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Background In the ‘Die Deutsche Diabetes Dialyse Studie’ (4D Study), treatment of patients with type 2 diabetes mellitus (T2DM) on haemodialysis (HD) with atorvastatin compared with placebo had no significant effect on the first composite primary major adverse cardiovascular event (MACE) endpoint of death from cardiac causes, fatal stroke, non-fatal myocardial infarction or non-fatal stroke. In this study we analysed first and recurrent events in 1255 patients from the 4D Study. Methods We conducted an event history analysis to investigate the effects of previous clinical events on the risk of different endpoints in the total patient group and after stratification by randomization group. Results During a median follow-up of 4 years, a total of 548 MACEs occurred, with 469 first and 79 recurrent events. The most frequent event was sudden cardiac death, followed by death due to infection/sepsis. Of the 548 total MACEs, 260 occurred in the atorvastatin group and 288 in the placebo group [hazard ratio 0.91 (95% confidence interval 0.76–1.07), P = .266]. Interestingly, analyses of the baseline hazard functions for first and recurrent events as a function of time after randomization demonstrated that the risks of the composite primary endpoint continually increased in the placebo group with increasing time in the study, whereas the risk in the atorvastatin group remained constant after ≈1.5 years. Conclusion This recurrent and total event analysis from the 4D Study underscores the high risk of sudden cardiac death and death due to infection/sepsis in patients with T2DM receiving HD and raises the hypothesis that atorvastatin may stabilize cardiovascular risk only after 1–2 years in this high-risk population.

Background The five-year mortality rate for haemodialysis patients is over 50%. Acute and chronic disturbances in salt and fluid homeostasis contribute to poor survival and are established as individual mortality risk factors. However, their interaction in relation to mortality is unclear. Methods We used the European Clinical Database 5 to investigate in a retrospective cohort analysis the relationship between transient hypo- and hypernatremia, fluid status and mortality risk of 72 163 haemodialysis patients from 25 countries. Incident haemodialysis patients with at least one valid measurement of bioimpedance spectroscopy were followed until death or administrative censoring from 1 January 2010 to 4 December 2020. Fluid overload and depletion were defined as > 2.5 Liters above, and −1.1 liters below normal fluid status, respectively. N = 2 272 041 recorded plasma sodium and fluid status measurements were available over a monthly time grid and analysed in a Cox regression model for time-to-death. Results Mortality risk of hyponatremia (plasma sodium Conclusions Plasma sodium and fluid status act independently as risk factors on mortality. Patient surveillance of fluid status is especially important in the high-risk subpopulation of patients with hyponatremia. Prospective patient-level studies should examine the effects of chronic hypo-, and hypernatremia, risk determinants, and their outcome risk.

We aimed to systematically review and meta-analyze the association of employees working in various kinds of open-plan offices with sick leave data, compared to those working in traditional cell offices. Databases of PubMed, PubPsych, and Psyndex were systematically searched following the PRISMA statement. Pooled summary estimates of odds ratio (OR) were calculated comparing sick leave of employees in cell offices with those working in small open-plan offices (4-9 people), and those in various open-plan office solutions (≥ 4 people). We used Forest plots visualizing study-specific estimates and the pooled fixed and random effects estimators. Five studies were identified (2008-2020) with a total of 13,277 (range 469-6,328) participants. Compared with employees working in cell offices, those working in small open-plan offices were associated with higher odds of sick leave days (OR=1.27; 95% CI 0.99-1.54; p=0.046) as well as those working in various kinds of open-plan offices with ≥ 4 colleagues (OR=1.24; 95% CI 0.96-1.51; p=0.004). Our results are consistent with those of earlier reviews focusing on other effects of open-plan office solutions such as health and well-being. Different solutions for office design and architectural lay-out should be the focus of future studies to balance pros and cons of open-plan offices.

