Disruption of metabolic homeostasis is an important factor in many diseases. Various metabolites have been linked to higher risk of morbidity and all-cause mortality using metabolomics in large population-based cohorts. In these studies, baseline metabolite levels were compared across subjects to identify associations with health outcomes, implying the existence of ‘healthy’ concentration ranges that are equally applicable to all individuals. Here, we focused on intra-individual changes in metabolite levels over time and their link to mortality, potentially allowing more personalized risk assessment. We analysed targeted metabolomics data for 134 blood metabolites from 1409 participants in the population-based CARLA cohort at baseline and after four years. Metabotypes of the majority of participants (59%) were extremely stable over time indicated by high correlation between the subjects’ metabolite profiles at the two time points. Metabotype instability and, in particular, decrease of valine were associated with higher risk of all-cause mortality in 7.9 years of follow-up (hazard ratio (HR) = 1.5(95%CI = 1.0–2.3) and 0.2(95%CI = 0.1–0.3)) after multifactorial adjustment. Excluding deaths that occurred in the first year after metabolite profiling showed similar results (HR = 1.8(95%CI = 1.1–2.8)). Lower metabotype stability was also associated with incident cardiovascular disease (OR = 1.2(95%CI = 1.0–1.3)). Therefore, changes in the personal metabotype might be a valuable indicator of pre-clinical disease.

Background and aims: Higher ventricular mass has been reported in non-white US-Americans with low educational status and in socially isolated people. To assess the impact of education on cardiac mass and function in the general population and to identify mediators.Methods and results: Data from a German population-based sample were used (CARLA cohort, n = 1779 at baseline, n = 1436 at the four-year follow-up). Ventricular mass indexed on height (LVMI) and ejection fraction, using Teichholz's formula (EFTZ), were measured. Education was assessed using the ISCED classification. Mediator analyses were performed using the R-macro 'mediation' to compute the average direct effect and the average causal mediated effect after confounder adjustment. Sensitivity analyses for unobserved confounders were performed. Considered mediators were BMI, waist-to-hip ratio, HbA1c, and systolic and diastolic blood pressures.We found differences in LVMI and EFTZ, both at baseline and follow-up, between educational levels in women (lowest vs highest educational level: 15.6 g, 95% CI: -25.7, -5.6), but not in men. Similarly, women (lowest vs highest educational level at baseline: 3.3%, 95% CI: 0.8-5.7),but not men, of higher educational levels had a higher EFTZ of comparable magnitude at baseline and follow-up. Of the considered mediators, BMI explained 55.9% at baseline and 54.1% at follow-up of the educational effect, while other potential mediators had no significant effect. Relations remained constant between baseline and follow-up.Conclusions: Women with low educational levels tend to have a higher ventricular mass and lower EF, which can be explained by a higher BMI in this group. (C) 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

This study aimed to assess the mediating role of anthropometric parameters in the relation of education and inflammation in the elderly. Cross-sectional data from the population-based CARdio-vascular Disease, Living and Ageing in Halle study were used after excluding subjects with a plasma level of high-sensitive C-reactive protein (hsCRP) above 10 mg L(-1) (916 men/760 women remaining). Education was categorized in accordance with International Standard Classification of Education. As inflammation parameters, the soluble tumour necrosis factor type 1 (sTNF-R1), hsCRP and interleukin 6 (IL-6) were taken into account. Anthropometric parameters were the body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHeR). We used covariate adjusted mixed models to assess associations. Effect measures were the natural indirect effect (NIE), controlled direct effect and total effect (TE). Education was associated with sTNF-R1, hsCRP and IL-6 in men, and sTNF-R1 and hsCRP in women. Anthropometric parameters correlated with all inflammation parameters after covariate adjustment. BMI and WHeR were strong mediators of educational differences in sTNF-R1 (percentage of NIE of TE: 28% in men; 33% in women) and hsCRP (percentage of NIE of TE: 35% in men; 52% in women), while WHR was the weakest mediator. General obesity mediates roughly one-third of the association of education with chronic inflammation in the elderly.

