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Abstract Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p

Abstract Background Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. Methods Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. Results Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41–0.56), while overweight (HR 2.03; 95% CI 1.41–2.94) and obesity (HR 1.89; 95% CI 1.02–3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40–0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. Conclusions Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Abstract Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Abstract We aimed to examine the concordance of type-2 diabetes, prediabetes and the metabolic syndrome in couples. In cross-sectional analyses, we used data from 1173 couples with index persons from the Heinz Nixdorf Recall Study (2011–2015), a population-based cohort study in Western Germany, and partners from the associated Heinz Nixdorf Multigeneration Study (2013–2016). Mean age (standard deviation) was 67.2 (6.6) years in index persons, and 67.8 (7.7) years in partners. The exposure was the presence of diabetes, prediabetes or metabolic syndrome in index persons, the outcome was the presence of the same health status in partners. Diabetes was defined by either self-reported diagnosis, intake of antidiabetic drugs or insulin, or HbA1c ≥ 6.5%. If the index person had prediabetes or diabetes, the partner was 1.46 (95% CI 1.07–2.00) times more likely to have diabetes than partners of index persons without the condition in the crude model (adjusted model: 1.33 (0.97–1.83)). For self-reported diabetes and for the metabolic syndrome, the corresponding prevalence ratios were 1.33 (0.90–1.97) and 1.17 (1.03–1.32), respectively (adjusted models: 1.23 (0.77–1.94), 1.04 (0.91–1.18)). In German couples, there was weak to moderate concordance of type-2 diabetes, prediabetes and the metabolic syndrome in crude, but poor concordance in adjusted models.

Abstract Background The COVID-19 pandemic restrictions posed challenges to maintaining healthy lifestyles and physical well-being. During the first mobility restrictions from March to mid-July 2020, the German population was advised to stay home, except for work, exercise, and essential shopping. Our objective was to comprehensively assess the impact of these restrictions on changes in physical activity and sedentary behavior to identify the most affected groups. Methods Between April 30, 2020, and May 12, 2020, we distributed a COVID-19-specific questionnaire to participants of the German National Cohort (NAKO). This questionnaire gathered information about participants’ physical activity and sedentary behavior currently compared to the time before the restrictions. We integrated this new data with existing information on anxiety, depressive symptoms, and physical activity. The analyses focused on sociodemographic factors, social relationships, physical health, and working conditions. Results Out of 152,421 respondents, a significant proportion reported altered physical activity and sedentary behavioral patterns due to COVID-19 restrictions. Over a third of the participants initially meeting the WHO’s physical activity recommendation could no longer meet the guidelines during the restrictions. Participants reported substantial declines in sports activities (mean change (M) = -0.38; 95% CI: -.390; -.378; range from -2 to + 2) and reduced active transportation (M = -0.12; 95% CI: -.126; -.117). However, they also increased recreational physical activities (M = 0.12; 95% CI: .117; .126) while engaging in more sedentary behavior (M = 0.24; 95% CI: .240; .247) compared to pre-restriction levels. Multivariable linear and log-binomial regression models indicated that younger adults were more affected by the restrictions than older adults. The shift to remote work, self-rated health, and depressive symptoms were the factors most strongly associated with changes in all physical activity domains, including sedentary behavior, and the likelihood to continue following the physical activity guidelines. Conclusions Mobility patterns shifted towards inactivity or low-intensity activities during the nationwide restrictions in the spring of 2020, potentially leading to considerable and lasting health risks.

Abstract The aim was to investigate prevalence of dry eye syndrome (DES) in a population-based sample in Germany. The association between coexisting eye diseases and DES was also of interest. We recontacted participants of the Heinz Nixdorf Recall study between 2018 and 2021 by postal questionnaire that included the Women’s Health Study questionnaire on DES. We estimated prevalence of DES and examined DES-associated factors among 2095 participants aged 62–91 years. We performed interaction analyses between sex and coexisting eye diseases in relation to the DES prevalence and performed bias analyses to examine the robustness of the results. The DES prevalence was 31.5% (34–36% after correction for potential non-response bias, 24.1% after correction for outcome misclassification) and it was almost 2.1-times higher in women than in men (women 42.3%, men 20.4%). Among DES subjects, 70.3% had received treatment in the previous 12 months. There was synergism between female sex and coexisting eye diseases (cataract, glaucoma, macular degeneration) in terms of DES prevalence. The extrapolated numbers of patients aged 62–91 years with DES in Germany are 1.1–1.3 million men and 6.1–6.8 million women. The observed synergism may be explained by differences in ocular physiology, subjective perception and response behavior. Women with eye diseases (cataract, glaucoma, macula degeneration) appear to have a markedly higher susceptibility to suffer from DES than men, so that a diagnostic workup of DES symptoms is particularly justified in women with these eye diseases.

Abstract In magnetic resonance imaging (MRI), the perception of substandard image quality may prompt repetition of the respective image acquisition protocol. Subsequently selecting the preferred high-quality image data from a series of acquisitions can be challenging. An automated workflow may facilitate and improve this selection. We therefore aimed to investigate the applicability of an automated image quality assessment for the prediction of the subjectively preferred image acquisition. Our analysis included data from 11,347 participants with whole-body MRI examinations performed as part of the ongoing prospective multi-center German National Cohort (NAKO) study. Trained radiologic technologists repeated any of the twelve examination protocols due to induced setup errors and/or subjectively unsatisfactory image quality and chose a preferred acquisition from the resultant series. Up to 11 quantitative image quality parameters were automatically derived from all acquisitions. Regularized regression and standard estimates of diagnostic accuracy were calculated. Controlling for setup variations in 2342 series of two or more acquisitions, technologists preferred the repetition over the initial acquisition in 1116 of 1396 series in which the initial setup was retained (79.9%, range across protocols: 73–100%). Image quality parameters then commonly showed statistically significant differences between chosen and discarded acquisitions. In regularized regression across all protocols, ‘structured noise maximum’ was the strongest predictor for the technologists’ choice, followed by ‘N/2 ghosting average’. Combinations of the automatically derived parameters provided an area under the ROC curve between 0.51 and 0.74 for the prediction of the technologists’ choice. It is concluded that automated image quality assessment can, despite considerable performance differences between protocols and anatomical regions, contribute substantially to identifying the subjective preference in a series of MRI acquisitions and thus provide effective decision support to readers.

