the prevention of caries lesions in primary molars among schoolchildren ages 6 to 7 in relation to their previous experience with caries . METHODS Two groups of schoolchildren of lower-middle socioeconomic level were followed up in a clinical trial : one group of 86 children , treated with a chlorhexidine-thymol varnish ( Cervitec ) and another group of 95 children who served as controls . The varnish was reapplied every 3 months , and the caries lesion increments were compared at 24 months . RESULTS There was no statistically significant difference between these 2 groups in the increment in decayed and filled primary molars . The children in the varnish group with no decayed or filled primary teeth at baseline showed a significantly lower ( P<.05 ) incidence of caries lesions in primary molars ( at 24 months ) compared with the control group . CONCLUSIONS Chlorhexidine-thymol varnish can be said to reduce caries lesions in the primary molars of schoolchildren ages 6 to 7 with no previous caries lesion experience Aim : To evaluate the effect of xylitol-containing tablets on mutans streptococci colonisation and caries development in preschool children . Study design : R and omised single-blind prospect i ve design . Methods : The material consisted of 132 healthy 2-year-old children , 71 boys and 61 girls and they were assigned to a xylitol tablet ( test ) group or a non-intervention control group . The mean age was 2 years + 1 month in both groups . The drop-out rate was 10.6 % during the 2-year trial . The test group was given 1`-2 xylitol tablets ( 0.5`-1 g ) per day during 1.5 years . Mutans streptococci ( MS ) enumeration was performed at baseline and semi-annually in the children and at baseline or shortly after in the mothers with a chair-side technique . Caries prevalence was scored at baseline and the age of 4 years . Results : No statistically significant differences in MS colonisation were disclosed between the test and control groups at baseline or any of the design ated follow-ups . A statistically significant positive relationship was found between the maternal salivary MS levels and the colonisation of the children in the control group at 2.5 years , 3 years and 3.5 years ( r=0.39 , r=0.35 ; r=0.30 ; p<0.01 , p<0.01 and p<0.05 ) but not in the xylitol tablet group ( p>0.05 ) . The mean caries prevalence was lower in the test group compared with the control group at 4 years of age ( dmfs 0.38 ±1.05 vs. 0.80 ±2.60 ) but the difference was not statistically significant . Conclusion : The findings do not support a low-dose xylitol tablet program for caries prevention in preschool children Objective : The purpose of this double-blind , cluster-r and omized clinical trial was to examine the effects of xylitol gummy bear snacks on dental caries progression in primary and permanent teeth of inner-city school children . Methods : A total of 562 children aged 5 - 6 years were recruited from five elementary schools in East Clevel and , Ohio . Children were r and omized by classroom to receive xylitol ( 7.8 g/day ) or placebo ( inulin fiber 20 g/day ) gummy bears . Gummy bears were given three times per day for the 9-month kindergarten year within a supervised school environment . Children in both groups also received oral health education , toothbrush and fluori date d toothpaste , topical fluoride varnish treatment and dental sealants . The numbers of new decayed , missing , and filled surfaces for primary teeth ( dmfs ) and permanent teeth ( DMFS ) from baseline to the middle of 2nd grade ( exit exam ) were compared between the treatment ( xylitol/placebo ) groups using an optimally-weighted permutation test for cluster-r and omized data . Results : The mean new d3 - 6mfs at the exit exam was 5.0 ± 7.6 and 4.0 ± 6.5 for the xylitol and placebo group , respectively . Similarly , the mean new D3 - 6MFS was 0.38 ± 0.88 and 0.48 ± 1.39 for the xylitol and placebo group , respectively . The adjusted mean difference between the two groups was not statistically significant : new d3 - 6mfs : mean 0.4 , 95 % CI -0.25 , 0.8 ) , and new D3 - 6MFS : mean 0.16 , 95 % CI -0.16 , 0.43 . Conclusion : Xylitol consumption did not have additional benefit beyond other preventive measures . Caries progression in the permanent teeth of both groups was minimal , suggesting that other simultaneous prevention modalities may have masked the possible beneficial effects of xylitol in this trial . © 2014 S. Karger AG , The aim of the study was to investigate the efficacy of the use of xylitol-containing tooth-wipes in preventing dental caries in young children . In a double-blinded r and omized controlled clinical trial , 44 mothers with active caries and their 6- to 35-month-old children were r and omized to xylitol-wipe or placebo-wipe groups . The children ’s caries scores were recorded at baseline and 1 year . Salivary levels of mutans streptococci and lactobacilli were enumerated at baseline , 3 , 6 , and 12 months . Data were analyzed by intent-to-treat modeling with imputation for caries lesions and a linear mixed-effect model for bacterial levels . Significantly fewer children in the xylitol-wipe group had new caries lesions at 1 year compared with those in the placebo-wipe group ( P < 0.05 ) . No significant differences between the two groups were observed in levels of mutans streptococci and lactobacilli at all time-points . Daily xylitol-wipe application significantly reduced the caries incidence in young children as compared with wipes without xylitol , suggesting that the use of xylitol wipes may be a useful adjunct for caries control in infants ( Clinical trials.gov registration number CT01468727 ) The inhibition of enamel demineralisation and the enhancement of remineralisation are positively but not linearly related to the concentration of fluoride , especially when high fluoride concentrations are used . The aim of this in situ experiment was to determine the maximum amount of enamel remineralisation that can be achieved with daily applications of very high concentrations of fluoride . For this purpose we compared the efficacy of a daily application of fluori date d topical gel ( 12,500 ppm F , partly as NaF , Olafluor and Dectafluor , pH 4.5 ) in combination with a fluori date d toothpaste ( 1,450 ppm F as NaF ) , with fluori date d toothpaste alone . Participants ( n = 26 , with partial dentures ) were fitted with a demineralised enamel specimen ( mean mineral loss of 1,674 vol%·µm ) and were instructed to use one of the two fluoride treatments . After 4 weeks of treatment , the specimens were retrieved , a section was cut and analysed with microradiography . The remainder of each of the specimens was used for analysis of the ‘ loosely bound ’ and ‘ bound ’ fluoride . Fluoride was measured with gas-liquid chromatography . After 4 weeks in the mouth , the original lesion was reduced in size by 54 % in the toothpaste + gel group ( n = 14 ) and by 44 % in the toothpaste-only group ( n = 12 ) , but the difference between the groups was not statistically significant . The mineral content profiles showed remineralisation of the lesions throughout the depth of the lesion . The enhancement of remineralisation by the high amounts of fluoride was most pronounced in the surface layer . For both the ‘ loosely bound ’ and ‘ bound ’ fluoride , a statistically significant increase in fluoride concentration could be found in the toothpaste + gel group . In the 4-week in situ period the use of high amounts of fluoride result ed in a maximum remineralisation rate . This is illustrated by an increase in remineralisation and higher fluoride concentrations in the toothpaste + gel group compared to the toothpaste-only group BACKGROUND Demineralization can be arrested or reversed when remineralization agents are applied to incipient carious or non-cavitated carious lesions . A large number of therapeutic agents including non-fluori date d products have been developed to promote enamel remineralization . OBJECTIVE This study aims to evaluate the efficacy of different bioactive elements containing toothpastes in remineralization of artificial enamel lesions . METHODS Artificial carious lesions were created on 40 human enamel slabs , and were r and omly divided into four groups : ( 1 ) control group ( no treatment ) , ( 2 ) casein phosphopeptide-amorphous calcium phosphate group ( CPP-ACP , GC Tooth Mousse ) , ( 3 ) 8 % arginine and calcium carbonate group ( ACC , Colgate Sensitive Pro-Relief ) , ( 4 ) calcium sodium phosphosilicate group ( CSP , NovaMin ® ) . All sample s were subjected to 15 days of pH-cycling . Subsequently , a one-hour acid resistance test was carried out . Surface hardness of the sample s was assessed using the Knoop hardness test , and surface morphology and roughness were assessed by scanning electron microscopy ( SEM ) and atomic force microscopy ( AFM ) . Data were analyzed using one-way ANOVA , Tukey 's test and paired t test . RESULTS The three tested toothpastes exhibited a significantly higher remineralization efficacy compared with the control group ( P < 0.05 for all ) . After pH-cycling , the specimens treated with Colgate Sensitive Pro-Relief and NovaMin ® showed a significant higher surface hardness ( P < 0.001 and P= 0.03 , respectively ) and lower surface roughness ( P < 0.05 for both ) compared those treated with GC Tooth Mousse . While after the acid resistance test , all groups showed a significant loss of surface hardness ( P < 0.001 for all ) and significant increase of surface roughness ( P < 0.05 ) . The specimens treated with Colgate Sensitive Pro-Relief and NovaMin ® still showed a significant higher surface hardness and lower surface roughness in comparison with those treated with GC Tooth Mousse ( P < 0.05 for all ) . No significant difference was found in surface hardness and roughness between Colgate Sensitive Pro-Relief and NovaMin ® during the pH-cycling test and acid resistance test ( P= 0.45 and P= 0.83 , respectively ) . CONCLUSIONS Colgate Sensitive Pro-Relief and NovaMin ® present an advantage in enhancing remineralization and inhibiting demineralization for early enamel carious lesions in comparison with GC Tooth Mousse

Conclusion DES for focal infrapopliteal lesions significantly inhibit vascular restenosis and thereby improve primary patency , decrease repeat procedures , improve wound healing , and prolong overall event-free survival

Introduction Drug-eluting stents ( DES ) have been proposed for the treatment of infrapopliteal arterial disease . We performed a systematic review to provide a qualitative analysis and quantitative data synthesis of r and omized controlled trials ( RCTs ) assessing infrapopliteal DES .

OBJECTIVE To assess 3- and 12-month angiographic restenosis rates and their clinical impact after infrapopliteal angioplasty . DESIGN Prospect i ve multicenter study . MATERIAL S AND METHODS We analyzed 68 critical ischemic limbs ( tissue loss : 58 limbs ) from 63 consecutive patients due to isolated infrapopliteal lesions who underwent angioplasty alone . Primary endpoint was 3-month angiographic restenosis rate ; secondary endpoints were 12-month angiographic restenosis rate , and 3- and 12-month rates of mortality , major amputation and reintervention . Three- and 12-month frequency of ambulatory status and of freedom from ischemic symptoms , and time to wound healing in the ischemic wound group , were compared between restenotic and non-restenotic groups . Angiographic restenosis predictors were assessed by multivariable analysis . RESULTS 95 % of cases had 3-month angiography ; restenosis rate was 73 % : 40 % restenosis and 33 % re-occlusion . Twelve-month follow-up angiography was conducted for the patients without 3-month angiographic restenosis , and restenosis rate at 12 months was 82 % . Non-administration of cilostazol and statin , and chronic total occlusion were 3-month angiographic restenosis predictors . Three- and 12-month mortality was 5 % and 12 % , respectively . Despite no patients having undergone amputation , 15 % had persistent ischemic symptoms , and 48 % of limbs underwent reintervention within 12 months . During the same study period , ambulatory status and limbs with complete healing were more frequently observed in the non-restenosis group than in the restenosis group . In the tissue loss group , time to wound healing in the restenosis group was longer than in the non-restenosis group ( 127 days vs. 66 days , p = 0.02 ) . CONCLUSION The extremely high angiographic restenosis rate after infrapopliteal angioplasty may adversely impact clinical status improvement Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVES The study investigated the efficacy and safety of a balloon exp and able , sirolimus-eluting stent ( SES ) in patients with symptomatic infrapopliteal arterial disease . BACKGROUND Results of infrapopliteal interventions using balloon angioplasty and /or bare stents are limited by a relatively high restenosis rate , which could be potentially improved by stabilizing the lesion with a SES . METHODS Two hundred patients ( total lesion length 27 ± 21 mm ) were r and omized to infrapopliteal SES stenting or percutaneous transluminal balloon angioplasty ( PTA ) . The primary endpoint was 1-year in-segment binary restenosis by quantitative angiography . RESULTS Ninety-nine and 101 patients ( mean age 73.4 years ; 64 % diabetics ) were r and omized to SES and PTA , respectively ( 8 crossover bailout cases to SES ) . At 1 year , there were lower angiographic restenosis rates ( 22.4 % vs. 41.9 % , p = 0.019 ) , greater vessel patency ( 75.0 % vs. 57.1 % , p = 0.025 ) , and similar death , repeat revascularization , index-limb amputation rates , and proportions of patients with improved Rutherford class for SES versus PTA . CONCLUSIONS SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease Purpose : To report the 6-month angiographic results from a prospect i ve single-center study investigating the efficacy and outcome of sirolimus-eluting stents used for bailout after infrapopliteal revascularization of patients with critical limb ischemia ( CLI ) . Methods : Twenty-nine patients ( 21 men ; mean age 68.7 years ) underwent infrapopliteal revascularization with bare metal stents ( group B ) implanted for bailout in 65 lesions ( 38 stenoses and 27 occlusions ) in 40 infrapopliteal arteries . Another 29 patients ( 21 men ; mean age 68.8 years ) underwent infrapopliteal bailout stenting with sirolimus-eluting stents ( group S ) in 66 lesions ( 46 stenoses and 20 occlusions ) in 41 vessels . Preliminary 6-month angiographic and clinical results were analyzed . Results : Hyperlipidemia and symptomatic cardiac and carotid diseases were more pronounced in group S ( p < 0.05 ) . Technical success was 96.6 % ( 28/29 limbs ) in group B versus 100.0 % in group S ( p=0.16 ) . Six-month primary patency was 68.1 % in group B versus 92.0 % in group S ( p < 0.002 ) . Binary in-stent and in-segment restenosis rates were 55.3 % and 66.0 % , respectively , in patients with bare stents versus 4.0 % and 32.0 % , respectively , in patients treated with the sirolimus-eluting stents ( both p < 0.001 ) . The target lesion reintervention rate at 6 months was 17.0 % in group B versus 4.0 % in group S ( p=0.02 ) . Limb salvage was 100 % in both groups . Six-month mortality and minor amputation rates were 6.9 % and 17.2 % , respectively , in group B versus 10.3 % and 3.4 % , respectively , in group S ( p=0.32 and p=0.04 , respectively ) . Conclusions : Sirolimus-eluting stents seem to restrict neointimal hyperplasia in the infrapopliteal vascular bed PURPOSE To determine the clinical outcome and the success of stent application for high- grade lesions of the infrapopliteal arteries compared with treatment with percutaneous transluminal angioplasty ( PTA ) in critical limb ischemia ( CLI ) . MATERIAL S AND METHODS In this ethics board-approved r and omized prospect i ve study , PTA or stent application was performed on 131 lesions in 88 patients with CLI . The primary end points were clinical improvement after endovascular treatment and limb salvage rate . Secondary end points were defined by the minimal lumen diameter ( MLD ) before and after the revascularization procedure , percentage of residual diameter stenosis ( DS ) , binary restenosis rate ( > 50 % DS and > 70 % DS ) , and incidence of target lesion revascularization at 9-month follow-up . RESULTS At 3 months , the clinical status in the PTA group was less improved than that in the stent group ( P = .008 ) . At 9 months , there had been five minor and two major amputations in the PTA group and five major and five minor amputations in the stent group . MLD was significantly larger and the percentage of DS was significantly less in the stent group at completion angiography . At 9 months , the angiographic control showed better trends for the stent group in comparison to the PTA group despite that no significant differences were detected ( MLD , 1.19 mm ± 0.92 vs 1.02 mm ± 1.02 ; DS , 38.68 % ± 25.47 vs 43.31 % ± 28.37 ) . CONCLUSION Infrapopliteal stent application is an effective treatment modality in CLI . The PTA and stent groups were essentially equal at 3 and 9 months except for the difference in clinical improvement in the stent group at 3 months OBJECTIVES We investigated the efficacy and safety of using balloon exp and able drug-eluting stents ( DES ) to prevent amputations in patients with below-the-knee critical limb ischemia . BACKGROUND Critical limb ischemia patients have a 1-year amputation rate of 30 % and a mortality rate of 25 % . Most patients with critical limb ischemia have severe below-the-knee arterial disease that limits the use of bypass surgery or balloon angioplasty . METHODS In all , 106 patients ( 118 limbs ) were treated with DES in this prospect i ve , nonr and omized trial . No patients were excluded because of comorbidities or unfavorable anatomy . Primary end points were major amputation and mortality , each stratified by Rutherford category . RESULTS The mean patient age was 74 + /- 9 years . There were 228 DES implanted ( 83 % Cypher [ Cordis , Johnson & Johnson , Warren , New Jersey ] , 17 % Taxus [ Boston Scientific , Maple Grove , Minnesota ] ) . The number of stents per limb was 1.9 + /- 0.9 , and 35 % of limbs received overlapping DES ( length of 60 + /- 13 mm ) . There were no procedural deaths , and 96 % of patients were discharged within 24 h. The 3-year cumulative incidence of amputation was 6 + /- 2 % , survival was 71 + /- 5 % , and amputation-free-survival was 68 + /- 5 % . Only 12 % of patients who died had a preceding major amputation . Rutherford category , age , creatinine level , and dialysis ( p < or= 0.001 to 0.04 ) were predictors of death but not amputation . Target limb revascularization occurred in 15 % of patients , and repeat angiography in 35 % of patients revealed a binary restenosis in 12 % . CONCLUSIONS Treating below-the-knee critical limb ischemia with DES is an effective and safe means of preventing major amputation and relieving symptoms . Procedural complications and limb revascularization rates were low . Limb salvage and survival rates in patients treated with DES exceed those of historic controls

Cell salvage did not appear to impact adversely on clinical outcomes . The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective cardiac and orthopaedic surgery . The use of cell salvage did not appear to impact adversely on clinical outcomes . As the trials were unblinded and lacked adequate concealment of treatment allocation , transfusion practice s may have been influenced by knowledge of the patients ' treatment status potentially biasing the results in favour of cell salvage

BACKGROUND Concerns regarding the safety of transfused blood have prompted reconsideration of the use of allogeneic ( from an unrelated donor ) red blood cell ( RBC ) transfusion , and a range of techniques to minimise transfusion requirements . OBJECTIVES To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes .

Purpose . To compare the use of a blood salvage and reinfusion system with st and ard allogeneic blood transfusion after total knee arthroplasty — a procedure associated with significant postoperative blood loss . Methods . Between June 2002 and May 2004 , 60 patients undergoing total knee arthroplasty were r and omly allocated into a reinfusion group ( n=26 ) or a control group ( n=34 ) . Patients in the reinfusion group had their blood reinfused from drains within 6 hours of surgery . Both groups received allogeneic blood transfusions according to specified transfusion criteria if the haemoglobin level fell below 90 g/l , or in the presence of severe anaemic symptoms . Haemoglobin levels and drain output were recorded daily for 3 consecutive days after surgery . Results . There was no significant difference between the 2 groups in demographic data , drain output , total blood loss , and mean postoperative haemoglobin levels . Significantly more allogeneic blood was required by the control group than by the reinfusion group ( p=0.022 ) . Conclusion . Postoperative reinfusion of drained blood reduced the need for blood transfusion after total knee arthroplasty , while having an effect on postoperative haemoglobin level equivalent to st and ard allogeneic blood transfusion To investigate the safety and efficacy of postoperative autologous blood transfusion ( AT ) using the Shiley hardshell venous reservoir , a prospect i ve , r and omised , controlled study was carried out in two matched groups of twenty patients undergoing elective coronary artery bypass surgery . The mean volume of shed mediastinal blood reinfused in the first 6 h postoperatively was 371.7 + /- 63.23 ml . Use of homologous blood was reduced from 760.5 + /- 108.37 ml in the control patients to 466.25 + /- 87.44 ml in the AT patients , a reduction of 38.7 % ( p less than 0.05 ) . There was no statistically significant difference in the clinical outcome , overall blood loss , use of platelets , fresh frozen plasma and colloids , haematological indices , renal and hepatic functions , or clotting mechanism , although there was a reduction in the fibrinogen level in the patients who received AT ( p less than 0.05 ) . Mediastinal blood did not clot and was defibrinogenated . It contained significant levels of haemoglobin ( 8.175 + /- 0.506 g/dl ) , platelets ( 96.55 + /- 10.39 per mm3 10(3 ) ) , protein ( 42.5 + /- 1.13 g/l ) , calcium ( 2.385 + /- 0.054 mmol/l ) and was well oxygenated ( PO2 = 20.46 + /- 0.81 kPa ) . No patients developed bacteraemia or had any AT-related infections . We conclude that postoperative autologous transfusion using the Shiley hardshell venous reservoir is a safe and efficient method for reducing postoperative homologous blood requirement after coronary artery bypass surgery A series of 40 patients undergoing primary unilateral total knee arthroplasty were entered into a r and omised controlled trial to assess the safety and efficacy of postoperative autologous blood salvage and reinfusion . The mean volume of autologous blood reinfused was 520 ml per patient ( 51 % of the mean total drainage ) . Homologous blood transfusion was required in only 35 % of patients in the study group compared with 95 % of patients in the control group ( P less than 0.001 ) . The mean volume of homologous blood transfused was 0.9 units per patient in the study group compared with 2.5 units in the control group ( P less than 0.001 ) , a saving of 64 % BACKGROUND Aprotinin therapy is now widely used during cardiac surgery . This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo . METHODS In a double blind , r and omized study , three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient ( AUS$ = Australian dollars ) , low-dose aprotinin costing AUS$220 per patient or placebo . Re source use influenced by aprotinin therapy was measured . RESULTS Both doses were effective in reducing chest drainage and postoperative transfusion requirements , high-dose being more effective than low-dose . Both doses reduced the rate of reoperations for hemostasis . A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient , respectively . If the demonstrated less significant reductions in operating room and ward stay are included , these savings become AUS$463 and AUS$715 , respectively . Alternately , if cross-matches are replaced by group- and -hold and cell savers are not used , the savings per patient would be AUS$196 and AUS$467 , respectively . CONCLUSIONS While high-dose aprotinin is clinical ly more effective than low-dose aprotinin , low-dose therapy demonstrates greater cost savings BACKGROUND : Previous trials have indicated that cell salvage may reduce allogeneic blood transfusion during cardiac surgery , but these studies have limitations , including inconsistent use of other blood transfusion-sparing strategies . We design ed a r and omized controlled trial to determine whether routine cell salvage for elective uncomplicated cardiac surgery reduces blood transfusion and is cost effective in the setting of a rigorous transfusion protocol and routine administration of antifibrinolytics . METHODS : Two-hundred-thirteen patients presenting for first-time coronary artery bypass grafting and /or cardiac valve surgery were prospect ively r and omized to control or cell salvage groups . The latter group had blood aspirate during surgery and mediastinal drainage the first 6 h after surgery processed in a cell saver device and autotransfused . All patients received tranexamic acid and were subjected to an algorithm for red blood cell and hemostatic blood factor transfusion . RESULTS : There was no difference between the two groups in the proportion of patients exposed to allogeneic blood ( 32 % in both groups , relative risk 1.0 P = 0.89 ) . At current blood products and cell saver prices , the use of cell salvage increased the costs per patient by a minimum of $ 103 . When patients who had mediastinal re-exploration for bleeding were excluded ( as planned in the protocol ) , significantly fewer units of allogeneic red blood cells were transfused in the cell salvage compared with the control group ( 65 vs 100 U , relative risk 0.71 P = 0.04 ) . CONCLUSION : In patients undergoing routine first-time cardiac surgery in an institution with a rigorous blood conservation program , the routine use of cell salvage does not further reduce the proportion of patients exposed to allogeneic blood transfusion . However , patients who do not have excessive bleeding after surgery receive significantly fewer units of blood with cell salvage . Although the use of cell savage may reduce the dem and for blood products during cardiac surgery , this comes at an increased cost to the institution To evaluate the safety and effectiveness of the collection and retransfusion of postoperatively shed mediastinal blood as part of a multifaceted approach to blood conservation following cardiac operation , 113 patients were r and omized into either an autotransfusion group ( 54 patients ) or a control group ( 59 patients ) . Intraoperative and postoperative hemodilution was practice d in all patients . The clinical safety of this technique was confirmed by the lack of septic , hematological , pulmonary , renal , or hepatic complications . However , in this setting where blood conservation is already aggressively practice d , the ability of the technique to further reduce the use of banked blood following cardiac surgical procedures was not demonstrated A controlled , r and omised , prospect i ve study was undertaken to assess the efficacy of the use of a blood re-infusion device in the reduction of allogenic blood requirements of patients undergoing bilateral simultaneous total knee replacements . Thirty-three consecutive patients were r and omised to receive allogenic blood only , or a combination of collected and re-infused blood . An average of 1000 ml of drainage blood was salvaged in the study group , result ing in a significant reduction in allogenic blood requirements from 6.3 to 3.8 units in total ( P value=0.002 ) . No patients suffered transfusion reactions . We conclude that autologous re-infusion is a safe and effective method of reducing allogenic blood requirements , and as a result , reducing the risks of transmission of infection , and the rate of post-operative infection BACKGROUND Autotransfusion of shed mediastinal blood may reduce the need for homologous blood transfusions in cardiac surgery . In an earlier study we have shown that the red blood cells ( RBCs ) of shed mediastinal blood have a normal membrane stability ( osmotic fragility ) compared with circulating RBCs after coronary artery bypass grafting and better than stored RBCs . This indicates that RBCs in shed mediastinal blood are not damaged further during salvage . It remains to be determined how autotransfusion affects the survival of RBCs from shed mediastinal blood . METHODS We performed a prospect i ve , r and omized , and controlled study involving 26 patients having elective , uncomplicated coronary artery bypass grafting . Dual-isotope labeling technique ( chromium 51 and technetium 99 m ) was used to investigate the 24-hour survival of RBCs from shed mediastinal blood and RBCs from circulating blood , and to estimate the mean survival time of RBCs . RESULTS There was no significant difference between the 24-hour survival of shed mediastinal RBCs and circulating RBCs . The estimated mean cell lifespan was 20.5 days ( range , 11.6 to 29.0 days ) for shed mediastinal RBCs and 22.7 days ( range , 14.4 to 36.2 days ) for circulating RBCs . CONCLUSIONS The survival of RBCs from shed mediastinal blood after autotransfusion is comparable with the survival of RBCs in the patients ' circulating blood PURPOSE The net benefit of routine intraoperative autotransfusion ( IAT ) in patients undergoing elective infrarenal aortic surgery was studied . METHODS One hundred patients undergoing abdominal aortic aneurysm ( AAA ) repair ( n = 50 ) or aortofemoral bypass ( AFB ) for occlusive disease ( n = 50 ) were r and omized to IAT and control groups . This experience accounted for 58 % of patients undergoing aortic surgery during the 16-month study period . RESULTS IAT and control groups were balanced for preoperative demographics , disease ( 50:50 split of AFB : AAA in each group ) , and risk factors . There were no significant differences between patients r and omized to IAT and control patients in estimated blood loss ( EBL ) , allogeneic blood transfusion ( units administered intraoperatively , postoperatively , and total ) , proportion of patients not receiving allogeneic blood ( 34 % of patients r and omized to IAT and 28 % of control patients ) , postoperative hemoglobin/hematocrit levels , and complications . IAT did not reduce allogeneic blood transfusion among all patients undergoing aortic surgery nor in any subgroups that might be more likely to benefit , such as those undergoing AAA repair , those with 1000 mL or more EBL , and those receiving larger volumes of IAT-processed blood . CONCLUSION We could find no net benefit of IAT in patients undergoing elective , infrarenal aortic surgery The purpose of the study reported here was the determination of the efficacy of a postoperative autologous blood drainage and transfusion device in reducing allogeneic red cell requirements in patients undergoing elective knee arthroplasty . The study was a r and omized controlled trial with adult patients undergoing unilateral elective arthroplastic knee surgery . Patients underwent suction drainage , attached to an autologous blood drainage and transfusion device , or st and ard suction drainage . Allogeneic red cells were given according to strict transfusion guidelines based on blood loss and postoperative hemoglobin values . Outcome measures included the mean number of allogeneic red cell concentrates required and the number of patients in each group who required no transfusion . Patients assigned to st and ard suction drainage had a mean allogeneic red cell utilization of 1.2 units ( SD 1.0 ) , as compared to a mean of 0.4 units ( SD 0.8 ) in the group undergoing drainage with the autologous blood drainage and transfusion device ( p = 0.0007 ) . The percentage of patients not requiring allogeneic red cells was significantly higher in the latter group ( 74.3 % vs. 32.5 % ; p = 0.002 ) . The postoperative drainage and transfusion device was efficacious in reducing the amount of allogeneic red cells required by patients undergoing knee arthroplasty , and its use result ed in a 42 percent reduction in the number of patients requiring allogeneic transfusion BACKGROUND The aim of this study was to ascertain whether cell salvage and autotransfusion after first time elective coronary artery bypass grafting is associated with a significant reduction in the use of homologous blood , a clinical ly significant derangement of postoperative clotting profiles , or an increased risk of postoperative bleeding . METHODS Patients were r and omized to autotransfusion ( n = 98 ) receiving autotransfused washed blood from intraoperative cell salvage and postoperative mediastinal fluid cell salvage after coronary artery bypass surgery or control ( n = 102 ) receiving stored homologous blood only after coronary artery bypass surgery . RESULTS There was no statistical difference between the groups in terms of demographics , comorbidity , risk stratification , or operative details . Mean volume of blood autotransfused was 367 + /- 113 mL. Patients in the autotransfusion group were significantly less likely to receive a homologous blood transfusion compared with controls ( odds ratio 0.40 , 95 % confidence interval [ CI ] 0.22 - 0.71 ) and received significantly fewer units of blood per patient compared with controls ( 0.43 + /- 1.5 vs 0.90 + /- 2.0 U , p = 0.02 ) . There was no difference between the groups in terms of postoperative blood loss , fluid requirements , blood product requirements , or in the incidence of adverse clinical events ( p = NS chi(2 ) ) . Autotransfusion did not produce any significant derangement of thromboelastograph values or laboratory measures of clotting pathway function ( prothrombin time , activated partial thromboplastin time , fibrinogen , and fibrinogen D-dimer levels ) when compared with the effect of homologous blood transfusion ( p = NS , repeated measures analysis of variance [ MANOVA ] ) . CONCLUSIONS Autotransfusion is a safe and effective method of reducing the use of homologous bank blood after routine first time coronary artery bypass grafting To study the effectiveness of autotransfusion of shed mediastinal blood in decreasing the need for homologous blood transfusion in the routine cardiac surgical patient , we prospect ively r and omized 35 consecutive patients into two groups . The experimental group ( n = 18 ) received autotransfusion for 12 hours after completion of the operative procedure . The control group ( n = 17 ) was treated with st and ard chest drainage and fluid replacement . Both groups received homologous blood transfusion when the hemoglobin level fell to less than 8.0 g/dL. Student 's t test , chi 2 analysis , and multivariate logistic regression analysis were used where appropriate . Packed red blood cells were required postoperatively in 6 of the 17 control and 6 of the 18 autotransfusion patients ( p = not significant ) . Postoperative colloid fluid replacement ( excluding autotransfusion fluid ) in the autotransfusion group ( 333 + /- 78 mL ; 95 % confidence bounds , 168 to 498 mL ) was less than in the control group ( 615 + /- 114 mL ; 95 % confidence bounds , 372 to 857 mL ; p = 0.048 ) . Total homologous blood product exposure tended to be higher in autotransfusion patients ( 83 % ) than in control patients ( 47 % ) ( p = 0.057 ) . Fibrin split products were elevated only in the serum of the autotransfusion patients ( p < 0.002 ) . No transfusion-related complications were apparent in either group . Although the sample size is small , autotransfusion of shed mediastinal blood does not appear to decrease the need for homologous blood transfusion in the routine cardiac surgical patient The efficacy of predeposited autologous blood transfusion ( PABT ) with and without intra/postoperative blood salvage to reduce or eliminate the need for homologous blood transfusion ( HBT ) in primary total hip or knee replacement surgery was investigated by retrospective and prospect i ve studies . Depending on the type of surgery , one to three units of PABT eliminated the need for HBT in 50 to 78 % of patients , but , intra/postoperative blood salvage alone reduced the need only in 11 to 29 % . In contrast , blood salvage , when combined with three units of PABT , eliminated the need for HBT in all patients undergoing primary joint replacement surgery . A cost comparison analysis showed that blood salvage was more expensive than PABT , and therefore it should be limited to patients who had predeposited fewer than three units of autologous blood This prospect i ve study was design ed to determine whether use of nonwashed shed mediastinal blood exacerbated platelet and related hematologic dysfunctions after cardiopulmonary bypass , compared with the alternative use of autologous and homologous st and ard liquid preserved blood for volume support . Thirty-two patients undergoing cardiopulmonary bypass for open heart operations were r and omized to receive either nonwashed shed mediastinal blood ( group 1 ; n = 16 ) or liquid preserved packed red blood cells ( group 2 ; n = 16 ) for transfusion therapy in the management of postoperative bleeding . Patient blood sample s and bleeding times were obtained preoperatively , after cardiopulmonary bypass but before transfusions , 2 and 24 hours after transfusion , and on postoperative days 2 , 3 , and 7 . Group 1 patients received an average of 710 + /- 90 mL ( range , 300 to 1,700 mL ) of nonwashed shed mediastinal blood containing significantly greater ( p < 0.0001 ) amounts of fibrin degradation products and D-dimer protein . Of the hematologic , microaggregate , and plasma protein measurements performed , only the protein C level was significantly greater in group 1 ( p < 0.05 ) after transfusion . Patient bleeding times were not significantly different between the groups at any of the time points , and the total postoperative blood loss was not different between the groups . There was a trend toward less need for homologous transfusion in group 1 ( p < 0.1 ) . This study documents the safety and ease of using nonwashed shed mediastinal blood as a primary blood volume support after an open heart operation BACKGROUND Autotransfusion of shed mediastinal blood reduces blood requirement after coronary artery bypass grafting . Recently , two nonr and omized trials indicated that autotransfusion elevates the levels of cardiac enzymes after cardiac operations . METHODS Prospect i ve , r and omized controlled studies involving 120 patients ( study A ) and 15 patients ( study B ) having elective uncomplicated coronary artery bypass grafting were performed . Autotransfusion of shed mediastinal blood was performed for 18 hours in the patients allocated to autotransfusion . Serum levels of cardiac enzymes were measured . In study B cardiac enzyme levels in shed mediastinal blood and circulating blood were measured 1 hour postoperatively . RESULTS Cardiac enzyme levels were significantly elevated in the patients receiving autotransfusion . In patients with a perioperative myocardial infa rct ion . The level of creatine kinase-MB was much higher than in the autotransfused patients without myocardial infa rct ion . The level of cardiac enzymes was higher in shed mediastinal blood compared with circulating blood . CONCLUSIONS Postoperative autotransfusion of shed mediastinal blood causes elevation of cardiac enzyme levels after coronary artery bypass grafting The clinical benefits of using intraoperative autologous blood transfusion during abdominal aortic aneurysm bypass surgery become increasingly apparent when use of autologous and homologous blood transfusions is compared . That homologous blood transfusions carry some risk is widely recognized . When autologous blood is used as a sole source of blood transfusion , the risk of transmission of infectious agents and potential immunologic side effects are avoided . A prospect i ve r and omized pilot study comparing autologous and homologous blood transfusion in patients undergoing elective infrarenal abdominal aortic aneurysm bypass surgery was undertaken . The purpose of this study was to determine whether autologous blood salvaged intraoperatively may serve as an alternative to homologous blood by comparing the rate of postoperative infection and duration of hospital stay for patients receiving autologous versus homologous blood transfusions . Fifty patients undergoing abdominal aortic aneurysm bypass surgery were prospect ively r and omly assigned to receive either a homologous or an autologous blood transfusion , with 27 receiving a homologous blood transfusion and 23 receiving an autologous blood transfusion . The data from this study show that the length of hospital stay of patients receiving an autologous blood transfusion intraoperatively was reduced by a mean of 3 days and the risk of postoperative complications such as a systemic inflammatory response or sepsis , was reduced by more than 50 % OBJECTIVE To determine the safety and effectiveness of autotransfusion of shed mediastinal blood after open heart surgery . METHODS Sixty patients undergoing coronary artery bypass grafting ( CABG ) were selected r and omly to receive either nonwashed shed mediastinal blood ( Group 1 , n = 30 ) or banked blood ( Group 2 , n = 30 ) . Drainage and transfusion volume were determined after the operation . Hb , RBC , HCT and PLT were detected immediately before and after the operation , as well as 24 hours and 7 days after the operation . Data were analyzed using Fisher 's exact test . A P < 0.05 was considered significant . RESULTS There were no significant differences in Hb , HCT , PLT or length of cardiopulmonary bypass ( CPB ) ( P > 0.05 ) . In the two groups , no significant difference in the mean blood loss was observed during 24 hours after the operation ( 660 + /- 300 ml in Group 1 and 655 + /- 280 ml in Group 2 , P > 0.05 ) . In Group 1 , the mean volume autotransfused was 280 + /- 160 ml , and the patients required 360 + /- 80 ml banked blood compared with 660 + /- 120 ml in Group 2 . In other words , the banked blood requirement in Group 1 was 40 % lower . CONCLUSIONS Autotransfusion of shed mediastinal blood after an open heart operation is safe and effective OBJECTIVES To determine if cell-salvaged autologous blood can serve as an alternative to homologous blood , and to examine the incidence of infected complications and length of postoperative stay . DESIGN A prospect i ve r and omised study comprising autologous and homologous blood transfusions in patients undergoing elective infrarenal abdominal aortic surgery . METHODS Fifty patients undergoing AAA surgery were prospect ively r and omised to homologous blood ( n = 27 ) , or autologous blood transfusion ( n = 23 ) , using a cell salvage autotransfusion device . RESULTS The haemoglobin at the time of hospital discharge was similar for both groups ( 11.0 vs. 10.8 g/dl ) with no difference in perioperative mortality . The length of stay was reduced in those patients who received autologous blood ( 9 days vs. 12 days , p < 0.05 Mann-Whitney U test ) . There were four infected cases in the autologous group and 12 in the homologous group ( p = n.s . , Fisher 's exact probability test ) . However , patients who received 3 - 4 units of homologous blood had an increased risk of infection compared to those who received a similar amount of autologous blood ( 50 % vs. 0 % ) . CONCLUSIONS Cell salvage autologous blood can safely replace , or at least decrease , exposure to homologous blood transfusion , with a reduction in the mean hospital stay OBJECTIVES The National Blood Service issues 2.2 million units of blood per year , 10 % of these ( 220000 ) are utilized in cardiac procedures . Transfusion reactions , infection risk and cost should stimulate us to decrease this transfusion rate . We test the efficacy of autotransfusion following surgery in a prospect i ve r and omized trial . METHODS One hundred and twelve patients undergoing CABG , valve or CABG + valve procedures were r and omized into two groups . Group A received washed postoperative drainage fluid and group C were controls . The indication for transfusion was a postoperative haemoglobin ( Hb ) < 10 g/l or a PCV < 30 . There was no significant difference in preoperative and operative variables between the groups . RESULTS Twenty-eight patients in group A and 46 in group C required homologous transfusion ( P = 0.0008 ) . Group A patients required 298+/-49 ml of banked blood per patient , group C 508+/-49 ml ( P = 0.003 ) . There was no difference in total blood required ( volume autotransfused + volume banked blood transfused ) between the groups ( group A 404+/-50 ml , group C 508+/-50 ml ) or in mean total mediastinal fluid drainage ( group A 652+/-51 ml , group C 686+/-50ml ) . The mean Hb concentration was significantly higher in group A on day 1 ( 11.2 g/dl+/-51 vs. 10.6 g/dl+/-13 ( P = 0.002 ) ) . No morbidity was associated with autotransfusion . CONCLUSION Autotransfusion can decrease the amount of homologous blood transfused following cardiac surgery . This represents a benefit to the patient and a decrease in cost to the health service We compared allogeneic blood usage for two groups of patients undergoing total knee replacement surgery ( TKR ) . Patients were r and omized to receive either their post-operative wound drainage as an autotransfusion ( n=115 ) after processing or to have this wound drainage discarded ( n=116 ) . Allogeneic blood was transfused in patients of either group whose haemoglobin fell below 9 g dl(-1 ) . Only 7 % of patients in the autotransfusion group required an allogeneic transfusion compared with 28 % in the control group ( P<0.001 ) . There was no hospital mortality and only 3 % mortality from all causes at the study completion , which spanned 6 months to 3 yr . There was a higher incidence of infection requiring intervention in the allogeneic group ( P<0.036 ) . Total patient costs were Pound Sterling 113 greater in the autotransfusion group . We conclude that in this type of surgery post-operative cell salvage is a safe and effective method for reducing allogeneic blood use In a r and omized prospect i ve study of patients having cardiac surgery , autologous blood collected from mediastinal tubes was autotransfused preferentially in 63 patients ( ATS ) , whereas 51 patients received bank blood for transfusion ( control ) . Comparison of the two groups showed no significant difference in regard to age , sex , operations performed , or total postoperative bleeding ( ATS 813 + /- 121 ml . per square meter versus control 711 + /- 93 ml . per square meter ; N.S. ) Although mean postoperative blood replacement was similar in the two groups ( ATS 4.3 + /- 0.6 units per patient versus control 4.8 + /- 0.6 units per patient ) , requirements for transfusion of stored bank blood were reduced by 50 percent in the ATS group ( ATS 2.4 + /- 0.3 units per patient versus control 4.8 + /- 0.6 units per patient ; p less than 0.005 ) . Coagulation studies demonstrated that this blood was defibrinogenated ; yet it contains significantly more platelets and clotting factors than does bank blood . In this study , autotransfusion of shed mediastinal blood was safe and simple . It significantly reduced bank blood requirements and result ed in substantial financial savings for the patients and the hospital The aim was to assess the cost-effectiveness of erythropoietin ( EPO ) to reduce patients ' exposure to perioperative allogenic blood products in orthopaedic surgery . The use of EPO was assessed for EPO used alone and for EPO , to augment preoperative autologous donation ( PAD ) . A decision analytical model was design ed incorporating ( i ) the risk of receiving allogeneic blood , ( ii ) the costs of blood products , ( iii ) the likelihood of developing transfusion-related diseases , ( iv ) the costs of transfusion-related diseases , ( v ) the impact of transfusion-related diseases on patient morbidity and mortality and ( vi ) the effect of EPO upon the probability of transfusion . The efficacy of EPO was derived from data from a meta- analysis of published r and omized trials . Estimates for the other parameters were obtained by a systematic review of the literature . EPO alone led to only modest incremental benefit compared to no intervention for orthopaedic surgery ( 0.000024 life-years gained per patient ) . As an augmentation to PAD , EPO also led to modest benefits ( 0.000006 life-years gained per patient ) . For EPO compared to no intervention , the incremental cost per life-year gained was $ 66 million ( Canadian ) . For EPO to augment PAD , the incremental cost per life-year gained was $ 329 million ( Canadian ) . Detailed sensitivity analysis did not reveal any circumstances in which the cost-effectiveness ratios reached a level generally considered attractive . On the basis of cost-effectiveness , the use of EPO to reduce perioperative allogeneic transfusions in orthopaedic surgery did not meet criteria conventionally considered acceptable OBJECTIVE Off-pump CABG is potentially associated with reduced intraoperative blood loss and homologous blood transfusion in comparison to on-pump CABG . In this r and omised controlled study we investigated the effects of autologous cell saver blood transfusion on blood loss and homologous blood transfusion requirements in patients undergoing CABG on- versus off-CPB . METHODS Eighty patients were r and omised into one of four groups : ( A ) on-CPB with cell saver blood transfusion ( CSBT ) , ( B ) on-CPB without CSBT , ( C ) off-pump with CSBT and ( D ) off-pump without CSBT . Volume of intraoperative autologous blood transfusion , postoperative mediastinal blood loss and homologous blood transfusion requirements were measured . Homologous blood was transfused when haemoglobin concentration fell below 8 g/dl postoperatively . Pre- and postoperatively prothrombin time and partial thromboplastin time were measured . RESULTS Preoperative patient characteristics were well matched among the four groups . The amount of salvaged mediastinal blood available for autologous transfusion was significantly higher in the on-pump group ( A ) compared to the off-CPB group ( C ) ( 433+/-155 ml vs 271+/-144 ml , P=0.001 ) . Volume of homologous blood transfusion was significantly higher in group B vs groups A , C and D ( 595+/-438 ml vs 179+/-214 , 141+/-183 and 230+/-240 ml , respectively , P<0.005 ) . The cell saver groups ( A and C ) received significantly less homologous blood than the groups without cell saver ( 160+/-197 ml vs 413+/-394 ml , respectively , P<0.005 ) . Patients undergoing off-CPB surgery received significantly less homologous blood than those undergoing on-CPB CABG irrespective of cell saver blood transfusion ( 184+/-214 ml vs 382+/-397 ml , P<0.05 ) . Postoperative blood loss was similar in the four groups ( 842+/-276 , 1023+/-291 , 869+/-286 and 903+/-315 ml in groups A to D , respectively , P>0.05 ) . Clotting test results revealed no significant difference between the groups . There was no significant difference in postoperative morbidity between groups . CONCLUSION Off-pump CABG is associated with significant reduction in intraoperative mediastinal blood loss and homologous transfusion requirements . Autologous transfusion of salvaged washed mediastinal blood reduced homologous transfusion significantly in the on-CPB group . Cell saver caused no significant adverse impact on coagulation parameters in on- or off-CPB CABG . Postoperative morbidity and blood loss were not affected by the use of CPB or autologous blood transfusion . We recommend the use of autologous blood transfusion in both on- and off-pump CABG surgery Abstract Objective : To assess the effectiveness of two mechanical methods of blood conservation in reducing the need for allogeneic red blood cells or coagulation products during cardiac surgery . Design : R and omised controlled trial . Setting : Regional cardiac centre in a teaching hospital in Southampton . Participants : 263 adults aged 18 - 80 years undergoing elective coronary artery bypass surgery entered the study , of whom 252 completed the trial . All patients received routine perioperative care . Patients were allocated to one of three treatment groups : intraoperative cell salvage , intraoperative cell salvage with acute perioperative normovolaemic haemodilution , or no mechanical blood conservation . There were 84 patients in each group . Main outcome measures : Numbers of patients who received allogeneic blood or coagulation products , and the mean number of units of blood transfused per patient . Results : Of the patients in the intraoperative cell salvage group , 26 were given a transfusion of allogeneic blood , compared with 43 in the control group ( odds ratio 0.43 ( 95 % confidence interval 0.23 to 0.80 ) ) . The mean number of units of allogeneic blood transfused per patient in the intraoperative cell salvage group was 0.68 units ( SD=1.55 ) , compared with 1.07 ( 1.56 ) units in the control group . 32 of the patients in the intraoperative cell salvage group were given any blood product , compared with 47 in the control group ( odds ratio 0.47 ( 0.25 to 0.89 ) ; P=0.019 ) . Combining acute perioperative normovolaemic haemodilution with intraoperative cell salvage conferred no additional benefits . Conclusions : An intraoperative cell salvage device should be used in elective coronary artery bypass grafting . Pharmacological strategies may achieve further reductions in blood transfusions . Yet further reductions in blood transfusions could be achieved if the lower safe limit of haemoglobin concentration in patients undergoing cardiac surgery were known Clinical , haematological or economic benefits of post-operative blood salvage with autologous blood re-transfusion have yet to be clearly demonstrated for primary total hip replacement . We performed a prospect i ve r and omised study to analyse differences in postoperative haemoglobin levels and homologous blood requirements in two groups of patients undergoing primary total hip replacement . A series of 158 patients was studied . In one group two vacuum drains were used and in the other the ABTrans autologous retransfusion system . A total of 58 patients ( 76 % ) in the re-transfusion group received autologous blood . There was no significant difference in the mean post-operative haemoglobin levels in the two groups . There were , however , significantly fewer patients with post-operative haemoglobin values less than 9.0 g/dl and significantly fewer patients who required transfusion of homologous blood in the re-transfusion group . There was also a small overall cost saving in this group A series of 135 adults undergoing cardiac surgery was r and omized to an autotransfusion group ( n = 67 ) or a control group ( n = 68 ) . In the autotransfusion group mediastinal blood was collected and reinfused during the first 6 postoperative hours . Blood from the reservoir was taken for bacteriologic culture at the end of that time . The postoperative blood was comparable in the two groups . The average requirement of bank blood was 2.7 units in the autotransfusion group and 3.3 units in the controls ( p less than 0.05 ) . The average volume of autotransfusion blood was 336 ml . There were no clinical infections in the autotransfusion group , although 19 % of the cultures were positive , and no apparent alteration of the coagulation mechanisms arose from infusion of autologous blood . No clinical ly significant intergroup differences were found in hematologic , renal or hepatic parameters , neurologic function or use of antibiotics To determine the safety , efficacy and user-friendliness of two different postoperative autologous blood re-infusion systems , an open , r and omized , controlled study was performed . Eligible consecutive primary and revision total hip and knee replacement patients were r and omized for one of the two systems or for a control group in which shed blood was not re-infused . The nursing staff scored user-friendliness . Patients were monitored after re-infusion . In all three patient groups , a restrictive transfusion trigger was used . Sixty-nine of 70 r and omized patients were evaluated . Ease of use , efficacy and safety of both re-infusion systems were comparable . There was no difference in allogeneic blood use between the groups . Thirty per cent of the patients re-infused with autologous blood developed a mainly mild , febrile transfusion reaction . No other adverse reactions were seen . Signs of coagulopathy after re-infusion were not found . In multivariate analysis , autologous re-infusion was an independent factor associated with a shorter hospital stay . Both postoperative autologous blood re-infusion systems were of equal efficacy and safety . The contribution of autologous wound blood re-infusion to reduce allogeneic transfusions must be investigated in a larger study We conducted a prospect i ve , r and omized , controlled trial comparing homologous blood consumption between groups of patients receiving conventional mediastinal drainage ( group 1 ) or reinfusion of shed mediastinal blood ( group 2 ) using hard-shell cardiotomy reservoir . One hundred consecutive patients who had elective coronary artery or valvular operations were studied . The two groups were comparable with regard to age , sex , weight , preoperative and postoperative hemoglobin levels , and surgical procedure . Group 2 patients had their shed mediastinal blood reinfused for up to 18 hours postoperatively ; otherwise , the two groups were treated identically . For groups 1 and 2 , average mediastinal blood losses were 705 + /- 522 and 822 + /- 445 mL and homologous blood consumption was 3.83 + /- 2.58 and 3.15 + /- 2.05 U , respectively ( neither measure was significantly different ) . However , if blood losses exceeded 500 mL , there was a statistically significant reduction in homologous blood requirements in group 2 as compared with matched controls in group 1 . This difference was most significant in patients with the greatest mediastinal losses OBJECTIVE To compare 2 important techniques of blood conservation , use of a cell saver and low-dose aprotinin , in terms of blood loss and homologous blood usage in patients undergoing cardiac valve surgery . DESIGN Prospect i ve , r and omized . SETTING Tertiary care hospital . PARTICIPANTS Sixty adult patients undergoing elective valve surgery . INTERVENTIONS The patients were divided into 3 groups of 20 each . In group 1 , aprotinin in the dose of 30,000 KIU/kg was added to the pump prime , with a further dose of 15,000 KIU/kg added at the end of each hour of cardiopulmonary bypass . In group 2 , a cell-saver system was used to collect all blood at the operation site for processing in preparation for subsequent reinfusion . Group 3 patients acted as a control group and underwent routine management , which included collection of autologous blood during the pre-cardiopulmonary bypass period . A hemoglobin of < 8 g/dL was considered as an indication for bank blood transfusion in the postoperative period . MEASUREMENTS AND MAIN RESULTS The chest tube drainage was significantly less in group 1 compared with groups 2 and 3 , with total drainage ( median [ interquartile range ] ) amounting to 250 mL [ 105 to 325 mL ] vs. 700 mL [ 525 to 910 mL ] in group 2 and 800 mL [ 650 to 880 mL ] in group 3 ( p < 0.001 ) . The patients in groups 1 and 2 required significantly less bank blood ( median [ interquartile range ] ) as compared with group 3 ( 350 mL [ 0 to 525 mL ] , 350 mL [ 0 to 350 mL ] , and 1050 mL [ 875 to 1050 mL ] ; p < 0.001 ) , respectively . Cell saver provided 410 + /- 130 mL of hemoconcentrated blood in group 2 . The average preoperative hemoglobin concentration was 11.3 g/dL , and it was around 9 g/dL on the 7th postoperative day . The hemoglobin concentration at various stages during hospitalization in all 3 groups was similar . CONCLUSIONS Low-dose aprotinin and a cell saver are effective and comparable methods of blood conservation . Aprotinin helps by decreasing the postoperative drainage , and a cell saver helps by making the patient 's own blood available for transfusion OBJECTIVE We evaluated , in a r and omized controlled trial , the safety and effectiveness of intraoperative cell salvage and autotransfusion of washed salvaged red blood cells after first-time coronary artery bypass grafting performed on the beating heart . METHODS Sixty-one patients undergoing off-pump coronary artery bypass grafting surgery were prospect ively r and omized to autotransfusion ( n = 30 ; receiving autotransfused washed blood from intraoperative cell salvage ) or control ( n = 31 ; receiving homologous blood only as blood-replacement therapy ) . Homologous blood was given according to unit protocol s. RESULTS The groups were well matched with respect to demographic and comorbid characteristics . Patients in the autotransfusion group had a significantly higher 24-hour postoperative hemoglobin concentration ( 11.9 g/dL ; SD , 1.41 g/dL ) than those in the control group ( 10.5 g/dL ; SD , 1.37 g/dL ) ( mean difference , 1.02 g/dL ; 95 % confidence interval , 1.60 - 0.44 g/dL ; P = .0007 ) , as well as a 20 % reduction in the frequency of homologous blood product use ( 11/31 vs 5/30 ; P = .095 ) . Autotransfusion of washed red blood cells was not associated with any derangement of thromboelastograph values or laboratory measures of clotting pathway function ( prothrombin time , activated partial thromboplastin time , and fibrinogen levels ) , increased postoperative bleeding , fluid requirements , or adverse clinical events . There was no statistical difference between groups in the total operation , hospitalization , and management costs per patient ( median difference , USD 1015.90 ; 95 % confidence interval , -USD 2260 to USD 206 ; P = .11 ) . Conclusions Intraoperative cell salvage and autotransfusion was associated with higher postoperative hemoglobin concentrations , a modest reduction in transfusion requirements , no adverse clinical or coagulopathic effects , and no significant increase in cost compared with controls . This study supports its routine use in off-pump coronary artery bypass grafting surgery BACKGROUND Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products . We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinical ly important consequences . METHODS In this multicenter , blinded trial , we r and omly assigned 2331 high-risk cardiac surgical patients to one of three groups : 781 received aprotinin , 770 received tranexamic acid , and 780 received aminocaproic acid . The primary outcome was massive postoperative bleeding . Secondary outcomes included death from any cause at 30 days . RESULTS The trial was terminated early because of a higher rate of death in patients receiving aprotinin . A total of 74 patients ( 9.5 % ) in the aprotinin group had massive bleeding , as compared with 93 ( 12.1 % ) in the tranexamic acid group and 94 ( 12.1 % ) in the aminocaproic acid group ( relative risk in the aprotinin group for both comparisons , 0.79 ; 95 % confidence interval [ CI ] , 0.59 to 1.05 ) . At 30 days , the rate of death from any cause was 6.0 % in the aprotinin group , as compared with 3.9 % in the tranexamic acid group ( relative risk , 1.55 ; 95 % CI , 0.99 to 2.42 ) and 4.0 % in the aminocaproic acid group ( relative risk , 1.52 ; 95 % CI , 0.98 to 2.36 ) . The relative risk of death in the aprotinin group , as compared with that in both groups receiving lysine analogues , was 1.53 ( 95 % CI , 1.06 to 2.22 ) . CONCLUSIONS Despite the possibility of a modest reduction in the risk of massive bleeding , the strong and consistent negative mortality trend associated with aprotinin , as compared with the lysine analogues , precludes its use in high-risk cardiac surgery . ( Current Controlled Trials number , IS RCT N15166455 [ controlled-trials.com ] . ) INTRODUCTION 10 % of blood issued by the National Blood Service ( 220,000 ) is utilised in cardiac procedures . Transfusion reactions , infection risk and cost should stimulate us to decrease this transfusion rate . We tested the efficacy of autotransfusion of washed postoperative mediastinal fluid in a prospect i ve r and omized trial . PATIENTS AND METHODS 166 patients undergoing coronary artery bypass grafting ( CABG ) , valve or CABG + valve procedures were r and omized into three groups . The indication for transfusion was a postoperative haemoglobin ( Hb ) < 10 g/l or a packed cell volume ( PCV ) < 30 . When applicable , group A patients received washed post-operative drainage fluid . Group B all received blood processed from the cardiopulmonary bypass ( CPB ) circuit following separation from CPB and if appropriate washed post-operative drainage fluid . Group C were controls . Groups were compared using analysis of variance . RESULTS There was no significant difference in age , sex , type of operation , CPB time and preoperative Hb and PCV between the groups . Blood requirements were as shown . [ table - see text ] Twelve patients in group A and 10 in group B did not require a homologous transfusion following processing of the mediastinal drainage fluid . CONCLUSION Autotransfusion of washed postoperative mediastinal fluid can decrease the amount of homologous blood transfused following cardiac surgery . There was no demonstrable benefit in processing blood from the CPB circuit as well as mediastinal drainage fluid We studied the management of postoperative drainage after total knee replacement ( TKR ) . 90 primary total knee joint arthroplasties were prospect ively r and omized into 3 groups : a ) no drain , b ) an autotransfusion system , c ) a st and ard disposable closed suction drainage system . We monitored hemoglobin and hematocrit values , drainage volume and transfusions ( homologous and autologous ) , range of knee motion , knee swelling and hospital stay . Parameters were recorded preoperatively , days 0 - 8 and 4 months postoperatively . No significant differences were seen between the groups in any of the parameters measured . The results show no benefit from using postoperative drainage systems in knee arthroplasties . Savings of SEK 400 ( USD 55 ) per patient would have result ed if drains had not been used at all The effect of intraoperative autotransfusion during coronary artery bypass grafting was studied in a r and omized double-blind trial involving 38 patients . Nineteen patients had the collected RBCs washed and autotransfused ( autotransfusion group ) , while the remaining patients had their washed cells discarded ( control group ) . Postoperative hemoglobin and hematocrit values were similar . Exposure to banked blood was markedly decreased in the autotransfusion group compared with the control group . In addition , the mean volume of banked packed RBCs transfused per patient was significantly less in the autotransfusion group compared with the control group . Platelet utilization also was markedly decreased in the autotransfusion group . Cryoprecipitate and fresh frozen plasma utilization also was less in the autotransfusion group than in the control group , but this did not reach statistical significance . We conclude that the intraoperative use of autotransfusion decreases the volume of homologous blood products transfused , which results in reduced exposure of the patients to banked blood products The purpose of our study was to determine the effectiveness of a postoperative autologous blood reinfusion system as an alternative to homologous , banked blood transfusions in total knee arthroplasty . We carried out a prospect i ve r and omised controlled study on 60 patients having unilateral total knee replacements . In all these patients , the same surgical team applied the same surgical technique , and all patients followed the same rehabilitation program . In 30 of these patients ( group A ) , a reinfusion system of unwashed salvaged blood was applied , and they were supplemented postoperatively with banked blood transfusions when required . A control group of 30 patients ( group B ) , in whom st and ard suction drains were used , received one unit of homologous banked blood transfusion intraoperatively and additional blood transfusions postoperatively when required . The administration of banked blood transfusion was determined by the haemoglobin value ( < 9 mg/dl ) and /or clinical signs ( blood pressure , pulse , etc . ) . The values of haemoglobin , haematocrit and platelets were recorded preoperatively and the first , fifth and 15th postoperative days , respectively . Five patients of group A required nine units of homologous blood ( 0.3 units/patient ) postoperatively . Ten patients of group B required an additional 15 banked blood units postoperatively ( in total 45 banked blood units for group B ; 1.5 units/patient ) . In the study group , the total homologous blood requirements were reduced by 80 % , while the postoperative blood requirements were reduced by 50 % . There was no significant difference in the postoperative haematocrit and haemoglobin values between the two groups . The cost of the blood management in the study group was reduced by 36 % . The use of an autologous blood reinfusion system reduces highly effectively the dem and s of homologous banked blood transfusion in total knee arthroplasty . RésuméLe but de cette étude était de déterminer l’efficacité d’un système de réinjection post-opératoire de sang autologue comme alternative à la transfusion homologue dans l’arthroplastie totale de genou . Nous avons fait une étude prospect i ve r and omisée sur 60 patients opérés d’une prothèse totale du genou unilatérale . Chez 30 patients ( groupe A ) un système de réinjection sans lavage du sang préservé était utilisé avec supplémentation post-opératoire par du sang de banque si nécessaire . Un groupe de contrôle de 30 patients ( groupe B ) , chez qui un drainage aspiratif classique était utilisé , recevait une unité de sang homologue pendant l’intervention et des transfusions post-opératoires si nécessaire . L’indication de transfusion homologue était posé sur un taux d’hémoglobine < 9mg/dL et/ou des signes cliniques . Les valeurs de l’hémoglobine , de l’hématocrite et des plaquettes étaient relevées avant l’intervention et les premier , cinquième et quinzième jours post-opératoires . 5 patients du groupe A eurent besoin après l’opération de 9 unités de sang homologue ( 0,3 unité par patient ) . 10 patients du groupe B eurent besoin de 15 unités supplémentaires de sang homologue après l’opération ( au total 45 unités de sang homologue pour le groupe B ; 1,5 unités par patient ) . Dans le groupe étudié la nécessité globale de sang homologue était réduite de 80 % et la nécessité de transfusion post-opératoire de 50 % . Le coût de la gestion du sang était réduite de 36 % dans le groupe étudié . l’utilisation d’un système de réinjection du sang autologue réduit significativement la nécessité de transfusion homologue dans l’arthroplastie totale du genou Autotransfusion has been included in the routine protocol in some units as an effort towards blood conservation . In this study we aim ed to measure the efficacy and limitations of autotransfusion and whether a heparin-bonded circuit had any advantage . One hundred five patients were r and omised to one of three post-operative treatments . Group 1 ( n = 34 ) was not autotransfused whereas groups 2 ( n = 36 ) and 3 ( n = 35 ) received autotransfusion with the circuit of group 3 coated with heparin . Homologous blood and blood products were given according to strict protocol s identical for all groups . Transfused and circulating blood was analysed for haemostatic variables and the requirement for homologous blood was recorded . Autotransfused blood contained no intact platelets and very high levels of D-Dimers ( a peptide fragment released when fibrin is lysed ) which result ed in high levels of systemic D-Dimers in patients receiving autotransfusion . Flow cytometric analysis revealed that whilst platelet glycoprotein 1 b receptors were severely reduced immediately following surgery , there was no additional damage caused by autotransfusion . Furthermore , there was no difference in platelet aggregation , von Willebr and factor ( vWF ) multimetric analysis or clotting profiles between the groups . Median ( interquartile range ) blood loss was 898 ml ( 638 - 1195 ) in group 1 , 853 ml ( 595 - 1348 ) in group 2 and 770 ml ( 615 - 1000 ) in group 3 ( Kruskal-Wallis P = 0.46 ) . Median transfusion requirements were 2 units in each group . Whilst auto-transfusion does not appear to compromise haemostasis , it does not reduce the requirement for homologous blood and heparin-bonding of the circuit has no impact OBJECTIVES Due to the discovery in the 1980s that blood transfusion can transmit HIV , there has been increased interest in technologies that reduce the amount of allogeneic blood used during and after surgery . These technologies include drugs ( aprotinin , tranexamic acid , epsilon-aminocaproic acid , erythropoietin ) , devices ( cell salvage ) , and techniques ( acute hemodilution , predeposited autologous donation ) . The purpose of this study was to ascertain the degree of practice variation , if any , that exists for eight technologies in nine countries in orthopedic and cardiac surgery . METHODS In each country , either all hospitals or a r and om sample of hospitals with medical/surgical beds were surveyed between 1995 and 1997 . Two instruments were used . The first instrument was a postcard that asked recipients whether the technologies were currently being used in their hospital for orthopedic and /or cardiac surgery to reduce perioperative allogeneic transfusion . The second question naire elicited information regarding the degree of use both in qualitative and quantitative terms . Data were collected , entered , and analyzed in each country , with summary results su bmi tted to the Canadian coordinating center on a st and ardized data collection form . RESULTS Pharmaceuticals were generally used in a much smaller proportion of hospitals in orthopedic than in cardiac surgery . Aprotinin and tranexamic acid were the drugs most frequently used in cardiac surgery . Nonpharmacological technologies were used to a greater degree than drugs in orthopedic surgery , although there was wide variation among technologies and countries . Acute hemodilution and cell salvage were used in a greater proportion of hospitals for cardiac surgery than orthopedic surgery . CONCLUSIONS The results of this survey indicate that there is considerable practice variation in the use of technologies to minimize exposure to perioperative allogeneic transfusion within and between countries Background : Autotransfusion of shed mediastinal blood after coronary artery bypass grafting ( CABG ) has been shown to reduce the requirement for allogeneic blood . We have previously demonstrated in non‐r and omized studies that the oxygen capacity of shed mediastinal blood is similar to the patient 's circulating blood and better than stored allogeneic blood . Therefore , we wanted to examine the influence of autotransfusion of shed mediastinal blood on oxygen transport capacity in patients undergoing CABG BACKGROUND Studies were conducted to measure the state of the United States ' national blood re source in 1992 and changes therein from 1989 . STUDY DESIGN AND METHODS With data supplied by the American Red Cross and the American Association of Blood Banks , as well as data from a stratified r and om- sample survey of 3350 non-American Association of Blood Banks hospitals , statistical methods were applied to estimate national blood activities in 1992 . RESULTS The total US blood supply in 1992 was 13,794,000 units , a decrease of 3.1 percent from 1989 . Some 11,307,000 red cell units were transfused to 3,772,000 patients , an average of 3.0 units per transfused patient . Preoperative autologous blood deposits totaled 1,117,000 units , a 70-percent increase over 1989 . Of this number , 566,000 units ( 50.7 % ) were transfused , 5,000 ( 4.4 % ) transferred to the allogeneic supply , and 546,000 ( 48.9 % ) discarded . Of 436,000 directed-donation units , 136,000 ( 31.2 % ) were transfused , 57,000 ( 13.1 % ) transferred to allogeneic supply , and 243,000 ( 55.7 % ) discarded . The total allogeneic blood supply , including imports , decreased by 7.4 percent from 1989 , and allogeneic blood transfusions , including those to children , decreased by 8.6 percent . Over 8,300,000 platelet units were transfused ; of these , some 3,600,000 were apheresis platelets . In addition , 2,255,000 units of plasma and 939,000 units of cryoprecipitate were transfused . CONCLUSION While the US blood supply was adequate for transfusion needs in 1992 , blood collection s and red cell transfusions had decreased substantially since 1989 BACKGROUND To determine whether a restrictive strategy of red-cell transfusion and a liberal strategy produced equivalent results in critically ill patients , we compared the rates of death from all causes at 30 days and the severity of organ dysfunction . METHODS We enrolled 838 critically ill patients with euvolemia after initial treatment who had hemoglobin concentrations of less than 9.0 g per deciliter within 72 hours after admission to the intensive care unit and r and omly assigned 418 patients to a restrictive strategy of transfusion , in which red cells were transfused if the hemoglobin concentration dropped below 7.0 g per deciliter and hemoglobin concentrations were maintained at 7.0 to 9.0 g per deciliter , and 420 patients to a liberal strategy , in which transfusions were given when the hemoglobin concentration fell below 10.0 g per deciliter and hemoglobin concentrations were maintained at 10.0 to 12.0 g per deciliter . RESULTS Overall , 30-day mortality was similar in the two groups ( 18.7 percent vs. 23.3 percent , P= 0.11 ) . However , the rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill -- those with an Acute Physiology and Chronic Health Evaluation II score of < or = 20 ( 8.7 percent in the restrictive- strategy group and 16.1 percent in the liberal- strategy group ; P=0.03 ) -- and among patients who were less than 55 years of age ( 5.7 percent and 13.0 percent , respectively ; P=0.02 ) , but not among patients with clinical ly significant cardiac disease ( 20.5 percent and 22.9 percent , respectively ; P=0.69 ) . The mortality rate during hospitalization was significantly lower in the restrictive- strategy group ( 22.3 percent vs. 28.1 percent , P=0.05 ) . CONCLUSIONS A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients , with the possible exception of patients with acute myocardial infa rct ion and unstable angina Functional coagulation analyses like Sonoclot and thromboelastography have not been evaluated during perioperative autotransfusion . We have prospect ively studied three different transfusion regimes in 45 patients undergoing total hip arthroplasty . Blood losses were replaced either with heterologous erythrocyte concentrate ( group I ) , intra‐ and postoperative autotransfusion of blood salvaged with cellsaver technique ( group II ) or predonated autologous erythrocyte concentrates together with salvaged blood ( group III ) . Routine and functional coagulation analyses with a Sonoclot were performed preoperatively , 6 hours postoperatively ( 6 h ) , day 1–5 and 10 . An early postoperative hypo‐ and late postoperadve hypercoagulative phase could be detected with Sonoclot signs of platelet function and fibrin deposition in all groups . Sonoclot coagulation analyses better correlated to both blood loss and dextran dosage than APTT and platelet count in the