Interleukin-16 is increased in dialysis patients but is not a cardiovascular risk factor.

Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the hypothesis that plasma oxalate would be associated with cytokine concentrations and cardiovascular outcomes in dialysis patients. In a cohort of 104 US patients with kidney failure requiring dialysis (cohort 1), we measured 21 inflammatory markers. As IL-16 was the only cytokine to correlate with oxalate, we focused further investigations on IL-16. We searched for associations between concentrations of IL-16 and mortality and cardiovascular events in the 4D cohort (1255 patients, cohort 2) and assessed further associations of IL-16 with other uremic toxins in this cohort. IL-16 levels were positively correlated with pOx concentrations (ρ = 0.39 in cohort 1, r = 0.35 in cohort 2) and were elevated in dialysis patients when compared to healthy individuals. No significant association could be found between IL-16 levels and cardiovascular events or mortality in the 4D cohort. We conclude that the cytokine IL-16 correlates with plasma oxalate concentrations and is substantially increased in patients with kidney failure on dialysis. However, no association could be detected between IL-16 concentrations and cardiovascular disease in the 4D cohort.

Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

Reducing sick leave, improving work ability, and quality of life in patients with mild to moderate Long COVID through psychosocial, physiotherapeutic, and nutritive supportive digital intervention (MiLoCoDaS): study protocol for a randomized controlled trial.

BACKGROUND: Following SARS-CoV-2 infection, a relevant proportion of patients suffer from persistent or recurring sequela, even after initially mild primary illness. Many patients experience exhaustion and fatigue, rendering them incapable of working. Long COVID exerts a substantial burden on society and the healthcare system: at least 65 million people are currently affected worldwide. The underlying pathobiology is a complex derangement in several organ systems. To date, causal pharmaceutical therapies remain elusive. Waiting lists for specialist care are long. Rapidly scalable digital interventions offering support for the frequent subgroup of patients with mild to moderate impairment from Long COVID are urgently needed. The MiLoCoDaS study compares three intensities of a potentially rapidly scalable digital intervention aiming to accelerate recovery. The overall objective is to figure out if there is a difference in the effect sizes between these modalities. METHODS: The online intervention uses a learning platform (LMS, TYPO3 framework) comprising 12 sessions of medical, psychological, physiotherapeutic, and nutritional content. The three modalities differ as follows: patient information only (sham intervention, control), information plus interactive digital workbook including practical exercises (digital intervention), and the digital workbook augmented by once-weekly online seminars and discussion groups (person and peer-contact). Eligible patients are 18-67 years old satisfying Long COVID diagnostic criteria. Patients are recruited through primary care physicians and randomly allocated. The primary endpoint is the number of sick leave days during the 6-month observation period; secondary endpoints are patient-reported symptoms, quality of life, and work ability. The study size provides a power of 80% at a type I error of < 0.05 to show an effect size of Cohen = 0.3 between the augmented and the sham intervention (N = 152 per arm, total accounting for attrition N = 600). DISCUSSION: If one of the two interventions is superior to providing information alone, MiLoCoDaS would provide the starting point for a rapidly scalable digital intervention for the frequent and currently underserved patient group with mild to moderate impairment from Long COVID. Several caveats pertain to the heterogeneity of Long COVID manifestation and duration prior to inclusion. It is conceivable that the possible effect of the intervention may differ across subgroups. Therefore, a priori defined secondary analysis will be conducted. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00028964. Registered on 24 August 2022.

Development and validation of a self-regulation scale within the German version of the Early Development Instrument.

BACKGROUND: Early childhood self-regulation (SR) is key for many health- and education-related outcomes across the life span. Kindergarten age is a crucial period for SR development, and within this developmental window, potential SR difficulties can still be compensated for (e.g., through interventions). However, efficient measurement of SR through brief, comprehensive, and easy-to-use instruments that identify SR difficulties are scarce. To address this need, we used items of an internationally applied kindergarten teacher questionnaire-the Early Development Instrument (EDI) - to develop and validate a specific SR measurement scale. METHODS: The psychometric evaluation and validation of the selected SR-items was performed in data collected with the German version of the EDI (GEDI), in two independent data sets - (a) the development dataset, with 191 children, and b) the validation dataset, with 184 children. Both included three- to six-year-old children and contained retest and interrater reliability data. First, three independent raters-based on theory-selected items eligible to form a SR scale from the two SR-relevant GEDI domains "social competence" and "emotional maturity". Second, exploratory and confirmatory factor analysis using structural equation modeling examined the item structure across both data sets. This resulted in a defined SR scale, of which internal consistency, test-retest and interrater reliability, cross-validation, and concurrent validity using correlation and descriptive agreements (Bland-Altman (BA) plots) with an existing validated SR-measuring instrument (the Kindergarten Behavioral Scales) were assessed. RESULTS: Confirmatory factor analysis across both data sets yielded the best fit indices with 13 of the GEDI 20 items initially deemed eligible for SR measurement, and a three-factor structure: a) behavioral response inhibition, b) cognitive inhibition, c) selective or focused attention (RMSEA: 0.019, CFI: 0.998). Psychometric evaluation of the resulting 13-item-GEDI-SR scale revealed good internal consistency (0.92), test-retest and interrater reliability (0.85 and 0.71, respectively), validity testing yielded stability across populations and good concurrent validity with the Kindergarten Behavioral Scales (Pearson correlation coefficient: mean 0.72, range 0.61 to 0.84). CONCLUSIONS: The GEDI contains 13 items suitable to assess SR, either as part of regular EDI developmental monitoring or as a valid stand-alone scale. This short 13-item (G)EDI-SR scale may allow early detection of children with SR difficulties in the kindergarten setting in future and could be the basis for public health intervention planning. To attain this goal, future research should establish appropriate reference values using a representative standardization sample.

