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Background and Purpose: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. Methods: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. Results: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15−8.63]; P =0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04−5.86]; P =0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18−8.99]; P =0.022 and odds ratio, 2.53 [95% CI, 1.07−5.98]; P =0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80−110.39]; P =0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%−23.6%) for the entire cohort, 30.2% (20.2%−42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%−51.1%) for children with brain stem CCM. Conclusions: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

To evaluate the predictive value of intraoperative neuromonitoring (IONM) in brainstem cavernous malformation (BSCM) surgery.Surgically treated patients with BSCM were included. All patients received IONM consisting of motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SSEPs). Neurologic examination was conducted preoperatively and at discharge and follow-up3 months after BSCM removal. Demographic, radiographic, and clinical features were assessed. Study end points were new motor or somatosensory deficits and functional disability.A total of 62 patients were included. MEP decrease was associated with new motor deficits at discharge (P = 0.022), and SSEP decrease was associated with new somatosensory deficits at discharge (P0.001) and follow-up (P0.001). Sensitivity and specificity values for MEPs (discharge: 31% and 93%; follow-up: 33% and 91%) and SSEPs (discharge: 82% and 80%; follow-up: 85% and 79%) were calculated, respectively. Receiver operating characteristic analyses with area under the curve (AUC) metrics revealed acceptable performance of MEPs (AUC, 0.75; P = 0.022) and SSEPs (AUC, 0.72; P = 0.004) in predicting early deficits. Intraoperative decrease of MEPs (P = 0.047) and SSEPs (P = 0.017) was associated with early functional disability. Surgery-related subdural air accumulation impaired IONM reliability in predicting early (P = 0.048) and long-term (P = 0.013) deficits.Established IONM warning criteria may be valid for BSCM removal. However, surgical approaches in the sitting position significantly limit the predictive value of IONM, to some extent because of intraoperative pneumocephalus.

Background To determine the prevalence of cardiovascular comorbidities and allergic diseases in patients with cavernous malformations of the central nervous system compared to the normal population. Methods Clinical and magnetic resonance imaging data of 1352 patients with cerebral cavernous malformations (CCM) from an observational, cross-sectional, single-institutional study were analyzed and compared to an age-and-gender stratified and matched sample from a population-based, epidemiological study assessing cardiovascular risk factors in the local normal population of the same area (RECALL study). Results Of 1352 patients, 810 (60%) were female. Mean age was 40.4 ± 16 years. 221 patients (16%) suffered from familial disease. Presence of cardiovascular risk factors and intake of certain drugs in the overall cohort was mostly equal to the normal population reference sample (n = 786). The prevalence of allergic diseases was found to be significantly higher in all CCM patients compared to the normal population (30% vs. 20%, odds ratio [OR] 1.35 [1.12-1.63]) and in sporadic CCM cases compared to the normal population and familial cases (32% vs. 20% (OR 1.46 [1.19-1.78], p = 0.0001) and 22% vs. 20%, respectively). Conclusions We present novel data on CCM using a large single-institution and population-based setup. The study elaborates disease characteristics of CCM patients in detail. For the first time, evidence for an unexplained high prevalence of allergic diseases in this patient population is described (differing between sporadic and familial cases), supporting the hypothesis that immune response is involved in the pathogenesis of CCM.

Background: To estimate the quality of life, anxiety, depression, and illness perception in patients with medically treated cerebral cavernous malformation (CCM) and associated epilepsy. Methods: Nonsurgically treated patients with CCM-related epilepsy (CRE) were included. Demographic, radiographic, and clinical features were assessed. All participants received established questionnaires (short-form 36 health survey, SF-36; hospital anxiety and depression score, HADS-A/D; visual analogue scale score, VAS) assessing the functional and psychosocial burden of disease. To some extent, calculated values were compared with reference values from population-based studies. Test results were related to seizure control. Results: A total of 37 patients were included. Mean age was 45.8 ± 14.4 years, and 54.1% were female. Diagnosis of CRE was significantly associated with attenuated quality of life and increased level of anxiety, affecting physical and psychosocial dimensions. The assessment of illness perception identified considerable burden. HADS was significantly associated with VAS and SF-36 component scores. Efficacy of antiepileptic medication had no restoring impact on quality of life, anxiety, depression, or illness perception. Conclusions: CRE negatively influences quality of life and mood, independent of seizure control due to antiepileptic medication. Screening for functional and psychosocial deficits in clinical practice might be useful for assessing individual burden and allocating surgical or drug treatment. OA Förderung 2022

Background and purpose To estimate health-related quality of life (HRQOL) in patients with untreated cavernous malformation of the CNS [cavernous cerebral malformations (CCMs)]. Methods We performed a cross-sectional observational study on patients with CCMs admitted to our department from 1 November 2017 to 10 January 2020 using standardized interviews [short-form-36 questionnaire, hospital anxiety and depression score (HADS-A/D), CCM perception questionnaire]. Included criteria were diagnosis of an untreated CCM and information about the diagnosis in a specialized CCM consultation. Health-related quality of life (HRQOL) data were analyzed and compared to the German normal population. Uni- and multivariate analyses were carried out to identify variables with impact on outcome. Results Two hundred nineteen (93%) of 229 eligible patients were included. Mean age was 46.3 ± 14.7 (18-86) years; 136 (62%) were female. Ninety-eight (45%) patients presented with symptomatic hemorrhage (SH), and 17 (8%) with repetitive SH. Ninety-two (42%) patients were asymptomatic. Thirty-seven patients (17%) suffered from cavernoma-related epilepsy. Twenty-eight patients (13%) suffered from familial CCMs. Patients showed significantly decreased component scores and subdomain scores compared to the normal population, with effects ranging from small to large. This accounted largely also for asymptomatic patients (except for physical component score and main physical subdomains). Multivariate regression analysis confirmed impact of functional impairment on physical component score. HADS-A was significantly increased. HADS-A/D strongly correlated with mental component score and individual perception of the CCM. Conclusions Patients with the diagnosis of a CCM showed decreased HRQOL compared to the normal population even when not suffering functional impairment or neurological symptoms. Our data may function as benchmarks in evaluation of different (future) management strategies.

