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Introduction: The aim of the study was to estimate the population-based dementia incidence in Germany over a period of two decades., Methods: We analyzed data from 4814 participants of the population-based Heinz Nixdorf Recall study (49.8% men, 45-75 years at baseline period 2000-2003), who have been monitored for the occurrence of cognitive decline and dementia. We calculated the cumulative incidence of dementia and its major subtypes and the incidence rate per 1000 person-years over two decades., Results: During a median follow-up of 18.2 (Q1-Q3: 11.3-20.6) years, a total of 298 participants (6.2%) developed dementia (22.1% Alzheimer´s disease, 23.5% vascular dementia, 15.1% mixed dementia, 9.1% other dementia, 30.2% unspecified). The overall incidence rate was 3.9 per 1000 person-years., Discussion: Our study is the only current population-based study in Germany that estimates the incidence of dementia. In order to reduce the high proportion of unspecific dementia diagnoses, diagnostics urgently need to be improved., Highlights: New data on the incidence of dementia in Germany in participants ≥45 years of age.Participants have been monitored for dementia incidence over two decades.The overall incidence in our cohort was 3.9 per 1000 person-years.Many patients had unspecific dementia diagnoses in their medical records.Further diagnostic evaluation should be available for all dementia patients., Competing Interests: All authors declare that they have no competing interests or conflicts. Author disclosures are available in the Supporting Information., (© 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Over 40% stage-III non-small-cell lung cancer (NSCLC) patients (pts) experience 5-year survival following multimodality treatment. Nevertheless, little is known about relevant late toxicities and quality-of-life (QoL) in the further long-term follow-up. Therefore, we invited pts from our randomized phase-III trial (Eberhardt et al., Journal of Clinical Oncology 2015) after 10 years from diagnosis to participate within a structured survivorship program (SSP) including follow-up imaging, laboratory parameters, cardio-pulmonary investigations, long-term toxicity evaluations and QoL questionnaires. Of 246 pts initially accrued, 161 were considered potentially resectable following the induction therapy and were randomized (80 to arm A: definitive chemoradiation; 81 to arm B: definitive surgery; 85 not randomized for different reasons; group C). 31 from 37 pts still alive after 10 years agreed to the SSP (13 in A; 12 in B; 6 in C). Clinically relevant long-term toxicities (grade 3 and 4) were rarely observed with no signal favoring any of the randomization arms. Furthermore, available data from the global QoL analysis did not show a signal favoring any definitive locoregional approach (Mean QoL in SSP A pts: 56.41/100, B pts: 64.39/100) and no late decline in comparison to baseline and early 1-year follow-up. This is the first comprehensive SSP of very late survival follow-up reported in stage-III NSCLC treated within a randomized multimodality trial and it may serve as important baseline information for physicians and pts deciding for a locoregional treatment option., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Little is known about the aetiology of thymoma. This study aims to identify medical risk factors for thymoma as a systematic approach to new hypotheses on the aetiology of this disease. A European multi-centre case-control study was conducted from 1995 to 1997, including incident cases aged 35-69 years with thymoma. Altogether, we accepted 85 cases and 3350 controls, of which we interviewed 77 cases and 2071 population controls about constitutional factors, medical examinations, and former diseases. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. Medical examinations with X-ray or radiotherapy performed >20 times at least one year before the thymoma diagnosis indicated a possible risk factor for thymoma (OR 1.58, 95% CI 0.93-2.69). Having the first radiotherapy treatment at least one year before the thymoma diagnosis yielded an OR for thymoma of 2.39; 95% CI (0.96-5.99), and if it was at least five years before, the OR for thymoma was 2.81; 95% CI (1.03-7.72). Having a red/auburn hair colour was associated with thymoma, (OR 3.6, 95% CI 1.4-9.5) whereas having pigmented skin was slightly associated with thymoma (OR 1.8, 95% CI 0.8-3.8). Over twenty instances of X-ray examinations or radiotherapy were identified as potential risk factors for thymoma, along with certain constitutional factors. The observed correlations between benign tumours and thymoma could stem from an inherent predisposition to tumour development or result from detection bias. Given that this is the initial analytical study examining medical risk factors for thymoma, all of the results should be approached with caution, acknowledging the possibility that some findings might be incidental.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process., (© 2024. The Author(s).)

Introduction: Several respiratory viruses have been shown to have seasonal patterns. The aim of our study was to evaluate and compare these patterns in immunocompetent and immunosuppressed patients for five different respiratory viruses., Methods: We performed a retrospective analysis of results for 13,591 respiratory tract samples for human metapneumovirus (HMPV), influenza virus, parainfluenza virus (PIV) and respiratory syncytial virus (RSV) in immunocompetent and immunosuppressed patients. A seasonal pattern was aligned to the data of immunocompetent patients through a logistic regression model of positive and negative test results., Results: A narrow seasonal pattern (January to March) was documented for HMPV. Most RSV infections were detected in the winter and early spring months, from December to March, but occasional cases of RSV could be found throughout the year. The peak season for PIV-3 was during the summer months, and that for PIV-4 was mostly in autumn. A narrow seasonal pattern emerged for influenza virus as most infections were detected in the winter, in January and February. The seasonal patterns of HMPV, RSV, PIV, and influenza virus were similar for both immunocompetent and immunocompromised patients., Conclusions: We found no difference in the seasonality of HMPV, RSV, PIV, and influenza virus infections between immunosuppressed and immunocompetent hosts.

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 < 5 × 10 -8 ) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units., (© 2024. The Author(s).)