Abstract Metadata from epidemiological studies, including chronic disease outcome metadata (CDOM), are important to be findable to allow interpretability and reusability. We propose a comprehensive metadata schema and used it to assess public availability and findability of CDOM from German population-based observational studies participating in the consortium National Research Data Infrastructure for Personal Health Data (NFDI4Health). Additionally, principal investigators from the included studies completed a checklist evaluating consistency with FAIR principles (Findability, Accessibility, Interoperability, Reusability) within their studies. Overall, six of sixteen studies had complete publicly available CDOM. The most frequent CDOM source was scientific publications and the most frequently missing metadata were availability of codes of the International Classification of Diseases, Tenth Revision (ICD-10). Principal investigators’ main perceived barriers for consistency with FAIR principles were limited human and financial resources. Our results reveal that CDOM from German population-based studies have incomplete availability and limited findability. There is a need to make CDOM publicly available in searchable platforms or metadata catalogues to improve their FAIRness, which requires human and financial resources.

Abstract Knowledge of the bleeding risk and the long-term outcome of conservatively treated patients with cavernous malformations (CM) is poor. In this work, we studied the occurrence of CM-associated hemorrhage over a 10-year period and investigated risk factors for bleeding. Our institutional database was screened for patients with cerebral (CCM) or intramedullary spinal cord (ISCM) CM admitted between 2003 and 2021. Patients who underwent surgery and patients without completed follow-up were excluded. Analyses were performed to identify risk factors and to determine the cumulative risk for hemorrhage. A total of 91 CM patients were included. Adjusted multivariate logistic regression analysis identified bleeding at diagnosis (p = 0.039) and CM localization to the spine (p = 0.010) as predictors for (re)hemorrhage. Both risk factors remained independent predictors through Cox regression analysis (p = 0.049; p = 0.016). The cumulative 10-year risk of bleeding was 30% for the whole cohort, 39% for patients with bleeding at diagnosis and 67% for ISCM. During an untreated 10-year follow-up, the probability of hemorrhage increased over time, especially in cases with bleeding at presentation and spinal cord localization. The intensity of such increase may decline throughout time but remains considerably high. These findings may indicate a rather aggressive course in patients with ISCM and may endorse early surgical treatment.

Abstract In this work, we propose a processing pipeline for the extraction and identification of meaningful radiomics biomarkers in skeletal muscle tissue as displayed using Dixon-weighted MRI. Diverse and robust radiomics features can be identified that may be of aid in the accurate quantification e.g. varying degrees of sarcopenia in respective muscles of large cohorts. As such, the approach comprises the texture feature extraction from raw data based on well established approaches, such as a nnU-Net neural network and the Pyradiomics toolbox, a subsequent selection according to adequate conditions for the muscle tissue of the general population, and an importance-based ranking to further narrow the amount of meaningful features with respect to auxiliary targets. The performance was investigated with respect to the included auxiliary targets, namely age, body mass index (BMI), and fat fraction (FF). Four skeletal muscles with different fiber architecture were included: the mm. glutaei, m. psoas, as well as the extensors and adductors of the thigh. The selection allowed for a reduction from 1015 available texture features to 65 for age, 53 for BMI, and 36 for FF from the available fat/water contrast images considering all muscles jointly. Further, the dependence of the importance rankings calculated for the auxiliary targets on validation sets (in a cross-validation scheme) was investigated by boxplots. In addition, significant differences between subgroups of respective auxiliary targets as well as between both sexes were shown to be present within the ten lowest ranked features by means of Kruskal-Wallis H-tests and Mann-Whitney U-tests. The prediction performance for the selected features and the ranking scheme were verified on validation sets by a random forest based multi-class classification, with strong area under the curve (AUC) values of the receiver operator characteristic (ROC) of 73.03 ± 0.70 % and 73.63 ± 0.70 % for the water and fat images in age, 80.68 ± 0.30 % and 88.03 ± 0.89 % in BMI, as well as 98.36 ± 0.03 % and 98.52 ± 0.09 % in FF.

Abstract The purpose of this study was to investigate the functional outcome following surgical resection of cerebral cavernous malformations (CCM) in pediatric patients. We screened our institutional database of CCM patients treated between 2003 and 2021. Inclusion regarded individuals younger or equal than 18 years of age with complete clinical baseline characteristics, magnetic resonance imaging dataset, and postoperative follow-up time of at least three months. Functional outcome was quantified using the modified Rankin Scale (mRS) score and assessed at admission, discharge, and last follow-up examination. The primary endpoint was the postoperative functional outcome. As a secondary endpoint, predictors of postoperative functional deterioration were assessed. A total of 49 pediatric patients with a mean age of 11.3 ± 5.7 years were included for subsequent analyses. Twenty individuals (40.8%) were female. Complete resection of the lesion was achieved in 44 patients (89.8%), and two patients with incomplete resection were referred for successive remnant removal. The mean follow-up time after surgery was 44 months (IQR: 13 – 131). The mean mRS score was 1.6 on admission, 1.7 at discharge, and 0.9 at the latest follow-up. Logistic regression analysis adjusted to age and sex identified brainstem localization (aOR = 53.45 [95%CI = 2.26 − 1261.81], p = .014) as a predictor of postoperative deterioration. This study indicates that CCM removal in children can be regarded as safe and favorable for the majority of patients, depending on lesion localization. Brainstem localization implies a high risk of postoperative morbidity and indication for surgery should be balanced carefully. Minor evidence indicates that second-look surgery for CCM remnants might be safe and favorable.

