Restriction of dietary sodium is routinely recommended for patients with chronic kidney disease (CKD). Whether or not sodium intake is associated with the progression of CKD and mortality remains controversial. We evaluated the association of urinary sodium excretion (as a surrogate for sodium intake) on the need for renal replacement therapy and mortality in patients with advanced CKD.2) were included. Using a time-to-event analysis, we examined the association of urinary sodium excretion as a continuous and also as a categorical variable (categorized as low sodium diet - LSD (<100 mEq/day), medium sodium diet - MSD (100–150 mEq/day), and high sodium diet - HSD (>150 mEq/day) and the outcomes of interest. The primary outcome was defined as composite of progression to end-stage renal disease requiring any type of renal replacement therapy and mortality. The secondary outcome was change in eGFR/year.We conducted a retrospective study of patients followed at a CKD clinic of a tertiary care hospital from January 2010 to December 2012. Adult patients with advanced CKD (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2/year. 105 patients (31 %) required renal replacement therapy and 10 (3 %) died. There was no association between urinary sodium excretion and change in the eGFR or need for renal replacement therapy and mortality in crude or adjusted models .341 patients  were included in the study (mean follow up of 1.5 years) with a mean eGFR decline of 2.7 ml/min/1.73 m2), sodium intake does not appear to impact the progression of CKD to end-stage renal disease; however, more definitive studies are needed.In patients with advanced CKD (eGFR < 30 ml/min/1.73 mThe online version of this article (doi:10.1186/s12882-016-0338-z) contains supplementary material, which is available to authorized users. Patients with chronic kidney disease (CKD) have a significantly higher mortality compared to the general population and this increases as the estimated glomerular filtration rate (eGFR) declines . Thus, p2). Studies that included individuals with advanced CKD have been limited by surrogate short-term outcomes or inclusion of non-diabetic patients [Recent international guidelines have incorporated sodium restriction into their recommendations. Kidney Disease Improving Global Outcomes (KDIGO) suggests a reduction to <2 g/day of sodium which corresponds to 5 g/day of salt for adult patients with CKD , althougpatients –6. As suThe aim of our study was to determine if urinary sodium excretion is associated with mortality and need for renal replacement therapy in patients with advanced CKD. We hypothesized that higher levels of urinary sodium excretion (used as a surrogate for sodium intake) would be associated with adverse clinical outcomes.This is a retrospective cohort study using prospectively collected data on adult patients (>18 years) followed in the progressive renal insufficiency clinic at The Ottawa Hospital, a 1,150 bed academic tertiary care center serving a population of approximately 1.2 million, located in Ontario, Canada. The progressive renal insufficiency clinic is a specialty multi-disciplinary care clinic in the CKD program for patients approaching ESRD. Patients with progressive kidney disease are referred to this clinic at the discretion of primary nephrologist in anticipation of needing renal replacement therapy. Attempts are made to collect 24 h urine for sodium excretion at least twice per year. Standardised instructions are given to each patient for collection of 24 h urine.2 calculated by the 4 variable MDRD formula [The study included patients with eGFR < 30 ml/min/1.73 mData on all patients were obtained through the clinic’s comprehensive database since its inception in January 1st, 2010. The accuracy of the data in the database is verified every six months by auditing 5 % of entries and accuracy has been > 95 %. Data collected included age, gender, blood pressure (BP), body-mass index (BMI), eGFR, urine excretion of sodium, protein and creatinine, cause of CKD, comorbidities, medications, date of death and date of dialysis start or renal transplantation. Blood pressure was measured in sitting position after at least five minutes of rest. Mean arterial blood pressure (MAP) was calculated using the formula: MAP = 2/3 diastolic BP + 1/3 systolic BP. Urine sodium, urine creatinine and urine protein were all measured on the Siemens Vista 1500 analyzer using manufacturers’ reagents. If 24- h urine protein was not available, spot urine protein to creatinine ratios were converted to 24 h urine protein excretion .Blood pressure, eGFR and proteinuria were measured at each clinic visit. 24-h USE was performed periodically to monitor compliance and assist in counseling patients regarding sodium restriction.A priori, we categorized the patients according to their mean 24-h USE into three groups: low sodium diet (LSD) -USE < 100 mEq/day, medium sodium diet (MSD) - USE 100–150 mEq/day and high sodium diet (HSD) - USE > 150 mEq/day. We selected these cut-off points first, to determine whether patients with advanced CKD have higher mortality or faster progression of CKD if their sodium intake is higher than currently recommended (>100 mEq/day), and second, to investigate whether daily sodium intake between 100 and 150 mEq (which is simpler to achieve than <100 mEq/day for most patients) is associated with different outcomes compared to LSD and HSD.Sodium intake for each patient was estimated from the average 24-h USE measured during the follow-up period. In order to account for inappropriate collection of 24-h urine, 24-h urine sodium excretion was corrected for expected creatinine excretion. Expected creatinine excretion was calculated by the following formulas: If male then creatinine excretion (mmol/day) = (28.2−(0.172*age))* 0.00884*weight (Kg); if female then creatinine excretion (mmol/day) = (21.9−(0.115*age))* 0.00884*weight (Kg) [The primary outcome was a composite of progression to ESRD requiring any type of renal replacement therapy  and mortality.2 per year.The secondary outcome was the decline in eGFR in ml/min/1.73 mContinuous variables are reported as mean (± SD) and categorical variables are reported as numbers and percentages. Analysis of variance with Tukey correction was used to compare continuous variables. If Levene's test for equality of error variances was positive, the data was log transformed. Chi squared test was used to compare categorical variables. Time-to-event analyses were conducted using the Kaplan-Meier (KM) method and Cox proportional hazards. The log rank test was used with the KM method to assess for statistical significance. To better quantify individual sodium exposure and account for within person data variability, sodium intake was modeled continuously using time-dependent Cox models using the mean 24-h urine sodium excretion. Potential confounders included in the Cox models were sex, age, baseline eGFR, mean arterial blood pressure (MAP), body mass index (BMI), diabetes, log transformed 24-h proteinuria, and renin-angiotensin system (RAS) blockers (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) use. MAP and log transformed 24-h proteinuria were treated as time dependent variables, and changes in their values over time were incorporated into the adjusted Cox analyses. Sensitivity analysis was performed for sodium uncorrected for expected creatinine excretion as well as after censoring for death.P < 0.05 was considered statistically significant.All statistical analyses were performed using SAS software (Version 9.3) and Medcalc (Version 13.2). 2). At baseline, MAP was 111 mmHg and the mean eGFR was 17.1 ml/min/1.73 m2. The most common cause of CKD was diabetic nephropathy. The majority of patients were hypertensive and diabetic (94 % and 58 % respectively). 53 % were on RAS blockade.The baseline characteristics of the study cohort are presented in Table 2) and were more proteinuric. The variability in sodium excretion in patients with more than one 24-h urine collection was assessed by intra-individual coefficient of variation (CV) defined as SD/Mean. The CV for the whole group was 55 %. We also assessed variability in sodium excretion by dividing patients into two groups by median of baseline eGFR and found that CV for the higher eGFR group was 56 % and for the lower eGFR group it was 53 % indicating similar variability in sodium excretion in the two groups.Based on the mean USE during the observational period, 82, 116, and 143 patients were categorized into low sodium diet , medium sodium diet , and high sodium diet  groups, respectively. At baseline, the three groups did not differ in gender, MAP, eGFR, or use of diuretics and RAS blockers. Patients from the HSD group were younger (mean age 60 years) with a higher BMI (33.7 kg/mP < 0.01), however, there was no significant difference in eGFR decline, RRT requirement or death (Table The mean follow-up time was 1.5 years. The average number of 24-h USE measurements per patient was 3.6 (±2.0). 54 patients had only one sodium measurement. The three groups differed in mean USE as expected  who reached the primary outcome (105 reached ESRD and 10 died), 25 (31 %) were from the LSD group, 38 (33 %) from the MSD group, and 52 (36 %) from the HSD group  and combined outcome of mortality and need for renal replacement therapy (RRT) or eGFR decline. Patients with high USE were more likely to be younger, had higher BMI, and were more proteinuric. There was no association between need for RRT and the mean USE as a categorical or continuous variable. Furthermore, there was no association between USE and the eGFR decline. Our study suggests USE (a surrogate for dietary sodium) may not play a significant role in the progression of CKD to end-stage renal disease in patients with severe kidney disease. To our knowledge, this is the first report on the association of USE on the need for renal replacement therapy and eGFR declines in a diverse CKD population with eGFR < 30 ml/min/1.73 m2) did not show any association between urine sodium and kidney failure  or the composite outcome of renal failure and all-cause mortality [There are no randomized control trials (RCTs) examining sodium intake and long-term renal outcomes, such as progression of CKD or ESRD and thus most of the evidence comes from observational studies. There are, however, short-term RCTs showing a beneficial effect of dietary sodium restriction on proteinuria and blood pressure , 10. Thiortality . Neitherortality . A limitortality  involvinortality  showed a2 over 10 years, showed an inverse association of urine sodium and ESRD – macroalbuminuric patients with the lowest sodium excretion had the highest cumulative incidence of ESRD. [More than half of the patients involved in our report had diabetes. The Finn Diane study that followed 2,807 type I diabetics with mean baseline eGFR > 80 ml/min/1.73 mof ESRD.  The postof ESRD. . The autIn our CKD study population, 58 % of patients (LSD and MSD group) had sodium intake within or close to the recommended target with HSD group represented a common salt intake of the general population in western and particularly in Asian countries . In spitOur study has two strengths: first, the data were obtained from a CKD patient population who received treatment based on current guidelines. Second, although it is an observational study, the data was prospectively collected and data entry was verified periodically with > 95 % of data being accurate.The major study limitation was short follow-up period. Although there is a trend to more ESRD and faster GFR decline with higher sodium intake, it is possible that follow-up was not long enough to demonstrate statistically significant impact on ESRD and GFR decline. The second limitation is the observational nature of the study, thus causal relationships cannot be discerned, and residual confounding could impact the results. Although we calculated the average of urinary sodium excretion for each patient, the number of measurements per patient was low (mean 3.4 USE measurements/patient), and therefore we cannot account for changes in sodium intake that occurred before or after urinary sodium testing. Moreover, there are day-to-day variability in sodium intake and excretion , which m2, sodium intake did not affect progression of CKD to dialysis. Given the limitations of our study outlined above, prospective studies are desirable to address the issue of appropriate counseling for sodium intake in patients with advanced CKD.In patients with eGFR < 30 ml/min/1.73 m