Background: Cortisol typically peaks in the morning after waking up and declines throughout the day, reaching its lowest levels during nighttime sleep. Shift work can cause misalignment between cortisol levels and sleep-wake timing. We analyzed this misalignment in female shift workers focusing on the timing and extent of these changes., Methods: We conducted a cross-sectional study involving 68 shift workers (aged 37 ± 10 years) and 21 non-shift workers (aged 45 ± 10 years) from a hospital. Shift workers were monitored through two day shifts and three night shifts, whereas non-shift workers were monitored during two day shifts. Each participant collected six to eight saliva samples (depending on their shift type) and provided sleep timing information, which was recorded via polysomnography and sleep diaries. Generalized additive mixed models were used to estimate shift-specific differences in cortisol smooth curves. Summary measures calculated for the cortisol smooth curves included cortisol awakening response, peak-to-bed slope, and total output., Results: Between shift workers and non-shift workers, we observed similar diurnal cortisol profiles with a steep negative diurnal slope during day shifts. In shift workers on night shifts, a flattened U-shaped cortisol profile after the post-awakening maximum was observed, with a peak-to-bed slope close to zero. When comparing night to day shifts in the group of shift workers, mean cortisol levels were lower between 42 and 56 minutes and 1.8-11.9 hours after waking up, and higher between 14.9 and 22 hours after waking up., Conclusion: Our findings indicate altered cortisol profiles in female hospital employees on night shifts. Specifically, cortisol levels were lower at night when higher levels would typically be necessary for work activities, and higher at bedtime after a night shift, when levels should normally be low., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Short telomeres are associated with cardiovascular disease (CVD). We aimed to investigate, if genetically determined telomere-length effects CVD-risk in the Heinz-Nixdorf-Recall study (HNRS) population. We selected 14 single-nucleotide polymorphisms (SNPs) associated with telomere-length (p<10-8) from the literature and after exclusion 9 SNPs were included in the analyses. Additionally, a genetic risk score (GRS) using these 9 SNPs was calculated. Incident CVD was defined as fatal and non-fatal myocardial infarction, stroke, and coronary death. We included 3874 HNRS participants with available genetic data and had no known history of CVD at baseline. Cox proportional-hazards regression was used to test the association between the SNPs/GRS and incident CVD-risk adjusting for common CVD risk-factors. The analyses were further stratified by CVD risk-factors. During follow-up (12.1±4.31 years), 466 participants experienced CVD-events. No association between SNPs/GRS and CVD was observed in the adjusted analyses. However, the GRS, rs10936599, rs2487999 and rs8105767 increase the CVD-risk in current smoker. Few SNPs (rs10936599, rs2487999, and rs7675998) showed an increased CVD-risk, whereas rs10936599, rs677228 and rs4387287 a decreased CVD-risk, in further strata. The results of our study suggest different effects of SNPs/GRS on CVD-risk depending on the CVD risk-factor strata, highlighting the importance of stratified analyses in CVD risk-factors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tannemann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The quantitative job-exposure matrix SYN-JEM consists of various dimensions: job-specific estimates, region-specific estimates, and prior expert ratings of jobs by the semi-quantitative DOM-JEM. We analyzed the effect of different JEM dimensions on the exposure-response relationships between occupational silica exposure and lung cancer risk to investigate how these variations influence estimates of exposure by a quantitative JEM and associated health endpoints., Methods: Using SYN-JEM, and alternative SYN-JEM specifications with varying dimensions included, cumulative silica exposure estimates were assigned to 16 901 lung cancer cases and 20 965 controls pooled from 14 international community-based case-control studies. Exposure-response relationships based on SYN-JEM and alternative SYN-JEM specifications were analyzed using regression analyses (by quartiles and log-transformed continuous silica exposure) and generalized additive models (GAM), adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk., Results: SYN-JEM and alternative specifications generated overall elevated and similar lung cancer odds ratios ranging from 1.13 (1st quartile) to 1.50 (4th quartile). In the categorical and log-linear analyses SYN-JEM with all dimensions included yielded the best model fit, and exclusion of job-specific estimates from SYN-JEM yielded the poorest model fit. Additionally, GAM showed the poorest model fit when excluding job-specific estimates., Conclusion: The established exposure-response relationship between occupational silica exposure and lung cancer was marginally influenced by varying the dimensions of SYN-JEM. Optimized modelling of exposure-response relationships will be obtained when incorporating all relevant dimensions, namely prior rating, job, time, and region. Quantitative job-specific estimates appeared to be the most prominent dimension for this general population JEM.

Background: Information about follow-up care in blood cancer survivors is limited. The questionnaire-based "Aftercare in Blood Cancer Survivors" (ABC) study aimed to identify patterns of follow-up care in Germany and compare different types of follow-up institutions., Methods: The study's 18-month prospective part compared the follow-up institutions identified in the preceding retrospective part (academic oncologists, community oncologists, primary care physicians). The questionnaires were completed by the follow-up physicians., Results: Of 1070 physicians named by 1479 blood-cancer survivors, 478 (44.7%) consented to participate. For provision of care, most oncologists relied on published guidelines, while most primary care physicians depended on information from other physicians. Survivors with a history of allogeneic transplantation or indolent lymphoma were mainly seen by academic oncologists, whereas survivors with monoclonal gammopathy, multiple myeloma, or myeloproliferative disorders were often seen by community oncologists, and survivors with a history of aggressive lymphoma or acute leukemia by primary care physicians. Detection of relapse and secondary diseases was consistently viewed as the most important follow-up goal. Follow-up visits were most extensively documented by academic oncologists (574 of 1045 survivors cared for, 54.9%), followed by community oncologists (90/231, 39.0%) and primary care physicians (51/203, 25.1%). Relapse and secondary disease detection rates and the patients' quality of life were similar at the three institutions. Laboratory tests were most often ordered by academic oncologists, and imaging by primary care physicians. Psychosocial issues and preventive care were more often addressed by primary care physicians than by oncologists., Conclusions: Patients at high risk of relapse or late complications were preferentially treated by academic oncologists, while patients in stable condition requiring continuous monitoring were also seen by community oncologists, and patients with curable diseases in long-term remission by primary care physicians. For the latter, transfer of follow-up care from oncologists to well-informed primary care providers appears feasible., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of this publication is to demonstrate similarities and differences in the association of risk factors with the prevalence of different manifestations of chronic venous disease (CVD), like varicose veins (VV), venous oedema (C3) and severe chronic venous insufficiency (CVI) in the population-based cross-sectional Bonn Vein Study 1 (BVS). Patients and methods: In the BVS 1 between 13.11.2000 and 15.3.2002, 3.072 participants, 1350 men and 1722 women, from a simple random sample of the general population of the city of Bonn and two rural townships aged 18-79 years were included. The overall response proportion was 59%. All participants answered a standardized questionnaire including information about socio-economic data, lifestyle, physical activity, medical history, and quality of life. Venous investigations were performed clinically and by a standardized duplex examination by trained investigators. The CEAP classification in the version of 1996 was used to classify the findings. Logistic regression models were performed for the association of possible risk factors with VV, venous edema (C3) and severe CVI (C4-C6). The predictive risk (PR) describes the association of the diseases and the possible influencing factors. Results: VV, venous oedema (C3) and severe CVI (C4-C6) have common risk factors like higher age, number of pregnancies, family history of VV and overweight or obesity. Female gender is significantly associated with VV and C3 but not with severe CVI (C4-C6). High blood pressure and urban living are only associated with C3 and C4-C6 disease whereas prolonged sitting is associated with C3 and lower social class with C4-C6 exclusively. Discussion: In many epidemiological studies risk factors were associated with chronic venous disorders in general. Our data show that VV, venous edema and severe CVI may have different risk profiles. Venous edema is more often associated with arterial hypertension and sedentary lifestyle whereas lower social class seems to be a risk factor for severe CVI including venous ulcers. Conclusions: The differences in the association of risk factors to VV, venous edema and severe CVI should be considered if prevention and treatment of chronic venous diseases are planned. As examples, compression stockings could be proposed in sitting profession to prevent oedema, VV patients with risk factors like obesity might benefit from early treatment for VV and obesity. More longitudinal evaluation of risk factors is necessary to evaluate the true risk profile of CVD.