Objective: Thyroid-stimulating hormone (TSH) is influenced by genetic and e nvironmental factors such as socioeconomic position (SEP). However, interactions between TSH-related genetic factors and indicators of SEP have not been investigated to date. The aim of the study was to determine whether education and income as SEP indicators may interact with TSH-related genetic effect allele sum scores (GES TSH_2013 and GESTSH_2020) based on two different GWAS meta-analyses that affect TSH values in a popu lation-based study. Methods: In 4085 participants of the Heinz Nixdorf Recall Study associations between SEP indicators, GESTSH and TSH were quantified using sex- and age-adjusted linear regr ession models. Interactions between SEP indicators and GESTSH were assessed by GESTSH × SEP interaction terms, single reference joint effects and calculatin g genetic effects stratified by SEP group. Results: Participants within the highest education group showed the strongest genetic effect with on average 1.109-fold (95% CI: 1.067–1.155) higher T SH values per GESTSH_2013 SD, while in the lowest education group, the genetic effect was less strong (1.061-fold (95% CI: 1.022–1.103)). In linear regression models including i nteraction terms, some weak indication for a positive GESTSH_2013 by education interaction was observed showing an interaction effect size estimate of 1.005 (95% CI: 1.000–1.01 0) per year of education and GESTSH_2013 SD. No indication for interaction was observed for using income as SEP indicator. Using the GESTSH_2020, similar results were observed. Conclusion: Our results gave some indication that education may affect the e xpression of TSH-related genetic effects. Stronger genetic effects in high- education groups may be explained by environmental factors that have an impact on gene expression and are more prevalent in high SEP groups.

Objectives: We analyze whether the prevalence of depressive symptoms differs among various migrant and non-migrant populations in Germany and to what extent these differences can be attributed to socioeconomic position (SEP) and social relations.Methods: The German National Cohort health study (NAKO) is a prospective multicenter cohort study (N = 204,878). Migration background (assessed based on citizenship and country of birth of both participant and parents) was used as independent variable, age, sex, Social Network Index, the availability of emotional support, SEP (relative income position and educational status) and employment status were introduced as covariates and depressive symptoms (PHQ-9) as dependent variable in logistic regression models.Results: Increased odds ratios of depressive symptoms were found in all migrant subgroups compared to non-migrants and varied regarding regions of origins. Elevated odds ratios decreased when SEP and social relations were included. Attenuations varied across migrant subgroups.Conclusion: The gap in depressive symptoms can partly be attributed to SEP and social relations, with variations between migrant subgroups. The integration paradox is likely to contribute to the explanation of the results. Future studies need to consider heterogeneity among migrant subgroups whenever possible.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Anemia is a common, treatable condition in patients with aneurysmal subarachnoid hemorrhage (SAH) and has been associated with poor outcome. As there are still no guidelines for anemia management after aneurysm rupture, we aimed to identify outcome-relevant severity of anemia in SAH. We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library for publications before Oct 23rd, 2022, reporting on anemia in SAH patients. The presence and severity of anemia were assessed according to the reported hemoglobin values and/or institutional thresholds for red blood cells transfusion (RBCT). Out of 1863 original records, 40 full-text articles with a total of 14,701 patients treated between 1996 and 2020 were included in the final analysis (mean 445.48 patients per study). A substantial portion of patients developed anemia during SAH (mean pooled prevalence 40.76%, range 28.3–82.6%). RBCT was administered in a third of the cases (mean 32.07%, range 7.8–88.6%), with institutional threshold varying from 7.00 to 10.00 g/dL (mean 8.5 g/dL). Anemia at the onset of SAH showed no impact on SAH outcome. In contrast, even slight anemia (nadir hemoglobin

Background and purpose: To assess the impact of posterior fossa pilocytic astrocytoma (PA) removal in pediatric patients, with special focus on postoperative neurological outcome after repeated surgery for tumor remnants. Methods: Our institutional database was screened for patients with PA treated between 2000 and 2019. Patients ≤ 18 years of age with complete clinical records, preoperative contrast enhanced magnetic resonance imaging (MRI) and postoperative follow-up time of ≥ 6 months were suitable for study inclusion. Functional outcome was quantified with the modified Ranking Scale (mRS) score and assessed at admission, at discharge and at every follow-up investigation. Predictors of hydrocephalus, cranial nerve deficits and tumor recurrence were evaluated. Results: A total of 57 pediatric patients with a mean age of 7.7 ± 4.8 years were included in the analysis. 27 (47.3%) children suffered from hydrocephalus at diagnosis, out of which 19 (33.3%) required a subsequent VP-Shunt. 22 (39.3%) patients had a partial resection, of which 9 (40.9%) went through second-look surgery. 2 patients with initially radiological confirmation of complete resection, had a tumor recurrence at FU and needed second-look surgery. Among the children requiring second-look surgery, 7 (63.6%) had a complete resection. Favorable outcome (mRS≤2) after initial and second-look surgery was observed in 52 patients (91.2%). Univariate analysis identified tumor location in the floor of the 4th ventricle (p = 0.030), and repeated surgery for tumor remnant removal (p = 0.043) as predictors for post-operative cranial nerve deficits. Multivariate analysis confirmed this independent association. The incidence of tumor recurrence occurred more often in patients with previous partial resection (p = 0.009) as well as in lesions located in the cerebellar peduncles (p = 0.043). Partial resection remained an independent predictor after multivariate logistic regression analysis (p = 0.045). Conclusions: Incomplete resection of posterior fossa PA is a risk factor for tumor recurrence and repeated surgery to remove tumor remnants increases the risk of new postoperative deficits. Thus, the risk of iatrogenic deterioration due to second look surgery should be implemented in the primary pre- and intraoperative decision-making.

