In a double-blinded randomized controlled trial, Anja Haase-Fielitz and colleagues find that an infusion of sodium bicarbonate during open heart surgery did not reduce the risk for acute kidney injury, compared with saline control. Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery.p = 0.009). Sodium bicarbonate increased urinary pH . More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients . After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint . A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control .In a multicenter, double-blinded , randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control , and formerly known as acute renal failure. Symptoms of AKI can be variable, with diagnosis of AKI based on laboratory findings (such as elevated blood urea nitrogen and creatinine), or clinical signs such as inability of the kidneys to produce sufficient amounts of urine. Globally, more than 10 million people are affected by AKI each year. AKI occurs in about one quarter of patients undergoing cardiac surgery and is associated with longer stays in the hospital and an increased risk of death. Treatment of AKI includes administration of intravenous fluids, diuretics, and, in severe cases, patients may require kidney dialysis.The mechanism for why AKI occurs during cardiac surgery is complex and thought to involve multiple factors relating to blood circulation, the immune system, and toxins released by the kidneys. In addition to treating AKI after it occurs, it is important to identify patients who are at risk for developing AKI prior to cardiac surgery and then apply techniques to prevent AKI during cardiac surgery. A number of interventions have been tested for preventing AKI during cardiac surgery, but there is currently no strong evidence for a standard way to prevent AKI. One intervention that has potential for preventing AKI is the administration of sodium bicarbonate during cardiac surgery. Sodium bicarbonate causes alkalinization of the urine, and it is thought that this could reduce the effect of toxins in the kidneys. A previous pilot study showed promising effects for sodium bicarbonate to reduce the likelihood of AKI. In a follow-up to this pilot study, here the researchers have performed an international randomized controlled trial to test whether administration of sodium bicarbonate compared to sodium chloride  during cardiac surgery can prevent AKI.350 patients undergoing open heart surgery with at least one risk factor for developing AKI were recruited across four sites in different countries . These patients were randomly assigned to receive either sodium bicarbonate (treatment) or saline control solution, given as a continuous infusion into the blood stream for 24 hours during surgery. Neither the researchers nor the patients were aware of which patients were assigned to the treatment group. The researchers measured the occurrence of AKI within the first 5 days after surgery and they found that a greater proportion of those patients receiving sodium bicarbonate developed AKI, as compared to those patients receiving saline control. On the basis of these findings the study was terminated before planned recruitment was completed. A key issue with this study is that a greater proportion of the patients in the sodium bicarbonate group had chronic kidney disease prior to open heart surgery. After adjusting for this difference in the statistical analysis, the researchers observed that the difference between the groups was not significant—that is, it could have happened by chance. The authors also observed that a significantly greater proportion of patients receiving sodium bicarbonate died in the hospital after surgery compared to patients receiving saline control.These findings suggest that giving an infusion of sodium bicarbonate to induce alkalinization of the urine during open heart surgery is not a useful treatment for preventing AKI. Furthermore, this treatment may even increase the likelihood of death. The researchers do not recommend the use of sodium bicarbonate infusion to reduce the risk of AKI after open heart surgery and stress the need for discontinuation of this therapy. Key limitations of this research study are the early termination of the study and the greater proportion of patients with chronic kidney disease prior to surgery.http://dx.doi.org/10.1371/journal.pmed.1001426.Please access these Web sites via the online version of this summary at acute kidney injuryThe Renal Association, a professional association for kidney doctors and researchers, provides information about The International Society for Nephrology and the International Federation of Kidney Foundations provide information about preventing acute kidney injury around the world and jointly initiated World Kidney Dayopen heart surgeryMedlinePlus has information on  Acute kidney injury is a global health problem with more than 10 million people affected annually Although the pathophysiology of cardiac surgery-associated acute kidney injury is complex, poorly liganded iron appears to be linked to its development suggesting that acute kidney injury, may, in part, be a sideropathy Given its biological rationale, a positive pilot trial, the broad discussion of the nephroprotective effects of bicarbonate infusion with positive risk benefit ratio, the lack of effective therapies, and the low costs, perioperative use of bicarbonate infusion has already impacted clinical practice of acute kidney injury prevention worldwide.Accordingly, we conducted a multicenter double-blinded randomized controlled trial to confirm or refute whether prophylactic urinary alkalinization with perioperative sodium bicarbonate infusion reduces the incidence of acute kidney injury and the magnitude of acute tubular damage compared to volume- and solute-equivalent sodium chloride infusion in a larger patient population undergoing open heart surgery.http://clinicaltrials.gov/ct2/show/NCT00672334).This study was an international, double-blinded, randomized controlled trial conducted at four university-affiliated hospitals Valvular surgery or concomitant valvular and coronary artery bypass graft surgeryRedo cardiac surgeryInsulin-dependent Type 2 diabetes mellitusEnd stage renal disease (serum creatinine concentration >300 µmol/l)Emergency cardiac surgeryPlanned off-pump cardiac surgeryKnown blood-borne infectious diseaseChronic inflammatory disease on immunosuppressionChronic moderate to high dose corticosteroid therapy Enrolled in conflicting research studyAge <18 yAllocation concealment to patients, anesthesiologists, cardiac surgeons, intensive care specialists, bedside nurses, outcome assessors, and investigators was ensured by central randomization through a clinical trial pharmacist who was not a co-investigator (Department of Pharmacy) at each study center. At each study center, the hospital pharmacy clinical trials coordinator used a Microsoft Excel-based (Microsoft Corp.) random number generator to create the randomization list using a permuted block strategy with blocks of six. The randomization list was kept locked on a password-secured computer that was placed in the Hospital Pharmacy Trials Area. Infusion bags were each delivered in separate shrink-wrapped black plastic bags that were identical in appearance. At each study center, the responsible hospital trial pharmacist was provided with emptied study medication infusion bags to assess intactness of the covering bag (shrink-wrapped black plastic bag). In two cases, the covering bag was damaged. The inner bag (beneath the black bag) was a neutral infusion bag which was not labeled with direct information about the study treatment. Treatment allocation was only revealed after the study had been completed, the database locked, and statistical analysis completed. During the initiation period of the study we assessed whether blinding of study treatment was still in place by frequent discussion with clinical and research personnel and participants. These discussions happened the day after surgery. The general response was that there was sufficient uncertainty regarding doubtless treatment allocation precluding the need for elaborate activities on blinding status.We used the same dosing of bolus of sodium bicarbonate and sodium chloride recently published in the prevention of cardiac surgery-associated acute kidney injury Apart from the addition of the infusion of study drug, clinical practice was not changed or modified for the purpose of the study. For non-study-related interventions, please see ACE inhibitors/angiotensin receptor 1 blockers:withdrawn on hospital admission Surgical approach and cardiopulmonary bypass:conducted according to the standard technique of each institutionAnesthetic techniques, including perioperative medications and fluid management:at the discretion of the attending anesthetist (documented)Analgesia:acetaminophen and morphine or tramadol with avoidance of non-steroidal anti-inflammatory drugsVancomycin and gentamicin:not used as perioperative anti-infective agentsPost-operative care, including hemodynamic, fluid, and analgesic management:at the discretion of the intensivists and nursing staff at each institutionThe primary endpoint was the number of patients who developed acute kidney injury. This was defined a priori as an increase in serum creatinine concentration greater than 25% or 0.5 mg/dl (44 µmol/l) from baseline to peak value at any time within the first 5 d after cardiopulmonary bypass. This endpoint has been used for previous studies of both cardiac surgery-associated acute kidney injury Secondary renal outcomes:changes of urinary NGAL concentration within the first 24 h after commencement of cardiopulmonary bypass were used to assess postoperative acute tubular damage as was previously done Number of patients who developed acute kidney injury according to the RIFLE criteria Number of patients who received acute renal replacement therapy during their hospital stayOther secondary outcomes:Changes in acid-base statusDuration of mechanical ventilation and length of intensive care unit and hospital stayIn-hospital mortality90-d mortalitySpecific adverse events:+]>150 mmol/l), hypokalemia ([K+]<3.5 mmol/l), alkalemia (pH>7.50), acidemia (pH<7.30), atrial fibrillation, acute kidney injury, initiation of acute renal replacement therapy and mortality  were recorded using the hospital electronic medical filing system or systematic telephone call of patients or their physicians at day 90Postoperative incidence of hypernatremia  on the ARCHITECT platform (Abbott Diagnostics) or ELISA (Antibodyshop), urine was sampled prior to induction of anesthesia, at 6 h and at 24 h after commencement of cardiopulmonary bypass. The laboratory investigators were blinded to the sample sources and clinical outcomes until the end of the study.p<0.05).Using data from a recently published randomized controlled trial on the use of bicarbonate for acute kidney injury prevention in cardiac surgical patients p<0.10. These variables were (i) clinically relevant : age, cardiopulmonary bypass time, chronic obstructive pulmonary disease, chronic kidney disease (eGFR <60 ml/min) p<0.10: center, previous myocardial infarction, and red blood transfusion.All following analyses were set a priori. All data were analyzed according to the intention-to-treat principle. In addition, the primary endpoint was analyzed per protocol. Per-protocol analysis