Traditional cardiovascular risk scores underestimate the incidence of cardiovascular diseases (CVD) in people living with HIV (PLH). This study compared the effect of HIV-specific cardiovascular risk factors (CRF) with traditional CRF at baseline for their association with incident CVD in PLH. The ongoing, prospective HIV HEART Aging (HIVH) study assesses CVD in PLH in the German Ruhr Area since 2004. PLH from the HIVH study with at least 5 years of follow-up were examined with the help of Cox proportional hazards models using inverse probability-of-censoring weights. The models were adjusted for age and sex. The obtained hazard ratios (HR) and 95% confidence limits (CL) assessed the strength of the associations between CRF and CVD. One thousand two hundred forty-three individuals (male 1,040, female 203; mean age of 43 ± 10 years) with 116 incident CVD events were analyzed. After adjusting for the traditional CRF, the HIV-specific CRF "a history of AIDS" and "higher age at diagnosis of HIV infection" (per 10 years) were associated with an increased CVD risk (HR 1.55, 95% CL: 1.05-2.28 and HR 1.55, 95% CL: 1.09-1.22, respectively). Higher CD4/CD8 ratio (per standard deviation), longer cumulative duration of antiretroviral therapies, and longer duration of HIV infection (per 10 years) showed indications for a decreased CVD risk (HR 0.75, 95% CL: 0.58-0.97, HR 0.71, 95% CL: 0.41-1.23, and HR 0.63, 95% CL: 0.44-0.90, respectively). Out of the traditional CRF, current smoking showed the strongest impact on CVD risk (HR 3.12, 95% CL: 2.06-4.74). In conclusion, HIV-specific factors, such as history of AIDS and CD4/CD8 ratio, were independently associated with an increased cardiovascular risk. Traditional CRF maintained a major effect on CVD. Clinical Trials Number (NCT04330287).

Objective: To describe the epidemiology and prognostic value of coronary artery calcium (CAC) in individuals with prediabetes., Research Design and Methods: We pooled participants free of clinical atherosclerotic cardiovascular disease (ASCVD) from four prospective cohorts: the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. Two definitions were used for prediabetes: inclusive (fasting plasma glucose [FPG] ≥100 to <126 mg/dL and hemoglobin A1c [HbA1c] ≥5.7% to <6.5%, if available, and no glucose-lowering medications) and restrictive (FPG ≥110 to <126 mg/dL and HbA1c ≥5.7% to <6.5%, if available, among participants not taking glucose-lowering medications)., Results: The study included 13,376 participants (mean age 58 years; 54% women; 57% White; 27% Black). The proportions with CAC ≥100 were 17%, 22%, and 37% in those with euglycemia, prediabetes, and diabetes, respectively. Over a median (25th-75th percentile) follow-up time of 14.6 (interquartile range 7.8-16.4) years, individuals with prediabetes and CAC ≥100 had a higher unadjusted 10-year incidence of ASCVD (13.4%) than the overall group of those with diabetes (10.6%). In adjusted analyses, using the inclusive definition of prediabetes, compared with euglycemia, the hazard ratios (HRs) for ASCVD were 0.79 (95% CI 0.62, 1.01) for prediabetes and CAC 0, 0.70 (0.54, 0.89) for prediabetes and CAC 1-99, 1.54 (1.27, 1.88) for prediabetes and CAC ≥100, and 1.64 (1.39, 1.93) for diabetes. Using the restrictive definition, the HR for ASCVD was 1.63 (1.29, 2.06) for prediabetes and CAC ≥100., Conclusions: CAC ≥100 is frequent among individuals with prediabetes and identifies a high ASCVD risk subgroup in which the adjusted ASCVD risk is similar to that in individuals with diabetes., (© 2024 by the American Diabetes Association.)

Background: Worldwide, lung cancer is the second leading cause of cancer death in women. The present study explored associations between occupational exposures that are prevalent among women, and lung cancer., Methods: Data from 10 case-control studies of lung cancer from Europe, Canada, and New Zealand conducted between 1988 and 2008 were combined. Lifetime occupational history and information on nonoccupational factors including smoking were available for 3040 incident lung cancer cases and 4187 controls. We linked each reported job to the Canadian Job-Exposure Matrix (CANJEM), which provided estimates of probability, intensity, and frequency of exposure to each selected agent in each job. For this analysis, we selected 15 agents (cleaning agents, biocides, cotton dust, synthetic fibers, formaldehyde, cooking fumes, organic solvents, cellulose, polycyclic aromatic hydrocarbons from petroleum, ammonia, metallic dust, alkanes C18+, iron compounds, isopropanol, and calcium carbonate) that had lifetime exposure prevalence of at least 5% in the combined study population. For each agent, we estimated lung cancer risk in each study center for ever-exposure, by duration of exposure, and by cumulative exposure, using separate logistic regression models adjusted for smoking and other covariates. We then estimated the meta-odds ratios using random-effects meta-analysis., Results and Conclusions: None of the agents assessed showed consistent and compelling associations with lung cancer among women. The following agents showed elevated odds ratio in some analyses: metallic dust, iron compounds, isopropanol, and organic solvents. Future research into occupational lung cancer risk factors among women should prioritize these agents., (© 2024 The Authors. American Journal of Industrial Medicine published by Wiley Periodicals LLC.)

This study aims to identify the distribution of the "Work-related behavior and experience patterns" (Arbeitsbezogenes Verhaltens-und Erlebnismuster, AVEM) in general practitioners and their teams by using baseline data of the IMPROVE job study. Members of 60 general practices with 84 physicians in a leadership position, 28 employed physicians, and 254 practice assistants participated in a survey in 2019 and 2020. In this analysis, we focused on AVEM variables. Age, practice years, work experience, and working time were used as control variables in the Spearman Rho correlations and analysis of variance. The majority of the participants (72.1%) revealed a health-promoting pattern (G or S). Three of eleven AVEM dimensions were above the norm for the professional group "employed physicians". The AVEM dimensions "striving for perfection" ( p < 0.001), "experience of success at work" ( p < 0.001), "satisfaction with life" ( p = 0.003), and "experience of social support" ( p = 0.019) differed significantly between the groups' practice owners and practice assistants, with the practice owners achieving the higher values, except for experience of social support. Practice affiliation had no effect on almost all AVEM dimensions. We found a high prevalence of AVEM health-promoting patterns in our sample. Nearly half of the participants in all professional groups showed an unambitious pattern (S). Adapted interventions for the represented AVEM patterns are possible and should be utilized for maintaining mental health among general practice teams.