routine coagulation analyses . Functional coagulation analysis has a potential use in individualizing plasmasubstitution and thromboprophylaxis regimes during autotransfusion in THR The quality of blood salvaged at operation and prepared with the Dideco Autotrans BT 795 autotransfusion device was compared with that of donor blood in 41 patients having cardiac surgery involving cardiopulmonary bypass . Saved blood had a higher haemoglobin concentration ( 17.3 v. 13.1 g dl-1 ; P less than 0.001 ) , a higher 2,3-diphosphoglycerate concentration ( 5.3 v. 1.1 mmol litre-1 ; P less than 0.00001 ) , higher white cell count ( 17.1 X 10(9 ) litre-1 v. 4.1 ; P less than 0.00001 ) , higher pH ( 7.5 v. 6.6 ; P less than 0.00001 ) and a more physiological potassium concentration ( 5.4 v. 8.8 mmol litre-1 ; P less than 0.00001 ) than donor blood . Saved blood platelet count was 34.5 X 10(9 ) litre-1 compared with 146.24 X 10(9 ) litre-1 ( P less than 0.00001 ) and its heparin concentration was 0.64 u. ml-1 . We conclude that this autotransfusor is a useful aid to blood conservation , producing good quality red cells with relatively normal pH and potassium values . However , modification of the centrifugation and washing is required to lessen the high white cell count and heparin concentrations found in the saved blood BACKGROUND Postoperative infusion of shed mediastinal blood has been used in an effort to decrease blood usage after cardiac operations . Recent experience has suggested that this practice may actually lead to a delayed increase in bleeding . METHODS In a prospect i ve , r and omized study , 40 patients undergoing coronary artery bypass grafting with shed mediastinal blood collected in a cardiotomy reservoir were divided into two equal groups and studied during their first 4 hours in the intensive care unit . Shed mediastinal blood was directly infused in group I ( n = 20 ) , whereas in group II ( n = 20 ) , it was not . In group II , if a sufficient volume of red cells was present to allow processing ( n = 5 ) , washed red cells were infused . Variables studied before and after infusion were the amount of blood lost and infused , homologous blood transfused , complete blood count and differential , serum fibrinogen , fibrin split products , D-dimers , clotting factors , prothrombin time , activated partial thromboplastin time , thromboelastograms , plasma-free hemoglobin , complement factors C3 and C4 , creatine kinase and its MB isoenzyme , and body temperature . RESULTS After infusion of shed mediastinal blood , elevated levels of fibrin split products and D-dimers were found in significantly more patients in group I. The thromboelastogram index was normal in 76 % of patients in group II but in only 12.5 % in group I. Group I also had an increase in b and neutrophils , a greater number of febrile patients , higher serum levels of creatine kinase , its MB isoenzyme , and plasma-free hemoglobin , and greater blood loss during hours 3 , 4 , and 5 in the intensive care unit . The volume of red cells in shed mediastinal blood ( hematocrit , 9 % to 10 % ) was small , result ing in clinical ly insignificant autotransfusion when infused directly , and insufficient for cell processing in most patients . CONCLUSIONS These data support those in previous studies that direct infusion of shed mediastinal blood does not save substantial amounts of autologous red cells and can cause a delayed coagulopathy and other adverse effects that may be harmful to patients postoperatively BACKGROUND Several authors study ing autotransfusion of shed mediastinal blood in patients undergoing heart operations have published conflicting results regarding reduction of the need for homologous blood transfusion . The effect on coagulation parameters is also unclear . METHODS In a prospect i ve r and omized study , 198 patients who underwent coronary artery bypass grafting or a valvular operation were divided into 2 groups : a group with autotransfusion of shed mediastinal blood after an operation and a control group . Continuous reinfusion of mediastinal blood was done until no drainage was present or for a period of 12 hours after the operation . The amount of blood lost and autotransfused , the number of homologous blood products transfused , and the coagulation parameters were monitored . RESULTS The number of patients requiring homologous blood transfusion was significantly different between the 2 groups ( 54/98 [ 55 % ] in autotransfused patients vs 73/100 [ 73 % ] in the control group , P = .01 ) . The number of re-explorations for excessive bleeding was similar in the 2 groups ( 7/98 [ 7.1 % ] vs 8/100 [ 8 % ] ) , but the amount of blood collected postoperatively was higher in the autotransfused patients compared with control patients ( 1200 + /- 201 mL vs 758 + /- 152 mL , P = .0007 ) . Coagulation parameters analyzed and complication rates were similar in the 2 groups after the operations . CONCLUSION Autotransfusion of shed mediastinal blood reduces the need for homologous blood transfusion in patients undergoing various cardiac operations . The cause of increased shed blood in patients undergoing autotransfusion remains unclear UNLABELLED The coagulation-fibrinolytic profile during cardiopulmonary bypass ( CPB ) has been widely documented . However , less information is available on the possible persistence of these alterations when autotransfusion is used in management of perioperative blood loss . This study was design ed to explore the influence of autotransfusion management on intravascular fibrin degradation and postoperative transfusions . Thirty patients , undergoing elective primary isolated coronary bypass grafting , were r and omly allocated either to a control group ( group A ; n=15 ) or an intervention group ( group B ; n=15 ) in which mediastinal and residual CPB blood was collected and processed by a continuous autotransfusion system before re-infusion . Intravascular fibrin degradation as indicated by D-dimer generation was measured at five specific intervals and corrected for hemodilution . In addition , chest tube drainage and need for homologous blood were monitored . D-dimer generation increased significantly during CPB in group A , from 312 to 633 vs. 291 to 356 ng/mL in group B ( p = .001 ) . The unprocessed residual blood ( group A ) revealed an unequivocal D-dimer elevation , 4131 + /- 1063 vs. 279 + /- 103 ng/mL for the processed residual in group B ( p < .001 ) . Consequently , in the first post-CPB period , the intravascular fibrin degradation was significantly elevated in group A compared with group B ( p = .001 ) . Twenty hours postoperatively , no significant difference in D-dimer levels was detected between both groups . However , a significant intra-group D-dimer elevation pre- vs. postoperative was noticed from 312 to 828 ng/mL in group A and from 291 to 588 ng/mL in group B ( p < .01 for both ) . Postoperative chest tube drainage was higher in the patients from group A , which also had the highest postoperative D-dimer levels . Patients in group A perceived a higher need for transfusions of red cells suspensions postoperatively . These data clearly indicate that autotransfusion management during and after CPB suppresses early postoperative fibrin degradation . KEYWORDS cardiopulmonary bypass , cardiotomy suction , coronary surgery , autotransfusion , fibrin degradation A prospect i ve study was undertaken to assess the efficacy and financial cost of the use of an autologous blood transfusion device in the reduction of allogeneic blood requirements of patients undergoing primary unilateral total knee arthroplasty . Forty-nine consecutive patients received either the CellTrans blood salvage device ( group A of 32 patients ) or the Redivac high vacuum drainage system ( group B of 17 patients ) . The preoperative and postoperative haemoglobin levels were recorded at 72 or 96 hours . Nine percent of group A patients received an allogeneic blood transfusion compared to 59 % in group B. There was an average saving of 1.1 unit of allogeneic blood per patient in group A ( p<0.001 ) . The total cost per patient was about Euro 111 less for the group A patients . Autologous re-infusion was found in this study to be an effective method of reducing allogeneic blood requirements and to afford significant cost savings in primary unilateral knee arthroplasty We performed a prospect i ve , r and omized study to determine the effect of postoperative collection and reinfusion of unwashed , filtered , salvaged blood on the transfusion requirements of 232 patients managed with a total hip replacement . Patients who were scheduled to have a primary or revision procedure were advised to predeposit two or four units of autologous blood , respectively , before the operation . In addition , intraoperative blood salvage was performed for all patients who had a revision procedure . The patients were r and omly assigned to one of two groups : the first group was managed with postoperative blood salvage with use of the Autovac Postoperative Orthopaedic Autotransfusion Canister and the second , with closed suction drainage with use of the Hemovac system . In the first group , blood was collected from wound drains for four hours postoperatively ; if at least 300 milliliters of blood was collected , the unwashed blood was reinfused through a microaggregate filter during a two-hour period . A maximum of 1000 milliliters of salvaged blood was reinfused ; any blood that had not been reinfused within six hours after the beginning of collection was discarded . No complications or episodes of hypotension , confusion , cardiac or pulmonary compromise , febrile reaction , or coagulopathy were observed during or after the reinfusion of the unwashed , filtered , salvaged blood . No reinfusions were interrupted or discontinued . We found that postoperative reinfusion of unwashed , filtered , salvaged blood was associated with a decreased prevalence of homologous transfusion after a total hip replacement among patients for whom preoperatively donated autologous blood was not available . ( ABSTRACT TRUNCATED AT 250 WORDS In a r and omised prospect i ve study the efficacy of autotransfusion was investigated in two groups of 25 patients , a study group in which autologous blood was collected from the mediastinal tubes and retransfused , and a second , control group , in which only stored blood was used . In the study group , a reduction of 50 % in the amount of stored blood required was observed . However , in two out of 25 patients the transfusion system could not be used due to clot formation in one of its components . From the total bloodloss per patient about 25 % became available for autotransfusion . No significant differences between the two groups were found for hemoglobine , hematocrite , white blood count , platelets and fibrinogen level . Coagulation studies of the drain blood indicate that an active process of mediastinal clotting , followed by fibrinolysis occurs during the losing and collecting . The blood available for retransfusion contained a considerable amount of small-sized debris . It is concluded that autotransfusion of drain blood is not to be recommended for routine use The efficacy of four different blood conservation techniques in decreasing the homologous blood requirement in cardiac operations was studied prospect ively in 100 patients undergoing myocardial revascularization . The patients were r and omly assigned to four groups of 25 each as follows : group I , retransfusion of oxygenator blood after termination of extracorporeal circulation ; group II , processing of oxygenator content by means of a cell separator ; group III , predonation of autologous blood and isovolumetric substitution of hydroxyethyl starch ( 10 ml/kg bodyweight ) after the induction of anesthesia in addition to the use of a cell separator ; and group IV , predonation and the use of a cell separator plus postoperative retransfusion of shed mediastinal blood . To form homologous groups , we accepted only male patients without impairment of left ventricular function for the study . In addition , patients with internal mammary artery grafts and a duration of extracorporeal circulation less than 45 minutes or more than 90 minutes were excluded . The bank blood requirement during hospitalization was 2132 + /- 824 ml in group I , 1371 + /- 928 ml in group II , 833 + /- 599 ml in group III , and 408 + /- 559 ml in group IV . The use of blood conservation techniques result ed in reductions of homologous blood requirements of 34 % , 60 % , and 80 % , respectively , in groups II to IV as compared with the requirement in group I. There were no complications related to autologous blood transfusion . We conclude that the use of blood conservation techniques can considerably reduce the homologous blood requirement in cardiac operations and therefore decrease transfusion-related risks A prospect i ve , r and omized , controlled study was performed to determine the haematological and biochemical changes and clinical safety of postoperative autotransfusion ( Solcotrans Orthopedic Plus ® system ) in patients undergoing spinal surgery . Fifty patients were studied and were r and omly allocated to Control ( n = 25 ) and Solcotrans ( n = 25 ) groups . Both groups had their postoperatively drained blood collected into the Solcotrans reservoir but only the Solcotrans group had this salvaged blood considered for reinfusion . After a 5–h postoperative collection period , analysis of the shed blood showed a haematocrit of 0.26± 0.11 , few platelets ( 80 ± 63 10g1‐1 ) , a fibronogen level of less than 0.1 gl‐1 and a high level of D‐dimers . The salvaged blood did not clot and aerobic and anaerobic culture produced no growth . The volume of blood collected was greater than 200 ml in 21 patients in the Solcotrans group who were autotransfused ( 384 ± 101 ml , range 200–600 ml ) , and in 16 patients in the Control group . Within 15 min following completion of reinfusion of the salvaged blood there was a significant , but moderate decrease in platelet count ( 181 ± 74 vs 223 ± 90 108 1‐1 , P < 0.001 ) and fibrinogen concentrations ( 2.1 ± 0.8 vs 2.3 ± 0.9 g 1‐1 , P < 0.02 ) , and an increase in circulating D – dimers ( P < 0.001 ) and plasma free haemoglobin concentrations ( 236 ± 155 vs 82 ± 79 mg l‐1 , P < 0.001 ) . Prothrombin time ( PT ) and activated partial thromboplastin time ( APTT ) did not increase , and potassium concentrations were not significantly affected . Because the haematocrit of shed blood was lower than that in the patients ' systemic blood , there was no significant increase in haematocrit following reinfusion . Cultures of systemic blood following reinfusion yielded no bacterial growth . No side – effects were observed . There were no significant differences in the haematological parameters ( haematocrit , platelet count , free haemoglobin , APTT , PT , fibrinogen , D – dimers ) between the two groups at the eighth ( 3 h after reinfusion ) and the 24th postoperative h. No predictive factor of the volume of blood collected during the postoperative period could be identified . Postoperative autotransfusion induced no clinical ly relevant haematological effects after spinal surgery . However , since important haematological modification were found in the shed blood , further studies are required to determine the maximum amount of shed blood that can be safely transfused during the postoperative period To study the quality and effect of blood produced by the cell saver compared with homologous blood in total hip arthroplasty , 40 patients were r and omly divided into two groups . One group received autologous blood using the cell saver , whereas the second group served as a control , and received homologous bank blood . Hematologic and coagulation parameters of the patients were assessed both preoperatively and postoperatively . Sample s from the autologous and the homologous blood were obtained before reinfusion , and were assessed as regards hematologic and biochemical parameters . The autologous blood satisfied all the intraoperative transfusion requirements of the autologous group and 75 percent of the total transfusion requirements . The operative and postoperative blood losses -- hence , the total blood loss -- were less in the autologous than in the control group . The autologous blood had a high hemoglobin , white blood cell , and plasma hemoglobin content and MCV compared with the homologous blood . Postoperatively , there were no differences as regards the hematologic parameters studied . There was no evidence of intravascular hemolysis in the autologous group . Postoperatively , in both groups , AT III , plasminogen , and protein C decreased . Other coagulation parameters were within normal limits in both groups . Intraoperative autotransfusion is safe and effective , and should be considered in hip arthroplasty to reduce the risks associated with homologous blood transfusion We prospect ively r and omised 104 consecutive patients undergoing primary cemented total knee arthroplasty into two groups of 52 patients each , with one group to receive a st and ard suction drain ( Redivac ) and the other , an autologous transfusion drain ( Bellovac ) . R and omisation was achieved using the software programme MINIM , which was set to r and omly allocate patients to either of the two groups based on their age , sex and body mass index ( BMI ) . All procedures were performed under pneumatic tourniquet . Drains were released in the recovery room 20 min after surgery and removed 24 h following surgery . Blood collected in the st and ard suction drain ( control group ) was discarded , while blood collected in the autologous transfusion drains ( study group ) was transfused unwashed back to the patient within 6 h of collection . Thirteen patients ( 25 % ) in the study group had two or more units of homologous blood transfused in addition to the blood collected postoperatively and re-transfused ( average : 438 ml ) . Twelve patients ( 23 % ) in the control group had two or more units of homologous blood transfused . No sepsis , transfusion reactions or coagulopathies were associated with the autologous blood transfused in the study group . The use of the autologous transfusion system ( Bellovac ) proved to be safe but failed to reduce the need for postoperative homologous blood transfusion following uncomplicated total knee arthroplasty . RésuméNous avons étudié , de façon prospect i ve r and omisée , 104 patients consécutifs ayant bénéficié d’une prothèse totale du genou cimentée . Chaque patient a reçu soit un drain aspiratif st and ard ( Redivac ) soit un drain permettant une retransfusion ( Bellovac ) . 52 patients ont été r and omisés dans chaque groupe à l’aide d’un programme software avec une excellente concomitance entre l’âge , le sexe et le BMI . Toutes les interventions ont été réalisées avec garrot . Les drains ont été mis en aspiration en salle de réveil , 20 minutes après la fin de l’acte chirurgical . Ces drains ont été ôtés 24 heures après la chirurgie . Le sang collecté dans le drain st and ard a été rejeté alors que le drain Bellovac a permis de récupérer le sang , le retransfuser sans lavage six heures après l’intervention . 39 patients ( 25 % ) dans le groupe st and ard ont eu deux , ou plus de deux , unités sanguines de transfusion en plus du sang récupéré dans le drain ( 438 ml en moyenne ) . 12 patients ( 23 % ) dans le groupe contrôle ont eu deux , ou plus de deux , transfusions . Il n’y a pas eu d’infection , de réaction sanguine après ré-infusion du sang du redon . L’utilisation d’un système de réutilisation du sang de type Bellovac n’entraîne pas de problèmes particuliers mais il ne permet pas de diminuer la nécessité de transfusions post-opératoires après une prothèse totale du genou st and ard sans complication BACKGROUND The indications for transfusion have never been evaluated in an adequately sized clinical trial . A pilot study was conducted to plan larger clinical trials . STUDY DESIGN AND METHODS Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were r and omly assigned to receive 1 ) symptomatic transfusion : that is , transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2 ) threshold transfusion : that is , patients receive 1 unit of packed RBCs at the time of r and om assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality , morbidity , functional status , and place of residence . RESULTS Among 84 eligible patients enrolled , mean ( + /- SD ) prer and omization hemoglobin was 9.1 ( + /- 0.6 ) g/ dL. The median number of units transfused in the threshold transfusion group was 2 ( interquartile range , = 1 - 2 ) , and that in the symptomatic transfusion group was 0 ( 6 ; interquartile range , = 0 - 2 ) ( p < 0.001 ) . Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group : for example , on Day 2 , 10.3 ( + /- 0.9 ) g per dL versus 9.3 ( + /- 1.2 ) g per dL , respectively ( p < 0.001 ) . At 60 days , death or inability to walk across the room without assistance occurred in 16 ( 39.0 % ) of the symptomatic transfusion group and 19 ( 45.2 % ) of the threshold transfusion group . Death occurred by 60 days in 5 ( 11.9 % ) of the symptomatic transfusion group and 2 ( 4.8 % ) in the threshold transfusion group ( relative risk = 2.5 ; 95 % CI , 0.5 - 12.2 ) . Other outcomes were similar for the two groups . CONCLUSIONS Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy . However , it is unknown whether these two clinical strategies have comparable mortality , morbidity , or functional status . A definitive trial is needed A controlled , r and omized , prospect i ve study was performed evaluating the need for perioperative blood salvage for primary total hip arthroplasty patients who had donated autologous blood before surgery . One hundred fifty-three patients able to donate at least 2 units of autologous blood were divided into four groups . In group 1 ( 35 patients ) , intraoperative and postoperative Cell-Saver ( Haemonetics , Braintree , MA ) was employed . In group 2 ( 40 patients ) , a postoperative Solcotrans ( Smith & Nephew Richards , Memphis , TN ) reinfusion protocol was followed . In group 3 ( 40 patients ) , a closed-suction Hemovac drain ( Zimmer , Warsaw , IN ) was placed . In group 4 , ( 38 patients ) , no drain was used . Decisions for transfusion were based on clinical and laboratory parameters and made in conjunction with medical consultation . All autologous blood was routinely reinfused . There was no statistically significant difference in transfusion requirements or wound complications among the four groups . Hemoglobin and hematocrit changes between groups also were not statistically significant , but a power test suggested insufficient patient numbers for absolute reliability of this observation . Only five patients ( 3.3 % ) in this study received homologous blood . Four of these patients were in the Solcotrans group and one was in the Cell-Saver group . Two reoperations were performed : one for hematoma ( Solcotrans group ) and one for a sewn-in drain . It is concluded that expensive perioperative blood salvage techniques are usually not needed in patients who have a primary total hip arthroplasty without cement and who have donated 2 units of blood before operation We prospect ively r and omized 415 total joint replacements for either a closed wound-drainage system or no postoperative drainage . Drainage was not used in 200 total joint replacements , of which 138 were total knee replacements and sixty-two , total hip replacements . Drainage was used in 215 total joint replacements , of which 137 were total knee replacements and seventy-eight , total hip replacements . All patients were evaluated for the presence of excessive postoperative drainage that necessitated cessation of the range-of-motion exercises , the amount of transfused blood ( homologous and autologous ) , and the preoperative and postoperative hemoglobin levels . The range of motion was assessed daily in the patients who had a total knee replacement . No statistical difference was found in the number of patients who had excessive postoperative drainage from a drained or non-drained wound . There was also no statistical difference with respect to the amount of transfused blood and the preoperative and postoperative hemoglobin levels . Furthermore , in the patients who had a total knee replacement , there were no statistical differences between drained and non-drained wounds with respect to the daily range of motion during the first seven days postoperatively . The mean amount of blood transfused was 157 milliliters in the total knee replacements with drains , 160 milliliters in the total knee replacements without drains , 188 milliliters in the total hip replacements with drains , and ninety-three milliliters in the total hip replacements without drains . ( ABSTRACT TRUNCATED AT 250 WORDS Despite the refinements in surgical technique , rates of homologous blood transfusion ( HBT ) in cardiac surgery remain high . The adverse effects of blood transfusion are well documented . Retransfusion of shed mediastinal blood reduces the requirement for HBTs during conventional coronary artery bypass grafting . However , some studies have found that autotransfusion leads to bleeding diathesis and paradoxical increase in blood transfusions . Through this prospect i ve r and omized trial , we have studied the safety and efficacy of this modality in patients undergoing off-pump coronary artery bypass grafting ( OPCAB ) . Fifty patients enrolled in the study and 49 fulfilled the study criteria . They were r and omly divided into group C ( cell saver ) and group N ( non-cell saver ) . Whereas the cell saver group received processed shed autologous blood and homologous blood if necessary , the non-saver group was transfused homologous blood only . The threshold for transfusion was haemoglobin of 9 g dL(-1 ) in both the groups . The cell saver group required significantly less number of HBTs ( 1.6 + /- 1.2 vs. 2.4 + /- 1.3 units ) . The incidence of re-exploration was zero in both the groups . The mean mediastinal drainage in both the groups was not significantly different ( 355 + /- 196 vs. 316 + /- 119.8 mL ) . The number of patients requiring any blood transfusion however was very high . All the patients in the non-saver group and 20 ( 83 % ) of the patients in the saver group received homologous blood . During OPCAB surgery , the use of cell saver reduced the requirement for HBT . Its use is not associated with any clinical ly significant bleeding diathesis OBJECTIVE To investigate the effectiveness of preoperative plateletpheresis combined with intraoperative autotransfusion on the blood coagulation of orthopaedic patients . METHODS Sixty patients ( ASA I-II ) undergoing selective orthopaedic surgery were r and omized into three groups ( n = 20 ) , that is , preoperative plateletpheresis combined with intraoperative autotransfusion for group I , intraoperative autotransfusion for group II , and group III without any managements of blood conservation . Coagulation parameters ( prothrombin time , partial thromboplastin time , fibrinogen ) , hemoglobin and hematocrit values , platelet counts and aggregability were evaluated before the anaesthesia , 10 minutes after plateletpheresis , 10 minutes before the infusion of platelet rich plasma or autologous blood , 10 minutes after infusion , 24 and 48 hours postoperation . Intra- and postoperation blood loss and homologous blood transfusion requirements were also recorded . RESULTS Among three groups , there were no differences in intraoperative blood loss , perioperative haemoglobin level ( Hb and Hct ) . As compared with group I , significant lower level of platelet counts and aggregability were observed in group II and III at the time of 24 and 48 hours after operation ( P < 0.05 ) , while postoperation blood loss and homologous blood-transfusion requirements increased at the same period ( P < 0.01 ) . CONCLUSIONS Preoperative plateletpheresis combined with intraoperative autotransfusion can ameliorate the blood coagulation in orthopaedic patients , and it is an effective way to decrease blood loss and homologous blood-transfusions requirements A prospect i ve r and omized study was undertaken to quantify the effect of reinfusion of postoperative shed blood drainage on the hemoglobin levels in patients undergoing elective primary total hip arthroplasty ( THA ) and total knee arthroplasty ( TKA ) . One hundred eleven patients were enrolled between December 1990 and August 1991 . There were 42 THAs and 69 TKAs . The study group consisted of 57 patients ( 35 TKAs and 22 THAs ) who received a CBC ConstaVac ( Stryker Surgical , Kalamazoo , MI ) reinfusion system . The control group consisted of 54 patients ( 34 TKAs and 20 THAs ) who received a ConstaVac collection unit . Postoperative drainage volumes were recorded for both groups . In addition , the volume of reinfused blood was recorded for the study group . Postoperative hemoglobins were recorded on postoperative days 1 , 3 , and 6 , the latter reflecting the discharge hemoglobin level . All patients were encouraged to predeposit two units of autologous blood for both THAs and TKAs . This study showed no statistically significant difference in the postoperative hemoglobin levels between the study and control groups at anytime . Additionally , there was no statistically significant difference between hemoglobin levels and drainage volumes in both the THA and TKA study groups , compared to their respective control groups . The results of this study suggest that reinfusion units are not necessary in THAs and TKAs as a matter of routine use The purpose of this study was to compare the costs and outcomes of the postoperative autoreinfusion device , the Constavac ™ , with the st and ard suction device , the Hemovac ™ , in which blood drainage is discarded , in patients undergoing total joint arthroplasty of the knee or hip . At the completion of the surgical procedure , a total of 91 subjects were r and omly assigned to one of the two device groups . The findings of this study , which included a limited homogeneous sample , do not support the use of the Constavac ™ device in patients undergoing total joint arthroplasty The efficacy of a postoperative blood salvage system was assessed in 239 consecutive patients undergoing total knee or total hip arthroplasty . Patients were r and omly allocated to either a control group using a st and ard drainage system or to the study group using the Solcotrans blood salvage canister . The median amount of homologous blood required after operation by the study group was reduced by 74 % from the amount required by the control group ( mean , 67 ml vs 256 ml , respectively ; P less than .0001 ) . Thirteen percent ( 13 % ) of the study group required postoperative homologous blood transfusions , as compared to 39 % of the control group ( P less than .0001 ) . Additionally , patients in the study group had higher hemoglobin levels beginning on the first postoperative day . This study indicates that a postoperative blood salvage system safely and effectively reduces the amount of homologous blood required and sustains higher hemoglobin levels after operation The aim of this study was to evaluate blood salvage provided by an intraoperative blood recovery system ( IBRS ) and a mediastinal drainage blood recovery system ( MBRS ) during and after cardiac surgery . Sixty-six patients undergoing aortocoronary bypass surgery were r and omly assigned to three groups of 22 patients each . In group I , patients received only homologous blood ( HB ) . Group II and group III patients received the blood content of the oxygenator after concentration by an IBRS at the end of the operation . In group III , patients also received their own mediastinal drainage blood , shed for 6 hours after operation , after concentration and washing in a MBRS . The patients were transfused with homologous blood if needed , in order to obtain a hematocrit of 28 % at the end of operation , 30 % the following day , and a hemoglobin level over 10 g/dL while on the cardiac surgery ward ( 8 to 10 days ) . The three groups were comparable with respect to age , body surface , preoperative and postoperative hematocrits , number of grafts , bypass duration , and postoperative mediastinal blood loss . The amount of HB that was transfused during the operation was significantly lower in groups II and III than in group I ( P less than 0.0001 ) . After the operation it was significantly lower in group II than in group I ( P less than 0.05 ) , and in group III versus group I. Thus , 13.6 % of patients in group II and 38 % of patients in group III did not require HB transfusion . No infection , renal dysfunction , or coagulation disorders were observed . It is concluded that the use of an IBRS allows a significant saving of HB . However , because it does not avoid all HB requirements , it should be associated with other techniques to avoid blood transfusion such as the MBRS or predonation The influence of two different methods of autologous transfusion , preoperative donor plasmapheresis ( Abbott Autotrans ) and postoperative autotransfusion ( intraoperative blood salvage , Dideco Autotrans ) , on the intravascular hemostatic system was investigated . Forty-two patients undergoing total hip surgery and preoperative donor plasmapheresis were prospect ively r and omized into three groups . For substitution of blood loss , patients in group 1 ( control group , n = 12 ) received in addition to cristalloids and colloids only homologous blood , group 2 ( n = 14 ) autologous blood , and group 3 ( n = 16 ) additionally intra- and postoperative autologous fresh frozen plasma ( FFP ) . The investigation included blood parameters ( hemoglobin , hematocrit , thrombocytes ) , clotting status ( prothrombin time , plasma thromboplastin time , thrombin time , fibrinogen , plasminogen , and antithrombin III ) , and immunological methods such as fibrinopeptide A ( FPA ) , thrombin-antithrombin III ( TAT ) , and protein C. No significant difference was found with respect to total amount of infusion , intraoperative blood loss , autologous transfusion , and blood parameters . Excellent quality of the autologous FFP was demonstrated by investigation of the specimens before administration . The autologous packed red cells showed high levels of TAT and FPA as an indicator of thrombin generation . Their administration caused a significant increase in TAT and FPA levels in groups 2 and 3 compared to group 1 . ( ABSTRACT TRUNCATED AT 250 WORDS We have carried out a r and omised , controlled trial on 70 patients having unilateral total knee replacement in which transfusion was either with homologous bank blood or by reinfusion of unwashed blood salvaged after operation . No complications or adverse effects were observed from reinfusion . The need for bank blood was reduced by 86 % in the reinfusion group but , more importantly , the number of infective episodes was significantly less when the use of bank blood was avoided . The mean length of stay in hospital was also reduced by more than two days We undertook a prospect i ve r and omised controlled trial to investigate the efficacy of autologous retransfusion drains in reducing the need for allogenic blood requirement after unilateral total knee replacement . We also monitored the incidence of post-operative complications . There were 86 patients in the control group , receiving st and ard care with a vacuum drain , and 92 who received an autologous drain and were retransfused postoperatively . Following serial haemoglobin measurements at 24 , 48 and 72 hours , we found no difference in the need for allogenic blood between the two groups ( control group 15.1 % , retransfusion group 13 % ( p = 0.439 ) ) . The incidence of post-operative complications , such as wound infection , deep-vein thrombosis and chest infection , was also comparable between the groups . There were no adverse reactions associated with the retransfusion of autologous blood . Based on this study , the cost-effectiveness and continued use of autologous drains in total knee replacement should be question ed This prospect i ve study was design ed to determine whether the autotransfusion of shed mediastinal blood ( ATS ) after open heart surgery is safe and effective . Forty-two patients undergoing cardiac operation were r and omized to receive either nonwashed shed mediastinal blood ( group 1 ; n = 22 ) or banked blood ( group 2 : n = 20 ) . No difference in mean age ( group 1 : 49 + /- 11 years ; group 2 : 45 + /- 12 years ) , coronary artery bypass grafting ( group 1 : n = 5 , 23 % ; group 2 : n = 6 , 30 % ) , valve replacement ( group 1 : n = 17 , 77 % , group 2 : n = 14 , 70 % ) , and mean preoperative hemoglobin level ( group 1 : 13.7 + /- 2.3 , group 2 : 14.4 + /- 1.6 ) was noted between non-ATS and ATS groups ( p = not significant ) . The mean hemoglobin levels after operation were similar in the two groups ( group 1 : 11.89 + /- 1.52 ; group 2 : 12.03 + /- 1.34 ) . No difference in the mean blood loss 4 , 6 and 24 hours after operation ( group 1 : 33 + /- 190 , 420 + /- 340 and 550 + /- 300 ; group 2 : 340 + /- 230 , 420 + /- 280 and 670 + /- 380 ) was observed between the two groups . The mean volume autotransfused in group I was 380 + /- 230 ml ( 200 approximately 1300 ml ) . In group I , the patients required bank blood 1080 + /- 720 , compared with 1780 + /- 1045 in group II . The bank blood requirement in group I reducted by 40 % . These data demonstrate that ATS after open heart surgery is safe and effective We carried out a prospect i ve , controlled trial of intra-operative autologous transfusion ( IOAT ) in cardiac surgery using the Haemonetics Cellsaver 4 , to determine the effects on transfusion requirements and early clinical outcome . Intra-operative autologous transfusion in unselected patients result ed in a reduction in the use of red cells in patients undergoing first-time operations ( IOAT median 3 units , controls median 4 units , P = 0.0023 ) , with no difference in the use of other blood products . Post-operative haemoglobin was higher in IOAT patients ( IOAT 11.6 g/dl + /- 1.1 versus controls 11.2 g/dl + /- 0.98 , P < 0.001 ) . There is therefore the potential for a further reduction in homologous blood use in the IOAT group . There was no difference in early clinical outcome in the two groups ; in particular the incidence of coagulopathies was not influenced by IOAT . The routine use of IOAT would add substantially to the cost of these operations . The decision to use it must therefore be based on an assessment of the value of the reduction in risk to the patient achieved by a small reduction in homologous donor exposures In order to evaluate the clinical and haematological implication s of salvage autotransfusion using the Haemolite device ( Haemonetics , Leeds , UK ) , 67 aortic reconstructions were studied . Bank blood transfused during the operation fell from a median of four units in the control group to zero using the cell saver ( P less than 0.0001 ) , and wound drainage decreased from 250 to 200 ml ( P = 0.12 ) . Evidence of fibrinolytic and platelet activation was found during salvage , but no bleeding diathesis was encountered . There was no morbidity or mortality related to the technique , and median hospital stay was reduced in autotransfused patients . The Haemolite is a safe effective device for autotransfusion in elective aortic surgery , and can substantially reduce exposure of both patients and staff to the dangers of homologous blood OBJECTIVES A substantial reduction in transfusion requirements for cardiac surgical procedures has been reported . Many of these reports have been described in patients undergoing coronary artery bypass grafting . Patients suffering from rheumatic heart disease in India are usually small and also anemic . This study was conducted to assess blood conservation methods for cardiac valve surgery in this subset of patients . DESIGN This was a prospect i ve , r and omized study . SETTING The study was performed in a New Delhi tertiary care hospital , and the patients were referred from the northern states of India . PARTICIPANTS One hundred fifty consecutive patients undergoing elective valve surgery using cardiopulmonary bypass were included . The mean age was 27.7 years and mean weight was 45.2 kg . INTERVENTIONS The patients were divided into three groups of 50 each . Group 1 received autologous fresh blood donated before bypass , and both a cell saver and membrane oxygenator were used . The oxygenator contents at the end of perfusion were processed by cell saver . Group 2 patients were reinfused with autologous blood only , and group 3 was a control group . In groups 2 and 3 , the blood that remained in the oxygenator at the conclusion of cardiopulmonary bypass was reinfused . A hematocrit of less than 25 % was considered an indication for transfusion in the postoperative period . MEASUREMENTS AND MAIN RESULTS The mean preoperative hematocrit was 35.5 % . A mean of 361.1 mL of autologous blood was collected from group 1 and 303.3 mL from group 2 . Group 1 required 15 units of bank blood , group 2 , 90 units ( p < 0.001 ) , and group 3 , 102 units ( p < 0.001 ) . Seventy-eight percent of group 1 patients did not receive any donor blood . There was no significant difference in chest tube drainage among the three groups . CONCLUSIONS In this unique group of patients whose mean body weight was only 45 kg , autologous blood alone did not decrease blood bank requirements but when combined with a cell saver and membrane oxygenator greatly reduced the need for donor blood BACKGROUND Allogeneic blood transfusions are associated with a number of well-recognized risks and complications . Postoperative retransfusion of filtered shed blood is an alternative to ( reduce ) allogeneic blood transfusion . The objectives of this study were to evaluate the clinical efficacy of retransfusion of filtered shed blood and to evaluate the complications , in particular febrile reactions . STUDY DESIGN AND METHODS In this clinical trial 160 patients undergoing primary total hip or knee replacement were r and omly assigned to receive either a retransfusion system ( Bellovac , AstraTech AB ) or a regular drain ( Abdovac , AstraTech AB ) . Patients with a preoperative hemoglobin ( Hb ) level of between 13.0 and 14.6 g per dL were included . The shed blood was returned 6 hours after operation . After surgery the anesthesiologist determined the transfusion trigger . When Hb level dropped below this trigger , an allogeneic blood transfusion was given . The following data were obtained : number of allogeneic blood transfusions , total volume of blood collected in the bag used for retransfusion , perioperative Hb levels , febrile reaction , and other complications . RESULTS In the control group 19 percent of the patients received at least one allogeneic blood transfusion . In the study group this percentage was 6 percent of the patients ( p = 0.015 ) . Comparing total knee and total hip arthroplasty ( control vs. study ) the percentages were , respectively , 16 percent versus 2 percent ( p = 0.040 ) and 21 percent versus 11 percent ( NS ) . On average 308 mL of filtered shed blood was retransfused in the study group . In the study group 18 percent of patients had febrile reactions compared to 20 percent in the control group . CONCLUSION Postoperative retransfusion of filtered shed blood is effective for decreasing allogeneic blood transfusions after total hip and knee arthroplasty . There was no relationship between retransfusions and postoperative febrile reactions Objectives . Off-pump coronary surgery reduces transfusions , however , many patients still receive blood . This trial aims to clarify the effect of using a cell saver intraoperatively . Design . In 60 patients shed blood was collected in the cell saver reservoir intraoperatively ; r and omization and processing or discharge were performed immediately after surgery . Primary outcome measures : proportion of patients receiving allogeneic blood , and average number of units per patient . Secondary outcome measures : blood loss , hemoglobin levels , complications , and costs . Results . Cell saver group versus control group ; received transfusions : 17/30 vs. 14/29 ( p = 0.28 ) , allogeneic units : median 1 ( interquartile range 0 – 2 ) vs. 2 ( IQR 0 – 7 ) ( p = 0.06 ) , intraoperative net blood loss : median 300 ml ( IQR 193 – 403 ) vs. 610 ml ( IQR 450 – 928 ) ( p < 0.001 ) . Control group patients had more complications leading to transfusion . Hemoglobin levels and costs were comparable between groups . Conclusions . Use of cell saver reduced intraoperative net blood loss and seemed to reduce transfusions by 1 unit per patient , however , this was probably attributable to more complications leading to transfusion in the control group . In the future larger trials are necessary To regain blood shed intraoperatively , two different systems are clinical ly established : washing and centrifuging red blood cells to produce autologous erythrocyte concentrates and devices for immediate reinfusion of whole blood after mere filtration . In a prospect ive-r and omised study to compare both methods regarding their efficiency , adverse effects , and economy , 20 patients of our department undergoing elective aortoiliac surgery received intraoperative autotransfusion by means of either cell-washing ( CS ) or salvage of whole blood ( WB ) . Patients were preoperatively r and omized into one of the two groups and were evaluated with respect to st and ard metabolic and haematological laboratory parameters preoperatively , during surgery , after transfer into the recovery room , 24 h after surgery , after transfer into the recovery room , 24 h after surgery , and at discharge . Both patient groups were well comparable in demographics , preoperative laboratory data , and indication for operation . H and ling was easier , the set-up time was shorter with the whole blood filtration device ( 10.2 + /- 2.3 versus 21 + /- 1.9 min , p = 0.0023 ) , and no additional personnel was needed to run the system . The whole blood device also allowed a greater percentage of aspirated blood to be returned intraoperatively compared to cell washing ( 73.5 % + /- 7.2 versus 51.1 % + /- 6.5 , p = 0.03 ) . Thrombocytopenia occurred in 7 ( CS ) and 3 ( WB ) patients intraoperatively with a significant difference in platelet count between the two groups ( 118 + /- 17 [ CS ] versus 170 + /- 12 [WB]*10(9)/L , p = 0.025 ) . Expected changes in the perioperative course of the clotting parameters such as highly increased PTT levels and moderately prolonged prothrombin times occurred in all cases . ( ABSTRACT TRUNCATED AT 250 WORDS Postoperative salvage autotransfusion of shed mediastinal blood , using the cardiotomy reservoir , is an inexpensive technique whose efficacy and safety are evaluated in this study . We r and omized 75 consecutive patients into two groups . The autotransfusion group ( n = 42 ) received autotransfusion after the completion of the coronary artery bypass grafting ( CABG ) until the drainage was < or = 50 mL per hour for 2 consecutive hours . The control group ( n = 33 ) was treated with st and ard chest drainage . Both groups received homologous blood transfusion when the hematocrit fell below 30 % . Packed red cells were required post-operatively in 84.8 % of the control group and 80.9 % of the autotransfusion group ( p = NS ) . Postoperative colloid fluid replacement ( excluding autotransfusion fluid ) did not differ significantly between the groups . The prothrombin time was significantly higher in the autotransfusion group 24 hours postoperatively ( p = 0.03 ) . The fibrin degradation products were elevated only in the serum of the autotransfusion patients ( p < 0.002 ) . More febrile patients were seen in the autotransfusion group although not significantly more than the controls . The autotransfusion group received more red cells than the control group , but it lost more red cells in the mediastinal drains . In conclusion , the autotransfusion of shed mediastinal blood has not proved beneficial in reducing the postoperative requirements in homologous blood in patients undergoing coronary artery bypass grafting ( CABG ) PURPOSE The purpose of this study was to attempt to identify a group of patients undergoing infrarenal aortic bypass in whom blood loss is consistently less than 2 units , making the routine use of autotransfusion devices unnecessary . METHODS Four groups of patients were prospect ively studied as follows : abdominal aortic aneurysm ( AAA ) repair with tube graft ( n = 21 ) , AAA repair with bifemoral or biiliac bypass ( n = 19 ) , and aortobifemoral bypass ( AFB ) or biiliac bypass for occlusive disease either with Cell Saver Autotransfusion Device ( Haemonetics Corp. , Braintree , Mass. ) ( n = 18 ) or without Cell Saver ( n = 18 ) . The latter two groups were r and omized on an alternating basis . RESULTS The following parameters were obtained on all patients : preoperative hemoglobin values , estimated blood loss , Cell Saver return volumes , intraoperative and postoperative homologous blood transfused , postoperative hemoglobin values on the day of surgery and on postoperative days 1 and 4 , complications , and length of hospital stay . In comparing the groups undergoing AFB with Cell Saver and AFB without Cell Saver by the above parameters , we found no statistically significant differences , except for a higher hemoglobin level on postoperative day 1 in the group undergoing AFB with Cell Saver ( mean 11.86 vs 10.74 , p = 0.02 ) . The estimated blood loss and Cell Saver return volumes were less for those patients undergoing AFB for occlusive disease compared with those undergoing AFB for aneurysmal disease . Interestingly , estimated blood loss and Cell Saver return volumes for patients with AAA with tube graft and patients undergoing AFB with Cell Saver were similar . CONCLUSIONS We conclude that routine setup and use of rapid autotransfusion devices may not be necessary in every patient undergoing routine aortofemoral bypass for occlusive disease . Furthermore , the possibility that some patients may undergo AAA repair with tube grafts without use of the Cell Saver may be deserving of further investigation Aprotinin decreases the hemoglobin content of shed blood significantly and thereby could potentially reduce the contribution of autotransfusion of shed blood to the blood-saving program . In part 1 , by means of a prospect i ve r and omized study , we evaluated the effect of autotransfusion ( AT ) of shed blood on the reduction and avoidance of donor blood requirements in 40 matched patients undergoing internal mammary artery bypass ( IMA ) surgery and treatment with low-dose aprotinin ( 2 million KIU ) . Twenty patients ( Group 1 ) received AT with a hard shell cardiotomy reservoir ; twenty patients ( Group 2 , control ) did not receive AT . In part 2 , we studied at r and om the hemoglobin and total-protein content of shed blood in 10 patients of group 2 and in 10 IMA patients not receiving aprotinin . Retransfused patients required 0.1 + /- 0.3 units of donor blood versus 0.8 + /- 0.2 units in non-retransfused patients ( not significant ) . The use of any blood product was avoided in 95 % and 80 % of the patients , respectively ( not significant ) . Patients receiving aprotinin lost 50 % less ( P < 0.05 ) hemoglobin ( 62 g ) and total-protein ( 28 g ) in their drainage system than patients not receiving aprotinin . It was calculated that autotransfusion of about 530 ml of shed blood in aprotinin-treated patients , is equivalent to 0.4 units of homologous packed cells . In conclusion , autotransfusion of shed blood may contribute to blood saving in IMA patients treated with aprotinin , which reduces the shed blood hemoglobin and total protein content by 50 % A prospect i ve , r and omized study was conducted in 24 patients using the Solcotrans Orthopaedic Drainage Reinfusion System ( Smith & Nephew Richards Inc , Memphis , Tenn ) for postoperative blood salvage in total joint arthroplasty . The amount of postoperative autologous blood salvage averaged 946 mL. Only 25 % of the study group required postoperative transfusions , compared to 83 % of the control group ( P = .016 ) . In total knee arthroplasties , only 11 % of the study group required transfusions , compared to 78 % of the control group ( P = .018 ) . There were no transfusion reactions , infectious complications , or coagulopathies . Postoperative blood salvage is a safe , reliable , and effective source of autologous blood In a prospect i ve , r and omized study of the efficacy and effects of autologous blood transfusion in revision hip arthroplasty , 30 patients were r and omly allocated into two groups . The Control Group received homologous blood transfusion . The Study Group deposited 2 - 3 units of blood preoperatively , intraoperative blood salvage was used , and no homologous blood was transfused intraoperatively . There was a smaller postoperative blood loss in the Study Group . The preoperative hemoglobin values were lower in the Study Group , but one week postoperatively they were higher than in the Control Group . The decrease in the values of AT III and protein C was lower in the Study Group . The combination of preoperative blood donation and intraoperative blood salvage reduced blood loss and homologous blood transfusion in revision hip arthroplasty In a prospect i ve , r and omized study of 20 patients undergoing elective open-heart surgery , up to c. one-third of the total intraoperative and postoperative transfusion requirement could be provided by autologous centrifuged blood . Retransfusion of washed , packed red blood cells freed from cellular debris , heparin and activated clotting factors significantly reduced blood loss during and after surgery . The cell separator is a valuable aid in autotransfusion technique We undertook a prospect i ve controlled clinical trial of 109 patients to determine whether postoperative blood salvage in patients undergoing total hip or knee arthroplasty decreased the need for transfusion with banked blood . The average amount of blood collected in our series was 493 ml , most of which was collected in the first four postoperative hours . In patients undergoing bilateral total knee arthroplasty , there was a 54 % reduction in banked blood utilisation . None of our patients developed adverse effects from the reinfused material . The cost of collecting and processing wound drainage using the Haemolite cell washer was $ 175 per patient , regardless of the volume processed , compared to $ 125 for a unit of banked blood . By reducing the requirement for homologous transfusion , blood salvage diminishes the risks of transmission of HIV and hepatitis viruses . In those cases where the equivalent of two units of blood are reinfused , blood salvage saves money . However , due to the small amounts of blood collected in unilateral hip or knee arthroplasty , we do not recommend its routine application in these cases 56 consecutive patients who had primary arthroplasties of the hip or the knee were r and omly selected for either autologous or homologous blood transfusion . For autologous transfusion , the Solcotrans Orthopaedic device was used . Patients who received autologous transfusion had 65 percent of the post-operatively drained blood reinfused ; compared to the control group the number of bank blood transfusions decreased in the hip group from 2.3 to 0.6 units , and in the knee group from 3.3 to 0.3 units Perioperative homologous blood transfusion ( HBT ) is associated with adverse reactions and risks transmission of infection . It has also been implicated as an immunosuppressive agent . Intraoperative autotransfusion ( IAT ) is a potential method of autologous transfusion BACKGROUND Cardiotomy suction and autotransfusion of mediastinal shed blood may contribute to the inflammatory response after cardiac surgery . We compared inflammatory activation , myocardial injury , bleeding , and hemoglobin levels in patients undergoing coronary surgery with or without retransfusion of cardiotomy suction blood and mediastinal shed blood . METHODS Twenty-nine patients were included in a prospect i ve r and omized study . Cardiotomy suction blood and mediastinal shed blood were either retransfused or discarded . Plasma concentrations of the cytokines tumor necrosis factor-alpha and interleukin-6 and complement factor C3a were measured preoperatively and 10 minutes , 2 hours , and 24 hours after cardiopulmonary bypass . C-reactive protein , erythrocyte sedimentation rate , troponin-T , and hemoglobin levels were analyzed preoperatively , and 24 and 48 hours after cardiopulmonary bypass . Postoperative bleeding the first 12 hours was registered . RESULTS Baseline data did not differ between the groups . Plasma concentrations of tumor necrosis factor-alpha , interleukin-6 , and C3a increased after surgery in both groups but significantly less in the group without cardiotomy suction and autotransfusion . The peak delta values in the no-retransfusion group was 36 % ( tumor necrosis factor-alpha ) , 47 % ( interleukin-6 ) , and 75 % ( C3a ) of the values in the retransfusion group . C-reactive protein , erythrocyte sedimentation rate , and troponin-T increased after surgery in both groups without intergroup differences . Postoperative bleeding and hemoglobin levels did not differ between the groups . No patient received homologous blood transfusion . CONCLUSIONS Coronary surgery without retransfusion of cardiotomy suction blood and mediastinal shed blood reduces the postoperative systemic inflammatory response We conducted a prospect i ve , r and omized study to assess the impact of cell salvage , auto transfusion on the requirements for allogeneic blood for patients undergoing a total knee replacement ( TKR ) . One hundred consecutive TKR patients were r and omly allocated to receive either autologous blood ( using cell salvage ) or an allogeneic blood transfusion as necessary . Patients allocated to the autologous group were rescued with allogeneic blood if the postoperative haemoglobin fell below 9 g dL-1 . Forty-two ( 84 % ) of 50 patients in the autologous group required no supplementary blood transfusion . Forty ( 80 % ) of 50 patients allocated to receive allogeneic blood required transfusion . There were no detrimental effects of autologous blood transfusion . We conclude that autologous blood transfusion , using the cell saver system , is a safe and effective method of reducing the need for allogeneic blood transfusion and , in doing so , reduces the risk of transmission of infections associated with allogeneic blood transfusion , whilst decreasing dem and on precious allogeneic blood reserves Two groups of 21 otherwise healthy patients undergoing coronary artery bypass grafting ( CABG ) for the first time were studied in order to evaluate the advantages and disadvantages of post-operative autotransfusion using a red cell ' salvage ' method . Group 1 patients ( control group ) were transfused using donor blood only . Group 2 patients were transfused with their own ( autologous ) blood , salvaged post-operatively , although donor blood was also available to them if needed . The two groups were further subdivided according to whether the patients received aspirin pre-operatively or not . The four subgroups thus formed were comparable pre- as well as intra-operatively , with respect to all available clinical and laboratory criteria . The post-operative data , however , showed that the combination of pre-operative aspirin and autotransfusion leads to excessive post-operative bleeding , together with increased donor blood requirement . It was also shown that autotransfusion without aspirin does reduce the need for donor blood transfusion without any increase in post-operative bleeding . Although aspirin alone did not increase post-operative bleeding or donor blood requirement , its combination with autotransfusion should be avoided