excluded patients who were not operated on cardiopulmonary bypass or who were not drug-adherent defined as not receiving study infusion bolus before commencement of cardiopulmonary bypass or receiving <80% of the total weight-adjusted dose of study medication within the study period. Whilst there were insufficient events to facilitate multivariable analysis for mortality, to ensure all other observed results were not due to center or baseline imbalances, intention-to-treat analysis was repeated in multivariable models including all baseline variables that were considered to be clinically relevant or different between groups with univariate We also performed post hoc subgroup analyses including exclusion of the German study center, patients with eGFR >60 ml/min, and those receiving non-study-related bicarbonate infusion see . Serum ct test  or the Mann-Whitney U test and for categorical data with the use of Fisher exact test or chi-square test where appropriate. All tests were two-tailed and we considered a p-value<0.05 to indicate statistical significance.Continuous data were examined for normal distribution using histograms. Between-group comparisons for continuous data were performed with the use of the Student's We report values as mean with standard deviation (SD), or median with 25th to 75th percentiles or as ORs with 95% CI estimate as appropriate. Analysis was performed using SPSS, version 18.0 (SPSS Inc.) and SAS version 9.2 .n = 200]; The Mazankowski Alberta Health Institute, University of Alberta, Edmonton, Canada [n = 98]; The Austin Hospital, Melbourne, Australia [n = 47] and, The University College Dublin, Ireland [n = 5]). Between May 2008 and June 2011, 350 patients were randomized to receive either intravenous sodium bicarbonate (n = 174) or sodium chloride (n = 176) infusion. Details of patients screened and participating in the study are shown in the CONSORT diagram . There was no significant difference between treatment groups in type and duration of operation, intraoperative hemodynamic variables, and interventions  mmol and 408 (349–474) mmol for sodium chloride, p = 0.652, both administered within the 24-h study period.Drug adherence was 95.4% (166/174) for patients receiving bicarbonate and 96.6% (170/176) for patients receiving chloride study infusion, p<0.001) whereas urinary pH level decreased in control patients  compared with the control group .After multivariable adjustment for group imbalances at baseline , a non-significant group difference was found for the primary endpoint (adjusted p = 0.135).Also, after adjustment of peak creatinine for the dilutional effect of corresponding fluid-balance, no significant group difference for the primary endpoint was found .Per-protocol analysis of the primary endpoint including 166 patients receiving bicarbonate infusion and 170 patients receiving sodium chloride infusion , showed p = 0.011.A greater median postoperative increase in urinary NGAL from preoperative to peak value within the first 24 h postoperatively in patients receiving bicarbonate infusion (24.3 ng/ml [6.0–149.9]) indicated more pronounced acute tubular damage after surgery compared to control patients (12.2 ng/ml [0.0–76.6]), p = 0.015), higher peak serum creatinine (p = 0.001), and higher peak serum urea (p = 0.020)  classification = 0.020) .p = 0.031  in the bicarbonate group and 2.8% (n = 5) in the control group; p = 0.056 (n = 13] versus control group: 6.3% [n = 11]); p = 0.651.Overall mortality within 90 d was 7.5%  patients with preoperative chronic kidney disease and (ii) patients from the Australian, Canadian, and Irish study centers . The latAnalysis of patients excluding those with non-study bicarbonate infusion showed essentially unchanged major endpoints .p<0.001). Thirty patients in the control group and 14 patients in the bicarbonate group had a pH level below 7.30 with a minimum value of 7.17 in both groups (p = 0.011). Non-significantly more patients receiving sodium bicarbonate  had a plasma potassium <3.5 mmol/l compared to control  with the lowest potassium value of 3.0 mmol/l in both groups, p = 0.280. There was no significant difference in the incidence of new-onset atrial fibrillation , p = 0.838.Four patients developed hypernatremia during the study period with peak sodium concentration of 151, 152, 154, 158 mmol/l, respectively. Thirteen patients in the control group and 37 patients in the bicarbonate group had a pH level greater than 7.50 with a peak value of 7.59 in both groups  Group identified acute kidney injury to be a potentially preventable complication and recommended definitive randomized controlled trials for evaluating promising interventions to prevent and mitigate acute kidney injury In the present study, using the same scoring system This study demonstrates that there is no reduction of acute kidney injury or tubular protection after open heart surgery in patients who are administered sodium bicarbonate despite achieving adequate plasma and urinary alkalinization. This finding challenges the theory of attenuation of urinary mis-liganded iron compounds to be achieved by systemic alkalinization with bicarbonate. Experimental and clinical trials testing the effect of local urinary alkalinization without blood alkalinization—usually achieved by carbonic anhydrase inhibitors—are needed. We cannot exclude that perioperative systemic application of sodium bicarbonate and alkalinization of the blood had negative effects on unadjusted hospital mortality. There were insufficient events to facilitate multivariable analysis for in-hospital mortality, to ensure observed results were not due to center or baseline imbalances specifically given the group difference for preoperative chronic kidney disease. Despite the fact that the majority of patients died later in the course and no relationship of study bicarbonate infusion with mortality in the pilot study was observed Given our findings, we do not recommend the routine prophylactic use of sodium bicarbonate infusion for the purpose of urinary alkalinization and acute kidney injury prevention in patients undergoing open heart surgery, nor can we recommend conduct of larger scale clinical research in this setting. Using a preoperative risk stratification scoring system Given the positive effect of bicarbonate in the pilot trial and the negative effect in this randomized controlled multicenter trial, for sample size estimation in future preventive trials, we recommend using a more severe acute kidney injury endpoint definition such as doubling of serum creatinine or commencement of postoperative renal replacement therapy or a combination thereof. Such endpoints may decrease the chance of type I errors and may increase the likelihood of successful phase IIb trials. Finally, mechanistic studies linking alkalotic blood pH with organ damage are needed.The timing and dose of bicarbonate bolus and the duration of bicarbonate maintenance infusion may have been insufficient. However, study medication was administered using exactly the same infusion protocol with a slightly increased dose of maintenance infusion compared to the previous successful pilot trial Most patients were enrolled in one study center and a greater proportion of patients receiving sodium bicarbonate presented with preoperative chronic kidney disease compared to control; however, (i) multivariable, (ii) center-specific, and (iii) subgroup analyses revealed no nephroprotective effect of sodium bicarbonate. The study was prematurely terminated because of lack of efficacy and suggestion of harm; however, excellent study protocol adherence, no significant loss to follow-up, the use of kidney functional and acute tubular damage markers, and the use of preset sensitivity analyses strengthen the findings and the observation of possible harm make the likelihood of a positive finding implausible. Also, the internal and external validity of the results was achieved by double-blinding and a multicenter international design. Given the above observations, it appears unlikely that the negative outcome of this trial is due to type II error. We were not able to control for intentionally unblinding of study treatment by directly measuring pH value of the study treatment solution. Clinicians may have been able to guess group assignment on the basis of urinary and plasma pH levels being more alkaline in the treatment group after surgery (significant differences at 6 h and 24 h after surgery). However, assessment of such an attempt during study initiation for the day after surgery showed sufficient doubt, since there was some overlap in these values between the groups.In conclusion, this study demonstrates that in patients at high risk of acute kidney injury following open heart surgery, bicarbonate infusion alkalinized both blood and urine but did not result in a decrease in the incidence of acute kidney injury or attenuation of acute tubular damage. Importantly, prophylactic bicarbonate might possibly have increased mortality. On this basis of our findings we do not recommend the prophylactic use of perioperative infusions of sodium bicarbonate to reduce the incidence or severity of acute kidney injury in this patient group. Accordingly, discontinuation of growing implementation of this intervention in this setting would appear justified.Table S1Center-specific management of cardiopulmonary bypass and perioperative hemodynamic management.(DOC)Click here for additional data file.Table S2Major endpoints in post hoc subgroup analysis.(DOC)Click here for additional data file.Table S3Outcomes separated by study center.(DOC)Click here for additional data file.Text S1Trial protocol.(DOC)Click here for additional data file.Text S2CONSORT checklist (DOC)Click here for additional data file.


Measurement of toe and ankle blood pressure is used to evaluate the peripheral arterial status of patients, yet the pre-test rest period is inconsistent in published studies and among practitioners, and could affect results. The aim of this systematic review was to evaluate all research that has investigated the effect of different periods of pre-test rest on toe and ankle systolic blood pressure.MEDLINE (from 1946), EMBASE (from 1947), CINAHL (from 1937), and Cochrane Central Register of Controlled Trials (CENTRAL) (from 1800) were searched up to April 2012. No language or publication restrictions were applied. Eighty-eight content experts and researchers in the field were contacted by email to assist in the identification of published, unpublished, and ongoing studies. Studies evaluating the effect of two or more pre-test rest durations on toe or ankle systolic blood pressure were eligible for inclusion. No restrictions were placed on participant characteristics or the method of blood pressure measurement. Outcomes included toe or ankle systolic blood pressure and adverse effects. Abstracts were independently assessed by two reviewers for potential inclusion.1658 abstracts were identified by electronic searching. Thirty three of the 88 content experts and researchers in the field replied, identifying five potentially relevant studies. No studies were eligible for inclusion.There is no evidence of the effect of different periods of pre-test rest duration on toe and ankle systolic blood pressure measurements. Rigorous trials evaluating the effect of different durations of pre-test rest are required to direct clinical practice and research.