Rationale: Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. Objectives: We aimed to examine the relationship between occupational benzene exposure and lung cancer. Methods: Subjects from 14 case-control studies across Europe and Canada were pooled. We used a quantitative job-exposure matrix to estimate benzene exposure. Logistic regression models assessed lung cancer risk across different exposure indices. We adjusted for smoking and five main occupational lung carcinogens and stratified analyses by smoking status and lung cancer subtypes. Measurements and Main Results: Analyses included 28,048 subjects (12,329 cases, 15,719 control subjects). Lung cancer odds ratios ranged from 1.12 (95% confidence interval, 1.03-1.22) to 1.32 (95% confidence interval, 1.18-1.48) ( P trend  = 0.002) for groups with the lowest and highest cumulative occupational exposures, respectively, compared with unexposed subjects. We observed an increasing trend of lung cancer with longer duration of exposure ( P trend  < 0.001) and a decreasing trend with longer time since last exposure ( P trend  = 0.02). These effects were seen for all lung cancer subtypes, regardless of smoking status, and were not influenced by specific occupational groups, exposures, or studies. Conclusions: We found consistent and robust associations between different dimensions of occupational benzene exposure and lung cancer after adjusting for smoking and main occupational lung carcinogens. These associations were observed across different subgroups, including nonsmokers. Our findings support the hypothesis that occupational benzene exposure increases the risk of developing lung cancer. Consequently, there is a need to revisit published epidemiological and molecular data on the pulmonary carcinogenicity of benzene.

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., (© 2024. The Author(s).)

Background: Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that lacks specific and validated patient-centered outcome measures (PCOMs). We aimed to develop and validate a health-related quality of life (HRQoL) questionnaire specific to HSP ("TreatHSP-QoL") that could be used as a PCOM., Results: The pilot-items of the TreatHSP-QoL (45 five-level Likert scale items, with values per item between 0 and 4) were developed based on a qualitative data analysis of 54 semi-structured interviews, conducted in person with 36 HSP patients and 18 caregivers. It was then reduced and modified through the validation process to 25 items. The main validation was performed using the online questionnaire in 242 HSP patients and 56 caregivers. The exploratory factor analysis defined five subdomains. Cronbach's alpha ranged from 0.57 to 0.85 for the subdomains and reached 0.85 for the total score. The test-retest Pearson correlation reached 0.86 (95% Confidence Interval (CI) [0.79, 0.91]). Pearson correlations with the EuroQol-5 Dimension (5 levels) (EQ-5D-5L) and Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) questionnaires varied strongly among the subdomains, with the total scores reaching 0.53 (95% CI [0.42, 0.61]) and -0.45 (95% CI [- 0.55, - 0.35]), respectively. The caregiver-patient response Pearson correlation ranged between 0.64 and 0.82 for subdomains and reached 0.65 (95% CI [0.38, 0.81]) for the total score., Conclusions: TreatHSP-QoL can be used in high-quality clinical trials and clinical practice as a disease-specific PCOM (i.e., HRQoL measure) and is also applicable as a proxy questionnaire. Score values between 0 and 100 can be reached, where higher value represents better HRQoL. The Pearson correlations to the EQ-5D-5L and FARS-ADL support the additional value and need of HSP-specific PCOM, while non-specific QoL-assessment and specific clinical self-assessment tools already exist. All in all, the results demonstrate good validity and reliability for this new patient-centered questionnaire for HSP., (© 2023. The Author(s).)

Background: There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer's disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed., Objective: The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones., Methods: In 290 participants (45% women, 69.7±7.4 years (mean±SD)) we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression., Results: The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: -95.3 [-324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); -261 [-493.1; -29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [-0.4;24.3] pg/ml) and DHEAS (1.4 [-0.5;3.3] pg/ml) with KLK8, while testosterone had no impact., Conclusions: The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer's disease pathology.

Introduction: Blood cancer survivors are at increased risk for medical complications., Methods: Our questionnaire-based study involved 1,551 blood cancer survivors with a ≥3-year interval since the last intense treatment. Its goal was to quantify health-related complications during follow-up and assess their impact on the patients' lives., Results: A total of 20.4% of the responding survivors reported a disease relapse, most often in indolent lymphomas. Second primary malignancies occurred in 14.1%, primarily in lymphoma and allogeneic transplantation survivors. The most frequent malignancy was basal cell carcinoma of the skin, but myeloid malignancies, melanoma, bladder, head-and-neck, and thyroid cancer also appeared disproportionately frequent. An increased infection rate was reported by 43.7%, most often after allogeneic transplantation. New cardiovascular diseases were reported by 30.2%, with a high rate of thromboembolic events in multiple myeloma (MM) and myeloproliferative diseases. Polyneuropathies were reported by 39.1%, most often by survivors with a history of MM or aggressive lymphoma. Disease relapse was perceived as the highest burden, followed by second primary malignancy, increased infection frequency, and polyneuropathy. In each area investigated, the range of perceived severities was wide., Conclusions: Health-related complications are frequent during blood cancer follow-up, with significant repercussions on the patients' lives., (© 2024 S. Karger AG, Basel.)

Background: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents., Objectives: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking., Methods: In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI)., Results: All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; p = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8)., Discussion: Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