Recurrent cardiovascular events in patients with type 2 diabetes and haemodialysis: analysis from the 4D Study.

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.

Renin-angiotensin system inhibitor discontinuation in COVID-19 did not modify systemic ACE2 in a randomized controlled trial.

Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.

Hyponatraemia and fluid overload are associated with higher risk of mortality in dialysis patients.

BACKGROUND: The 5-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 2019. Fluid overload and depletion were defined as >2.5 L above, and -1.1 L 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 <135 mmol/L) was slightly increased when fluid status was normal [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.18-1.35], increased by half when patients were fluid depleted (HR 1.56, 95% CI 1.27-1.93) and accelerated during fluid overload (HR 1.97, 95% CI 1.82-2.12). 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.

Association of open-plan offices and sick leave-a systematic review and meta-analysis.

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.

Soluble suppression of tumorigenesis-2 is a strong predictor of all-cause, cardiovascular and infection-related mortality risk in haemodialysis patients with diabetes mellitus.

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 (<20.1 ng/mL) quartile exhibited a 2-fold higher all-cause mortality risk {[HR 2.06 95% confidence interval (CI) 1.61-2.61]; P < .001}. High sST concentrations (fourth versus first quartile) were strongly associated with the risk of cardiac death [HR 2.29 (95% CI 1.55-3.39); P < .001]. Analysis of individual components of cardiac causes of death showed an increased risk of sudden death [HR 2.24 (95% CI 1.33-3.77); P < .001], death due to myocardial infarction [HR 2.12 (95% CI 0.9-5.0); P = .087] and heart failure [HR 3.34 (95% CI 1.15-9.75); P = .027] in participants with sST2 levels in the highest compared with the lowest quartile. Likewise, participants with the highest sST2 levels had an increased risk of fatal stroke [HR 1.92 (95% CI 1.17-3.14); P = .009] and fatal infections [HR 2.01 (95% CI 1.2-3.37); P = .008]. In contrast to fatal CV events, sST2 was not associated with the risk of non-fatal myocardial infarction [HR 0.68 (95% CI 0.41-1.12); P = .132] or non-fatal stroke [HR 1.28 (95% CI 0.64-2.53); P = .485]. 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.

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET).

BACKGROUND: Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. METHODS: This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. DISCUSSION: Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

A scoring system for predicting individual treatment effects of statins in type 2 diabetes patients on haemodialysis.

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 <26 (458 patients; 36%), the hazard ratio (95% confidence interval) was 1.54 (1.16-2.03), suggesting harm; for 26-31 (331 patients; 26%), it was 1.03 (0.72-1.48), suggesting a neutral effect; and for >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.

High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients.

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.

Estimating the potential reduction in future sickness absence from optimizing group-level psychosocial work characteristics: a prospective, multicenter cohort study in German industrial settings.

BACKGROUND: Absence 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. METHODS: We 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. RESULTS: Data 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. CONCLUSIONS: Psychosocial 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.

Risk factors for retinopathy in hemodialysis patients with type 2 diabetes mellitus.

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.

Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes.

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.

Genetic variants in 17q12-21 locus and childhood asthma in Brazil: Interaction with Varicella zoster virus seropositivity.