In particular, the MOH pattern of large drop/non-recovery (MOH-3) resembles the syndrome of supine hypertension–orthostatic hypotension (SH-OH), which is a treatment challenge for clinicians. The aim of this study was to characterise MOH-3 in the first wave of The Irish Longitudinal Study of Ageing (TILDA), with particular attention to concurrent symptoms of orthostatic intolerance (OI), prescribed medications and association with history of faints and blackouts.Our previously proposed The study included all TILDA wave 1 participants who had a Finometer® active stand. Automatic data signal checks were carried out to ensure that active stand data were of sufficient quality. Characterisation variables included demographics, cardiovascular and neurological medications (WHO-ATC), and self-reported information on comorbidities and disability. Multivariable statistics consisted of logistic regression models.small drop, overshoot), 2,230 (50%) to MOH-2 , and 781 (18%) to MOH-3 . In the logistic regression model to predict MOH-3, statistically significant factors included being on antidepressants  and beta blockers . MOH-3 was an independent predictor of OI after full adjustment , together with being on hypnotics or sedatives . In addition, OI was an independent predictor of history of falls/blackouts after full adjustment .Of the 4,467 cases, 1,456 (33%) were assigned to MOH-1 (Antidepressants and beta blockers were independently associated with MOH-3, and should be used judiciously in older patients with SH-OH. Hypnotics and sedatives may add to the OI effect of MOH-3. Several trials have demonstrated the benefits of treating older hypertensive patients with cardiovascular medications that were not associated with adverse outcomes in our study. Therefore, the evidence of benefit does not necessarily have to conflict with the evidence of potential harm. Orthostatic hypotension (OH) is generally defined as a drop in blood pressure on standing, which in a given subject is regarded as abnormal purely on the basis of its magnitude. As such, OH is a clinical sign and may be symptomatic or asymptomatic .Orthostatic blood pressure changes can be measured by different methods. Most commonly, clinicians use the auscultatory or oscillometric method with sphygmomanometer . As applsupine hypertension and orthostatic hypotension (SH-OH) poses a particular therapeutic dilemma, as treatment of one aspect of the condition may worsen the other [OH is an independent cardiovascular risk factor and may be practically estimated by systolic reaction only . It is rhe other . Indeed,he other , and litAlthough most patients with OH are asymptomatic or have few non-specific symptoms , a markeper se[if OH triggers OI symptoms, then syncope is more likely. However, in many real-life situations the latter theoretical sequence is interrupted, as marked OH can be asymptomatic [It has been suggested that postural symptoms (i.e. OI) correlate much more strongly with (pre-)syncope and falls than does OH (i.e. the isolated blood pressure drop sign) per se,21. In optomatic ,23 and nptomatic ,24.morphological classification of OH (MOH) was proposed [small drop/fast over-recovery (MOH-1), 27.5% in the medium drop/slow recovery (MOH-2) and 44.6% in the large drop/non-recovery group (MOH-3) (P < 0.001). We also showed a gradient of baseline SBP across MOH groups, suggesting that MOH-3 is, in fact, a syndrome of SH-OH. To date, there had been no studies of the SH-OH syndrome using non-invasive beat-to-beat finger arterial blood pressure monitoring.In a previous investigation, a proposed  as an approposed -28 orthohttp://www.tcd.ie/tilda), with especial attention to the MOH-3 pattern as a beat-to-beat analogue of SH-OH; (2) to characterise the MOH-3 group with especial attention to associations with cardiovascular and neurological medications, concurrent OI, and history of fainting; (3) to identify predictors of MOH-3 response in the presence of potential confounders; and (4) to assess the effect of MOH-3 towards OI, and the effect of MOH-3 and OI towards fainting history, in the presence of confounders. The latter can be seen as a cross-sectional evaluation of the above-mentioned three pathophysiological steps (OH → OI → fainting). A comprehensive investigation of factors associated with each of those three steps has not been conducted to date but would be helpful in order to gain insights into potentially modifiable factors to prevent OH and OI-related faints, particularly in relation to association with prescribed medications in the SH-OH syndrome. The identified factors will then be investigated longitudinally in TILDA.In view of the above, the aims of the present study were: (1) to replicate the MOH patterns in a large, population-based sample such as the first wave of The Irish Longitudinal Study on Ageing  is a large prospective cohort study of the social, economic, and health circumstances of community-dwelling older people in Ireland. This study is based on the first wave of data, which was collected between October 2009 and July 2011. The sampling frame is the Irish Geodirectory, a listing of all residential addresses in the Republic of Ireland. A clustered sample of addresses was chosen, and household residents aged 50 and older and their spouses/partners (of any age) were eligible to participate. The household response rate was 62.0%. In the present study, the analytic sample consisted of those aged ≥ 50 from TILDA wave 1.The Irish Longitudinal Study on Ageing .Subjects underwent a lying-to-standing orthostatic test (active stand) with non-invasive beat-to-beat blood pressure monitoring using digital photoplethysmography . We aimed at the beat interval between physiocals being 30 beats or higher before the start of the active stand. Just prior to standing, the physiocal was switched off to ascertain a continuous recording during the orthostatic blood pressure changes, and remained switched off until the end of the test.The active stand protocol included the use of the automatic The height correction unit (HCU) of the Finometer® was zeroed and implemented as per manufacturer’s specifications , and was® R2011b. Data records where the HCU had not been properly applied  were removed from the analysis.Active stand data analysis required a number of steps including: 1) data quality screening and artefact rejection; 2) pre-processing and filtering; and 3) blood pressure waveform feature extraction. Data were imported and processed in MatlabAdditional checks were carried out on the data such as ensuring data met the requirement of a minimum length of stand (≥ 90 seconds). A further check examined the total noise in the baseline and stand sections. For this, each record was divided into two sections; baseline pre-stand (baseline) and standing activity (stand) demarked by times before and after the stand. Each of the sections - baseline and stand - was scored in terms of artefact presence separately. The total number of beats within the baseline and stand sections was counted. The proportion of total time containing significant motion artefact as a fraction of the total signal time were used to quantify the amount of noise in the signal using a validated automated algorithm ,34. Signet al. [For the final dataset to be used in the analysis, beat-to-beat values were averaged according to the 5-second averages method described by van der Velde et al. , in ordeThe following measures were recorded:● Baseline systolic (SBP), diastolic blood pressure (DPB), and heart rate (HR): defined as the mean value in the time interval −60 seconds to −30 seconds prior to standing.● SPB, DBP and HR at the lowest blood pressure value after standing .● SPB, DBP and HR at 30 seconds post-stand.● SPB, DBP and HR at 60 seconds post-stand.● SPB, DBP and HR at 90 seconds post-stand.● SPB, DBP and HR at 110 seconds post-stand.● Delta  was defined as the difference between the respective baselines and nadirs.● We also computed the percentage of SBP recovery (with respect to baseline) by 30 seconds, 60 seconds, and 110 seconds after the stand.Demographics: age, sex.● Orthostatic intolerance (OI): self-reported symptoms of dizziness, light-headedness or unsteadiness during the active stand (yes or no).● Ever had a blackout or fainted: yes or no.● Medications, based on the WHO Anatomical Therapeutic Chemical (ATC) classification system (http://www.whocc.no/atc_ddd_index/):● ○ Cardiovascular medications:▪ C01A: cardiac glycosides.▪ C01B: antiarrhythmics, class I and III.▪ C07A: beta blocking agents.▪ C03: diuretics.▪ C09A: ACE inhibitors, plain.▪ C09C: angiotensin II antagonists, plain.▪ C08C: selective calcium channel blockers with mainly vascular effects.▪ C08D: selective calcium channel blockers with direct cardiac effects.▪ C02C: antiadrenergic agents, peripherally acting.▪ C01D: vasodilators used in cardiac diseases.▪ C04A: peripheral vasodilators.○ Neurological medications:▪ N03A: antiepileptics.▪ N05A: antipsychotics.▪ N05B: anxiolytics.▪ N05C: hypnotics and sedatives.▪ N06A: antidepressants.○ Polypharmacy was defined as the simultaneous use of 5 or more medications.Comorbidities (self-reported):● ○ Hypertension.○ Angina.○ Heart attack.○ Heart failure.○ Diabetes.○ Stroke.○ Transient ischaemic attack (TIA).○ Abnormal heart rhythm.○ Parkinson’s disease.○ Three or more chronic diseases.Disability (self-reported): any disability from the list of Independent Activities of Daily Living (IADL).● Cognition: Mini-Mental State Examination (MMSE) score.● All statistical analyses were performed with SPSS (version 18). Descriptives for dichotomous variables were given as percentages (%). Continuous variables were described as mean with standard deviation (SD).K-means Cluster Analysis procedure, which assigns cases to a fixed number of groups (clusters) whose characteristics are not yet known but are based on a set of specified (clustering) variables. We chose three (k = 3) as the number of clusters because three were the previously described [k = 3.To classify the sample into MOH groups we used, as before , an autoescribed -28 orthoclustering variables  were chosen as key morphological descriptors of the beat-to-beat orthostatic blood pressure response that we intended to model. The influence of outliers on the K-means cluster analysis was minimised by the pre-processing and data cleaning steps as outlined above.The K-means analysis, the clustering variables were entered unstandardised. It was decided not to standardise the clustering variables as some have argued that standardisation  can result in misleading conclusions when true group structure is present [In the  present . The finTo compare baseline characteristics between those with and without MOH data, we used the t-test or Mann–Whitney U test (as appropriate) for continuous variables, and the Chi-square test for count data.To test for a linear trend (i.e. gradient) across MOH clusters, we used the Chi-square for trend for dichotomous variables and the Spearman’s rank correlation coefficient for continuous variables.P < 0.05 and for removal was set at P < 0.1.Multivariable analyses were based on binary logistic regression . This stepwise method of variable selection involves entry testing based on the significance of the score statistic, and removal testing based on the probability of a likelihood-ratio statistic based on conditional parameter estimates. The significance level for entry into the model was set at Multicollinearity diagnostics (tolerance and variance inflation factors: VIF) were checked. The multivariable models were repeated in the subsample of those aged ≥70 in order to explore