Little is known about changes in the personal living conditions of long-term blood cancer survivors in Germany. To gather information about social relationships, work life, overall well-being, and religion, we performed a questionnaire-based retrospective study on 1551 survivors who had been on follow-up for ≥ 3 years (median, 9 years). Most survivors reported that marital status and relationships with relatives and friends remained constant before and after blood cancer. Vocational activities were temporarily impaired for 47.5%, with a median time of 11 months to return to work. More than a third of the patients (35.6%) discontinued work permanently, with disability and retirement pension rates of 7.9% and 38.1%, respectively, at the time of the survey. Financial problems due to reduced income were reported by 26.2%, in particular after relapse or allogeneic transplantation. Patient reports addressing their quality of life showed large variations. It was best in acute leukemia survivors without a history of allogeneic transplantation and worst in patients with myeloproliferative disorders. Religion tended to become more important after blood cancer. In conclusion, vocational impairment and financial problems are frequent among German blood cancer survivors. Efforts should be made at an early stage to reestablish the patients' ability to work., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Aims: In clinical practice, factors associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary artery calcium (CAC) are often known, but not incorporated in cardiovascular risk prediction models. The aims of the current study were to evaluate a methodology for the flexible addition of risk modifying characteristics on top of SCORE2 and to quantify the added value of several clinically relevant risk modifying characteristics., Methods and Results: Individuals without previous CVD or DM were included from the UK Biobank; Atherosclerosis Risk in Communities (ARIC); Multi-Ethnic Study of Atherosclerosis (MESA); European Prospective Investigation into Cancer, The Netherlands (EPIC-NL); and Heinz Nixdorf Recall (HNR) studies (n = 409 757) in whom 16 166 CVD events and 19 149 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using competing risk-adjusted Fine and Gray models. The risk modifying characteristics were applied to individual predictions with a flexible method using the population prevalence and the subdistribution hazard ratio (SHR) of the relevant predictor. Risk modifying characteristics that increased discrimination most were CAC percentile with 0.0198 [95% confidence interval (CI) 0.0115; 0.0281] and hs-Troponin-T with 0.0100 (95% CI 0.0063; 0.0137). External validation was performed in the Clinical Practice Research Datalink (CPRD) cohort (UK, n = 518 015, 12 675 CVD events). Adjustment of SCORE2-predicted risks with both single and multiple risk modifiers did not negatively affect calibration and led to a modest increase in discrimination [0.740 (95% CI 0.736-0.745) vs. unimproved SCORE2 risk C-index 0.737 (95% CI 0.732-0.741)]., Conclusion: The current paper presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers., Competing Interests: Conflict of interest: Dr. Matsushita received funding from the National Institutes of Health during the study and personal fees from Fukuda Denshi, Kowa Company, and the American Medical Group Association outside of the submitted work. L.P. is funded by a BHF Programme Grant (RG/18/13/33946) S.K. is funded by a BHF Chair award (CH/12/2/29428)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Blood cancer survivors are at increased risk for second primary malignancies, cardiovascular diseases, and infections. Little is known about preventive care in blood cancer survivors., Methods: Our questionnaire-based study included blood cancer patients diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval from the last intense treatment. One section of the retrospective study covered preventive care (cancer screening, cardiovascular screening, vaccination)., Results: Preventive care was delivered by a general practitioner for 1100 of 1504 responding survivors (73.1%), by an oncologist for 125 (8.3%), by a general practitioner together with an oncologist for 156 (10.4%), and by other disciplines for 123 (8.2%). Cancer screening was more consistently performed by general practitioners than by oncologists. The converse was true for vaccination, with particularly high vaccination rates in allogeneic transplant recipients. Cardiovascular screening did not differ between care providers. Cancer and cardiovascular screening rates in survivors eligible for statutory prevention programs were higher than in the general population (skin cancer screening 71.1%; fecal occult blood testing 70.4%; colonoscopy 64.6%; clinical breast examination 92.1%; mammography 86.8%; cervical smear 86.0%; digital rectal examination 61.9%; blood pressure test 69.4%; urine glucose test 54.4%; blood lipid test 76.7%; information about overweight 71.0%). The Streptococcus pneumoniae vaccination rate was higher (37.0%) and the influenza vaccination rate was lower (57.0%) than in the general population., Conclusions: Utilization of preventive care is high among German blood cancer survivors. To ensure widespread delivery and avoid redundancy, communication between oncologists and preventive care providers is essential., (© 2023. The Author(s).)

Objective: To assess the prevalence of acute mountain sickness (AMS) in 1370 mountaineers at four different altitudes in the Western Alps. We also examined the influence of potential risk factors and the knowledge about AMS on its prevalence., Methods: In this observational cross-sectional study AMS was assessed on the day of ascent by the Lake Louise score (LLS, cut-off ≥3, version 2018) and the AMS-Cerebral (AMS-C) score of the environmental symptom questionnaire (cut-off ≥0,70). The latter was also obtained in the next morning. Knowledge regarding AMS and high-altitude cerebral edema (HACE) and the potential risk factors for AMS were evaluated by questionnaires., Results: On the day of ascent, the prevalence of AMS assessed by the LLS and AMS-C score was 5.8 and 3.9% at 2850 m, 2.1 and 3.1% at 3050 m, 14.8 and 10.1% at 3650 m, and 21.9 and 15% at 4559 m, respectively. The AMS prevalence increased overnight from 10.1 to 14.5% and from 15 to 25.2% at 3650 m and 4559 m, respectively, and was unchanged at 2850 m and 3050 m. A history of AMS, higher altitude, lower degree of pre-acclimatization, and younger age were identified as risk factors for developing AMS. Slow ascent was weakly associated with AMS prevalence, and sex and knowledge about AMS and HACE were indistinct., Conclusion: AMS is common at altitudes ≥ 3650 m and better knowledge about AMS and HACE was not associated with less AMS in mountaineers with on average little knowledge., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Berger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Follow-up care provides long-term support for cancer survivors. Little is known about follow-up care in hematologic malignancies., Methods: Our questionnaire-based study included blood cancer survivors diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval since the last intense treatment. The primary goal of the retrospective study was the identification and characterization of follow-up institutions., Results: Of 2386 survivors meeting the inclusion criteria, 1551 (65.0%) consented to participate, with a follow-up duration > 10 years in 731. The university hospital provided care for 1045 participants (67.4%), non-university oncologists for 231 (14.9%), and non-oncological internists or general practitioners for 203 (13.1%). Seventy-two participants (4.6%) abstained from follow-up care. The disease spectrum differed among follow-up institutions (p < 0.0001). While allogeneic transplant recipients clustered at the university hospital, survivors with monoclonal gammopathy, multiple myeloma, myeloproliferative disorders, or indolent lymphomas were often seen by non-university oncologists, and survivors with a history of aggressive lymphoma or acute leukemia by non-oncological internists or general practitioners. Follow-up intervals mirrored published recommendations. Follow-up visits were dominated by conversations, physical examination, and blood tests. Imaging was more often performed outside than inside the university hospital. Satisfaction with follow-up care was high, and quality of life was similar in all follow-up institutions. A need for improvement was reported in psychosocial support and information about late effects., Conclusions: The naturally evolved patterns identified in the study resemble published care models: Follow-up clinics for complex needs, specialist-led care for unstable disease states, and general practitioner-led care for stable conditions., (© 2023. The Author(s).)