Background Smoking intensity, which is generally based on self-reported average cigarettes per day (CPD), is a major behavioural risk factor and strongly related to socioeconomic status (SES). To assess the validity of the CPD measure, correlations with objective markers of tobacco smoke exposure – such as urinary nicotine metabolites – were examined. Yet, it remains unclear, whether this correlation is affected by SES, which may indicate imprecise or biased self-reports of smoking intensity. Methods We investigated the role of SES in the association between CPD and nicotine metabolites in current smokers among the participants of the population-based, prospective Heinz Nixdorf Recall Study. We determined urinary cotinine and additionally trans-3′-hydroxy-cotinine. SES was assessed by the International Socio-Economic Index of occupational status, and education. We calculated correlations (Pearson’s r) between logarithmised CPD and cotinine in subgroups of SES and analysed SES and further predictors of cotinine in multiple linear regression models separately by gender. Results Median reported smoking intensity was 20 CPD in male and 19 CPD in female smokers. Men showed higher cotinine concentrations (median 3652 μg/L, interquartile range (IQR) 2279–5422 μg/L) than women (3127 μg/L, IQR 1692–4920 μg/L). Logarithmised CPD correlated moderately with cotinine in both, men and women (Pearson’s r 0.4), but correlations were weaker in smokers with lower SES: Pearson’s r for low, intermediate, and high occupational SES was 0.35, 0.39, and 0.48 in men, and 0.28, 0.43, and 0.47 in women, respectively. Logarithmised CPD and urinary creatinine were main predictors of cotinine in multiple regression models, whereas SES showed a weak negative association in women. Results were similar for trans-3′-hydroxy-cotinine. Conclusions Decreasing precision of self-reported CPD was indicated for low SES in men and women. We found no strong evidence for biased self-reports of smoking intensity by SES.

(1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.

Purpose The COVID-19 pandemic and public measures have a direct impact on the nutrition situation; studies show changes in food consumption, eating behavior or body weight but complex pattern analyses of changes rarely exist. Methods During the first German lockdown, a web-based survey was conducted among adults. It included 33 questions about changes in food intake, eating habits and physical activity, as well as anthropometrics and sociodemographic factors. Patterns of change were calculated based on changes in food intake and eating habits using two-step cluster analysis. To identify influencing factors for assignment to the patterns of change, binary logistic regression analyses were performed. Results Data from 2103 participants (81% female, 40 ± 14 years) were considered for analysis. Increased stockpiling, cooking, and variation in preparation was reported by 50–70%. The constant pattern (C-P, 36%) reported little change besides the above. The health-oriented pattern (HO-P; 37%) reported eating more healthy foods, avoiding unhealthy foods, and eating less and less frequently. The emotional-driven pattern (ED-P; 28%) exhibits higher influence of emotions on eating behavior, less avoidance of unhealthy foods, and increased consumption of sweets, pastries, and alcohol. The odds of changing eating behavior either to HO-P or ED-P were higher in women, people with migration background, younger participants, and increased with BMI categories. Conclusion Both, the ED-P and HO-P, exhibit distinctive reactions in eating habits and food intake when dealing with a distressing experience. In subgroups, these may lead to disturbances in eating behavior and increase the risk for eating disorders and obesity.

ObjectiveTo examine how different aspects of social relationships are associated with incident cardiovascular events and all-cause mortality.MethodsIn 4139 participants from the population-based Heinz Nixdorf Recall study without previous cardiovascular disease (mean (SD) age 59.1 (7.7) years, 46.7% men), the association of self-reported instrumental, emotional and financial support and social integration at baseline with incident fatal and non-fatal cardiovascular events and all-cause mortality during 13.4-year follow-up was assessed in five different multivariable Cox proportional hazards regression models: minimally adjusted model (adjusting for age, sex, social integration or social support, respectively); biological model (minimally adjusted+systolic blood pressure, low-density and high-density lipoprotein cholesterol, glycated haemoglobin, body mass index, antihypertensive medication, lipid-lowering medication and antidiabetic medication); health behaviour model (minimally adjusted+alcohol consumption, smoking and physical activity); socioeconomic model (minimally adjusted+income, education and employment); and depression model (minimally adjusted+depression, antidepressants and anxiolytics).Results339 cardiovascular events and 530 deaths occurred during follow-up. Lack of financial support was associated with an increased cardiovascular event risk (minimally adjusted HR=1.30(95% CI 1.01 to 1.67)). Lack of social integration (social isolation) was associated with increased mortality (minimally adjusted HR=1.47 (95% CI 1.09 to 1.97)). Effect estimates did not decrease to a relevant extent in any regression model.ConclusionsPerceiving a lack of financial support is associated with a higher cardiovascular event incidence, and being socially isolated is associated with increased all-cause mortality. Future studies should investigate how persons with deficient social relationships could benefit from targeted interventions.

Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45-75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19-0.76) for women and 0.48 (95% CI 0.10-1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS.

Background The prevalence of migraine and non-migraine headache declines with age. Methods Data from the third visit (2011–2015) of the population-based Heinz Nixdorf Recall study were analysed (n = 2038, 51% women, 65–86 years). Possible risk factors for headache activity (obesity, education, smoking, sports, alcohol, partnership status, living alone, having children, sleep quality, depression, hypertension, diabetes mellitus, stroke, coronary heart disease, medication), and headache symptoms were assessed. We estimated the lifetime prevalence and the prevalence of current active headache of migraine with and without aura, and non-migraine headache. The associations between possible risk factors and headache activity (active vs. inactive) were estimated by age and sex-adjusted odds ratios and 95% confidence intervals (OR [95% CI]) using multiple logistic regression. Results The lifetime prevalence of migraine was 28.6% (n = 584). One hundred and ninety-two (9.4%) had still-active migraine, 168 (3.5%) had migraine with aura, and 416 (5.9%) had migraine without aura. One hundred and sixty-eight (8.2%) had “episodic infrequent migraine, 0–8 headache days/month”, 10 (0.5%) had “episodic frequent migraine, 9–14 headache days/month”, and five (0.2%) had “chronic migraine, ≥15 headache days/month”. Overall, 10 (0.5%) had “chronic headache, any headache on ≥15 days/month”. Female gender and younger age were the most important associated migraine risk factors. Depression (1.62 [1.06; 2.47]) and poor sleep (1.06 [1.00; 1.12]) were associated with migraine and headache activity in general. Antihypertensives were associated with headache remission (0.80 [0.64; 1.00]). Additionally, undertaking less sports (0.72 [0.51; 1.03]) was associated with higher migraine activity. Conclusions Headaches and migraines are not rare in the older population. They are related to mood and sleep disturbance, and migraine even to less physical activity. Antihypertensives are related to headache remission.

Social inequalities in health and disease are well studied. Less information is available on inequalities in biomarker levels indicating subclinical stages of disease such as cystatin C, an early diagnostic marker of renal dysfunction and predictor for cardiovascular disease. We evaluated the relationship between cystatin C, socioeconomic position (SEP) and established cardiovascular risk factors in a population-based study. In 4475 men and women aged 45–75 years participating in the baseline examination of the Heinz Nixdorf Recall Study cystatin C was measured from serum samples with a nephelometric assay. SEP was assessed by education and household income. Linear regression models were used to analyse the association between SEP and cystatin C as well as the impact of cardiovascular risk factors (i.e., body mass index, blood pressure, blood glucose, diabetes mellitus, blood lipids, C-reactive protein, smoking) on this association. After adjustment for age and sex cystatin C decreased by 0.019 mg/l (95% confidence interval (CI) − 0.030 to − 0.008) per five years of education. While using a categorical education variable cystatin C presented 0.039 mg/l (95% CI 0.017–0.061) higher in men and women in the lowest educational category (≤ 10 years of education) compared to the highest category (≥ 18 years). Concerning income, cystatin C decreased by 0.014 mg/l (95% CI − 0.021 to − 0.006) per 1000 € after adjustment for age and sex. For men and women in the lowest income quartile cystatin C was 0.024 mg/l (95% CI 0.009–0.038) higher compared to the highest income quartile. After adjusting for established cardiovascular risk factors the observed associations were substantially diminished. Social inequalities seem to play a role in subclinical stages of renal dysfunction, which are also related to development of cardiovascular disease. Adjustment for traditional cardiovascular risk factors showed that these risk factors largely explain the association between SEP and cystatin C.

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA.Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex.In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated.The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time.HINTERGRUND: Asthma bronchiale stellt über alle Bildungsschichten hinweg eine der häufigsten chronischen Erkrankungen im Kindes- und Erwachsenenalter dar. Im Erwachsenenalter erstmals auftretendes Asthma (Adult-onset Asthma, AOA) ist im Vergleich zu Childhood-onset Asthma (COA) mit einer schlechteren Prognose assoziiert, was verstärkte Untersuchungen in diesem Bereich erfordert. Ziel der Arbeit war es, Häufigkeiten und das Alter bei Erstdiagnose aus Selbstangaben zu Asthma bei Erwachsenen in der NAKO Gesundheitsstudie darzustellen und mit Daten der Studie zur Gesundheit Erwachsener in Deutschland (DEGS) zu vergleichen.Unsere Analyse beruht auf einem Datensatz zur Halbzeit der NAKO-Basiserhebung mit 101.284 Personen. Verwendete Variablen waren die Selbstangabe zum jemals ärztlich diagnostizierten Asthma, Alter bei Erstdiagnose, Behandlung in den letzten 12 Monaten, Alter und Geschlecht.Laut Datenbasis zur Halbzeit berichteten in der NAKO 8,7 % der Frauen und 7,0 % der Männer, dass bei ihnen jemals Asthma diagnostiziert wurde. Etwa bei einem Drittel der Teilnehmenden mit Asthma wurde die Diagnose bereits im Kindes‑/Jugendalter (18 Jahre) gestellt. Dabei waren 2,2 % der Frauen und 2,8 % der Männer von COA betroffen und 6,5 % der Frauen und 4,2 % der Männer von AOA. In den vorangegangenen 12 Monaten gaben 33 % der COA-Fälle und 60 % der AOA-Fälle an, ärztlich behandelt worden zu sein.Die Häufigkeit von Asthma in der NAKO Gesundheitsstudie in Abhängigkeit von Alter und Geschlecht entspricht weitgehend den Daten aus anderen Studien wie DEGS. Allerdings ist der AOA-Anteil höher als in der Literatur beschrieben. Der Anstieg der kumulativen Asthmadiagnosen ist bei den jüngeren Geburtsjahrgängen deutlich steiler, was für eine Zunahme über die Zeit spricht.