Patients with generalized anxiety disorder (GAD) usually present with various neurological symptoms, but the mechanisms remain unclear. We aimed to analyze the characteristics of dynamic cerebral autoregulation (dCA) in patients with GAD.Patients (aged ≥18 years) who were diagnosed with GAD were enrolled in this study. Medically and psychiatrically healthy volunteers were recruited as controls. Subjects received the Hamilton Rating Scale for Anxiety (HAMA) and 17-item Hamilton Depression Rating Scale (HAMD) evaluation. Noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity were recorded simultaneously from each subject. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference, gain, and coherence function.A total of 57 patients with GAD and 40 healthy volunteers were enrolled. We found that the phase difference values were significantly compromised in patients with GAD. In the Spearman correlation analysis, the phase difference values were negatively correlated with the HAMA scores and the HAMD scores. In the multiple linear regression analysis, GAD is negatively correlated with the phase difference values, whereas age is positively correlated with the phase difference values.Our results suggested that the dCA was compromised in patients with GAD and negatively correlated with the score of anxiety. Improving the dCA may be a potential therapeutic method for treating the neurological symptoms of GAD patients. Generalized anxiety disorder (GAD) is one of the most common mental disorders in the world , 2 and cCerebral autoregulation, which protects the brain tissue from hyperperfusion or hypoperfusion, is critical in regulating cerebral hemodynamics and has been found to play an important role in many neurological diseases –7. PreviCerebral autoregulation is divided into static cerebral autoregulation and dynamic cerebral autoregulation (dCA), and the dCA is more sensitive to pathological situations , 15. WheIn this study, we hypothesize that dCA is compromised in patients with GAD. If our hypothesis is valid, dCA may serve as a potential therapeutic target to improve the neurological symptoms in patients with GAD.Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for GAD [The prospective study design was approved by the ethics committee of the First Hospital of Jilin University under the guidelines of the Helsinki Declaration of 1975/1983. Written informed consent was obtained from all subjects. Patients whose chief complaint was poor sleep were selected for screening. Patients (aged ≥18 years) who met the  for GAD  were rec for GAD  and the  for GAD . MedicalThe examination of dCA was performed as reported in previous research , 7, 23. H(f) denotes the frequency response. Spp(f) is the auto-spectrum of arterial blood pressure, and Spv(f) is the cross-spectrum between arterial blood pressure and cerebral artery blood flow velocity. For each subject, Spp(f) and Spv(f) were averaged over the segments to improve statistical reliability. The gain |H(f)| and phase difference ϕ(f) can then be computed as,HR(f) and HI(f) are the real and imaginary parts of H(f), respectively. Low phase difference and high gain values at a low frequency band (0.06-0.12 Hz) indicate that cerebral artery blood flow velocity follows changes of arterial blood pressure passively, thus suggesting impairment of autoregulation [The dCA analysis was performed as previously reported , 7 and wgulation , 17. We P values < 0.05 were considered statistically significant.The Statistical Package for the Social Sciences Version 17.0  was used to analyze the data. Continuous data are expressed as mean and standard deviation. Comparison between two groups were analyzed using Student’s t-tests. The discrete variables are expressed as the rate (percentage) and were analyzed using chi-squared and Fisher’s exact tests. The Spearman correlation analysis was used to analyze the relationship between phase difference values and HAMA scores and the relationship between phase difference values and HAMD scores. Multiple linear regression analysis was used to explore the effects of covariates on phase or gain. Calculated two-tailed In total, 57 patients with GAD  and 40 healthy volunteers were enrolled in the study. The baseline characteristics are presented in Table The patients with GAD showed no difference in phase difference values between the left and right hemispheres. However, when compared with the healthy controls, the phase difference values of both hemispheres of GAD patients were significantly lower than the corresponding hemisphere of the healthy controls. In addition, there was no significant difference in the gain values between GAD patients and healthy controls in both the left and right hemispheres Fig. .Fig. 2a r = − 0.365, p < 0.001; right: r = − 0.348, p < 0.001). Similarly, both the left and right phase difference values were negatively correlated to HAMD scores .In the Spearman correlation analysis, both the left and right phase difference values were negatively correlated to HAMA scores  indicates that blood flow changes in pace (passively) with fluctuations of blood pressure, suggesting that the distal arterioles and capillary do not respond to the changes of blood pressure. In contrast, notable phase difference (larger time delay) suggests that the phase of arterial blood pressure is outpaced by the phase of cerebral artery blood flow velocity, implying that the distal arterioles and capillary do not comply with the changes in blood pressure. The reason why patients with GAD present with impaired dCA remains unclear and needs further investigation. As a chronic stress disease, lower cardiac vagal control and hyperactivity of the sympathetic and hypothalamic-pituitary-adrenal axis were reported in patients with GAD –29, leadThe integrity of structure and function of the endothelium is essential to maintain a functional cerebral autoregulation –33. HoweAs described above, the changes in neuroregulation, endothelial regulation, and myogenic response may collectively result in the impairment of dCA, leading to unstable cerebral blood flow in patients with GAD. A previous study by Kalk, et al. supports our findings . They foIt is worth mentioning that phase difference values were negatively correlated with the HAMA scores, which suggests that as the HAMA scores increase, the phase difference values, i.e., dCA, tend to decrease. In addition, the negative correlation between phase difference values and HAMD scale suggests a potential impact of depressive symptoms on phase difference values. This phenomenon deserves further study in patients with major depressive disorder. The impairment of dCA in patients with GAD indicates that cerebral vascular function is a therapeutic target of GAD. Thus, methods to improve dCA may potentially relieve the neurological symptoms in patients with GAD.Both the studies from Ortega-Gutierrez and Yams suggested that dCA remains intact in the elderly, though their intracranial arteries may be affected by atherosclerosis , 42. In This study has some limitations. The first is the gender mismatch of the GAD group and controls. Because gender affect cerebral blood flow via complex mechanisms , we coulOur results suggested that the dCA was compromised in patients with GAD and negatively correlated with the score of anxiety. Improving the dCA may be a potential therapeutic method for treating the neurological symptoms of GAD patients.


Despite advances in asthma treatment, severe asthma (SA) still results in high morbidity and use of health resources. Our hypothesis was that SA patients would achieve adequate control with a systematic protocol, including oral corticosteroids, budesonide/formoterol maintenance and reliever therapy and a multidisciplinary approach to improve adherence.Non-controlled (NC) SA patients were enrolled to receive 2 weeks of oral corticosteroids and 12 weeks of formoterol + budesonide. Assessments included asthma control questionnaire (ACQ), asthma control test (ACT), daily symptom diary, lung function and health-related quality of life (HRQoL) questionnaires.p = 0.03). Both groups had low HRQoL at baseline with improvement after intervention.Of 51 patients, 13 (25.5%) achieved control. NC patients had higher utilization of health resources and higher exacerbation rates. Both controlled (C) and NC patients had significantly reduced ACQ scores after oral corticosteroid treatment. After 12 weeks, C patients continued improving. NC patients did not have significant changes. A similar pattern was found regarding lung function, use of rescue medication, and days free of symptoms. After 2 weeks of oral corticosteroids, an increase occurred in those who achieved the ACQ cut off; however, 53.8% of C patients had an ACQ < 1.57 versus 21.1% of NC patients .Retrospectively registered at ClinicalTrial.gov on 22 February 2010 ( There is still debate if severe asthma (SA) patients may acquire symptoms control with available treatment. Our findings support that the application of a systematic, low-cost, easy to conduct protocol can prevent up to 25% of uncontrolled SA patients from up titrating their treatments to new and complex therapies.The knowledge of the pathogenesis, pathophysiology and treatment of asthma has made great progress in recent decades. However, several surveys have shown that a significant part of patients do not achieve adequate control of the disease despite proper management according to guidelines , 2. FactThese factors have a particularly significant impact in severe asthma (SA), in which this small proportion of patients is subject to high morbidity and disproportionate use of health resources , 5. In tSeveral validated tools are available to evaluate asthma control, such as diaries for symptoms, clinical questionnaires, and inflammatory/functional measurements , 8. EachWe have previously published the characteristics of a group of patients who did not reach full clinical control and maintained persistent airflow limitations, despite regular monitoring and treatment for at least 4 years - Brazilian Severe Asthma São Paulo (BRASASP) cohort . Here, wThis was a prospective study including a group of SA patients already followed in a specialised SA centre (BRASASP cohort) at least for 1 year. Patients were between 18 and 65 years old, had confirmed SA treated for at least 1 year, documented airway reversibility, presence of at least one asthma exacerbation in the previous year, were non-smokers or former smokers of ≤ 30 pack-years, and receiving high-dose IC plus LABA. If the patient was a smoker, asthma symptoms must have been present before the onset of smoking, and the patient could not smoke more than 10 cigarettes/day. The local Institutional Review Board approved this study (CAPPesq 757/05). All enrolled patients signed an informed consent. The project was retrospectively registered at ClinicalTrial.gov on 22 February 