Little is known about the impact of long-term ambient air pollution (AP) and noise exposure on change in cognitive function over years in the elderly. In this study, we wanted to examine the association between long-term exposure to AP and noise with the rate of cognitive decline in a population aged 50 and older and susceptible groups with mild cognitive impairment or at a genetically higher risk of Alzheimer's disease (Apolipoprotein E ε4 positive). Participants in the German population-based Heinz Nixdorf Recall study carried out five neuropsychological tests. Individual tests scores at the first (T 1  = 2006-2008) and second (T 2  = 2011-2015) follow-up for each test were used as outcomes after standardization using predicted means adjusted for age and education. Global cognitive score (GCS) was defined as sum of five standardized scores of individual tests. Long-term exposures to particulate matter (PM 2.5 , PM 10 , PM 2.5 absorbance), accumulation mode particle number (PN acc ), a proxy of ultrafine particles, and nitrogen dioxide were estimated by the land-use regression and chemistry transport models. Noise exposures were assessed as outdoor weighted nighttime road traffic noise (L night ) means. We performed linear regression analyses adjusted for sex, age, individual and neighborhood socio-economic status, and lifestyle variables. Effect modification in vulnerable groups was estimated using multiplicative interaction terms between exposure and a modifier. Overall, 2554 participants (49.5% men, median age is 63 (IQR = 12)) were included. We found weak associations between higher exposure to PM 10 and PM 2.5 with faster decline in the immediate verbal memory test. Adjustment for potential confounders and for co-exposures did not change the results. We saw no effects on GCS, and no effect of noise exposure. In susceptible groups, higher AP and noise exposure were tended to be associated with faster decline in GCS. Our results suggest that AP exposure may accelerate cognitive decline in older ages, particularly in susceptible groups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Strong primary care leaders are needed to assure high quality services for patient populations. This study analysed general practitioners' (GP) leadership skills comparing practice-level self and staff assessments based on the full range of leadership model and the leader-member exchange (LMX)., Setting: The questionnaire survey was conducted among German general practice leaders and their staff participating in the IMPROVE job trial., Participants: The study population comprised 60 German general practices with 366 participants: 84 GP practice leaders and 282 employees (28 physicians and 254 practice assistants)., Primary and Secondary Outcome Measures: Leadership skills of the practice leaders were measured using the Integrative Leadership Questionnaire (German Fragebogen für integrative Führung) and the LMX-7 questionnaire. Leaders rated themselves and practice staff rated their leaders. The data was analysed by paired mean comparisons on the practice level., Results: For most leadership dimensions, practice leaders rated themselves higher than their employees rated them. Differences were found for transformational leadership (p<0.001, d=0.41), especially for the dimensions 'innovation' (p<0.001, d=0.69) and 'individuality focus' (p<0.001, d=0.50). For transactional leadership, the dimension 'goal setting' differed significantly (p<0.01, d=0.30) but not the other dimensions. Scores for negative leadership were low and showed no differences between leaders and employees. Interestingly, employed physicians' rated their practice leaders higher on the two transformational ('performance development', 'providing a vision') and all transactional dimensions. The LMX-7 scale showed high quality relationships between leaders and employees., Conclusions: This 180° analysis of GPs' leadership skills with self and employee ratings indicated good relationships. There is a potential to improve leadership regarding goal-setting, innovation and focusing on individual team members. These results allow for the development of targeted interventions., Trial Registration Number: German Clinical Trials Register, DRKS00012677. Registered 16 October 2019., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC -expressing neurons. On the basis of these findings, we treated POMC -hypermethylated obese individuals ( n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.

A survey conducted by the German Socio-Economic Panel during the early phase of the SARS-CoV‑2 pandemic in spring 2020 showed that the perceived risks of SARS-CoV‑2 infection were a massive overestimation of the actual risks. A total of 5783 people (2.3% missing data) stated how likely they thought it was that SARS-CoV‑2 would cause a life-threatening illness in them in the next 12 months. The average subjective probability was 26%. We consider how such an overestimation could have occurred and how a more realistic risk assessment could be achieved in the population in a future pandemic. We show that qualitative attributes of the pandemic, the reporting of the media, and psychological features may have contributed to the overestimation of SARS-CoV‑2 risks. In its early stages, the SARS-CoV‑2 pandemic had qualitative characteristics known to lead to an overestimation of risks: The risks associated with the pandemic were new, unfamiliar, perceived as poorly controllable, and were taken involuntarily. Phenomena known from cognitive psychology such as the availability and anchor heuristics can also explain the overestimation of pandemic risks. Characteristics of media coverage such as the focus on individual fates and the associated neglect of the denominator also contributed to the gap between perceived and objective risk. In a potential future pandemic, people need to be vigilant but not in a panic. Better risk communication-for example, with better prepared figures and graphically presented percentages while avoiding the denominator neglect-could help the population to perceive risks of future pandemics more realistically., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

This research addresses the assessment of adipose tissue (AT) and spatial distribution of visceral (VAT) and subcutaneous fat (SAT) in the trunk from standardized magnetic resonance imaging at 3 T, thereby demonstrating the feasibility of deep learning (DL)-based image segmentation in a large population-based cohort in Germany (five sites). Volume and distribution of AT play an essential role in the pathogenesis of insulin resistance, a risk factor of developing metabolic/cardiovascular diseases. Cross-validated training of the DL-segmentation model led to a mean Dice similarity coefficient of >0.94, corresponding to a mean absolute volume deviation of about 22 ml. SAT is significantly increased in women compared to men, whereas VAT is increased in males. Spatial distribution shows age- and body mass index-related displacements. DL-based image segmentation provides robust and fast quantification of AT (≈15 s per dataset versus 3 to 4 hours for manual processing) and assessment of its spatial distribution from magnetic resonance images in large cohort studies.

Background: Blood kallikrein-8 is supposed to be a biomarker for mild cognitive impairment (MCI) due to Alzheimer's disease (AD), a precursor of AD dementia. Little is known about the association of kallikrein-8 and non-AD type dementias., Objective: To investigate whether blood kallikrein-8 is elevated in individuals with non-amnestic MCI (naMCI), which has a higher probability to progress to a non-AD type dementia, compared with cognitively unimpaired (CU) controls., Methods: We measured blood kallikrein-8 at ten-year follow-up (T2) in 75 cases and 75 controls matched for age and sex who were participants of the population-based Heinz Nixdorf Recall study (baseline: 2000-2003). Cognitive performance was assessed in a standardized manner at five (T1) and ten-year follow-up. Cases were CU or had subjective cognitive decline (SCD) at T1 and had naMCI at T2. Controls were CU at both follow-ups. The association between kallikrein-8 (per 500 pg/ml increase) and naMCI was estimated using conditional logistic regression: odds ratios (OR) and 95% confidence intervals (95% CI) were determined, adjusted for inter-assay variability and freezing duration., Results: Valid kallikrein-8 values were measured in 121 participants (45% cases, 54.5% women, 70.5±7.1 years). In cases, the mean kallikrein-8 was higher than in controls (922±797 pg/ml versus 884±782 pg/ml). Kallikrein-8 was not associated with having naMCI compared to being CU (adjusted; OR: 1.03 [95% CI: 0.80-1.32])., Conclusion: This is the first population-based study that shows that blood kallikrein-8 tends not to be elevated in individuals with naMCI compared with CU. This adds to the evidence of the possible AD specificity of kallikrein-8., Competing Interests: SS, NK, UR, KHJ, and MJ have no competing interests. AH and KK are inventors on the patent “Agents inhibiting Kallikrein-8 for use in the prevention or treatment of Alzheimer’s Disease”; patent no. 3353214, issued by The European Patent Office on 22/07/2021., (© 2023 – The authors. Published by IOS Press.)