In epidemiologic studies, standardised measurement of socio-demographic and employment-related factors is becoming increasingly important, as variables such as gender, age, education or employment status are factors influencing health and disease risks.The article gives an overview of the scientific background and assessment of socio-demographic factors in the German National Cohort Study. In addition, the distribution of individual characteristics in the cohort as well as relationships with health-related measures are presented by way of example.The analysis is based on the data of the first half of the baseline survey (n = 101,724). On this basis, we present the distribution of key socio-demographic characteristics and analyse relationships with exemplary selected health indicators (body mass index, self-reported health) to assess the validity of socio-demographic data measurements.On average, study participants were 52.0 years old (SD = 12.4). Of the participants, 53.6% were women, 54.3% had high education, 60.1% were married and 72% were employed while 3.4% were unemployed. Well-established correlations between socio-demographic factors and health could be reproduced with the German National Cohort data. For example, low education, old age and unemployment were associated with an increased prevalence of obesity and poor self-reported health.The German National Cohort provides a comprehensive measurement of socio-demographic characteristics. Combined with a wide range of health data and the longitudinal measurements available in the future, this opens up new opportunities for health science and social epidemiological research in Germany.

High levels of adiposity in the population have a major impact on various diseases, but previous epidemiologic studies have largely been restricted to simple anthropometric measures such as the body mass index (BMI), an imperfect predictor of disease risk. There is a critical need for the use of improved measures of relative weight and body composition in large-scale, population-based research.The current article presents initial descriptive results of body composition and fat distribution based on the midterm baseline dataset of the German National Cohort, which included 101,817 participants who were examined in 18 study centers in Germany between March 2014 and March 2017. The anthropometric measures encompassed body weight, height, waist and hip circumference, bioelectrical impedance analysis (BIA), sonography of abdominal adipose tissue, 3D-body scanning, and magnetic resonance imaging.BMI analyses showed that 46.2% of men and 29.7% of women were overweight and 23.5% of men and 21.2% of women were obese. On average, women in almost all age groups demonstrated more subcutaneous adipose tissue layer thickness than men. The mean values of visceral adipose tissue layer thickness, on the other hand, were higher among men than among women in all age groups and increased continuously across age groups in both sexes.The comprehensive assessment of body composition and fat distribution provides novel future opportunities for detailed epidemiologic analyses of overweight and adiposity in relation to the development of chronic diseases.

Patients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy.From 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma.SPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3-11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0-11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5-13.8] vs. IR 3.2 [95% CI: 1.0-7.5]; p 0.05). In the subgroup without previous radiotherapy SPM were only observed in patients with regular penetrance variants (IR 6.3 [95% CI: 3.0-11.5]). Carriers of incomplete penetrance variants developed similar tumour entities as those with regular penetrance.Patients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.

Objectives Midregional pro atrial natriuretic peptide (MR-proANP) is a cardiac biomarker and the maternal serum levels could be different in preeclampsia (PE) or intrauterine growth restriction (IUGR) at third trimester of pregnancy. Methods This prospective study measured serum levels of MR-proANP between 32 and 37 weeks of pregnancy: 32 patients suffered from PE and 22 developed IUGR. 676 patients exhibited no pregnancy complications. Results The median level of MR-proANP was significantly higher in PE (64.9 pmol/l (interquartile range (IQR) 36.3-105.2) and IUGR (59.7 pmol/l (IQR 39.7- 163.0) groups compared to controls (38.7 pmol/l (IQR 29.7-49.2). Linear regression analysis showed association between PE and MR-proANP levels (Exp(s)= 1.56; 95% CI: 1.34-1.81). Area under the curve (AUC) estimates showed a predictive value for PE (AUC: 0.72) and IUGR (AUC: 0.71). Conclusions Measuring MR-proANP in maternal serum at third trimester could predict PE and IUGR presenting after 34 weeks of pregnancy. Thus, we assume that MR-proANP may be an additional biomarker which mirrors the maternal cardiosvascular status next to sFlt-1/PLGF representing the angiogenic status.

Vitamin D (vitD) is involved in immune regulation, and its receptor has been identified in several tissues including lung, adipose tissue, brain, and skin. Based on these observations, it has been suggested that vitD has an essential role not only in bone metabolism but also in other diseases such as atopic dermatitis (AD), bronchial asthma (BA), attention-deficit/hyperactivity disorder (ADHD), and obesity because the affected tissues express vitD receptors. Furthermore, obesity, AD, and BA are regarded as inflammatory diseases. Therefore, we hypothesized that vitD concentrations are lower in children with AD, BA, ADHD, and obesity compared to healthy children. We measured 25-hydroxyvitamin D concentrations in 235 children (60% boys, age 9.3±1.7years) with obesity, BA, AD, or ADHD and compared them to those of 3352 children from a healthy population. Additionally, parathyroid hormone was measured in the children with obesity, ADHD, BA, and AD. VitD concentrations were not lower in children with obesity, ADHD, BA, and AD compared to healthy children. In multiple regression analyses adjusted to migration background, time period of blood sample, age, and sex, VitD levels correlated significantly with the severity of AD measured by SCORing Atopic Dermatitis index and attention deficit measured by Conners questionnaire in ADHD. VitD levels were not linked to hyperactivity in ADHD, the severity of BA measured as forced expiration volume in the first second, or body mass index standard deviation score. Parathyroid hormone was not associated with the activity of any analyzed disease. In conclusion, most of our findings do not support the hypothesis that vitD is involved in the pathogenesis of these entities.