2010 (NCT 01089322).The study design is shown in Fig. At baseline, all patients self-reported their past medical history and had their medical records evaluated. Comorbidities were evaluated prior to the protocol intervention as the standard clinical practice of our institution and aimed to confirm or exclude known diseases related to non-controlled asthma such as vocal cord dysfunction, gastroesophageal reflux disease, chronic rhinosinusitis, and other pulmonary diseases. Whenever present, these comorbidities were treated according to the same attending physician.Exacerbation was characterized based on the expert panel of 2009 . PatientWe used ACQ 7 score to measure our primary objective of asthma control achievement at W12. Patients who maintained ACQ scores >1.57 were classified as the non-controlled group (NC) .Secondary clinical outcomes included ACQ 7 score at W2, the Asthma Control Test (ACT) , lung fu1 and asthma duration) to try do identify predictors of asthma control. The statistical package Sigma Stat version 3.5, Sigma Plot version 10, and PASW Statistics (SPSS) version 18 were used for statistical analysis. Statistical significance was considered p < 0.05.All continuous variables were evaluated for normality using Kolmogorov-Smirnoff or Shapiro-Wilk tests and are shown as mean ± standard deviation or median (IQ25% – 75%). ANOVA repeated measures were used to compare variables at three moments  with Bonferroni’s correction. Unpaired t (independent groups) was used to analyse the measures between groups. Wilcoxon Signed-Rank and Mann–Whitney tests were used for non-parametric variable analysis. Categorical variables are presented as numbers and percentages and were analysed with the chi-square test. Correlations were performed using Pearson or Spearmen tests whenever appropriate. Multivariable logistic regression analysis was performed (C versus NC) with pre-defined relevant clinical variables  did not reach the controlled criteria of our primary objective (ACQ < 1.57), thus were classified as the NC group, and 13 (25.5%) achieved control and were classified as the controlled group (C). Table p = 0.05). Regarding hospitalization in the last year, no difference existed between groups (NC 37% versus C 23%). Nearly 40% of patients of both groups had undergone previous orotracheal intubation. Regarding comorbidities, there was no difference between self-reported diseases at baseline.NC patients had higher previous health care system utilization. Of NC patients, 71% had more than five hospitalizations compared with 38% in C patients (p = 0.03). Despite not achieving asthma control, the majority of patients presented a clinically significant improvement in their symptoms at the end of the study, represented by a decrease of at least 0.5 in ACQ (C = 86.7% versus NC = 66.7% - p = 0.13). We were unable to identify predictors of asthma control in multivariable analysis.ACQ analysis showed that both C and NC had a significant reduction in ACQ score after oral corticosteroid treatment W2). After 12 weeks of follow-up, C continued to improve, while NC did not . A significant correlation was noted between ACQ and ACT scores in NC patients at the end of the protocol , but not in C patients.ACT values were significantly higher in C compared to NC after the course of oral corticosteroids W2) and at the end of the protocol (W12)  patients experienced at least one exacerbation. No difference existed between C and NC groups  in NC compared with C (0.46 ± 0.5).p =0.058) compared with NC, indicating clinical improvement in HRQL. In the SF-36 questionnaire, the two groups reported lower HRQoL at baseline. As observed in the SGRQ questionnaire, C had greater improvement in SF-36 measurements than NC had at the end of protocol.Both groups had low HRQoL at baseline involving all SGRG domains. At the end of the intervention, the C had significantly better HRQoL in all SGRQ domains Table . The C gr = 0.681; p <0001) and all independent domains . SF-36 correlated with ACQ score in all domains, except pain.The ACQ score showed a good correlation with HRQoL baseline and ending questionnaires, mainly with SGRQ. Total SGRQ score was positively correlated to ACQ  would lead to disease control.All patients were uncontrolled despite regular use of inhaled corticosteroids associated with LABA, including the run-in period. During the 12-week study, we applied a maintenance and reliever strategy with formoterol and budesonide proven to be effective in patients with moderate to severe asthma, especially in symptom scores and number of exacerbations . In the 1 measurement) and a 1-week recall time. It assesses the adequacy of asthma control and the change in asthma control over time. A change in score of > 0.5 is considered to be clinically important and an ACQ score of 1.57 discriminates between controlled and non-controlled asthma [This strategy was clearly effective in a subset of patients. The ACQ incorporates seven items  and ACT (3 points) after the use of oral corticosteroids, as well as significant improvement in FEV1. On the other hand, virtually no patients were daily free of symptoms during the period. In the following 10 weeks, despite a higher dose of inhaled corticosteroids compared to the control group (shown by the number of rescue doses of formoterol/budesonide), there was a trend to a clinical and spirometric worsening. Similar response to a course of systemic corticosteroids have been previously reported. ten Brinke et al. demonstrated a reduction in rescue medication and an increase in FEV1 2 weeks after intramuscular triamcinolone in patients with severe asthma who were using inhaled corticosteroids or chronic oral prednisone . In a reWe identified a similar profile of patients characterized by predominantly female gender, long term disease, and overweight and atopic patients compared to other large cohorts of SA such as SARP and ENFUMOSA , 24. We There are some limitations in our study. The relatively low number of patients in the C group limits the statistical power to some correlations, although the data were consistent with those previously published , 18, 25.Our study has important clinical implications. Patients classified as GINA steps 4 and 5 followed at our asthma clinic for at least 4 years, with free access to anti-inflammatory therapies, educational programs and proper evaluation of factors associated with non-control composed our population –31. GiveOur findings support that in patients with severe uncontrolled asthma in daily practice an automatic step up in treatment may lead to unnecessary increase in expenses and risks related to new treatments, since the control can be achieved with a clinical targeted treatment approach. Nevertheless, despite rigorous and optimized follow-up treatment, the majority of patients with SA did not achieve adequate symptom control, and had high exacerbation rates and impaired QoL. These findings indicate the necessity to redefine the goals and monitoring tools related to SA. The application of a systematic, low-cost, easy to conduct protocol can prevent up to 25% of SA patients from up titrating their treatments to new and complex therapies, thus reducing costs (possibly) and morbidity (certainly).


Mortality among the patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains high because of the very high incidence of cardiovascular disease (CVD) such as coronary artery disease, cardiac hypertrophy, and heart failure. Identifying CVD in patients with CKD/ESRD remains a significant hurdle and the early diagnosis and therapy for CVD is crucial in these patients. Therefore, it is necessary for the better management to identify and utilize cardiovascular (CV) biomarkers in profiling CVD risk and enabling stratification of early mortality. This review summarizes current evidence about renocardiovascular biomarkers: CV biomarkers in patients with CKD as well as with ESRD, emphasizing on the emerging biomarkers: B-type natriuretic peptide, cardiac troponins, copeptin, the biomarker of renal injury , and the mineral and bone disorder hormone/marker (fibroblast growth factor-23). Furthermore, it discusses their potential roles especially in ESRD and in future diagnostic and therapeutic strategies for CVD in the context of managing cardiorenal syndrome. Chronic kidney disease is frequently associated with a progressive decrease in glomerular filtration rate (GFR), which leads to ESRD. The number of patients with CKD as well as ESRD is increasing markedly worldwide, with poor outcomes and high cost. Cardiovascular disease (CVD) is closely associated with CKD and ESRD and is well shown as the leading cause of morbidity and mortality in the patients with CKD, most notably those on ESRD or dialysis . The preA number of biomarkers have been evaluated in CVD or CKD/ESRD, and biomarkers pertinent to the CV and renal interface are defined as renocardiovascular biomarkers . From thAmong the biomarkers listed in Table r2 = 0.89, P < 0.001) in HF patients with normal creatinine levels, and they found that this relationship was more robust than any other parameter previously reported  or an inactive fragment, NT-proBNP . The hemodynamic load  is the most important stimulus for BNP and NT-proBNP secretion, based on the results of both basic and clinical studies. Iwanaga et al. have demonstrated an excellent correlation between BNP and LV end-diastolic wall stress (EDWS)  in 165 hypertensive subjects . Furthermore, they found in a multivariate regression analysis that cardio-related factors such as blood pressure, LV mass, and eGFR, but not FE, were significantly associated with NPs concentrations.The relationship between BNP/NT-proBNP levels and renal dysfunction is complex. Any change in value may be influenced by renal dysfunction due to change in clearance. When renal dysfunction causes cardiac damage/stress, directly or indirectly, this will cause increased BNP/NT-proBNP values. It remains unclear whether, in patients with CKD and ESRD, increased plasma BNP levels might be due to more hemodynamic stimuli or might result from other factors such as anemia, obesity, and cachexia or impaired renal clearance of natriuretic peptide, despite similar hemodynamic stimuli. Multiple studies have shown an inverse moderate, but significant, correlation between estimated glomerular filtration ratio (eGFR) and BNP or NT-proBNP concentrations. Niizuma et al. have recently shown that renal dysfunction (reduced eGFR) may contribute to increased BNP levels (inverse correlation) independent of EDWS , anemia, HF type, and BMI in a wide spectrum of HF patients with both CKD and ESRD . Some resubjects . They weAmong patients with HD or peritoneal dialysis (PD), considerable heterogeneity in BNP and NT-proBNP levels has been recognized and seems to increase exponentially, which may have caused some confusion in interpreting results. In ESRD or dialysis patients, the question of whether increased plasma NP levels are due to cardiac hemodynamic stimuli, accompanying comorbidities or impaired renal clearance of NPs is also a matter of controversy. Recent reports in ESRD patients suggest that the NT-proBNP/BNP ratio increases even further in patients receiving HD . In dialThe best cut-off values for detecting HF may need to be raised when the eGFR is less than 60 mL/min. It should be noted that the diagnostic accuracy of plasma BNP and NT-proBNP for HF is reduced in this setting, and natriuretic peptide testing for HF should be discouraged in patients especially on dialysis. Recently, Mishra et al. reported in the large CKD cohort without HF that NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction . Also, sAfter myocardial cell damage, cardiac troponin (cTn) T