Abstract Large epidemiological studies such as the UK Biobank (UKBB) or German National Cohort (NAKO) provide unprecedented health-related data of the general population aiming to better understand determinants of health and disease. As part of these studies, Magnetic Resonance Imaging (MRI) is performed in a subset of participants allowing for phenotypical and functional characterization of different organ systems. Due to the large amount of imaging data, automated image analysis is required, which can be performed using deep learning methods, e. g. for automated organ segmentation. In this paper we describe a computational pipeline for automated segmentation of abdominal organs on MRI data from 20,000 participants of UKBB and NAKO and provide results of the quality control process. We found that approx. 90% of data sets showed no relevant segmentation errors while relevant errors occurred in a varying proportion of data sets depending on the organ of interest. Image-derived features based on automated organ segmentations showed relevant deviations of varying degree in the presence of segmentation errors. These results show that large-scale, deep learning-based abdominal organ segmentation on MRI data is feasible with overall high accuracy, but visual quality control remains an important step ensuring the validity of down-stream analyses in large epidemiological imaging studies.

Abstract N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an established biomarker for diagnosis of heart failure. The study aims to explore whether known cardiovascular risk factors, including education and income as indicators of socioeconomic position (SEP), may interact with the genetic effect of NT-proBNP-related single nucleotide polymorphisms (SNP) to influence plasma levels of NT-proBNP in a population-based study sample. Information on effect alleles of three SNPs previously reported to be related to NT-proBNP was combined individually for 4,520 participants of the Heinz Nixdorf Recall Study to calculate a genetic risk allele sum score (GRSNT-proBNP). Linear Regression models were used to examine the association of cardiovascular risk factors and GRSNT-proBNP with log-transformed NT-proBNP levels, as well as cardiovascular risk factor by GRSNT-proBNP interactions. The GRSNT-proBNP was associated with NT-proBNP showing 1.13-fold (95% CI 1.10–1.16) higher plasma levels per additional effect allele. Interaction terms included in the regression models gave some indication for interaction of the GRSNT-proBNP with the SEP indicator income as well as with C-reactive protein. In regression models stratified by income quartiles the strongest genetic effect was observed in the third income quartile showing 1.18-fold (95% CI 1.12–1.25) higher average NT-proBNP levels per additional allele compared to the lowest income quartile with 1.08-fold (95% CI 1.01–1.15) higher NT-proBNP levels. The results of the present study indicate that genetic effects of NT-proBNP increasing alleles are stronger in higher SEP groups. This may be due to a stronger influence of non-genetic cardiovascular risk on NT-proBNP in low SEP groups.

OBJECTIVE: The aim of this study was to identify the occupational risk for a SARS-CoV-2 infection in a nationwide sample of German workers during the first wave of the COVID-19 pandemic (1 February–31 August 2020). METHODS: We used the data of 108 960 workers who participated in a COVID follow-up survey of the German National Cohort (NAKO). Occupational characteristics were derived from the German Classification of Occupations 2010 (Klassifikation der Berufe 2010). PCR-confirmed SARS-CoV-2 infections were assessed from self-reports. Incidence rates (IR) and incidence rate ratios (IRR) were estimated using robust Poisson regression, adjusted for person-time at risk, age, sex, migration background, study center, working hours, and employment relationship. RESULTS: The IR was 3.7 infections per 1000 workers [95% confidence interval (CI) 3.3–4.1]. IR differed by occupational sector, with the highest rates observed in personal (IR 4.8, 95% CI 4.0–5.6) and business administration (IR 3.4, 95% CI 2.8–3.9) services and the lowest rates in occupations related to the production of goods (IR 2.0, 95% CI 1.5–2.6). Infections were more frequent among essential workers compared with workers in non-essential occupations (IRR 1.95, 95% CI 1.59–2.40) and among highly skilled compared with skilled professions (IRR 1.36, 95% CI 1.07–1.72). CONCLUSIONS: The results emphasize higher infection risks in essential occupations and personal-related services, especially in the healthcare sector. Additionally, we found evidence that infections were more common in higher occupational status positions at the beginning of the pandemic.

IntroductionFamily history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment.MethodsAnalyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses.ResultsHigher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%–12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect.DiscussionThe present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent.

Hyperspectral imaging (HSI) is a non-invasive technology that provides information on biochemical tissue properties, including skin oxygenation and perfusion quality. Microcirculatory alterations are associated with organ dysfunction in septic COVID-19 patients. This prospective observational study investigated associations between skin HSI and organ dysfunction severity in critically ill COVID-19 patients. During the first seven days in the ICU, palmar HSI measurements were carried out with the TIVITA® tissue system. We report data from 52 critically ill COVID-19 patients, of whom 40 required extracorporeal membrane oxygenation (ECMO). HSI parameters for superficial tissue oxygenation (StO2) and oxygenation and perfusion quality (NPI) were persistently decreased. Hemoglobin tissue content (THI) increased, and tissue water content (TWI) was persistently elevated. Regression analysis showed strong indications for an association of NPI and weaker indications for associations of StO2, THI, and TWI with sequential organ failure assessment (SOFA) scoring. StO2 and NPI demonstrated negative associations with vasopressor support and lactate levels as well as positive associations with arterial oxygen saturation. These results suggest that skin HSI provides clinically relevant information, opening new perspectives for microcirculatory monitoring in critical care.