Objectives The aim of this study was to investigate, whether maternal serum levels of sFlt-1, PlGF and PAPP-A at third trimester of pregnancy are associated with late-onset PE and intrauterine growth retardation (IUGR) after 34 weeks of pregnancy. Methods This was a prospective study measuring the maternal serum levels of soluble tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 32–37 weeks of pregnancy: 730 patients were enrolled and 676 had neither intrauterine growth restriction (IUGR) nor preeclampsia (PE) or pregnancy induced hypertension (PIH) throughout the pregnancy. 22 patients developed IUGR, 32 PE and 24 PIH. Results Linear regression analyses after adjusting for maternal age, gestational age at the blood sampling and maternal BMI showed associations between PE and serum sFlt-1 levels (Exp(s) = 3.29; 95% CI: 2.69–4.04), serum PlGF levels (Exp(s) = 0.18; 95% CI: 0.13–0.24), sFlt-1/PlGF ratio (Exp(s) = 15.59; 95% CI: 10.64–22.84) and serum PAPP-A (Exp(s) = 1.48; 95% CI 1.15–1.89). sFlt-1, PlGF and sFlt-1/PlGF-Ratio showed comparable area under the curve (AUC) estimates with a predictive ability to discriminate pregnancies developing PE and IUGR from controls. The predictive ability of PAPP-A for PE was only slightly better than chance. Conclusions This study supported the ability of a single measurement of sFlt-1/PlGF ratio at third trimester to predict PE and IUGR occurring after 34 weeks of pregnancy. However, larger multicentre studies are needed to replicate our results.

Background Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. Methods Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. Results Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. Conclusion As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data. Electronic supplementary material The online version of this article (10.1186/s12879-019-3691-2) contains supplementary material, which is available to authorized users.

Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol

BackgroundAssociations of socioeconomic status (SES) and smoking-related diseases depend on uniform validity of self-reported smoking habits in different SES groups. We investigated the influence of SES on validity of self-reported smoking status by means of urinary cotinine.MethodsWe determined total urinary cotinine in the baseline population of the Heinz Nixdorf Recall Study. Participants with cotinine>200 µg/L were potential current smokers. We defined upper and lower 20% of the gender-specific distribution of the International Socio-Economic Index (ISEI) as high and low SES, respectively, else as intermediate. We analysed the association of self-reported smoking status and cotinine by ISEI and additional SES measures, stratified by gender. In self-reported non-smokers, we estimated age-adjusted ORs with 95% CI to detect differences by SES in the validity of self-reported smoking status.ResultsIn 2004 men and 1887 women, 78% and 80%, respectively, reported to be non-smokers. Median cotinine concentrations were 2 µg/L in non-smokers, and 3651 µg/L in male and 3127 µg/L in female smokers. Based on cotinine in non-smokers, 2.0 % of men (n = 32) and 1.8 % of women (n = 27) were potential smokers, with lower proportions in the subgroup of never-smokers (men: 0.7%, women: 0.5%). The validity of self-reported smoking status did not substantially differ by SES. Tendencies for increased underreporting were indicated for women with low ISEI (OR 1.35; 95% CI 0.54 to 3.39) and men in blue-collar jobs (OR 1.39; 95% CI 0.67 to 2.87).ConclusionValidity of self-reported smoking status in this elderly German cohort was high and did not depend on SES.

Investigating potential value of maternal serum Visfatin, sFlt-1, PlGF, AFP, PAPP-A levels at first trimester for prediction of small for gestational age (SGA) at birth.Measurements were performed in 20 SGA and 65 control cases. Logistic regression analysis adjusted for age and weeks of pregnancy at data collection was performed to estimate odds ratios (OR), 95% confidence intervals (95% CI) and p values separately for each potential predictor. A multiple regression model was used to assess the impact of all the promising predictors adjusted for each other. Receiver operating characteristic (ROC) analysis was used to indicate the ability to discriminate between SGA cases and controls.There was an association of serum PlGF levels (OR 0.53 per interquartile range [IQR] increase in PlGF; 95% CI 0.24-1.16), sFlt-1/PlGF ratio (OR 1.42 per IQR increase in sFlt-1/PlGF; 95% CI 1.03-1.96), serum Visfatin levels (OR 0.31 per IQR increase in Visfatin; 95% CI 0.10-0.95) and smoking (OR 4.24; 95% CI 1.10-16.37) with SGA at birth.Associations between SGA and lower PlGF, Visfatin levels as well as increased sFlt-1/PlGF ratio and smoking status were detected which may contribute to predict SGA.