and I are released from the myocytes and their levels are detectable 3–12 h after the injury and mean time to peak cTn level is approximately 12–48 h. The concentration returns to the normal range after 5–14 days, which is four times longer than for the creatine kinase myocardial band isoenzyme (CK-MB) fraction. The increasing sensitivity of cTn assays has had a dramatic impact on the use of cTn testing, which is now an essential component of the diagnostic workup and management of acute coronary syndromes (ACS). More importantly, the test has prognostic value because it identifies ACS patients who are at substantially increased risk of death or recurrent MI . Also, tElevated cTns may be detected in conditions other than ACS, including HF, cardiomyopathies, myocarditis, tachyarrhythmia, and pulmonary embolism, and even after strenuous exercise in healthy individuals . Levels via the kidney might contribute to the elevated cTnT in HF patients with CKD by measuring the difference of TnT concentration between coronary sinus and aortic root  are mediated by three receptor types: V1aR, V1bR, and V2R. V1aR-dependent vasoconstriction that increases afterload, ventricular stress, and cardiac hypertrophy may result in systemic vascular resistance and a decrease in cardiac output and contractility while V2R is the receptor that governs water retention by activating the aquaporin-2 channel on the apical plasma membrane of the collecting duct cells . DespiteDuring the last few years, plasma copeptin concentration has been measured in a number of clinical investigations. Significant associations have been found between baseline copeptin level and the incidence or progression of various pathological situations such as HF, diabetes, and CKD, suggesting that AVP may play causal roles. Other studies have shown that plasma copeptin may be a useful diagnostic marker in patients with AMI, sepsis, or unexplained hyponatremia. Furthermore, the prognostic values of copeptin have already been shown in patients with HF, CAD, and with acute stroke. It should be noted that most findings as the diagnostic and prognostic marker of CVD were from subjects without renal dysfunction.In CKD, a few data exist evaluating copeptin concentrations, which found copeptin to be associated with renal function . It mighAlthough acute kidney injury (AKI) and CKD are conditions that substantially increase morbidity and mortality, the both diagnosis is still made with surrogate markers of GFR, such as SCr, urine output, and creatinine based estimating equations. The creatinine-base equations are an unreliable indicator during acute and chronic changes in kidney function, and new biomarkers should have the potential to identify earlier patients with AKI and CKD and in the future potentially intervene to modify outcomes. Among them, NGAL is considered one of excellent biomarkers in urine and plasma for the early prediction of AKI as well as CKD detection , 76.Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2, is a 25-kDa secretary glycoprotein and a member of lipocalin superfamily of proteins and has been shown to be induced rapidly in renal tubules in response to acute injury. NGAL seems to be one of the earliest kidney markers of ischemic or nephrotoxic injury in animal models and is detected in the blood and urine of humans soon after AKI. A meta-analysis by Haase et al. demonstrated that NGAL was an early predictor of subclinical AKI, with early elevations in plasma NGAL levels compared to SCr . MoreoveAghel et al. recently reported that elevated admission serum NGAL levels was associated with heightened risk of subsequent development of worsening renal function (WRF) in 91 patients who admitted with acute HF . NGAL coHowever, recent evidence demonstrates a diversity of expression and function of NGAL. NGAL in plasma is also generated by a systemic inflammation, which induces NGAL synthesis by extrarenal tissues and the release of NGAL from neutrophils. It has been implicated not only as a marker of renal function but also as that of neutrophil activation, a protective factor against apoptosis and oxidative stress. Recent reports have suggested that NGAL could be a biomarker of atherosclerosis or CVD as well as in AKI and CKD progression . IncreasRecently, among patients with CKD, urine levels of NGAL, were reported to be associated independently with future ischemic atherosclerotic events, but not with HF events or deaths . Higher Fibroblast growth factor-23 (FGF-23) is a recently discovered member of the FGF family, involved in the regulation of the body’s calcium-phosphate metabolism . It incrElevated FGF-23 levels are associated with an increased risk of adverse outcomes, including all-cause mortality, CV events, and progression of CKD . Isakovavia the FGF receptor–dependent activation of the calcineurin-NFAT-signaling pathway independent of klotho (the co-receptor of FGF-23 only expressed in kidney and parathyroid glands). Treatment with an FGF receptor blocker is also reported to attenuate LVH. In contrast, observational studies reported conflicting results on the association of FGF-23 with arterial calcification, which is another prominent pattern of CV injury in CKD. In the largest study to date, FGF-23 was not independently associated with coronary artery calcification in patients with CKD stages 2–4 (P = 0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, LV mass index, and ejection fraction. Their findings suggest that FGF-23 could represent a novel mechanism of CHF that mediates at least a portion of excess CVD risk attributable to CKD. Recently, additional analysis in their study showed the association of FGF-23 with atrial fibrillation in CKD, which is frequently observed and has clinical impact in patients with CKD  have been evaluated as emerging biomarkers for CV or renal disease. For example, miR-21 is associated with organ fibrosis and the measurement may be useful in the detection of renal or myocardial fibrosis , 94. SevThe contribution of each author on this work was as follows: SN and YI, the primary investigator; TY, the secondary investigator ; and SM, the consultant and supervisor.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


While chronic kidney disease (CKD) is regularly evaluated among patients with diabetes, kidney function may be significantly impaired before diabetes is diagnosed. Moreover, disparities in the severity of CKD in such a population are likely. This study evaluated the extent of CKD in a national cohort of 36,764 US veterans first diagnosed with diabetes between 2003 and 2013 and prior to initiating oral antidiabetic therapy. Evidence of CKD (any stage) at the time of diabetes diagnosis was determined using eGFR and urine-albumin-creatinine ratios, the odds of which were assessed using logistic regression controlling for patient characteristics. CKD was evident in 31.6% of veterans prior to being diagnosed with diabetes , over half of whom had at least moderate kidney disease (stage 3 or higher). The odds of CKD tended to increase with age , hemoglobin A1C , systolic blood pressure , and BMI . Both Asian Americans  and African Americans  had higher adjusted odds of CKD compared to whites, and prevalence was highest in the Upper Midwest and parts of the Mid-South. Results suggest that evidence of CKD is common among veterans before a diabetes diagnosis, and certain populations throughout the country, such as minorities, may be afflicted at higher rates. Approximately 10% of the general US population, more than 20 million people, has chronic kidney disease (CKD), and this condition is especially prevalent among patients with diabetes mellitus (DM) –6.While multiple treatment options exist for patients with CKD, none are able to cure the patient of this affliction. However, multiple options do exist to delay progression of CKD, particularly for diabetic kidney disease, but early detection is paramount so that interventions may be introduced as soon as possible to effectively slow the disease’s progress –9. WhileThe purpose of this investigation was to evaluate the extent to which CKD is present in patients prior to being diagnosed with and beginning treatment for DM. Using data from a nationwide electronic health record system, these analyses will add needed interpretation of the extent of racial and regional disparities among newly-diagnosed diabetes in whom evidence of CKD exists.th Revision, Clinical Modification [ICD-9-CM] codes), and the Vital Status Files. This study was reviewed and approved by institutional review boards at both the University of Tennessee Health Science Center and the Memphis VA Medical Center, and the need for consent was waived by these ethics committees.This was a retrospective observational study using data from the VA Corporate Data Warehouse from 2002 through 2014. These data included extracts from the VA Decision Support System National Data Extracts, Inpatient and Outpatient Medical SAS Datasets  for the first time , been prescribed an oral antidiabetic drug (OAD) as their first-line therapy for the first time , and at least one year of data prior to and two years of data following their initial DM diagnosis. Patients were excluded if they were insulin dependent, had been diagnosed with a diabetes-related micro-vascular complication prior to or in conjunction with their DM diagnosis  were used allowing for a window of 90 days past the index date for a lab value to be considered valid.2) [2 increments), and the presence of several comorbid conditions/events included in the Deyo Charlson Comorbidity Index in the year prior to the initial DM diagnosis  [The main outcome of this study was the presence of CKD in veterans prior to or at the time of their initial DM diagnosis. Evidence of CKD was determined in accordance with guidelines where normal kidney function was defined as a UACR ≤30 and an eGFR ≥60; CKD was categorized from stages 1 through, and also based on combinations of the levels of UACR  and eGFR  . The oddarction) . Codes uth-75th percentile), or counts (percent), as appropriate. Comparisons between categories of CKD stage were made using one-way ANOVA, correlation analysis, and the Cochran-Armitage test for trend. The adjusted odds of any stage of CKD  were determined using multivariable logistic regression. To provide population-level estimates, crude prevalence rates were adjusted using population weights from the 2010 US census, and state-level estimates by race were derived using the 2011–2015 American Community Survey 5-Year Estimates [Data were described as means (standard deviations), medians  throughout the country. VA markets represent geographic areas sufficiently large to support a full healthcare delivery system, and this level of analysis allows for assessing patients whose care is more likely to be similar than at either a state or VISN level. Since the VA markets in general follow geographic boundaries of the US, this distinction also allows the broader assessment of CKD prevalence along traditional geographic distribution. ArcGIS version 10.4  was used to generate the map and a projection using VA markets from fiscal year 2011 created the boundaries to more accurately reflect the underlying patient data used .2 (SD: 18.46) and median UACR was 8.1 mL/min/1.73 m2 (IQR: 4.1–20.7), and a higher proportion of patients with CKD were on either an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) by the time they were diagnosed with diabetes (p<0.0001). However, most patients with CKD were not on either therapy, irrespective of stage, and the proportion of patients on an ACE or ARB was markedly different based on year of diagnosis. Beginning in 2005, at least 31% of all patients (regardless of