BACKGROUND AND AIMS Chronic HD-patients have a 50% 5-year survival and unphysiological fluid and sodium shifts are key pathophysiological contributors. Several studies have shown that hyponatremia is associated with worse outcomes in haemodialysis patients. However, the association of all-cause mortality with volume status in hyponatremic patients is uncertain. Body composition monitoring has provided a more precise tool to estimate fluid status in dialysis patients. The primary aim of this international observational study performed in a large patient database (EUCLID5) was to quantify the association between salt exposure, fluid overload (FO) and mortality risk in haemodialysis patients. METHOD We included 71 706 incident haemodialysis patients from 1 January 2010 to 4 December 2020 in an extended Cox regression model for a time to death analysis. Exposure variables were defined as predialysis serum sodium and fluid overload (in liters as determined by the BCM—Body Composition Monitor using bioimpedance spectroscopy) on a monthly time grid. Effect modifiers, mediators, confounders and predictors were defined a priori. Adults were included with at least one valid BCM measurement within 3 months from first haemodialysis treatment and followed up until death or administrative censoring. All patients included in the study cohort were treated in the NephroCare–FMC dialysis centre network operating in 26 countries. Data were retrieved from the central EuCliD5 database. RESULTS In hyponatremic patients (serum sodium 90th percentile of physiological hydration), was increased by 56% [HR = 1.56 (1.27–1.93)] in underhydrated patients (142 mmol/L), (Table 1). Generally, the risk increased with rising FO and declining sodium concentration. CONCLUSION The observed associations to the risk of death reflecting the interplay between states of hypo-, iso- and hypernatremia and states of under, normal and over hydration deserve further study to understand the underlying complex mechanisms and identify therapeutic approaches. When assessing the risk level of different sodium concentrations, fluid status should be taken into account.

There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis.

Purpose Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. Patients and methods Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. Results In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. Conclusion According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.

Background Soluble suppression of tumorigenesis-2 (sST2) is a strong prognostic biomarker of cardiovascular (CV) disease. End-stage kidney disease (ESKD) patients are at high risk of CV events and infections. Herein we investigated the utility of sST2 to predict all-cause and cause-specific mortality in haemodialysis (HD) patients with diabetes mellitus. Methods sST2 concentrations were measured in plasma samples of 1196 participants of the German Diabetes and Dialysis (4D) study who had type 2 diabetes mellitus and received maintenance HD for ESKD. Hazard ratios (HRs) for prespecified, adjudicated endpoints were determined according to sST2 levels at baseline by multivariate Cox proportional hazards analysis. Results Participants (mean age 66 years, 54% male) had a median sST2 concentration of 25 ng/mL and were followed up for 4 years. After adjustment for possible confounders, participants with sST2 concentrations in the highest (>32.6 ng/mL) compared with the lowest ( Conclusions In HD patients with diabetes mellitus, high concentrations of sST2 were strongly and independently associated with an increased risk of all-cause mortality, CV mortality and death due to infection but not non-fatal CV events.

Background The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. Methods To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. Results A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. Conclusions Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.

BackgroundAbsence from work due to sickness impairs organizational productivity and performance. Even in organizations with perfect work conditions, some inevitable baseline sickness absence exists amongst working populations. The excess sickness absence observed above this baseline rate has become the focus of traditional health promotion efforts, addressing preventable physical illness, health behavior and mental health at the personal level. However, a health and safety approach following the TOP-rule would consider work-group psychosocial work characteristics as a potential risk factor amenable to organizational measures. To date, there is a scarcity of studies relating psychosocial work characteristics to possible reduction of excess sickness-absence rates.MethodsWe aimed to estimate the potentially avoidable excess fraction of absence attributable to work-group psychosocial characteristics. We considered work-group averaged perception of psychosocial work characteristics as a proxy to the methodologically elusive objective assessment of organizational characteristics. Participants were recruited from multiple sites of a German automotive manufacturer with individuals nested within work groups. We predicted 12-month follow-up work-group sickness absence rates using data from a baseline comprehensive health examination assessing work characteristics, health behavior, and biomedical risk factors. We considered the quartile of work-groups yielding favorable psychosocial work characteristics as a realistic existing benchmark. Using the population attributable fraction method we estimated the potentially amenable sickness absence from improving work-group psychosocial characteristics.ResultsData from 3992 eligible participants from 29 work groups were analyzed (39% participation rate, average age 41.4 years (SD = 10.3 years), 89.9% males and 49% manual workers.). Work-group absence rates at follow up varied from 2.1 to 8.9% (mean 5.1%, 11.7 missed days). A prediction model of seven psychosocial work characteristics at the work group level explained 70% of the variance of future absence rates. The estimated reduction from improving psychosocial work characteristics to the benchmark level amounted to 32% of all sickness absence, compared to a 31% reduction from eliminating health behavioral and medical risk factors to the benchmark target.ConclusionsPsychosocial characteristics at the work-group level account for a relevant proportion of all sickness absence. Health promotion interventions should therefore address psychosocial characteristics at the work group level.