Lay-led self-management education programmes may lead to small , short-term improvements in participants ' self-efficacy , self-rated health , cognitive symptom management , and frequency of aerobic exercise . There is currently no evidence to suggest that such programmes improve psychological health , symptoms or health-related quality of life , or that they significantly alter healthcare use .

BACKGROUND Lay-led self-management programmes are becoming widespread in the attempt to promote self-care for people with chronic conditions . OBJECTIVES To assess systematic ally the effectiveness of lay-led self-management programmes for people with chronic conditions .

Abstract Objective This study evaluated the 6-week Chronic Disease Self-Management Program ( CDSMP ) in Hong Kong . Methods A total of 148 subjects with chronic illness were recruited . Subjects were matched on duration of illness and gender , and then r and omly allocated to experimental and comparison groups . The experimental group participated in the CDSMP , while the comparison group joined a Tai-Chi interest class in a mass-activity format . Subjects completed evaluation question naires before beginning their program and 1 week following the program . Results Analysis of covariance showed that the CDSMP participants demonstrated significantly higher self-efficacy in managing their illness , used more cognitive methods to manage pain and symptoms , and felt more energetic than the subjects in the comparison group . The CDSMP participants also demonstrated changes in their profile of coping strategies , having a tendency to adopt the cognitive methods of diverting attention , reinterpreting pain , ignoring sensations , and making positive self-statements . Conclusion The short-term evaluation results showed that the CDSMP primarily increased the self-efficacy , exercise behavior , and application of cognitive coping strategies of the participants . Practice Implication The effect of the CDSMP in a Chinese population is similar to that found in studies in Western cultures , and the CDSMP could be applied effectively in a Chinese population OBJECTIVES We sought to determine the effects of a community-based , culturally tailored diabetes lifestyle intervention on risk factors for diabetes complications among African Americans and Latinos with type 2 diabetes . METHODS One hundred fifty-one African American and Latino adults with diabetes were recruited from 3 health care systems in Detroit , Michigan , to participate in the Racial and Ethnic Approaches to Community Health ( REACH ) Detroit Partnership diabetes lifestyle intervention . The curriculum , delivered by trained community residents , was aim ed at improving dietary , physical activity , and diabetes self-care behaviors . Baseline and postintervention levels of diabetes-specific quality -of-life , diet , physical activity , self-care knowledge and behaviors , and hemoglobin A1C were assessed . RESULTS There were statistically significant improvements in postintervention dietary knowledge and behaviors and physical activity knowledge . A statistically significant improvement in A1C level was achieved among REACH Detroit program participants ( P<.0001 ) compared with a group of patients with diabetes in the same health care system in which no significant changes were observed ( P=.160 ) . CONCLUSIONS A culturally tailored diabetes lifestyle intervention delivered by trained community residents produced significant improvement in dietary and diabetes self-care related knowledge and behaviors as well as important metabolic improvements Abstract Objective To develop and refine a complex intervention for diabetes support and education in minority ethnic groups , delivered through bilingual health advocates . Design Action research framework — a variety of methods used in an emergent and developmental manner , in partnership with clinicians , managers , and service users , drawing especially but not exclusively on narrative methods . Setting Deprived inner London district . Interventions Development and evaluation of three components of the complex intervention : a group based learning set for bilingual health advocates , in which stories about clients with diabetes formed the basis for action learning ; advocate led support and education groups for people with diabetes , which used personal stories as the raw material for learning and action ; organisational support to help to develop these new models and embed them within existing services . Results Both advocate groups and user groups were popular and well evaluated . Through storytelling , advocates identified and met their own educational needs in relation to diabetes and the unmet needs of service users . In the advocate led user groups , story fragments were exchanged in a seemingly chaotic way that the research team initially found difficult to facilitate or follow . Stories were not so much told as enacted and were often centred on discussion of “ what to do . ” Whereas some organisations welcomed , successfully implemented , and sustained the advocate led groups , others failed to do so . A key component of the complex intervention was organisational support . Conclusions An action research approach allowed engagement with an underserved group of health service staff and with hard to reach service users . The study produced subjective benefits to these groups locally as well as a worked-up complex intervention that will now be formally tested in a r and omised controlled trial OBJECTIVES To assess whether group exercise and coping classes reduce physical and psychological impairments and functional disability in older women with prevalent vertebral fractures ( VFs ) . DESIGN R and omized , controlled trial ( modified cross-over ) with site as unit of assignment ; testing at baseline and 3 , 6 , 9 , and 12 months . SETTING Nine North Carolina retirement communities . PARTICIPANTS One hundred eighty-five postmenopausal Caucasian women ( mean age 81 ) , each with at least one VFs . INTERVENTION The intervention group had 6 months of exercise ( 3 meetings weekly , 45 minutes each ) and coping classes ( 2 meetings weekly , 45 minutes each ) in Phase 1 , followed by 6 months of self-maintenance . The control group had 6 months of health education control intervention ( 1 meeting weekly , 45 minutes ) in Phase 1 , followed by the intervention described above . MEASUREMENTS Change in trunk extension strength , change in pain with activities , and change in psychological symptoms . RESULTS Between-group differences in the change in trunk extension strength ( 10.68 foot pounds , P<.001 ) and psychological symptoms ( -0.08 , P=.011 ) were significant for Phase 1 . Changes in pain with activities did not differ between groups ( -0.03 , P=.64 ) ; there was no change in the pain endpoint . In Phase 2 , controls showed significant changes in trunk strength ( 15.02 foot pounds , P<.001 ) and psychological symptoms ( -0.11 , P=.006 ) from baseline . Change in pain with activities was not significant ( -0.03 , P=.70 ) . During self-maintenance , the intervention group did not worsen in psychological symptoms , but improved trunk extension strength was not maintained . CONCLUSION Weak trunk extension strength and psychological symptoms associated with VFs can be improved in older women using group treatment , and psychological improvements are retained for at least 6 months PURPOSE The Women to Women Diabetes Project tested the use of telecommunication technology to deliver diabetes education and social support to rural women with diabetes . The aims were to ( 1 ) test the effects of the computer intervention in providing support , information , and education on selected outcomes , and ( 2 ) evaluate the women 's attitudes toward and satisfaction with the intervention and the support provided . METHODS Thirty women were r and omized into computer and noncomputer groups and participated for 10 months . For 5 months , one group participated in a self-help support and educational group via the computer ; the other group continued to use their usual modes of support and communication . Psychosocial well-being scales were administered and attitudes were surveyed . RESULTS Improving health and higher educational levels positively influenced measures of social support and quality of life . Women who were married or who reported greater support had higher scores on the Personal Re source Question naire . The women expressed positive effects of the computer-based support group on their lives . CONCLUSIONS The intervention was enthusiastically accepted , and could be conducted effectively in isolated rural areas A 10-session , self-management training program was design ed specifically for persons over 60 years of age having Type II diabetes . It targeted social learning variables , especially problem-solving skills and self-efficacy , found to be related to diabetes self-care in earlier correlational research . One hundred two adults were r and omized to immediate or delayed intervention conditions . At posttest , subjects in the immediate intervention condition showed significantly greater reductions in caloric intake and percent of calories from fat than control subjects . The intervention also produced greater weight reductions and increases in the frequency of glucose testing than did the control condition . Improvements among immediate intervention subjects were generally maintained at a 6-month follow-up . Intervention results from subjects receiving delayed intervention closely replicated those for immediate intervention subjects . We conclude that a relatively short-term program can improve self-management skills of older diabetic adults , and that there is an important need for such interventions OBJECTIVE Studies have suggested that the Arthritis Self-Management Program ( ASMP ) course is effective at reducing arthritis pain and health care costs in volunteer participants . There have been no reports of trials of the ASMP in the context of primary care physicians ' practice s , where the potential for spreading the program may be greatest . We conducted a r and omized controlled trial of the ASMP course in a large primary care physician network . METHODS Patients with osteoarthritis , rheumatoid arthritis , or fibromyalgia were recruited for the study . Subjects in the intervention practice s received the 6 week course and those in the control practice s received only the ASMP book , without course . Disability , pain , self-efficacy , mental health , and satisfaction were measured using vali date d instruments at baseline and at 4 months . RESULTS One hundred thirteen patients were recruited for the ASMP course ( intervention ) and completed baseline and 4 month followup question naires . Eighty-four percent completed at least 4 of 6 classes . Seventy-four patients received the ASMP manual ( controls ) and completed both question naires . Patients in the intervention and control groups had similar baseline pain ( p = 0.94 ) , self-efficacy to control pain ( p = 0.90 ) , mental health ( p = 0.10 ) , and vitality scores ( p = 0.21 ) , but those in the intervention arm had slightly less disability ( p = 0.04 ) . At 4 months , there was no significant improvement from baseline in any endpoint and no difference between patients in the intervention and control groups ( all p > 0.2 ) . Patient satisfaction with arthritis care and outcomes was no different for intervention and control patients ( all p > 0.3 ) . All types of health care re source use were similar at baseline and followup for both intervention and control groups ( all p > 0.2 ) . CONCLUSION While the ASMP course has been found to be effective in other patient groups , there were no significant clinical benefits noted at 4 months in patients recruited from primary care practice OBJECTIVES This study evaluated the effectiveness ( changes in health behaviors , health status , and health service utilization ) of a self-management program for chronic disease design ed for use with a heterogeneous group of chronic disease patients . It also explored the differential effectiveness of the intervention for subjects with specific diseases and comorbidities . METHODS The study was a six-month r and omized , controlled trial at community-based sites comparing treatment subjects with wait-list control subjects . Participants were 952 patients 40 years of age or older with a physician-confirmed diagnosis of heart disease , lung disease , stroke , or arthritis . Health behaviors , health status , and health service utilization , as determined by mailed , self-administered question naires , were measured . RESULTS Treatment subjects , when compared with control subjects , demonstrated improvements at 6 months in weekly minutes of exercise , frequency of cognitive symptom management , communication with physicians , self-reported health , health distress , fatigue , disability , and social/role activities limitations . They also had fewer hospitalizations and days in the hospital . No differences were found in pain/physical discomfort , shortness of breath , or psychological well-being . CONCLUSIONS An intervention design ed specifically to meet the needs of a heterogeneous group of chronic disease patients , including those with comorbid conditions , was feasible and beneficial beyond usual care in terms of improved health behaviors and health status . It also result ed in fewer hospitalizations and days of hospitalization A Roy adaptation model-based support and education intervention for women with early-stage breast cancer was tested in a three-group , three-phase r and omized clinical trial of a sample of 125 women . The experimental group received 13 months of combined individual telephone and in-person group support and education , Control Group 1 received 13 months of telephone-only individual support and education , and Control Group 2 received one-time mailed educational information . The experimental group and Control Group 1 reported less mood disturbance at the end of all three phases , less loneliness at the end of Phases II and III , and a higher- quality relationship with a significant other at the end of Phase II than did Control Group 2 . No group differences were found for cancer-related worry or well-being . The findings suggest that individual telephone support may provide an effective alternative to in-person support groups . Further study of telephone interventions is recommended using ethnically and economically heterogeneous sample Background : Older adults after myocardial infa rct ion ( MI ) are a vulnerable group who may benefit from interventions to improve health outcomes . The use of a peer advisor or an advanced practice nurse ( APN ) to provide a self-efficacy intervention is a promising method of improving health outcomes after MI . Aims : The purpose of this paper was to compare the effect of two self-efficacy interventions , a peer advisor and an APN , to a group who received st and ard care after MI . Methods : The study was a three-group r and omized clinical trial with a peer advisor intervention group , an APN intervention group , and a st and ard care group . Outcome data were collected in the hospital after MI and by telephone at 12 weeks after hospital discharge , after the interventions were completed . Results : At 12 weeks after MI , there were no significant differences between the 3 groups in health outcomes . There were similar changes in self-efficacy for performing recovery behaviors , the actual performance of recovery behavior , physical and mental health across both intervention groups and the st and ard care group . Conclusions : Although the data did not vali date the benefits of these self-efficacy interventions , future efforts at identifying changes in health outcomes may need to use more discrete measurements that are more sensitive to changes in the older unpartnered adult after an MI One hundred subjects with arthritis were r and omized into lay-taught , or professional-taught 12-h arthritis self-management courses , or a control group . Outcomes , knowledge , exercise , relaxation , disability , pain , and number of physician visits were measured aat baseline and 4 months . Professional-taught groups demonstrated greater knowledge gain while lay-taught groups had greater changes in relaxation ( p less than .01 ) and a tendency toward less disability . Although it is impossible to draw definitive conclusions , this study suggests that lay leaders can teach arthritis self-management courses with results similar to those achieved by professionals OBJECTIVE The goal of the study was to determine whether an intervention by a trained arthritis patient educator could have a positive impact on the health status , knowledge , and satisfaction with services of arthritis patients attending an ambulatory rheumatology care clinic by providing education and support . METHODS One hundred eight arthritis patients were r and omly assigned to have an intervention by an arthritis patient educator as well as st and ard rheumatologic care ( n = 47 ) or were assigned to the control group receiving only st and ard rheumatologic care ( n = 61 ) . Both groups completed the Arthritis Impact Measurement Scales 2 and the Arthritis Self-Efficacy Scale at baseline arrival to the clinic . After the appointment with the rheumatologist , each patient of the study group met with an arthritis patient educator . This session included educational and social support . A week later this group of patients received a followup telephone call from an arthritis patient educator to determine whether the patient had unanswered questions or needed additional support . Eight weeks later , both groups completed the baseline question naire again , a basic arthritis knowledge test , and a satisfaction survey . RESULTS Eight weeks after the interventions , basic knowledge scores , on a scale of 1 to 8 , were significantly different for the study group and the control group ( 6.48 + /- 0.31 versus 5.35 + /- 0.35 , respectively , P = 0.02 ) . A greater percentage of patients who received the intervention by an arthritis patient educator was able to identify two of the educational re sources available to them compared with patients in the control group ( 92.6 + /- 0.05 % versus 64.50 + /- 0.08 % , P = 0.015 , 77.7 + /- 0.08 % versus 54.8 + /- 0.09 % , P = 0.041 ) . A greater percentage of persons in the active intervention group was also able to identify one self-help aid compared with the control group ( 88.8 + /- 0.06 % versus 67.74 + /- 0.08 % , P = 0.028 ) . Overall satisfaction with care was rated " good " or " excellent " more often by the study group when compared with the control group ( 88.5 + /- 0.24 % versus 61.3 + /- 0.32 % , P = 0.01 ) . Of the study group , 69 % found the session helpful , and 58 % desired further interactions ; 16 % of the control group also requested future appointments with the arthritis patient educators . CONCLUSION Arthritis patient educators can provide a meaningful and useful addition to traditional rheumatology care , positively affecting patient knowledge and satisfaction with clinic services OBJECTIVE To evaluate the effectiveness of the Shanghai Chronic Disease Self-Management Program ( CDSMP ) . METHODS A r and omized controlled trial with six-month follow-up compared patients who received treatment with those who did not receive treatment ( waiting-list controls ) in five urban communities in Shanghai , China . Participants in the treatment group received education from a lay-led CDSMP course and one copy of a help book immediately ; those in the control group received the same education and book six months later . FINDINGS In total , 954 volunteer patients with a medical record that confirmed a diagnosis of hypertension , heart disease , chronic lung disease , arthritis , stroke , or diabetes who lived in communities were assigned r and omly to treatment ( n = 526 ) and control ( n = 428 ) groups . Overall , 430 ( 81.7 % ) and 349 ( 81.5 % ) patients in the treatment and control groups completed the six-month study . Patients who received treatment had significant improvements in weekly minutes of aerobic exercise , practice of cognitive symptom management , self-efficacy to manage own symptoms , and self-efficacy to manage own disease in general compared with controls . They also had significant improvements in eight indices of health status and , on average , fewer hospitalizations . CONCLUSION When implemented in Shanghai , the CDSMP was acceptable culturally to Chinese patients . The programme improved participants ' health behaviour , self-efficacy , and health status and reduced the number of hospitalizations six months after the course . The locally based delivery model was integrated into the routine of community government organizations and community health services . Chinese lay leaders taught the CDSMP courses as successfully as professionals This study investigated 2 methods of disseminating a cognitive-behavioral intervention for panic disorder ( PD ) . Thirty-six Ss who met diagnostic criteria for PD according to the Anxiety Disorders Interview Schedule-Revised were r and omly assigned to 1 of 3 conditions : bibliotherapy ( BT ) , group therapy ( GT ) , or a waiting-list control ( WL ) condition . Interventions lasted 8 weeks and were followed by a posttest , along with 3- and 6-month follow-up assessment s. Results indicated that both the BT and GT treatments were more effective than the WL condition in reducing frequency of panic attacks , severity of physical panic symptoms , catastrophic cognitions , agoraphobic avoidance , and depression and that the BT and GT treatments were more effective in increasing self-efficacy . Both interventions maintained their effects throughout the follow-up periods and produced clinical ly significant levels of change among the majority of treated Ss OBJECTIVE To evaluate the impact of primary care group visits ( chronic care clinics ) on the process and outcome of care for diabetic patients . RESEARCH DESIGN AND METHODS We evaluated the intervention in primary care practice s r and omized to intervention and control groups in a large-staff model health maintenance organization ( HMO ) . Patients included diabetic patients > or = 30 years of age in each participating primary care practice , selected at r and om from an automated diabetes registry . Primary care practice s were r and omized within clinics to either a chronic care clinic ( intervention ) group or a usual care ( control ) group . The intervention group conducted periodic one-half day chronic care clinics for groups of approximately 8 diabetic patients in their respective doctor 's practice . Chronic care clinics consisted of st and ardized assessment s ; visits with the primary care physician , nurse , and clinical pharmacist ; and a group education/peer support meeting . We collected self-report question naires from patients and data from administrative systems . The question naires were mailed , and telephoned interviews were conducted for nonrespondents , at baseline and at 12 and 24 months ; we queried the process of care received , the satisfaction with care , and the health status of each patient . Serum cholesterol and HbA1c levels and health care use and cost data was collected from HMO administrative systems . RESULTS In an intention-to-treat analysis at 24 months , the intervention group had received significantly more recommended preventive procedures and helpful patient education . Of five primary health status indicators examined , two ( SF-36 general health and bed disability days ) were significantly better in the intervention group . Compared with control patients , intervention patients had slightly more primary care visits , but significantly fewer specialty and emergency room visits . Among intervention participants , we found consistently positive associations between the number of chronic care clinics attended and a number of outcomes , including patient satisfaction and HbA1c levels . CONCLUSIONS Periodic primary care sessions organized to meet the complex needs of diabetic patients imrproved the process of diabetes care and were associated with better outcomes This paper describes a r and omized study to evaluate the effects of a comprehensive lifestyle management intervention for 279 postmenopausal women with type 2 diabetes who are at elevated risk for coronary heart disease ( CHD ) . The intervention , called the Mediterranean Lifestyle Trial , is focused on dietary factors , physical activity , social support and stress management . The Mediterranean Lifestyle Trial relies on a synthesis of Social Cognitive Theory and Social Ecologic Theory , as well as goal -systems theory , to explicitly inform the lifestyle intervention and to address maintenance . Thus , the trial should help illuminate the theoretical mechanisms responsible for lifestyle change . Primary outcome variables are dietary , stress management and physical activity behavior change , quality of life , and CHD-related biological risk factors . Hypothesized mediating variables include self-efficacy , coping , and social and environmental support . Following the initial 6-month intervention , participants in the intervention condition are r and omized to one of two groups design ed to enhance maintenance of effects : either a peer-led support group or a personalized multilevel community re sources maintenance condition . Unlike the peer group , the personalized approach focuses on multiple levels of community re sources to promote healthful lifestyle change . Because this research focuses on issues of generalization and translation to practice , the RE- AIM evaluation framework is being used to evaluate Reach , Effectiveness , Adoption , Implementation and Maintenance . This framework will help to translate research into practice by directing research ers ' attention to important but seldom-investigated strategies for enhancing longer-term maintenance . Specifically , the study tests how long-term maintenance may be improved through the use of existing community re sources , an intervention based on multiple environmental factors and multiple lifestyle behaviors , and lay leaders versus personalized professional support Abstract Objective : To determine the effect of a peer led programme for asthma education on quality of life and related morbidity in adolescents with asthma . Design : Cluster r and omised controlled trial . Setting : Six high schools in rural Australia . Participants : 272 students with recent wheeze , recruited from a cohort of 1515 students from two school years ( mean age 12.5 and 15.5 years ) ; 251 ( 92.3 % ) completed the study . Intervention : A structured education programme for peers comprising three steps ( the “ Triple A Program ” ) . Main outcome measures : Quality of life , school absenteeism , asthma attacks , and lung function . Results : When adjusted for year and sex , mean total quality of life scores showed significant improvement in the intervention than control group . Clinical ly important improvement in quality of life ( > 0.5 units ) occurred in 25 % of students with asthma in the intervention group compared with 12 % in the control group ( P=0.01 ) . The number needed to treat was 8 ( 95 % confidence interval 4.5 to 35.7 ) . The effect of the intervention was greatest in students in year 10 and in females . Significant improvements occurred in the activities domain ( 41 % v 28 % ) and in the emotions domain ( 39 % v 19 % ) in males in the intervention group . School absenteeism significantly decreased in the intervention group only . Asthma attacks at school increased in the control group only . Conclusion : The triple A programme leads to a clinical ly relevant improvement in quality of life and related morbidity in students with asthma . Wider dissemination of this programme in schools could play an important part in reducing the burden of asthma in The objective of this study was to determine whether the Arthritis Self-Management Programme ( ASMP ) improves perceptions of control , health behaviours and health status , and changes use of health care re sources . The design was a pragmatic r and omized controlled study ; participants were allocated to ASMP ( Intervention Group ) or a 4-month waiting-list Control Group . The Intervention Group completed a 12-month follow-up . In total , 544 people with arthritis were recruited from the community--311 in the Intervention Group and 233 in the Control Group . Main outcome measures included : arthritis self-efficacy , health behaviours ( exercise , cognitive symptom management , diet and relaxation ) and health status ( pain , fatigue , anxiety , depression and positive affect ) . At 4 months follow-up , the ASMP had a significant effect on arthritis self-efficacy for other symptoms and pain subscales . Performance of a range of health behaviours ( cognitive symptom management , communication with physicians , dietary habit , exercise and relaxation ) was significantly greater among the Intervention Group . The Intervention Group were significantly less depressed and had greater positive mood . In addition , trends towards decreases on fatigue and anxiety were noted . Physical functioning , pain and GP visits remained stable at 4 months . A similar pattern of findings was found at 12 months follow-up for the Intervention Group . Furthermore , a significant improvement was found on pain and visits to GPs had decreased . Apart from a small improvement on physical functioning among the Intervention Group participants with osteoarthritis 12 months , all effects were independent of the type of arthritis . The findings suggest that the ASMP is effective in promoting improvements in perception of control , health behaviours and health status , when delivered in UK setting OBJECTIVES The current study was conducted to compare the effectiveness of delivering diabetes education in either a group or individual setting using a consistent , evidence -based curriculum . RESEARCH DESIGN AND METHODS A total of 170 subjects with type 2 diabetes were r and omly assigned to either group ( n = 87 ) or individual ( n = 83 ) educational setting s. Subjects received education in four sequential sessions delivered at consistent time intervals over a 6-month period . Outcomes included changes in knowledge , self-management behaviors , weight , BMI , HbA(1c ) , health-related quality of life , patient attitudes , and medication regimen . Changes were assessed at baseline and after the 2-week , 3-month , and 6-month education sessions . RESULTS Both educational setting s had similar improvements in knowledge , BMI , health-related quality of life , attitudes , and all other measured indicators . HbA(1c ) decreased from 8.5 + /- 1.8 % at baseline to 6.5 + /- 0.8 % at 6 months ( P < 0.01 ) in the study population as a whole . Subjects assigned to the individual setting had a 1.7 + /- 1.9 % reduction in HbA(1c ) ( P < 0.01 ) , whereas subjects assigned to the group setting had a 2.5 + /- 1.8 % reduction in HbA(1c ) ( P < 0.01 ) . The difference in HbA(1c ) improvement was marginally greater in subjects assigned to group education versus individualized education ( P = 0.05 ) . CONCLUSIONS This study demonstrates that diabetes education delivered in a group setting , when compared with an individual setting , was equally effective at providing equivalent or slightly greater improvements in glycemic control . Group diabetes education was similarly effective in delivering key educational components and may allow for more efficient and cost-effective methods in the delivery of diabetes education programs BACKGROUND A prerequisite to translating research findings into practice is information on consistency of implementation , maintenance of results , and generalization of effects . This follow-up report is one of the few experimental studies to provide such information on Internet-based health education . METHODS We present follow-up data 10 months following r and omization on the " Diabetes Network ( D-Net ) " Internet-based self-management project , a r and omized trial evaluating the incremental effects of adding ( 1 ) tailored self-management training or ( 2 ) peer support components to a basic Internet-based , information-focused comparison intervention . Participants were 320 adult type 2 diabetes patients from participating primary care offices , mean age 59 ( SD = 9.2 ) , who were relatively novice Internet users . RESULTS All intervention components were consistently implemented by staff , but participant website usage decreased over time . All conditions were significantly improved from baseline on behavioral , psychosocial , and some biological outcomes ; and there were few differences between conditions . Results were robust across on-line coaches , patient characteristics , and participating clinics . CONCLUSIONS The basic D-Net intervention was implemented well and improvements were observed across a variety of patients , interventionists , and clinics . There were , however , difficulties in maintaining usage over time and additions of tailored self-management and peer support components generally did not significantly improve results Objective : The objective of this study was to test the effectiveness of a mail-delivered , tailored self-management intervention ( SMART ) and to compare it with the classic Arthritis Self-Management Program ( ASMP ) . Methods : We performed 2 r and omized controlled trials : 1 ) a study of 1090 participants r and omized to SMART or USUAL CARE , and 2 ) a study of 341 participants r and omized to SMART or ASMP . Dependent variables included disability , pain , depression , role function , global severity , doctor visits , and self-efficacy . SMART interventions were provided in months 0–18 and not reinforced . Results were assessed at 1 , 2 , and 3 years using analyses of covariance ( ANCOVA ) . Results : Compared with USUAL CARE , SMART participants at 1 year had decreased disability , improved role function , and increased self-efficacy ( all P < 0.01 ) . At 2 years , decreases in global severity , doctor visits , and increases in self-efficacy ( all P < 0.01 ) were noted . At 3 years without reinforcement , no statistically significant effects remained . Compared with ASMP , SMART at 1 year had greater decreases in disability ( P = 0.02 ) and increases in self-efficacy ( P = 0.01 ) . There were no differences at 2 years . At 3 years , role function ( P = 0.04 ) and doctor visit ( P = 0.03 ) were improved in ASMP as compared with SMART . Improvements from baseline were seen for nearly all variables in both groups . Conclusions : A mail-delivered arthritis self-management program , SMART , was similarly effective to the classic ASMP , with slightly better results in the first year and a slightly more rapid attenuation over the next 2 years . Results suggest that both programs are effective , and that the addition of a mail-delivered program could improve accessibility to arthritis self-management treatment Thirty-four patients with irritable bowel syndrome were r and omly assigned to 1 of 3 treatment conditions : individualized cognitive treatment ( CT ) , self-help support group ( SG ) , or symptom-monitoring waiting-list control ( WL ) . Each of the 3 conditions lasted approximately 8 weeks . Pre- to posttreatment analyses revealed significantly greater reductions in both individual gastrointestinal ( GI ) symptoms and in a composite index for GI symptom change for the CT condition than for the SG or WL conditions . When compared with the SG and WL conditions , the CT condition also showed significant improvement on psychological measures of depression and anxiety . At 3-month follow-up , the results for the CT condition were maintained and revealed further numerical improvements The most effective means of educating children with asthma and their families has not been clearly demonstrated in previous studies . Peer education is uniquely suited to the complex problems encountered in underserved population s. The purpose of this study was to show the feasibility of delivering a peer education program for children with asthma and the effect of the program on indoor allergen levels in an inner-city population in Chicago . Overall , the program was well received . Baseline allergen levels were consistent with some previous studies in showing low levels of mite allergens and high levels of cockroach allergens , with 79.6 % of sample s having levels > 8 U/g . A total of 28.2 % of sample s had cat allergen levels > 2 microg/g , although only 9.7 % of homes had cats , confirming previous reports that cat allergen is ubiquitous . Mold levels were seasonal , with the highest levels in the summer . Results from this study suggest that intervention programs should focus more on elimination of cockroaches than was previously appreciated , while minimizing the use of pesticides , and on identification of the sources of cat allergen . Structural and psychosocial issues in homes need to be addressed in future studies . This study has demonstrated the feasibility of delivering peer education in a inner-city population and highlighted the need for comprehensive intervention strategies addressing complex issues facing underserved neighborhoods Objective : Supporting patients ’ self care could have a major effect on the management of long-term conditions , which has led to worldwide interest in effective self care interventions . In Engl and , self care support is being developed through the “ Expert Patients Programme ” , which provides lay-led generic courses to improve patients ’ self care skills . However , the clinical and cost effectiveness of such courses remains unclear . Methods : Two-arm pragmatic r and omised controlled trial design with waiting list control in community setting s in Engl and . 629 patients with a wide range of self-defined long-term conditions were studied . The lay-led self care support group involved 6-weekly sessions to teach self care skills . Primary outcomes were self-efficacy , reported energy and routine health services utilisation at 6 months . A cost-effectiveness analysis was also conducted . Results : Patients receiving immediate course access reported considerably greater self-efficacy and energy at 6-month follow-up , but reported no statistically significant reductions in routine health services utilisation over the same time period . The cost-effectiveness analysis showed that patients receiving immediate course access reported considerably greater health related quality of life , and a small reduction in costs . If a quality adjusted life year was valued at £ 20 000 ( $ 39 191 ; € 30 282 ) , there was a 70 % probability that the intervention was cost effective . Conclusions : Lay-led self care support groups are effective in improving self-efficacy and energy levels among patients with long-term conditions , and are likely to be cost effective over 6 months at conventional values of a decision-maker ’s willingness to pay . They may be a useful addition to current services in the management of long-term conditions In this r and omized trial patients with non-insulin-dependent diabetes were allocated to one of four programs : a minimal instruction program ( n=59 ) . an education program of individual visits ( n=57 ) , an education program incorporating a group education course ( n=66 ) , and a behavioral program ( n=59 ) . Individual and group education programs had higher attrition rates than the behavioral and minimal programs . The four programs , which involved different amounts of patient contact time , delivery format , and instructional strategies . all produced reductions in HbA atid BMI , with no significant differences between the programs . There were no differences between groups over three time periods in total cholesterol , HDL cholesterol , systolic blood pressure , or proportion of patients consulting an ophthalmologist . The behavioral program ploduced a greater reduction in diastolic blood pressure over 12 months that the education programs and a greater reduction in the cholesterol risk ratio over 3 months than the other programs . The behavioral program patients were more likely to have visited a podiatrist after 6 months and reported higher satisfaction BACKGROUND We report a clinical trial comparing the effectiveness of education-based and peer discussion -based group interventions on adjustment to breast cancer . METHODS Women with stage I , II , or III breast cancer ( n = 312 ) were r and omly assigned to 1 of 4 group conditions : control , education , peer discussion , or education plus peer discussion ( combination ) . Seven groups ( each comprising 8 - 12 women ) were conducted in each of the 4 conditions ( 28 groups total ) . Adjustment was measured before the intervention , immediately after the intervention , and 6 months after the intervention . RESULTS Consistently positive effects on adjustment were seen in the education groups both immediately following and 6 months after the intervention . There were no benefits of participation in peer discussion groups , and some indications of adverse effects on adjustment at both follow-up examinations . The effects could be explained by changes in self-esteem , body image , and intrusive thoughts about the illness . CONCLUSIONS Education-based group interventions facilitated the initial adjustment of women diagnosed with early stage breast cancer . There was no evidence of benefits from peer discussion group interventions OBJECTIVE We evaluated the effect of a self-management program ( SMP ) on primary care patients with acute low back pain ( ALBP ) from low income , inner city neighborhood health centers and an emergency department of a public teaching hospital . METHODS We r and omized 211 primary care patients who visited a physician for ALBP ( < 90 days duration ) to usual care or an SMP . The SMP consisted of 3 group sessions and telephone followup that focused on underst and ing back pain , increasing physical activity , and dealing with fears and frustrations . RESULTS Of the eligible patients , 52 % expressed interest in participation and 39 % of all eligible patients were r and omized into the study . Among patients in the treatment group , 28.3 % attended at least 1 group class , 62.3 % received the intervention by mail , telephone , and audiotapes , and 9.4 % received no intervention . Interviewers , blinded to the treatment given , collected data at baseline and at 4 months following r and omization . Compared with the control group , the intervention group reported significantly better emotional functioning ( P < 0.01 ) , increased self efficacy to manage ALBP ( P = 0.03 ) , and less fear of movement ( P = 0.05 ) after 4 months . CONCLUSION This SMP produced short-term improvements in emotional functioning and self efficacy to manage symptoms among patients with ALBP living in the inner city . However , methods of program delivery other than group classes are needed to reach a greater portion of the inner city patients Background Behavioral interventions to address the complex medical and HIV risk reduction needs of HIV-seropositive ( HIV-positive ) injection drug users ( IDUs ) are urgently needed . We describe the development of Interventions for Seropositive Injectors— Research and Evaluation ( INSPIRE ) , a r and omized controlled trial of an integrated intervention for HIV-positive IDUs , and the characteristics of the baseline sample . Methods HIV-positive IDUs were recruited from community setting s in 4 US cities . After completing a baseline assessment , participants who attended the first session were r and omly assigned to ( 1 ) a 10-session peer mentoring intervention design ed to improve utilization of HIV care , to improve adherence to HIV medications , and to reduce sexual and injection risk or ( 2 ) an 8-session videotape control . Periodic follow-up for 12 months is ongoing . Results A total of 1161 HIV-positive IDUs completed the baseline assessment , and 966 ( 83 % ) were r and omized . Retention rates are greater than 80 % for all follow-up periods . Approximately 79 % of baseline participants reported a recent medical visit , 49 % were taking highly active antiretroviral therapy , and 19 % had an undetectable viral load . Use of injection and noninjection substances was prevalent , and sexual and injection risks were each reported by more than 25 % of participants . Conclusion There is a need for an integrated intervention for HIV-positive IDUs , and these data show the acceptability of such an approach OBJECTIVE To assess whether knowledge or psychosocial and glycemic benefits of a diabetes education program are enhanced by a support group for older patients . DESIGN A partially r and omized controlled trial involving two groups of patients : Group A , subjects who received an education program followed by 18 months of support group sessions ; Group B , only the diabetes education program . A third convenience sample , Group C , received neither intervention . Groups A and B were assessed before and immediately after the education program , and all groups were assessed 2 years after the education program . SETTING Diabetes clinic at a Veterans Affairs Medical Center . PATIENTS All subjects were male ( mean age = 68 + /- 1.3 years , range = 57 - 82 years ; duration of diabetes = 10 + /- 2 years , range 3 - 16 ) . Sample sizes were 11 in Group A , 13 in Group B , and 8 in Group C. INTERVENTION The education program consisted of six weekly sessions covering aspects of diabetes self-care . The support group consisted of 18 monthly sessions for continuing education , discussion , and structured social activities . OUTCOME MEASURES Diabetes knowledge , psychosocial factors ( self-care-related quality of life , stress , family involvement in care , and social involvement ) , depression , and glycemic control . RESULTS Group A scored better ( at least P less than 0.05 ) on knowledge , quality of life , and depression than the other groups . Groups A and B showed less stress , greater family involvement , better glycemic control , but less involvement in social activities than Group C. CONCLUSION Diabetes education programs can have long term benefits on knowledge , psychosocial functioning , and glycemic control for older diabetic patients . The addition of support groups enhances diabetes knowledge and psychosocial functioning OBJECTIVE This study investigated the effectiveness of the Chronic Disease Self-management Program ( CDSMP ) when delivered to for people from Vietnamese , Chinese , Italian and Greek background s living in Victoria , Australia . METHOD The CDSMP was administered to 320 people with chronic illnesse(es ) in selected low income areas in the State of Victoria , Australia . At 6 months , they were compared with r and omised wait-list control subjects ( n=154 ) using analyses of covariance . RESULTS Participants in the intervention group had significantly better outcomes on energy , exercise , symptom management , self-efficacy , general health , pain , fatigue and health distress . There were no significant effects for health services utilisation . Interactions across language groups were observed with the Vietnamese and Chinese speaking participants gaining greater benefit . CONCLUSION Self-management programs can be successfully implemented with culturally and linguistically diverse population s in Australia . Further research is needed to evaluate long-term outcomes ; explore effects on service utilisation ; and to determine whether the benefits obtained from participating in a self-management program can be maintained . PRACTICE IMPLICATION S Self-management programs should be considered for people from culturally and linguistically diverse background s. Care also needs to be taken in design ing recruitment strategies to minimize withdrawal rates and to ensure harder to reach people are given encouragement to participate There has been a lack of research regarding nonpharmacologic interventions in heart failure . The objective was to determine the effect of behavioral management on health related quality of life ( HRQL ) in patients with heart failure . Participants ( N = 116 ) were r and omly assigned to one of two groups : usual care for heart failure ( n = 58 ) and the 15-week behavioral management program ( n = 58 ) . Outcomes included exercise performance ( 6-min walk ) , physical and mental functioning ( SF-36 ) , general health perceptions ( SF-36 ) , and disease specific HRQL ( Minnesota Living with Heart Failure Question naire-MLHF ) . Outcomes were assessed at baseline , 4 , 10 and 16 months . Participants were mostly male ( 95 % ) and Caucasian ( 75 % ) , with a mean age of 67 years ( S.D. = 10 ) . Intervention patients showed significantly improved self-reported disease specific HRQL ( MLHF physical dimension scores ) over time compared to control patients . There were no group differences in exercise performance , physical functioning , mental functioning or general health perceptions The efficacy of an adult asthma self-management program , Wheezers Anonymous ( WA ) , was tested utilizing 79 adult asthmatic patients . Subjects were r and omly assigned to a treatment or waiting-list control group . Baseline data gathered included measures of symptom severity , health-care utilization , knowledge of asthma , attitudes about asthma , and self-efficacy . All subjects completed the same measures 1 , 2 , and 3 months following the WA intervention . Knowledge about asthma increased in the treatment group relative to the waiting-list controls ; the number of attacks decreased in the treatment group only , thus demonstrating the efficacy of the WA program OBJECTIVE To evaluate the acceptability , practicality , and short-term efficacy of a health education program to improve disease self-management in patients with symptomatic HIV/AIDS . DESIGN R and omized controlled trial , baseline and 3-month follow-up question naire assessment s. SETTING San Francisco Bay communities . PARTICIPANTS Seventy-one men with symptomatic HIV or AIDS were r and omly assigned to a seven-session group educational intervention ( N=34 ) or a usual-care control group ( N=37 ) . INTERVENTION Interactive health education groups were used to teach wide-ranging disease self-management skills and information : symptom assessment and management , medication use , physical exercise , relaxation , doctor-patient communication , and nutrition . Each group was led by two trained peer-leaders ( one of whom was HIV-positive ) recruited from the community . MAIN OUTCOME MEASURES The primary outcome of interest was symptom status . Secondary outcomes were self-efficacy and health behaviors . Analysis of covariance was used to compare experimental and control group mean outcomes , adjusting for baseline value differences . RESULTS The symptom severity index ( number of symptoms moderate or greater severity ) decreased in the experimental , and increased in the control group ( -0.9 versus + 0.5 ; p < .03 ) . Pain , fatigue , and psychological symptoms were not significantly different between groups . Self-efficacy for controlling symptoms improved in the experimental , and decreased in the control group ( + 4 versus -7 ; p < .02 ) . Changes in stress/relaxation exercises and HIV/AIDS knowledge were not different between groups . A trend was shown toward more frequent physical exercise in the experimental group compared with less in the control group ( + 1.3 versus -0.5 times/week ; p=.06 ) . CONCLUSIONS Health education emphasizing self-management skills for HIV/AIDS patients can be implemented and evaluated and was accepted by patients , peer-leaders , and health care providers . Whether this educational program can lead to prolonged improvement in HIV symptoms and behaviors can be adequately addressed only by a larger trial of longer duration OBJECTIVE To test the effects ( on coping , social interactions , loneliness , functional health status , and life satisfaction ) of an intervention aim ed at teaching people with rheumatic diseases to cope actively with their problems . METHODS A total of 168 patients with chronic rheumatic disorders affecting the joints were r and omly assigned to a coping intervention group , a mutual support control group , or a waiting list control group . Measurements were by self-report question naires . RESULTS Post-intervention measurements showed that the coping intervention increased action-directed coping and functional health status , but these effects did not persist up to 6-months followup . In patients who attended at least half of the 10 sessions , the coping intervention contributed to decreased loneliness at post-intervention and to improvements in social interactions and life satisfaction at 6-months followup . CONCLUSION Teaching patients with rheumatic diseases to cope actively with their problems had positive impacts . Consequently it is recommended that the coping intervention be incorporated into regular care . Maintenance sessions are advisable The feasibility of a 9-month educational diabetes programme ( tailored to Turkish patients , provided by Turkish bicultural female educators ) was assessed in terms of dropout rate , patient and GP satisfaction , and GP 's perceived workload . Of the 54 Turkish patients ( 39 % males ) that signed informed consent , 45 actually started the education . Dropout rate during the programme was 41 % ( main reason : going abroad for a long period ( 18 % ) ) . The individual education sessions and the consultations with the GP were highly appreciated by 87 % of the patients and the group sessions by 66 % . Although all nine interviewed GPs experienced a higher workload , overall appreciation of the programme was high in six GPs . Although implementation of an ethic-specific diabetes programme in general practice is well appreciated by both patients and GPs , the high dropout rate indicates that the programme needs to be more finely tuned to the individual patient Abstract Objective To evaluate clinical effectiveness of a self management programme for arthritis in patients in primary care with osteoarthritis . Design R and omised controlled trial . Setting 74 general practice s in the United Kingdom . Participants 812 patients aged 50 and over with osteoarthritis of hips or knees ( or both ) and pain or disability ( or both ) . Intervention Participants were r and omised to six sessions of self management of arthritis and an education booklet ( intervention group ) or the education booklet alone ( control group ) . Main outcome measures Primary outcome was quality of life , as assessed by the short form health survey ( SF-36 ) . Several other physical and psychosocial secondary outcomes were assessed . Data were collected at baseline , four months , and 12 months . Results Response rates were 80 % and 76 % at four and 12 months . The two groups showed significant differences at 12 months on the anxiety subscore of the hospital anxiety and depression scale ( mean difference −0.62 , 95 % confidence interval −1.08 to −0.16 ) , arthritis self efficacy scale for pain ( 0.98 , 0.07 to 1.89 ) , and self efficacy for other aspects of management ( 1.58 , 0.25 to 2.90 ) . Results were similar for intention to treat and per protocol analyses . No significant difference was seen in number of visits to the general practitioner at 12 months . Conclusions The self management of arthritis programme reduced anxiety and improved participants ' perceived self efficacy to manage symptoms , but it had no significant effect on pain , physical functioning , or contact with primary care . Trial registration Current Controlled Trials IS RCT N79115352 [ controlled-trials.com ] Study Design . R and omized , controlled trial . Objective . To evaluate a four‐session self‐management group intervention for patients with pain in primary care , led by trained lay persons with back pain . The intervention was design ed to reduce patient worries , encourage self‐care , and reduce activity limitations . Background Data . R and omized trials of educational interventions suggest that activating interventions may improve back pain outcomes . Expert opinion increasingly regards effective self‐management of back pain as important in achieving good outcomes . In this study , an educational intervention design ed to activate patients and support effective self‐management was evaluated . Methods . Six to 8 weeks after a primary care visit for back pain , patients were invited to participate in an educational program to improve back pain self‐management . Those showing interest by returning a brief question naire became eligible for the study . Participants ( n = −255 ) r and omly were assigned to either a self‐management group intervention or to a usual care control group . The effect of the intervention , relative to usual care , was assessed 3 , 6 , and 12 months after r and omization , controlling for baseline values . The intervention consisted of a four‐session group applying problem‐solving techniques to back pain self‐management , supplemented by educational material s ( book and videos ) supporting active management of back pain . The groups were led by lay persons trained to implement a fully structured group protocol . The control group received usual care , supplemented by a book on back pain care . Results . Participants r and omly assigned to the self‐management groups reported significantly less worry about back pain and expressed more confidence in self‐care . Rol and Disability Question naire Scores were significantly lower among participants in the self‐management groups relative to the usual care controls at 6 months ( P = 0.007 ) , and this difference was sustained at 12 months at borderline significance levels ( P = 0.09 ) . Among self‐management group participants , 48 % showed a 50 % or greater reduction in Rol and Disability Question naire Score at 6 months , compared with 33 % among the usual care controls . Conclusions . Self‐management groups led by trained lay persons following a structured protocol were more effective than usual care in reducing worries , producing positive attitudes toward self‐care , and reducing activity limitations among patients with back pain in primary care Background : This study compared the effects of a supportive-expressive group intervention ( GI ) with an educational control condition ( EC ) on long-term psychosocial adjustment in gay men with HIV infection . Method : Subjects ( n = 85 ) were r and omized after stratification for disease stage and use of antiretroviral medication . GI consisted of 4 months of weekly group sessions followed by 5 monthly maintenance sessions plus written educational material , whereas the EC subjects received educational material only . Results : There were no between-group differences in effects on distress , coping or social support in analyses examining 4 time points over 15 months . Both conditions decreased in distress over time on the Hopkins Symptom Checklist and Beck Depression Inventory . Conclusions : Several explanations are offered for the reason why no additional benefit of the GI was found on outcome measures studied when compared with the EC condition and recommendations are made for future psychosocial intervention research with HIV-infected persons Background In light of health disparities and the growing prevalence of chronic disease , there is a need for community-based interventions that improve health behaviors and health status . These interventions should be based on existing theory . Objective This study aim ed to evaluate the health and utilization outcomes of a 6-week community-based program for Spanish speakers with heart disease , lung disease , or type 2 diabetes . Method The treatment participants in this study ( n = 327 ) took a 6-week peer-led program . At 4 months , they were compared with r and omized wait-list control subjects ( n = 224 ) using analyses of covariance . The outcomes for all the treatment participants were assessed at 1 year , as compared with baseline scores ( n = 271 ) using t-tests . Results At 4 months , the participants , as compared with usual-care control subjects , demonstrated improved health status , health behavior , and self-efficacy , as well as fewer emergency room visits ( p < .05 ) . At 1 year , the improvements were maintained and remained significantly different from baseline condition . Conclusions This community-based program has the potential to improve the lives of Hispanics with chronic illness while reducing emergency room use Peer support has been used effectively in a variety of patient population s , but its effectiveness in improving outcomes in persons with chronic heart failure has not been explored . We trained 9 persons with heart failure to mentor other heart failure patients and tested the effectiveness of this approach in a r and omized controlled clinical trial . A low proportion ( 37 % ) of the eligible population of hospitalized patients agreed to participate . At the end of the 3-month trial , there was significantly higher heart failure self-care in the intervention group ( P < .05 ) . The only difference in social support was a significant decline in perceived support reciprocity in the intervention group ( F = 5.94 , P = .004 ) . No significant group differences in heart failure readmissions , length of stay , or cost were evident at 90-days , although the heart failure readmission rate was 96 % higher in the intervention group when compared to that in the control group . The reasons for low overall enrollment and high readmission rates in the intervention group require further study . Including additional self-care education by a professional , rather than leaving all the education to the mentor , could strengthen the peer support intervention trialed in this study . Small group meetings may be less intrusive and more desirable for this patient population Internet-based support groups are a rapidly growing segment of mutual aid programs for individuals with chronic illnesses and other challenges . Previous studies have informed us about the content of online exchanges between support group members , but we know little about the ability of these interventions to change participants ' perceptions of support . A r and omized trial of 160 adult Type 2 diabetes patients provided novice Internet users with computers and Internet access to 1 of 4 conditions : ( a ) diabetes information only , ( b ) a personal self-management coach , ( c ) a social support intervention , or ( d ) a personal self-management coach and the support intervention . After 3 months , individuals in the 2 support conditions reported significant increases in support on a diabetes-specific support measure and a general support scale . Participants ' age was significantly related to change in social support , but intervention effects were still significant after accounting for this relationship . This report is a critical first step in evaluating the long-term effects of Internet-based support for diabetes self-management . The discussion identifies directions for future research Introduction : Functional abdominal symptoms are very common and account for nearly two million primary care consultations in Britain every year and produce significant morbidity . The aims of this study were to evaluate the impact of two self-help interventions on consultation rates and symptom severity in patients with a primary care diagnosis of irritable bowel syndrome . Methods : A total of 420 patients from 54 primary care centres were r and omised either to receive self-help information in the form of a guidebook or the guidebook plus a “ self-help ” group meeting or to be in a control group receiving neither intervention . Data were collected using question naires and primary care records . Results : At one year , patients in the guidebook group had a 60 % reduction in primary care consultations ( p<0.001 ) and a reduction in perceived symptom severity ( p<0.001 ) compared with controls . Allocation to the self-help group conferred no additional benefit . Actual symptom scores did not change significantly in any group . Costs per patient were reduced by £ 73 ( confidence interval £ 43 , £ 103 ) or 40 % per year . Conclusion : Introduction of a self-help guidebook results in a reduction in primary care consultations , a perceived reduction in symptoms , and significant health service savings . This suggests that patients attending their primary care physician with functional abdominal symptoms should be offered self-help information as part of their management Arthritis is a common chronic disease causing pain and progressive disability to millions of people . The purpose of the study was to examine the effectiveness of group patient education for people with one form of arthritis , ankylosing spondylitis ( AS ) , in terms of change in : arthritis self-efficacy ; psychological well-being ; physical well-being ; and home exercise activities . The Self-Management Course-Ankylosing Spondylitis ( SMC-AS ) demonstrated positive effects on arthritis self-efficacy and psychological well-being at 6-month follow-up . Analysis of change over time in the intervention group showed improvements in depression , self-efficacy and severity at 3 weeks , with trends towards continued improvement evident at 6 months . In contrast , the positive effects on range and frequency of home exercise activities at 3 weeks were not maintained at 6 months . In conclusion , the effectiveness of short , intensive patient education courses was demonstrated . However , the need for strategies to sustain improvements in exercise behaviour need to be explored OBJECTIVES To determine 4-month and 1-year health-related outcomes of a 6-week , lay-led , and community-based arthritis self-management program for Spanish-speaking participants and to determine the role of self-efficacy in predicting health status for this population . METHODS Three hundred and thirty one subjects were r and omized to the program or to a 4-month wait list control group . One hundred ninety eight subjects continued in a 1-year longitudinal study . Data were collected via mailed question naires with telephone follow up . RESULTS At 4 months , treatment subjects , compared with controls , demonstrated positive changes in exercise , disability , pain , and self-efficacy ( P < 0.05 ) . At 1 year , compared with baseline , treatment subjects demonstrated improvements in exercise , general health , disability , pain , self-efficacy , and depression ( P < 0.05 ) . Baseline and 4-month changes in self-efficacy predicted health status at 1 year . CONCLUSIONS Spanish-speaking participants of an arthritis self-management program demonstrate short- and long-term benefits ( improved health behaviors , health status , and self-efficacy ) BACKGROUND Reducing the impact of chronic disease in minority ethnic groups is an important public health challenge . Lay-led education may overcome cultural and language barriers that limit the effectiveness of professionally-led programmes . We report the first r and omised trial of a lay-led self-management programme - the Chronic Disease Self-Management Programme ( CDSMP ) ( Expert Patient Programme ) - in a south Asian group . AIM To determine the effectiveness of a culturally-adapted lay-led self-management programme for Bangladeshi adults with chronic disease . DESIGN OF STUDY R and omised controlled trial . SETTING Tower Hamlets , east London . METHOD We recruited Bangladeshi adults with diabetes , cardiovascular disease , respiratory disease or arthritis from general practice s and r and omised them to the CDSMP or waiting-list control . Self-efficacy ( primary outcome ) , self-management behaviour , communication with clinician , depression scores , and healthcare use were assessed by blinded interviewer-administered question naires in Sylheti before r and omisation and 4 months later . RESULTS Of the 1363 people invited , 476 ( 34 % ) agreed to take part and 92 % ( 439/476 ) of participants were followed up . The programme improved self-efficacy ( difference : 0.67 , 95 % confidence interval [ CI ] = 0.08 to 1.25 ) and self-management behaviour ( 0.53 ; 95 % CI = 0.01 to 1.06 ) . In the 51 % ( 121/238 ) of intervention participants attending three or more of the 6-weekly education sessions the programme led to greater improvements in self-efficacy ( 1.47 ; 95 % CI = 0.50 to 1.82 ) and self-management behaviour ( 1.16 ; 95 % CI = 0.50 to 1.82 ) , and reduced HADS depression scores ( 0.64 ; 95 % CI = 0.07 to 1.22 ) . Communication and healthcare use were not significantly different between groups . The programme cost pound123 ( 181 ) per participant . CONCLUSION A culturally-adapted CDSMP improves self-efficacy and self-care behaviour in Bangladeshi patients with chronic disease . Effects on health status were marginal . Benefits were limited by moderate uptake and attendance OBJECTIVE To evaluate the effectiveness of Stanford 's Chronic Disease Self-Management Program ( CDSMP ) for chronic low back pain ( LBP ) in older Americans . DESIGN R and omized controlled trial . SETTING Community-based program offered at 12 locations . SUBJECTS Community-dwelling seniors ( n = 109 ) aged 60 and older with chronic LBP of mechanical origin . METHODS Patients were r and omly allocated to the CDSMP or to a 6-month , wait-list control group . The program included one 2.5-hour session per week for 6 weeks . Outcomes evaluated at 6 months included 100-point modified Von Korff pain and disability scales ; days with pain and disability ; SF-36 general health , energy-fatigue , and emotional well-being scales ; 2 scales from the Arthritis Self-Efficacy Scale , self-care attitudes/behaviors , and health services utilization . RESULTS For pain at 6 months , the primary outcome , the adjusted mean difference between the program and control , was -1.0 ( P = .835 ) . There was a sizable advantage for the program in disability averaged over the course of the entire 6-month study ( -9.2 , P = .027 ) , but not at the 6-month follow-up ( -5.8 , P = .278 ) . There was an interaction between intervention and baseline disability days favoring the program for higher baseline values ( P = .007 ) . The CDSMP affected emotional well-being ( 7.6 , P = .037 ) and energy-fatigue ( 5.1 , P = .274 ) . There were no differences for self-efficacy , pain days , and general health . CONCLUSION There was no advantage for the CDSMP over a wait-list control for improving pain , general health , self-efficacy , and self-care attitudes in older Americans with chronic LBP . A benefit was suggested for emotional well-being , fatigue , functional disability , and days with disability OBJECTIVE Evaluation of a self-management program for patients with osteoarthritis ( OA ) of the hip or knee . The program , which consisted of 6 weekly sessions of 2 hours , included health education by a peer and physical exercises taught by a physical therapist . METHODS R and omized controlled trial . Inclusion criteria were diagnosis of OA of the hip or knee according to ACR clinical and radiographic criteria and age 55 to 75 years . EXCLUSION CRITERIA on waiting list for joint replacement . There were pretest , posttest , and followup ( 6 months ) assessment s. The experimental group consisted of 56 patients , the control group 49 . Outcome variables were pain , quality of life , activity restrictions , knowledge about OA , self-efficacy , body mass index ( BMI ) , and mobility measures . Attention was also paid to effects on health care utilization and lifestyle behavior . RESULTS Significant MANOVA group x time effects ( p < 0.05 , one-sided ) were found for pain , quality of life , strength of the left M. quadriceps , knowledge , self-efficacy , BMI , physically active lifestyle , and visits to the physical therapist . Most effects were moderate at posttest assessment and smaller at followup . No effects were found for range of motion and functional tasks . CONCLUSION The program was reasonably effective , but more attention should be paid to proactive followup interventions and to the selection of participants BACKGROUND Disability in basic activities of daily living ( ADLs ) implies a loss of independence and increases the risk for hospitalization , nursing home admission , and death . Little is known about ways by which ADL disability can be prevented or reversed . The authors evaluated the efficacy of the Health Enhancement Program in preventing and reducing ADL disability in community-dwelling older adults . METHODS The authors analyzed data from a 12-month , r and omized , single-blinded , controlled trial of a disability prevention , chronic disease self-management program involving 201 adults aged 70 years and older that was conducted from February 1995 to June 1996 at a senior center in western Washington state . Activities of daily living disability incidence , improvement , and worsening were assessed using intention-to-treat methods . RESULTS The cumulative incidence of ADL disability among those who were not ADL disabled at baseline ( n = 56 in the intervention group , n = 57 in the control group ) was modestly lower in the intervention group than in the control group at 12 months ( 14.3 % vs 21.3 % , p = .466 ) . Cumulative improvement in ADL function among those who reported any ADL disability at baseline ( n = 41 in the intervention group , n = 43 in the control group ) was greater in the intervention group at 12 months ( 80.5 % vs 46.5 % , p = .026 ) . The likelihood for ADL improvement was greater in the intervention group compared with controls at 12 months ( adjusted hazard ratio , 1.84 ; 95 % confidence interval , 1.05 to 3.22 ; p = .020 ) . Cumulative worsening of ADL function was slightly lower in the intervention group at 12 months ( 18.6 % vs 26.5 % , p = .237 ) . Intervention participants tended to be at lower risk for ADL worsening ( adjusted hazard ratio , 0.71 ; 95 % confidence interval , 0.38 to 1.30 ; p = .266 ) compared with control participants . CONCLUSION The Health Enhancement Program intervention led to improved ADL functioning in those who were disabled initially and thereby offers a promising strategy for limiting or reversing functional decline in disabled elderly persons BACKGROUND We evaluated the effect of a self-management program for low-income primary care patients with acute low back pain ( ALBP ) from inner-city neighborhood health centers . METHODS We conducted a r and omized controlled trial of a self-management program compared with usual care at university-affiliated neighborhood health centers and an emergency department of an inner-city public teaching hospital . We enrolled 211 patients who visited a physician for ALBP ( < 90 days ' duration ) . The self-management program consisted of 3 group sessions and telephone follow-up that focused on underst and ing back pain , increasing physical activity , and dealing with fears and frustrations . RESULTS At baseline , 4 months , and 12 months , blinded interviewers assessed back pain physical function ( Rol and Disability Question naire ) , health status ( Arthritis Impact Measurement Scales ) , self-efficacy , and time spent in physical activity . Compared with patients receiving usual care , intervention patients reported significantly better scores on the Rol and Disability Question naire ( P = .009 ) , mental functioning ( P = .009 ) , self-efficacy to manage ALBP ( P = .03 ) , time spent in physical activity ( P = .047 ) , and reduced fears of movement/reinjury ( P = .005 ) after 12 months . CONCLUSION A self-management program can improve and maintain functional status , mental functioning , and self-efficacy to manage future symptoms for 1 year among primary care patients with ALBP living in the urban , inner city The aim of the present r and omized , controlled study was to evaluate the effect of a 5-day teaching program for diabetic patients on their quality of life 1 and 2 years afterwards . Three hundred and nineteen insulin-treated patients , of mean age 38.2+/-14.1 years and mean duration of the disease 9.0+/-6.9 years were followed up at reeducation sessions 1 and 2 years after the program . A group of 241 insulin-treated patients were also followed up and served as a control group . At baseline and 1 and 2 years later , we have assessed patients ' well-being , using a st and ard 22-item question naire . There was a significant increase in overall well-being of patients one ( P < 0.0001 ) and 2 years ( P < 0.001 ) after the program , due to reduction in depression and anxiety and increase in positive well-being after 1 year and decrease in depression and increase in positive well-being after 2 years as compared to the control group . There was an improvement in glycaemic control of the educated patients as compared to the control group ( P < 0.01 ) . The results from the present study demonstrate that structured patient education improves patients ' well-being 1 and 2 years after the teaching program Objectives : We developed a patient centred approach to chronic disease self management by providing information design ed to promote patient choice . We then conducted a r and omised controlled trial of the approach in inflammatory bowel disease ( IBD ) to assess whether it could alter clinical outcome and affect health service use . Design : A multicentre cluster r and omised controlled trial . Setting : The trial was conducted in the outpatient departments of 19 hospitals with r and omisation by treatment centre , 10 control sites , and nine intervention sites . For patients at intervention sites , an individual self management plan was negotiated and written information provided . Participants : A total of 700 patients with established inflammatory bowel disease were recruited . Main outcome measures : Main outcome measures recorded at one year were : quality of life , health service re source use , and patient satisfaction . Secondary outcomes included measures of enablement — confidence to cope with the condition . Results : One year following the intervention , self managing patients had made fewer hospital visits ( difference −1.04 ( 95 % confidence interval ( CI ) −1.43 to −0.65 ) ; p<0.001 ) without increase in the number of primary care visits , and quality of life was maintained without evidence of anxiety about the programme . The two groups were similar with respect to satisfaction with consultations . Immediately after the initial consultation , those who had undergone self management training reported greater confidence in being able to cope with their condition ( difference 0.90 ( 95 % CI 0.12–1.68 ) ; p<0.03 ) . Conclusions : Adoption of this approach for the management of chronic disease such as IBD in the NHS and other managed health care organisations would considerably reduce health provision costs and benefit disease control

To date there is only a small and heterogeneous body of evidence on the effectiveness of family oriented approaches for bipolar disorder , and it is not yet possible to draw any definite conclusions to support their use as an adjunctive treatment for bipolar disorder .

BACKGROUND Pharmacological treatments are the principal intervention for bipolar disorder . Alone , however , they are not sufficient to control symptoms and maintain psychosocial functioning . Adjunctive psychosocial interventions may help to improve the patient 's condition and the course of the illness . Family interventions are deserving of special attention , since they may help to relieve the burden of care borne by relatives and caregivers , which in turn may facilitate the task of supporting the patient . OBJECTIVES The objective of this review was to investigate the effectiveness of family interventions in the treatment of bipolar disorder compared with no intervention and other forms of intervention .