Objective: To investigate the association between inflammation and selective echocardiographic parameters (EP) characteristic for ventricular hypertrophy in cross-sectional and longitudinal population-based analyses.Methods: Baseline (711 men, 659 women: 45-83 years) and 4-year follow-up data (622 men, 540 women) of the prospective, population-based CARdio-vascular disease, Living and Ageing in Halle (CARLA) study after exclusion of participants with cardiacvascular diseases were analysed. Inflammation parameters: soluble tumour necrosis factor receptor 1 (sTNF-R1), high-sensitivity C reactive protein (hsCRP) and interleukin 6 (IL-6). EPs: left ventricular mass (LVM), left atrial systolic dimension (LADS), interventricular septum diameter (IVSD), posterior wall dimension (PWD), left ventricular diastolic diameter (LVDD), ejection fraction according to Teichholz (EF). For the longitudinal analyses baseline to follow-up differences were considered. Effect sizes were determined by using multiple linear regression and mixed models. Missing values were replaced by means of multiple imputations.Results: Men had higher sTNF-R1 levels; means of hsCRP and IL-6 were similar in men and women. In multiple regression models, sTNF-R1 was associated with LADS (1.4 mm/1000 pg/mL sTNF-R1, 95% CI 0.6 to 2.1) in men. Respecting confounder hsCRP was associated with LVM (5.2 g/10 mg/L hsCRP, 95% CI 1.6 to 8.8), IVSD (0.2 mm/10 mg/L hsCRP, 95% CI 0 to 0.3) and PWD (0.2 mm/10 mg/L hsCRP, 95% CI 0.1 to 0.3) in women, while there were no relevant effects in analysis of IL-6 in both sexes. The baseline to follow-up change in EPs was not relevantly associated with sTNF-R1, hsCRP or IL-6.Conclusions: STNF-R1, hsCRP and IL-6 were inadequate predictors for structural changes of the heart at follow-up, while weak cross-sectional associations are restricted to certain EPs and depend on sex.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto’s thyroiditis), as well as autoimmune hyperthyroidism (Graves’ disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations ( P , 5 6 10 2 8 ) were detected at TPO -rs11675434, ATXN2 -rs653178, and BACH2- rs10944479 for TPOAb-positivity, and at TPO- rs11675434, MAGI3 -rs1230666, and KALRN -rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P =8.1 6 10 2 8 ), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P =2.9 6 10 2 6 ), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P =6.5 6 10 2 4 ). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves’ disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2 6 10 2 7 and OR: 1.25, 95% CI 1.12–1.39, P =6.2 6 10 2 5 ). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P =1.9 6 10 2 3 ). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

AIM:To validate the German Diabetes Risk Score within the population-based cohort of the Cardiovascular Disease - Living and Ageing in Halle (CARLA) study. METHODS:The sample included 582 women and 719 men, aged 45-83 years, who did not have diabetes at baseline. The individual risk of every participant was calculated using the German Diabetes Risk Score, which was modified for 4 years of follow-up. Predicted probabilities and observed outcomes were compared using Hosmer-Lemeshow goodness-of-fit tests and receiver-operator characteristic analyses. Changes in prediction power were investigated by expanding the German Diabetes Risk Score to include metabolic variables and by subgroup analyses. RESULTS:We found 58 cases of incident diabetes. The median 4-year probability of developing diabetes based on the German Diabetes Risk Score was 6.5%. The observed and predicted probabilities of developing diabetes were similar, although estimation was imprecise owing to the small number of cases, and the Hosmer-Lemeshow test returned a poor correlation (chi-squared = 55.3; P = 5.8*10⁻¹²). The area under the receiver-operator characteristic curve (AUC) was 0.70 (95% CI 0.64-0.77), and after excluding participants ≥66 years old, the AUC increased to 0.77 (95% CI 0.70-0.84). Consideration of glycaemic diagnostic variables, in addition to self-reported diabetes, reduced the AUC to 0.65 (95% CI 0.58-0.71). A new model that included the German Diabetes Risk Score and blood glucose concentration (AUC 0.81; 95% CI 0.76-0.86) or HbA(1c) concentration (AUC 0.84; 95% CI 0.80-0.91) was found to peform better. CONCLUSIONS:Application of the German Diabetes Risk Score in the CARLA cohort did not reproduce the findings in the European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study, which may be explained by cohort differences and model overfit in the latter; however, a high score does provide an indication of increased risk of diabetes.