Mortality is high among patients undergoing hemodialysis for whom cardiac troponin concentration is a strong predictor of outcome. Modern troponin assays allow measurement of very low concentrations.Using data from a randomized controlled trial, a cohort analysis to evaluate the prognostic value of very low cardiac troponin T (TnT) concentrations.1,255 patients with end-stage renal disease and type 2 diabetes mellitus undergoing maintenance hemodialysis from the German Diabetes and Dialysis Study (4D) who had a median follow-up of 4 years.Cardiac TnT was measured using a high-sensitivity assay (hs-TnT) and a conventional assay (conventional TnT) in a subpopulation (n=1,034) with valid measurements for both assays. Outcome measures were all-cause mortality and a composite cardiovascular end point including cardiac death, myocardial infarction, or stroke.Among the 1,034 study participants, 505 died and 377 had a cardiovascular event. Both hs-TnT and conventional TnT concentrations were associated with mortality and cardiovascular events in models adjusted for cardiovascular risk factors and dialysis-associated variables. 455 (44%) patients with very low TnT concentrations (hs-TNT 50ng/L) would have been classified as normal by the conventional TnT assay. Among these patients, hs-TnT concentrations were also associated with mortality.The study of patients with type 2 diabetes may limit generalizability. These findings have not been externally validated.In patients with type 2 diabetes mellitus receiving hemodialysis, cardiac TnT is associated with long-term mortality and cardiovascular outcomes. Concentrations of TnT not measurable with acceptable precision using a conventional TnT assay were associated with a poor prognosis when measured using a high-sensitivity assay.

Background Fluid overload and interdialytic weight gain (IDWG) are discrete components of the dynamic fluid balance in haemodialysis patients. We aimed to disentangle their relationship, and the prognostic importance of two clinically distinct, bioimpedance spectroscopy (BIS)-derived measures, pre-dialysis and post-dialysis fluid overload (FOpre and FOpost) versus IDWG. Methods We conducted a retrospective cohort study on 38 614 incident patients with one or more BIS measurement within 90 days of haemodialysis initiation (1 October 2010 through 28 February 2015). We used fractional polynomial regression to determine the association pattern between FOpre, FOpost and IDWG, and multivariate adjusted Cox models with FO and/or IDWG as longitudinal and time-varying predictors to determine all-cause mortality risk. Results In analyses using 1-month averages, patients in quartiles 3 and 4 (Q3 and Q4) of FO had an incrementally higher adjusted mortality risk compared with reference Q2, and patients in Q1 of IDWG had higher adjusted mortality compared with Q2. The highest adjusted mortality risk was observed for patients in Q4 of FOpre combined with Q1 of IDWG [hazard ratio (HR) = 2.66 (95% confidence interval 2.21–3.20), compared with FOpre-Q2/IDWG-Q2 (reference)]. Using longitudinal means of FO and IDWG only slightly altered all HRs. IDWG associated positively with FOpre, but negatively with FOpost, suggesting a link with post-dialysis extracellular volume depletion. Conclusions FOpre and FOpost were consistently positive risk factors for mortality. Low IDWG was associated with short-term mortality, suggesting perhaps an effect of protein-energy wasting. FOpost reflected the volume status without IDWG, which implies that this fluid marker is clinically most intuitive and may be best suited to guide volume management in haemodialysis patients.

BACKGROUNDThe inverse relationship between HDL cholesterol and cardiovascular mortality is weakened in coronary artery disease (CAD). We aimed to investigate the associations of HDL particle concentrations with cardiovascular mortality and the impact of CAD on these associations. We also sought to comparatively evaluate HDL cholesterol and HDL particle concentrations in predicting cardiovascular mortality.METHODSTotal and subclass HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy in 2290 participants of the LUdwigshafen RIsk and Cardiovascular Health study referred for coronary angiography. The participants were prospectively followed over a median (interquartile range) duration of 10.0 (6.1–10.6) years.RESULTSThe mean (SD) age of the participants (1575 males, 715 females) was 62.9 (10.4) years; body mass index, 27.6 (4.1) kg/m2; HDL cholesterol, 39 (11) mg/dL [1 (0.29) mmol/L]; and total HDL particle concentration, 24.1 (5.8) μmol/L. Of the participants, 434 died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (hazard ratio for third vs first tertile = 0.55, P < 0.001). This association was primarily mediated by small HDL particles (P < 0.001). Adding total or small HDL particle concentrations rather than HDL cholesterol to multivariate prediction models improved performance metrics for cardiovascular mortality. The presence of CAD had no impact on the associations between HDL particle concentrations and cardiovascular mortality.CONCLUSIONSHigh HDL particle concentration is consistently and independently of CAD associated with decreased cardiovascular mortality. Whether the inverse relationship between HDL particle concentration and cardiovascular mortality may be translated into novel therapies is under investigation.