whether the overall findings also applied to those of more advanced age.P < 0.01).For the purpose of the discussion, and given the elevated number of characterisation variables used, we focused on the most statistically significant associations  had a Health Centre Assessment. Amongst the latter, 4,919 (98%) completed the active stand test. Active stand data were deemed of sufficient quality for analysis in 4,475 participants (91% of active stands). Complete data for defining the MOH groups was available for 4,467 participants. The flowchart of participants is shown in Figure N = 4,467) and without (N = 570) MOH data. Those without MOH data were older , had higher sitting SBP , were taking a higher number of medications , had higher burden of cardiovascular disease  and higher disability burden .Table K-means analysis on N = 4,467, all clustering variables significantly contributed to the solution (P < 0.001). Table small drop and overshoot), 2,230 (50%) to MOH-2 (characterised by a medium drop and slower but full recovery), and 781 (18%) to MOH-3 (characterised by a large drop and incomplete recovery).In the P < 0.001 and P = 0.065, respectively).Across MOH groups, there was a significant gradient in OI and a non-significant gradient in history of faints/blackouts, in the expected direction .Twenty-one percent of participants in MOH-3 were on polypharmacy, as opposed to 17% of participants in MOH-1 and MOH-2. Sixteen percent of MOH-3 participants were on beta blockers, compared to 10% in MOH-1 and MOH-2.P < 0.001). There was also an increasing burden of peripherally acting antiadrenergic agents  (P = 0.004)  Table .P = 0.058) , female sex , beta blockers , and age . In addition, those on peripheral calcium channel blockers were less likely to have a MOH-3 response . In the subsample of those aged 70 or more, antidepressants, sex, beta blockers, age and peripheral calcium channel blockers still had 95% CIs not including 1 (Table In the multivariable binary logistic regression model to predict MOH-3 membership (Table P < 0.001), MOH-3 , and history of heart attack . In addition, advancing age  and female sex  were associated with less OI during active stand. In the subsample of those aged 70 or more, being on antiepileptics and having 3 or more chronic diseases seemed to be associated with greater OI, while peripheral calcium channel blockers seemed protective , history of abnormal heart rhythm , history of TIA , female sex , antidepressants , polypharmacy , and OI during active stand . In the subsample of those aged 70 or more, antiepileptics, history of abnormal heart rhythm, female sex and polypharmacy were directly associated with history of blackouts or faints.In the multivariable binary logistic regression model to predict history of blackouts or faints Table , statistIn all multivariable models, all VIF were less than 2, excluding significant multicollinearity.In the present study, we replicated and characterised the MOH groups and assessed the association of MOH-3  on concurrent OI and fainting history. The advantage of the present study is that it is based on a large population-based sample, as opposed to the previous study , which wResults highlighted the association of MOH-3 with non-modifiable risk factors such as age and sex, even in the subsample of those aged 70 or more. Consistent with previous literature, advancing age is associated with hypertension  and greaantidepressants and beta blockers) in contributing to an SH-OH response (even in those aged ≥70), which may potentially lead to clinically adverse consequences (e.g. complaints of OI). In particular, results strengthen the hypothesis on the relationship between OH and antidepressant pharmacotherapy [In terms of potentially modifiable factors, our findings highlight the important influence of certain types of medications  medications against MOH-3 , which is supported by the literature. For example, in a previous study, the peripheral CCB Nilvadipine did not aggravate OH in a sample of patients with Alzheimer’s disease, despite significant reduction in the SBP of treated patients . In anotOn bivariate analyses, we found an increasing burden of peripherally acting antiadrenergic agents  across MOH groups. It is likely that the number of patients on alpha blockers was too small to detect an independent effect in multivariable analyses. Yet, the alpha(1)-adrenergic receptor pathway is known to be critical in the recovery from initial OH to prevent cerebral hypoperfusion and ultimately syncope , so the Our results support previous findings that OI is a wider, more complex syndrome than the mere sign of having an impaired orthostatic hemodynamic response . In the both the orthostatic hemodynamic response (i.e. more MOH-3) and the awareness of the latter (i.e. less OI). Indeed, we know that awareness of orthostatic hypotension is influenced by age: in younger subjects it is usually brief but symptomatic whereas in older individuals the situation is reversed [Although the age and sex effects are non-modifiable, they could be relevant in terms of the postulated sequence of pathophysiological steps (OH → OI → fainting). In short, female and older participants were more likely to have an MOH-3 pattern Table . And whereversed ,57.In terms of the differential effects of sex in the pathophysiological sequence OH → OI → fainting, it is difficult to explain why women had more MOH-3, more history of faints, but less OI. OI is much more common in young women relative to men, children or older women ,59, and According to our full sample results, OI is more likely to be reported by more co-morbid and disabled patients with MOH-3 hemodynamic pattern, on whom it would be prudent to avoid the use of hypnotics and sedatives. Indeed, hypnotics and sedatives may add to the OI effect of MOH-3, and this is consistent with previous observations on the reduced tolerability of benzodiazepines in the elderly  and the People with history of faints or blackouts may suffer from conditions not directly related to OH such as epilepsy or cardiac syncope (hence the association with anti-epileptics and anti-arrhythmics). However, in both full and older samples, polypharmacy (i.e. being on five or more regular medications) was independently associated with history of blackouts or faints. We know that age-related physiologic impairments of heart rate, blood pressure, baroreflex sensitivity, and cerebral blood flow, in combination with a higher prevalence of comorbid disorders and concomitant medications (including polypharmacy), account for the increased susceptibility of older persons to syncope .per se[mediator[In the full sample, phasic OI was more common in those with history of faints or blackouts, suggesting that part of the latter syndrome may be of hemodynamic nature . Interesper se,21. Inde[mediator.syndrome of supine hypertension–orthostatic hypotension (SH-OH), as applied to beat-to-beat orthostatic blood pressure data. We agree with previous recommendations that, of all patients with SH‒OH, those who have OI require the most clinical attention [As in the previous pilot MOH investigation , there wttention . In patittention .Interestingly, antihypertensive types that have shown consistent benefits in the treatment of hypertension in the very elderly  wereA number of limitations in this study must be noted. Firstly, its observational cross-sectional design precludes the inference of causality relationships and direct extrapolation of associations. As we stated above, results are to be interpreted with caution and represent ‘insights’ rather than confirmed signals.Secondly, despite the large total sample size, we know that the 38% of participants who did not have a Health Centre assessment were more likely to have lower socio-economic status, higher levels of physical disability, and were weaker (handgrip strength) and slower  than Health Centre respondents . In addiK-means cluster analysis is exploratory in nature, and the scale and variability of the clustering variables may affect results in unstandardised analyses [K-means clustering method as previously conducted in a different, smaller and convenient sample [The statistical techniques employed in our analyses also have limitations. Indeed, the analyses . Howevert sample , leadingAs stated above, some of the results from the logistic regression models should be interpreted with caution due to the nature of how the multivariate logistic models were developed, and especially due to the presence of a large number of covariates in the models. In addition, only few participants were on medications potentially associated to MOH-3 such as peripheral vasodilators or antiarrhythmics, so results for the latter classes may have been underpowered.A limitation of the active stand protocol is that information was lacking on precise dosages, time of ingestion of, and compliance with, the reported medications. Even though polypharmacy was used as a control variable in all models, specific drug interactions towards the outcomes of interest could not be investigated. Limitations of the active stand test itself include its known diurnal variability and relationship with meals .frailty on orthostatic hemodynamic responses, OI and faints/blackouts. Given that the latter are complex disorders involving multiple physiological systems, the inclusion of frailty may have complemented the inclusion of comorbidity, disability and cognition in the models. For example, older adults without measured hypertension, who are not on an anti-hypertensive medication, appear to have high physiological reserve in general [Finally, a limitation of the present study is the impact of  general . Unsurpr general . This ismorphological classification of orthostatic hypotension  in the first wave of The Irish Longitudinal Study on Ageing, and we found that the clinical associations were similar as previously reported (e.g. association with OI) [In the present study, we replicated our previously proposed with OI) . In addiOur findings offer cross-sectional insights that, if further validated, may inform the development of clinical guidelines for the treatment of SH-OH. Based on the results of the current study, in a typical clinical setting using phasic orthostatic blood pressure measurements, MOH-3 should be recognised by the presence of baseline hypertension (>140 mmHg), an initial orthostatic blood pressure drop greater than 40 mmHg, and failure to recover 90% of the baseline blood pressure after 2 minutes of standing. If a patient fulfilling those criteria has complaints of OI, then his/her risk of (pre-)syncope, falls and blackouts is higher and clinicians should avoid (if possible) medications that may exacerbate OH and OI , and make a judicious use of antihypertensives that are less likely to aggravate postural blood pressure changes. Naturally, this should be done within a wider multifaceted approach.The authors declared that they have no competing interest.All authors: 1) made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) were involved in drafting the manuscript or revising it critically for important intellectual content; and 3) gave final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/13/73/prepub