whether they had evidence of CKD) were on either therapy, but the proportion of those on an ACE or ARB remained consistently higher among patients with any stage of CKD, year-over-year. Out of the original cohort of 187,349 veterans, 36,764 remained eligible after considering the requisite lab values needed for this analysis. Across all patients included, mean eGFR was 78.5 mL/min/1.73 mEvidence of CKD (at any stage) was observed in 31.6% of veterans by the time they were diagnosed with DM, and over 16% exhibited at least moderately reduced eGFR (stages 3a-5) , which iStandardized to the general population by age and sex, the prevalence rate of any stage of CKD was approximately 241.8 cases per 1,000 people (95% CI: 218.3–265.4). Specific to men (96% of the sample), the age-adjusted rate was 247.7 per 1,000 people (95% CI: 230.2–265.2). Among the two largest racial categories, unadjusted values indicated that slightly more White veterans had evidence of CKD than African American veterans prior to being diagnosed with diabetes. Among patients with CKD, more advanced stage was moderately related to increased age  while those who self-identified as a racial minority (p<0.0001) were observed in higher proportions among less severe stages of CKD (Stages 1 or 2 versus 3 or higher). Additionally, hemoglobin A1C and systolic blood pressure tended to be lower among those with more advanced CKD  while the number of comorbidities tended to slightly increase with more severe CKD . No differences were observed between stages of CKD in terms of patient BMI.After adjusting for baseline characteristics, the odds of CKD (any stage) tended to increase with older age , higher hemoglobin A1C , higher systolic blood pressure , and higher BMI . The odds of CKD  were alsSimilarly, regional variation in the odds of CKD were noted. Using the northeastern portion of the country as a reference, all other regions of the United States had a higher odds of CKD: Midwest , South , and West . Among the regions, the Midwest had the highest proportion of its veterans (32.9%) demonstrating CKD, and several pockets of the country exhibited markedly higher rates of CKD where unadjusted prevalence was at least 30% . SpecifiUsing data from the nationwide VA electronic health record system, we observed that among veterans who were eventually diagnosed with DM nearly one-third of them had evidence of CKD by the time of their initial DM diagnosis. Most of these patients had early stages of CKD . Similar to the general US population, significant racial disparities in the prevalence and severity of CKD were observed when adjusting for multiple patient characteristics. Additionally, some regional variation in CKD prevalence was noted, and several areas of the country had a particularly high number of cases.According to data from the National Health and Nutrition Examination Survey (NHANES), the prevalence of CKD in patients with DM has been estimated to be 40% or higher while the rate among the non-diabetic population was estimated to be 11.3% ,18, 19. These results also highlight an opportunity for broadening screening efforts among patients that may be at increased risk for developing CKD, such as patients with high comorbidity burden. Moreover, it raises awareness to the importance of earlier identification of DM to prevent organ damage. Consequently, broader screening efforts, for both CKD and DM, should be advocated in order to limit kidney damage, particularly if cardiovascular comorbidities or other risk factors are known.The observation that certain groups of patients, namely African American and Asian American veterans, had a higher adjusted odds of CKD reinforce findings from earlier studies demonstrating such a disparity in these populations, both in the general public and specific to veterans ,20–23. HOur analysis also expanded the evidence behind geographic disparities in CKD by identifying sections of the country where prevalence was noticeably higher. Importantly, our study analyzed CKD prevalence using VA markets, which allowed us to investigate the presence of disease within regions of patients with more similar healthcare and characteristics-a more granular level than previous, similar assessments . MoreoveA variety of mechanisms have been hypothesized to contribute to disparities among patients with CKD with results consistently identifying lower socioeconomic status as a leading indicator of increased risk for disease and its progression to ESRD –34. AddiThis study was limited in several ways. First, only data from the VA’s electronic health record system were used to provide estimates of disease prevalence; therefore, results may not be generalizable to the general US or other populations. Secondly, data used were drawn straight from the electronic record without adjudication; therefore, errors made in the system while documenting laboratory values could have impacted our analyses. Also, exclusion criteria for the larger associated study that were not related to the current analysis may have introduced selection bias as two years’ worth of follow-up data were required for inclusion to the overall study cohort, meaning survival over this time period was required. Specific selection criteria that may limit interpretation includes the excluding of patients initiating diabetes treatment on insulin as well as those with existing diagnoses for microvascular complications, which removed patients with more advanced disease who were also potentially more likely to have some form of CKD. Therefore, our interpretation of the prevalence of CKD in the study population is likely biased by the fact that the analyzed cohort excluded sicker patients or those who died prior to meeting eligibility requirements. Additionally, while select cardiovascular events, such as myocardial infarction, were used as predictors of CKD in this analysis, a complex interrelationship exists between CKD and cardiovascular complications. Consequently, as these conditions existed simultaneously among the study population, we are not able to comment on the directionality of causation between CKD and the selected outcomes ,42.In spite of these limitations, the current study adds insight to the extent of both racial and regional variations in the prevalence of CKD while calling attention to the magnitude of this disease among patients prior to being diagnosed with DM. The current analysis suggests that expanded CKD and DM screening efforts may be necessary among veterans who are minorities, especially if cardiovascular comorbidities are present, in order to control the underlying kidney damage and narrow the disparities that exist in this population related to kidney disease, both independent of and in conjunction with DM.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (NUaV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24‐h ambulatory BP monitoring before and during two‐day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate  was measured as intrarenal RAAS; urinary dopamine excretion rate  as intrarenal dopaminergic system; heart rate variabilities  of non‐Gaussianity index λ25s as sympathetic nerve activity; and power of high‐frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with AGTVU  and positively with DAVU . HF was a determinant of night/day BP ratio , rather than DC or λ25s. During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime NUaV preceded restoration of BP rhythm, accompanied by decreased AGTVU  and increased DAVU , but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.We have revealed that even in humans, activated intrarenal renin–angiotensin–aldosterone system ( Na) (Kimura and Brenner NaV) in patients with chronic kidney disease (CKD)  also impairs renal sodium excretion, eliciting the nondipper BP rhythm in patients with IgA nephropathy  of treatment  to UNaV ratio, indicating suppression of function of the epithelial sodium channel (ENaC)   and nondipper type circadian BP rhythm are strongly associated with each other. Dahl et al., showed that salt sensitivity of BP is determined by the kidney . Patients had to fulfill the following eligibility criteria: (1) age ≥16 years; (2) diagnosis of CKD based on Kidney Disease Outcomes Quality Initiative (K/DOQI) criteria  for at least 3 months. GFR was estimated by Japanese equation for eGFR  decision of attending doctor to administer azilsartan ; (4) average sodium to creatinine ratio in spot urine measured at three different times for 4 weeks prior to enrollment <85–120 mmol/gCre (corresponding to ~6 g NaCl for daily intake based on expected daily urinary creatinine excretion as referred to hereinafter); and (5) written informed consent obtained. Patients were excluded if they had (1) treatment with ARBs or diuretics 2 months before enrollment; (2) change of antihypertensive agents in the 2 months before enrollment; (3) contraindication to azilsartan ; (4) the presence or possibility of pregnancy or current breastfeeding; (5) hemoglobin A1C (HbA1c) ≥9.0%; (6) GOT >100 or GPT >85; (7) endocrine hypertension; (8) accelerated or malignant hypertension  >120–130 mmHg; (9) serious conditions with congestive heart failure, coronary disease, arrhythmia, or systemic diseases; (10) nephrotic syndrome ; and (11) any reason for ineligibility suggested by the attending doctor . All subjects were enrolled after providing informed consent to participation in the study. The study protocol was approved by the Institutional Review Board (IRB) of Nagoya City University Hospital  and was conducted in accordance with the Declaration of Helsinki, and the helm of the Ministry of Health, Labour and Welfare.A single‐arm, open label study was performed during hospitalization in 20 consecutive patients with CKD : 23.0 ± 3.8 kg/mAt the time of enrollment, 11 patients were taking no antihypertensive agents and nine were taking calcium channel blockers. Office BP was measured with a validated automated oscillometric sphygmomanometer  after subjects had been seated for at least 5 min. Office systolic and diastolic BP (SBP and DBP) determined as averages of two BP readings in two visits were 150 ± 16 and 87 ± 14 mmHg, respectively, and the spot‐urine sodium to creatinine ratio was 98 ± 18 mmol/gCre.NaV, and intrarenal RAAS and dopaminergic system and HRV during the acute phase of ARB treatment in patients with CKD under hospitalization, during which patients ate a diet containing 6 g/day of salt. The patients received nutritional instructions to eat this diet for at least 4 weeks before enrollment, and were asked to get up at 06:00 and to start bed rest at 21:00 during the study period. Measurements were made before initiation of ARB treatment (baseline) and 2 days after the start of oral administration of an ARB, azilsartan (acute phase). After baseline examinations, subjects received single daily doses of azilsartan once in the morning. The daily dose was determined based on the average of two office SBP readings in two visits: ≥160 mmHg, 40 mg; ≥125 and <160 mmHg, 20 mg; and <125 mmHg, 10 mg. The number of patients taking azilsartan 40, 20, and 10 mg/day were 2, 12, and 6, respectively. During the two‐day study period, a change in dosage of azilsartan or other antihypertensive agents and additional administration of antihypertensives or diuretics were not allowed; if these were needed, the patient was excluded from the study. When SBP, which was measured thrice a day on the arm opposite to that used for 24‐h ambulatory BP monitoring (ABPM), fell below 100 or 95 mmHg, or the patient felt postural dizziness, the dose of the antihypertensive agent was decreased and the study was discontinued for the patient.The study was performed to evaluate relationships among circadian BP rhythm, UNa), SNa × GFR. Tubular Na reabsorption (tNa) was calculated as the difference between filtered Na load and absolute urinary Na excretion  was then calculated as the tNa to filtered Na load ratio. “Steady state treatment with an ARB” was defined as 24‐h UNaV returning to the same as the baseline level, and “lower Na balance on steady state” as (1) filtered tubular Na load reduced, (2) tubular Na reabsorption reduced, and (3) 24‐h UNaV returning to the same as the baseline level.At baseline and in the acute phase of ARB treatment, 24‐h ABPM and urine collection were conducted separately in the daytime (06:00–21:00) and night‐time (21:00– 06:00), and ambulatory 24‐h ECG was recorded on the same day during normal daily activities. Collected urine was combined to calculate 24 h values. The adequacy of 24‐h urine collection was judged by the amount of urinary creatinine excretion: males aged <50 years, 18.5–25.0; females aged <50 years, 16.5–22.4; males aged ≥50 years, 15.7–20.2; and females aged ≥50 years, 11.8–16.1 mg/kg body weight per day. Incomplete or excessive urine collection in daytime or night‐time samples was judged based on the night/day urinary creatinine excretion ratio of <0.5 or >2.0, respectively. 