Soluble urokinase plasminogen activator receptor is a novel biomarker strongly predictive of cardiovascular outcomes implicated in the pathogenesis of kidney disease. Soluble urokinase plasminogen activator receptor levels, however, correlate with declining kidney function. It is unclear whether soluble urokinase plasminogen activator receptor levels remain associated with outcomes in patients with ESRD.We measured plasma soluble urokinase plasminogen activator receptor levels in 1175 patients (mean age =66±8 years old, 54% men) with type 2 diabetes mellitus on hemodialysis participating in the German Diabetes and Dialysis Study followed for a median of 4 years for outcomes including all-cause death, cardiovascular events, and infection-related mortality. Survival analysis was performed using stepwise Cox proportional hazards models adjusted for potential confounders. Also, adjustments were made for inflammatory markers (C-reactive protein and leukocyte count) and the oxidative stress marker asymmetric dimethyl arginine to investigate potential mediators of the relationship between soluble urokinase plasminogen activator receptor and outcomes.Median soluble urokinase plasminogen activator receptor levels were 10,521 pg/ml (interquartile range, 9105-12,543 pg/ml). When stratified by tertiles, patients with soluble urokinase plasminogen activator receptor11,633 pg/ml (third tertile) had adjusted 1.6-fold higher mortality (hazard ratio, 1.60; 95% confidence interval, 1.27 to 2.03) compared with those with low soluble urokinase plasminogen activator receptor9599 pg/ml (first tertile). Risks of sudden death and stroke were higher (adjusted hazard ratio, 1.98; 95% confidence interval, 1.27 to 3.09 and adjusted hazard ratio, 1.74; 95% confidence interval, 1.05 to 2.90, respectively), together accounting for higher incidence of cardiovascular events (adjusted hazard ratio, 1.48; 95% confidence interval, 1.15 to 1.89). Associations with outcomes persisted after adjusting for C-reactive protein, leukocyte count, and asymmetric dimethyl arginine. Addition of soluble urokinase plasminogen activator receptor to a risk factor model modestly improved risk discrimination for all-cause death (The association of soluble urokinase plasminogen activator receptor levels with outcomes persists in patients on hemodialysis. Additional study is warranted to characterize the underlying pathways of that association, which may yield opportunities to develop new therapeutic strategies.

BACKGROUND In chronic kidney disease (CKD) arginine vasopressin (AVP) cannot efficiently act via renal V2-receptors. AVP is upregulated leading to augmented activation of V1a- and V1b-receptors, which might contribute to the increase in cardiovascular and infectious complications in CKD. Here, we evaluate copeptin, a surrogate of AVP, and its association with cause specific mortality among patients within the whole spectrum of renal function. METHODS Copeptin was measured in baseline samples from the LURIC (n = 3131 patients with coronary angiograms) and the 4D-Study (n = 1241 type 2 diabetic hemodialysis patients). Patients were stratified into 4 groups: estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2, 60–89 mL/min/1.73 m2, RESULTS Median copeptin increased with decreasing eGFR: 5.6 [interquartile range (IQR), 3.1–8.1] pmol/L (eGFR ≥90 mL/min/1.73 m2), 6.7 (2.9–10.5) pmol/L (eGFR 60–89 mL/min/1.73 m2), 15.3 (6.7–23.9) pmol/L (eGFR CONCLUSIONS Copeptin concentrations were independently associated with coronary, infectious, and all-cause mortality in patients with renal impairment. In patients with normal renal function no significant association was found.

Background/Aims: Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). Methods: We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF Results: All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). Conclusion: Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy.

In children, autonomic nervous function is related to various highly prevalent health problems and might therefore represent an early indicator of ill health.We aimed to investigate the role of early-life exposures and physical activity (PA) as potential determinants of autonomic function at preschool age.We used an existing longitudinal data set of repeated vagal tone measurements (assessed via heart rate recovery (HRR)) and retrospectively assessed early-life exposures in 1052 children (mean age: 59.4months, 47.5% girls) from 52 preschools in Germany recruited from 2008 to 2010.HRR 1min after submaximal exercise served as primary outcome. Through multilevel linear regression analysis adjusted for demographic and socioeconomic factors, we assessed the association between repeatedly measured HRR and pregnancy smoking status, breastfeeding and objectively measured PA.Besides significant regression coefficients for previously described correlates of HRR (sex, age), we could show positive associations of HRR with breastfeeding (six versus zero months: +4.2 beats per minute (BPM), p=0.004) and PA (+1.0BPM for 10min increase of moderate-to-vigorous PA/day, p0.001). Smoking before and during pregnancy showed no significant association with HRR in the total sample. However, we found interactions between sex and smoking before and during pregnancy as well as between sex and breastfeeding, suggesting significant associations with HRR only in girls.Besides PA, early pre- and postnatal exposures seem to have long-lasting effects on children's autonomic function, still recordable at preschool age. Our data suggest that these effects might be sex-dependent.