Objectives: To determine whether recruitment of rural students and uptake of extended rural placements are associated with students’ expressed intentions to undertake rural internships and students’ acceptance of rural internships after finishing medical school, and to compare any associations.

BACKGROUND:In clinical practice there is considerable variation in the timing of initiation of dialysis. The IDEAL trial (Initiating Dialysis Early and Late study) showed that planned early initiation of dialysis in patients with stage 5 chronic kidney disease (CKD) was not associated with an improvement in clinical outcome, but was associated with increased costs. The predominant dialysis modality worldwide is hemodialysis (HD). This subanalysis of the IDEAL trial examined whether the timing of the initiation of dialysis in those who had chosen HD influenced survival and the occurrence of complications.METHODS:Patients on the IDEAL trial were older than 18 years and had progressive advanced CKD. They were randomly assigned to commence dialysis at an estimated glomerular filtration rate (eGFR) of 10-14 ml/min (early start) or when the eGFR was 5-7 ml/min (late start). The primary outcome was death from any cause.RESULTS:Between 2000 and 2008, 362 of the 828 patients (43.7%) randomized in the trial planned to commence HD. 322 (88.9%) of these subsequently commenced HD and 17 (4.7%) commenced peritoneal dialysis, with a median time to the initiation of dialysis of 1.63 months in the early-start group and 6.93 months in the late- start group. During a median follow-up time of 3.81 years, 50 of 171 patients in the early-start group (29.2%) and 59 in the late-start group (30.1%) died (hazard ratio with early initiation=0.97: 95% CI: 0.66-1.41; p=0.86). There was no significant difference in the frequency of cardiovascular events, infections, or access-related events, but there was a significantly higher frequency of fluid and electrolyte events in the late-start group (p=0.02).CONCLUSION:In this subanalysis of the IDEAL trial, patients commencing dialysis early with stage 5 CKD for whom the planned dialysis modality was HD did not have an improvement in survival or any reduction in most clinical outcomes apart from fluid and electrolyte events.

Introduction/objectives Individual socioeconomic status (SES) is a determinant of cardiovascular risk factors (RF). Recent studies suggest an independent association of neighbourhood SES with cardiovascular RF, but the mechanisms have not fully been understood. Our aim was to assess the association of neighbourhood and individual SES with cardiovascular RF in an Eastern German population. Methods We used cross-sectional data of 1779 participants aged 45–83 years of the population-based CARLA study. We calculated linear mixed models to assess the age-adjusted influence of neighbourhood-specific unemployment rates and individual SES on smoking, systolic blood pressure (SBP), and body mass index (BMI). Spatial dependencies within and between neighbourhoods were adjusted for by using ICAR models. Results Neighbourhood-specific unemployment rates varied between 6.3 and 35.3%. Per 1% increase in the neighbourhood's unemployment rate, the number of cigarettes smoked/day increased by 0.11 in men (95% CI 0.09 to 0.12) and 0.05, (CI 0.04 to 0.07) in women. In women, SBP increased by 0.04 mm Hg with unemployment rate (CI 0.03 to 0.06), while there was no statistically significant association of SBP with SES in men. BMI was only in women significantly associated with unemployment (increase in BMI per 1% increase in unemployment rate 0.04 (CI 0.02 to 0.05)). Associations of RF with individual SES were stronger than with neighbourhood SES in multiple models. Conclusions Our findings confirm the previously described association of neighbourhood SES with smoking independent of individual SES, while we found inconsistent associations with SBP and BMI. The neighbourhood environment may be more relevant for behavioural than for biomedical risk factors.