24‐h creatinine clearance (ml/min) was used as an index for GFR. The glomerulotubular Na balance was defined as follows: the amount of Na filtered from glomerulus and loaded into renal tubules (filtered tubular Na load) was calculated as the product of the GFR and plasma Na concentration ; and hANP by chemiluminescent enzyme immunoassay (CLEIA) at an external center . Plasma AD and DA concentrations fell below the lower limit of detection in six and nine patients, respectively. For these patients, the data were taken to be 50% of the detection limit . Urinary angiotensinogen (AGT) was measured using a Human Total AGT ELISA Kit   and urinary DA excretion  were used as indicators of activities of the intrarenal RAAS and dopaminergic system, respectively. For reference, urinary excretion rates of AD and NAD  were calculated.Blood samples at baseline and in the acute treatment phase were collected at 06:00, the boundary between day and night. Plasma Na and K (ion‐selective electrode method) and creatinine (enzymatic method), and urinary concentrations of Na and K (ion‐selective electrode method), creatinine (enzymatic method), and albumin (turbidimetric immunoassay) were measured at the institutional central laboratory. Blood samples for evaluating plasma renin activity (PRA), plasma concentrations of aldosterone (PAC), Ang I, Ang II, adrenaline (AD), noradrenaline (NAD), dopamine (DA), and human atrial natriuretic peptide (hANP), and urine samples for AD, NAD, and DA were centrifuged at 1500 During 24‐h BP monitoring, BP was monitored noninvasively every 30 min with a validated automatic device . BP and heart rate (HR) values were not considered valid for analysis if data were missing continuously for 2 h or if the patient awoke during the night and had difficulty falling asleep again. Mean arterial pressure (MAP) was calculated as DBP plus one‐third of the pulse BP. Daytime BP was calculated as the average of the 30 readings between 06:00 and 21:00, and night‐time BP as the average of the remaining 18 readings. Patients whose nocturnal fall in MAP was ≥10% from day to night were classified as dippers and those with a nocturnal MAP fall <10% as nondippers. Nocturnal hypertension was defined as night‐time BP ≥120/70 mmHg.λ25s as an indicator of sympathetic nerve activity, and power of high frequency  and deceleration capacity (DC) for parasympathetic nerve activity. We hypothesized that DC could be attributable to both sympathetic and parasympathetic nerve activities . Ambulatory ECG signals were digitized at 125 Hz and 12 bits with an ECG scanner , on which QRS complexes were detected and labeled automatically and all possible errors in labeling were reviewed and edited manually by experienced technicians. Recordings with a total analyzable length <23.5 h were excluded from the study. Data were also excluded when ventricular and supraventricular ectopic beats were >10% of all recorded beats. Only normal‐to‐normal R‐R interval data thus obtained were used for HRV analysis. Among HRVs, we used n = 20). For ethical reasons, the ARB was not started in these 20 persons.Control data for the HRV analysis were obtained from age‐, gender‐, and BMI‐matched same number of persons, including individuals who underwent 24‐h ambulatory ECG for evaluation of chest discomfort without medication with antihypertensive agents, but were proven not to have cardiac and kidney diseases or hypertension, or healthy volunteers .Results are expressed as mean ± SD or as median  according to the data distribution, which was tested using a Kolmogorov–Smirnov test. Variables that were not normally distributed were analyzed after log transformation. Differences in parameters between control and baseline, or baseline and ARB treatment were examined by Student's t‐test for paired samples or by Wilcoxon signed‐rank test, as appropriate. Correlations among quantitative variables were evaluated by the least‐squares method. Relationships between changes in variables were analyzed by linear regression through the origin. Considering the statistical power of our study, which included 20 patients, we could use only 2–3 covariates for multiple regression analysis. Therefore, we used forward stepwise multiple regression analysis only when we evaluated the important clinical questions. In particular, forward stepwise multiple regression analysis was conducted to compare the contribution of 2. BP, HR, and urinary excretion of sodium and potassium are shown in Table r = −0.43, P = 0.05), daytime , and night‐time  SBP. The relationship between GFR and FRNa exhibited an upward convex relationship , rather than a first‐order regression line .At baseline, the median (IQR) for albuminuria was 370 (67–870) mg/gCre and the mean±SD GFR was 60 ± 42 mL/min/1.73 mDAV was higher in patients whose plasma DA fell below the detection limit compared to those with a detectable plasma DA concentration , whereas UADV was 6.9 ± 5.6 and 6.7 ± 4.0 pg/gCre in patients whose plasma AD could and could not be determined, respectively (P = 0.9). Night/day SBP ratio correlated inversely with PRA  and PAC , but not with other endocrine variables (Table 4). GFR correlated positively with UDAV  and inversely with UAGTV  and hANP , but not with others (Table AGTV) [log(μg/gCre)] did not correlate with 24‐h, daytime, night‐time, and night/day ratios of SBP. UAGTV correlated positively with 24‐h UNaV  and hANP , but not with other endocrine variables or urinary albumin excretion rate (UAlbV). UAGTV and FRNa exhibited an upward convex relationship , rather than a first‐order regression line ]2. The peak coordinate of the upward convex curve corresponded approximately to UAGTV of 43.9 μg/gCre, and FRNa of 99.49%. UDAV [log(pg/gCre)] correlated positively with 24‐h filtered Na load , but not with HF or λ25s. 24‐h λ25s did not show a significant correlation with 24‐h, daytime, night‐time, and night/day ratios of SBP. 24‐h DC correlated inversely with night‐time SBP , but not with other SBP variables. 24‐h HF correlated inversely with night‐time SBP  and night/day SBP ratio . 24‐h λ25s, DC, and HF did not have a significant relationship with endocrine variables , HF was the main determinant of night/day SBP ratio , rather than DC or λ25s.HRVs at baseline are shown in Table P = 0.2), serum sodium , and serum potassium  remain unchanged, and serum creatinine increased . Albuminuria changed from 370  to 270  mg/gCre (P = 0.2), and GFR from 60 ± 42 to 57 ± 44 mL/min (P = 0.4). Clinical variables before and during treatment are shown in Tables λ25s, DC, and HF between baseline and the acute phase of treatment . Change in daytime UNaV correlated inversely with change in PRA , but not with changes in other endocrine or HRV variables. Changes in 24‐h UKV/UNaV ratio correlated inversely with change in UDAV , but not with changes in other variables. Change in UAGTV did not correlate with changes in endocrine or HRV variables.Change in filtered Na load did not correlate with changes in hANP, UNaV. However, the other four patients with restoration of nondipper BP rhythm had an increase in daytime UNaV, consistent with our previous reports  and positively with change in UDAV , but did not correlate with changes in hANP, λ25s, HF, and DC. Change in UDAV was positively correlated with change in filtered tubular Na load . In stepwise multiple regression analysis , change in UDAV was the main determinant of change in filtered tubular Na load , rather than changes in UAGTV and λ25s.As mentioned above, of the 15 patients with nondipper BP rhythm and nocturnal hypertension at baseline, five changed to dipper. One of these five patients had excess BP reduction during the acute phase of azilsartan therapy and his restoration of nondipper BP rhythm was not accompanied by an increase in daytime UP = 0.4), tubular sodium reabsorption 12116 ± 8619 to 11607 ± 9002 (P = 0.4), and urinary sodium excretion, 86 ± 46 to 70 ± 34 (P = 0.04).The changes in glomerulotubular balances of sodium before and during the acute phase of azilsartan therapy were tubular sodium load 12202 ± 8624 to 11677 ± 9013  a salt‐sensitive rat (S) that becomes hypertensive under a high‐salt diet, and (2) a salt‐resistant rat (R) that remains normotensive under the same condition. Dahl also found that renal homograft from the R‐ to S‐rat made the rat salt‐resistive, whereas renal homograft from the S to R made the rat salt sensitive  of treatment  can incur sodium retention during the day, which prevents night‐time BP dip   of ARB treatment in CKD patients  and dopaminergic (natriuretic) systems. Thus, AngII inhibits the natriuretic effect of dopamine  = / = 1 − UNaV/(SNa × GFR). Thus, FRNa is corresponding to UNaV adjusted by SNa and GFR, indicating that relationship between UAGTV and FRNa is controlled by GFR. UNaV and [SNa × GFR] ranged from 50 to 110, and 8300 to 21,000 mmol/day, respectively; therefore, [SNa × GFR] was several orders of magnitude higher than UNaV. UAGTV had an inverse correlation with GFR, and thus, higher values of UAGTV represent reduced GFR. Furthermore, GFR and FRNa also had an upward convex relationship, and this may be why UAGTV showed an upward convex relationship with FRNa in this study. Consequently, in patients with preserved GFR, FRNa may have a positive relationship with UAGTV  is saddled with the issue of sensitization and desensitization, we performed this study during the acute phase of ARB treatment, rather than the chronic phase. A further study is needed to investigate whether the systemic sympathetic nervous system and intrarenal dopaminergic system are both significant for renal sodium handling, or whether the dopaminergic system rather than the sympathetic nerve system is significant, in the chronic phase of ARB treatment.The present study did suggest a solution to the issue of HRV in relation to circadian BP rhythm. Night/day BP ratio and nocturnal BP were attributable to HF, rather than DC or In conclusion, as renal function deteriorated, diminished sodium excretion caused the nondipper type of circadian BP rhythm, which can be attributed to intrarenal RAAS and dopaminergic system and injured parasympathetic nerve activity. During the acute phase of treatment, the sympathoinhibitory effect of ARBs cannot contribute to an increase in natriuresis or decrease in nocturnal BP. Instead, ARBs inhibit intrarenal RAAS to enhance urinary sodium excretion and restore circadian BP rhythm in cooperation with the intrarenal dopaminergic system.None declared.