Aims Haemodialysis patients have high cardiovascular disease risk. Although statins reduce this risk in chronic kidney disease, randomised trials in haemodialysis patients show no benefit. Post-hoc analyses of the German Diabetes Dialysis (4D) study identified patient-specific markers associated with heterogeneous treatment effects. We combined these markers to develop a score for predicting individual effects of statins in these patients. Methods and results We used data from the 4D study, enrolling 1255 haemodialysis patients with type 2 diabetes mellitus, randomised to atorvastatin or placebo and followed for a composite cardiovascular endpoint. We calculated two scores: score 1 based on all 23 predictive markers and score 2 based on 17 clinically accessible markers. Groups stratified by score 1 showed differential treatment effects: for score 31 (466 patients; 38%), it was 0.43 (0.30–0.60), suggesting a benefit. Statins also significantly reduced all-cause mortality in the benefit group. Stratification by score 2 yielded similar results but a smaller group gaining benefit (360 patients). Conclusion Statin effects in haemodialysis patients can be predicted by markers associated with plausible relevant mechanisms including cholesterol metabolism, atherosclerosis, protein energy wasting, or competing risks. In clinical practice, the score could aid in risk stratification, not only to select patients who benefit from statins but also to identify those whom treatment could harm.

Purpose Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. Patients and Methods Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. Results In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. Conclusion According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.

ObjectiveTo systematically review the effect of oral intake of bacterial probiotics on 15 variables related to obesity, diabetes and non-alcoholic fatty liver disease.DesignSystematic review and meta-analysis.Data sourcesMedline, EMBASE and COCHRANE from 1990 to June 2018.Eligibility criteriaRandomised controlled trials (≥14 days) excluding hypercholesterolaemia, alcoholic liver disease, polycystic ovary syndrome and children ResultsOne hundred and five articles met inclusion criteria, representing 6826 subjects. In overweight but not obese subjects, probiotics induced improvements in: body weight (k=25 trials, d=−0.94 kg mean difference, 95% CI −1.17 to −0.70, I²=0.0%), body mass index (k=32, d=−0.55 kg/m², 95% CI −0.86 to −0.23, I²=91.9%), waist circumference (k=13, d=−1.31 cm, 95% CI −1.79 to −0.83, I²=14.5%), body fat mass (k=11, d=−0.96 kg, 95% CI −1.21 to −0.71, I²=0.0%) and visceral adipose tissue mass (k=5, d=−6.30 cm², 95% CI −9.05 to −3.56, I²=0.0%). In type 2 diabetics, probiotics reduced fasting glucose (k=19, d=−0.66 mmol/L, 95% CI −1.00 to −0.31, I²=27.7%), glycated haemoglobin (k=13, d=−0.28 pp, 95% CI −0.46 to −0.11, I²=54.1%), insulin (k=13, d=−1.66 mU/L, 95% CI −2.70 to −0.61, I²=37.8%) and homeostatic model of insulin resistance (k=10, d=−1.05 pp, 95% CI −1.48 to −0.61, I²=18.2%). In subjects with fatty liver diseases, probiotics reduced alanine (k=12, d=−10.2 U/L, 95% CI −14.3 to −6.0, I²=93.50%) and aspartate aminotransferases (k=10, d=−9.9 U/L, 95% CI −14.1 to -5.8, I²=96.1%). These improvements were mostly observed with bifidobacteria (Bifidobacterium breve, B. longum), Streptococcus salivarius subsp. thermophilus and lactobacilli (Lactobacillus acidophilus, L. casei, L. delbrueckii) containing mixtures and influenced by trials conducted in one country.ConclusionsThe intake of probiotics resulted in minor but consistent improvements in several metabolic risk factors in subjects with metabolic diseases.Trial registration numberCRD42016033273.