Epidemiological data reveal that the overall risk for kidney stones disease is lower for women compared to age-matched men. However, the beneficial effect for the female sex is lost upon menopause, a time corresponding to the onset of fall in estrogen levels. The aim of this study was to describe the serum estradiol (E2) and testosterone (T) characteristics of naturally postmenopausal women with kidney stones.113 naturally postmenopausal women with newly diagnosed kidney stones (aged 57.4±4.98 years) and 84 age frequency matched stone-free controls (56.9±4.56 years) were validly recruited in the case-control study. The odds ratios (ORs) for the associations between sex hormones and kidney stones were estimated with logistic regression models, adjusting for demographic data and medical history. Patients were also stratified analyzed according to stone components .Serum E2 (21.1 vs. 31.1 pg/ml) was significantly lower in kidney stones patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by COS patients (p<0.001). According to tertiles of the E2 levels, a significant higher frequency of COS was seen in the lowest E2 group (p <0.001). Multiple logistic regression analysis identified E2 level as a strong factor that was independently associated with the risk for COS . However, serum T levels did not significantly differ among the groups.Naturally postmenopausal women with higher remaining estradiol levels appear less likely to suffer from kidney calcium oxalate stones. However, no correlation was found between serum T level and kidney stones. These findings support the hypothesis that higher postmenopausal endogenous estrogens may protect against kidney stones with ageing. There is persuasive evidence that kidney stone formation is modulated by sex hormones in human. For example, in women with calculi a second peak in the incidence of stone formation has been reported to occur during the sixth decade of life, a time that corresponds to the onset of menopause with a fall of estrogen levels ,2. EpideAndrogens and estrogens have long been suspected of being etiologically important in the formation of calcium oxalate stones. In general, androgens appear a promotion action and estrogens appear a inhibition action on kidney stone formation, which were reported in experimental animal studies -8. HowevThe study protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Guangzhou Medical University in China. Written informed consent was obtained from all subjects before study participation.We conducted a hospital-based case-control study of total 113 female patients with newly diagnosed kidney stones after menopause and 84 age frequency matched stone-free female controls. All subjects were genetically Han Chinese from Guangzhou City and surrounding regions in Southern China. Female patients who were confirmed diagnosis of kidney stones based on at least two imageological modalities (e.g. NCCT or KUB or ultrasonography or intravenous urography) were consecutively recruited between between September 2012 and December 2012 at the ward of the Urology Department of our hospital, with a response rate of 96.9%. The stones-free controls were subjects who participated in healthy checkup programs in Medical Examination Center of our hospital during the same time period when the cases were recruited. Among them, controls with frequency matched to the cases by age (±3 years) were randomly selected with a response rate of 91.3%. All individuals underwent structured questionnaire and clinical measurements.In-person interviews were conducted for all cases and controls by blinding-trained interviewers using a structured questionnaire. Detailed questions were asked about age, medical history , water drink consumption (2L/d less or more), working environment temperature (28°C lower or higher), areas of life , age at menopause, time since menopause, body mass index (BMI). Menopause was defined as the absence of menses for a minimum of half year. Height and weight were measured with the subject in standing position wearing indoor clothes and no shoes. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Cases and controls were also asked whether a doctor had ever informed that they had specific stone-related diseases reported in EUA guideline .All participants were female who had experienced a natural menopause. The ages ranged 50-70 years. All the women recruited should have an intact uterus and at least one intact ovary, have no use of sex steroids after the reported date of last menstruation, and have no possible endocrinopathies chronic diseases evaluated by clinically physical examination or structured questionnaire. All the subjects were also excluded if they suffered from some specific causing stone-related diseases. Only patients with kidney stones diagnosed after menopause were included in the case group.Stone sample was obtained in each patient at the end of the surgery treatment . Stones were analyzed with the Vector 22 Fourier transformation infrared spectrometer  according to the manufacturer protocol. The relative proportions of the various stone components were quantified by analysis of a global powder of the sample. Calculi were classified on the basis of their main component . Then patients with kidney stones were divided into two subgroups according to stone components . Calcium oxalate mono- and dehydrate were grouped into the single category of calcium oxalate stones (COS), and other component forms of stones were grouped into the category of non-calcium oxalate stones (NCOS).Venous blood samples were collected in a tube containing 2% heparin in the morning between 8 and 10 a.m. after an overnight fast. Serum and plasma were separated and frozen at -70°C. Serum concentrations of estradiol (E2) and testosterone (T) were measured using chemiluminescence immunoassay (CLIA) on the Immulite Beckman DXI800 . The limits of detection and the intra- and inter-assay coefficients of variation, respectively, were 2 pg/ml, 2% and 5% for E2; 10 pg/ml, 2% and 4% for T. E2 and T levels below the assay limits were assigned the value of the assay limits. Thirteen women had E2 levels below the limits of the assay. 125 cases and 95 controls experienced the sex hormone detection in this study. However, of these, eight patients and eight controls were excluded because their high E2 levels (> 100 pg/ml) suggested their unreported estrogen use, while a further four and three were excluded because of total testosterone levels outside the normal physiological range (> 0.8 ng/ml). Therefore, the remaining 113 patients and 84 controls was the final cohort of this report.Statistical analyses were performed using SPSS for Windows (version 13·0). The data were presented as means with standard deviations and range for continuous variables, or numbers and percentages for categorical variables. Comparisons of dichotomous risk factors between cases and controls were conducted using Chi-square test; comparisons of means were conducted using Wilcoxon signed rank test. Differences were considered significant at p<0.05. Post-hoc analyses  were corrected for multiple testing. The association between sex hormone levels and kidney stones, measured by the odds ratio (OR) and its corresponding 95% confidence interval (CI), was estimated using unconditional logistic regression, without or with adjustment for demographic data and medical history . The data were further stratified by stone composition to evaluate the stratum variable-related ORs. Spearman’s correlation was performed by using estradiol (E2) and testosterone (T) as dependent variables in all 197 subjects. Hormonal data were modeled as continuous variables and also stratified in tertiles to explore whether non-linear or threshold effects were present. Distributions of characteristics of total subjects were expressed according to the tertiles of E2level.Kidney stones patients had significantly lower serum E2  than controls, while serum T2  was observed no difference in both groups. Stone composition analysis identified 74 COS and 39 NCOS in the 113 patients. The post-hoc analysis demonstrated that, within the kidney stones group, COS patients accounted for this effect . Serum E2 levels tended to be lower in COS patients than in NCOS patients , but was not significantly different between NCOS patients and controls (p=0.142).Spearman correlations using estradiol (E2) and testosterone (T) as a dependent variables are shown in Logistic regression models examining the association of sex hormones as continuous variables with the presence of kidney stones are shown in Hormonal data were modeled as continuous variables, and also stratified in tertiles to explore whether non-linear or threshold effects were present . A signiIn our case-control study first investigating serum E2 and T values of postmenopausal women with kidney stones, lower serum E2 levels were significantly associated with the odds for increased risk of kidney stones. The effect was mainly driven by COS patients. However, no correlation was found between serum T level and kidney stones in this cohort.We found E2 levels were not associated with age, age at menopause, time since menopause but positively associated with BMI. These findings are consistent with previously reported postmenopausal evolution of sex steroid serum concentrations, with intraindividual E2 levels remaining relatively stable from 1 year after postmenopausal decline . The pri2 [Interestingly, in our population serum E2 levels increased with BMI, and frequency of kidney stones decreased with higher serum E2 levels, but higher BMI did not protect against kidney stones. Fat mass or higher BMI was not related to stones, which suggests the importance of other sources of estradiol production than adipose tissue in postmenopausal women. In fact, extragonadal oestrogen biosynthesis occurs in a number of sites, including adipose tissue, bone, various sites of the brain, and vascular endothelial and smooth muscle cells . On the 2 , which i2 -15.Serum T levels were not significantly different between patients and controls in our study. However, Li et al.  and JustEstrogen has been shown to inhibit bone resorption and enhance renal tubular calcium re-absorption ,19. Prev2+-ATPase, and Na+/Ca2+-exchanger) involved in distal renal tubule calcium re-absorption [In experimental animal studies, Lee , Lguchi sorption -27.Serum E2 levels were not significantly different between NCOS patients and controls. This result may motivate to future studies focusing on putative interaction pathways between estradiol and kidney calcium oxalate stones only. The difference of E2 levels between COS and NCOS patients may be due to sample size, but also to the fact that testosterone promotes and estradiol inhibits the liver glycolate oxidase, which converts glycine to oxalate, affecting urinary oxalate excretion . TogetheAlthough this study is one of the few to test the association of sex hormones and kidney stones and is the first focusing on populations of female. However, we did not evaluate serum sex hormone in pre-menopause female since it was difficult to exclude the effect of physiological fluctuation due to the menstrual cycle. Our study also had other limitations. Sample size was not large and hormone levels were only measured at a single time point. Finally, our study does not contain information on 24-hour urinary composition, thus limiting the conclusions that can be made about the role of sex hormones on urinary composition, which was an important factor of kidney stone formation.In conclusion, naturally postmenopausal women with higher ‘remaining’ estradiol levels appear less likely to suffer from kidney calcium oxalate stones. This effect seems independent of age at menopause, time since menopause but correlated with body mass index. However, no correlation was found between serum T level and kidney stones regardless the stone components in this age group. Further studies are needed to examine underlying mechanisms and evaluate therapeutic options in this group of women.