Left ventricular (LV) systolic function was assessed as the primary endpoint, according to conventional and strain-echocardiography measurements. Also, left atrial (LA) morphofunctional indices were investigated at baseline and at the final visit. Results were expressed as median with interquartile range (IQ). A significant improvement of LV ejection fraction (20.3 (IQ 12.5) vs. −1.67 (IQ 24.8); p = 0.040)), and LA area fractional change (11.1 (IQ 22.6) vs. 2.8 (9.5); p = 0.034)) were observed in genistein patients compared to the controls, following 12 months of treatment. In addition, body surface area indexed LA systolic volume and peak LA longitudinal strain significantly changed from basal to the end of the study in genistein-treated patients. One-year supplementation with 54 mg/day of pure genistein improved both LV ejection fraction and LA remodeling and function in postmenopausal women with MetS.Genistein, a soy-derived isoflavone, may improve cardiovascular risk profile in postmenopausal women with metabolic syndrome (MetS), but few literature data on its cardiac effects in humans are available. The aim of this sub-study of a randomized double-blind case-control study was to analyze the effect on cardiac function of one-year genistein dietary supplementation in 22 post-menopausal patients with MetS. Participants received 54 mg/day of genistein ( Estrogen favorably influences calcium homeostasis, serum lipid levels, blood pressure control, inflammatory status, and vascular reactivity in women ,2,3,4,5.The aim of this study was therefore to investigate whether genistein therapy might influence heart function in postmenopausal patients with MetS.A group of postmenopausal women, affected by type-2 DM and free from previous CV events, was enrolled from the population of postmenopausal women referred to the Department of Clinical and Experimental Medicine  for MetS. All patients were of Caucasian origin. This study was planned as a sub-study aimed to investigate the influence of genistein on heart function, from the original randomized multicenter clinical trial  managed in collaboration with the University of Palermo  and the University of Magna Graecia  . All patDiagnosis of MetS was made considering the presence of at least three criteria among those provided by the modified US National Cholesterol Education Program Adult Treatment Panel III , as foll2), waist circumference (cm) and body mass index , routine laboratory sampling , triglyceride levels), fasting serum insulin, and the insulin resistance index by the homeostasis model assessment for insulin resistance (HOMA-IR) were carried out at baseline, 6 months, and 12 months of therapy. Visfatin, adiponectin, and homocysteine (HCY) serum levels were also evaluated, as previously described , as well as LA and LV longitudinal shortening, were calculated according to recommendations of both the American and European Societies of Echocardiography . CardiacLeft ventricular systolic function strongly related to ejection fraction. Moreover, LV shape, LV strain analysis, mitral annulus posterior systolic excursion (MAPSE), and longitudinal function (tissue S’ velocity) were also evaluated.We also investigated LV diastolic function by PW-Doppler, sampling the mitral inflow early and late diastolic velocities  and tissue–Doppler velocity both at basal septum level and lateral mitral annulus .A dedicated strain software package  was used for both LA and LV longitudinal strain . Good quDescriptive statistical analyses were performed to evaluate basal demographic and clinical characteristics. All results were expressed as medians with interquartile range (IQ) for continuous variables, and absolute and percentage frequencies for categorical variables.All variables were evaluated at basal time and after 12 months of treatment, and percentage changes from baseline were evaluated at the end of the treatment in both genistein and placebo patients to determine the differences between groups.The Kolmogorov-Smirnov test for normality was performed to evaluate normal distribution. Since some of the numerical variables were not normally distributed and the low sample number did not guarantee valid asymptotic results, a non-parametric approach was used.The U Mann–Whitney test for independent values was applied to compare characteristics of the randomized subjects, according to treatment group. In addition, differences within group for paired measurements were tested by the Wilcoxon signed-rank test analysis.p < 0.05 was considered statistically significant.Statistical analyses were performed using Statistical Package for Social Science  software for Windows package. A total of 22 patients, aged 55 (IQ 6) years, were enrolled from the main randomized controlled trial: 11 from the genistein and 11 from the control group, respectively. No differences in clinical, laboratory, or morphofunctional values between groups were shown at basal. Adherence to diet and exercise was similar between groups. All patients met the criteria for MetS diagnosis. Eighteen patients (82%), nine in each group, showed mild to moderate systemic hypertension with no differences in systolic-diastolic mean pressure between groups. Waist circumference >88 cm was measured in eight (73%) genistein patients and nine (82%) controls (ns). Five (45%) and six (54%) patients were obese in the genistein and placebo groups, respectively. The characteristics of patients in each group at basal and after 12 months are described in p = 0.007), visfatin (p = 0.016), and homocysteine (p = 0.034) significantly decreased in the genistein group compared to the controls. Conversely, serum adiponectin increased in the genistein, but not significantly, compared to the control group at the end of the treatment (All patients completed the study. Genistein levels increased from 15 nmol/L (95%CI 7.3–22.6) at baseline to 780 nmol/L (95%CI 741.7–818.3) at 12 months in treated subjects. BMI and waist values were similar at the end of follow-up in both groups. Resting blood pressure was on target in the majority of patients (90%) and no differences from basal to the end of follow-up or between groups were observed. Fasting glucose and insulin levels were similar at the beginning and at the end of follow-up in both groups. After 12 months of treatment, HOMA-IR (reatment . Changesp = 0.040) and LA fractional area change (p = 0.034) significantly increased in the genistein patients compared the to controls during the treatment.Adequate ultrasound imaging was attained from each patient. Changes in cardiac morphology and function are described in p = 0.009), tissue systolic wave velocity at lateral mitral annulus (p = 0.022), LA volume (p = 0.041), LA fractional area change (p = 0.035), and PALS (p = 0.021) also significantly improved in genistein-treated patients compared to basal, whereas no differences were shown in the control group. Advanced echo-strain analysis showed no relevant changes in LV radial, circumferential, and longitudinal global deformation (Additionally, LV ejection fraction (ormation . No advaNo clinically relevant side effects, flushing, or palpitations were reported. Nobody experienced serious arrhythmias or cardiac symptoms.Recent findings indicate that approximately 25% of the USA population shows traits of MetS, and the constellation of symptoms becomes of clinical concern particularly in postmenopausal patients with DM and hyperlipemia, whose CV risk is higher than that in the general population. Moreover, low adherence to treatment with lipid-lowering drugs is particularly high in female patients, strongly influenced by reimbursement criteria revision, and educational programs in primary care result in challenging efficacy in reaching the clinical targets. ,9,24,25.Our group has previously recognized an improvement in the HOMA-IR and several markers of CV risk of MetS postmenopausal patients treated with genistein ,15,16. FUsing the strain deformation analysis, the most advanced technique to discover early and subclinical LV impairment at the present time , our resTherefore, the present study suggests that genistein could also reduce the LA afterload and potential dysfunction. In fact, hypertensive, diabetic, and overweight patients have an increased risk of atrial dysfunction. Significant changes in LA volume and longitudinal deformation might contribute to the reduction of LA dilatation, fibrosis, and the occurrence of atrial fibrillation, regardless of the loading conditions at the time of examination ,28.The cardioprotective effects of genistein could be partially justified by the improvement in the adipokine profile. Adiponectin increased significantly over the 12 months in both groups and the change was not significantly different between groups. Adiponectin promotes insulin-sensitizing effects and peripheral glucose use, as previously reported . Low cirOn the contrary, the pro-inflammatory visfatin was reduced by genistein after one year of treatment. Visfatin increase in type-2 DM patients was related to heart failure and acute coronary syndromes ,37,38,39Among the pro-inflammatory factors, homocysteine, which has been suggested as an independent risk factor for endothelial dysfunction and atherosclerosis , was alsDespite the intriguing present results, some limitations of the study should be taken into account. Our results were obtained from a population without signs of cardiac dysfunction and all women were of Caucasian origin, thus we do not know if the same effects could be reproduced in different ethnic groups. The small sample size is a limitation of the present study and no definitive conclusions can be drawn from our proof of concept study. However, this study was able to demonstrate, for the first time, that genistein significantly improved cardiovascular function in postmenopausal women with metabolic syndrome. Accordingly, using this preliminary information, a future larger study expressly designed to evaluate the effect of genistein on cardiac function is encouraged.In conclusion, our preliminary data suggest that a daily supplementation with 54 mg of pure genistein improves both LA remodeling and LV function in postmenopausal women with MetS.