The cardioprotective effect of HDL is thought to be largely determined by its cholesterol efflux capacity, which was shown to inversely correlate with atherosclerotic cardiovascular disease in populations with normal kidney function. Patients with ESRD suffer an exceptionally high cardiovascular risk not fully explained by traditional risk factors. Here, in a post hoc analysis in 1147 patients with type 2 diabetes mellitus on hemodialysis who participated in the German Diabetes Dialysis Study (4D Study), we investigated whether the HDL cholesterol efflux capacity is predictive for cardiovascular risk. Efflux capacity was quantified by incubating human macrophage foam cells with apoB-depleted serum. During a median follow-up of 4.1 years, 423 patients reached the combined primary end point (composite of cardiac death, nonfatal myocardial infarction, and stroke), 410 patients experienced cardiac events, and 561 patients died. Notably, in Cox regression analyses, we found no association of efflux capacity with the combined primary end point (hazard ratio [HR], 0.96; 95% confidence interval [95% CI], 0.88 to 1.06; P=0.42), cardiac events (HR, 0.92; 95% CI, 0.83 to 1.02; P=0.11), or all-cause mortality (HR, 0.96; 95% CI, 0.88 to 1.05; P=0.39). In conclusion, HDL cholesterol efflux capacity is not a prognostic cardiovascular risk marker in this cohort of patients with diabetes on hemodialysis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Despite increasing evidence in favor of prophylactic valganciclovir treatment in kidney transplant recipients for the prevention of cytomegalovirus (CMV) infection, the impact of preemptive vs. prophylactic treatment on long-term clinical outcomes is unclear. In this retrospective study, 187 kidney transplant recipients with serologic intermediate-risk constellation (recipient CMV IgG positive) received either preemptive or prophylactic treatment with valganciclovir. Patient survival (primary endpoint), graft survival, viremia rates, and other CMV-related outcomes were analyzed. Prophylactic therapy reduced the rates for CMV viremia during the first year (hazard ratio: 0.48, 95% confidence interval [CI] 0.30-0.75; p < 0.001). There was a trend for higher three-yr patient mortality in the prophylactic group (hazard ratio: 5.08, 95% CI 0.62-41.3; p = 0.091), and the rate of graft loss was not reduced (hazard ratio: 0.93, 95% CI 0.32-2.68; p = 0.894). Estimated glomerular filtration rate over three yr was on average 6.8 mL/min/1.73 m(2) lower in the prophylactic group (95% CI -11.68 to -1.81; p = 0.007) using a multivariate random effects model but showed more improvement over time. Prophylactic valganciclovir treatment reduced the rate of CMV infections during the first year post-transplant but no effects of prophylactic treatment on patient and graft survival or kidney function over three yr were observed.

Background and objectives Impairment of HDL function has been associated with cardiovascular events in patients with kidney failure. The protein composition of HDLs is altered in these patients, presumably compromising the cardioprotective effects of HDLs. This post hoc study assessed the relation of distinct HDL-bound proteins with cardiovascular outcomes in a dialysis population. Design, setting, participants, & measurements The concentrations of HDL-associated serum amyloid A (SAA) and surfactant protein B (SP-B) were measured in 1152 patients with type 2 diabetes mellitus on hemodialysis participating in The German Diabetes Dialysis Study who were randomly assigned to double-blind treatment of 20 mg atorvastatin daily or matching placebo. The association of SAA(HDL) and SP-B(HDL) with cardiovascular outcomes was assessed in multivariate regression models adjusted for known clinical risk factors. Results High concentrations of SAA(HDL) were significantly and positively associated with the risk of cardiac events (hazard ratio per 1 SD higher, 1.09; 95% confidence interval, 1.01 to 1.19). High concentrations of SP-B(HDL) were significantly associated with all-cause mortality (hazard ratio per 1 SD higher, 1.10; 95% confidence interval, 1.02 to 1.19). Adjustment for HDL cholesterol did not affect these associations. Conclusions In patients with diabetes on hemodialysis, SAA(HDL) and SP-B(HDL) were related to cardiac events and all-cause mortality, respectively, and they were independent of HDL cholesterol. These findings indicate that a remodeling of the HDL proteome was associated with a higher risk for cardiovascular events and mortality in patients with ESRD.

ObjectiveOrganizational justice refers to perceived fairness at the workplace. Individual perceptions of injustice have been linked to reduced mental and physical health. However, perceptions of injustice also exist at the aggregate level of departments, reflecting a shared perception, denoted as justice climate. There is evidence that this shared perception independently predicts individual distress levels (e.g., anxiety, depression), which might negatively affect somatic symptom perception and reporting. Hence, the objective of this study was to examine whether individual perceptions of poor justice as well as a poor justice climate are related to elevated somatic complaints. In addition, this study examined if justice climate moderates the relationship between individual-level justice perceptions and somatic symptom reporting.MethodsCross-sectional data from a large industrial manufacturing company was used, involving 1,102 employees in 31 departments. A validated scale covering interactional and procedural justice assessed individual-level organizational justice. A 19-item symptom checklist measured somatic complaints. Multilevel analyses estimated individual-level associations (within-department effects) with somatic complaints, department-level associations (between-department effects), and the cross-level interaction of both.ResultsIndividual-level justice perceptions were negatively associated with somatic complaints. Collective justice climate was likewise significantly associated with somatic complaints. There was no indication for a moderation effect of justice climate.ConclusionA poor justice climate correlated positively with individual somatic complaints while controlling for individual perceptions, i.e., above and beyond individual justice perceptions. These findings may imply that interventions targeting department-level perceptions of justice may have the potential to reduce individual somatic complaints beyond the effects of individual-level interventions.