Background Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways. Methods Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci. Results Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P

Background: There is an ongoing discussion whether thyroid hormones are involved in the development and course of attention deficit/hyperactivity disorder (ADHD). Since obesity is associated with both higher thyroid-stimulating hormone (TSH) and free triiodothyronine (fT3) concentrations and increased rates of ADHD, we hypothesized that overweight children with ADHD show higher TSH and fT3 concentrations compared to overweight children without ADHD. Methods: TSH, fT3, fT4, and leptin levels were analyzed in 230 children (60.9% boys, 9.3 ± 1.7 years old, 35.7% migration background). The children were divided into four groups (I = 26 overweight children with ADHD, II = 56 normal-weight children with ADHD, III = 66 overweight children without ADHD, and IV = 82 normal-weight children without ADHD). Severity of ADHD was determined by the parent version of the Connors 3® rating scales. Results: Overweight children with ADHD did not differ significantly from overweight children without ADHD with respect to TSH, fT3, or fT4 concentrations. Comparing the thyroid hormones between the four groups also demonstrated no significant differences for TSH and fT4 concentrations. fT3 concentrations were significantly higher in normal-weight children with ADHD compared to normal-weight children without ADHD. Inattention and hyperactivity/impulsivity scores were not significantly related to TSH or fT3 in multiple regression analyses adjusted for age, gender, and migration background. In these analyses, TSH was associated with BMI SDS (β coefficient 0.19 ± 0.12, p = 0.002) and leptin (exp[β coefficient] 1.87 ± 1.36, p < 0.001). fT3 (β coefficient 0.06 ± 0.05, p = 0.009) and leptin (exp[β coefficient] 1.17 ± 1.13, p = 0.009) were also associated with BMI SDS. Conclusions: Our findings confirm the relation between overweight and thyroid hormones but point against the hypothesis that thyroid hormones might link overweight and ADHD in children.

Sonographic features of polycystic ovaries consist of elevated antral follicle count or ovarian volume of at least one ovary. The aim of this prospective cross-sectional study was to estimate intraindividual differences in sonographic measurements between the both ovaries of PCOS patients and controls and clinical consequences.Both ovaries of 85 PCOS patients and 48 controls were scanned transvaginally and agreement of sonographic measurements was analyzed using the Bland-Altman method. Concordance correlation coefficients (CCC) were computed.Mean differences between right and left ovaries were 0.24 (95% confidence interval [95% CI]: -0.32-0.80) follicles for AFC and 1.14 (95% CI: 0.34-1.92)ml for OV in the whole study population, 0.14 (95% CI: -0.68-0.96) follicles for AFC and 1.48 (95% CI: 0.39-2.58)ml for OV in PCOS patients, 0.42 (95% CI: -0.19-1.02) follicles for AFC and 0.53 (95% CI: -0.50-1.56)ml for OV in controls. Rather wide limits of agreement and low CCCs (0.7 for all estimates) indicated poor agreement between the ovaries for both sonographic measurements. Width between lower and upper limits of agreement was higher for PCOS patients than for controls. 23.5% of the PCOS patients showed polycystic ovarian morphology (PCOM) only in one ovary, resulting in 9.4% potentially missed PCOS diagnosis according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Substantial differences in antral follicle count and ovarian volume between the right and left ovary were observed. In approximately 10% of the PCOS patients in our study only the examination of both ovaries has led to a reliable diagnosis of PCOS. In clinical practice it is recommended to scan both ovaries for a reliable diagnosis of abnormal sonographic findings in PCOM and PCOS diagnosis.

Background and aims As a modifiable lifestyle factor, diet is hypothesized to play an important role in the progression of atherosclerosis. The aim of this study was to explore associations of comprehensive dietary patterns derived by cluster analysis with degree and progression of coronary artery calcification (CAC) over five years of follow-up. Methods and results In the population-based Heinz Nixdorf Recall study, 3718 participants (45–75 years; 47.6% men) without coronary heart disease completed a food frequency questionnaire at baseline. Five distinct dietary patterns were identified using cluster analysis: “Health-conscious”, “Traditional German/Less alcohol”, “Mediterranean-like”, “Western” and “Animal fat/Alcohol” (used as reference). CAC was measured using electron-beam computed tomography at baseline and five years later. CAC after five years was predicted based on sex- and age-specific baseline percentiles. After comparing observed and predicted CAC Scores, CAC progression was classified as slow, expected, or rapid. Compared to “Animal fat/Alcohol” diet, a “Mediterranean-like” diet was associated with a relative risk (RR) for a rapid CAC progression in both sexes (men: 0.61; 95%-confidence interval [95%-CI]: 0.41; 0.90; women: 0.59; 95%-CI: 0.45; 0.78). Furthermore, reduced RRs were observed in women with a “Health-conscious” and a “Traditional German/Less alcohol” diet (0.63; 95%-CI: 0.47; 0.84, respectively 0.69; 95%-CI: 0.52; 0.90). No association was observed for a “Western” diet for both sexes. Similar results were revealed for degree of CAC. Conclusion The study results support the hypothesis that a “Mediterranean-like” diet is associated with a lower CAC-progression and lower degree of CAC in men and women.

Background— Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.3 common variant interacts with socioeconomic status (SES) to influence CAC and incident coronary events in a population-based cohort. Methods and Results— 9p21.3 single nucleotide polymorphism rs2891168 was genotyped in 4116 participants of the Heinz Nixdorf Recall study. SES indicators (education and income) and CAC were assessed at baseline. Incident coronary events were ascertained over a median follow-up of 9.3 years. Multiple regression models were fitted to estimate genetic effects on log e (CAC+1) and incident coronary events. Genetic effects were highest in the lower income tertile with a 53.1% (95% confidence interval, 30.6%–79.6%; P =1.8×10 – 7 ) increase in CAC and a hazard ratio of 1.44 (95% confidence interval, 1.01–2.07; P =0.049) for incident coronary events per additional risk allele. After including genotype×SES interaction terms in the regression models, genotype×income interactions were observed for CAC (exp[β g×income ]=0.85 [95% confidence interval, 0.74–0.98; P g×income =0.02] per 1000€/mo increase and additional risk allele) and for incident coronary events (hazard ratio g×income =0.69 [95% confidence interval, 0.48–0.98; P g×income =0.04] per 1000€/mo increase and additional risk allele). No interaction was observed using education as SES indicator. Conclusions— A 9p21.3 common variant seems to interact with SES to influence CAC and incident coronary events in a population-based cohort. This supports the hypothesis that better material, psychosocial, and lifestyle conditions enable higher SES groups to reduce the expression of their genetic susceptibility to coronary artery disease.