The accuracy of blood pressure measurement is variable in office-based settings. Even when staff training programs are effective, knowledge and skills decay over time, supporting the need for ongoing staff training. We evaluated whether a web-based continuing education program in blood pressure measurement reinforced knowledge and skills among clinical staff and promoted sustainability of an existing quality improvement program.Medical assistants and nurses at six primary care clinics within a health system enrolled in a 30-min online educational program designed to refresh their knowledge of blood pressure measurement. A 20-question pre- and post-intervention survey addressed learners’ knowledge and attitudes. Direct observation of blood pressure measurement technique before and after the intervention was performed. Differences in responses to pre- and post-module knowledge and attitudes questions and in observation data were analyzed using chi-square tests and simple logistic regression.p < 0.01). Scores improved significantly among staff from all job types. Licensed practical nurses and staff who had been in their current job at least a year were more likely to answer questions correctly than registered nurses and those in their current job less than a year. Attitudes toward correct blood pressure measurement were high at baseline and did not improve significantly. Prior to the intervention, staff adhered to 9 of 18 elements of the recommended technique during at least 90% of observations. Following the program, staff was more likely to explain the protocol, provide a rest period, measure an average blood pressure, and record the average blood pressure, but less likely to measure blood pressure with the arm at heart level and use the right arm.All 88 clinical staff members participated in the program and completed the evaluation survey. Participants answered 80.6% of questions correctly before the module and 93.4% afterwards  contains supplementary material, which is available to authorized users. Office-based blood pressure measurement is variable, even among clinical staff accustomed to measuring blood pressure –3. FailuHowever, implementation and sustainability of quality improvement programs such as these may be hindered by factors such as lack of integration with existing workflow, degradation of knowledge or skills, lack of resources, and competing demands . For exaInstitutionalisation refers to the process by which organizations provide the resources and conditions needed to support a new practice. Routinisation refers to the process by which a new practice becomes a routine activity for workers within that organization. In other words, a program’s sustainability depends both on the extent to which an organization integrates a new practice into its physical infrastructure, policies, and management activities; and on workers developing a culture in which the new practice is treated as, “the way we do things here.” Although both conditions must be present to ensure a new practice’s sustainability, organizational leaders typically have more direct control over processes related to institutionalisation [Sustainability, defined as “making an innovation routine until it reaches obsolescence,” may be conceptualized as depending on two conditions: institutionalisation and routinisation , 16. InsWeb-based training has gained popularity as a modality for delivering up-to-date, standardized, accessible content that can be integrated with existing training systems, facilitating both institutionalisation across multiple sites and routinisation . Web-basWe designed, implemented, and evaluated a concise web-based educational program to improve knowledge, skills, and attitudes in blood pressure measurement and use of an automated device among nurses and medical assistants in ambulatory care. In this paper we report on the effectiveness as well as the institutionalisation of this intervention.The study was conducted as part of Project ReD CHiP (Reducing Disparities and Controlling Hypertension in Primary Care), a pragmatic trial designed to evaluate multiple interventions for improving blood pressure control and reducing hypertension-related racial disparities conducted in six primary care practices within the Johns Hopkins Community Physicians (JHCP) health system .In 2011, approximately 2 years prior to this study, we trained clinic staff to use the Omron HEM-907XL automated blood pressure measurement devices in a manner consistent with AHA guidelines . As partWe conducted a pre- and post-intervention assessment of knowledge, attitudes, and behaviors among JHCP staff who participated in this online training program. All certified medical assistants (CMAs), licensed practical nurses (LPNs), and registered nurses (RNs) at intervention practices were invited to enroll. Prior to enrolling in this study, all staff members had already been trained and deemed proficient in performing the ReD CHiP blood pressure measurement process, including use of the automated device, which had become the study clinics’ standard blood pressure measurement technique. Initial training at hire consisted of group didactics and individual tests of proficiency via direct observation by JCHP nurse educators.This study was approved and HIPAA waiver granted by the Institutional Review Board at Johns Hopkins University School of Medicine (NA_00037622) and the Johns Hopkins Community Physicians Education Committee. As the procedures were classified by the IRB as comprising quality improvement endeavors, written consent was not obtained.The training program consisted of two 15-min videos and 20 pre- and post-module multiple choice questions that were delivered via Course Development , an online educational platform that was available to the entire health system. All questions were vetted by program leadership and the web development team. For this study, clinical staff members viewed the videos during a 1 month period between April–May, 2013 and were required to score ≥ 80% on knowledge questions to pass. Those who did not score at least 80% were required to re-watch the training modules and re-take the post-module test. Module topics included the rationale behind blood pressure measurement, patient positioning, importance of a rest period and taking multiple measurements, key features of the automated device, troubleshooting device errors, and measuring blood pressure in emergency settings and special populations such as obese and physically disabled patients. To promote peer validation, two CMAs from one of the practices demonstrated correct blood pressure measurement techniques in the training videos [Knowledge and attitude outcomes were assessed using pre- and post-module questions, which consisted of a 15-question knowledge test and a 5-item survey of participants’ attitudes towards the blood pressure measurement program  observed a semi-random convenience sample of CMAs measuring blood pressure during the 4–8 weeks prior to and after the intervention, with a goal of observing between 2 and 3 patients per CMA at the clinical site. RAs were instructed to obtain observations during both morning and afternoon sessions throughout the week. RAs approached the first patient who presented to the clinic for registration. If the patient agreed to being observed, RAs collected demographic information and accompanied the patient to the exam room, where the RA recorded observations about blood pressure measurement using a structured form . Variables for observer, site, and time of day also were recorded with direct observations.Responses to knowledge questions were classified as correct or incorrect and tallied by individual participant and overall by pre- or post-module. For behavior outcomes, independent variables were observer and site. Dependent variables were aspects of blood pressure measurement. After the intervention, we learned that an incorrect response had been posted in the pre-assessment but not the post-assessment. The question, regarding patient positioning, gave the correct answer as “the patient’s arm should be held away from his/her body” rather than “the patient’s back should be supported during blood pressure measurement.” This question was therefore removed from data analysis.We also conducted a post-hoc, secondary analysis to assess for links between when an education topic was delivered, duration of time allocated to that topic or quality of educational content, and staff members’ knowledge. To assess timing and duration of an educational topic, we coded the time when each aspect of blood pressure measurement technique was introduced, and the duration of time allocated to discussing a given technique. To assess quality of educational content, we first coded whether the module only verbally described an aspect of recommended blood pressure measurement technique or whether it also showed the underlying reason for why that aspect of technique is important. We also coded content on whether the module described a given aspect of technique verbally, visually, with written descriptors, or with a combination of these methods.Differences in responses to pre- and post-module knowledge and attitudes questions and in observation data were analyzed using chi-square tests and simple logistic regression. STATA 11IC  was used to perform all analyses.All 88 invited clinical staff completed the continuing education program including the pre- and post-test  (Table p < 0.01) (Table p = 0.04). Demographic factors including age, gender, race and ethnicity were not associated with higher scores. No baseline differences in knowledge were found between the 3 sites with predominantly underserved populations and the other 3 sites. No correlation was seen between time allocated to the learning objective in the video and score on the knowledge assessment. All learning objectives were provided using verbal plus visual and/or text-based instruction, and all except one provided the reasoning for the technique as well as the recommendation.Mean attitudes scores toward correct blood pressure measurement was positive at baseline (mean score 4.2 out of 5) and did not improve significantly post-module , measure an average blood pressure , provide a rest period prior to blood pressure measurement , and record in the electronic medical record (EMR) the average of 3 readings . Following training, staff was less likely to measure blood pressure with the arm at heart level  and use the right arm to measure blood pressure ; patients were less likely to remain still during cuff inflation .Two hundred ten observations were completed, 122 (2.7 observations per CMA) prior to the continuing education program and 88 (2 observations per CMA) subsequently Table . Prior tProvider and staff education are a critical component of implementing and institutionalizing quality improvement programs. Health system leaders must disseminate information about new initiatives, protocols, and techniques effectively in order to ensure that clinicians and staff members provide standardized care across settings . Major bThis study highlights important features of online education through the perspective of a program designed to improve blood pressure measurement. Knowledge of correct blood pressure measurement technique improved significantly among both medical assistants and nurses at these practices following a brief online continuing education program. Direct observation data revealed that following completion of the program clinical staff was significantly more likely to explain the protocol to patients, provide a rest period prior to blood pressure measurement, and measure and record the average blood pressure, but less likely to measure blood pressure with the arm at heart level and to use the right arm to measure blood pressure.Sustainable healthcare interventions tend to be those that have a defining mission, are well integrated into the organizational culture, have an institutional champion, are adaptable, and can be conducted without a strain on existing resources , 23. OurWe found baseline knowledge gaps in basic blood pressure measurement among active clinical staff, even though all had been deemed proficient in the ReD CHiP program’s techniques at program implementation or at the time of hire (if they were employed after implementation). This is consistent with prior literature demonstrating knowledge gaps among outpatient staff , 2. The The training program did not improve attitudes towards accurate blood pressure measurement. Baseline attitudes toward accurate blood pressure measurement were quite high, perhaps due to ongoing training associated with the quality improvement project. Formats other than online training may be more effective in changing attitudes toward effective blood pressure measurement. Awareness of organization and site-level barriers and tailoring interventions to address these obstacles may be one way to change attitudes and behaviors of clinical staff .Direct observation data revealed that completing the training program was associated with improvement in certain steps in the blood pressure protocol, including explaining the protocol to patients, providing a rest period, use of average mode, and recording the average reading in the EMR. Several of these were linked behaviors, as the use of average mode on the device included a rest period and calculated the average blood pressure for recording in the EMR. Subsequent to the training, staff was less likely to use the right arm for blood pressure measurement and to support the arm at heart level. This latter point may be due to the incorrect response recorded during the pre-assessment. Failure to emphasize this information in the training program may also be responsible. Studies of both online and in-person training programs have described a decrement in immediate post-program knowledge gains back to pre-training values several months following the program, indicating a role for supervised practice to promote knowledge retention , 26.Limitations to this study include short follow-up time to assess knowledge, attitudinal, and behavioral outcomes, and a single health system in one specialty. We do not know the generalisability of our findings to other specialties or practices, nor whether knowledge gains were maintained among staff. As this training program was purely an educational intervention and did not address other potential barriers to blood pressure control such as knowledge of guidelines and clinical inertia, we do not know whether improvements in knowledge and behaviors will translate to improved blood pressure control. Prior studies have shown that adherence to AHA blood pressure guidelines impacts treatment decisions as well as measured blood pressure values . The HawIn conclusion, a brief online continuing education program, integrated into an existing organizational training structure, was associated with improvements in knowledge of correct blood pressure measurement techniques, explaining behaviors to patients, and taking multiple measurements using an automated blood pressure device among medical assistants and nurses at six practice sites. To our knowledge, this is the first published study to address use of an online educational program towards sustainable quality improvement across a health system. Such training holds the promise of promoting sustainability of education that requires ongoing reinforcement or knowledge. However, improving attitudes and skills may require a multimodal approach, including a combination of web-based and live training tailored to the existing organizational culture.