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p

Homoarginine is a novel biomarker for cardiovascular diseases. In the present large cohort study, we evaluate how homoarginine is linked to kidney function and examine the potential interaction of homoarginine and kidney function as predictors of cardiovascular outcomes.Serum homoarginine (mean: 2.41 ± 1.05 µmol/L), cystatin C and creatinine-based estimated GFR (eGFR, mean: 86.2 ± 23.0 mL/min per 1.73 m(2)) were measured in 3037 patients (mean age: 62.8 ± 10.6 years; 31.5% women) who were referred to coronary angiography.Homoarginine was positively associated with eGFR (age- and gender-adjusted partial correlation coefficient: 0.20, P0.001); using multiple regression analysis, eGFR emerged as an independent predictor of serum homoarginine (β = 0.10, SE 0.01, P0.001). Overall cardiovascular mortality was 18.5% (563 cardiovascular deaths) after 9.9 years. Multivariate Cox proportional hazard analysis revealed that compared with participants in the highest gender-specific homoarginine tertile, those in the lowest tertile were at increased risk of cardiovascular death [multivariate-adjusted HR 1.47; 95% confidence interval (95% CI) 1.15-1.87, P = 0.002]. After adjustment for confounders, both homoarginine and eGFR were associated independently with cardiovascular mortality, with a strong synergistic interaction (P for interaction 0.005). After stratifying the cohort into persons with eGFRs60 and ≥60 mL/min per 1.73 m(2), there was a stronger association between homoarginine and cardiovascular mortality in patients within eGFR below 60 (mean: 46.5 ± 12.0 mL/min per 1.73 m(2); HR per log SD increment of homoarginine 0.78; 95% CI 0.65-0.95, P = 0.013) compared to those with eGFR values ≥60 mL/min per 1.73 m(2). Subgroup analysis revealed that homoarginine is exclusively associated with death due to heart failure in subjects with eGFR values60 mL/min per 1.73 m(2) (HR per log SD 0.56; 95% CI 0.37-0.85; P = 0.006).Low homoarginine is strongly related to decreased kidney function, adverse cardiovascular events and death due to heart failure. The relationship between low homoarginine and adverse cardiovascular outcomes is most obvious when kidney function is impaired.

Background Previous studies on physical activity interventions in preschools have reported limited effectiveness. Participatory community-based approaches hold promise for increasing intervention effectiveness and involving parents as key stakeholders in a sustainable way. Purpose To assess whether a participatory parent-focused approach using parents as agents of behavioral change enhances the efficacy of a preschool physical activity (PA) intervention. Design Two-armed, cluster-RCT with preschool as unit of randomization and children as unit of analysis. Setting/participants 39 South German preschools applying for an existing state-sponsored PA program with 826 children (52% boys, aged 5.0±0.2 years), with 441 allocated to the intervention arm. Intervention Control preschools received a state-sponsored program consisting of twice-weekly gym classes over 6 months. In intervention preschools, this program was augmented by motivating parents to develop and implement their own project ideas for promoting children's PA. Main outcome measures Primary outcomes included mean accelerometry counts and time spent in moderate- to vigorous-intensity PA or sedentary behavior. Secondary outcomes were BMI, percentage body fat, quality of life, sleep quality, and general health. Outcomes were measured at baseline and at 6 and 12 months in both study arms (time period: 2008–2010). Using an intention-to-treat-analysis, linear multilevel regression models assessed change over time and across study arms, adjusted for age, gender, season, and preschool location. Analysis was conducted in 2011. Results In 15 intervention preschools, parents implemented 25 PA projects. Compared with controls, intervention arm children were 11 minutes less sedentary per day (95% CI=5.39, 17.01, p =0.014); had significantly more mean accelerometry counts (1.4 counts/15 seconds [95% CI=0.22, 2.54], p =0.019); and showed benefits in perceived general health and quality of life. All other outcomes showed no difference between study arms. Conclusions A participatory preschool intervention focusing on parents as agents of behavioral change may be able to promote PA and reduce sedentary behavior in preschoolers. These benefits may go beyond the effects of existing nonparticipatory interventions. Trial registration This study is registered at clinicaltrials.gov NCT00987532.