BACKGROUND Levels of expressed emotion ( EE ) in relatives are consistent predictors of relapse among bipolar and other mood disordered patients followed naturalistically . However , few studies have examined whether levels of EE predict the course of illness for patients engaged in psychosocial interventions . METHODS This study examined whether EE levels among caregivers moderated the success of family-based psychosocial interventions for patients with bipolar disorder . EE was examined as a predictor of symptomatic outcome in two groups : ( 1 ) bipolar patients receiving family-focused psychoeducational treatment ( FFT ) or integrated family and individual treatment ( IFIT ) , and ( 2 ) bipolar patients receiving crisis management ( CM ) , a less intensive intervention design ed to emulate community care . Bipolar patients ( N = 125 ) began the study in an acute illness episode , were stabilized on st and ard pharmacotherapy regimens , and followed for up to 2 years . RESULTS Family EE status was not associated with time to relapse in either group . However , patients with high EE relatives reported higher levels of depression over the 2-year term of follow-up , regardless of treatment condition . An examination of the dimensions of EE ( critical comments and emotional overinvolvement ) indicated that a higher frequency of critical comments predicted higher levels of mania and depression at follow-up . Additionally , the association between EE criticism and levels of mania symptoms was stronger among patients in CM than among patients in family treatment . LIMITATIONS The participants were recruited from two separate treatment protocol s. Patients in the IFIT protocol were not r and omly assigned to treatments . CONCLUSIONS EE is a predictor of symptom severity among bipolar patients undergoing pharmacological and psychosocial treatments , but family intervention may mitigate this association In a sample of 62 patients with Bipolar I disorder , the authors used a repeated measures longitudinal design to examine whether global family functioning was associated with the presence of a concurrent bipolar episode as well as whether global family functioning was associated with the presence of manic and depressive episodes in the following 3 months . Participants were recruited for a r and omized clinical trial examining the efficacy of family treatments combined with pharmacotherapy for bipolar disorder . Global family functioning was repeatedly measured with both clinician-rated and patient-rated assessment instruments over the 28-month study period . Results indicated that mood episodes were associated with concurrent global family functioning within individuals , but global family functioning was not associated with episode status in the subsequent 3 months . The repeated measures nature of these results suggests that global family functioning and bipolar episodes may fluctuate in concert with each other but that global family functioning is not associated with subsequent change in episode status The present study investigated the greater symptom severity and poorer treatment response found in patients with bipolar illness and anxiety comorbidity , and examined depression as a potential mediator of this relationship . The sample consisted of 92 patients in an acute episode of Bipolar I Disorder with a current or past history of an anxiety disorder . Diagnoses were based on structured clinical interview , and participants were assessed at pre-treatment and then r and omly assigned to pharmacotherapy alone or pharmacotherapy plus family intervention . Patients were assessed on a monthly basis by blind assessors over 28 months . Compared to patients without anxiety comorbidity , individuals with bipolar disorder and an anxiety disorder possessed greater current symptom severity , even after controlling for depression severity . Logistic regression analysis identified that being female and having higher current depression but not manic severity predicted comorbid anxiety . Comorbid anxiety was associated with poorer treatment response in the sample regardless of treatment type , particularly in subsequent depressive symptoms . Multiple regression analyses indicated that current depression but not manic severity partially mediated the relationship between comorbid anxiety and treatment outcome . Results from the current study investigating comorbid anxiety disorders are consistent with past research limited to anxiety symptoms . Depression only partially accounted for the link between comorbid anxiety and greater symptom severity and poorer treatment response , and examination of other factors is warranted . Because of the clinical relevance of comorbid anxiety in severe affective disorders , treatments design ed to specifically address both concerns are needed Bipolar disorder ( BPD ) has received increasing attention from public and professional sources . Although pharmacologic treatments are considered the sine qua non in the treatment of youth with BPD , psychosocial interventions are critical to assist the child and family cope with symptoms that carry with them significant morbidity and mortality . Treatments developed to date are few in number ; all are psychoeducationally based , using cognitive-behavioral and family systems interventions within a biopsychosocial framework . This paper review s possible mediators of outcome , including caregiver concordance , children 's social skills , hopelessness , and family stress . The author has developed two family-based psychoeducational interventions for the treatment of youth with BPD : multifamily psychoeducation groups ( MFPG ) and individual family psychoeducation ( IFP ) . These treatments are both described and the results from a previously published r and omized clinical trial ( RCT ) of MFPG are summarized . Then , new findings from an RCT of IFP are presented , along with preliminary pilot data from an exp and ed version of IFP . The paper concludes with recommendations for future research In recent years , lower serum levels have been recommended for maintenance therapy with lithium . We studied 94 patients with bipolar disorder in a r and omized , double-blind , prospect i ve trial of two different doses of lithium for maintenance therapy : the " st and ard " dose , adjusted to achieve a serum lithium concentration of 0.8 to 1.0 mmol per liter , and a " low " dose , result ing in a serum concentration of 0.4 to 0.6 mmol per liter . The group medians of the patients ' average serum lithium levels were 0.83 mmol per liter for the patients in the st and ard-range group and 0.54 mmol per liter for those in the low-range group . Six of 47 patients ( 13 percent ) assigned to receive lithium doses that would produce serum levels in the st and ard range had relapses while on protocol , as compared with 18 of 47 ( 38 percent ) assigned to the low-dose range . The risk of relapse was 2.6 times higher ( 95 percent confidence interval , 1.3 to 5.2 ) among patients in the low-range group than among those in the st and ard-range group . Side effects , including tremor , diarrhea , urinary frequency , weight gain , and a metallic taste in the mouth , were more frequent in the st and ard-range group . We conclude that doses result ing in serum lithium levels from 0.8 to 1.0 mmol per liter are more effective in treating bipolar disorder than those that result in lower serum lithium concentrations , although the higher doses are associated with a higher incidence of side effects . Recent findings about the limited nephrotoxicity of lithium , along with our observations , suggest that physicians should attempt to maintain serum lithium levels between 0.8 and 1.0 mmol per liter in most patients with bipolar disorder and that they should attempt to enhance patients ' underst and ing of and compliance with this regimen BACKGROUND Family therapy is sometimes used as adjunctive treatment to pharmacotherapy to help patients recover from mood episodes of bipolar I disorder . However , the efficacy of this practice is not known . METHODS Ninety-two patients meeting criteria for a current bipolar I mood episode were r and omly assigned to family therapy plus pharmacotherapy , multifamily psychoeducational group therapy plus pharmacotherapy , or pharmacotherapy alone . Time to recovery was analyzed with survival analysis . RESULTS The proportion of subjects within each treatment group who recovered did not significantly differ , nor did time to recovery . LIMITATIONS The analyses did not include other outcomes such as psychosocial functioning , prophylaxis against recurrences of mood episodes , or compliance with pharmacotherapy . CONCLUSIONS Neither adjunctive family therapy nor adjunctive multifamily psychoeducational group therapy significantly improves the rate of recovery from mood episodes of bipolar I disorder , compared to treatment with pharmacotherapy alone Family psychoeducational programs are efficacious adjuncts to pharmacotherapy for patients with schizophrenic and bipolar disorders , but little is known about what these programs change about families . The authors assessed changes in face-to-face interactional behavior over 1 year among families of bipolar patients who received a 9-month family-focused psychoeducational therapy ( FFT ; n = 22 ) or crisis management with naturalistic follow-up ( CMNF ; n = 22 ) , both administered with maintenance pharmacotherapy . Members of families who received FFT showed more positive nonverbal interactional behavior during a 1-year posttreatment problem-solving assessment than families who received CMNF , although no corresponding decreases were seen in negative interactional behaviors . The positive effect of family treatment on patients ' symptom trajectories over 1 year was partially mediated by increases in patients ' positive nonverbal interactional behaviors during this same interval CONTEXT Evidence of psychosocial disability in bipolar disorder is based primarily on bipolar I disorder ( BP-I ) and does not relate disability to affective symptom severity and polarity or to bipolar II disorder ( BP-II ) . OBJECTIVE To provide detailed data on psychosocial disability in relation to symptom status during the long-term course of BP-I and BP-II . DESIGN A naturalistic study with 20 years of prospect i ve , systematic follow-up . SETTING Inpatient and outpatient treatment facilities at 5 US academic centers . Patients One hundred fifty-eight patients with BP-I and 133 patients with BP-II who were followed up for a mean ( SD ) of 15 ( 4.8 ) years in the National Institute of Mental Health Collaborative Depression Study . MAIN OUTCOME MEASURES The relationship , by r and om regression , between Range of Impaired Functioning Tool psychosocial impairment scores and affective symptom status in 1-month periods during the long-term course of illness from 6-month and yearly Longitudinal Interval Follow-up Evaluation interviews . RESULTS Psychosocial impairment increases significantly with each increment in depressive symptom severity for BP-I and BP-II and with most increments in manic symptom severity for BP-I. Subsyndromal hypomanic symptoms are not disabling in BP-II , and they may even enhance functioning . Depressive symptoms are at least as disabling as manic or hypomanic symptoms at corresponding severity levels and , in some cases , significantly more so . At each level of depressive symptom severity , BP-I and BP-II are equally impairing . When asymptomatic , patients with bipolar disorder have good psychosocial functioning , although it is not as good as that of well controls . CONCLUSIONS Psychosocial disability fluctuates in parallel with changes in affective symptom severity in BP-I and BP-II . Important findings for clinical management are the following : ( 1 ) depressive episodes and symptoms , which dominate the course of BP-I and BP-II , are equal to or more disabling than corresponding levels of manic or hypomanic symptoms ; ( 2 ) subsyndromal depressive symptoms , but not subsyndromal manic or hypomanic symptoms , are associated with significant impairment ; and ( 3 ) subsyndromal hypomanic symptoms appear to enhance functioning in BP-II This clinical project compares the relative impact of two types of multiple family groups on psychiatric in patients and their families . Forty patients with a diagnosis of affective disorder , and their family members , were r and omly assigned to a traditional multiple family group with a process orientation that emphasized support , destigmatization , and self-help about common problems ; or to a psychoeducational multiple family group that emphasized the provision of information about the patient 's illness and methods of coping with it effectively . Both groups , which met for four hours on a Saturday afternoon , were an integral part of an ongoing inpatient program specializing in the treatment of affective disorders . Pre- and post- measures were obtained regarding family and patient knowledge about affective disorders , level of personal distress , attitudes about the illness , and dyadic adjustment . In addition , both patients and family members were asked to rate their satisfaction with the group experience . A number of differences in knowledge , attitude and dyadic adjustment were found in the participants of both groups immediately following their respective group sessions , but there were only a few statistically significant differences between the two groups . Those who attended the psychoeducational session , however , reported significantly more satisfaction with the experience Family affect was examined as a predictor of difficulty implementing a 9-month , manual-based , psychoeducational family therapy for recently manic bipolar patients . Prior to therapy , family members were administered measures to assess both their expressed emotion and affective behavior during a family interaction task . Following family treatment , both therapists and independent observers rated the overall difficulty of treating the family , and therapists also rated each participant 's problem behaviors during treatment , in the areas of affect , communication , and resistance . Therapists regarded affective problems among relatives and resistance among patients as central in determining the overall difficulty of treating the family . Relatives ' critical behavior toward patients during the pretreatment interaction task predicted both independent observers ' ratings of overall treatment difficulty and therapists ' perceptions of relatives ' affective problems during treatment . Moreover , patients ' residual symptoms predicted independent observers ' ratings of overall difficulty and therapists ' perceptions of patients ' resistance to the family intervention . Results suggest that difficulties in conducting a manual-based family intervention can be predicted from systematic , pretreatment family and clinical assessment BACKGROUND Few studies have examined the combined effects of psychosocial treatment and pharmacotherapy for bipolar disorder . This study used a r and omized , controlled design to examine a 9-month , manual-based program of family-focused psychoeducational treatment ( FFT ) . METHODS Bipolar patients ( N = 101 ) were recruited shortly after an illness episode and r and omly assigned to 21 sessions of FFT ( n = 31 ) or to a comparison treatment involving two family education sessions and follow-up crisis management ( CM ; n = 70 ) . Both treatments were delivered over 9 months ; patients were simultaneously maintained on mood stabilizing medications . Patients were evaluated every 3 months for 1 year as to relapse status , symptom severity , and medication compliance . RESULTS Patients assigned to FFT had fewer relapses and longer delays before relapses during the study year than did patients in CM . Patients in FFT also showed greater improvements in depressive ( but not manic ) symptoms . The most dramatic improvements were among FFT patients whose families were high in expressed emotion . The efficacy of FFT could not be explained by differences among patients in medication regimes or compliance . CONCLUSIONS Family-focused psychoeducational treatment appears to be an efficacious adjunct to pharmacotherapy for bipolar disorder . Future studies should evaluate family treatment against other forms of psychotherapy matched in amount of therapist-patient contact Recently hospitalized bipolar , manic patients ( N = 53 ) were r and omly assigned to a 9-month , manual-based , family-focused psychoeducational therapy ( n = 28 ) or to an individually focused patient treatment ( n = 25 ) . All patients received concurrent treatment with mood-stabilizing medications . Structured follow-up assessment s were conducted at 3-month intervals for a 1-year period ofactive treatment and a 1-year period of posttreatment follow-up . Compared with patients in individual therapy , those in family-focused treatment were less likely to be rehospitalized during the 2-year study period . Patients in family treatment also experienced fewer mood disorder relapses over the 2 years , although they did not differ from patients in individual treatment in their likelihood of a first relapse . Results suggest that family psychoeducational treatment is a useful adjunct to pharmacotherapy in decreasing the risk of relapse and hospitalization frequently associated with bipolar disorder The relative benefit of adding a structured psychoeducational intervention to st and ard medication treatment for married patients with bipolar disorder and their spouses was assessed . Patients were r and omly assigned to receive either medication management or medication management plus a marital intervention with their spouses for an 11-month period . Patients ' symptoms , functioning , and adherence to their medication regimens were measured at study entry and at 11 months . Significant effects favoring the combined treatments were observed for overall patient functioning but not for symptom levels . The marital intervention was associated with improved medication adherence . Combined psychosocial and medication treatment does not affect patients ' symptom levels beyond the effects of medication alone , but it does result in significant incremental gains in overall patient functioning The present study assessed fidelity to the behavioral family management ( BFM ) model for treating bipolar disorder patients and their families . The BFM Therapist Competency/Adherence Scale ( BFM-TCAS ) was developed to evaluate clinicians ' competency and adherence to BFM , as outlined by Miklowitz ' ( 1989 ) BFM Manual for use with bipolar patients . Therapist competency and treatment adherence was also evaluated with regard to two family characteristics : overall level of family difficulty and family expressed emotion ( EE ) status . The BFM-TCAS was used to code 78 videotaped sessions of 26 families with a bipolar member , selected from a larger treatment study of bipolar disorder patients . The findings suggest that , overall , clinicians adhered closely to the BFM manual . Specific areas in which there was high competency and treatment adherence were ( a ) skill in conveying factual information about bipolar illness , ( b ) establishment of a therapeutic environment , and ( c ) ability to take comm and of therapy sessions . The one area in which there was less competency and relatively weak adherence to the manual was the use of between-session homework assignments to assist families in mastering the BFM exercises . Results of this study also suggest that , for the most part , therapist competency and adherence ratings were not related to overall level of difficulty or to family EE status This paper reports the results at follow-up of a r and omized clinical trial of combining family intervention with drug treatment during hospitalization for patients with affective disorder . The results suggest that female bipolar patients and their families benefited from family intervention , whereas unipolar patients and families did not . Patient outcome was positively correlated with the achievement of the goals of family intervention BACKGROUND Research has begun to eluci date the optimal pharmacological treatments for pediatric-onset bipolar patients , but few studies have examined the role of psychosocial interventions as adjuncts to pharmacotherapy in maintenance treatment . This article describes an adjunctive family-focused psychoeducational treatment for bipolar adolescents ( FFT-A ) . The adult version of FFT has been shown to be effective in forestalling relapses in two r and omized clinical trials involving bipolar adults . METHODS FFT-A is administered to adolescents who have had an exacerbation of manic , depressed , or mixed symptoms within the last 3 months . It is given in 21 outpatient sessions of psychoeducation , communication enhancement training , and problem solving skills training . We describe modifications to the adult FFT model to address the developmental issues and unique clinical presentations of pediatric-onset patients . RESULTS An open treatment trial involving 20 bipolar adolescents ( 11 boys , 9 girls ; mean age 14.8+/-1.6 ) found that the combination of FFT-A and mood stabilizing medications was associated with improvements in depression symptoms , mania symptoms , and behavior problems over 1 year . LIMITATIONS These early results are based on a small-scale open trial . CONCLUSIONS Results from an ongoing r and omized controlled trial will clarify whether combining FFT-A with pharmacotherapy improves the 2-year course of adolescent bipolar disorder . If the results are positive , then a structured manual-based psychosocial approach will be available for clinicians who treat adolescent bipolar patients in the community Abstract Background : The effectiveness of family intervention in schizophrenia has mainly been tested by controlled trials which recruited patients after hospital discharge . Less is known about its effectiveness when chronic schizophrenics displaying negative rather than positive symptoms are engaged in treatment . This study was conducted in two community-based rehabilitation units for chronic psychiatric patients and was planned to test : ( 1 ) whether family intervention combined with individual psychosocial treatment is more effective than individual psychosocial treatment in improving the clinical and social prognosis of schizophrenic patients belonging to high expressed emotion ( high-EE ) families , and ( 2 ) whether family intervention exerts its effect on the patients through the reduction of EE in their families . Methods : Forty patients from high-EE families , all under neuroleptic medication and in remission at intake , were evenly assigned to individual psychosocial treatment or to psychoeducational family intervention plus individual psychosocial treatment . Individual treatment consisted of vocational and social skills training ; family intervention mainly comprised 13 group sessions with relatives . Patients were treated for 12 months and were followed-up for the next 2 years . Measures of clinical outcome comprised relapse , hospitalization and clinical exacerbation . Measures of social outcome included social functioning and role performance . Re-employment served as an additional measure at the follow-up assessment s. Results : The experimentals were free of relapses and hospitalizations during the 1st year of follow-up . The difference in relapse rates between experimentals and controls over the same period was statistically significant ( P = 0.05 ) , especially if drop-outs were included in the statistical analysis . The difference in hospitalization rates did not yield any statistical significance . All differences declined in the 2nd year of follow-up . Family intervention was found to be positively , but not significantly , associated with higher reversal rates from high to low EE , especially among full attenders of relatives ' group sessions . High EE was identified as a predictor of relapse , but not of hospitalization , over the 2-year follow-up period . Conclusion : Results support the importance of encompassing family members in the community care and tertiary prevention of schizophrenia BACKGROUND Several studies have established the efficacy of psychosocial interventions as adjuncts to pharmacotherapy in the symptom maintenance of bipolar disorder . This study concerned a new psychosocial approach - integrated family and individual therapy ( IFIT ) - that synthesizes family psychoeducational sessions with individual sessions of interpersonal and social rhythm therapy . METHOD Shortly after an acute illness episode , 30 bipolar patients ( DSM-IV criteria ) were assigned to open treatment with IFIT ( up to 50 weekly sessions of family and individual therapy ) and mood-stabilizing medications in the context of a treatment development study . Their outcomes over 1 year were compared with the outcomes of 70 patients from a previous trial who received st and ard community care , consisting of 2 family educational sessions , mood-stabilizing medications , and crisis management ( CM ) . Patients in both sample s were evaluated as to symptomatic functioning at entry into the project and then every 3 months for 1 year . RESULTS Patients in IFIT had longer survival intervals ( time without relapsing ) than patients in CM . They also showed greater reductions in depressive symptoms over 1 year of treatment relative to their baseline levels . The results could not be explained by group differences in baseline symptoms or pharmacologic treatment regimens . CONCLUSION Combining family and individual therapy with medication may protect episodic bipolar patients from early relapse and ongoing depressive symptoms . Further examination of this integrative model within r and omized controlled trials is warranted The course of bipolar I disorder is characterized by frequently fluctuating levels of manic and depressive symptoms . In the current study , we sought to characterize the month-by- month course of this disorder in 61 patients who were originally enrolled in a clinical trial and were followed for a mean of 23.7 months ( SD = 6.1 ) . All patients in the trial received medication management ; some received family psychosocial interventions as well . On a monthly basis , we assessed symptom severity using the Modified Hamilton Rating Scale for Depression ( MHRSD ) and the Bech-Rafaelson Mania Scale ( BRMS ) . Each month , we categorized each participant as fully symptomatic , partially symptomatic , or asymptomatic in terms of both depressed and manic symptoms . We found that the median percent time fully symptomatic was 8 % , the median percent time partially symptomatic was 22 % , and the median percent time asymptomatic was 59 % . Using DSM-IV-TR criteria for defining an acute mood episode , we found that the median length of episode was 1 month , and participants experienced , on average , one episode every 8 months . Estimates concerning percent time fully symptomatic and asymptomatic converge with those reported in other data sets Background : Environmental stress has an important role in the course of bipolar disorder . Some findings have shown that family beliefs about the illness could predict family burden , and this burden could influence the outcome of bipolar disorder . To the best of our knowledge , there is scant information about the effects of family intervention on the caregiver ’s burden in bipolar disorder . The aim of this study was to assess the effects of psychoeducational family intervention on bipolar patients ’ caregivers , including the assessment of the caregiver ’s burden . Methods : 45 medicated euthymic bipolar out patients were r and omized into an experimental and a control group . Relatives of patients from the experimental group received 12 psychoeducational , 90-min sessions about bipolar disorder and coping skills . The caregivers ’ knowledge of bipolar disorder , the relationship subscales of the Family Environment Scale , and the family burden subscales from an adapted version of the Social Behavior Assessment Schedule were assessed for both caregiver groups before and after the intervention . Results : Psychoeducated caregivers significantly improved their knowledge of bipolar disorder and reduced both the subjective burden and the caregiver ’s belief about the link between the objective burden and the patient . No significant differences were found in the objective burden nor in the family relationship subscales . Conclusions : These preliminary results suggest that psychoeducational intervention on caregivers of bipolar patients may improve the caregiver ’s knowledge of the illness , reduce their distress or subjective burden and alter their beliefs about the link between the disruptions in their life and the patient ’s illness BACKGROUND Bipolar patients are at risk for relapses of their illness even when undergoing optimal pharmacotherapy . This study was performed to determine whether combining family-focused therapy ( FFT ) with pharmacotherapy during a postepisode interval enhances patients ' mood stability during maintenance treatment . METHODS In a r and omized controlled trial , 101 bipolar patients were assigned to FFT and pharmacotherapy or a less intensive crisis management ( CM ) intervention and pharmacotherapy . Outcome assessment s were conducted every 3 to 6 months for 2 years . Participants ( mean + /- SD age , 35.6 + /- 10.2 years ) were referred from inpatient or outpatient clinics after onset of a manic , mixed , or depressed episode . FFT consisted of 21 sessions of psychoeducation , communication training , and problem-solving skills training . Crisis management consisted of 2 sessions of family education plus crisis intervention sessions as needed . Both protocol s lasted 9 months . Patients received pharmacotherapy for 2 study years . Main outcome measures included time to relapse , depressive and manic symptoms , and medication adherence . RESULTS Rates of study completion did not differ across the FFT ( 22/31 , 71 % ) and CM groups ( 43/70 , 61 % ) . Patients undergoing FFT had fewer relapses ( 11/31 , 35 % ) and longer survival intervals ( mean + /- SD , 73.5 + /- 28.8 weeks ) than patients undergoing CM ( 38/70 , 54 % ; mean + /- SD , 53.2 + /- 39.6 weeks ; hazard ratio , 0.38 ; 95 % confidence interval , 0.20 - 0.75 ; P = .003 ; intent to treat ) . Patients undergoing FFT showed greater reductions in mood disorder symptoms and better medication adherence during the 2 years than patients undergoing CM . CONCLUSION Combining family psychoeducation with pharmacotherapy enhances the postepisode symptomatic adjustment and drug adherence of bipolar patients OBJECTIVE The purpose of this study was to evaluate the outcome of bipolar disorder in the context of maintenance pharmacotherapy . METHOD Eighty-two bipolar out patients were followed prospect ively for a mean of 4.3 years ( minimum of 2 years ) ; symptom rating and psychosocial outcome scales were used , and pharmacotherapy was rated on a 5-point scale . RESULTS Despite continual maintenance treatment , survival analysis indicated a 5-year risk of relapse into mania or depression of 73 % . Of those who relapsed , two-thirds had multiple relapses . Relapse could not be attributed to inadequate medication . Even for those who did not relapse , considerable affective morbidity was observed . A measure of cumulative affective morbidity appeared to be a more sensitive correlate of psychosocial functioning than was the number of relapses . Poor psychosocial outcome paralleled poor syndromal course . Poor psychosocial functioning , especially occupational disruption , predicted a shorter time to relapse . Depressions were most strongly related to social and family dysfunction . CONCLUSIONS Even aggressive pharmacological maintenance treatment does not prevent relatively poor outcome in a significant number of bipolar patients OBJECTIVE To test whether the statistically significant results of a r and omized clinical trial of an inpatient family intervention were clinical ly significant for hospital practice , the authors reanalyzed outcome data using a measure of clinical significance based on the extent to which patients had recovered during the course of the intervention . METHODS A total of 169 hospitalized subjects and their families were r and omly assigned to a psychoeducational inpatient family intervention or to a comparison group . Patient and family outcome measures were assessed at admission , discharge , and six and 18 months after admission . Analyses of statistically significant differences in outcome suggested that inpatient family intervention was effective for certain patient subgroups identified by gender and diagnosis . Global Assessment Scale scores two or more st and ard deviations above the pretreatment ( admission ) mean were used as indicators for clinical ly significant improvement . RESULTS The re analysis confirmed that inpatient family intervention was associated with clinical ly significant improvement at discharge , especially for female patients and patients with chronic schizophrenia and bipolar disorder . These effects were maintained six months after admission before attenuating at 18 months . CONCLUSIONS Inpatient family intervention results in clinical ly meaningful outcomes for certain subgroups of patients and their families In a r and omized clinical trial of Inpatient Family Intervention ( IFI ) for 169 in patients with schizophrenia , affective disorder , and a residual group of other diagnoses , results suggested significant effects favoring IFI for patients and their families . The treatment effects were limited to females and to two diagnostic groups : chronic schizophrenia patients and the bipolar subgroup of affective disorders OBJECTIVES Multi-family psychoeducation groups ( MFPG ) have been developed and tested for adults , but not for children with bipolar disorder ( BPD ) . We present data from a pilot study of our manual-driven MFPG treatment for families of children with mood disorders and address two questions : Do families of children with BPD and families of children with major depressive disorder/dysthymic disorder ( MDD/DD ) : 1 ) differ at treatment entry ? ; 2 ) benefit equally from intervention ? METHOD A total of 35 children ( n=16 , BPD ; n=19 , MDD/DD ) aged 8 - 11 years and their parents were r and omized into immediate MFPG plus treatment as usual ( TAU ) or wait-list + TAU and assessed periodically . RESULTS At baseline , there was a trend toward parents in BPD families being more knowledgeable about mood symptoms than parents in MDD/DD families ( p < 0.04 ) . Additionally at baseline , children with BPD evidence d greater mood severity historically and a trend toward more hospitalizations , day treatment , outpatient treatment , medication trials , and placement in special education classrooms than children with MDD/DD . Immediately following and 4 months post-treatment , both BPD and MDD/DD families described having gained knowledge , skills , support , and positive attitudes during treatment . MDD/DD families increased their knowledge of symptoms to the same level as BPD families . CONCLUSIONS While BPD families enter treatment with more impaired children and more extensive treatment histories , both BPD and MDD/DD families benefit from intervention . The clinical issues concerning combining families of children with bipolar and depressive spectrum illnesses in groups are discussed . Clinical impressions suggest that such combinations are clinical ly feasible and potentially beneficial This study examined the impact of adjunctive multi-family psychoeducation groups ( MFPG ) on mood-disordered children aged 8 to 11 and their families . Participants were 35 children and 47 parents from families r and omly assigned to either immediate MFPG plus treatment as usual ( n = 18 ) or a 6-month wait-list condition plus treatment as usual ( n = 17 ) . At the 6 month follow up , immediate treatment families reported : Increased parental knowledge about childhood mood symptoms ; increased positive family interactions as reported by the parent ; increased perceptions of parental support as reported by children ; and increased utilization of appropriate services by families . Expected impact on decreasing negative family interactions was not found . Results are largely consistent with hypothesized findings and support the need to further investigate the adjunctive role of psychoeducation in the treatment of childhood mood disorders

Conclusion : Pharmacy technicians are utilized most often to support MTM through assistance in medication reconciliation . St and ardized training for pharmacy technicians that delineates administrative support from pharmacists ' role of clinical decision making could help pharmacists obtain greater efficiency in MTM delivery

Background : Documented barriers to Medication Therapy Management ( MTM ) delivery , such as limited time and inefficient workflow may be overcome by utilizing support staff for administrative services . However , it is unknown how pharmacy technicians have been historically utilized to assist pharmacists in MTM‐delivery . Objective : To characterize literature describing pharmacy technicians ' participation in actions commonly undertaken in the provision of MTM services .

BACKGROUND The collection of a complete , verified medication history is essential to patient safety . The involvement of clinical pharmacists has been shown to improve the completeness and accuracy of medication histories ; however , to our knowledge , involvement of pharmacy technicians has not been studied . OBJECTIVE Our aim was to determine whether verification of medication histories by pharmacy technicians in the emergency department ( ED ) would result in fewer errors in inpatient medication regimens compared to verification by the admitting physician team . METHODS We performed a prospect i ve cohort study of adult ED patients admitted for continuing care . In the intervention group , medication reconciliation was performed by pharmacy technicians in the ED before the creation of physician admitting orders . In the control group , pharmacy technicians conducted their history taking later , after admission . Initial admitting orders were then compared to the pharmacy technicians ' medication reconciliation taken before admission ( intervention group ) or after admission ( control group ) . Medication discrepancies were classified and determined to be justified or unjustified . Unjustified discrepancies were rated for harm potential . RESULTS In our cohort of 113 intervention and 75 control subjects , the mean age was 55 years ( st and ard deviation [ SD ] 16 years ) ; 96 patients ( 51 % ) were male . In the intervention group , 566 changes to home medications were observed on admission ; 352 ( 62 % ) were unjustified . Among controls , 406 changes to home medications were observed ; 228 ( 56 % ) were unjustified . This difference was not statistically significant ( p = 0.0586 ) . The rate of unjustified medication changes per patient was likewise not significantly different ( 3.14 [ SD 2.98 ] in interventions vs. 3.17 [ SD 2.81 ] in controls ; p = 0.9570 ) . The rate of medical errors did not differ between study groups , nor did severity ratings of unjustified changes . CONCLUSIONS Medication reconciliation by pharmacy technicians in the ED did not lead to a significant reduction in unjustified medication discrepancies BACKGROUND Medication reconciliation reduces potential medication discrepancies and adverse drug events . The role of pharmacy technicians in obtaining best possible medication histories ( BPMHs ) and performing reconciliation at the admission and transfer interfaces of care for pediatric patients has not been described . OBJECTIVES To compare the completeness and accuracy of BPMHs and reconciliation conducted by a pharmacy technician ( pilot study ) and by nurses and /or pharmacists ( baseline ) . The severity of identified unintentional discrepancies was rated to determine their clinical importance . METHODS This prospect i ve cohort comparison study involved patients up to 18 years of age admitted to and /or transferred between the Cardiology ward and the Cardiac Critical Care Unit of a pediatric tertiary care teaching hospital . A pharmacy resident conducted two 3-week audits : the first to assess the completeness and accuracy of BPMHs and reconciliation performed by nurses and /or pharmacists and the second to assess the completeness and accuracy of BPMHs and reconciliation performed by a pharmacy technician . RESULTS The total number of patients was 38 in the baseline phase and 46 in the pilot period . There were no statistically significant differences between the baseline and pilot audits in terms of completion of BPMH ( 82 % [ 28/34 ] versus 78 % [ 21/27 ] , p = 0.75 ) or completion of reconciliation ( 70 % [ 23/33 ] versus 75 % [ 15/20 ] , p = 0.76 ) within 24 h of admission . Completeness of transfer reconciliation was significantly higher during the pilot study than at baseline ( 91 % [ 31/34 ] versus 61 % [ 11/18 ] , p = 0.022 ) . No significant differences between the baseline and pilot audits were found in the proportions of patients with at least one BPMH discrepancy ( 38 % [ 13/34 ] versus 22 % [ 6/27 ] , p = 0.27 ) , at least one unintentional discrepancy upon admission ( 21 % [ 7/33 ] versus 10 % [ 2/20 ] , p = 0.46 ) , or at least one unintentional discrepancy at the transfer interface ( 6 % [ 1/18 ] versus 3 % [ 1/34 ] , p = 0.58 ) . None of the 16 unintentional discrepancies were rated as causing severe patient discomfort or clinical deterioration . CONCLUSIONS A trained pharmacy technician can perform admission and transfer medication reconciliation for pediatric patients with completeness and accuracy comparable to those of nurses and pharmacists . Future studies should explore the sustainability and cost-effectiveness of this practice model BACKGROUND Medicare Part D is a voluntary prescription drug benefit for Medicare beneficiaries . As part of the coverage , medication therapy management services ( MTMS ) are m and ated for beneficiaries with chronic diseases who take multiple medications covered under part D and who are likely to incur annual costs that exceed a specified level . OBJECTIVE To predict the behavioral intention of pharmacists to provide Medicare medication therapy management services ( MTMS ) using the theory of planned behavior ( TPB ) and to determine the relationship between pharmacists ' characteristics and intention to provide MTMS . METHODS The population for this cross-sectional descriptive study consisted of all community pharmacists in Iowa . Data collection occurred through a self-administered anonymous mail survey . Two surveys each were mailed to 500 pharmacies selected through a stratified r and om sample , 1 survey for the pharmacy manager and 1 survey for a staff pharmacist if applicable . Descriptive statistics and scale reliability were calculated for each of the 4 TPB scales ( attitude , subjective norm , perceived behavioral control , and intention ) . Linear regression was used to predict intent as a function of the other 3 TPB factors , demographic factors , experience , and type of pharmacy . RESULTS Out of 212 surveys received , 203 had usable data . The usable response rate ranged from 21 % to 41 % . Pharmacists ' intent to provide MTMS was generally positive but varied in strength with a mean score of 22.47 ( + /-4.00 ) and a range of 7 - 30 . Pharmacists mostly agreed that they had appropriate training to provide MTMS but lacked time and support . The linear regression analysis found the constructs of attitude , subjective norm , and perceived behavioral control to be significant predictors of intent ( P<.05 ) . Pharmacists with stronger intent to provide MTMS were those who felt they had more control over providing MTMS , felt their peers approved of the provision of MTMS , and had a positive attitude about providing MTMS . Type of pharmacy and pharmacist demographic variables were not significant predictors of intent to provide MTMS . CONCLUSION Pharmacists showed generally positive intent to provide MTMS . Perceived behavioral control , subjective norm , and attitude were significant predictors of intent ( P<.05 ) . Strategies to help pharmacists provide MTMS should focus on finding time and support to provide MTMS rather than individual educational needs OBJECTIVE To assess the effectiveness and sustainability of a 6-month Team Education and Adherence Monitoring ( TEAM ) intervention for black patients with hypertension in community chain pharmacies . DESIGN Cluster r and omized trial . SETTING 28 chain pharmacies ( 14 TEAM and 14 control ) in five Wisconsin cities from December 2006 to February 2009 . PARTICIPANTS 576 black patients with hypertension . INTERVENTION Trained pharmacist-technician teams implemented a 6-month intervention using scheduled visits , Brief Medication Question naires ( BMQs ) , and novel toolkits for facilitating medication adherence and pharmacist feedback to patients and physicians . Control participants received patient information only . MAIN OUTCOME MEASURES Refill adherence ( ≥80 % days covered ) and changes in systolic blood pressure ( SBP ) , diastolic blood pressure , and blood pressure control using blinded assessment s at 6 and 12 months . RESULTS At baseline , all patients had blood pressure of 140/90 mm Hg or more . Of those eligible , 79 % activated the intervention ( mean 4.25 visits ) . Compared with control participants at 6 months , TEAM participants achieved greater improvements in refill adherence ( 60 % vs. 34 % , P < 0.001 ) , SBP ( -12.62 vs. -5.31 mm Hg , P < 0.001 ) , and blood pressure control ( 50 % vs. 36 % , P = 0.01 ) . Six months after intervention discontinuation , TEAM participants showed sustained improvements in refill adherence ( P < 0.001 ) and SBP ( P = 0.004 ) , though the difference in blood pressure control was not significant ( P < 0.05 ) compared with control participants . Analysis of intervention fidelity showed that patients who received the full intervention during months 1 through 6 achieved significantly greater 6- and 12-month improvements in refill adherence and blood pressure control compared with control participants . CONCLUSION A team-based intervention involving community chain pharmacists , pharmacy technicians , and novel toolkits led to significant and sustained improvements in refill adherence and SBP in black patients with hypertension The impact on the care of breast cancer patients , of a pharmacy technician-led medication review and counselling clinic , provided in an outpatient setting , was investigated using a controlled r and omised study . Compared to the controls , clinic patients showed a significantly improved level of underst and ing of their chemotherapy support medication ( 95 % CI for difference in mean knowledge rating scores=2.165–2.826 , P<0.001 ) and a significant reduction in the median number of support items required ( two compared to five in the control , P<0.001 ) . This result ed in a significant reduction in mean medication expenditure per patient ( £ 26.70 vs £ 10.20 , 95 % CI for the mean difference in cost £ 6.72–£26.26 , P<0.001 ) . The clinic was also associated with significant reductions in chemotherapy delays ( P<0.001 ) and dose reductions due to side effects ( P=0.003 ) . Other benefits from the clinic were a reduction in pharmacy dispensing time and a highly significant reduction in pharmacy time spent resolving post-clinic prescription queries ( P<0.001 ) . Taking into account the initial technician training cost , the scheme represented an annual saving to the Trust of over £ 15 000 . The clinic serves as a model for those wishing to improve outpatient services to breast cancer patients PURPOSE The ability of a pharmacy technician to support the patient screening and documentation-related functions of a pharmacist-driven osteoporosis management service was evaluated . METHODS A two-phase prospect i ve study was conducted within a large integrated health system to assess a pharmacy technician 's performance in supporting a multisite team of clinical pharmacy specialists providing postfracture care . In phase I of the study , a specially trained pharmacy technician provided support to pharmacists at five participating medical offices , helping to identify patients requiring pharmacist intervention and , when applicable , collecting patient-specific clinical information from the electronic health record . In phase II of the study , the amount of pharmacist time saved through the use of technician support versus usual care was evaluated . RESULTS The records of 127 patient cases were review ed by the pharmacy technician during phase I of the study , and a pharmacist agreed with the technician 's determination of the need for intervention in the majority of instances ( 92.9 % ) . An additional 91 patient cases were review ed by the technician in phase II of the research . With technician support , pharmacists spent less time review ing cases subsequently determined as not requiring intervention ( mean ± S.D. , 5.0 ± 3.8 minutes per case compared with 5.2 ± 4.5 minutes under the usual care model ; p = 0.78 ) . In cases requiring intervention , technician support was associated with a reduction in the average pharmacist time spent on care plan development ( 13.5 ± 7.1 minutes versus 18.2 ± 16.6 minutes with usual care , p = 0.34 ) . CONCLUSION The study results suggest that a pharmacy technician can accurately determine if a patient is a c and i date for pharmacist intervention and collect clinical information to facilitate care plan development BACKGROUND Obtaining an accurate and complete medication list ( i.e. , the best possible medication history [ BPMH ] ) is the first step in completing medication reconciliation . The ability of pharmacy technicians to obtain medication histories , relative to that of pharmacists , has not been formally assessed . OBJECTIVES To determine whether pharmacy technicians at the authors ' institution could obtain a BPMH as accurately and completely as pharmacists and if both groups met national norms for unintentional discrepancies and the success index for medication reconciliation . METHODS Pharmacy technicians were trained in obtaining a BPMH at the beginning of the study , before any patients were enrolled . Patients presenting to the emergency department were prospect ively enrolled to be interviewed separately by both a pharmacist and a technician , with information recorded on st and ard medication reconciliation forms . The completed forms for each patient were compared following each set of interviews , and discrepancies were clarified with the patient . RESULTS Fifty-nine patients were included in the study , and 3 pharmacists and 2 technicians obtained the histories . There was no significant difference between pharmacists and technicians in terms of discrepancies involving prescription drugs ( χ(2 ) = 0.52 , df = 1 , n = 118 , p = 0.47 , Cramer 's V for effect size = 0.07 ) or over-the-counter medications ( χ(2 ) = 0.09 , df = 1 , n = 118 , p = 0.77 , Cramer 's V = 0.03 ) . The mean number of discrepancies per patient did not differ significantly between the pharmacists and technicians ( t = 0.15 , df = 58 , p = 0.88 for prescription drugs ; t = -0.22 , df = 58 , p = 0.83 for over-the-counter products ) . For both groups , the number of unintentional discrepancies per patient was significantly lower and the success index for medication reconciliation significantly higher than the national average . CONCLUSIONS Trained pharmacy technicians at the authors ' institution were able to obtain a BPMH with as much accuracy and completeness as pharmacists . Both groups were significantly superior to the national average in terms of unintentional discrepancies and success index for medication reconciliation Background Medication errors occur regularly in surgical patients , especially due to transfer problems at the time of hospital admission . A method for decreasing the error rate is medication reconciliation by hospital pharmacists as part of a preoperative clinic . The role of pharmacy technicians in this process has not been studied . Objective To study the use of pharmacy technicians in medication reconciliation by measuring the effect of early reconciliation in the preoperative clinic on medication and allergy discrepancies and on inadvertent continuation of antithrombotics . A secondary objective was to study the effect of community pharmacist follow-up on recommendations to discontinue antithrombotic therapy . Methods During the pre intervention measurement period , patients received usual care by anesthesiologists , who recorded the medication and documented allergies of the patient . The intervention consisted of the addition of a pharmacy technician to the preoperative screening clinic to perform the same tasks as anesthesiologists as related to medication reconciliation . If necessary , the patient was advised on stopping the antithrombotic . On the day that the patient was supposed to stop the antithrombotic , that person 's community pharmacist contacted the patient to determine whether this had been done . The main outcome measures were the proportions of patients with one or more medication discrepancy , one or more allergy discrepancy , and one or more antithrombotic error . Results In the preintervention period , 204 patients were evaluated ; 93 were included in the postintervention analysis . The proportion of patients with one or more medication discrepancy ( RR 0.29 ; 95 % CI 0.12 to 0.71 ) was statistically significantly reduced in the postintervention group . The proportions of patients with one or more allergy discrepancy ( RR 0.76 ; 95 % CI 0.35 to 1.64 ) and one or more antithrombotic errors ( RR 0.18 ; 95 % CI 0.02 to 1.33 ) were reduced , but not significantly . Follow-up by the community pharmacist did not identify any patients who had not followed the preoperative clinic 's advice on temporarily withholding their antithrombotics . Conclusions The results of this study show that pharmacy technicians can be successfully assigned to a preoperative clinic , result ing in a statistically significant decrease in medication discrepancies Objective : Incomplete medication histories obtained on hospital admission are responsible for more than 25 % of prescribing errors . This study aim ed to evaluate whether pharmacy technicians can assist hospital physicians ’ in obtaining medication histories by performing medication reconciliation and prescribing review s. A secondary aim was to evaluate whether the interventions made by pharmacy technicians could reduce the time spent by the nurses on administration of medications to the patients . Methods : This observational study was conducted over a 7 week period in the geriatric ward at Odense University Hospital , Denmark . Two pharmacy technicians conducted medication reconciliation and prescribing review s at the time of patients ’ admission to the ward . The review s were conducted according to st and ard operating procedures developed by a clinical pharmacist and approved by the Head of the Geriatric Department . Findings : In total , 629 discrepancies were detected during the conducted medication reconciliations , in average 3 for each patient . About 45 % of the prescribing discrepancies were accepted and corrected by the physicians . “ Medication omission ” was the most frequently detected discrepancy ( 46 % of total ) . During the prescribing review s , a total of 860 prescription errors were detected , approximately one per medication review . Almost all of the detected prescription errors were later accepted and /or corrected by the physicians . “ Dosage and time interval errors ” were the most frequently detected error ( 48 % of total ) . The time used by nurses for administration of medicines was reduced in the study period . Conclusion : This study suggests that pharmacy technicians can contribute to a substantial reduction in medication discrepancies in acutely admitted patients by performing medication reconciliation and focused medication review s. Further r and omized , controlled studies including a larger number of patients are required to eluci date whether these observations are of significance and of importance for securing patient safety PURPOSE The role of pharmacists in the emergency department ( ED ) of an acute care hospital is described . SUMMARY The ED staff at Carolinas Medical Center-NorthEast care for approximately 80,000 patients per year , with approximately 215 patient visits per day . In July 2007 , clinical pharmacy services were implemented in the ED , and four dedicated ED pharmacists were hired with the primary responsibilities of medication reconciliation for admitted patients and prospect i ve review of physician orders . As these pharmacists became more involved with clinical interventions and physician consultations , two pharmacy technicians were placed in the ED to manage medication reconciliation under the supervision of a pharmacist . This allowed the ED pharmacists to assume additional clinical responsibilities , including management of patients ' antimicrobial regimens , answering of medication-related telephone calls from discharged patients and the outpatient pharmacy , multidisciplinary team involvement , formal rounding , and participation in cardiopulmonary resuscitation . CONCLUSION ED pharmacists at one institution exp and ed their clinical role by taking on more direct patient care responsibilities . Pharmacists ' interventions were well received by ED physicians , with an acceptance rate of 98 % Background Medication discrepancies are common when patients cross organisational boundaries . However , little is known about the frequency of discrepancies within mental health and the efficacy of interventions to reduce discrepancies . Objective To evaluate the impact of a pharmacy-led reconciliation service on medication discrepancies on admissions to a secondary care mental health trust . Setting In-patient mental health services . Methods Prospect i ve evaluation of pharmacy technician led medication reconciliation for admissions to a UK Mental Health NHS Trust . From March to June 2012 information on any unintentional discrepancies ( dose , frequency and name of medication ) ; patient demographics ; and type and cause of the discrepancy was collected . The potential for harm was assessed based on two scenarios ; the discrepancy was continued into primary care , and the discrepancy was corrected during admission . Logistic regression identified factors associated with discrepancies . Main outcome measure Mean number of discrepancies per admission corrected by the pharmacy technician . Results Unintentional medication discrepancies occurred in 212 of 377 admissions ( 56.2 % ) . Discrepancies involving 569 medicines ( mean 1.5 medicines per admission ) were corrected . The most common discrepancy was omission ( n = 464 ) . Severity was assessed for 114 discrepancies . If the discrepancy was corrected within 16 days the potential harm was minor in 71 ( 62.3 % ) cases and moderate in 43 ( 37.7 % ) cases whereas if the discrepancy was not corrected the potential harm was minor in 27 ( 23.7 % ) cases and moderate in 87 ( 76.3 % ) cases . Discrepancies were associated with both age and number of medications ; the stronger association was age . Conclusions Medication discrepancies are common within mental health services with potentially significant consequences for patients . Trained pharmacy technicians are able to reduce the frequency of discrepancies , improving safety Purpose The results of the 2015 National Certified Pharmacy Technician Workforce Survey are described . Methods A survey was e‐mailed to a r and omized sample of 5,000 certified pharmacy technicians ( CPhTs ) throughout the United States , with response reminders employed . Survey items eliciting demographic and work characteristics and work life attitudes were generated from the literature and qualitative interviews . This study aim ed to describe job satisfaction , sources of stress , profession and employer commitment , education and training , and reasons for entry into the profession among CPhTs and determine relationships between those variables and CPhTs ’ level of involvement in various work activities , with particular attention paid to differences in practice setting . Frequency statistics , correlation analysis , and means testing were used to meet study objectives and identify significant differences . Results A total of 516 CPhTs currently working as a pharmacy technician responded to the survey . The CPhTs reported high levels of involvement in more traditional activities but less involvement in those that involve greater cognitive load . Respondents reported moderate levels of job satisfaction and commitment and somewhat high levels of stress overall . Most CPhTs chose to be a pharmacy technician because they desired to enter a healthcare field and help people and were recruited . CPhTs derived benefit from all aspects of education and training evaluated and most from on‐the‐job training . Perceived value of education and training was associated with higher satisfaction and commitment and with lower stress . There were a number of differences in these work life attitudes across practice setting s and by involvement in various job functions . Conclusion The results of the survey indicated that job satisfaction and commitment were moderate and that stress levels were somewhat high among CPhTs . There were a number of differences in work life attitudes across practice setting s and by involvement in various job activities PURPOSE To evaluate the percentage , frequency , and types of medication history errors made by pharmacy technicians compared with nurses in the emergency department ( ED ) to determine if patient safety and care can be improved while reducing nurses ' workloads . METHODS Medication history errors were evaluated in a pre-post study comparing a historical control group ( nurses ) prior to the implementation of a pharmacy technician program in the ED to a prospect i ve cohort group ( pharmacy technicians ) . Two certified pharmacy technicians were trained by the post-graduate year one ( PGY1 ) pharmacy practice resident to conduct medication history interviews in a systematic fashion , with outside re sources ( i.e. , assisted living facility , pharmacy , physician 's office , or family members ) being consulted if any portion of the medication history was unclear or lacking information . The primary outcome compared the percentage of patients with accurate medication histories in each group . Secondary outcomes included differences between groups regarding total medication errors , types of errors , documentation of patient allergies and drug reactions , and documentation of last administration times for high-risk anticoagulant/antiplatelet medications . Accuracy was determined by review ing each documented medication history for identifiable errors , including review of electronic generated prescriptions within the hospital system as well as physician notes or histories documented on the same day ( for potential discrepancies ) . This review was performed by the pharmacy resident . The categories of errors included a drug omission , a drug commission , an incorrect or missing drug , an incorrect or missing dose , or an incorrect or missing frequency . Anonymous surveys were distributed to ED nurses to assess their feedback on the new medication reconciliation program using pharmacy technicians . RESULTS A total of 300 medication histories from the ED were evaluated ( 150 in each group ) . Medication histories conducted by pharmacy technicians were accurate 88 % of the time compared with 57 % of those conducted by nurses ( P < 0.0001 ) . Nineteen errors ( 1.1 % ) were made by pharmacy technicians versus 117 ( 8.3 % ) by nurses ( relative risk [ RR ] , 7.5 ; P < 0.0001 ) . The most common type of error was an incorrect or missing dose ( 10 versus 59 , P < 0.001 ) , followed by an incorrect or missing frequency ( 0 versus 30 , P < 0.0001 ) , and a drug commission ( 5 versus 23 , P = 0.004 ) . There were no differences between groups regarding the documentation of patient allergies . Documentation rates of high-risk anticoagulant and antiplatelet administration times were greater for pharmacy technicians than for nurses ( 76 % versus 13 % , P < 0.001 ) . CONCLUSION This study demonstrates that trained pharmacy technicians can assist prescribers and nurses by improving the accuracy of medication histories obtained in the ED Background : Primary medication nonadherence ( PMN ) occurs when patients do not fill new prescriptions . Interventions to reduce PMN have not been well described . Objectives : To determine whether 2 pharmacy-based interventions could decrease PMN . Design : Two sequential interventions with a control group were evaluated after completion . The automated intervention began in 2007 and consisted of phone calls to patients on the third and seventh days after a prescription was processed but remained unpurchased . The live intervention began in 2009 and used calls from a pharmacist or technician to patients who still had not picked up their prescriptions after 8 days . Subjects : Patients with newly prescribed cardiovascular medications received at CVS community pharmacies . Patients with r and omly selected birthdays served as the control population . Measures : Patient ab and onment of new prescription , defined as not picking up medications within 30 days of initial processing at the pharmacy . Results : The automated intervention included 852,612 patients and 1.2 million prescriptions , with a control group of 9282 patients and 13,178 prescriptions . The live intervention included 121,155 patients and 139,502 prescriptions with a control group of 2976 patients and 3407 prescriptions . The groups were balanced by age , sex , and patterns of prior prescription use . For the automated intervention , 4.2 % of prescriptions were ab and oned in the intervention group and 4.5 % in the control group ( P>0.1 ) , with no significant differences for any individual classes of medications . The live intervention was used in a group that had not purchased prescriptions after 8 days and thus had much higher PMN . In this setting 36.9 % of prescriptions were ab and oned in the intervention group and 41.7 % in the control group , a difference of 4.8 % ( P<0.0001 ) . The difference in ab and oned prescriptions for antihypertensives was 6.9 % ( P<0.0001 ) but for antihyperlipidemics was only 1.4 % ( P>0.1 ) . Conclusions : Automated reminder calls had no effect on PMN . Live calls from pharmacists decreased antihypertensive PMN significantly , although many patients still ab and oned their prescriptions Background / Objective Medication reconciliation at transitions of care decreases medication errors , hospitalizations , and adverse drug events . We compared inpatient medication histories and reconciliation across disciplines and evaluated the nature of discrepancies . Methods We conducted a prospect i ve cohort study of patients admitted from the emergency department at our 760-bed hospital . Eligible patients had their medication histories conducted and reconciled in order by the admitting nurse ( RN ) , certified pharmacy technician ( CPhT ) , and pharmacist ( RPh ) . Discharge medication reconciliation was not altered . Admission and discharge discrepancies were categorized by discipline , error type , and drug class and were assigned a criticality index score . A discrepancy rating system systematic ally measured discrepancies . Results Of 175 consented patients , 153 were evaluated . Total admission and discharge discrepancies were 1,461 and 369 , respectively . The average number of medications per participant at admission was 8.59 ( 1,314 ) with 9.41 ( 1,374 ) at discharge . Most discrepancies were committed by RNs : 53.2 % ( 777 ) at admission and 56.1 % ( 207 ) at discharge . The majority were omitted or incorrect . RNs had significantly higher admission discrepancy rates per medication ( 0.59 ) compared with CPhTs ( 0.36 ) and RPhs ( 0.16 ) ( P < .001 ) . RPhs corrected significantly more discrepancies per participant than RNs ( 6.39 vs 0.48 ; P < .001 ) ; average criticality index reduction was 79.0 % . Estimated prevented adverse drug events ( pADEs ) cost savings were $ 589,744 . Conclusions RPhs committed the fewest discrepancies compared with RNs and CPhTs , result ing in more accurate medication histories and reconciliation . RPh involvement also prevented the greatest number of medication errors , contributing to considerable pADE-related cost savings The validity and cost-effectiveness of three methods for detecting medication errors were examined . A stratified r and om sample of 36 hospitals and skilled-nursing facilities in Colorado and Georgia was selected . Medication administration errors were detected by registered nurses ( R.N.s ) , licensed practical nurses ( L.P.N.s ) , and pharmacy technicians from these facilities using three methods : incident report review , chart review , and direct observation . Each dose evaluated was compared with the prescriber 's order . Deviations were considered errors . Efficiency was measured by the time spent evaluating each dose . A pharmacist performed an independent determination of errors to assess the accuracy of each data collector . Clinical significance was judged by a panel of physicians . Observers detected 300 of 457 pharmacist-confirmed errors made on 2556 doses ( 11.7 % error rate ) compared with 17 errors detected by chart review ers ( 0.7 % error rate ) , and 1 error detected by incident report review ( 0.04 % error rate ) . All errors detected involved the same 2556 doses . All chart review ers and 7 of 10 observers achieved at least good comparability with the pharmacist 's results . The mean cost of error detection per dose was $ 4.82 for direct observation and $ 0.63 for chart review . The technician was the least expensive observer at $ 2.87 per dose evaluated . R.N.s were the least expensive chart review ers at $ 0.50 per dose . Of 457 errors , 35 ( 8 % ) were deemed potentially clinical ly significant ; 71 % of these were detected by direct observation . Direct observation was more efficient and accurate than review ing charts and incident reports in detecting medication errors . Pharmacy technicians were more efficient and accurate than R.N.s and L.P.N.s in collecting data about medication errors OBJECTIVE To evaluate the effectiveness of a telephonic medication therapy management ( MTM ) service on reducing hospitalizations among home health patients . SETTING Forty r and omly selected , geographically diverse home health care centers in the United States . DESIGN Two-stage , r and omized , controlled trial with 60-day follow-up . All Medicare- insured home health care patients were eligible to participate . Twenty-eight consecutive patients within each care center were recruited and r and omized to usual care or MTM intervention . The MTM intervention consisted of the following : ( 1 ) initial phone call by a pharmacy technician to verify active medications ; ( 2 ) pharmacist-provided medication regimen review by telephone ; and ( 3 ) follow-up pharmacist phone calls at day seven and as needed for 30 days . The primary outcome was 60-day all-cause hospitalization . DATA COLLECTION Data were collected from in-home nursing assessment s using the OASIS-C. Multivariate logistic regression modeled the effect of the MTM intervention on the probability of hospitalization while adjusting for patients ' baseline risk of hospitalization , number of medications taken daily , and other OASIS-C data elements . PRINCIPAL FINDINGS A total of 895 patients ( intervention n = 415 , control n = 480 ) were block-r and omized to the intervention or usual care . There was no significant difference in the 60-day probability of hospitalization between the MTM intervention and control groups ( Adjusted OR : 1.26 , 95 percent CI : 0.89 - 1.77 , p = .19 ) . For patients within the lowest baseline risk quartile ( n = 232 ) , the intervention group was three times more likely to remain out of the hospital at 60 days ( Adjusted OR : 3.79 , 95 percent CI : 1.35 - 10.57 , p = .01 ) compared to the usual care group . CONCLUSIONS This MTM intervention may not be effective for all home health patients ; however , for those patients with the lowest-risk profile , the MTM intervention prevented patients from being hospitalized at 60 days

Children born at ELBW were reported by parents and teachers to be at significantly greater risk than NBW controls for inattention and hyperactivity , internalizing , and externalizing symptoms . ELBW children were also at greater risk for conduct and oppositional disorders , autistic symptoms , and social difficulties . Risks for parent-reported inattention and hyperactivity , internalizing , and social problems were greater in adolescents born at ELBW . In contrast , ELBW teens self-reported lower inattention , hyperactivity , and oppositional behavior levels than their NBW peers . Depression , anxiety , and social difficulties were elevated in ELBW survivors in adulthood . Group differences were robust to region of birth , era of birth , and the presence of neurosensory impairments .