Background Evidence has accumulated for the association between low vitamin D serum concentrations and mental health disorders in both children and adults. We performed a cross-sectional analysis in a population-based sample of children and adolescents to detect associations between 25(OH)-vitamin D serum [25(OH)D] concentrations and scores of the five Strengths and Difficulties Questionnaire (SDQ) subscales and the total difficulties score in different age groups (age ≥3

Anti-Mullerian-hormone (AMH) does not seem to fluctuate significantly during the menstrual cycle in healthy women. However, little is known about cycle fluctuations of AMH levels in patients with polycystic ovarian syndrome (PCOS). The purpose of this study was to examine AMH fluctuations during the follicular phase in PCOS patients receiving antiestrogens or recombinant follicle-stimulating hormone (FSH). About 40 PCOS patients diagnosed according to Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 19 controls were prospectively enrolled. PCOS patients received either antiestrogens or recombinant FSH for monoovulation induction and controls received antiestrogens. AMH levels were determined (1) between the 2nd and the 5th day of follicular phase and (2) when a single large dominant follicle ≥18 mm had appeared. Our study shows that AMH levels do not change during follicular development in controls as well as in PCOS patients with AMH levels 5 ng/ml, irrespective of antiestrogen or FSH therapy. However, in PCOS patients with AMH levels ≥5 ng/ml, AMH declines significantly during follicular development (p 0.01). We conclude that AMH levels should be determined in the early follicular phase in PCOS patients without the influence of antiestrogens or exogenous FSH, because these interventions may lower AMH values in patients with high levels.

Features of polycystic ovarian syndrome (PCOS) including sonographic aspects, androgens, LH and LH/FSH ratio as well as Anti-Mullerian Hormone (AMH) were evaluated according to their diagnostic potency in detecting different degrees of PCOS severity. 80 women with PCOS diagnosed according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 48 controls were enrolled between 2011 and 2013. PCOS patients fulfilling all Rotterdam criteria were defined as having severe PCOS (n = 59), while patients showing oligo-/amenorrhoea and polycystic ovaries but without hyperandrogenemia were defined as having mild PCOS (n = 21). All patients were treated at the University Hospital of Essen, Germany. The strongest group difference between controls and severe PCOS patients was observed for AMH showing an age-adjusted odds ratio of 2.56 [95 % confidence interval (CI) 2.00–3.27; p

Objective Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. Study design The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon–Nemenyi–McDonald–Thompson post hoc test. Results The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. Conclusion Follistatin can induce ovarian arrest during pregnancy.

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed

Problem To determine the association between maternal soluble B7-H4 (sB7-H4) and the preterm premature rupture of the amniotic membranes (pPROM), the blood serum concentration levels of sB7-H4 were studied. Method of study Maternal serum levels of sB7-H4 were determined with enzyme-linked immunosorbent assay (ELISA) in patients between 11 and 13 weeks’ gestation who later on in the pregnancy developed pPROM (n=21), premature rupture of the amniotic membranes at term (n=18), and in control group (n=27). Results The highest serum levels of sB7-H4 were found in patients who developed pPROM. An OR of 1.39 (95%-CI: 1.17–1.77; P=.002) per ng/mL sB7-H4 indicated an increased risk for developing pPROM, with some predictive ability to discriminate between pPROM cases and controls (AUC=.81). Conclusion Increased serum levels of sB7-H4 in early pregnancy in pPROM cases may indicate the dynamics of the immune response at the feto-maternal interface and, thus, may serve as a predictive marker for this pregnancy complication.