Background: White matter hyperintensities of presumed vascular origin (WMH) are frequent in cerebral magnetic resonance imaging of older people. They are promoted by vascular risk factors, especially hypertension, and are associated with cognitive deficits at the group level. It has been suggested that not only the severity, but also the location, of lesions might critically influence cognitive deficits and represent different pathologies., Methods: In 560 participants (65.2 ± 7.5 years, 51.4% males) of the population-based 1000BRAINS study, we analyzed the association of regional WMH using Fazekas scoring separately for cerebral lobes, with hypertension and cognition., Results: WMH most often affected the frontal lobe (83.7% score >0), followed by the parietal (75.8%), temporal (32.7%), and occipital lobe (7.3%). Higher Fazekas scores in the frontal, parietal, and temporal lobe were associated with higher blood pressure and antihypertensive treatment in unadjusted ordinal regression models and in models adjusted for age, sex, and vascular risk factors (e.g., age- and sex-adjusted odds ratio = 1.14, 95% confidence interval = 1.03-1.25 for the association of frontal lobe WMH Fazekas score with systolic blood pressure [SBP] [per 10 mm Hg]; 1.13 [1.02-1.23] for the association of parietal lobe score with SBP; 1.72 [1.19-2.48] for the association of temporal lobe score with antihypertensive medications). In linear regressions, higher frontal lobe scores were associated with lower performance in executive function and non-verbal memory, and higher parietal lobe scores were associated with lower performance in executive function, verbal-, and non-verbal memory., Conclusions: Hypertension promotes WMH in the frontal, parietal, and temporal lobe. WMH in the frontal and parietal lobe are associated with reduced executive function and memory., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

There is an ongoing debate on the COVID-19 infection fatality rate (IFR) and the impact of COVID-19 on overall population mortality. Here, we addressed these issues in a community in Germany with a major superspreader event analyzing deaths over time and auditing death certificates in the community.18 deaths that occurred within the first six months of the pandemic had a positive test for SARS-CoV-2. Six out of 18 deaths had non-COVID-19 related causes of death (COD). Individuals with COVID-19 COD typically died of respiratory failure (75%) and tended to have fewer reported comorbidities (p = 0.029). Duration between first confirmed infection and death was negatively associated with COVID-19 being COD (p = 0.04). Repeated seroprevalence essays in a cross-sectional epidemiological study showed modest increases in seroprevalence over time, and substantial seroreversion (30%). IFR estimates accordingly varied depending on COVID-19 death attribution. Careful ascertainment of COVID-19 deaths is important in understanding the impact of the pandemic., (© 2023. The Author(s).)

Aim of the Study: The aim of the project was to investigate regional differences in thyroid stimulating hormone (TSH), and free thyroxine (fT4) concentrations and iodine status in comparable German and European cohort studies., Methods: Sex- and age-stratified TSH, fT4, and urine iodine concentrations of thyroid-healthy participants (age group 45-75 years) of the HNR (Heinz Nixdorf Recall) Study in the Ruhr region of Germany, the southern German KORA (Cooperative Health Research in the Augsburg Region) and northeastern German SHIP (Study of Health in Pomerania) studies, as well as the Norwegian HUNT (Nord-Trøndelag Health) study (age group 40-79 years), the English EPIC (European Prospective Investigation of Cancer)-Norfolk study, and the Dutch Rotterdam study were compared. The TSH reference range for the HNR study population was calculated and compared to the KORA and SHIP studies., Results: Regional differences showed a stronger influence on TSH and fT4 concentrations than sex and age of the subjects in the 45- to 75-year age group. The estimated difference in medians, as measured by the HNR study, was lowest in the SHIP study, -0.47 (95% CI: -0.53; -0.41) for men and -0.41 (-0.53; -0.41) for women. The Rotterdam study had the highest difference in medians for both men and women (men: 0.56 with 0.44; 0.68 and women: 0.62 with 0.46; 0.78). The lowest median TSH concentrations, across all age categories considered, were seen in the German cohorts., Conclusions: Comparison of thyroid function parameters and iodine in elderly subjects between six comparable cohort studies from Germany and Europe showed a significant influence of region, which exceeded the sex and age dependence of the parameters., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The aim of the long-term Heinz Nixdorf Recall Study (observation period 20 years) was to establish the extent to which computed tomography (CT) improves the predictability of cardiovascular events relative to determination of risk factors alone., Methods: In the period 2000-2003, study staff examined 4355 probands (53% of them female) aged 45-75 years with no signs of cardiovascular disease. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated on the basis of demographic data and cardiovascular risk factors. Cardiac CT was carried out over the same period and coronary artery calcification (CAC) was graded according to the Agatston score., Results: The median duration of follow-up was 18.2 years for men and 17.8 years for women. Myocardial infarction or stroke occurred in 458 (11%) of the 4154 participants with complete data. Overall, estimation of risk using a combination of ASCVD score and CAC grade was superior to the ASCVD score alone-even after 10 and 20 years. Classification into established risk categories improved by 12.2% (95% confidence interval: [5.3%; 18.1%]). In the highest ASCVD risk category, we observed occurrence of a cardiovascular event over 20 years for 14% [5.0%; 23.1%] of probands with a CAC score = 0 but for 34.2% [27.5%; 41.4%] of those with a CAC score ≥ 400. In the lowest ASCVD risk category, an event occurred in 2.4% [1.4%; 3.7%] of probands with a CAC score = 0 and in 23.5% [2.3%; 35.8%] of those with a CAC score ≥ 400., Conclusion: Even after 20 years, individual risk prediction is improved by addition of CT-based determination of coronary artery calcification to the ASCVD score. Therefore, assessment of ASCVD risk factors should be complemented more widely by cardiac CT in the primary prevention of cardiovascular disease.

Objective: Thyroid-stimulating hormone (TSH) is influenced by genetic and environmental 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 (GESTSH&#95;2013 and GESTSH&#95;2020) based on two different GWAS meta-analyses that affect TSH values in a population-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 regression models. Interactions between SEP indicators and GESTSH were assessed by GESTSH × SEP interaction terms, single reference joint effects and calculating 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 TSH values per GESTSH&#95;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 interaction terms, some weak indication for a positive GESTSH&#95;2013 by education interaction was observed showing an interaction effect size estimate of 1.005 (95% CI: 1.000-1.010) per year of education and GESTSH&#95;2013 SD. No indication for interaction was observed for using income as SEP indicator. Using the GESTSH&#95;2020, similar results were observed., Conclusion: Our results gave some indication that education may affect the expression 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.