Although individuals born at extremely low birth weight ( ELBW ; < 1,000 g ) are the most vulnerable of all preterm survivors , their risk for mental health problems across the life span has not been systematic ally review ed . The primary objective of this systematic review and meta- analysis was to ascertain whether the risk for mental health problems is greater for ELBW survivors than their normal birth weight ( NBW ) peers in childhood , adolescence , and adulthood .

CONTEXT Traditionally , educational attainment , getting a job , living independently , getting married , and parenthood have been considered as markers of successful transition to adulthood . OBJECTIVE To describe and compare the achievement and the age at attainment of the above markers between extremely low-birth-weight ( ELBW ) and normal birth-weight ( NBW ) young adults . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve , longitudinal , population -based study in central -west Ontario , Canada , of 166 ELBW participants who weighed 501 to 1000 g at birth ( 1977 - 1982 ) and 145 sociodemographically comparable NBW participants assessed at young adulthood ( 22 - 25 years ) . Interviewers masked to participant status administered vali date d question naires via face-to-face interviews between January 1 , 2002 , and April 30 , 2004 . MAIN OUTCOME MEASURES Markers of successful transition to adulthood , including educational attainment , student and /or worker role , independent living , getting married , and parenthood . RESULTS At young adulthood , 149 ( 90 % ) of 166 ELBW participants and 133 ( 92 % ) of 145 NBW participants completed the assessment s at mean ( SD ) age of 23.3 ( 1.2 ) years and 23.6 ( 1.1 ) years , respectively . We included participants with neurosensory impairments ( ELBW vs NBW : 40 [ 27 % ] vs 3 [ 2 % ] ) and 7 proxy respondents . The proportion who graduated from high school was similar ( 82 % vs 87 % , P = .21 ) . Overall , no statistically significant differences were observed in the education achieved to date . A substantial proportion of both groups were still pursuing post secondary education ( 47 [ 32 % ] vs 44 [ 33 % ] ) . No significant differences were observed in employment/school status ; 71 ( 48 % ) ELBW vs 76 ( 57 % ) NBW young adults were permanently employed ( P = .09 ) . In a sub analysis , a higher proportion of ELBW young adults were neither employed nor in school ( 39 [ 26 % ] vs 20 [ 15 % ] , P = .02 by Holm 's correction ) ; these differences did not persist when participants with disabilities were excluded . No significant differences were found in the proportion living independently ( 63 [ 42 % ] vs 70 [ 53 % ] , P = .19 ) , married/cohabitating ( 34 [ 23 % ] vs 33 [ 25 % ] , P = .69 ) , or who were parents ( 16 [ 11 % ] vs 19 [ 14 % ] , P = .36 ) . The age at attainment of the above markers was similar for both cohorts . CONCLUSION Our study results indicate that a significant majority of former ELBW infants have overcome their earlier difficulties to become functional young adults OBJECTIVES To investigate the prevalence , correlates , and antecedents of autism spectrum disorders ( ASD ) in extremely preterm children . STUDY DESIGN We conducted a prospect i ve study of all births < 26 weeks gestation in the United Kingdom and Irel and in 1995 . Of 307 survivors at 11 years , 219 ( 71 % ) were assessed and compared with 153 term-born classmates . Parents completed the Social Communication Question naire ( SCQ ) to assess autism spectrum symptoms , and ASD were diagnosed by using a psychiatric evaluation . An IQ test and clinical evaluation were also administered . Longitudinal outcome data were available for extremely preterm children . RESULTS Extremely preterm children had significantly higher SCQ scores than classmates ( mean difference , 4.6 points ; 95 % CI , 3.4 - 5.8 ) . Sixteen extremely preterm children ( 8 % ) were assigned an ASD diagnosis , compared with none of the classmates . By hospital discharge , male sex , lower gestation , vaginal breech delivery , abnormal cerebral ultrasound scanning results , and not having had breast milk were independently associated with autism spectrum symptoms . By 6 years , independent associates were cognitive impairment , inattention and peer problems , withdrawn behavior at 2.5 years , and not having had breast milk . CONCLUSIONS Extremely preterm children are at increased risk for autism spectrum symptoms and ASD in middle childhood . These symptoms and disorders were associated with neurocognitive outcomes , suggesting that ASD may result from abnormal brain development in this population Replacement therapy with exogenous surfactant has been studied for both prevention and treatment of respiratory distress syndrome . Although reports demonstrate improved survival rates for surfactant-treated infants with RDS , the impact of this therapy on outcome of extremely low birth weight infants is unknown . TM Previous studies have not reported outcome after surfactant treatment for the subset of premature infants who are born at ELBWs and who are at the highest risk for complications of prematurity . We report the outcome of infants born with birth weights between 600 and 750 gm who underwent prospect i ve r and om selection to receive either surfactant or placebo as part of a multidose prevention study Poor executive function ( EF ) has been linked to attention-deficit/hyperactivity disorder ( ADHD ) . Children born at extremely low birth weight ( ELBW ; < 1000 g ) have been found to show both poor EF , as well as elevated levels of symptoms of ADHD . In the present study , we examined whether fluid intelligence moderates the link between birth weight and later ADHD symptoms by prospect ively following a cohort of 179 survivors who were born at ELBW . When participants were 8 years-old , they were matched with 145 normal birth weight ( NBW ; ≥2500 g ) control participants . At age 8 , fluid intelligence was measured , and during young adulthood ( ages 22–26 ) , participants ' self-reported levels of ADHD symptoms were examined . We found that ELBW survivors , who also showed poor fluid intelligence , had the highest rates of ADHD symptoms , and particularly , symptoms of inattention . These findings point to the importance of examining developmental trajectories that contribute to risk for psychopathology in those exposed to intrauterine adversity Discrepancies often arise among multiple informants ' reports of child and adolescent psychopathology and related constructs ( e.g. , parenting , family relationship quality and functioning , parental monitoring ) . Recently , studies using various design s ( laboratory , longitudinal , r and omized controlled trial , meta- analysis ) have revealed that discrepancies among informants ' reports ( a ) yield important information regarding where children express behaviors ( time course , features of the context [ s ] of behavioral expression ) and about the informants who observe their expression , ( b ) demonstrate stability over time in both community and clinic setting s , ( c ) predict poor child and adolescent outcomes in ways that the individual informants ' reports do not , and ( d ) can be used to identify meaningful treatment outcomes patterns within r and omized controlled trials . Using existing data sources , the articles in this special section exp and upon this emerging body of research . In particular , the articles illustrate how clinical science and practice can use informant discrepancies to increase underst and ing of the causes and consequences of , as well as treatments for , child and adolescent psychopathology Fetal programming of the hypothalamus-pituitary-adrenal ( HPA ) axis was proposed as one mechanism underlying the link between prenatal stress , adverse birth outcomes ( particularly low birth weight ) and an enhanced vulnerability for several diseases later in life . In recent studies , birth weight was significantly related to basal cortisol levels as well as to cortisol responses to pharmacological stimulation . In order to investigate the association between cortisol responses to psychological challenge , birth weight and length of gestation , 106 young healthy males were exposed to the ' Trier Social Stress Test ' . Salivary cortisol responses to the stress exposure were significantly and inversely related to the subjects ' birth weight , while the analysis of the impact of gestational age yielded inconsistent results . This finding is consistent with the concept of fetal programming of the HPA axis and provides the first preliminary evidence for an association between birth weight and adrenocortical responses to psychosocial stress . As the investigated subjects were twins , possible implication s of this sample characteristic for the present findings are discussed OBJECTIVES Our goals were to determine the mortality risk for infants weighing 501 to 1500 gm according to gestational age , birth weight , and gender and to document birth weight-related changes in mortality and morbidity over a 5-year time period . STUDY DESIGN In this observational study perinatal data were prospect ively collected by the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from May 1991 through December 1992 and compared with the corresponding data from 1987 through 1990 . St and ard definitions were used to record sociodemographic factors , perinatal events , and the neonatal course to 120 days of life , discharge , or death . RESULTS The 1991 and 1992 cohort included 4279 in-born infants . Among their mothers 10 % were < 18 years old ; 55 % were black , 31 % were white , and 11 % were Hispanic ; 14 % had received no prenatal care ; and 20 % had received antenatal corticosteroids . Multiple gestations accounted for 20 % of the births . Fifty percent of the infants were delivered by cesarean section . During 1991 and 1992 the overall survival for infants weighing 501 to 1500 gm at birth was 81 % , compared with 74 % in 1987 and 1988 . Survival at birth weight 501 to 750 gm was 44 % ; it was 81 % at 751 to 1000 gm , 92 % at 1001 to 1250 gm , and 95 % between 1251 and 1500 gm . Female infants had a significantly greater chance of surviving than male infants at similar birth weights and gestational ages . At any given gestational age , smaller infants were less likely to survive . Survival in all birth weight categories increased between 1987 and 1992 , without accompanying increases in medical morbidity . Major morbidity increased with decreasing birth weight and included late-onset septicemia 22 % , chronic lung disease ( oxygen dependence at 36 weeks ' corrected age ) 18 % , severe intraventricular hemorrhage ( grade s III and IV ) 11 % , and necrotizing enterocolitis 5 % . Twelve percent of all infants were treated with corticosteroids for chronic lung disease , including 36 % of infants who were oxygen dependent at age 28 days . The mean length of hospital stay was 69 days for survivors and 18 days for infants who died . CONCLUSIONS Mortality for infants between 501 and 1500 gm at birth has declined over the past 5 years . There are interactions between birth weight , gestational age , gender , and survival rate . This increase in survival was not accompanied by an increase in medical morbidity OBJECTIVE : To determine the risk for psychiatric disorders among extremely low birth weight ( ELBW ) survivors in their early to mid-30s and to determine whether those born small for gestational age or those exposed to a full course of antenatal corticosteroids ( ACS ) were at particularly high risk . METHODS : A prospect i ve , longitudinal , population -based cohort of 84 ELBW survivors and 90 normal birth weight ( NBW ) control participants born in Ontario , Canada from 1977 to 1982 were assessed by interviewers naive to birth weight status using the Mini-International Neuropsychiatric Interview . RESULTS : ELBW survivors had lower odds of an alcohol or substance use disorder but higher odds of current non – substance-related psychiatric problems ( odds ratio [ OR ] = 2.47 ; 95 % confidence interval [ CI ] , 1.19–5.14 ) . Those born ELBW and SGA exhibited the same patterns with larger effects . ACS-exposed ELBW survivors had even higher odds of any current non – substance-related psychiatric disorder ( OR = 4.41 ; 95 % CI , 1.65–11.82 ) , particularly generalized anxiety disorder ( OR = 3.42 ; 95 % CI , 1.06–11.06 ) , the generalized type of social phobia ( OR = 5.80 ; 95 % CI , 1.20–27.99 ) , and the inattentive subtype of attention-deficit/hyperactivity disorder ( OR = 11.45 ; 95 % CI , 2.06–63.50 ) . CONCLUSIONS : In their early to mid-30s , ELBW survivors were less likely to have alcohol or substance use disorders but may be at greater risk for other psychiatric problems . Those exposed to ACS were at especially high risk and manifested no reduction in alcohol or substance use disorders . ELBW survivors exposed to ACS may be a special group at risk for psychopathology in adulthood Objectives . To investigate behavioral and emotional problems and positive adjustment of 15-to 16-year-olds who were born at extremely low gestational age ( ELGA ) , from the perspective of parents , teachers , and teenagers . Methods . Prospect i ve follow-up was conducted of birth cohorts , with classroom control subjects . All infants who were born before 29 weeks in 1983–1984 ( mean gestational age : 27 weeks ) to mothers who resided in 3 regions of the United Kingdom were studied . A total of 82 % ( 179 of 218 ) of survivors were traced at age 15 to 16 . The 150 in mainstream school were compared with age- and gender-matched classroom control subjects ( n = 108 ) . Behavioral and emotional problems , delinquency , peer relations , self-esteem , and hobbies , were assessed by st and ardized , well-vali date d instruments , including the Strengths and Difficulties Question naire , administered by mail to parents , teenagers , and teachers . Results . Parents were more likely to rate ELGA teenagers than control subjects as in the “ abnormal ” range for hyperactivity ( 8 % vs 1 % ; difference : 7 % ; ( 95 % confidence interval [ CI ] : 2–12 ) , peer relationship problems ( 19 % vs 5 % ; difference : 14 % ; 95 % CI : 6 - 21 ) , and emotional problems ( 18 % vs 7 % ; difference : 11 % ; 95 % CI : 3 - 19 ) , but not conduct problems ( 10 % vs 5 % ; difference : 5 % ; 95 % CI : −1 to 12 ) ) . Teachers reported a similar pattern . In contrast , compared with control subjects , ELGA teenagers did not rate themselves as having more problems with peers , hyperactivity , conduct , depression , or low self-esteem . They reported more emotional problems but less delinquency , alcohol , cannabis , and other drug use . Conclusions . Compared with mainstream classmates , children who are born extremely early continue to have higher levels of parent- and teacher-reported emotional , attentional , and peer problems well into their teens . However , despite these problems , they do not show signs of more serious conduct disorders , delinquency , drug use , or depression Providing less invasive surfactant administration ( LISA ) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia ( BPD ) in r and omised controlled trials . This large cohort study compared these outcome measures between LISA‐treated infants and controls OBJECTIVE Our objective was to test the hypothesis that prenatal maternal corticosteroids would improve the subsequent response of infants to surfactant treatments . STUDY DESIGN We used the data bases of two recently published large multicenter trials of multidose surfactant treatments to retrospectively evaluate the possible interactions between maternal corticosteroids and r and omized surfactant treatments on short-term ventilatory effects , complications of respiratory distress syndrome and prematurity , and 28-day death rates . RESULTS The combined use of corticosteroids and surfactant significantly decreased overall death and death caused by respiratory distress syndrome relative to either treatment alone . Ventilatory variables at 72 hours were improved in those infants receiving both treatments , and other major complications of prematurity also tended to have decreased incidences . CONCLUSION The combined use of prenatal corticosteroids , when indicated , and postnatal surfactant improves neonatal outcome OBJECTIVE To determine whether the introduction of surfactant therapy was associated with decreased mortality for high-risk preterm neonates weighing 601 to 1300 g at birth . DESIGN Before-after observational study . SETTING Eight tertiary care neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network . PATIENTS The outcomes for neonates with birth weight 601 to 1300 g admitted in the 2 years before surfactants became available ( n = 2780 ) were compared with those of neonates admitted in the year beginning 2 months after surfactants became available ( n = 1413 ) . MAIN OUTCOME MEASURES The primary outcome measure was in-hospital mortality ; secondary outcome measures included duration s of assisted ventilation , length of hospitalization , and neonatal morbidity . RESULTS Forty percent of neonates in the postsurfactant group received surfactant ( range 28 % to 69 % at the centers ) . Mortality decreased from 27.8 % before to 19.9 % after surfactant therapy was introduced ( Mantel-Haenszel chi 2 = 31.4 , P = .001 ) . The adjusted odds ratio for mortality after surfactants became available was 0.73 ( 95 % confidence interval 0.55 to 0.95 ) . The duration of assisted ventilation and length of hospitalization increased after surfactants were introduced ( P = .0001 for both outcomes ) . CONCLUSION Mortality for neonates weighing 601 to 1300 g decreased after surfactant therapy was introduced , suggesting that the efficacy of surfactants demonstrated in r and omized controlled trials will translate into effectiveness in routine clinical care Objectives To determine the incidence of and factors predicting management strategies used for procedural pain in Canadian neonatal intensive care units and to determine whether the incidence of procedures and their management has changed since our 1997 study . Patients Five hundred eighty-two neonates who were hospitalized in any of the participating study centers were included . Methods A prospect i ve observational study was conducted in 14 Canadian neonatal intensive care units ( level III A and III B ) . Infants were followed for 1 week regarding all invasive procedures . Data were collected prospect ively by unit staff using a checklist and verified by research assistants . Results A total of 3508 tissue damaging ( mean=5.8 , SD=15 ) and 14,085 ( mean=25.6 , SD=15 ) nontissue damaging procedures were recorded . Half of procedures ( 46 % tissue damaging and 57 % nontissue damaging ) had no analgesic interventions . Opiates were used for 14.5 % of tissue-damaging procedures and sweet taste was used for 14.3 % of the tissue-damaging procedures . Factors predicting use of pharmacologic management of tissue-damaging procedures were being less ill at birth , receiving high frequency ventilatory support , and being transferred to the study center . Parental presence predicted use of sweet taste or nonpharmacologic analgesia for tissue-damaging procedures . Study site practice s varied widely with 1 unit providing analgesia for 90 % of tissue-damaging procedures . InterpretationAlthough the number of tissue-damaging procedures has decreased from 1997 and the use of analgesics has increased , the management of these procedures falls far below the recommended guidelines of the Canadian Pediatric Society . That 1 unit reached a high level of analgesic use suggests that it is possible to achieve this goal . That parental presence had a positive influence on comfort strategies supports offering encouragement and support for parents to remain with their infant during procedures OBJECTIVE This study was undertaken to determine the effects of repeated courses of antenatal corticosteroids on childhood behavior and disabilities , including cognitive delay and cerebral palsy . STUDY DESIGN Nonr and omized regional cohort of 541 very preterm infants born in Western Australia from singleton pregnancies and alive at 3 years were included in the study . MAIN OUTCOME MEASURES Physical , cognitive , and psychological assessment s up to 6 years . RESULTS Increasing numbers of antenatal corticosteroid courses were associated with a reduction in the rate of cerebral palsy . Three or more courses were also associated with increased rates of aggressive/destructive , distractible , and hyperkinetic behavior and these effects were present at both ages 3 and 6 years . Measures of internalizing behavior and intelligence quotient were unaffected by antenatal corticosteroid use . CONCLUSION Repeated antenatal courses of corticosteroids may protect against cerebral palsy but are associated with hyperactivity later in childhood BACKGROUND In southern Sc and inavia most babies with respiratory distress syndrome are initially treated with nasal continuous positive airway pressure . We performed a multicenter trial to investigate whether the addition of a single dose of porcine surfactant administered during a short intubation before the occurrence of serious deterioration could reduce the subsequent need for mechanical ventilation . METHODS We r and omly assigned 35 infants with moderate-to-severe respiratory distress syndrome to surfactant therapy ( Curosurf , 200 mg per kilogram of body weight ) plus nasal continuous positive airway pressure and 33 infants to nasal continuous positive airway pressure alone . The study was not blinded . The indications for mechanical ventilation were a ratio of arterial to alveolar oxygen tension of less than 0.15 , severe apneic attacks , or both . RESULTS Six hours after r and omization , when the median age of the babies was 18 hours , the mean ratio of arterial to alveolar oxygen tension was 0.37 in the surfactant-treated babies , as compared with 0.25 in the controls ( P < 0.001 ) . The need for subsequent mechanical ventilation was reduced with surfactant therapy ( to 43 percent of the surfactant-treated babies as compared with 85 percent of the controls ; P = 0.003 ) . When 17 infants with ratios of arterial-to-alveolar oxygen tension of less than 0.15 at r and omization were excluded , the need for mechanical ventilation was still significantly reduced in the surfactant-treated group ( to 33 percent [ 9 of 27 babies ] , as compared with 83 percent [ 20 of 24 babies ] in the control group ; ( P < 0.001 ) . After 28 days , two of the surfactant-treated babies had died , as compared with five of the control babies . CONCLUSIONS In babies with moderate-to-severe respiratory distress syndrome treated with nasal continuous positive airway pressure , a single dose of surfactant reduced the need for subsequent mechanical ventilation OBJECTIVES To test the cortisol response to adrenocorticotrophic hormone ( ACTH ) in a population of very low birth weight newborns at the end of the first week of life , and to evaluate the relationship of this response to the subsequent development of bronchopulmonary dysplasia and to the total length of oxygen dependence . METHODS Appropriate for gestational age newborns < 1500 g birth weight were enrolled prospect ively . Response to ACTH stimulation was tested on days 5 , 6 , or 7 . Baseline cortisol , stimulated cortisol , and magnitude of response were compared between babies who developed bronchopulmonary dysplasia ( BPD ) , defined as oxygen dependence at 28 days , and those who recovered without BPD . RESULTS In this population , the cortisol response to ATCH increased with increasing birth weight ( P < .001 ) . Using birth weight as a cofactor , analysis of variance showed that patients who developed BPD ( n = 34 , BW 974 + /- 192 g , mean + /- S.D. ) had significantly reduced responses to ACTH at 5 to 7 days of age compared to those who recovered ( n = 25 , BW 1251 + /- 194 g ) , P = .006 . Additionally , 84 % of patients who recovered without BPD , but only 26 % of BPD patients , achieved a prospect ively defined positive cortisol response to ACTH ( > or = 9 micrograms/dL ; P < .005 ) . Supplemental oxygen was discontinued at a younger postconceptional age in babies with a positive cortisol response to ACTH ( P < .01 ) and fewer of those babies were on supplemental oxygen at 36-week postconceptional age ( P < .01 ) . CONCLUSIONS At the end of the first week of life , infants who subsequently developed BPD and prolonged oxygen dependence had significantly lower cortisol secretion in response to ACTH than infants who recovered without BPD . We speculate that these babies may be unable to secrete adequate amounts of cortisol in a setting of increased stress , leaving them vulnerable to continuing lung injury Prenatal maternal stress has been shown to impair birth outcome and behavioral functioning in nonhuman primate offspring . Little is known about the effects of prenatal stress on behavioral development in humans . We assessed the effect of self-reported prenatal stress on behavioral characteristics of 81 newborns using the Neonatal Behavioral Assessment Scale ( NBAS ) . We suspected that high levels of perceived chronic stress during pregnancy may negatively affect the brain development of the fetus , reflected in poorer behavioral maturity and higher irritability . We found a poorer performance of newborns from high stressed mothers in the NBAS Objective To determine the survival and neurological outcome at 2 years of age of extremely low birthweight ( ELBW , birth weight 500–999 g ) infants born in the state of Victoria compared with term controls , and contrasted with ELBW cohorts from previous eras . Design and setting A population -based cohort study of consecutive ELBW infants born during 2005 in the state of Victoria , and also in 1979–1980 , 1985–1987 , 1991–1992 and 1997 . Participants All 257 live births free of lethal malformations weighing 500–999 g in 2005 , 220 r and omly selected term , normal birthweight ( birth weight > 2499 g ) controls , and equivalent cohorts born in earlier eras . Main outcome measures Survival rates and quality -adjusted survival rates at 2 years of age , contrasted between cohorts . Results Of 257 ELBW live births in 2005 , 66.9 % survived to 2 years of age , significantly lower than the survival rate of 75.2 % for 1997 ( odds ratio ( OR ) 0.67 , 95 % CI 0.45 to 0.99 , p=0.046 ) , but not after adjustment for confounders of birth weight , gestational age and gender ( adjusted OR 0.73 , 95 % CI 0.46 to 1.16 , p=0.18 ) . This was a reversal of the steady increase in survival rates up to 1997 . Rates of blindness , severe developmental delay and severe disability were significantly lower in 2005 than in ELBW survivors from previous eras . Consequently the difference in the quality -adjusted survival rates between 2005 and 1997 was only −3.8 % ( 95 % CI −11.4 % to 3.7 % , p=0.32 ) . Conclusions Regional survival rates for ELBW infants have plateaued since the late 1990s , but the neurosensory outcome in survivors has improved in 2005 Our aim was to evaluate long-term effects of exogenous surfactant therapy on pulmonary functional outcome in children born very preterm . We examined 40 children aged 7 - 12 years who were born before 30 weeks of gestation with an immature surfactant system , and were r and omized to one of three treatment groups : human surfactant given at birth ( prophylactic ) , human surfactant given after development of neonatal respiratory distress syndrome ( rescue ) , and placebo ( air ) treatment . Spirometric parameters of preterm born children were compared with those of 20 children born at term . In addition , spirometric parameters were monitored twice daily for 4 weeks using a home spirometer . All spirometric parameters were significantly lower in the preterm groups than in the controls , except for the forced vital capacity ( FVC ) in the prophylactically treated group . Bronchial obstruction was found in 53 % of the prophylactically treated group , in 36 % of the rescue group , in 67 % of the placebo group , and in 0 % of the control group . Peak expiratory flow ( PEF ) and FVC values were higher in those children who received surfactant compared with the placebo group ( P < 0.05 ) . In 16 children ( 40 % ) born preterm , a beta2-agonist induced an increase in PEF > or = 15 % at least three times during 2 weeks of home monitoring ; eight children ( 20 % ) had abnormal diurnal PEF variation . Multiple regression analysis indicated that the independent variables associated with favorable outcomes in spirometric parameters were surfactant therapy ( P = 0.012 - 0.045 ) and short intubation time after birth ( P = 0.0009 - 0.0044 ) . Bronchial obstruction , responsiveness to a beta2-agonist , and high diurnal PEF variation are common in children born before 30 gestational weeks . Surfactant supplementation reducing the need for mechanical ventilation or supplementary oxygen after birth may decrease the severity of immaturity related bronchial obstruction in childhood BACKGROUND Very preterm ( VP ; gestational age < 32 weeks ) and very low birth weight ( VLBW ; < 1500 grams ) is related to attention problems in childhood and adulthood . The stability of these problems into adulthood is not known . METHODS The Bavarian Longitudinal Study is a prospect i ve cohort study that followed 260 VP/VLBW and 229 term-born individuals from birth to adulthood . Data on attention were collected at 6 , 8 , and 26 years of age , using parent reports , expert behavior observations , and clinical ADHD diagnoses . RESULTS At each assessment , VP/VLBW individuals had significantly more attention problems , shorter attention span , and were more frequently diagnosed with ADHD than term-born comparisons . In both VP/VLBW and term-born individuals , overall , attention span increased and attention problems decreased from childhood to adulthood . Attention problems and attention span were more stable over time for VP/VLBW than term-born individuals . Similarly , ADHD diagnoses showed moderate stability from childhood to adulthood in VP/VLBW , but not in term-born individuals . However , when those with severe disabilities were excluded , differences between VP/VLBW and term-born individuals reduced . CONCLUSIONS Despite improvement in attention regulation from childhood to adulthood , children born very preterm remained at increased risk for attention problems in adulthood . In contrast , term-born children with clinical attention problems outgrew these by adulthood . As inattentive behavior of VP/VLBW children may be overlooked by teachers , it may be necessary to raise awareness for school intervention programs that reduce attention problems in VP/VLBW children BACKGROUND The increased survival chances of extremely low-birthweight ( ELBW ) infants ( weighing < 1000 g at birth ) has led to concern about their behavioural outcome in childhood . In reports from several countries with different assessment s at various ages , investigators have noted a higher frequency of behavioural problems in such infants , but cross-cultural comparisons are lacking . Our aim was to compare behavioural problems in ELBW children of similar ages from four countries . METHODS We prospect ively studied 408 ELBW children aged 8 - 10 years , whose parents completed the child behaviour checklist . The children came from the Netherl and s , Germany , Canada , and USA . The checklist provides a total problem score consisting of eight narrow-b and scales . Of these , two ( aggressive and delinquent behaviour ) give a broad-b and externalising score , three ( anxious , somatic , and withdrawn behaviour ) give a broad-b and internalising score , and three ( social , thought , and attention problems ) indicate difficulties fitting neither broad-b and dimension . For each cohort we analysed scores in ELBW children and those in normal- birthweight controls ( two cohorts ) or national normative controls ( two cohorts ) . Across countries , we assessed deviations of the ELBW children from normative or control groups . FINDINGS ELBW children had higher total problem scores than normative or control children , but this increase was only significant in European countries . Narrow-b and scores were raised only for the social , thought , and attention difficulty scales , which were 0.5 - 1.2 SD higher in ELBW children than in others . Except for the increase in internalising scores recorded for one cohort , ELBW children did not differ from normative or control children on internalising or externalising scales . INTERPRETATION Despite cultural differences , types of behavioural problems seen in ELBW children were very similar in the four countries . This finding suggests that biological mechanisms contribute to behavioural problems of ELBW children OBJECTIVE To describe the mental and emotional well-being of children born at different birth weights assessed at school age and to identify neonatal , intervening health , and sociodemographic and environmental factors associated with mental and emotional well-being . METHODS To address this issue , we used a prospect i ve cohort study involving two previously studied cohorts , which were recontacted at 8 to 10 years of age to provide a multisite sample of 247 children weighing 1000 g or less at birth , 364 weighing 1001 to 1500 g , 724 weighing 1501 to 2500 g , and 533 weighing more than 2500 g. Maternal reports were obtained on three st and ardized measures of mental and emotional well-being ( the R and General Well-being Scale , the Behavior Problem Index , and the Harter Scale of Child Competence ) and on intervening health , sociodemographic , and environmental variables . Neonatal variables were derived from records at birth . Statistical techniques included analysis of variance and ordinary least squares multiple regression . RESULTS Lower birth weight children did not differ on the General Well-being Scale but were more likely to have behavior problems and to be considered less competent . Other important correlates of mental and emotional well-being included childhood illness , maternal mental health , home environment score , and exposure to household cigarette smoking . CONCLUSION Although lower birth weight children have poorer mental and emotional well-being , a substantial portion of this adverse outcome reflects modifiable environmental factors Objective To assess changes in survival for infants born before 26 completed weeks of gestation . Design Prospect i ve cohort study in a geographically defined population . Setting Former Trent health region of the United Kingdom . Subjects All infants born at 22 + 0 to 25 + 6 weeks ’ gestation to mothers living in the region . Terminations were excluded but all other births of babies alive at the onset of labour or the delivery process were included . Main outcome measures Outcome for all infants was categorised as stillbirth , death without admission to neonatal intensivecare , death before discharge from neonatal intensivecare , and survival to discharge home in two time periods : 1994 - 9 and 2000 - 5 inclusive . Results The proportion of infants dying in delivery rooms was similar in the two periods , but a significant improvement was seen in the number of infants surviving to discharge ( P<0.001 ) . Of 497 infants admitted to neonatal intensive care in 2000 - 5 , 236 ( 47 % ) survived to discharge compared with 174/490 ( 36 % ) in 1994 . These changes were attributable to substantial improvements in the survival of infants born at 24 and 25 weeks . During the 12 years of the study none of the 150 infants born at 22 weeks ’ gestation survived . Of the infants born at 23 weeks who were admitted to intensive care , there was no significant improvement in survival to discharge in 2000 - 5 ( 12/65 ( 18 % ) in 2000 - 5 v 15/81 ( 19 % ) in 1994 - 9 ) . Conclusions Survival of infants born at 24 and 25 weeks of gestation has significantly increased . Although over half the cohort of infants born at 23 weeks wasadmitted to neonatalintensive care , there was no improvement in survival at this gestation . Care for infants born at 22 weeks remained unsuccessful To examine the concordance of mother and teacher ratings of children born at different birth weights on measures of school functioning , behavioral problems , and social competencies , we used a prospect i ve cohort study involving children in two previously studied multisite birth cohorts whom we recontacted at 8 to 10 years of age . This provided a multisite sample of 784 low birth weight children and 334 normal birth weight children . Teacher reports of children 's behaviors were obtained from 80 % of the 1400 teachers contacted . We found that birth weight and neonatal health were associated with both maternal and teacher reports ; that maternal characteristics , e.g. , low levels of education and poor mental health , were associated with the greatest discrepancies in reports ; and that although mothers ' reports of objective measures were accurate , their assessment s of behavioral problems and social competence often differed from those of teachers . J Dev Behav Pediatr 18:295 - 303 , 1997 AIM Enuresis is defined as involuntary or intentional repeated voiding of urine into clothes or bed at least twice a week for a period of three consecutive months in children older than five years old . It is one of the most frequent chronic childhood disorders . The aim of this study was to investigate the frequency of behavioural problems in children with enuresis . MATERIAL AND METHODS The research compared 30 children aged between 7 and 11 years who had consulted to Bakırköy Prof. Dr. Mazhar Osman Mental Health and Neurological Diseases Training and Research Hospital , Child and Adolescent Psychiatry Clinics and diagnosed with enuresis with their 30 peers who were r and omly selected from a state elementary school . The Child Behaviour Checklist was applied to both groups . RESULTS The subdimension scores of both groups were compared , it was observed that children with enuresis had higher scores compared to their peers in all sub-tests except for the Sluggish Cognitive Tempo , Anxiety Disorders , and Obsessive Compulsive Disorder sub-tests . Enuretic children had higher scores in externalizing ( p<0.001 ) , internalizing ( p=0.001 ) and total problem ( p<0.001 ) scales . CONCLUSION The results of this study indicate that children with enuresis exhibit behavioral problems with a higher rate compared to their healthy peers . The results are in line with the literature . Moreover , compered to the results of the studies conducted in different countries , significantly higher scores in internalizing problems were obtained . It was thought is possible that this might be related with cultural factors . However , these findings need to be verified with data from larger scale studies Background . Advances in perinatal care have result ed in increased survival rates for extremely low birth weight children . We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods , before and after the introduction of surfactant therapy in 1990 . Methods . Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I ( 1982–1989 ) ( mean body weight : 762 g ; mean gestational age : 25.8 weeks ) and 682 during period II ( 1990–1998 ) ( mean body weight : 756 g ; mean gestational age : 25.5 weeks ) . Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses , with adjustment for gestational age . Results . Survival rates increased from 49 % during period I to 67 % during period II . Neonatal morbidity rates also increased during period II , including rates of sepsis ( from 37 % to 51 % ) , periventricular leukomalacia ( from 2 % to 7 % ) , and chronic lung disease , defined as oxygen dependence at 36 weeks of corrected age ( from 32 % to 43 % ) . Rates of severe cranial ultrasound abnormalities were similar ( 22 % vs 22 % ) . Among children monitored , the rate of neurologic abnormalities , including cerebral palsy , increased from 16 % during period I to 25 % during period II and the rate of deafness increased from 3 % to 7 % . The overall rate of neurodevelopmental impairment ( major neurosensory abnormality and /or Bayley Mental Developmental Index score of < 70 ) increased from 26 % to 36 % . Compared with period I , in period II there were decreased rates of death ( odds ratio [ OR ] : 0.3 ; 95 % confidence interval [ CI ] : 0.2–0.4 ) and increased rates of survival with impairment ( OR : 2.3 ; 95 % CI : 1.7–3.3 ) but also increased rates of survival without impairment ( OR : 1.7 ; 95 % CI : 1.3–2.2 ) . Compared with period I , for every 100 infants with birth weights of 500 to 999 g born in period II , 18 additional infants survived , of whom 7 were unimpaired and 11 were impaired . Conclusions . The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment . Prospect i ve parents of extremely low birth weight infants should be advised of this substantial risk , to facilitate decision-making in the delivery room BACKGROUND Preterm birth confers risk for poor outcome , including mental health problems . Survival of extremely preterm ( EP ; < 28 weeks ' gestation ) or extremely low birthweight ( ELBW ; < 1000 g ) infants increased in the 1990s but psychiatric outcomes in older adolescents born preterm since 1990 are not well documented . This study aim ed to characterize mental health and personality traits in a prospect i ve geographical cohort of adolescents born EP/ELBW in Victoria , Australia in 1991 and 1992 . METHOD At age 18 years , 215 EP/ELBW and 157 normal birthweight ( > 2499 g ) control adolescents completed the Structured Clinical Interview for DSM-IV Disorders , Axis 1 Non-Patient version ( SCID-I/NP ) , the Children 's Interview for Psychiatric Syndromes ( ChIPS ) attention deficit hyperactivity disorder ( ADHD ) module , and question naires assessing recent depression and anxiety symptoms and personality traits . RESULTS ADHD prevalence was significantly elevated in EP/ELBW adolescents compared with controls [ 15 % v. 7 % ; odds ratio ( OR ) 2.67 , 95 % confidence interval ( CI ) 1.08 - 6.58 ] . Aside from ADHD , however , EP/ELBW and control adolescents reported very similar outcomes , with other lifetime diagnoses identified in 23 % of EP/ELBW and 21 % of controls . These were predominantly mood and anxiety disorders ( 21 % EP/ELBW , 20 % controls ) . The groups did not differ in recent depression or anxiety symptoms assessed using question naires , and personality traits were also similar . CONCLUSIONS ADHD was more prevalent in EP/ELBW adolescents than controls , which is consistent with some , but not all , reports on preterm survivors born before the 1990s , and younger preterm children born in the 1990s . The high rates of anxiety and mood disorders were similar in both groups , and comparable with population -based estimates BACKGROUND Preterm children are at risk for developing behavioral and emotional problems , as well as being less socially competent . Premature birth causes chronic distress in the parents . AIMS The aim of the paper is to discover whether parental psychological well-being is associated with the social , behavioral , and functional development of very low birth weight ( VLBW , ≤1500 g ) children at 5years of age . STUDY DESIGN A longitudinal prospect i ve cohort study . SUBJECTS A cohort of 201 VLBW infants ( ≤1500 g , < 37weeks of gestation ) born during 2001 - 2006 in Turku University Hospital , Finl and was studied . OUTCOME MEASURES At 4-year chronological age of their child , parents independently completed vali date d question naires ( Beck Depression Inventory , Parenting Stress Index and Sense of Coherence Scale ) . At 5years , parents and day-care providers evaluated the development of the child by completing the Five to Fifteen question naire . RESULTS The parents of VLBW children reported significantly more problems in child development compared to the Finnish normative data . Depressive symptoms and weaker sense of coherence in mothers , but not in fathers , were associated with more problems in child development . Parenting stress , for both mothers and fathers , was associated with developmental problems in their child at 5years of age . CONCLUSIONS Maternal depressive symptoms and parenting stress of both parents may be risk factors for the social , behavioral , and functional development of 5-year-old preterm children . On the other h and , stronger maternal sense of coherence may be a protective factor

Interactions with robopets were described as having a positive impact on aspects of well-being including loneliness , depression and quality of life by residents and staff , although there was no corresponding statistically significant evidence from meta- analysis for these outcomes . Not everyone had a positive experience of robopets . Engagement with robopets appears to have beneficial effects on the health and well-being of older adults living in care homes , but not all chose to engage . IMPLICATION S FOR PRACTICE Robopets have the potential to benefit people living in care homes , through increasing engagement and interaction . With the robopet acting as a catalyst , this engagement and interaction may afford comfort and help reduce agitation and loneliness

BACKGROUND Robopets are small animal-like robots which have the appearance and behavioural characteristics of pets . OBJECTIVE To bring together the evidence of the experiences of staff , residents and family members of interacting with robopets and the effects of robopets on the health and well-being of older people living in care homes .