Objectives This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). Background Plant sterol–enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. Methods The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. Results In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247 , rs6576629 , and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376 , rs6576629 , and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. Conclusions High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.

The cardioprotective effect of HDL (High-Density Lipoprotein) is largely determined by its cholesterol efflux capacity, which was shown to correlate inversely with atherosclerotic cardiovascular disease in populations with normal kidney function. Patients with end-stage renal disease suffer an exceptionally high cardiovascular risk not fully explained by traditional risk factors. Here, we investigated in a post-hoc analysis in 1147 patients with type 2 diabetes mellitus on hemodialysis participating in the 4D Study (The German Diabetes Dialysis Study), if the HDL cholesterol efflux capacity is predictive of cardiovascular risk. Efflux capacity was quantified by incubating human macrophage foam cells with apolipoprotein B-depleted serum. During a median follow-up of 4.1 years n=423 patients reached the combined primary endpoint (composite of cardiac death, nonfatal myocardial infarction and stroke), n=410 experienced cardiac events and n=561 died (all-cause mortality). Strikingly, in Cox regression analysis we found no association of efflux capacity with the combined primary endpoint (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.88 – 1.06, p =0.417), cardiac events (HR, 0.92; CI, 0.83-1.02; p =0.108) or all-cause mortality (HR 0.96; 95% CI, 0.88-1.05; p =0.390). In conclusion, HDL cholesterol efflux capacity is not a prognostic cardiovascular risk marker in diabetic patients on hemodialysis.

BACKGROUND: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) persist in the environment and are found in relatively high concentrations in animal livers. Studies in humans have reported inconsistent associations between PFOA and liver enzymes. OBJECTIVES: We examined the cross-sectional association between serum PFOA and PFOS concentrations with markers of liver function in adults. METHODS: The C8 Health Project collected data on 69,030 persons; of these, a total of 47,092 adults were included in the present analysis. Linear regression models were fitted for natural log (ln)-transformed values of alanine transaminase (ALT), γ-glutamyltransferase (GGT), and direct bilirubin on PFOA, PFOS, and potential confounders. Logistic regression models were fitted comparing deciles of PFOA or PFOS in relation to high biomarker levels. A multilevel analysis comparing the evidence for association of PFOA with liver function at the individual level within water districts to that at the population level between water districts was also performed. RESULTS: ln-PFOA and ln-PFOS were associated with ln-ALT in linear regression models [PFOA: coefficient, 0.022; 95% confidence interval (CI): 0.018, 0.025; PFOS: coefficient, 0.020; 95% CI: 0.014, 0.026] and with raised ALT in logistic regression models [with a steady increase in the odds ratio (OR) estimates across deciles of PFOA and PFOS; PFOA: OR = 1.10; 95% CI: 1.07, 1.13; PFOS: OR = 1.13; 95% CI: 1.07, 1.18]. There was less consistent evidence of an association of PFOA and GGT or bilirubin. The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels. CONCLUSIONS: These results show a positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage.

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case-control, five nested case-control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.

Background Diarrhoea remains a leading cause of morbidity and mortality but is difficult to measure in epidemiological studies. Challenges include the diagnosis based on self-reported symptoms, the logistical burden of intensive surveillance and the variability of diarrhoea in space, time and person. Methods We review current practices in sampling procedures to measure diarrhoea, and provide guidance for diarrhoea measurement across a range of study goals. Using 14 available data sets, we estimated typical design effects for clustering at household and village/neighbourhood level, and measured the impact of adjusting for baseline variables on the precision of intervention effect estimates. Results Incidence is the preferred outcome measure in aetiological studies, health services research and vaccine trials. Repeated prevalence measurements (longitudinal prevalence) are appropriate in high-mortality settings where malnutrition is common, although many repeat measures are rarely useful. Period prevalence is an inadequate outcome if an intervention affects illness duration. Adjusting point estimates for age or diarrhoea at baseline in randomized trials has little effect on the precision of estimates. Design effects in trials randomized at household level are usually

SUMMARYThis study investigated individual and contextual factors associated with the duration of diarrhoeal episodes in 693 young children living in a large Brazilian city who were followed-up for at least 3 months. The outcome is analysed as a continuous variable, by means of a hierarchical conceptual model organizing the factors in meaningful blocks. A total of 2397 episodes were recorded (median duration 2 days, interquartile range 1–3 days). Low percentage of households connected to the sewerage system in the neighbourhood, low family purchasing power, high agglomeration, mother aged 6 months.