Study question Do parameters which are involved in pathogenesis of polycystic ovarian syndrome (PCOS) predict the dosage of recombinant FSH required to achieve monofollicular development for ovulation induction? Summary answer Anti-Mullerian hormone (AMH) appeared to be an independent predictor of the required dosage of FSH to achieve monofollicular development for ovulation induction in a study sample of clomiphene-resistant PCOS patients. What is known already AMH plays a key role in the pathogenesis of PCOS. This is the first study that has evaluated the association between AMH and the required FSH dosage to achieve the development of a large follicle of at least 18 mm, in the presence of additional predictors of ovarian responsiveness. In the few studies to date which have evaluated predictors of ovarian responsiveness in PCOS patients, fasting insulin has been shown to be a significant predictor. Study design, size, duration A total of 48 infertile PCOS patients aged 18-43 years were enrolled in this prospective, observational study between 2009 and 2013. Study participants received between one and six cycles of ovarian stimulation with recombinant FSH using a step-up protocol. The mean total FSH dosage per cycle for reaching a monofollicular development for ovulation induction was evaluated to investigate its association with AMH, LH, FSH, LH/FSH-ratio, sex hormone-binding globulin (SHBG), androstendione, testosterone, free testosterone index, antral follicle count, ovarian volume, body mass index (BMI) and the age of patients. Participants/materials, setting, methods We used AMH-Gen-II ELISA (Beckman Coulter, Immunotech, Webster, TX, USA) for the assessment of AMH levels. Crude and multiple linear regression models were fitted to explore potential predictors of the required FSH dosage. Main results and the role of chance An interquartile range (IQR) increase in AMH was associated with a 51.4% [95% confidence interval (CI): 24.7-79.0%; P = 0.0003] increase in the mean total FSH dosage per cycle (in IU) in a crude regression model, corresponding to a 7.2% increase in the mean total FSH dosage per cycle per ng/ml AMH. Adjustment for BMI augmented the effect of AMH, with a 58.3% (95% CI: 33.2-84.2%; P = 1.8 × 10(-5)) increase in FSH dosage per IQR AMH (corresponding to an 8.2% increase per ng/ml AMH) and a 46.2% (95% CI: 16.5-76.6%; P = 0.003) increase per IQR BMI (corresponding to a 3.7% increase per kg/m(2)). AMH was the only independent variable for which the effect on FSH dosage was statistically significant in the crude regression model as well as after adjustment for other promising predictors. The association of BMI with FSH dosage was statistically significant while adjusted for AMH, but not in the crude model. Limitations, reasons for caution The impact of metabolic parameters such as insulin resistance on the reported association between AMH and FSH dosage was not assessed. Wider implications of the findings Knowledge about the predictors of ovarian sensitivity to FSH can facilitate a physician's decision-making in providing the optimal infertility therapy for PCOS patients. Study funding/competing interests Funding was provided by the University Hospital of Essen.

Background: The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort. Methods. We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95\%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni's method (BF $\sim$ 0.005). In addition, we explored the association of a genetic risk score with socioeconomic status. Results: Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association. Conclusions: Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes. \copyright 2014 Schmidt et al.; licensee BioMed Central Ltd.

The German National Cohort (GNC) is a joint interdisciplinary endeavour of scientists from the Helmholtz and the Leibniz Association, universities, and other research institutes. Its aim is to investigate the causes for the development of major chronic diseases, i.e. cardiovascular diseases, cancer, diabetes, neurodegenerative/-psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases, and their pre-clinical stages or functional health impairments. Across Germany, a random sample of the general population will be drawn by 18 regional study centres, including a total of 100,000 women and 100,000 men aged 20-69years. The baseline assessments include an extensive interview and self-completion questionnaires, a wide range of medical examinations and the collection of various biomaterials. In a random subgroup of 20% of the participants (n=40,000) an intensified examination ("Level 2") programme will be performed. In addition, in five of the 18 study centres a total of 30,000 study participants will take part in a magnetic resonance imaging examination programme, and all of these participants will also be offered the intensified Level 2 examinations. After 4-5years, all participants will be invited for a re-assessment. Information about chronic disease endpoints will be collected through a combination of active follow-up (including questionnaires every 2-3years) and record linkages. The GNC is planned for an overall duration of 25-30years. It will provide a major, central resource for population-based epidemiology in Germany, and will help to identify new and tailored strategies for early detection, prediction, and primary prevention of major diseases.

Background: AMH levels determined by the conventional AMH assay declined during pregnancy and postpartum. A new Beckman Coulter AMH Gen II assay removes the potentially assay-interfering complement which is activated in pregnancy. The aim of this study was to evaluate if the decline of AMH levels in the serum of pregnant women during the course of pregnancy and peripartum was assay-dependent and thus artificial. Methods: In this cross-sectional study prepartal blood samples were collected from 62 patients (median age 30.6 years [interquartile range: 25.6 - 34.5]) in the third trimester of pregnancy and again 1–4 days after delivery between 2011 and 2012. In another cohort of 11 patients (median age 34.1 years [interquartile range: 32.6 - 37.8]) blood samples were taken in different trimesters of pregnancy between 1995 and 2001. The conventional and the modified AMH assay were performed in the same patient serum samples. We used the conventional and the modified AMH-Gen-II ELISA (Beckman Coulter, Immunotech, Webster, USA) for the assessment of AMH levels. The Wilcoxon signed rank test was used for determining differences between AMH levels pre- and postpartum. The method of Bland and Altman was applied for analyzing the agreement of both methods for determining AMH levels. Results: AMH values peripartum were lower than those expected in fertile non-pregnant women of comparable age. An overall mean difference of 0.44 ng/ml was observed between the conventional and the modified assay. Measurements with the modified assay showed a significant decline of postpartal levels compared with prepartal levels which is consistent with values obtained using the conventional assay (both p

Neuropsychological studies reported that shift workers show reduced cognitive performance and circadian dysfunctions which may impact structural and functional brain networks. Here we tested the hypothesis whether night shift work is associated with resting-state functional connectivity (RSFC), cortical thickness and gray matter volume in participants of the 1000BRAINS study for whom information on night shift work and imaging data were available. 13 PRESENT and 89 FORMER night shift workers as well as 430 control participants who had never worked in shift (NEVER) met these criteria and were included in our study. No associations between night shift work, three graph-theoretical measures of RSFC of 7 functional brain networks and brain morphology were found after multiple comparison correction. Preceding multiple comparison correction, our results hinted at an association between more years of shift work and higher segregation of the visual network in PRESENT shift workers and between shift work experience and lower gray matter volume of the left thalamus. Extensive neuropsychological investigations supplementing objective imaging methodology did not reveal an association between night shift work and cognition after multiple comparison correction. Our pilot study suggests that night shift work does not elicit general alterations in brain networks and affects the brain only to a limited extent. These results now need to be corroborated in studies with larger numbers of participants.