ABSTRACT Objectives : We undertook a cluster-r and omised controlled trial exploring the effect of a therapeutic companion robot ( PARO ) compared to a look-alike plush toy and usual care on dementia symptoms of long-term care residents . Complementing the reported quantitative outcomes , this paper provides critical reflection and commentary on individual participant responses to PARO , observed through video recordings , with a view to informing clinical practice and research . Method : A descriptive , qualitative design with five participants selected from the PARO intervention arm of the trial . The trial is registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12614000508673 ) . Results : The five participants and their responses to PARO are presented in terms of three issues : i. ) Different pre-intervention clinical presentations and different responses ; ii . ) Same individual , different response – the need for continual assessment and review ; and iii . ) The ethics of giving and retrieving PARO . Implication s for clinical practice and future research are discussed in relation to each issue . Conclusion : The findings suggest that one approach does not fit all , and that there is considerable variation in responses to PARO . A number of recommendations are discussed to aid the delivery of psychosocial interventions with PARO in practice , as well as to guide future research Background : Behavioral problems may affect individuals with dementia , increasing the cost and burden of care . Pet therapy has been known to be emotionally beneficial for many years . Robotic pets have been shown to have similar positive effects without the negative aspects of traditional pets . Robotic pet therapy offers an alternative to traditional pet therapy . Objective : The study rigorously assesses the effectiveness of the PARO robotic pet , an FDA approved biofeedback device , in treating dementia-related symptoms . Methods : A r and omized block design with repeated measurements guided the study . Before and after measures included reliable , valid tools such as : RAID , CSDD , GDS , pulse rate , pulse oximetry , and GSR . Participants interacted with the PARO robotic pet , and the control group received st and ard activity programs . Five urban secure dementia units comprised the setting . Results : 61 patients , with 77 % females , average 83.4 years in age , were r and omized into control and treatment groups . Compared to the control group , RAID , CSDD , GSR , and pulse oximetry were increased in the treatment group , while pulse rate , pain medication , and psychoactive medication use were decreased . The changes in GSR , pulse oximetry , and pulse rate over time were plotted for both groups . The difference between groups was consistent throughout the 12-week study for pulse oximetry and pulse rate , while GSR had several weeks when changes were similar between groups . Conclusions : Treatment with the PARO robot decreased stress and anxiety in the treatment group and result ed in reductions in the use of psychoactive medications and pain medications in elderly clients with dementia Background and Objectives Recent years have seen social robotic pets introduced as a means of treating behavioral and psychological symptoms of dementia , and many show promising potential . In this study , we sought to explore family members ' perceptions of the Japanese-developed baby harp seal , Paro ( version 9 ) , and a look-alike , nonrobotic Plush Toy , when used by their relative with dementia for 15 min , 3 afternoons per week for 10 weeks . Research Design and Method The study employed a descriptive qualitative approach , which was nested within a larger cluster r and omized controlled trial . A convenience sample of 20 family members ( n = 10 each from the Paro and Plush Toy conditions ) with relatives in 9 long-term care facilities in Queensl and , Australia , completed individual semi-structured interviews ( telephone or face-to-face ) . Inductive , data -driven thematic analysis of the data was undertaken with the assistance of the qualitative management software , ATLAS.ti ® . Results Family members of long-term care residents with dementia expressed positive perceptions of the Paro , perceiving that it improved mood , reduced agitation , and provided opportunity for communication for their relative . Negative perceptions of the Plush Toy were given by family members , primarily because of its lack of movement and engagement . Conclusion Family members were keen for their older relative with dementia to use a social robot that moved and engaged with them , and Plush Toys that were static and unresponsive were perceived as being unimportant in improving quality of life . However , the current cost of Paro was identified by family members as a major limitation to use OBJECTIVES The robotic seal , PARO , has been used as an alternative to animal-assisted therapies with residents with dementia in long-term care , yet underst and ing of its efficacy is limited by a paucity of research . We explored the effects of PARO on motor activity and sleep patterns , as measured by a wearable triaxial accelerometer . STUDY DESIGN Cluster-r and omised controlled trial , involving 28 facilities in Queensl and , Australia . Nine facilities were r and omised to the PARO group ( individual , non-facilitated , 15-min sessions three afternoons per week for 10 weeks ) , 10 to a plush toy ( PARO with robotic features disabled ) and nine to usual care . MAIN OUTCOME MEASURES Changes in day- and nighttime motor activity and sleep after the 10-week intervention , as measured by SenseWear ® armb and s , worn by participants continuously for 24 h at baseline , during two single intervention days in weeks 5 and 10 respectively , and post-intervention ( week 15 ) . Analyses followed intention-to-treat , using repeated- measures mixed-effects models . RESULTS After 10 weeks , the PARO group showed a greater reduction in daytime step count than usual care ( p = 0.023 ) , and in nighttime step count ( p = 0.028 ) and daytime physical activity ( p = 0.026 ) compared with the plush toy group . At post-intervention , the PARO group showed a greater reduction in daytime step count than the plush toy group ( p = 0.028 ) , and at nighttime compared with both the plush toy group ( p = 0.019 ) and the usual-care group ( p = 0.046 ) . The PARO group also had a greater reduction in nighttime physical activity than the usual-care group ( p = 0.015 ) . CONCLUSIONS PARO may have some effect on motor activity of older people with dementia in long-term care , but not on sleep patterns . Australian New Zeal and Clinical Trials Registry ( ACTRN12614000508673 ) AIM The aim of this study was to investigate effects of robot-assisted group activity with Paro on quality of life in older people with dementia . BACKGROUND Nursing home residents with severe dementia often experience social withdrawal and lower quality of life , which are suggested to be enhanced by non-pharmacological interventions . DESIGN A cluster-r and omized controlled trial . Ten nursing home units were r and omized to robot-assisted intervention or control group ( treatment as usual ) . METHODS Data were collected between March 2013-September 2014 . 27 participants participated in group activity for 30 minutes twice a week over 12 weeks , 26 participated in the control group . Change in quality of life was assessed by local nurses through the Quality of Life in Late-Stage Dementia scale at baseline , after end of intervention and at 3 months follow-up . The scale and regular psychotropic medication were analysed stratified by dementia severity . Analysis using mixed model , one-way anova and linear regression were performed . RESULTS An effect was found among participants with severe dementia from baseline to follow-up showing stable quality of life in the intervention group compared with a decrease in the control group . The intervention explained most of the variance in change in the total scale and in the subscales describing Tension and Well-being for the group with severe dementia . The intervention group used significantly less psychotropic medication compared with the control group after end of intervention . CONCLUSION Pleasant and engaging activities facilitated by nursing staff , such as group activity with Paro , could improve quality of life in people with severe dementia . The trial is in adherence with the CONSORT statement and is registered at www . clinical trials.gov ( study ID number : NCT01998490 ) [ corrected ] OBJECTIVES To investigate the affective , social , behavioral , and physiological effects of the companion robot Paro for people with dementia in both a day care center and a home setting . DESIGN A pilot block r and omized controlled trial over 12 weeks . Participants were r and omized to the intervention ( Paro ) or control condition ( st and ard care ) . SETTING Two dementia day care centers and participants ' homes in Auckl and , New Zeal and . PARTICIPANTS Thirty dyads ( consisting of a care recipient with dementia and their caregiver ) took part in this study . All care recipients attended dementia day care centers at Selwyn Foundation and had a formal diagnosis of dementia . INTERVENTION Thirty-minute unstructured group sessions with Paro at the day care center were run 2 to 3 times a week for 6 weeks . Participants also had Paro at home for 6 weeks . MEASUREMENTS At the day care centers , observations of the care recipients ' behavior , affect , and social responses were recorded using a time sampling method . Observations of interactions with Paro for participants in the intervention were also recorded . Blood pressure and salivary cortisol were collected from care recipients before and after sessions at day care . In the home setting , level of cognition , depressive symptoms , neuropsychiatric symptoms , behavioral agitation , and blood pressure were measured at baseline , 6 weeks , and 12 weeks . Hair cortisol measures were collected at baseline and at 6 weeks . RESULTS Observations showed that Paro significantly improved facial expressions ( affect ) and communication with staff ( social interaction ) at the day care centers . Subanalyses showed that care recipients with less cognitive impairment responded significantly better to Paro . There were no significant differences in care recipient dementia symptoms , nor physiological measures between the intervention and control group . CONCLUSION Paro shows promise in enhancing affective and social outcomes for certain individuals with dementia in a community context . Larger r and omized controlled trials in community setting s , with longer time frames , are needed to further specify the context s and characteristics for which Paro is most beneficial OBJECTIVES To explore whether severity of cognitive impairment and agitation of older people with dementia predict outcomes in engagement , mood states , and agitation after a 10-week intervention with the robotic seal , PARO . DESIGN Data from the PARO intervention-arm of a cluster-r and omized controlled trial was used , which involved individual , nonfacilitated , 15-minute sessions with PARO 3 afternoons per week for 10 weeks . SAMPLE AND PARTICIPANTS One hundred thirty-eight residents-aged ≥60 years , with dementia-from 9 long-term care facilities . MEASURES A series of stepwise multiple linear regressions were conducted . Dependent variables were participants ' levels of engagement , mood states , and agitation at week 10 [ assessed by video observation and Cohen Mansfield Agitation Inventory-Short Form ( CMAI-SF ) ] . Predictor variables were baseline levels of cognitive impairment [ assessed by Rowl and Universal Dementia Assessment Scale ( RUDAS ) ] and agitation ( CMAI-SF ) . RESULTS Five models were produced . The strongest finding was that participants with more severe agitation at baseline had higher levels of agitation at week 10 ( R2 = .82 , P < .001 ) . Predictors of positive response were less significant . Low levels of agitation at baseline predicted greater positive behavioral engagement with PARO ( R2 = .054 , P = .009 ) and fewer observed instances of agitation ( R2 = .033 , P = .045 ) at week 10 , whereas greater visual engagement was predicted by both lower levels of agitation and cognitive impairment ( R2 = .082 , P = .006 ) . Less severe cognitive impairment predicted greater pleasure at week 10 ( R2 = .067 , P = .004 ) . CONCLUSIONS / IMPLICATION S Participants with severe agitation had poor response to PARO . Lower levels of agitation and higher cognitive functioning were associated with better responses . In clinical practice , we recommend PARO should be restricted to people with low-moderate severity of agitation . Further research is needed to determine the optimal participant characteristics for response to PARO We recently reported that a companion robot reduced residents ' loneliness in a r and omised controlled trial at an aged‐care facility . This report aims to provide additional , previously unpublished data about how the sessions were run , residents ' interactions with the robot and staff perspectives Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVES To examine effects on symptoms of agitation and depression in nursing home residents with moderate to severe dementia participating in a robot-assisted group activity with the robot seal Paro . DESIGN A cluster-r and omized controlled trial . Ten nursing home units were r and omized to either robot-assisted intervention or a control group with treatment as usual during 3 intervention periods from 2013 to 2014 . SETTING Ten adapted units in nursing homes in 3 counties in eastern Norway . PARTICIPANTS Sixty residents ( 67 % women , age range 62 - 95 years ) in adapted nursing home units with a dementia diagnosis or cognitive impairment ( Mini-Mental State Examination score lower than 25/30 ) . INTERVENTION Group sessions with Paro took place in a separate room at nursing homes for 30 minutes twice a week over the course of 12 weeks . Local nurses were trained to conduct the intervention . MEASUREMENTS Participants were scored on baseline measures ( T0 ) assessing cognitive status , regular medication , agitation ( BARS ) , and depression ( CSDD ) . The data collection was repeated at end of intervention ( T1 ) and at follow-up ( 3 months after end of intervention ) ( T2 ) . Mixed models were used to test treatment and time effects . RESULTS Statistically significant differences in changes were found on agitation and depression between groups from T0 to T2 . Although the symptoms of the intervention group declined , the control group 's symptoms developed in the opposite direction . Agitation showed an effect estimate of -5.51 , CI 0.06 - 10.97 , P = .048 , and depression -3.88 , CI 0.43 - 7.33 , P = .028 . There were no significant differences in changes on either agitation or depression between groups from T0 to T1 . CONCLUSION This study found a long-term effect on depression and agitation by using Paro in activity groups for elderly with dementia in nursing homes . Paro might be a suitable nonpharmacological treatment for neuropsychiatric symptoms and should be considered as a useful tool in clinical practice Traditional pet therapy enhances individual wellbeing . However , there are situations where a substitute artificial companion ( i.e. , robotic pet ) may serve as a better alternative because of insufficient available re sources to care for a real pet , allergic responses to pets , or other difficulties . This pilot study , which compared the benefits of a robotic cat and a plush toy cat as interventions for elderly persons with dementia , was conducted at a special care unit of a large , not-for-profit nursing home . Various aspects of a person 's engagement and affect were assessed through direct observations . Though not identical , similar trends were seen for the two cats . Interacting with the cats was linked with decreased agitation and increased pleasure and interest . The study is intended to pave the way for future research on robotherapy with nursing home residents OBJECTIVES To investigate the psychosocial effects of the companion robot , Paro , in a rest home/hospital setting in comparison to a control group . DESIGN R and omized controlled trial . Residents were r and omized to the robot intervention group or a control group that attended normal activities instead of Paro sessions . Sessions took place twice a week for an hour over 12 weeks . Over the trial period , observations were conducted of residents ' social behavior when interacting as a group with the robot . As a comparison , observations were also conducted of all the residents during general activities when the resident dog was or was not present . SETTING A residential care facility in Auckl and , New Zeal and . PARTICIPANTS Forty residents in hospital and rest home care . MEASUREMENTS Residents completed a baseline measure assessing cognitive status , loneliness , depression , and quality of life . At follow-up , residents completed a question naire assessing loneliness , depression , and quality of life . During observations , behavior was noted and collated for instances of talking and stroking the dog/robot . RESULTS In comparison with the control group , residents who interacted with the robot had significant decreases in loneliness over the period of the trial . Both the resident dog and the seal robot made an impact on the social environment in comparison to when neither was present . Residents talked to and touched the robot significantly more than the resident dog . A greater number of residents were involved in discussion about the robot in comparison with the resident dog and conversation about the robot occurred more . CONCLUSION Paro is a positive addition to this environment and has benefits for older people in nursing home care . Paro may be able to address some of the unmet needs of older people that a resident animal may not , particularly relating to loneliness OBJECTIVES To investigate the suitability of a new eldercare robot ( Guide ) for people with dementia and their caregivers compared with one that has been successfully used before ( Paro ) , and to generate suggestions for improved robot enhanced dementia care . DESIGN Cross-sectional study . A research er demonstrated both robots in a r and om order to each staff member alone , or to each resident together with his/her relative(s ) . The research er encouraged the participants to interact with each robot and asked staff and relatives a series of open ended questions about each robot . SETTING A secure dementia residential facility in Auckl and , New Zeal and . PARTICIPANTS Ten people with dementia and 11 of their relatives , and five staff members . MEASUREMENTS Each robot interaction was video-taped and coded for the number of times the resident looked at , smiled , touched , and talked to and about each robot , as well as relative interactions with the resident . Qualitative analysis was used to code the open ended questions . RESULTS Residents smiled , touched and talked to Paro significantly more than Guide . Paro was found to be more acceptable to family members , staff , and residents , although many acknowledged that Guide had the potential to be useful if adapted for this population in terms of ergonomics and simplification . CONCLUSION Healthcare robots in dementia setting s have to be simple and easy to use as well as stimulating and entertaining . This research highlights how eldercare robots may be adapted to have the best effects in dementia setting s. It is concluded that Paro 's sounds could be modified to be more acceptable to this population . The ergonomic design of Guide could be review ed and the software application could be simplified and targeted to people with dementia OBJECTIVES To test the effects of individual , nonfacilitated sessions with PARO ( version 9 ) , when compared against a look-alike plush toy and usual care , on the emotional and behavioral symptoms of dementia for people living in long-term care facilities . DESIGN Parallel , 3-group , cluster-r and omized controlled trial conducted between June 14 , 2014 , and May 16 , 2015 . SETTING Twenty-eight long-term care facilities operated by 20 care organizations located in South-East Queensl and , Australia . PARTICIPANTS Four hundred fifteen participants aged ≥60 years , with a documented diagnosis of dementia . INTERVENTION Stratified by private/not-for-profit status and r and omized using a computer-generated sequence , 9 facilities were r and omized to the PARO group ( individual , nonfacilitated , 15-minute sessions 3 times per week for 10 weeks ) ; 10 to plush toy ( same , but given PARO with robotic features disabled ) ; and 9 to usual care . Treatment allocation was masked to assessors . MEASUREMENTS Primary outcomes were changes in levels of engagement , mood states , and agitation after a 10-week intervention , assessed by coded video observations ( baseline , weeks 1 , 5 , 10 , and 15 ) and Cohen-Mansfield Agitation Inventory-Short Form ( baseline , weeks 10 and 15 ) . Analyses followed intention-to-treat , using repeated measures mixed effects models . Australian New Zeal and Clinical Trials Registry ( ACTRN12614000508673 ) . RESULTS Video data showed that participants in the PARO group were more verbally [ 3.61 , 95 % confidence interval ( CI ) : 6.40 - 0.81 , P = .011 ] and visually engaged ( 13.06 , 95 % CI : 17.05 - 9.06 , P < .0001 ) than participants in plush toy . Both PARO ( -3.09 , 95 % CI : -0.45 to -5.72 , P = .022 ) and plush toy ( -3.58 , 95 % CI : -1.26 to -5.91 , P = .002 ) had significantly greater reduced neutral affect compared with usual care , whilst PARO was more effective than usual care in improving pleasure ( 1.12 , 95 % CI : 1.94 - 0.29 , P = .008 ) . Videos showed that PARO was more effective than usual care in improving agitation ( 3.33 , 95 % CI : 5.79 - 0.86 , P = .008 ) . When measured using the CMAI-SF , there was no difference between groups . CONCLUSIONS Although more effective than usual care in improving mood states and agitation , PARO was only more effective than a plush toy in encouraging engagement ABSTRACT Objectives : Social robots such as Paro , a therapeutic companion robot , have recently been introduced into dementia care as a means to reduce behavioural and psychological symptoms of dementia . The purpose of this study was to explore care staff perceptions of Paro and a look-alike non-robotic animal , including benefits and limitations in dementia care . Methods : The study assumed a descriptive qualitative approach , nested within a large cluster-r and omised controlled trial . We interviewed a sub sample of 20 facility care staff , from nine long-term care facilities in Southeast Queensl and , Australia . Thematic analysis of the data , which was inductive and data -driven , was undertaken with the assistance of the qualitative software , ATLAS.ti ® . Results : The findings refer to four categories : increasing excitement for Paro and decreasing enthusiasm for Plush Toy ; value and function of Paro ; opportunities for engagement ; and alternatives vs. robustness . Conclusion : Staff caring for people with dementia preferred Paro compared to a look-alike Plush Toy . Staff identified that Paro had the potential to improve quality of life for people with dementia , whereas the Plush Toy had limitations when compared to Paro . However , participants expressed concern that the cost of Paro could reduce opportunities for use within aged care OBJECTIVES To examine the within-trial costs and cost-effectiveness of using PARO , compared with a plush toy and usual care , for reducing agitation and medication use in people with dementia in long-term care . DESIGN An economic evaluation , nested within a cluster-r and omized controlled trial . SETTING Twenty-eight facilities in South-East Queensl and , Australia . PARTICIPANTS A total of 415 residents , all aged 60 years or older , with documented diagnoses of dementia . INTERVENTION Facilities were r and omized to 1 of 3 groups : PARO ( individual , nonfacilitated 15-minute sessions , 3 afternoons per week for 10 weeks ) ; plush toy ( as per PARO but with artificial intelligence disabled ) ; and usual care . MEASUREMENTS The incremental cost per Cohen-Mansfield Agitation Inventory-Short Form ( CMAI-SF ) point averted from a provider 's perspective . Australian New Zeal and Clinical Trials Registry ( BLINDED FOR REVIEW ) . RESULTS For the within-trial costs , the PARO group was $ 50.47 more expensive per resident compared with usual care , whereas the plush toy group was $ 37.26 more expensive than usual care . There were no statistically significant between-group differences in agitation levels after the 10-week intervention . The point estimates of the incremental cost-effectiveness ratios were $ 13.01 for PARO and $ 12.85 for plush toy per CMAI-SF point averted relative to usual care . CONCLUSION The plush toy used in this study offered marginally greater value for money than PARO in improving agitation . However , these costs are much lower than values estimated for psychosocial group activities and sensory interventions , suggesting that both a plush toy and the PARO are cost-effective psychosocial treatment options for agitation BACKGROUND Previous studies have suggested that visiting dogs can have positive effects on elderly people in nursing homes . We wanted to study the effects of biweekly dog visits on sleep patterns and the psychiatric well-being of elderly people . METHODS A total of 100 residents ( median age : 85.5 years ; [ 79 ; 90 ] ) from four nursing homes were r and omly assigned to receive biweekly visits for 6 weeks from a person accompanied by either a dog , a robot seal ( PARO ) , or a soft toy cat . Sleep patterns were measured using actigraphy technology before , during ( the third and sixth week ) , and after the series of visits . The participants were weighed and scored on the Geriatric Depression Scale , the Gottfries-Bråne-Steen Scale , and the Mini-Mental State Examination before and after the visit period . RESULTS We found that sleep duration ( min ) increased in the third week when visitors were accompanied by a dog rather than the robot seal or soft toy cat ( dog : 610 ± 127 min ; seal : 498 ± 146 min ; cat : 540 ± 163 min ; F2,37 = 4.99 ; P = 0.01 ) . No effects were found in the sixth week or after the visit period had ended . We found that visit type had no effect on weight ( F2,88 = 0.13 ; P > 0.05 ) , body mass index ( F2,86 = 0.33 ; P > 0.05 ) , Geriatric Depression Scale ( F2,82 = 0.85 ; P > 0.05 ) , Gottfries-Bråne-Steen Scale ( F2,90 = 0.41 ; P > 0.05 ) , or Mini-Mental State Examination ( F2,91 = 0.35 ; P > 0.05 ) . Furthermore , we found a decrease in the Geriatric Depression Scale during the experimental period ( S = -420 ; P < 0.05 ) , whereas cognitive impairment worsened as shown by a decrease in Mini-Mental State Examination score ( S = -483 ; P < 0.05 ) and an increase in the Gottfries-Bråne-Steen Scale ( t = 2.06 ; P < 0.05 ) . CONCLUSION Visit type did not affect the long-term mental state of the participants . The causal relationship between sleep duration and dog-accompanied visits remains to be explored This pilot study aim ed to compare the effect of companion robots ( PARO ) to participation in an interactive reading group on emotions in people living with moderate to severe dementia in a residential care setting . A r and omized crossover design , with PARO and reading control groups , was used . Eighteen residents with mid- to late-stage dementia from one aged care facility in Queensl and , Australia , were recruited . Participants were assessed three times using the Quality of Life in Alzheimer 's Disease , Rating Anxiety in Dementia , Apathy Evaluation , Geriatric Depression , and Revised Algase W and ering Scales . PARO had a moderate to large positive influence on participants ' quality of life compared to the reading group . The PARO intervention group had higher pleasure scores when compared to the reading group . Findings suggest PARO may be useful as a treatment option for people with dementia ; however , the need for a larger trial was identified

Laquinimod had potential benefits in reducing relapse rates and was safe for most patients with RRMS in the short term . The published study suggests that laquinimod at a dose of 0.6 mg orally administered once daily may be safe and have potential benefits for most patients with RRMS in the short term .

BACKGROUND Multiple sclerosis ( MS ) is a chronic immune-mediated , inflammatory , demyelinating , neurodegenerative disorder of the central nervous system , and it causes major socioeconomic burden for the individual patient and for society . An inflammatory pathology occurs during the early relapsing stage of MS and a neurodegenerative pathology dominates the later progressive stage of the disease . Not all MS patients respond adequately to currently available disease-modifying drugs ( DMDs ) . Alternative MS treatments with new modes of action are required to exp and the current options for disease-modifying therapies ( DMTs ) and to aim for freedom from relapses , inflammatory lesions , disability progression and neurodegeneration . Laquinimod has dual properties of immunomodulation and neuroprotection and is a potentially promising new oral DMD in the treatment of relapsing MS . OBJECTIVES To assess the effectiveness and safety profile of laquinimod as monotherapy or combination therapy versus placebo or approved DMDs ( interferon-β , glatiramer acetate , natalizumab , mitoxantrone , fingolimod , teriflunomide , dimethyl fumarate ) for modifying the disease course in patients with MS .

Introduction Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis ( MS ) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents . In this study , we evaluate the rate of cerebral atrophy in a 6-month period , investigate the predictive and explanatory value of other magnetic resonance imaging ( MRI ) measures in relation to cerebral atrophy , and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure . Methods One hundred thirty-five relapsing – remitting multiple sclerosis patients underwent six monthly MRI scans from which the percentage brain volume change ( PBVC ) and the number and volume of gadolinium (Gd)-enhancing lesions , T2 lesions , and persistent black holes ( PBH ) were determined . By means of multiple linear regression analysis , the relationship between focal MRI variables and PBVC was assessed . Sample size calculations were performed for all patients and subgroups selected for enhancement or a high T2 lesion load at baseline . Results A significant atrophy occurred over 6 months ( PBVC = −0.33 % , SE = 0.061 , p < 0.0001 ) . The number of baseline T2 lesions ( p = 0.024 ) , the on- study Gd-enhancing lesion volume ( p = 0.044 ) , and the number of on- study PBHs ( p = 0.003 ) were associated with an increased rate of atrophy . For a 50 % decrease in rate of atrophy , the sample size calculations showed that approximately 283 patients per arm are required in an unselected sample d population and 185 patients per arm are required in a selected population . Conclusion Within a 6-month period , significant atrophy can be detected and on- study associations of PBVC and PBHs emphasizes axonal loss to be a driving mechanism . Application as primary outcome measure in short-term clinical trials with feasible sample size requires a potent drug to obtain sufficient power Background : Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis ( MS ) . The purpose of this study was to evaluate safety , tolerability , and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS . Methods : In this multicenter , double-blind , r and omized trial , patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks . Gadolinium-enhanced brain MRI scans were performed at screening , every eighth week during treatment , and 8 weeks after end of treatment . The primary efficacy variable was the cumulative number of active lesions over 24 weeks . Safety measures included adverse events , physical examination , and laboratory variables . Results : Of 256 screened patients , 209 were r and omized ( 67 to 74 patients per group ) in 20 centers . There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure ( mean cumulative number of active lesions reduced by 44 % ) . In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced ( 52 % ) . No differences with respect to clinical variables ( relapses , disability ) were found . The safety profile was favorable ; there were no clinical signs of undesired inflammatory manifestations . Conclusion : Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis Multiple sclerosis ( MS ) has serious negative effects on health- , social- , and work-related issues for the patients and their families , thus causing significant socioeconomic burden . The objective of the study was to determine healthcare costs and indirect illness costs in MS patient in a national sample . We used all national records from the Danish National Patient Registry ( 1998 - 2006 ) , and identified 10,849 MS patients which were compared with 43,396 r and omly age- , sex- and social matched citizens . Healthcare sector costs included frequencies and costs of hospitalizations and weighted outpatient use , frequencies of visits and hospitalizations and costs from primary sectors , and the use and costs of drugs . Productivity costs ( the value of lost productivity from time off from work due to illness ) and all social transfer payments were also calculated . Patients with MS had significantly higher rates of health-related contact and medication use and very low employment rate which incurred a higher socioeconomic cost . The income level of employed MS patients was significantly lower than that of control subjects . The annual total health sector costs and productivity costs were € 14,575 for MS patients vs. € 1163 for control subjects ( p<0.001 ) , corresponding to an annual mean excess health-related cost of € 13,413 for each patient with MS . In addition , the MS patients received an annual mean excess social transfer income of € 6843 . MS present social and economical consequences more than eight years before diagnosis . We conclude that MS causes major socioeconomic consequences for the individual patient and for society . Productivity costs are a far more important economic factor , especially due to reduced employment , which are enhanced by the early age of diagnose onset CONTEXT Interferon beta is widely prescribed to treat multiple sclerosis ( MS ) ; however , its relationship with disability progression has yet to be established . OBJECTIVE To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS . DESIGN , SETTING , AND PATIENTS Retrospective cohort study based on prospect ively collected data ( 1985 - 2008 ) from British Columbia , Canada . Patients with relapsing-remitting MS treated with interferon beta ( n = 868 ) were compared with untreated contemporary ( n = 829 ) and historical ( n = 959 ) cohorts . MAIN OUTCOME MEASURES The main outcome measure was time from interferon beta treatment eligibility ( baseline ) to a confirmed and sustained score of 6 ( requiring a cane to walk 100 m ; confirmed at > 150 days with no measurable improvement ) on the Exp and ed Disability Status Scale ( EDSS ) ( range , 0 - 10 , with higher scores indicating higher disability ) . A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment . Analyses also included propensity score adjustment to address confounding by indication . RESULTS The median active follow-up times ( first to last EDSS measurement ) were as follows : for the interferon beta-treated cohort , 5.1 years ( interquartile range [ IQR ] , 3.0 - 7.0 years ) ; for the contemporary control cohort , 4.0 years ( IQR , 2.1 - 6.4 years ) ; and for the historical control cohort , 10.8 years ( IQR , 6.3 - 14.7 years ) . The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8 % , 5.3 % , and 23.1 % in the 3 cohorts , respectively . After adjustment for potential baseline confounders ( sex , age , disease duration , and EDSS score ) , exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort ( hazard ratio , 1.30 ; 95 % CI , 0.92 - 1.83 ; P = .14 ) or the historical control cohort ( hazard ratio , 0.77 ; 95 % CI , 0.58 - 1.02 ; P = .07 ) were considered . Further adjustment for comorbidities and socioeconomic status , where possible , did not change interpretations , and propensity score adjustment did not substantially change the results . CONCLUSION Among patients with relapsing-remitting MS , administration of interferon beta was not associated with a reduction in progression of disability BACKGROUND A 24-week phase II trial has shown that 0.3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions . We assessed the effect of oral daily 0.3 and 0.6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind , placebo-controlled phase IIb study . METHODS The study was done in 51 centres in nine countries . Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing ( GdE ) lesion on screening MRI . Of 720 patients screened , 306 eligible patients were enrolled . Patients , aged 18 - 50 years , were r and omly assigned to placebo ( n=102 ) , laquinimod 0.3 mg a day ( n=98 ) , or 0.6 mg a day ( n=106 ) . Brain MRI scans and clinical assessment s were done at week -4 , baseline , and monthly from week 12 to week 36 . The primary outcome was the cumulative number of GdE lesions at weeks 24 , 28 , 32 , and 36 . The principal analysis of the primary endpoint was done on the intention-to-treat cohort . This study is registered with Clinical Trials.gov , number NCT00349193 . FINDINGS Compared with placebo , treatment with laquinimod 0.6 mg per day showed a 40.4 % reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans ( simple means 4.2 [ SD 9.2 ] vs 2.6 [ 5.3 ] , p=0.0048 ) ; treatment with 0.3 mg per day showed no significant effects ( 3.9 [ 5.5 ] vs placebo , p=0.6740 ) . Both doses of laquinimod were well tolerated , with some transient and dose-dependent increases in liver enzymes . A case of Budd-Chiari syndrome-ie , a thrombotic venous outflow obstruction of the liver-occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0.6 mg laquinimod . Anticoagulant treatment result ed in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation . INTERPRETATION In patients with relapsing-remitting multiple sclerosis , 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated The aim of this study was to determine evolution of T1 unenhanced hypointense lesions ( acute or chronic black holes ( ABHs , CBHs ) ) by measuring their magnetization transfer ratio ( MTR ) changes over 12 months . 40 glatiramer acetate (GA)-naive patients with relapsing-remitting MS who presented with 1 or more contrast-enhancing lesions ( CELs ) at baseline underwent 1.5-T MRI at baseline and after 12 months . Lesions were classified into 4 patterns based on differences in lesion isointensity or hypointensity over 12 months . Of 115 CELs detected at baseline , 64 , after 12 months , followed pattern A ( isointense-isointense ) , 6 pattern B ( isointense-hypointense ) , 33 pattern C ( hypointense-isointense ) , and 12 pattern D ( hypointense-hypointense ) . MTR significantly increased for all unenhanced T1 hypointense lesions ( p = 0.02 ) . Highest MTR increases were observed for patterns C ( ABHs + 18.2 % , p less than 0.001 ) and D ( CBHs + 34.2 % , p = 0.023 ) , but significant improvement was also detected for pattern A ( + 1.4 % , p = 0.046 ) ; no significant MTR changes were found for pattern B. GA treatment significantly recovered MTR in ABHs and CBHs , possibly indicating a greater potential for remyelination Background : Laquinimod , an oral novel immunomodulator , was shown to reduce MRI-measured disease activity in relapsing — remitting MS ( RRMS ) patients . Objectives : To determine whether the safety and efficacy profile of laquinimod , as shown in a placebo-controlled 36-week trial ( LAQ/5062 ) , is sustained and reproducible . Methods : Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase . Clinical assessment s were performed at weeks 4 , 12 and every 12 weeks thereafter . Results : Two hundred and thirty nine ( 93 % ) patients completed the extension phase and 222 ( 86.3 % ) had a final scan available . Gadolinium-enhanced ( GdE ) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses ( 52 % , p = 0.0006 ) . In patients initially r and omized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension . The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31 % to 47 % at the end of the extension phase ( p = 0.01 ) . The most prominent safety signal was elevations of liver enzymes , reversible in all cases . Conclusions : The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study BACKGROUND Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis . METHODS We conducted a r and omized , double-blind , phase 3 study at 139 sites in 24 countries . A total of 1106 patients with relapsing-remitting multiple sclerosis were r and omly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months . The primary end point was the annualized relapse rate during the 24-month period . Secondary end points included confirmed disability progression ( defined as an increase in the score on the Exp and ed Disability Status Scale that was sustained for at least 3 months ) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging . RESULTS Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean ( ±SE ) annualized relapse rate ( 0.30±0.02 vs. 0.39±0.03 , P=0.002 ) and with a reduction in the risk of confirmed disability progression ( 11.1 % vs. 15.7 % ; hazard ratio , 0.64 ; 95 % confidence interval , 0.45 to 0.91 ; P=0.01 ) . The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo ( 1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07 , respectively ; P<0.001 for both comparisons ) . Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod ( 5 % ) and 8 receiving placebo ( 2 % ) . CONCLUSIONS In this phase 3 study , oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis . ( Funded by Teva Pharmaceutical Industries ; Clinical Trials.gov number , NCT00509145 . ) Background : Hypointense lesions on T1 weighted MRI , referred to as black holes ( BH ) , are a marker of demyelination/axonal loss in multiple sclerosis ( MS ) . There is some evidence that glatiramer acetate ( GA ) may decrease the conversion of new brain lesions to BH . Methods : Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS r and omised to GA or Interferon β-1b ( IFNβ1b ) in the BECOME study . Findings : Of 1224 newly enhancing lesions ( NEL ) appearing at baseline through 24 months in 61 patients , 767 ( 62.7 % ) showed an acute BH ( ABH ) . The majority of ABH were transient and of similar duration by treatment group . Of 571 ABH in which MRI follow-up scans were available for ⩾1 year , 103 ( 18.8 % ) were still visible ⩾12 months after onset and were considered chronic BH ( CBH ) . Only 12.1 % of the 849 NEL with MRI follow-up ⩾1 year converted to CBH , 9.8 % with IFNβ1b and 15.2 % with GA ( p = 0.02 ) . The conversion from ABH to CBH was also lower with IFNβ1b ( 15.2 % ) than with GA ( 21.4 % ) , of borderline significance ( p = 0.06 ) . The majority of patients who developed NEL did not develop CBH ; however , about a quarter had conversion rates from ABH to CBH greater than 20 % . Interpretation : Only a minority of new brain lesions in patients with MS treated with GA or IFNβ1b convert to CBH

AUTHORS ' CONCLUSIONS There is insufficient evidence of differences in live birth , miscarriage , stillbirth or clinical pregnancy to choose between TLS and conventional incubation .

BACKGROUND Embryo incubation and assessment is a vital step in assisted reproductive technology ( ART ) . Traditionally , embryo assessment has been achieved by removing embryos from a conventional incubator daily for assessment of quality by an embryologist , under a light microscope . Over recent years time-lapse systems ( TLSs ) have been developed which can take digital images of embryos at frequent time intervals . This allows embryologists , with or without the assistance of computer algorithms , to assess the quality of the embryos without physically removing them from the incubator . The potential advantages of a TLS include the ability to maintain a stable culture environment , therefore limiting the exposure of embryos to changes in gas composition , temperature and movement . Additionally a TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through monitoring embryo development . OBJECTIVES To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART .

OBJECTIVE To determine if the addition of continuous morphokinetic data improves reproductive outcomes when all embryos are cultured in a closed system . DESIGN Prospect i ve , r and omized , controlled study . SETTING Single academic center . PATIENT(S ) A total of 235 patients undergoing fresh autologous IVF cycles with at least four embryos , cultured in the Embryoscope : 116 patients r and omized to conventional once-daily morphologic embryo screening ( CS ) and 119 to additional time-lapse kinetic monitoring ( TLM ) for selection . INTERVENTION(S ) TLM versus CS . MAIN OUTCOME MEASURE(S ) Intrauterine clinical pregnancy ( CPR ) and implantation ( IR ) rates . RESULT ( S ) CPR and IR were similar overall ( TLM vs. CS , respectively : CPR 68 % vs. 63 % ; IR 51 % vs. 45 % ) and with blastocyst transfers ( CPR 74 % vs. 67 % ; IR 56 % vs. 51 % ) . CPR with day 5 transfer was threefold higher than day 3 transfer , but group ( TLM vs. CS ) was not a significant predictor of clinical pregnancy or implantation . Significantly more multinucleation was detected when CS embryos were retrospectively review ed with the use of TLM ( 7.0 % vs. 35.3 % ) , and multinucleation was independently associated with decreased rates of implantation . Time to the start of blastulation of < 100 hours after insemination and the morphokinetic scoring system used in the TLM group were independently associated with implantation . CONCLUSION ( S ) The addition of time-lapse morphokinetic data did not significantly improve clinical reproductive outcomes in all patients and in those with blastocyst transfers . Absence of multinucleation , timing of blastulation , and morphokinetic score were found to be associated with blastocyst implantation rates . CLINICAL TRIAL REGISTRATION NUMBER NCT02081859 OBJECTIVE To quantify the effect on reproductive outcome of culturing and selecting embryos using a novel time-lapse monitoring system ( TMS ) . DESIGN Retrospective observational cohort study . SETTING University-affiliated private center . PATIENT(S ) Donation and autologous intracytoplasmic sperm injection ( ICSI ) cycles from ten IVF clinics using similar procedures , cultured in TMS ( n = 1,390 ) or in a st and ard incubator ( SI ; n = 5,915 ) . INTERVENTION(S ) None . MAIN OUTCOME MEASURE(S ) Clinical pregnancy rate confirmed by ultrasound in week 7 . RESULT ( S ) A logistic regression analysis , which included all significant confounding factors , was used to evaluate the effect of culturing and selecting embryos with the use of TMS . Comparing clinical pregnancy rates per oocyte retrieval with TMS and SI treatments gave a crude effect of odds ratio [ OR ] 1.190 ( 95 % confidence interval [ CI ] 1.058 - 1.337 ) . Oocyte source , maternal age , day of transfer , and number of retrieved oocytes were identified as significant confounding factors . After accounting for confounding factors , the effect of TMS culture was OR 1.201 ( 95 % CI 1.059 - 1.363 ) . Limiting analysis to treatments with embryo transfer and including number of transferred embryos as a confounding factor likewise gave a significant effect of TMS with OR 1.157 ( 95 % CI 1.018 - 1.315 ) . CONCLUSION ( S ) Analysis of retrospective data indicated that culturing and selecting embryos by TMS significantly improved the relative probability of clinical pregnancy ( + 20.1 % per oocyte retrieval , + 15.7 % per embryo transfer ) . The elevated clinical pregnancy rate was attributed to a combination of stable culture conditions and the use of morphokinetic parameters for embryo selection OBJECTIVE To determine whether incubation in the integrated EmbryoScope time-lapse monitoring system ( TMS ) and selection supported by the use of a multivariable morphokinetic model improve reproductive outcomes in comparison with incubation in a st and ard incubator ( SI ) embryo culture and selection based exclusively on morphology . DESIGN Prospect i ve , r and omized , double-blinded , controlled study . SETTING University-affiliated private in vitro fertilization ( IVF ) clinic . PATIENT(S ) Eight hundred forty-three infertile couples undergoing intracytoplasmic sperm injection ( ICSI ) . INTERVENTION(S ) No patient intervention ; embryos cultured in SI with development evaluated only by morphology ( control group ) and embryos cultured in TMS with embryo selection was based on a multivariable model ( study group ) . MAIN OUTCOME MEASURE(S ) Rates of embryo implantation , pregnancy , ongoing pregnancy ( OPR ) , and early pregnancy loss . RESULT ( S ) Analyzing per treated cycle , the ongoing pregnancy rate was statistically significantly increased 51.4 % ( 95 % CI , 46.7 - 56.0 ) for the TMS group compared with 41.7 % ( 95 % CI , 36.9 - 46.5 ) for the SI group . For pregnancy rate , differences were not statistically significant at 61.6 % ( 95 % CI , 56.9 - 66.0 ) versus 56.3 % ( 95 % CI , 51.4 - 61.0 ) . The results per transfer were similar : statistically significant differences in ongoing pregnancy rate of 54.5 % ( 95 % CI , 49.6 - 59.2 ) versus 45.3 % ( 95 % CI , 40.3 - 50.4 ) and not statistically significant for pregnancy rate at 65.2 % ( 95 % CI , 60.6 - 69.8 ) versus 61.1 % ( 95 % CI , 56.2 - 66.1 ) . Early pregnancy loss was statistically significantly decreased for the TMS group with 16.6 % ( 95 % CI , 12.6 - 21.4 ) versus 25.8 % ( 95 % CI , 20.6 - 31.9 ) . The implantation rate was statistically significantly increased at 44.9 % ( 95 % CI , 41.4 - 48.4 ) versus 37.1 % ( 95 % CI , 33.6 - 40.7 ) . CONCLUSION ( S ) The strategy of culturing and selecting embryos in the integrated EmbryoScope time-lapse monitoring system improves reproductive outcomes . CLINICAL TRIAL REGISTRATION NUMBER NCT01549262 Purpose To assess the effects of light from an integrated optical microscope and evaluate the safety of time-lapse observations using a built-in microscope incubator . Methods We prospect ively compared the fertilization rate and embryonic morphology after intracytoplasmic sperm injection between embryos cultured with time-lapse observations every 15 min in an incubator with an integrated optical microscope and embryos with intermittent observations ( once a day ) in conventional incubators . Results No significant differences were observed in the fertilization rate ( 57.5 % vs. 57.5 % ) or the rate of excellent-good cleavage embryos ( 36.0 % vs. 36.0 % ) . Conclusions These results suggest that time-lapse observations using an incubator with an integrated optical microscope may therefore be safely utilized in clinical practice Background Pharmacokinetic studies with XM17 ( Ovaleap ® ) , a recombinant human follicle-stimulating hormone ( r-hFSH , follitropin alfa ) , have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down-regulated with a long agonist protocol . In these studies , Ovaleap ® pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product ( Gonal-f ® ) . The objective of the present study is to determine whether Ovaleap ® is equivalent to Gonal-f ® with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology ( ART ) therapy . Methods This multinational , multicenter , r and omized ( 1:1 ) , active-controlled , assessor-blind , comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m2 and regular menstrual cycles of 21 to 35 days undergoing ART therapy . During a 5-day fixed-dose phase , women received 150 IU/day of Ovaleap ® ( n = 153 ) or Gonal-f ® ( n = 146 ) , followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days , up to a maximum of 450 IU/day . Ovaleap ® was to be deemed equivalent to Gonal-f ® if the two-sided 0.95 confidence interval ( CI ) for the difference in the number of oocytes retrieved fell within the equivalence range of ±3 oocytes . Results Similar numbers of oocytes were retrieved in the 2 treatment groups . The mean ± SD number of oocytes retrieved was 12.2 ± 6.7 in the Ovaleap ® group and 12.1 ± 6.7 in the Gonal-f ® group ( intent-to-treat [ ITT ] population ) . Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups ( 95 % CI : −0.76 - 0.82 ) , which was well within the prespecified equivalence range of ±3 oocytes . Ovaleap ® and Gonal-f ® showed favorable and comparable safety profiles , with no unexpected safety findings . Conclusions Ovaleap ® has shown the same efficacy and safety as Gonal-f ® for stimulation of follicular development in infertile women ( up to 37 years of age ) who are undergoing ART therapy . Trial Registration EudraCT : 2009 - 017674 - 20 . Current controlled trials : IS RCT N74772901 . Date of trial registration : 19 March 2010 STUDY QUESTION Does culture in a closed system result in an increased number of good quality embryos ( GQE ) on Day 2 compared with culture in a conventional system ? SUMMARY ANSWER Culture in a closed system up to 2 days after microinjection results in similar embryo development and morphological quality compared with culture in a conventional incubation system . WHAT IS KNOWN ALREADY Time-lapse imaging ( TLI ) incubators are rapidly being introduced into IVF laboratories worldwide , despite the lack of large prospect i ve r and omized trials demonstrating improvement in embryo development or pregnancy rates . STUDY DESIGN , SIZE , DURATION A r and omized controlled trial including 364 patients ( 365 cycles ) was conducted between May 2010 and February 2014 . After oocyte collection , r and omization was carried out and all of a patients ' oocytes were allocated to culture in either a conventional incubator or a closed incubator system in proportion 1:2 until embryo transfer on Day 2 . A total of 1979 oocytes were injected and cultured in the closed system , and 1000 in the st and ard incubator . The primary end-point was the number of GQE in the two groups . PARTICIPANTS / MATERIAL S , SETTING S , METHODS In total , 364 patients undergoing their first IVF cycle using ICSI , where at least one oocyte was retrieved , were r and omized in a university hospital setting . Two hundred and forty patients were r and omized for culture in a closed system and 124 patients for culture in the conventional incubator system ( control group ) . Embryo assessment s and final morphological scoring before transfer and cryopreservation were carried out at the same time points for embryos cultured in the conventional incubator and in the closed system . MAIN RESULTS AND THE ROLE OF CHANCE There was no significant difference in the mean ± SD number of GQEs between groups : 2.41 ± 2.27 for the closed system group and 2.19 ± 1.82 for the control group ( P = 0.34 , difference 0.23 , 95 % confidence interval 0.69 ; -0.24 ) . No significant differences were found in the number of 4-cell embryos , implantation- , pregnancy- or ongoing pregnancy rates . A significantly higher miscarriage rate was found in the TLI group compared with the control group ( 33.3 and 10.2 % , P = 0.01 ) . LIMITATIONS , REASONS FOR CAUTION Culture media , temperature and gas levels were similar in the open and closed incubator systems , but different culture dishes were used . Culturing embryos for longer time period ( to the blastocyst stage ) may give different results . Only ICSI patients were included , which may limit the generalizability of the results . Finally , the number of GQEs on Day 2 was used as a surrogate outcome for live birth . WIDER IMPLICATION S OF THE FINDINGS The results are consistent with other , smaller r and omized trials showing no difference in embryo quality when comparing culture in a conventional incubator with that of a closed TLI incubator system Background Recent advances in time-lapse monitoring in IVF treatment have provided new morphokinetic markers for embryonic competence . However , there is still very limited information about the relationship between morphokinetic parameters , chromosomal compositions and implantation potential . Accordingly , this study aim ed at investigating the effects of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing on pregnancy and implantation outcomes for patients undergoing preimplantation genetic screening ( PGS ) . Methods A total of 1163 metaphase II ( MII ) oocytes were retrieved from 138 PGS patients at a mean age of 36.6 ± 2.4 years . These sibling MII oocytes were then r and omized into two groups after ICSI : 1 ) Group A , oocytes ( n = 582 ) were cultured in the time-lapse system and 2 ) Group B , oocytes ( n = 581 ) were cultured in the conventional incubator . For both groups , whole genomic amplification and array CGH testing were performed after trophectoderm biopsy on day 5 . One to two euploid blastocysts within the most predictive morphokinetic parameters ( Group A ) or with the best morphological grade available ( Group B ) were selected for transfer to individual patients on day 6 . Ongoing pregnancy and implantation rates were compared between the two groups . Results There were significant differences in clinical pregnancy rates between Group A and Group B ( 71.1 % vs. 45.9 % , respectively , p = 0.037 ) . The observed implantation rate per embryo transfer significantly increased in Group A compared to Group B ( 66.2 % vs. 42.4 % , respectively , p = 0.011 ) . Moreover , a significant increase in ongoing pregnancy rates was also observed in Group A compared to Group B ( 68.9 % vs. 40.5 % . respectively , p = 0.019 ) . However , there was no significant difference in miscarriage rate between the time-lapse system and the conventional incubator ( 3.1 % vs. 11.8 % , respectively , p = 0.273 ) . Conclusions This is the first prospect i ve investigation using sibling oocytes to evaluate the efficiency of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing for PGS patients . Our data clearly demonstrate that the combination of these two advanced technologies to select competent blastocysts for transfer results in improved implantation and ongoing pregnancy rates for PGS patients STUDY QUESTION Can a generally applicable morphokinetic algorithm suitable for Day 3 transfers of time-lapse monitored embryos originating from different culture conditions and fertilization methods be developed for the purpose of supporting the embryologist 's decision on which embryo to transfer back to the patient in assisted reproduction ? SUMMARY ANSWER The algorithm presented here can be used independently of culture conditions and fertilization method and provides predictive power not surpassed by other published algorithms for ranking embryos according to their blastocyst formation potential . WHAT IS KNOWN ALREADY Generally applicable algorithms have so far been developed only for predicting blastocyst formation . A number of clinics have reported vali date d implantation prediction algorithms , which have been developed based on clinic-specific culture conditions and clinical environment . However , a generally applicable embryo evaluation algorithm based on actual implantation outcome has not yet been reported . STUDY DESIGN , SIZE , DURATION Retrospective evaluation of data extracted from a data base of known implantation data ( KID ) originating from 3275 embryos transferred on Day 3 conducted in 24 clinics between 2009 and 2014 . The data represented different culture conditions ( reduced and ambient oxygen with various culture medium strategies ) and fertilization methods ( IVF , ICSI ) . The capability to predict blastocyst formation was evaluated on an independent set of morphokinetic data from 11 218 embryos which had been cultured to Day 5 . PARTICIPANTS / MATERIAL S , SETTING , METHODS The algorithm was developed by applying automated recursive partitioning to a large number of annotation types and derived equations , progressing to a five-fold cross-validation test of the complete data set and a validation test of different incubation conditions and fertilization methods . The results were expressed as receiver operating characteristics curves using the area under the curve ( AUC ) to establish the predictive strength of the algorithm . MAIN RESULTS AND THE ROLE OF CHANCE By applying the here developed algorithm ( KIDScore ) , which was based on six annotations ( the number of pronuclei equals 2 at the 1-cell stage , time from insemination to pronuclei fading at the 1-cell stage , time from insemination to the 2-cell stage , time from insemination to the 3-cell stage , time from insemination to the 5-cell stage and time from insemination to the 8-cell stage ) and ranking the embryos in five groups , the implantation potential of the embryos was predicted with an AUC of 0.650 . On Day 3 the KIDScore algorithm was capable of predicting blastocyst development with an AUC of 0.745 and blastocyst quality with an AUC of 0.679 . In a comparison of blastocyst prediction including six other published algorithms and KIDScore , only KIDScore and one more algorithm surpassed an algorithm constructed on conventional Alpha/ESHRE consensus timings in terms of predictive power . LIMITATIONS , REASONS FOR CAUTION Some morphological assessment s were not available and consequently three of the algorithms in the comparison were not used in full and may therefore have been put at a disadvantage . Algorithms based on implantation data from Day 3 embryo transfers require adjustments to be capable of predicting the implantation potential of Day 5 embryo transfers . The current study is restricted by its retrospective nature and absence of live birth information . Prospect i ve R and omized Controlled Trials should be used in future studies to establish the value of time-lapse technology and morphokinetic evaluation . WIDER IMPLICATION S OF THE FINDINGS Algorithms applicable to different culture conditions can be developed if based on large data sets of heterogeneous origin . STUDY FUNDING /COMPETING INTEREST(S ) This study was funded by Vitrolife A/S , Denmark and Vitrolife AB , Sweden . B.M.P. ’s company BMP Analytics is performing consultancy for Vitrolife A/S. M.B. is employed at Vitrolife A/S. M.M. ’s company ilabcomm GmbH received honorarium for consultancy from Vitrolife AB . D.K.G. received research support from Vitrolife AB OBJECTIVE To determine if an automated time-lapse test ( TL-test ) combined with traditional morphology for embryo selection and day 3 transfer results in improved clinical outcomes . DESIGN Prospect i ve concurrent-controlled pilot study . SETTING IVF clinic and laboratory . PATIENT(S ) A total of 319 female patients < 41 years old , with day 3 embryo transfer , fewer than three failed IVF cycles , and at least four zygotes ( 2-pronuclear ) on day 1 . INTERVENTION(S ) Automated time-lapse embryo assessment combined with morphologic assessment in the study ( test ) group compared with morphologic assessment only ( control group ) . MAIN OUTCOME MEASURE(S ) Embryo implantation , pregnancy , and multiple pregnancy rates . Sub analysis of implantation potential of embryos based on the TL-test ( TL-high vs. TL-low ) scores . RESULT ( S ) Implantation and clinical pregnancy rates were significantly higher in the test group compared with the control group ( implantation rates 30.2 % vs. 19.0 % , clinical pregnancy rates 46.0 % vs. 32.1 % , respectively ) . Multiple pregnancy rates were not statistically different ( 26.7 % vs. 18.3 % ) . Test group patients receiving at least one TL-high embryo had significantly higher implantation rates than patients receiving only TL-low embryos ( 36.8 % vs. 20.6 % ) . TL-high compared with TL-low embryos had significantly higher implantation rates ( 44.7 % vs. 20.5 % ) . Among morphologically good embryos , TL-high embryos were more likely to implant than TL-low embryos ( 44.1 % vs. 20.6 % ) . CONCLUSION ( S ) This is the first report demonstrating improved implantation rates in patients receiving day 3 embryo transfers based on the combined use of a TL-test along and traditional morphology . Our findings confirm that the noninvasive TL-test adds valuable information to traditional morphologic grading . CLINICAL TRIAL REGISTRATION NUMBER NCT01671657 Purpose In the current study , our aim was to demonstrate that EmbryoScope incubation conditions is comparable to st and ard laboratory incubation circumstances by comparing embryo quality , development and ongoing pregnancy rates between the EmbryoScope ( ES ) and a st and ard incubator ( SI ) . We analyzed 478 embryos from 60 couples undergoing oocyte donation were included in the study . Methods All embryos retrieved from a patient were r and omly distributed in the ES or SI . We calculated blastocyst development rate , blastocyst viability and ongoing pregnancy rate for embryo transfers from ES , SI and mixed ( one embryo from the ES and one from the SI ) . Statistical analysis was conducted by Chi square tests , considering p < 0.05 significant . Results No significant differences were found between the ES and SI from all the parameters evaluated . Conclusions Thus we concluded that time-lapse monitoring in the EmbryoScope does not impair embryo quality while allowing for morphological , spatial and temporal analysis of embryo development Purpose Time-lapse monitoring allows for a flexible embryo evaluation and potentially provides new dynamic markers of embryo competence . Before introducing time-lapse monitoring in a clinical setting , the safety of the instrument must be properly documented . Accordingly , the aim of this study was to evaluate the safety of a commercially available time-lapse incubator . Methods In a two center , r and omized , controlled , clinical trial 676 oocytes from 59 patients in their 2nd or third treatment cycle , age < 38 years and ≥8 oocytes retrieved were cultured in the time-lapse incubator or in a conventional incubator . The primary outcome was proportion of 4-cell embryos on day 2 . Secondary outcomes were proportion of 7–8 cell embryos on day 3 and proportion of blastocysts on day 5 . Implantation pregnancy rates were registered based on presence of fetal heart activity visualized by ultrasound 8 weeks after embryo transfer . Results No significant difference was found between the time-lapse incubator ( TLI ) and conventional incubator ( COI ) in proportion of 4-cell embryos on day 2 irrespective of whether data was analyzed according to ITT ( RRTLI/COI : 0.81 ( 0.65 ; 1.02 ) ) or PP ( RRTLI/COI : 0.80 ( 0.63 ; 1.01 ) ) . Nor were any significant differences detected in the secondary endpoints ; i.e. proportion of 7–8-cell embryos on day three ITT ( RRTLI/COI : 0.96 ( 0.73 ; 1.26 ) ) ; PP ( RRTLI/COI : 0.95 ( 0.72 ; 1.26 ) ) and proportion of blastocysts on day five ITT ( RRTLI/COI : 1.09 ( 0.84 ; 1.41 ) ) ; PP ( RRTLI/COI : 1.09 ( 0.83 : 1.41 ) ) . We found no differences in clinical pregnancy rate or implantation rate . Conclusion Culture in the time-lapse incubator supports embryonic development equally to a conventional incubator OBJECTIVE To study whether a culture medium that allows undisturbed culture supports human embryo development to the blastocyst stage equivalently to a well-established sequential media . DESIGN R and omized , double-blinded sibling trial . SETTING Independent in vitro fertilization ( IVF ) clinics . PATIENT(S ) One hundred twenty-eight patients , with 1,356 zygotes r and omized into two study arms . INTERVENTION(S ) Embryos r and omly allocated into two study arms to compare embryo development on a time-lapse system using a single-step medium or sequential media . MAIN OUTCOME MEASURE(S ) Percentage of good- quality blastocysts on day 5 . RESULT ( S ) Percentage of day 5 good- quality blastocysts was 21.1 % ( st and ard deviation [ SD ] ± 21.6 % ) and 22.2 % ( SD ± 22.1 % ) in the single-step time-lapse medium ( G-TL ) and the sequential media ( G-1/G-2 ) groups , respectively . The mean difference ( -1.2 ; 95 % CI , -6.0 ; 3.6 ) between the two media systems for the primary end point was less than the noninferiority margin of -8 % . There was a statistically significantly lower number of good- quality embryos on day 3 in the G-TL group [ 50.7 % ( SD ± 30.6 % ) vs. 60.8 % ( SD ± 30.7 % ) ] . Four out of the 11 measured morphokinetic parameters were statistically significantly different for the two media used . The mean levels of ammonium concentration in the media at the end of the culture period was statistically significantly lower in the G-TL group as compared with the G-2 group . CONCLUSION ( S ) We have shown that a single-step culture medium supports blastocyst development equivalently to established sequential media . The ammonium concentrations were lower in the single-step media , and the measured morphokinetic parameters were modified somewhat . CLINICAL TRIAL REGISTRATION NUMBER NCT01939626 R and omised controlled trials are widely accepted as the most reliable method of determining effectiveness , but most trials have evaluated the effects of a single intervention such as a drug . Recognition is increasing that other , non-pharmacological interventions should also be rigorously evaluated.1 - 3 This paper examines the design and execution of research required to address the additional problems result ing from evaluation of complex interventions —that is , those “ made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper ( www.mrc.ac.uk/complex_packages.html ) . We focus on r and omised trials but believe that this approach could be adapted to other design s when they are more appropriate . # # # # Summary points Complex interventions are those that include several components The evaluation of complex interventions is difficult because of problems of developing , identifying , documenting , and reproducing the intervention A phased approach to the development and evaluation of complex interventions is proposed to help research ers define clearly where they are in the research process Evaluation of complex interventions requires use of qualitative and quantitative evidence There are specific difficulties in defining , developing , documenting , and reproducing complex interventions that are subject to more variation than a drug . A typical example would be the design of a trial to evaluate the benefits of specialist stroke units . Such a trial would have to consider the expertise of various health professionals as well as investigations , drugs , treatment guidelines , and arrangements for discharge and follow up . Stroke units may also vary in terms of organisation , management , and skill mix . The active components of the stroke unit may be difficult to specify , making it difficult to replicate the intervention . The box gives other examples of complex interventions . # # # # Examples of complex interventions Service delivery and organisation : Stroke units Hospital at home Interventions directed at health professionals ' behaviour : Strategies for implementing guidelines Computerised decision support Community interventions : Community OBJECTIVE To assess the first computer-automated platform for time-lapse image analysis and blastocyst prediction and to determine how the screening information may assist embryologists in day 3 ( D3 ) embryo selection . DESIGN Prospect i ve , multicenter , cohort study . SETTING Five IVF clinics in the United States . PATIENT(S ) One hundred sixty women ≥ 18 years of age undergoing fresh IVF treatment with basal antral follicle count ≥ 8 , basal FSH < 10 IU/mL , and ≥ 8 normally fertilized oocytes . INTERVENTION(S ) A noninvasive test combining time-lapse image analysis with the cell-tracking software , Eeva ( Early Embryo Viability Assessment ) , was used to measure early embryo development and generate usable blastocyst predictions by D3 . MAIN OUTCOME MEASURE(S ) Improvement in the ability of experienced embryologists to select which embryos are likely to develop to usable blastocysts using D3 morphology alone , compared with morphology plus Eeva . RESULT ( S ) Experienced embryologists using Eeva in combination with D3 morphology significantly improved their ability to identify embryos that would reach the usable blastocyst stage ( specificity for each of three embryologists using morphology vs. morphology plus Eeva : 59.7 % vs. 86.3 % , 41.9 % vs. 84.0 % , 79.5 % vs. 86.6 % ) . Adjunctive use of morphology plus Eeva improved embryo selection by enabling embryologists to better discriminate which embryos would be unlikely to develop to blastocyst and was particularly beneficial for improving selection among good-morphology embryos . Adjunctive use of morphology plus Eeva also reduced interindividual variability in embryo selection . CONCLUSION ( S ) Previous studies have shown improved implantation rates for blastocyst transfer compared with cleavage-stage transfer . Addition of Eeva to the current embryo grading process may improve the success rates of cleavage-stage ETs

Reports of adverse effects from topical fluoride applications were rare and unlikely to be significant . AUTHORS ' CONCLUSIONS This review found a low level of certainty that 12,300 ppm F foam applied by a professional every 6 to 8 weeks throughout fixed orthodontic treatment , might be effective in reducing the proportion of orthodontic patients with new DLs .