We thank van Tongeren et al for responding to our study on occupational disparities in SARS-CoV-2 infection risks during the first pandemic wave in Germany (1). The authors address the potential for bias resulting from differential testing between occupational groups and propose an alternative analytical strategy for dealing with selective testing. In the following, we want to discuss two aspects of this issue, namely (i) the extent and reasons of differential testing in our cohort and (ii) the advantages and disadvantages of different analytical approaches to study risk factors for SARS-CoV-2 infection. Our study relied on nationwide prospective cohort data including more than 100 000 workers in order to compare the incidence of infections between different occupations and occupational status positions. We found elevated infection risks in personal services and business administration, in essential occupations (including health care) and among people in higher occupational status positions (ie, managers and highly skilled workers) during the first pandemic wave in Germany (2). Van Tongeren’s et al main concern is that the correlations found could be affected by a systematic bias because people in healthcare professions get tested more often than employees in other professions. A second argument is that better-off people could be more likely to use testing as they are less affected by direct costs (prices for testing) and the economic hardship associated with a positive test result (eg, loss of earnings in the event of sick leave). We share the authors’ view that differential testing must be considered when analysing and interpreting the data. Thus, in our study, we examined the proportion of tests conducted in each occupational group as part of the sensitivity analyses (see supplementary figure S1, accessible at www.sjweh.fi/article/4037). As expected, testing proportions were exceptionally high in medical occupations (due to employer requirements). However, we did not observe systematic differences among non-medical occupations or when categorising by skill-level or managerial responsibility. This might be explained by several reasons. First, SARS-CoV-2 testing was free of charge during the first pandemic wave in Germany, but reporting a risk contact or having symptoms was a necessary condition for testing ( https://www.bundesgesundheitsministerium.de/coronavirus/chronik-coronavirus.html (accessed 5 September 2022). The newspaper article cited by van Tongeren et al is misleading as it refers to a calendar date after our study period. Second, different motivation for testing due to economic hardship in case of a positive test result is an unlikely explanation, because Germany has a universal healthcare system, including paid sick leave and sickness benefits for all workers (3). Self-employed people carry greater financial risks in case of sickness. We therefore included self-employment in the multivariable analyses to address this potential source of bias. While the observed inverse social gradient may be surprising, it actually matches with findings of ecological studies from Germany (4, 5), the United States (6, 7) as well as Spain, Portugal, Sweden, The Netherlands, Israel, and Hong Kong (8), all of which observed higher infection rates in wealthier neighbourhoods during the initial outbreak phase of the pandemic. One possible explanation is the higher mobility of managers and better educated workers, who are more likely to participate in meetings and engage in business travel and holiday trips like skiing. Given the increasing number of studies providing evidence for this hypothesis, we conclude that the inverse social gradient in our study likely reflects different exposure probabilities and is not a result of systematic bias. This also holds true for the elevated infection risks in essential workers, which is actually corroborated by a large body of research (9–11). Regarding differential likelihood of testing, van Tongeren et al state that “[i]t is relatively simple to address this problem by using a test-negative design” (1). As van Tongeren et al describe, this is a case–control approach only including individuals who were tested (without considering those who were not tested). However, the proposed analytical strategy can lead to another (more serious) selection bias if testing proportions and/or testing criteria differ between groups (12). This can be easily illustrated when comparing the results based on a time-incidence design with those obtained by a test-negative design as shown in table 1 (see PDF). Both approaches show similar results in terms of vertical occupational differences. Infection was more common if individuals had a high skill level or had a managerial position, but associations were stronger in the time-incidence design and did not reach statistical significance in the test-negative design (as indicated by the confidence intervals overlapping “1”). Unfortunately, the test-negative approach relies on a strongly reduced sample size and thus results in greater statistical uncertainty and loss of statistical power (13). In contrast, the test-negative design yields a different picture when estimating the association between essential occupation and infection risk: In this analysis, essential workers did not differ from non-essential workers in their chance of being infected with SARS-CoV-2 (the test-negative design even exhibits a lower chance for essential workers). This is rather counter-intuitive and is not in accordance with what we know about the occupational hazards of healthcare workers during the pandemic (14). The main problem is that proportions of positive tests are highly unreliable when testing proportions and/or testing criteria differ between groups. As essential workers were tested more often without being symptomatic (due to employer requirements), a lower proportion of positive tests in this group does not necessarily correspond to a lower risk of infection. Consequently, we are not convinced that the test-negative design should be the ‘gold standard’ for studying risk factors for SARS-CoV-2 infections (15). Especially problematic is the loss of statistical power (increasing the probability of a type II error) and the low validity of the test-positivity when test criteria and/or test proportions differ between groups. References 1. van Tongeren M, Rhodes S, Pearce N. Occupation and SARS-CoV-2 infection risk among workers during the first pandemic wave in Germany: potential for bias. Scand J Work Environ Health 2022;48(7):586-587. https://doi.org/10.5271/sjweh.4052. 2. Reuter M, Rigó M, Formazin M, Liebers F, Latza U, Castell S, et al. Occupation and SARS-CoV-2 infection risk among 108 960 workers during the first pandemic wave in Germany. Scand J Work Environ Health 2022;48:446–56. https://doi.org/10.5271/sjweh.4037. 3. Busse R, Blümel M, Knieps F, Bärnighausen T. Statutory health insurance in Germany: a health system shaped by 135 years of solidarity, self-governance, and competition. Lancet 2017;390:882–97. https://doi.org/10.1016/S0140-6736(17)31280-1. 4. Wachtler B, Michalski N, Nowossadeck E, Diercke M, Wahrendorf M, Santos-Hövener C, et al. Socioeconomic inequalities in the risk of SARS-CoV-2 infection – First results from an analysis of surveillance data from Germany. J Heal Monit 2020;5:18–29. https://doi.org/10.25646/7057. 5. Plümper T, Neumayer E. The pandemic predominantly hits poor neighbourhoods? SARS-CoV-2 infections and COVID-19 fatalities in German districts. Eur J Public Health 2020;30:1176–80. https://doi.org/10.1093/eurpub/ckaa168. 6. Abedi V, Olulana O, Avula V, Chaudhary D, Khan A, Shahjouei S, et al. Racial, Economic, and Health Inequality and COVID-19 Infection in the United States. J Racial Ethn Heal Disparities 2021;8:732–42. https://doi.org/10.1007/s40615-020-00833-4. 7. Mukherji N. The Social and Economic Factors Underlying the Incidence of COVID-19 Cases and Deaths in US Counties During the Initial Outbreak Phase. Rev Reg Stud 2022;52. https://doi.org/10.52324/001c.35255. 8. Beese F, Waldhauer J, Wollgast L, Pförtner T, Wahrendorf M, Haller S, et al. Temporal Dynamics of Socioeconomic Inequalities in COVID-19 Outcomes Over the Course of the Pandemic—A Scoping Review. Int J Public Health 2022;67:1–14. https://doi.org/10.3389/ijph.2022.1605128. 9. Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo C-G, Ma W, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Heal 2020;5:e475–83. https://doi.org/10.1016/S2468-2667(20)30164-X. 10. Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers. Ann Intern Med 2020;173:120–36. https://doi.org/10.7326/M20-1632. 11. Stringhini S, Zaballa M-E, Pullen N, de Mestral C, Perez-Saez J, Dumont R, et al. Large variation in anti-SARS-CoV-2 antibody prevalence among essential workers in Geneva, Switzerland. Nat Commun 2021;12:3455. https://doi.org/10.1038/s41467-021-23796-4. 12. Accorsi EK, Qiu X, Rumpler E, Kennedy-Shaffer L, Kahn R, Joshi K, et al. How to detect and reduce potential sources of biases in studies of SARS-CoV-2 and COVID-19. Eur J Epidemiol 2021;36:179–96. https://doi.org/10.1007/s10654-021-00727-7. 13. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd Editio. New York: Routledge; 2013. https://doi.org/10.4324/9780203771587. 14. The Lancet. The plight of essential workers during the COVID-19 pandemic. Lancet 2020;395:1587. https://doi.org/10.1016/S0140-6736(20)31200-9. 15. Vandenbroucke JP, Brickley EB, Pearce N, Vandenbroucke-Grauls CMJE. The Evolving Usefulness of the Test-negative Design in Studying Risk Factors for COVID-19. Epidemiology 2022;33:e7–8. https://doi.org/10.1097/EDE.0000000000001438.