BACKGROUND:Planned early initiation of dialysis therapy based on estimated kidney function does not influence mortality and major comorbid conditions, but amelioration of symptoms may improve quality of life and decrease costs. STUDY DESIGN:Patients with progressive chronic kidney disease and a Cockcroft-Gault estimated glomerular filtration rate of 10-15 mL/min/1.73 m(2) were randomly assigned to start dialysis therapy at a glomerular filtration rate of either 10-14 (early start) or 5-7 mL/min/1.73 m(2) (late start). SETTING & POPULATION:Of the original 828 patients in the IDEAL (Initiation of Dialysis Early or Late) Trial in renal units in Australia and New Zealand, 642 agreed to participate in this cost-effectiveness study. STUDY PERSPECTIVE & TIMEFRAME: A societal perspective was taken for costs. Patients were enrolled between July 1, 2000, and November 14, 2008, and followed up until November 14, 2009. INTERVENTION:Planned earlier start of maintenance dialysis therapy. OUTCOMES:Difference in quality of life and costs. RESULTS:Median follow-up of patients (307 early start, 335 late start) was 4.15 years, with a 6-month difference in median duration of dialysis therapy. Mean direct dialysis costs were significantly higher in the early-start group ($10,777; 95% CI, $313 to $22,801). Total costs, including costs for resources used to manage adverse events, were higher in the early-start group ($18,715; 95% CI, -$3,162 to $43,021), although not statistically different. Adjusted for differences in baseline quality of life, the difference in quality-adjusted survival between groups over the time horizon of the trial was not statistically different (0.02 full health equivalent years; 95% CI, -0.09 to 0.14). LIMITATIONS:Missing quality-of-life questionnaires and skewed cost data, although similar in each group, decrease the precision of results. CONCLUSION:Planned early initiation of dialysis therapy in patients with progressive chronic kidney disease has higher dialysis costs and is not associated with improved quality of life.

Background: Several studies show an association of childhood socio-economic status (SES) with adult smoking; however, mostly paternal occupation only or aggregated indices are used. We investigated the role of different childhood SES indicators for adult smoking behaviour. Methods: Cross-sectional data of the CARLA Study (Cardiovascular disease, Living and Ageing in Halle) including 1779 men and women aged 45–83 were analysed. The four indicators of childhood SES were school education and occupational position of each parent. We used logistic regression models to calculate sex-stratified age-adjusted odds ratios (OR) with 95% confidence intervals (CI) of current smoking by the individual childhood SES indicators, the highest SES category being the reference. Results: Twenty-three percent of men and 14.4% of women were current smokers. In men, school education of both parents was statistically significantly associated with smoking. Men with unknown paternal education had the highest risk (OR 2.3, CI 1.1–4.6). With increasing paternal education, ORs decreased. For men whose mother had a low or medium education, ORs were lower compared to those with highly educated mothers. After adjustment for the three other childhood SES indicators and adult SES, social differences partly increased. Small differences were observed by father's occupation, while men with a blue collar mother had a nearly 2fold risk of being a smoker than men with white collar mothers. In women, none of the childhood SES indicators was statistically significantly associated with adult smoking, although there was a strong social gradient for maternal education. Women with unknown maternal education had a 2.4fold risk of smoking; the lowest risk was found in women whose parent was self-employed or farmer. Conclusions: For men, parental education was associated with adult smoking; however, different patterns emerged for father's and mother's education. No statistically significant relation of childhood socio-economic indicators with smoking was observed in women.