BACKGROUND Early dental decay or demineralised lesions ( DLs , also known as white spot lesions ) can appear on teeth during fixed orthodontic ( brace ) treatment . Fluoride reduces decay in susceptible individuals , including orthodontic patients . This review compared various forms of topical fluoride to prevent the development of DLs during orthodontic treatment . This is the second up date of the Cochrane Review first published in 2004 and previously up date d in 2013 . OBJECTIVES The primary objective was to evaluate whether topical fluoride reduces the proportion of orthodontic patients with new DLs after fixed appliances . The secondary objectives were to examine the effectiveness of different modes of topical fluoride delivery in reducing the proportions of orthodontic patients with new DLs , as well as the severity of lesions , in terms of number , size and colour . Participant-assessed outcomes , such as perception of DLs , and oral health-related quality of life data were to be included , as would reports of adverse effects .

The purpose of this study was to compare the effectiveness of a 1100 ppm fluoride toothpaste used alone , or together with a 0.05 % NaF rinse used once daily or a 0.4 % SnF2 gel applied twice daily , in controlling the decalcification that often accompanies orthodontic treatment . Ninety-five consecutively treated adolescent patients were matched for age and sex and assigned to one of these three regimens . Single blind assessment s of decalcification were performed on all labial surfaces of all erupted teeth before appliances were placed and 3 months after appliances were removed . Because the first molars had the highest decalcification scores , data for the whole mouth and for first molars were analyzed separately . When pre-treatment levels of decalcification were subtracted from post-treatment values , significantly lower decalcification scores ( p < 0.05 ) were found for both whole mouth and first molars in the rinse and gel groups as compared with the control group ( toothpaste alone ) . Although the gel group consistently had less decalcification than the rinse group , this difference only approached statistical significance . These results indicate that twice daily use of a 1100 ppm fluoride toothpaste and either a once-daily 0.05 % NaF rinse or a twice-daily 0.4 % SnF2 gel provides additional protection against decalcification beyond that achieved with toothpaste alone OBJECTIVES The aims of this study were to compare the local and systemic uptake of fluoride released from a compomer material ( Dyract Ortho ) and a resin-modified glass ionomer cement ( Vitremer ) with that of a conventional resin adhesive ( Right-On ) and to compare the cariostatic ability of each of the test material s with that of the resin control . METHODS Twenty six patients were r and omly allocated to have a bracket bonded to a premolar on one side of the arch with one of the test material s and on the opposite side with the control material . Premolars destined for extraction as part of an orthodontic treatment plan were selected for bonding . A non-fluoride toothpaste was used by all participants for 4 weeks prior to bracket bonding and throughout the 4 week trial period . Fluoride release was measured in saliva , plaque and urine sample s taken pre-bonding and 4 weeks post-bonding . Enamel demineralisation was assessed by scoring the buccal surface of each extracted tooth using a caries index . RESULTS Neither Vitremer nor Dyract Ortho altered salivary or urinary fluoride concentration significantly 4 weeks post-bonding but plaque fluoride concentration increased significantly around premolars bonded with Vitremer . The test material s as a combined group were associated with significantly less demineralisation than the control material but there was no significant difference in cariostatic ability detected between either Dyract Ortho or Vitremer when each group was compared separately with the control . CONCLUSIONS Fluoride released from Dyract Ortho or Vitremer is likely to exert a local and not a systemic effect . In a 4-week clinical study , the cariostatic ability of the fluoride-releasing cements , as a combined group , was superior to that of the non-fluoride releasing control but there was no significant difference in cariostatic ability between the two test material s when each test group was compared separately with the control The study aim ed to compare the survival time and cariostatic potential of a compomer to that of a resin adhesive when used to bond stainless steel orthodontic brackets to labial segment teeth only . The effect of the patients ' sex , age at the start of treatment and presenting malocclusion on bracket survival time was assessed also . Forty-five consecutive patients who attended for fixed appliance therapy were r and omly selected . Four hundred twenty-six brackets were bonded ( 213 with compomer and 213 with resin adhesive ) with a split mouth design ; the right or left side allocation of compomer in either arch was alternated . Color transparencies of the maxillary incisors , m and ibular incisors , or both , and transparencies of the canines , were taken before treatment . At the debond stage , the transparencies were projected ( 20x ) and assessed by an experienced examiner , who used a caries index . The survival time distributions for brackets bonded with each bonding agent were not significantly different ( P = .74 , paired Prentice-Wilcoxon test ; P = .75 , Akritas test ) , with bracket failure rates of 17 % and 20 % recorded for compomer and resin adhesive , respectively . Neither the patients ' sex ( P = .85 ) nor malocclusion ( P = .26 ) appear to affect significantly bracket survival , but patient age was identified as a useful prognostic indicator of bracket survival ( P < .001 ) . On average , there was more decalcification related to brackets bonded with resin adhesive than with compomer ( P = .0075 ) . Survival time distributions of brackets bonded with compomer or resin adhesive appear comparable , but decalcification was reduced significantly by bonding with compomer INTRODUCTION Despite the many advances to improve the practice of orthodontics , white spot lesions , or decalcifications , remain a common complication in patients with poor oral hygiene . The purpose of this study was to assess the perceptions and level of awareness of patients , parents , orthodontists , and general dentists toward the development of white spot lesions during orthodontic treatment . METHODS This was a prospect i ve epidemiologic survey of the perceptions of orthodontic patients ( n = 315 ) , parents ( n = 279 ) , orthodontists ( n = 305 ) , and general dentists ( n = 191 ) regarding the significance , prevention , and treatment of white spot lesions . RESULTS All surveyed groups indicated that white spot lesions detracted from the overall appearance of straight teeth , attributed primary responsibility for the prevention of white spot lesions to the patients themselves , and thought that the general dentist should be responsible for treating white spot lesions . Patients regarded themselves as ultimately responsible for the prevention of white spot lesions ( P < 0.05 ) . CONCLUSIONS The patients , parents , orthodontists , and general dentists had similar perceptions regarding the significance , prevention , and treatment of white spot lesions . All groups indicated that patients were the most responsible for the prevention of white spot lesions . Communication among patients , parents , orthodontists , and general dentists needs to improve to decrease the incidence of white spot lesions in the orthodontic population INTRODUCTION Enamel demineralization is a problem in orthodontics . Fluoride is partially effective in addressing this problem , but additional treatment options are needed . The objective of this prospect i ve r and omized controlled trial was to determine the effectiveness of a new product , MI Paste Plus ( GC America , Alsip , Ill ) , in the prevention or reduction of white spot lesions in orthodontic patients . METHODS Sixty patients who were undergoing routine orthodontic treatment were recruited for this prospect i ve r and omized clinical trial . A double-blind method of r and omization was used to determine whether each patient received the MI Paste Plus or a placebo paste ( Tom 's of Maine , Salisbury , United Kingdom ) . Each patient was asked to administer the paste by using a fluoride tray for a minimum of 3 to 5 minutes each day at night after brushing . Photographic records obtained in a light-controlled environment were used to record the presence or absence of white spot lesions in both groups . The enamel decalcification index was used to determine the number of white spot lesions per surface at each time interval . Patients were followed at 4-week intervals for 3 months . A scoring system from 0 to 6 was used to determine the level of caries or cavitations . This system was also used for each tooth at each time interval . RESULTS Fifty patients ( 26 using MI Paste Plus , 24 using the placebo paste ) completed the study . The enamel decalcification index scores for all surfaces were 271 and 135 at the start of treatment and 126 and 258 at the end of treatment for the MI Paste Plus and placebo paste groups , respectively . The enamel decalcification index scores in the MI Paste Plus group reduced by 53.5 % , whereas the placebo group increased by 91.1 % during the study period . A 3-way analysis of variance ( ANOVA ) was done for the average enamel decalcification index scores . The surface type , the product/time interactions , and the product/surface interactions of the mean enamel decalcification index scores were significant ( P < 0.05 ) . CONCLUSIONS MI Paste Plus helped prevent the development of new white spot lesions during orthodontic treatment and decreased the number of white spot lesions already present . The placebo paste had no preventive action on white spot development during orthodontic treatment ; the number of lesions actually increased . MI Paste Plus reduced white spots on the gingival surfaces ; the placebo paste had the opposite effect . The incisal surface effect on the mean enamel decalcification index scores over time and between products was highly significant . The incisal enamel decalcification index scores were consistently higher than those for the other surfaces ( mesial , distal , and gingival ) The purpose of this study was to compare the effectiveness of toothbrushing followed by fluoride rinsing , fluoride gel brushing , or fluoride gel dentifrice brushing alone in controlling the demineralization that often follows orthodontic treatment . Seventy-eight consecutive adolescent patients undergoing orthodontic care were divided into 3 groups : group 1 ( control ) used a low-potency , high-frequency fluoride rinse ; group 2 used a high-potency , high-frequency fluoride brush-on gel ; and group 3 used a high-potency , high-frequency fluoride gel dentifrice . When pretreatment levels of demineralization were subtracted from posttreatment values , both gel groups displayed a significant difference ( P < .05 ) in smooth surface demineralization sites when compared to controls . Reversal of white-spot lesions occurred in 15 % of sites that exhibited pathology as a result of the fluoride and preventive regimen . These results indicate that a daily use of a 5000-ppm fluoride gel along with toothbrushing with a fluoride paste or brushing twice daily with a 5000-ppm fluoride dentifrice alone provides greater protection beyond that of tooth-brushing with a fluoride paste ( 1000 ppm ) and rinsing with a 0.05 % sodium fluoride rinse A prospect i ve examination of 10 consecutively treated orthodontic patients was undertaken to examine the effectiveness of fluoride varnish in reducing enamel demineralization . Pairs of dental quadrants for each patient 's mouth ( ie , maxillary right and m and ibular left ; maxillary left and m and ibular right ) were r and omly assigned to an experimental or control group . After placement of resin-bonded orthodontic brackets , fluoride varnish was applied to the 2 experimental dental quadrants for each patient . Subsequent applications were done every 3 months during 12 months of orthodontic treatment . A double-blinded examination of intraoral photographs of the 100 experimental and 100 control teeth was done . The presence of white spot lesions was registered using the enamel decalcification index and the 2 groups were compared using paired Student t tests with a significance level of 5 % ( P < .05 ) . There was no statistically significant difference between the mean enamel decalcification index for the control and experimental groups before or after treatment , since demineralization increased for both groups . Most importantly , the change in mean enamel decalcification index was significantly smaller for the experimental group ( 0.34 ) , compared to the control group ( 0.51 ) . In other words , there was 44.3 % ( P < .05 ) less demineralization noted for teeth that had been treated with fluoride varnish during orthodontic treatment Background The ' Hawthorne Effect ' may be an important factor affecting the generalisability of clinical research to routine practice , but has been little studied . Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge , no attempt has been made to quantify them . Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia . Methods Participants in a dementia trial were r and omised to intensive follow-up ( with comprehensive assessment visits at baseline and two , four and six months post r and omisation ) or minimal follow-up ( with an abbreviated assessment at baseline and a full assessment at six months ) . Our primary outcomes were cognitive functioning ( ADAS-Cog ) and participant and carer-rated quality of life ( QOL-AD ) . Results We recruited 176 participants , mainly through general practice s. The main analysis was based on Intention to treat ( ITT ) , with available data . In the ANCOVA model with baseline score as a co-variate , follow-up group had a significant effect on outcome at six months on the ADAS-Cog score ( n = 140 ; mean difference = -2.018 ; 95%CI -3.914 , -0.121 ; p = 0.037 favouring the intensive follow-up group ) , and on participant-rated quality of life score ( n = 142 ; mean difference = -1.382 ; 95%CI -2.642 , -0.122 ; p = 0.032 favouring minimal follow-up group ) . There was no significant difference on carer quality of life . Conclusion We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia result ed in a better outcome than minimal follow-up , as measured by their cognitive functioning . Trial registration Current controlled trials : IS RCT The aim of this study was to test a particular type of intra-oral fluoride releasing device ( IFRD ) , design ed to release 0.04 mg/day of fluoride over a period of 6 months , using customized holders , in patients receiving orthodontic treatment . Discomfort , holder detachment , plaque accumulation near the device , and the presence of gingivitis , bleeding , white spot lesions , and /or decay was recorded in 76 orthodontic patients ( 53 experimental and 23 controls ) before and after wearing the device for 12 months . The system proved to be easy and quick to use , and did not cause discomfort . There were no significant differences between the treated and the control groups for plaque index , bleeding , or the presence of gingivitis . In addition , no carious and /or white spot lesions occurred during the duration of this study in the test group Background Caries is an undesirable side-effect of treatment with fixed orthodontic appliances . Therefore , it is crucial to underst and how orthodontic treatment and different fluoride regimens affect caries risk and individual risk factors . Objective To evaluate the effects of orthodontic treatment and different fluoride regimens on caries risk and caries risk factors , including cariogenic bacteria . Trial design Three-armed , parallel group , r and omized , controlled trial . Methods Patients referred to the Specialist Clinic of Orthodontics , Mölndal Hospital , Sweden , were distributed r and omly into the following groups : group I ( Control group ) , 1450 ppm fluoride ( F ) toothpaste ; group II , 1450 ppm F toothpaste plus 0.2 per cent sodium fluoride ( NaF ) mouth rinse ; and group III , 5000 ppm F toothpaste . The inclusion criteria were : age 12 - 20 years ; and bimaxillary treatment with fixed appliances . The primary outcome variables were : caries risk ; and the numbers of cariogenic bacteria . Radiographs were taken before treatment to determine the caries status . Data were collected before treatment and after 1 year with a fixed appliance . The variables were compiled into a Cariogram to assess the caries risk . Comparisons were made over time within and between the groups . The generation of r and omization sequence was performed in blocks of 30 . Blinding was employed during the data analysis and the caries registration . Recruitment The clinical study duration was from October 2010 to December 2012 . Results Overall , 270 patients were r and omized , of which 15 were excluded from the study . Therefore , 255 patients were included in the analyses . The caries risk increased significantly during orthodontic treatment in group I ( P < 0.0001 ) , whereas groups II and III had unchanged caries risks . All the groups showed statistically significant increases in the numbers of cariogenic bacteria . Harms No harms were reported during the trial . Conclusions To avoid an increased risk of caries during orthodontic treatment , everyday use of high-fluoride toothpaste ( 5000 ppm F ) or mouth rinse ( 0.2 % NaF ) in combination with ordinary toothpaste is recommended . Registration The trial was not registered The presence of decalcification ( white spots ) after the removal of orthodontic appliances still remains a problem . A method to deliver fluoride to the area beneath and around the bonded attachments , independent of patient compliance , could be very helpful . Therefore special attention is being currently directed to the so-called " fluoride releasing bonding adhesives . " A clinical trial was carried out to compare the effect of a visible light-cured fluoride-releasing ( F-releasing ) material with a chemically cured nonfluoride resin on white spot formation during fixed orthodontic therapy . Fifty patients entered the trial , and 762 brackets were bonded in a crossover design . Intraoral slides were taken before and after treatment and were evaluated for white spot formation . Statistical data analysis was carried out by means of a chi-square test . The results of this clinical study indicate that there was no significant difference between the decalcification rates for both types of adhesives . When the appearance of white spots was evaluated in an overall manner , there was significantly more upper than lower decalcification The time to first failure , the position of b and failure at deb and , and the change in enamel white spot lesions of teeth bonded with a modified composite or a conventional glass ionomer were compared in a r and omized half-mouth trial over the full course of orthodontic treatment . One hundred forty b and pairs were cemented in 98 subjects . Overall b and failure rates of 5 % and 2.8 % were recorded for the modified composite and the conventional glass ionomer , respectively , with no significant difference found between their times to first b and failure . At the end-of-treatment deb and , the position of b and failure was predominantly at the enamel-cement interface for the modified composite and at the b and -cement interface for the conventional glass ionomer ( P < .001 ) . A comparison of changes in mean enamel white spot lesion scores during treatment did not reveal significant differences between the cement groups ( P = .16 ) A r and omized prospect i ve clinical study , with 220 patients scheduled for fixed orthodontic therapy , was conducted to test the hypothesis that application of an antimicrobial varnish in combination with a fluoride varnish ( group 1 ) is significantly more efficient in reducing white spot lesions on the labial surfaces than application of the fluoride varnish alone ( group 2 ) . The effects of the antimicrobial varnish on the occurrence of gingivitis and plaque formation were also studied . A third aim was to investigate whether white spot lesion development could be predicted early during treatment . The antimicrobial varnish significantly reduced the number of mutans streptococci in plaque during the first 48 weeks of treatment . This effect did not result in significantly less development of white spot lesions on the labial surfaces compared with the group receiving only the fluoride varnish application . There was however a clear trend that the combination of the antimicrobial and fluoride varnishes more effectively reduced the increments of new lesions on the maxillary incisors . It was speculated that this could be due partly to an inhibiting effect of the antimicrobial varnish in an area with low oral clearance ( with low pH and loss of fluoride ) and partly to an inhibiting effect of the varnish on mutans streptococci . No significant differences between the groups with respect to gingivitis and plaque were found . Lesion development was difficult to predict early after bonding , despite a number of caries-relevant parameters of orthodontic importance . The best predictors for white spot lesions at debonding were visible plaque and mutans streptococci ( eg , the level of oral hygiene and thus the cariogenic challenge ) around the appliance shortly after bonding Decalcification during orthodontic treatment is a serious problem . A glass ionomer agent is now available to bond orthodontic brackets as an alternative to composite resins . This prospect i ve study was a clinical trial to determine if a glass ionomer bonding system ( Fuji Ortho LC ) decreases the incidence of decalcification without increasing the amount of bonding failures . A prospect i ve clinical trial with 16 patients encompassing a total of 298 teeth was conducted . The 149 control teeth were bonded with a light-cured composite resin ( Reliance Light Bond ) whereas the 149 experimental teeth were bonded with the light-cured glass ionomer agent . Patients were followed for a period of 12 to 14 months . All teeth were evaluated for breakage ( bonding failure rate ) , and all maxillary anterior teeth ( 96 ) were evaluated for decalcification on a grade d scale . The glass ionomer failure rate was 24.8 % , and was higher than the composite resin failure rate of 7.4 % ( P < .001 ) . There were more glass ionomer bond failures in 12 of 16 patients ( P < .001 ) . Enamel decalcification was similar in the 2 bonding systems Because the risk of dental caries increases with the use of orthodontic appliances and its control can not depend only on the patient 's self-care , this study evaluated the effect of a glass ionomer cement on reducing enamel demineralization around orthodontic brackets . Fourteen orthodontic patients were r and omly divided into 2 groups of 7 ; they received 23 brackets fitted to their premolars , bonded with either Concise ( 3 M Dental Products , St Paul , Minn ) , a composite resin ( control group ) , or Fuji Ortho LC ( GC America , Chicago , Ill ) , a resin-modified glass ionomer cement ( experimental group ) . The volunteers lived in a city that has fluori date d water , but they did not use fluori date d dentifrices during the study . After 30 days , the teeth were extracted and longitudinally sectioned ; in the enamel around the brackets , demineralization was assessed by cross-sectional microhardness . The determinations were made at the bracket edge cementing limits , and at occlusal and cervical points 100 and 200 microm away from them . In all of these positions , indentations were made at depths from 10 to 90 microm from enamel surface . Analysis of variance showed statistically significant effects for position , material , depth , and their interactions ( P<.05 ) . The Tukey test showed that the glass ionomer cement was statistically more efficient than the control , reducing enamel demineralization in all analyses ( P<.05 ) . The use of glass ionomer cement for bonding can be encouraged because it decreases the development of caries around orthodontic brackets Decalcification and caries during orthodontic treatment still remains a problem . A method to protect the susceptible area beneath and adjacent to bonded attachments , independent of patient compliance , would be extremely beneficial . A clinical trial was performed using a dual-cured lightly filled BIS-GMA fluoride-releasing sealant . The barrier effect of this material on white spot formation , gingival irritation , and plaque accumulation during fixed orthodontic therapy was examined . Twenty patients with a total of 225 metal brackets placed on anterior teeth participated in this study . Brackets were placed in both arches in a conventional manner with a chemically cured , unfilled bonding resin ; 112 teeth ( every other tooth ) received the barrier material after bracket placement , while the remaining 113 teeth served as controls . Intraoral photographic slides were taken before and after treatment and were evaluated blindly by 7 observers for white spot formation . Gingival and plaque indexes were recorded initially and consecutively every 6 months . Observation time ranged from 5 to 18 months . The results of this prospect i ve clinical study indicated that there was no significant difference ( P > .05 ) between the decalcification rates of the treatment or control groups . Likewise there was no added benefit with respect to plaque accumulation or gingival irritation INTRODUCTION Enamel decalcification during orthodontic treatment is a persistent problem . Resin-based sealants have been developed to protect enamel from decalcification . The purpose of this in-vivo study was to compare the effect of a fluoride-releasing filled enamel sealant with that of an unfilled nonfluoride control . METHODS A total of 177 teeth in 18 patients were evaluated over a period of 12 to 18 months . A split-mouth design was used ; half the teeth were treated with the fluoride-releasing sealant ( Pro Seal , Reliance Orthodontic Products , Itasca , Ill ) , and the contralateral teeth received the control ( Transbond MIP , 3 M Unitek , Monrovia , Calif ) . The teeth were photographed before ( T1 ) and after ( T2 ) treatment . A panel of 12 orthodontic faculty and residents evaluated the photographs for decalcification on a grade d scale . RESULTS Sixty-nine percent of the teeth treated with Pro Seal showed progressive decalcification from T1 to T2 vs 72 % of those treated with Transbond MIP . In the comparison of the contralateral paired teeth , there was a small average net disadvantage of -0.06 of a tooth per patient ( 95 % CI , -0.97 to 0.85 ) for Pro Seal compared with Transbond MIP . That difference of 0.06 of a tooth is neither statistically significant ( P = 0.90 ) nor clinical ly important . CONCLUSIONS The 2 products tested were equivalent in their inhibition of decalcification during orthodontic treatment . The additional time and expense of using the fluoride-releasing sealant to prevent decalcification does not appear to be justified The presence of clinical ly detectable areas of decalcification ( observable as whitened areas ) following the removal of orthodontic appliances is well recognized . The aim of the present study was to determine quantitatively the amount of demineralization and the ability of commercially available products to inhibit or reverse orthodontically related demineralization . Twenty orthodontic patients scheduled to have premolars extracted were r and omly divided into four groups -- one control and three test groups . The extracted premolars ( numbering 58 ) were bracketed using an acid-etch composite system ; each patient was given precise oral hygiene instructions and supplied with a sodium fluoride ( 1,100 ppm fluoride ) dentifrice and an orthodontic toothbrush . The control group brushed only with the supplied dentifrice . In addition to brushing with the dentifrice , those in test group I rinsed once each night with a sodium fluoride ( 0.05 % ) mouthrinse ; group II received a weekly topical APF treatment ( 1.2 % fluoride ) ; and Group III received a weekly topical APF treatment and rinsed once each night with the sodium fluoride mouthrinse . All premolars were extracted after 1 calendar month . Mineral profiles were determined on cross-sectioned teeth 50 to 75 micron occlusal and cervical to the brackets , directly underneath the brackets , and 500 micron away from the brackets . The control teeth ( dentifrice only ) demonstrated up to 15 % demineralization to a depth of 50 micron . All of the test teeth produced rehardening and /or inhibition of demineralization ( P less than 0.01 ) . Those in test group III showed a particularly hard outer layer . The study demonstrated that measurable demineralization occurred around orthodontic appliances after only 1 month and this demineralization can be completely inhibited and /or reversed by the use of commercially available fluoride products OBJECTIVE To determine whether fluoride releasing elastomeric modules reduced the incidence of decalcification around orthodontic brackets during a complete course of orthodontic treatment . DESIGN A r and omised controlled , split mouth design . SETTING The study was carried out in the orthodontic department of Newcastle-upon-Tyne Dental Hospital , UK . SUBJECT AND METHODS 21 consecutive patients ( 126 teeth ) undergoing fixed appliance therapy were studied . A split mouth technique was adopted to examine the upper labial segment , where one side ( left or right ) was r and omly assigned to the experimental group , and the opposite side served as a control throughout their course of orthodontic treatment . INTERVENTIONS The control teeth were ligated to the archwire using conventional modules . The experimental teeth were ligated to the archwire using Fluoride releasing elastomeric modules . OUTCOME MEASURES St and ardised photographs were taken of the upper labial segment before and after completion of orthodontic treatment , and the degree of decalcification assessed in each tooth quadrant , using a modification of the Enamel Defect Score . RESULTS Decalcification was found to occur in both treatment groups , though to a significantly greater degree on the control side ( p = 0.002 ) . The fluoride module side showed significantly fewer serious decalcified lesions than the control ( p = 0.013 ) . No patients withdrew from the study . CONCLUSIONS It would appear that the use of fluoride releasing elastomeric modules reduces the degree of decalcification experienced during orthodontic treatment Chlorhexidine ( CHX ) is probably the most widely used and the most potent chemical plaque inhibitory agent , whereas fluoride ( F- ) is the only truly accepted anticaries agent available at present . As they have discrete mechanisms of action , a combination effect of these agents on human dental caries may exist . The inhibitory effect of CHX on the formation of , and acid production in , plaque may reduce a relatively extreme cariogenic challenge sufficiently for it to be overcome by the local F- concentrations achieved by brushing or rinses . The aim of this study was to evaluate the possible caries inhibitory effect of combining 2.2 mM CHX mouthrinses used twice daily with daily 11.9 mM NaF rinses in an in vivo human caries model using plaque-retaining b and s on premolars scheduled for extraction . Nine subjects ( a total of 28 teeth ) were fitted with the b and s for 4 wk . Saliva and plaque sample s were collected before and after the study period for bacterial cultures , and the tooth surfaces were analyzed by microradiography after careful tooth extraction s. The combination of CHX and F- rinses result ed in enamel mineral loss only slightly higher than that observed in " sound " enamel and clearly less than with F- rinses alone . Both total plaque bacteria and Streptococcus mutans were reduced by CHX rinses , confirming the discrete mechanisms of action A clinical trial comparing a conventional adhesive , Concise ® , with a new fluoride-containing composite cement is described . The bond failure rate , plaque score , gingival health , and enamel decalcification were assessed for each material after a minimum period of 1 year . The preliminary results show no significant difference between the two material s for each of the variables examined , although there was a reduction in the number of white spot lesions using the fluoride-containing composite . The level of fluoride ion concentration required to inhibit the growth of oral micro-organisms is discussed A prospect i ve controlled clinical trial was undertaken to evaluate the effectiveness of stannous fluoride-releasing elastomeric modules ( Fluor-I-Ties ) and chain ( Fluor-I-Chain ) in the prevention of enamel decalcification during fixed appliance therapy . Forty-nine patients ( 782 teeth ) were included in the experimental group , where the fluoride-releasing elastomerics were used . Forty-five patients ( 740 teeth ) who received non fluoride-releasing elastomerics formed the control group . All patients had their elastomerics replaced at each visit . Enamel decalcification incidence and distribution were recorded using an index by direct clinical observation . In the control group enamel decalcification occurred in 73 per cent of patients and in 26 per cent of all teeth . In the experimental group the corresponding incidence was 63 and 16 per cent , respectively . The overall reduction in score per tooth produced by the fluoride-releasing elastomerics was 49 per cent , a highly significant difference ( P < 0.001 ) . A significant difference was seen in all but the occlusal enamel zones . The majority ( over 50 per cent ) of lesions occurred gingivally . The teeth most severely affected were the maxillary lateral incisors and m and ibular second premolars . There was no difference in treatment duration between groups Demineralization around orthodontic appliances is a problem . Suboptimal oral hygiene , long intervals between appointments , and potentially poor patient cooperation with using fluoride dentifrices and mouth rinses necessitate a compliance-free means of preventing tooth decay . The hypothesis of this study was that fluoride released by glass ionomer cement inhibits the formation of carious lesions around orthodontic brackets in vivo . Brackets were bonded on 2 first premolars in 21 r and omized , consecutively selected patients 11 to 18 years old . Eleven test-group subjects were bonded with fluoride-releasing glass ionomer cement , and 10 control subjects were bonded with composite resin ( no fluoride ) . The teeth were extracted after 4 weeks , sectioned , and evaluated quantitatively by cross-sectional microhardness testing . Fluoride levels in patient saliva were measured by the Taves diffusion method in sample s taken at days 0 ( baseline ) , 1 , 2 , 3 , 7 , 14 , 21 , and 28 to determine whether fluoride from the glass ionomer cement influenced the overall intraoral fluoride levels . The results demonstrated significantly more demineralization around the brackets of the control patients ( P < .01 , Wilcoxon signed rank test ) . For whole-mouth salivary fluoride levels , no significant overall difference between the groups ( P > .05 ) and no noticeable trend within groups ( P > .05 ) were found . These results indicate that using fluoride-releasing glass ionomer cement for bonding orthodontic brackets successfully inhibited caries in vivo . This cariostatic effect was localized to the area around the brackets and was statistically significant after 4 weeks Forty r and omly selected patients had brackets bonded on one side of the of the maxillary labial segment with glass ionomer cement . Teeth on the opposite side were bonded with a resin adhesive . Teeth were assessed for decalcification pretreatment , at debond , and at review using a st and ardized photographic technique and a modified DDE index . The mean number of teeth affected by decalcification and the mean extent of decalcification per tooth increased during the treatment period , but from debond to review both of these measurements decreased for teeth bonded with either material (p)<0.01 , t-test ) . Decalcification appears to become less severe posttreatment , but does not appear to be significantly affected during 12 to 18 months of orthodontic treatment by bonding with glass ionomer cement . Dietary and other environmental factors , including fluoride preparations , may be of greater importance in the prevention of decalcification during fixed appliance therapy The aim of this study was to examine the effect of combined use of a toothpaste/mouthrinse containing amine fluoride/stannous fluoride ( AmF/SnF2 ; meridol ) on the development of white spot lesions , plaque , and gingivitis on maxillary anterior teeth in orthodontic patients . A prospect i ve , r and omized , double-blind study with 115 orthodontic patients ( 42 males and 73 females , average age 14.4 years , drop outs 18 ) was design ed . Group A ( 50 ) brushed twice daily with an AmF/SnF2 toothpaste ( 1400 ppm F ) and rinsed every evening with an AmF/SnF2 solution ( 250 ppm F ) . Group B ( 47 ) brushed twice daily with a sodium fluoride ( NaF ) toothpaste ( 1400 ppm F ) and rinsed every evening with a NaF solution ( 250 ppm F ) . Visible plaque index ( VPI ) , gingival bleeding index ( GBI ) and white spot lesion index ( WSL ) were recorded on the six maxillary anterior teeth at bonding and after debonding , and evaluated with t tests . In group A no significant differences between bonding and debonding were recorded for WSL ( 1.02 + /- 0.08 versus 1.05 + /- 0.13 , P = 0.14 ) , VPI ( 0.10 + /- 0.21 versus 0.12 + /- 0.21 , P = 0.66 ) or GBI ( 0.13 + /- 0.21 versus 0.16 + /- 0.22 , P = 0.47 ) , whereas statistically significant differences were found in group B between bonding and debonding for WSL ( 1.00 + /- 0.02 versus 1.08 + /- 0.17 , P = 0.01 ) , VPI ( 0.06 + /- 0.13 versus 0.17 + /- 0.25 , P = 0.01 ) and GBI ( 0.06 + /- 0.12 versus 0.16 + /- 0.21 , P = 0.01 ) . The increase in lesions on the upper anterior teeth was 4.3 per cent in group A and 7.2 per cent in group B. It was concluded that the combined use of an AmF/SnF2 toothpaste/mouthrinse had a slightly more inhibitory effect on white spot lesion development , plaque and gingivitis on maxillary anterior teeth during fixed orthodontic treatment compared with INTRODUCTION Even with advances in material s and techniques , demineralization around brackets during orthodontic treatment continues to be a problem . The purpose of this in-vivo study was to evaluate the effect of a fluoride varnish on enamel demineralization adjacent to bonded brackets . METHODS Fifteen patients who needed at least 2 premolars extracted for orthodontic reasons were selected . In each patient , 1 premolar was considered the test tooth , and the other was the control . Brackets were bonded , and T-loops were engaged on all premolars , but only the test teeth received fluoride varnish . The premolars were extracted after 85 to 95 days , and buccolingual sections 50 to 70 microm in thickness were evaluated with polarized light microscopy . The mean depth of demineralization in each lesion was measured 3 times on photographs by an operator blinded to the groups ( intraclass correlation of the 3 measurements was 0.988 ) . RESULTS The mean lesion depths were 57.0 + /- 5.5 microm in the test group and 94.3 + /- 6.7 microm in the control group . There was significant reduction ( approximately 40 % ) in depth of demineralization in the test group ( P < .001 ) . CONCLUSIONS Fluoride varnish can be beneficial as a preventive adjunct in reducing demineralization adjacent to brackets OBJECTIVE To evaluate the effectiveness of daily tooth brushing with high-fluoride toothpaste on white spot lesion ( WSL ) formation in adolescents during treatment with fixed orthodontic appliances ( FOA ) . MATERIAL S AND METHODS Four hundred and twenty-four healthy 11- to 16-year-old patients , referred to five Orthodontic Specialist Clinics , were r and omized to use either toothpaste containing 5000 ppm fluoride or regular toothpaste with 1450 ppm fluoride . To be eligible for inclusion , the patients had to be scheduled for bimaxillary treatment with FOA for an expected duration of at least 1 year . The primary and secondary outcome measures were prevalence and incidence of WSL , as registered from digital photos of the maxillary incisors , canines , and premolars taken before onset and immediately after debonding . The photos were evaluated separately by two blinded and calibrated clinicians using a 4-step score . A r and om sample of 50 cases was reassessed to check intra- and interexaminer reliability ( Kappa = 0.70 ; 0.74 ) . RESULTS The use of high-fluoride toothpaste result ed in fewer WSL ( P = 0.042 ) with a prevented fraction of 32 % . The lateral incisor was most commonly affected in both groups . CONCLUSION To prevent WSL during treatment of FOA , daily use of high-fluoride toothpaste may be recommended INTRODUCTION The hypothesis of this study was that toothpaste slurry rinsing , combined with other simple postbrushing steps ( the modified fluoride toothpaste technique [ MFTT ] ) , would reduce the number of decayed and filled tooth surfaces . METHODS The study population consisted of 100 orthodontic patients r and omly divided into 2 groups , 51 in the test group ( mean age , 16.2 + /- 4 years ) and 49 in the control group ( mean age , 16.9 + /- 4 years ) . Each patient was examined before starting orthodontic treatment ( baseline ) and shortly after debonding ( follow-up ) in a 2-year study period . At each of these 2 visits , the patients were examined in the following order : interviewed by using a st and ardized question naire , plaque index registration , intraoral clinical examination , and radiographic examination ( bitewings ) . The test group patients were instructed to use the MFTT . The control group patients were given the same fluori date d toothpaste as the test group and the routine clinical oral hygiene instructions . RESULTS Compared with the control group , the test group had significantly better plaque index scores at the end of the study . At follow-up , the clinical ( P < 0.001 ) , radiographic ( P < 0.001 ) , and clinical plus radiographic ( P < 0.001 ) incidences of decayed and filled surfaces were significantly reduced : 87 % , 78 % , and 83 % , respectively , in the test group compared with the control group . CONCLUSIONS Compared with routine oral hygiene instructions with fluoride toothpaste , the use of the MFTT significantly reduced the incidence of new carious lesions in orthodontic patients . We believe that this simple regimen should be considered in orthodontic clinics The purpose of this study was to determine whether an additional application of Fluor Protector before b and cementation with glass ionomer cement reduces white spot formation compared with b and cementation with glass ionomer cement . In the in vitro study , 80 premolars were divided in half , creating a control and a test group . All specimens were divided into four different groups to simulate different clinical situations and stored in a demineralizing solution to induce white spot formation . In the in vivo investigation , 18 orthodontic patients were incorporated in the study . One lower and one upper first molar b and ( r and omly selected ) were coated with Fluor Protector and then cemented with a glass ionomer cement ( test group ) . The other two uncoated first molars were cemented with glass ionomer cement and served as the control group . The application of Fluor Protector in combination with Aquacem did not contribute to a reduction of white spot formation underneath molar b and s compared with the use of Aquacem for b and ing In the present in vivo study , the cariostatic potential of a titanium tetrafluoride ( TiF4 ) solution applied topically around orthodontic brackets was investigated with quantitative microradiography . Also characteristics of the TiF4-treated enamel surface were examined with scanning electron microscopy ( SEM ) . Ten pairs of premolars to be extracted for orthodontic treatment were used in the first part of this study . Brackets were bonded on all teeth with an orthodontic adhesive , and 10 r and omly selected premolars served as controls , whereas a similar number were treated with 1 % TiF4 around brackets for 60 seconds . After 4 weeks with no topical fluoride supplementation , all teeth were extracted and stored for analysis . Results indicated the 1 % TIF4 solution reduced lesion depths and total mineral loss , at the bracket periphery , significantly during the 4-week period . The presence of a surface coating was demonstrated by SEM micrographs . It was concluded that TiF4 may provide a high level performance as a prophylactic agent for orthodontic purpose Abstract Objective . To investigate the effect of daily intake of fluori date d milk on enamel demineralization adjacent to fixed orthodontic brackets assessed with quantitative light-induced fluorescence ( QLF ) . Material s and methods . Sixty-four healthy adolescents ( 13–18 years ) undergoing orthodontic treatment with fixed appliances were enrolled and r and omly allocated to a r and omized controlled trial with two parallel groups . The intervention group was instructed to drink one glass of milk ( ∼ 200 ml ) supplemented with fluoride ( 5 ppm ) once daily and the subjects of the control group to drink the same amount of milk without fluoride . The intervention period was 12 weeks and the end-point was mineral gain or loss in enamel , assessed by QLF on two selected sites from each individual . The attrition rate was 12.5 % and 112 sites were included in the final evaluation . Results . There was no statistically significant difference between the groups concerning fluorescence ( ΔF ) values and lesion area ( A mm2 ) at baseline . After 12 weeks , a significant decrease ( p < 0.05 ) in ΔF was registered in the fluori date d milk group and a significant increase in the non-fluoride control group ( p < 0.05 ) . The mean reduction in the test group was somewhat lower ( 14 % ) than the increase in the control group ( 18 % ) , but individual variations were evident . Only minor alterations of lesion area were recorded over the 12-week period and no statistically significant differences compared with baseline were found in any of the groups . Conclusion . Daily intake of fluori date d milk may aid remineralization of white spot lesions adjacent to fixed orthodontic appliances A clinical trial was undertaken to assess the value of incorporating fluoride released from a commercially available bonding adhesive ( Rely-a-Bond ) to determine the extent of any protection provided against enamel decalcification . Fifty patients undergoing fixed appliance therapy were included in the trial . Contralateral quadrants were used as controls where no fluoride was present in the adhesive . Enamel decalcification after treatment and bond failure rates during treatment were investigated . A total of 366 experimental and 371 control teeth were included in the study . The results showed that 50 per cent of patients and 13.5 per cent of teeth exhibited post-treatment decalcification . The addition of fluoride to the adhesive did not significantly reduce the incidence of enamel decalcification . Bond failure rates were satisfactory for both experimental and control teeth ( all under 5 per cent ) PURPOSE The decalcification of enamel is a serious clinical problem in orthodontic patients and is usually observed as white spot lesions surrounding brackets . This study 's purpose was to evaluate the effect of professionally applied 1.23 percent fluoride foam on reducing the formation of white spot lesions ( WSLs ) in patients with fixed orthodontic appliances . METHODS In a r and omized , double-blind , placebo-controlled trial , 100 participants were r and omly divided into two groups . The two groups received fluoride foam and placebo foam , respectively , every two months during the treatment . The examinations before bonding and after debonding were performed by one examiner and included the presence and severity of WSLs on incisors , canines , and premolars . RESULTS The incidence of WSLs was approximately 13 percent in the fluoride foam group and 51 percent in the placebo group ( P<.001 ) . The mean increment of WSLs score was significantly lower in the fluoride foam group ( 0.71 ± 2.80 ) than in the placebo group ( 4.36 ± 5.41 ; P<.001 ) . The preventive fraction was approximately 76 percent , and the number needed to treat was calculated as 2.6 . CONCLUSIONS Professional application of 1.23 percent fluoride foam during orthodontic treatment effectively reduced the development of white spot lesions . A prophylactic regimen based on the routine use of fluoride foam during orthodontic treatment is recommended Introduction : In this study , we aim ed to compare the incidence of new demineralized lesions and bond failures between 2 groups of participants wearing fixed orthodontic appliances bonded with either light‐cured resin‐modified glass ionomer cement or light‐cured composite . Methods : This trial was a multicenter ( 6 centers : 2 teaching hospitals , 4 specialist orthodontic practice s ) , single‐blinded , r and omized controlled trial with 2 parallel groups . Patients aged 11 years or older , in the permanent dentition , and about to start fixed orthodontic treatment in these 6 centers were r and omly allocated to have either resin‐modified glass ionomer cement or light‐cured composite for bonding brackets , forward of the first molars . Pretreatment and day‐of‐debond digital photographic images were taken of the teeth and assessed by up to 5 clinical and 3 lay assessors for the presence or absence of new demineralized lesions and the esthetic impact . The assessors were masked as to group allocation . Results : We r and omized 210 participants , and 197 completed the trial . There were 173 with complete before‐ and after‐digital images of the teeth . The incidence of new demineralized lesions was 24 % ; but when the esthetic impact was taken into account , this was considerably lower ( 9 % ) . There was no statistically significant difference between the bracket adhesives in the numbers with at least 1 new demineralized lesion ( risk ratio,1.25 ; 95 % confidence interval , 0.74‐2.13 ; P = 0.403 ) or first‐time bracket failure ( risk ratio,0.88 ; 95 % confidence interval , 0.67‐1.16 ; P = 0.35 ) . There were no adverse effects . Conclusions : There is no evidence that the use of resin modified glass ionomer cement over light‐cured composite for bonding brackets reduces the incidence of new demineralized lesions or bond failures . There might be other reasons for using resin modified glass ionomer cement . Registration : This trial was registered at Clinical Trials.gov NCT01925924 . Protocol : The protocol is available from the corresponding author on request