Abstract Environmental, genetic, and social factors are suggested to jointly influence monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma. Aim of this study was to investigate interactions between MGUS-related genetic variants and socioeconomic position (SEP) indicators education and income on MGUS in a population-based study. Two different MGUS-related genetic risk allele sum scores (GRS) were calculated based on recent genome-wide meta-analyses. Odds Ratios (OR) were estimated in 4329 participants including 238 MGUS cases to assess associations and multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction. Both GRSs were associated with MGUS. A multiplicative interaction between one GRS and education was observed with genetic effects of OR 1.34 (95% CI 1.11–1.62) per risk allele in the highest and OR 1.06 (95% CI 0.86–1.31) in the lowest education group. A RERI of 0.10 (95% CI 0.05–0.14) also indicated additive interaction. Further, additive GRS by income interaction (RERI 0.07; 95% CI 0.01–0.13) for the same GRS was also indicated. Results indicate interaction between MGUS-related genetic risk and SEP. Non-genetic MGUS risk factors more common in higher education groups may influence the expression of MGUS-related genetic variants.

Abstract 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.

Abstract 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.

Abstract Register-based studies indicate a possible association of monoclonal gammopathy of undetermined significance (MGUS) and prostate cancer (PCa). Aim of the present study was to investigate the relationship between MGUS and PCa considering potentially shared risk factors. Data from the prospective population-based Heinz Nixdorf Recall cohort study of 2.385 men (age 45–85) were analyzed. MGUS was determined at three points in time; cases of cancer were assessed annually. Potentially shared risk factors were assessed at baseline. Hazard ratios (HR), adjusted for age and educational attainment, and corresponding 95%-confidence intervals (95%-CI) were calculated. 157 cases of MGUS and 143 incident cases of PCa were detected. Of 19 participants diagnosed with both, MGUS and incident PCa, only in one case MGUS did not clearly occur before PCa. MGUS was associated with PCa presenting a HR of 2.00 (95%-CI: 1.23–3.25). Stratified by isotype, IgM-MGUS showed the strongest association with PCa. There was no relevant change of the effect estimate when adjusting for potentially shared risk factors. We were able to give supporting evidence for an association between MGUS and PCa and pointed out its temporality. There was no indication that the observed association is due to shared risk factors. The present study indicated that different isotypes of MGUS differ in the strength of the effect on PCa-risk. Based on these findings, future studies investigating the pathophysiological background of the association will be needed.

Abstract 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.

Abstract High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels are influenced by both genes and the environment. The aim was to investigate whether education and income as indicators of socioeconomic position (SEP) interact with lipid-increasing genetic effect allele scores (GES) in a population-based cohort. Using baseline data of 4516 study participants, age- and sex-adjusted linear regression models were fitted to investigate associations between GES and lipids stratified by SEP as well as including GES×SEP interaction terms. In the highest education group compared to the lowest stronger effects per GES standard deviation were observed for HDL-C (2.96 mg/dl [95%-CI: 2.19, 3.83] vs. 2.45 mg/dl [95%-CI: 1.12, 3.72]), LDL-C (6.57 mg/dl [95%-CI: 4.73, 8.37] vs. 2.66 mg/dl [95%-CI: −0.50, 5.76]) and TC (8.06 mg/dl [95%-CI: 6.14, 9.98] vs. 4.37 mg/dl [95%-CI: 0.94, 7.80]). Using the highest education group as reference, interaction terms showed indication of GES by low education interaction for LDL-C (ßGES×Education: −3.87; 95%-CI: −7.47, −0.32), which was slightly attenuated after controlling for GESLDL-C×Diabetes interaction (ßGES×Education: −3.42; 95%-CI: −6.98, 0.18). The present study showed stronger genetic effects on LDL-C in higher SEP groups and gave indication for a GESLDL-C×Education interaction, demonstrating the relevance of SEP for the expression of genetic health risks.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non–familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi‐Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low‐density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low‐density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high‐risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low‐density lipoprotein cholesterol