BACKGROUND: Asthma is a complex disease with worldwide public health relevance, is related to environmental causes and a genetic predisposition. The chromosomal 17q12-21 locus has been consistently demonstrated to be associated with asthma risk. The effects of variants in the 17q12-21 locus on childhood asthma were first identified in a genome wide- association study. Since that time, those findings have been replicated in different populations but not in South American populations. OBJECTIVE: This study aimed to investigate the role of variants in the 17q12-21 locus on asthma in a sample of Brazilian children. METHODS: This was a cross-sectional study conducted on a cohort of 1247 children. These analyses used 50 Single Nucleotide Variants (SNVs) in the 17q12-21 locus were genotyped as part of a genome wide association study (GWAS). RESULTS: Four SNVs (rs4065275, rs12603332, rs73985228 and rs77777702) were associated with childhood asthma. The rs73985228 exhibited the strongest association across the different genetic models (OR, 95%CI 2.8, 1.44-3.21, p < 0.01). In an analysis that was stratified by atopy, two SNVs (rs73985228 and rs2715555) were found to be associated with atopic and non-atopic asthma. For the first time, we observed a significant interaction with seropositivity for the Varicella zoster virus (for rs4065275, p = 0.02, and for rs12603332, p = 0.04); i.e., the association was found in those who were seropositive but not in those who were seronegative for this virus. CONCLUSIONS: We confirmed the associations of variants in the 17q12-21 locus with atopic and non-atopic asthma and identified an interaction with seropositivity for the Varicella zoster virus.

Impact of bacterial probiotics on obesity, diabetes and non-alcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To systematically review the effect of oral intake of bacterial probiotics on 15 variables related to obesity, diabetes and non-alcoholic fatty liver disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, EMBASE and COCHRANE from 1990 to June 2018. ELIGIBILITY CRITERIA: Randomised controlled trials (≥14 days) excluding hypercholesterolaemia, alcoholic liver disease, polycystic ovary syndrome and children <3 years. RESULTS: One 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. CONCLUSIONS: The intake of probiotics resulted in minor but consistent improvements in several metabolic risk factors in subjects with metabolic diseases. TRIAL REGISTRATION NUMBER: CRD42016033273.

Organizational justice, justice climate, and somatic complaints: A multilevel investigation.

OBJECTIVE: Organizational 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. METHODS: Cross-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. RESULTS: Individual-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. CONCLUSION: A 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.

Greater fluid overload and lower interdialytic weight gain are independently associated with mortality in a large international hemodialysis population.

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.

Subclases de Lipoproteínas de Alta Densidad, Enfermedad Coronaria y Mortalidad Cardiovascular / High Density Lipoprotein Subclasses, Coronary Artery Disease, and Cardiovascular Mortality

Antecedentes: La relación inversa entre el colesterol HDL y la mortalidad cardiovascular se debilita en presencia de enfermedad coronaria (EC). El objetivo de este trabajo fue investigar las asociaciones de las concentraciones de partículas de HDL con la mortalidad cardiovascular y el impacto de la EC en estas asociaciones. También se buscó evaluar comparativamente las concentraciones de colesterol HDL y partículas de HDL en la predicción de la mortalidad cardiovascular. Métodos: Las concentraciones totales de HDL y sus sub-clases se midieron mediante espectroscopía de resonancia magnética nuclear en 2.290 participantes del estudio LUdwigshafen RIsk and Cardiovascular Health remitidos para angiografía coronaria. Los participantes fueron seguidos prospectivamente durante una mediana (rango intercuartílico) con una duración de 10,0 (6,1-10,6) años. Resultados: La media de la edad (DE) de los participantes (1.575 hombres, 715 mujeres) fue de 62,9 (10,4) años, índice de masa corporal 27,6 (4,1) kg/m², colesterol-HDL 39 (11) mg/dL [1 (0,29) mmol/L], y la concentración total de partículas de HDL 24,1 (5,8) μmol/L. Cuatroscientos treinta y cuatro de los participantes murieron de enfermedad cardiovascular. En análisis multivariados, los tercilos de las concentraciones totales de partículas de HDL se relacionaron inversamente con la mortalidad cardiovascular (Hazard Ratio para 3° frente a 1° tercilo = 0,55; p<0,001). Esta asociación fue mediada principalmente por las partículas de HDL pequeñas (p<0,001). La adición a los modelos de predicción multivariada de las concentraciones de partículas HDL totales o pequeñas, en lugar de colesterol HDL, mejoró las métricas de rendimiento para predicción de mortalidad cardiovascular. La presencia de EC no tuvo impacto en las asociaciones entre las concentraciones de partículas de HDL y la mortalidad cardiovascular. Conclusiones: La alta concentración de partículas de HDL se encuentra asociada con una disminución de la mortalidad cardiovascular de manera consistente e independiente de la EC. Sin embargo, si esta relación inversa entre la concentración de partículas de HDL y la mortalidad cardiovascular se puede traducir en nuevas estrategias terapéuticas está aún bajo investigación.

Background: The 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. Methods: Total and subclass HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy in 2,290 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. Results: The mean (SD) age of the participants (1,575 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. 434 persons died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (HR for 3rd vs. 1st 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. Conclusions: High 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.