Background: High blood pressure (BP) is an established risk factor for cardiovascular disease. However, BP measurement conditions in epidemiological studies vary, leading to different estimates of hypertension frequencies. The aim of the study was to evaluate the dependence of BP estimates on different measurement conditions. Methods: This analysis uses data of 1778 participants (45–83 years) of the baseline investigation of the CARLA study. BP measurements using oscillometric devices included three sitting measurements at the left arm, one simultaneous supine measurement at both arms, and three supine measurements at the arm with the higher BP. We calculated means and 95% confidence intervals of differences between measurements and used linear regression to evaluate determinants of BP differences. Furthermore, we assessed the dependence of the prevalence of high BP (≥140/90mmHg) on the choice of BP measures used. Results: Mean diastolic BP (DPB) was slightly higher on left arm (mean DBP difference=0.98mmHg) whereas no differences were observed in systolic BP (SBP). Sitting SBP and DBP were higher than the corresponding supine BP (mean SBP difference=4.02mmHg; DBP=2.97mmHg). The BP difference by body position depends strongly on age and BP. Mean sitting and supine BP declined from first to second and second to third measurement by SBP=1.64 (sitting)/1.64 (supine) and 1.29/0.66 and DBP=0.51/0.94 and 0.21/0.33mmHg, respectively. The degree of BP decline depends on age, BP and BMI. The highest prevalence of high BP was found by using the first sitting measurement (63.60%), the lowest by using the third supine measurement (47.11%). Conclusion: Measured BP strongly depends on posture, number and combination of subsequent BP readings. BP measurements should only be compared between studies applying equal measurements conditions. The first BP measurement should not be used to define hypertension since it overestimates mean BP.

BACKGROUNDIn clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease.METHODSWe randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m2 of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause.RESULTSBetween July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval [CI], 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis).CONCLUSIONSIn this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Funded by the National Health and Medical Research Council of Australia and others; Australian New Zealand Clinical Trials Registry number, 12609000266268.)

Background/objectives Socio-economic status (SES) has long been recognized as determinant of cardiovascular risk factors and disease. Recent studies suggest an association of neighbourhood SES with risk factors independent of the individual9s own SES, but the mechanisms have not fully been understood. Our aim was to assess the association of neighbourhood and individual SES with cardiovascular risk factors in an Eastern German population with exceptionally high cardiovascular mortality and unemployment rates. Methods We used cross-sectional data of 1779 inhabitants of the city of Halle (Saale), aged 45–83 years, who participated in the population-based CARLA study. We calculated linear mixed models to assess the age-adjusted influence of neighbourhood SES (defined as neighbourhood-specific unemployment rates for 39 administrative districts of the city) and individual SES (defined as number of education years) on smoking (defined as number of currently smoked cigarettes/day), systolic blood pressure (SBP), and body mass index (BMI). Spatial dependencies within and between neighbourhoods were adjusted for by using ICAR models. Results The unemployment rate ranged from 6.3 to 35.3% between neighbourhoods. For smoking, there was a statistically significant increase of 0.11 cigarettes smoked/day per 1% increase in the neighbourhood9s unemployment rate in men (95% CI 0.09 to 0.12), and a decrease of 0.59 per increase in education years (CI −0.62 to −0.56), but a weaker association in women (regression coefficients (β) for unemployment rate and education years 0.054 (CI 0.039 to 0.067), and −0.21 (CI −0.24 to −0.19)). There was no statistically significant association of SBP with SES in men (β=−0.07 (CI −0.22 to 0.08) for unemployment rate, and −0.15 (CI −0.69 to 0.38) for education years), while in women, there was a statistically significant decrease in SBP of 0.79 mmHg per increase in education years (CI −0.82 to −0.76), and an increase with unemployment rate (β=0.04, CI 0.03 to 0.06). BMI was statistically significantly associated with education in men and women (0.11 decrease in BMI per increase in education years in men (CI −0.14 to −0.08), and 0.35 in women (CI −0.38 to −0.33)), but only for women with unemployment (increase in BMI per 1% increase in unemployment rate 0.008 (CI −0.008 to 0.02) in men, and 0.036 (CI −0.38 to −0.33) in women. Spatial correlations within and between neighbourhoods were small for all of the assessed outcomes. Conclusions Our findings confirm the previously described association of neighbourhood SES with smoking independent of individual SES, while we found inconsistent associations with SBP and BMI. The neighbourhood environment may be more relevant for behavioural than for biomedical risk factors.