The Stroke remains one of the major chronic diseases worldwide, and is considered a major cause of disability, which results not only in persistent neurological deficits, but also in the high physical deconditioning, nevertheless there are not many forms of assessing functional capacity in this population. We aimed to investigate the feasibility of the Six Minute Walk Teste and the Six-Minute Step Test (6MST) in post-stroke patients and compare the behavior of physiological variables during the 6MST and the Six-Minute Walk Test (6MWT), by correlating the functional performance obtained in both tests.The 6MWT was carried out according to the American Thoracic Society (ATS) and the 6MST was performed in six minutes in order to compare it to the 6MWT in a 20 cm step. Was included post-stroke individuals able to walk without aid. All of them did the 6MWT and the 6MST.12 patients participated in the study. There was no statistical difference in the parameters analyzed when tests were compared. There was poor correlation between the functional performance in both tests.The 6MWT and the 6MST is feasible for post-stroke patients and physiological responses are equal during the performance of both tests. However, there was no correlation with respect to functional performance, which was assessed by the distance walked in the 6MWT and by the number of steps climbed in the 6MST. Stroke still is one of the major chronic diseases around the world -4. It isAmong other physical disabilities, the functional walk is compromised after the stroke . A factoAmong some measures frequently used to determine the functional capacity ,13, are The 6MST differs from the 6MWT, because allows the exercise capacity to be determined during routine consultations, increasing the frequency of functional assessment of patients, facilitating its application for it does not require much physical space .Considering the above, the purpose of this study is to investigate the feasibility of conducting the 6MST and the 6MWT in post-stroke patients and compare the behavior of the physiological variables during the 6MST and the 6MWT.This study evaluated 12 individuals with diagnosis of stroke who were being assisted by the physiotherapy services of the clinical school of the University. Walking without aid was established as the criterion for inclusion. The study was approved by the ethics committee with research protocol no. 13562439, CAAE, 0387.0.000.186-11. All patients signed an informed consent form before performing the tests. There were no sample losses.In order to characterize the sample, scales Fugl-Meyer (FM) , OrpingtThe 6MWT was carried out according to the American Thoracic Society –ATS standards . AdditioWe decided not to do both tests on the same day in order to prevent differences in perceived exertion and vital signs. Patients were interspersed according to the test that would be performed first.Statistical Analysis were performed by the SigmaStat software version 3.5 and the Kolmogorov-Smirnov was applied to the quantitative variables in order to verify if the distribution of variables was normal. The Levine's test was used to verify the homogeneity of variances. The paired t-test and/or t-test was used for variables Oxygen Saturation, Diastolic Blood Pressure, Heart Frequency, Respiratory Frequency, Borg Scale for dyspnea and lower limb fatigue, and Double Product, which presented normal distribution. For Systolic Blood Pressure, Difference of Systolic Blood Pressure, and Difference of Double Product variables, Wilcoxon test and/or Mann–Whitney test was used. Spearman coefficient was used to correlate the distance walked and the number of steps. To evaluate the correlation between physiological and hemodynamic measures on the 6MWT and 6MST, we used the intraclass correlation coefficient (ICC), Pearson correlation coefficient and Bland and Altman approach. A significance level of 0.05 (5%) with confidence intervals of 95% was set for this study.As to the descriptive analysis, the 12 patients (6 men and 6 women) had a mean age of 54 ± 9 years. The mean age for the male gender was 54 years and for female gender was 55.5 years. The mean weight was 74 kilograms with average height of 1.66 meter.Characterization data are shown in Table As to the results of the feasibility of conducting the 6MST and the 6MWT in post-stroke individuals, all of them understood the instructions and concluded the first test proposed properly.In the comparison of the physiological variables (beginning and end of the test) for the 6MWT there was a statistically significant difference for all variables, except for Diastolic Blood Pressure and Oxygen Saturation Table .Equally, there was statistically significant difference for all physiological variables in the comparisons from the beginning and end of the test for the 6MST Table .In order to compare both tests (6MWT × 6MST), we calculated the difference between the beginning and end through t-test or Mann–Whitney test. There was no statistical difference in the parameters analyzed when both tests were compared. Table The Maximal Heart Rate (HRmax) and Submaximal Heart Rate (SHR) were calculated with HRmax: 220-age and the SHR: 85% of the HRmax and in both tests no patient reached HRmax.p > 0,05).As a complementary analysis, the following correlations were made: Lower Limbs, Balance and Total Fugl Meyer Scale × 6MWT and 6MST. In all correlations made, the Spearman coefficient was low, showing slight correlation (r < 0.3) between the variables . However, there was no correlation with respect to functional performance, which was assessed by the distance walked in the 6MWT and by the number of steps climbed in the 6MST. This study showed that the 6MWT and the 6MST may be used to evaluation and prognosis in post-stroke patients.The authors declare that they have no competing interest.All authors participated in the acquisition of data and revision of the manuscript. TDS, CF, CTP, CBMM, OATJ, EPO and RDR conceived of the study, determined the design, performed the statistical analysis, interpreted the data and drafted the manuscript. VEV, LCA and FA determined the design and drafted the manuscript. All authors read and gave final approval for the version submitted for publication.