Different therapeutic apheresis techniques have been clinically tested to delay preterm delivery in the case of eoPE (early-onset preeclampsia). Our study evaluated the feasibility of TPE (therapeutic plasma exchange) compared to standard-of-care treatment. Twenty patients treated with 95 TPE sessions were included in the final analysis and retrospectively matched with 21 patients with comparable placental dysfunction. Gestational age at admission was 23.75 ± 2.26 versus 27.57 ± 2.68 weeks of gestation (WoG) in the control group (p = < 0.001), mean sFlt-1/PlGF ratio was 1946.26 ± 2301.63 versus 2146.70 ± 3273.63 (p = 0.821) and mean sEng was 87.63 ± 108.2 ng/mL versus 114.48 ± 88.78 ng/mL (p = 0.445). Pregnancy was prolonged for 8.25 ± 5.97 days when TPE was started, compared to 3.14 ± 4.57 days (p = 0.004). The median sFlt-1/PlGF Ratio was 1430 before and 1153 after TPE (−18.02%). Median sEng fell from 55.96 ng/mL to 47.62 mg/mL (−27.73%). The fetal survival rate was higher in TPE-treated cases. NICU (Neonatal Intensive Center Unit) stay was in the median of 63 days in the TPE group versus 48 days in the standard-of-care group (p = 0.248). To date, this monocentric retrospective study, reports the largest experience with extracorporeal treatments in eoPE worldwide. TPE could improve pregnancy duration and reduce sFlt-1 and sEng in maternal serum without impairing neonatal outcomes.

Abstract Background No standards exist for the handling and reporting of data quality in health research. This work introduces a data quality framework for observational health research data collections with supporting software implementations to facilitate harmonized data quality assessments. Methods Developments were guided by the evaluation of an existing data quality framework and literature reviews. Functions for the computation of data quality indicators were written in R. The concept and implementations are illustrated based on data from the population-based Study of Health in Pomerania (SHIP). Results The data quality framework comprises 34 data quality indicators. These target four aspects of data quality: compliance with pre-specified structural and technical requirements (integrity); presence of data values (completeness); inadmissible or uncertain data values and contradictions (consistency); unexpected distributions and associations (accuracy). R functions calculate data quality metrics based on the provided study data and metadata and R Markdown reports are generated. Guidance on the concept and tools is available through a dedicated website. Conclusions The presented data quality framework is the first of its kind for observational health research data collections that links a formal concept to implementations in R. The framework and tools facilitate harmonized data quality assessments in pursue of transparent and reproducible research. Application scenarios comprise data quality monitoring while a study is carried out as well as performing an initial data analysis before starting substantive scientific analyses but the developments are also of relevance beyond research.

Abstract 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.

Background: One measure to quantify the degree of dysregulation is allostatic load (AL). Typically, AL incorporates information on diverse biomarkers and is associated with health outcomes such as cardiovascular diseases or the incidence of coronary events (C-E). Aims: This study investigates the predictive performance of different AL scoring methods on the incidence of coronary events (C-E). This study also elaborates sex differences in the baseline risks of C-E and the AL associated risks of C-E. Design: Longitudinal data analysis of the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcification, and Lifestyle) of 4327 participants free of C-E at study baseline aged 45–75. The data contains over 13 biomarkers measuring AL. Methods: After conducting multiple imputations on missing values on AL for 826 participants, the analysis sample consisted of N = 4327 participants. We applied the two most commonly used methods of AL scoring AL (count-based and Z-score) and a recently developed logistic regression weighting method (LRM) approach. Cox regression was used to predict the incidence of C-E for each AL score. Results were estimated without (M0) and with (M1) covariate adjustment, and in a final model (M2), with an interaction between AL and sex. Results: We found no violation of the proportional hazard assumption and significant differences in the survival curves between the sexes for C-E (Log-rank test: prob. > Chi2 = 0.000). In M0, all AL-scoring methods predicted C-E significantly, with the LRM based AL-score having the best performance (hazard ratio = 3.133; CI: [2.630, 3.732]; Somer's D = 0.717). After covariate inclusion, differences between the scoring methods levelled, though the count-based method and LRM performed better than the Z-scoring method. The interaction analysis in M2 showed a significant multiplicative interaction for the count-based method (1.254; [1.066, 1.475]) and for the LRM (1.746; [1.132, 2.692]). The additive relative excess risk due to interaction (RERI) measure was negative for the count-based method (RERI = −1.967; [-3.778; −0.156]) and the LRM (RERI = −1.909 [-3.910; 0.091]), indicating subadditivity. Conclusion: AL scores are suitable for predicting C-E. Differences between the AL-scoring algorithms were only present after including interactions. We value the count-based method as suitable for clinical practice since its calculation is relatively simple, and performance was among the best. Interaction analysis revealed that despite strong sex differences in baseline C-E, the effect of AL is more pronounced for females at high levels of AL; thus, females could benefit more from a potential intervention on AL. We suggest further investigation of sex differences concerning the mediation by physiological and psychological intermediates.

Abstract 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.