The impact of serum uric acid (SUA) on arteries of hypertensive subjects remains to be fully established. This study investigated the relationship between SUA and carotid structural and hemodynamic parameters in hypertensive men and women.Three hundred and thirty eight patients (207 women and 131 men) were cross-sectionally evaluated by clinical, laboratory, hemodynamic and carotid ultrasound analysis. Common carotid diameters, circumferential wall tensions, Young’s Elastic Modulus, Stiffness Index, Arterial Compliance and intima-media thickness (IMT) were determined. Internal carotid artery resistive index (ICRI), a hemodynamic measure that reflects local vascular impedance and microangiopathy, was also assessed.p < 0.001) in women, but not in men, and hyperuricemic women presented higher ICRI than normouricemic ones . Stepwise and logistic regression analyses adjusted for potential confounding factors showed that ICRI was independently associated with SUA and hyperuricemia in women.Univariate analysis showed no significant correlation of SUA with carotid diameters, elasticity/stiffness indexes, IMT and circumferential wall tensions in both genders. Conversely, SUA correlated with ICRI (r = 0.34; This study demonstrated that SUA was associated with ICRI in hypertensive women, suggesting that there might gender-related differences in the relationship between SUA and vascular damage in subjects with systemic hypertension. Serum uric acid (SUA) has been considered an independent predictor of cardiovascular events in hypertensive patients . ExperimIn general, there has been no difference in the association between SUA and cardiovascular risk in men and women ,2. HowevThe present study investigated the relationship between SUA and carotid hemodynamic and structural parameters in hypertensive subjects and the role of gender in this regard.Three hundred and thirty eight hypertensive subjects (207 women and 131 men) were cross-sectionally evaluated by clinical, laboratory, hemodynamic and carotid ultrasound analysis. The subjects were randomly selected from those attending an outpatient clinic of a university hospital. Exclusion criteria were age under 18 years, neoplastic disease and identifiable causes of secondary hypertension. The research was carried out in accordance with the Declaration of Helsinki of the World Medical Association. This study was approved by the Human Research Ethics Committee of the State University of Campinas. All subjects gave written informed consent to participate.2). Waist circumference was measured at the midpoint between the lowest rib and the iliac crest. Fasting blood total cholesterol, low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol, triglycerides, creatinine, glucose and C-reactive protein levels were measured using standard laboratory techniques [Body mass index was calculated as body weight divided by height squared . Systolic volume was generated from Doppler interrogation of transaortic flow at the aortic annular level and aortic cross-sectional area using a Vivid 3 Pro apparatus  equipped with a 2.5-MHz transducer . CardiacCarotid ultrasonography was performed by a single physician using a Vivid 3 Pro apparatus equipped with a 10-MHz linear-array transducer as previously described . A regioYoung’s Elastic Modulus gives an estimate of arterial stiffness that is independent of wall (intima-media) thickness by the formula: ([systolic blood pressure – diastolic blood pressure] x diastolic diameter)/([systolic diameter – diastolic diameter]/IMT). Artery Compliance measures the ability of the arteries to expand as a response to pulse pressure caused by cardiac contraction and relaxation and was calculated as: ([systolic diameter – diastolic diameter]/diastolic diameter)/(systolic blood pressure – diastolic blood pressure). Stiffness Index is considered to be relatively independent of blood pressure and was calculated by the formula: (systolic blood pressure/diastolic blood pressure)/([systolic diameter – diastolic diameter]/diastolic diameter) .Circumferential wall tension measurements were calculated according to Laplace’s law: Peak circumferential wall tension = systolic blood pressure x peak-systolic internal diameter/2; Mean circumferential wall tension = mean blood pressure x /3)/2.Intraobserver and interobserver carotid IMT and diameters variabilities were <5%, while intraobserver and interobserver variabilities of ICRI measurements were <4%.χ2 was used to compare categorical variables whereas unpaired t-test and Mann–Whitney test compared continuous variables with and without normal distribution, respectively. Assessment of univariate correlations between variables was examined using Pearson’s correlation coefficient for normally distributed data and Spearman’s rank correlation coefficient for non-normally distributed data. Fisher’s z-test was used to compare correlation coefficients. Forward stepwise and logistic regression analysis evaluated the independent predictors of ICRI. Variables that exhibited significant correlation coefficients (p < 0.05) with ICRI were included as independent variables in stepwise regression analysis, while variables that were statistically different between hyperuricemic and normouricemic women were included as independent variables in logistic regression analysis. A p-value <0.05 was considered significant.Continuous variables with and without normal distribution are presented as mean ± standard error and median (25–75th percentile), respectively. The Kolmogorov–Smirnov test was used to test for normal distribution of the variables. p < 0.001) in females but not in males . The difference between these aforementioned correlation coefficients was statistically significant (p < 0.001) as assessed by Fisher’s z-test (Table p < 0.001), age , menopause status , creatinine clearance , creatinine , C-reactive protein , body mass index  and smoking  in women. SUA and ICRI showed no significant relationship with systemic vascular resistance. Similarly, results of Spearman’s correlation analysis revealed that carotid variables did not correlate with use of any antihypertensive medication, statins or allopurinol in both genders.Clinical, hemodynamic and laboratory characteristics of enrolled subjects are presented in Table st Table . FurtherClinical and carotid features of enrolled subjects were then evaluated according to the presence or not of hyperuricemia. No significant differences in carotid variables were detected between normouricemic and hyperuricemic men. On the other hand, hyperuricemic women presented similar carotid and clinical features in comparison to normouricemic ones, except for higher ICRI, body mass index, age, creatinine and triglycerides values and higher prevalence of metabolic syndrome and menopause Table .p < 0.001] in a model that still included body mass index ≥ 30 kg/m2, age > 55 years, triglycerides > 150 mg/dL, creatinine clearance > 60 mL/min, menopause and metabolic syndrome as independent variables. On the other hand, forced inclusion of antihypertensive classes and allopurinol in the logistic regression model did not change the results.Stepwise regression analysis was performed to evaluate whether SUA was independently related to ICRI in hypertensive women. A significant association between ICRI and SUA was found in a model that also included pulse pressure, age, C-reactive protein, body mass index, smoking, creatinine clearance and menopause as independent variables Table . Forced Several lines of evidence demonstrated that SUA is an independent predictor of worse cardiovascular outcomes in hypertensive patients ,3. In adp < 0.001), a finding that not only strengthens the idea that SUA is associated with subclinical systemic inflammation in hypertensive subjects [The relationship between SUA and ICRI can be justified by the ability of uric acid to induce vasoconstriction and vascular remodeling. Uric acid is known to induce proliferation and oxidative stress in cultured vascular smooth-muscle cells, promote endothelial dysfunction and activate the renin–angiotensin system ,2. Convesubjects , but alsIt was very interesting that the increased level of SUA was related to ICRI only in women. Generally speaking, there has been no difference in the association between SUA and cardiovascular risk in men and women -3, but oSUA was not related to carotid elasticity/stiffness indexes and IMT in our sample. These findings agree with previous studies showing no relationship between SUA and the structure of large arteries in hypertensive subjects ,8, but aA potential limitation of our study was that its cross-sectional design may limit our ability to infer a causal relationship between SUA and ICRI. Furthermore, it must be acknowledged that the majority of patients were using antihypertensive medications, which might be a confounding factor in the analysis. In this regard, thiazide and loop diuretics are known to increase SUA levels , while tThe results of the present study demonstrated a previous unknown association between SUA and ICRI solely in hypertensive women. Further studies are warranted to evaluate whether this association contributes to explain uric acid-related adverse cardiovascular prognosis in hypertensive subjects of this gender.SUA, Serum uric acid; IMT, Intima-media thickness; ICRI, Internal carotid artery resistive index.The authors declare that they have no competing interests.JAAC, JRMS and WNJ designed research; JAAC, JRMS, MCFS, RPM, VRB and JAPM conducted research and collected data; JAAC, JRMS and WNJ analyzed and interpreted data; JAAC and WNJ wrote paper; All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/52/prepub


To compare survival and incident cardiovascular disease between normotensive, untreated hypertensive, treated and poorly-controlled hypertensive and treated and well-controlled hypertensive adults.Data from the British Regional Heart Study (men) and British Women's Heart and Health Study (women) were used (N = 6476). Blood pressure and treatment were assessed at baseline (1998–2001) when participants were aged 60–79 years and participants were followed up for a median of 8 years. Date and cause of death were obtained from death certificates and non-fatal cardiovascular disease events were obtained from repeat detailed medical record reviews. Of the whole cohort 52% of women and 49% of men had untreated hypertension and a further 22% and 18%, respectively, had poorly treated hypertension. Just 3% of women and 4% of men had treated and well controlled hypertension and 23% and 29%, respectively, were normotensive. Compared to normotensive individuals, incident cardiovascular disease  was increased in those with poorly-controlled hypertension (Hazard Ratio (HR): 1.88; 95%CI: 1.53, 2.30), those with untreated hypertension  and those who were well-controlled hypertension . Adjustment for baseline differences in mean blood pressure between the groups resulted in attenuation of the increased risk in the poorly-controlled  and untreated groups , but did not change the association in the well-controlled group. All-cause mortality was also increased in all three hypertension groups but estimates were imprecise with wide confidence intervals.Half of women and men aged 60–79 in Britain had untreated hypertension and only a very small proportion of those with diagnosed and treated hypertension were well controlled. Those with hypertension, irrespective of whether this was treated and controlled or not, were at greater risk of future cardiovascular disease than those who are normotensive. Hypertension and high blood pressure are a major contribution to premature mortality, disease burden and reduced quality of life A large number of randomised controlled trials in different populations have shown that treatment with antihypertensives reduces the risk of all-cause mortality and fatal and non-fatal coronary heart disease (CHD) and stroke, with the magnitudes of these associations being proportional to the extent of blood pressure reduction achieved by treatment greater in 686 hypertensive men who were regularly seen, treated and well-controlled compared to 6810 normotensive men. However, that study was conducted in the 1970s amongst men who were all attending a secondary care outpatient clinic and results may not be generalisable to a contemporary population managed in primary care, where most treatment of hypertension takes place.One previous study has compared survival in treated and well-controlled hypertensives to that in normotensives The aim of this study is to compare all-cause and cardiovascular mortality and incident cardiovascular disease between normotensive, untreated hypertensive, treated poorly-controlled hypertensive (here after referred to as poorly-controlled) and treated and well-controlled hypertensive (referred to as well-controlled) older adults.UK local and multi-centre medical research ethics committee' approvals were obtained for both studies and participants gave written informed consent for review of their medical records and data collected as part of this study to be used.Data from two prospective cohort studies - the British Regional Heart Study (BRHS) and the British Women's Heart and Health Study (BWHHS) – collected between 1998 and 2001 using similar protocols were used For all participants blood pressure and blood pressure treatment were assessed in clinics that took place between 1998 and 2001 when participants were aged 60–79 years. A Dinamap 1846SX vital sign monitor was used to measure blood pressure with correction for systematic over-estimation At the research nurse interview, all participants brought their current medications and gave details of their drug history which were coded to the British National Formulary (BNF) st December 2007 for BWHHS and 1st June 2007 for BRHS. CVD mortality was defined as an underlying cause of death coded with any of the following international disease code 10 (ICD10) codes: I200–259 (ischeamic heart disease), I516 (cardiovascular disease unspecified), I600–679 (cerebrovascular disease), I690–699 (sequelae of cerebrovascular disease), G450–453  or G460–469 . Non-fatal CVD events were obtained from medical record reviews that systematically collected information on diagnosed myocardial infarction, angina and stroke every two years.All participants in both cohort studies have been flagged with the National Health Service Central Register (NHSCR) which provided data on death certificates for participants who died up to 31Participants attended the assessment clinic having fasted for a minimum of 8 hours. Participants were instructed to take all medication as normal during this fast and that drinking water was acceptable; those with insulin controlled diabetes were instructed not to fast. Plasma glucose was measured by a glucose oxidase Trinder method Participants were categorised on the basis of their baseline blood pressure assessment and antihypertensive treatment into one of four mutually exclusive groups:Normotensive - systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg and not on antihypertensive medication;Untreated hypertensive - systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg and not on antihypertensive medication;Treated and poorly-controlled hypertensive - systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg and on antihypertensive medication;Treated and well-controlled hypertensive - systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg and on antihypertensive medication.st June 2007 and (iv) date of non-fatal CVD event . Multivariable analyses were adjusted for differences in baseline cardiovascular disease risk factors  to determine whether these explained any differences in survival between the groups. Fasting glucose, insulin and triglyceride levels were positively skewed and therefore geometric means and 95% confidence intervals are presented for these variables in descriptive analyses and their logged values were used in regression models. Initially, all analyses were conducted separately for women (BWHHS) and men (BRHS). There was no evidence of difference in associations between women and men  and therefore analyses used combined data and adjusted for gender. Proportionality assumptions of the Cox models were assessed using Schoenfeld residuals, which showed no evidence of any departure from proportional hazards in the analysis of observed data with no missing covariables.Data were analysed using Cox proportional hazards regression models, with participants' age as the time axis and the date of the baseline assessment (1998–2001) as the start of follow-up for each participant. Contributions to risk were censored at the earlier of: (i) date of death; (ii) date of emigration outside of Britain; (iii) 1Of the 3425 eligible women 243 (7%) had missing blood pressure and a further 726 (21%) had missing data on at least one covariable; equivalent numbers for men were 9 (0.3%) and 702 (23%); outcome data were available for all participants. The amount of missing data for any single covariable was small ). To explore whether missing data might have resulted in selection bias we completed two sets of analyses: one including the 4797 participants (2456 women) with complete data on exposure and all covariables, and one including all eligible participants  with missing exposure or covariable data imputed. We used multiple multivariate imputation, using all variables included in any analyses, the censoring indicator and the log of survival time for Cox models, to impute missing values for those variables with some missing data Of the 3182 women with information on blood pressure and treatment, 1641 (52%) had untreated hypertension, 696 (22%) had poorly-controlled hypertension, 101 (3%) well-controlled hypertension and 744 (23%) had normal blood pressure (as noted above 243 (7%) women had missing blood pressure or treatment data). The distribution of blood pressure categories for all 3425 eligible women, including those for whom blood pressure was imputed when it was missing was similar: 54% with untreated hypertension, 20% with poorly-controlled hypertension, 3% with well-controlled hypertension and 23% normotensive. Of the 3042 men 1497 (49%) had untreated hypertension, 545 (18%) had poorly-controlled hypertension, 113 (4%) well-controlled hypertension and 887 (29%) had normal blood pressure (9 (0.3%) had missing blood pressure or treatment data). Thus, for both genders in over 80% of those on treatment, blood pressure was poorly-controlled.Among the 3425 women, there were 409 deaths over a median follow-up time of 7.6 years, giving a mortality rate of 16.3/1000 person-years. This includes 70 deaths due to cardiovascular disease, giving a cardiovascular mortality rate of 2.8/1000 person-years. A further 325 women experienced a non-fatal cardiovascular disease event, giving a total rate of fatal or non-fatal cardiovascular disease of 16.8/1000 person-years. Among the 3051 men, there were 585 deaths over a median follow-up time of 8.1 years, giving a mortality rate of 25.3/1000 person-years. This includes 95 deaths due to cardiovascular disease, giving a cardiovascular mortality rate of 4.1/1000 person-years. A further 484 men experienced a non-fatal cardiovascular disease event, giving a total rate of fatal or non-fatal cardiovascular disease of 27.2/1000 person-years.In men only we had information on duration of antihypertensive treatment shown in . In the Despite a large sample size (6476) and 8 years of follow-up we found that we had limited statistical power to determine whether those who are well controlled on treatment had similar risks to those who were normotensive at baseline; largely due to the very small proportion who were treated and well-controlled. The sample size that would be required to demonstrate non-inferior survival compared to the normotensive group (i.e. a return in those with well controlled hypertension to similar levels as those who were normotensive) is over 40,000 participants. This is based on calculations assuming the same ratio of normotensives to well controlled hypertensives and the same incidence of CVD for normotensives as in our study, a maximum clinically irrelevant hazard ratio of 1.1, and Type I and Type II errors of 10%.It is notable that in this cohort of 60–79 year British men and women, who were initially examined between 1998 and 2001, around half were found to have untreated hypertension. A further 25% of women and 22% of men were being treated for hypertension but the majority of these (over 80% in both genders) were poorly controlled (ie. >140/90 mmHg). Using the British Hypertension Society treatment targets, (≤140/85 mmHg) the proportion who were well controlled on treatment decreased slightly from 113 (3.7%) to 94 (3.1%) in women and from 101 (3.0%) to 96 (2.8%) in men.Women and men with hypertension (irrespective of whether they were on treatment or if so whether their blood pressure was well controlled) had increased risk of all cause and CVD mortality. With respect to CVD mortality , the increased risk in those with untreated hypertension and treated but poorly controlled hypertension was importantly influenced by differences in mean baseline blood pressure between these groups and those who were normotensive, with substantial attenuation to the null once this was adjusted for in multivariable models. However, the elevated risk in the well-controlled group compared to the normotensive group was not explained by baseline differences in blood pressure. Our finding of increased risk of all-cause and cardiovascular disease mortality in those who were on treatment and well controlled is consistent with one previous study of men only It is clear from randomised controlled trials that treatment and good control of hypertension reduces the risk of CVD events and increases survival compared to no treatment As our results, and those of other studies The main strength of this study is that it addresses an important clinical question that has only been addressed previously in one published study that only included men who were attending secondary care clinics for treatment of their hypertension. The population are a random sample of women and men from across the UK. However, we cannot assume that our results would be generalisable to a younger population. An important limitation is the lack of time updated information on blood pressure and antihypertensive medication, and further study with repeat measurements of these would be valuable. It is possible that those who were well-controlled at baseline became less so over time and those who were poorly controlled became more so with these two opposite changes resulting in similar risk of outcomes in these two groups. Thus, our findings should be interpreted as representing differences in risk over an eight-year follow-up period amongst groups of women and men whose hypertensive status was defined at the start of that period only. Blood pressure was measured twice for each participant and the mean of these two measurements used, but both measurements were at one clinic setting and whilst this is consistent with how hypertension is used in epidemiological research, in clinical practice a diagnosis of hypertension would require a second elevated measurement on a separate occasion. In addition we have no information in this study on adherence to prescribed treatment. We know that the participants stated that they were taking their medication but we did not check this in any formal way. The male participants (BRHS) in this cohort consisted of survivors from a cohort that started 20 years prior to the assessment that we used as baseline here. This could have resulted in some selection (survivor) bias. However, we found no evidence that findings in men differed from those in the BWHHS women, who were newly recruited at the time of baseline assessment for this study. An additional limitation is that the very small proportion of those with hypertension who are treated and well-controlled means that we have limited statistical power to precisely estimate risk in this group. As is common in epidemiological studies we used two measures of blood pressure taken at the same clinic, whereas hypertension in clinical practice is based on repeat measurements on different days over a three-month period. Thus, our estimate of untreated hypertensives may overestimate what would be found in clinical practice.Whilst treatment of hypertension clearly reduces risk of CVD and improves survival compared to no treatment