IntroductionPoor sleep is a risk factor for adverse health events. For health prevention, it may be helpful to know whether poor sleep or sleep disorders in individuals are associated with sleep problems in their partners or children.MethodsIn the MultiGeneration Study (MGS, conducted from 2013 to 2016), 1237 partners (aged 27 to 90 years) and 1660 adult children (aged 18 to 66 years) of index persons were recruited. Index persons are participants of the Heinz Nixdorf Recall Study, a population-based cohort study in the Ruhr area (study start 1999-2001, 4841 participants aged 45-75 years). We used two analysis populations: one with 1181 index persons whose partners were in MGS, and one with 1083 index persons with at least one adult child in MGS. Sleep characteristics were assessed using questionnaires (including the Pittsburgh Sleep Quality Index). The exposure was the presence of a sleep characteristic of the index subject.ResultsChildren showed the investigated sleep characteristics more often if these were also present in their parent (e.g., RR (relative risk) = 1.28 (95% CI: 1.06-1.55) for poor sleep quality). In partners, strong associations were observed for rising times and napping, but only weak associations for snoring, poor sleep quality and sleep disorders. Snoring of the bed partner is a risk factor for poor sleep (e.g., RR = 1.67 (0.91-3.07) for difficulties falling asleep).ConclusionAggregation is observed for many sleep characteristics in people living in partnerships as well as in parents and their adult children.

ObjectivesN-Terminal pro Brain Natriuretic Peptide (NT-proBNP) is a diagnostic marker for heart failure and a prognostic factor for cardiovascular disease (CVD). The aim of this study was to examine the association of socioeconomic position (SEP) with NT-proBNP while assessing sex-differences and the impact of CVD risk factors and prevalent CVD on the association.MethodsBaseline data of 4598 participants aged 45-75 years of the Heinz Nixdorf Recall Study were used. Income and education were used as SEP indicators. Age- and sex-adjusted linear regression models were fitted to calculate effect size estimates and 95% confidence intervals (95%-CIs) for the total effect of SEP indicators on NT-proBNP, while potential mediation was assessed by additionally accounting for traditional CVD risk factors (i.e., systolic blood pressure, HDL cholesterol, LDL cholesterol, diabetes, anti-hypertensive medication, lipid-lowering medication, BMI, current smoking). Education and income were included separately in the models.ResultsWith an age- and sex-adjusted average change in NT-proBNP of -6.47% (95%-CI: -9.91; -2.91) per 1000€, the association between income and NT-proBNP was more pronounced compared to using education as a SEP indicator (-0.80% [95%-CI: -1.92; 0.32] per year of education). Sex-stratified results indicated stronger associations in men (-8.43% [95%-CI: -13.21; -3.38] per 1000€; -1.63% [95%-CI: -3.23; -0.001] per year of education) compared to women (-5.10% [95%-CI: -9.82; -0.01] per 1000€; -1.04% [95%-CI: -2.59; 0.50] per year of education). After adjusting for CVD risk factors some of the observed effect size estimates were attenuated, while the overall association between SEP indicators and NT-proBNP was still indicated. The exclusion of participants with prevalent coronary heart disease or stroke did not lead to a substantial change in the observed associations.ConclusionsIn the present study associations of education and income with NT-proBNP were observed in a population-based study sample. Only parts of the association were explained by traditional CVD risk factors, while there were substantial sex-differences in the strength of the observed association. Overt coronary heart disease or stroke did not seem to trigger the associations.

Abstract 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

Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, which are major regulators of energy homeostasis, on the RNA level. Methods: We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro, and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student's t-test for independent samples was applied, and effect sizes using Cohen's d with 95% confidence intervals were therefore calculated. Results: In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11 (-3.53, -2.70)), Irf9 (689Leu; d = 44.65 (-2.57, -2.26)), and Isg15 (150Arg; d = 20.35 (-2.19, -1.57))). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 (Cap1 (150Arg; d = 7.48 (-0.62, -0.24)), Mapk1 (343Met; d = -6.80 (0.17, 0.45)), and Sorbs1 (689Leu; d = 7.82 (-1.60, -0.64))). Conclusion: The increased expression of genes in the leptin (JAK/STAT or AKT) signaling pathway implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.

Body mass index (BMI) is influenced by genetic, behavioral and environmental factors, while interactions between genetic and socioeconomic factors have been suggested. Aim of the study was to investigate whether socioeconomic position (SEP) interacts with a BMI-related genetic sum score (GRSBMI) to affect BMI in a population-based cohort. SEP-related health behaviors and a GRS associated with educational attainment (GRSEdu) were included in the analysis to explore potential interactions underlying the GRSBMIxSEP effect. Baseline information on SEP indicators (education, income), BMI, smoking, physical activity, alcohol consumption and genetic risk factors were available for 4,493 participants of the Heinz Nixdorf Recall Study. Interaction analysis was based on linear regression as well as on stratified analyses. In SEP-stratified analyses, the highest genetic effects were observed in the lowest educational group with a 0.24 kg/m2 higher BMI (95%CI: 0.16; 0.31) and in the lowest income quartile with a 0.14 kg/m2 higher BMI (95%CI: 0.09; 0.18) per additional risk allele. Indication for a GRSBMIxSEP interaction was observed for education (ßGRSbmixeducation = -0.02 [95%CI:-0.03; -0.01]) and income (ßGRSbmixincome = -0.05 [95%CI: -0.08; -0.02]). When adjusting for interactions with the GRSEdu and SEP-related health behaviors, effect size estimates of the GRSBMIxSEP interaction remained virtually unchanged. Results gave indication for an interaction of BMI-related genetic risk factors with SEP indicators, showing substantially stronger genetic effects in low SEP groups. This supports the hypothesis that expression of genetic risks is higher in socioeconomically disadvantaged environments. No indication was observed that the GRSBMIxSEP interaction was affected by other SEP-related factors included in the analysis.

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-