Background: The European Working Group on Sarcopenia in Older People (EWGSOP) updated in 2018 the cut-off points for low grip strength to assess sarcopenia based on pooled data from 12 British studies., Objective: Comparison of the EWGSOP2 cut-off points for low grip strength to those derived from a large German sample., Methods: We assessed the grip strength distribution across age and derived low grip strength cut-off points for men and women (peak mean -2.5 × SD) based on 200,389 German National Cohort (NAKO) participants aged 19-75 years. In 1,012 Cooperative Health Research in the Region of Augsburg (KORA)-Age participants aged 65-93 years, we calculated the age-standardised prevalence of low grip strength and time-dependent sensitivity and specificity for all-cause mortality., Results: Grip strength increased in the third and fourth decade of life and declined afterwards. Calculated cut-off points for low grip strength were 29 kg for men and 18 kg for women. In KORA-Age, the age-standardised prevalence of low grip strength was 1.5× higher for NAKO-derived (17.7%) compared to EWGSOP2 (11.7%) cut-off points. NAKO-derived cut-off points yielded a higher sensitivity and lower specificity for all-cause mortality., Conclusions: Cut-off points for low grip strength from German population-based data were 2 kg higher than the EWGSOP2 cut-off points. Higher cut-off points increase the sensitivity, thereby suggesting an intervention for more patients at risk, while other individuals might receive additional diagnostics/treatment without the urgent need. Research on the effectiveness of intervention in patients with low grip strength defined by different cut-off points is needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The link between exposure to ambient air pollution and mortality from cardiorespiratory diseases is well established, while evidence on neurodegenerative disorders including Parkinson's Disease (PD) remains limited., Objective: We examined the association between long-term exposure to ambient air pollution and PD mortality in seven European cohorts., Methods: Within the project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven cohorts among six European countries. Annual mean residential concentrations of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), black carbon (BC), and ozone (O 3 ), as well as 8 PM 2.5 components (copper, iron, potassium, nickel, sulphur, silicon, vanadium, zinc), for 2010 were estimated using Europe-wide hybrid land use regression models. PD mortality was defined as underlying cause of death being either PD, secondary Parkinsonism, or dementia in PD. We applied Cox proportional hazard models to investigate the associations between air pollution and PD mortality, adjusting for potential confounders., Results: Of 271,720 cohort participants, 381 died from PD during 19.7 years of follow-up. In single-pollutant analyses, we observed positive associations between PD mortality and PM 2.5 (hazard ratio per 5 µg/m 3 : 1.25; 95% confidence interval: 1.01-1.55), NO 2 (1.13; 0.95-1.34 per 10 µg/m 3 ), and BC (1.12; 0.94-1.34 per 0.5 × 10 -5 m -1 ), and a negative association with O 3 (0.74; 0.58-0.94 per 10 µg/m 3 ). Associations of PM 2.5 , NO 2 , and BC with PD mortality were linear without apparent lower thresholds. In two-pollutant models, associations with PM 2.5 remained robust when adjusted for NO 2 (1.24; 0.95-1.62) or BC (1.28; 0.96-1.71), whereas associations with NO 2 or BC attenuated to null. O 3 associations remained negative, but no longer statistically significant in models with PM 2.5 . We detected suggestive positive associations with the potassium component of PM 2.5 ., Conclusion: Long-term exposure to PM 2.5 , at levels well below current EU air pollution limit values, may contribute to PD mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: (Excess) mortality and years of life lost are important measures of health risks from the Corona pandemic. The aim of this paper was to identify methodological factors that affect the calculation of mortality and further to point out possible misinterpretations of years of life lost., Methodology: Standardized mortality ratios (SMRs) can be used to compare mortalities (e. g., an SMR of 1.015 means excess mortality of 1.5%, an SMR of 0.990 means that mortality is reduced by 1.0%). In this study, SMRs as a measure of association for mortality in Germany were calculated for 2020 using different methods. In particular, the influence of different data sources and reference periods was examined. Furthermore, its influence on the calculated mortality was also examined to take into account increasing life expectancy. In addition, published results on years of life lost were critically analyzed., Results: Using January 2022 data from the Federal Statistical Office on mortality for 5-year age groups resulted in higher SMR values than using preliminary data from February 2021 with 20-year age groups (SMR=0.997, 95% confidence interval (CI): 0.995-0.999 versus SMR=0.976 (95% CI: 0.974-0.978)). The choice of the reference period had a large impact on calculated mortality (for men, SMR=1.024 (95% CI: 1.022-1.027) with 2019 as the reference year versus SMR=0.998 (95% CI: 0.996-1.001) with 2016 to 2019 as the reference period). Analyses in which declining mortality in 2016 to 2019 was carried forward into 2020 when calculating expected deaths resulted in significantly higher SMR values (for men SMR=1.024 (95% CI: 1.021-1.026) with, and SMR=0.998 (95% CI: 0.996-1.001) without carrying forward declining mortality). Figures for pandemic-related years of life lost per person who died from COVID-19 should be interpreted with caution: Calculation from remaining life reported in mortality tables can lead to misleading results., Conclusion: When calculating mortality and years of life lost during the pandemic, a number of methodological assumptions must be made that have a significant impact on the results and must be considered when interpreting the results., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

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., (© 2022. The Author(s).)

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), black carbon (BC), ozone (O 3 ), and 8 PM 2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO 2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m 3 ), PM 2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m 3 ), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10 -5 /m) with psychiatric disorders mortality, as well as with suicide (NO 2 : HR = 1.13 [95 % CI: 0.92, 1.38]; PM 2.5 : HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O 3 and 8 PM 2.5 components with any of the three mortality outcomes. Long-term exposure to NO 2 , PM 2.5 , and BC may lead to premature mortality from psychiatric disorders and suicide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: White matter hyperintensities (WMH) of presumed vascular origin are frequent in cerebral MRI of older people. They represent a sign of small vessel disease, are promoted by arterial hypertension, and relate to cognitive deficits. The interdependence of blood pressure and its treatment, WMH, and cognitive performance has not systematically been studied in population-based studies., Methods: Consequently, we analysed the interdependence of SBP, DBP, and antihypertensive medications, as well as BP/treatment category, with WMH and cognitive performance in 560 participants of the population-based 1000BRAINS study., Results: BP, its treatment, and BP/treatment category were moderately associated with cognitive performance (e.g. unadjusted β  = -0.10, 95%CI = -0.19 to -0.02 for the association of SBP (per standard deviation of 17.2 mmHg) with global cognition (per standard deviation of 0.5 z score)]. The harmful effect of BP on cognition was strongly mediated by periventricular hyperintensities (PVH), which were significantly associated with both SBP [ β  = 0.24, 95% CI = 0.14-0.34 (per 1-point-increase in Fazekas score)] and global cognition ( β  = -0.22, 95%CI =  -0.32 to -0.13). Thus, PVH mediated as much as 52% of the effects of SBP on cognitive performance. Mediation was less strong for deep white matter hyperintensities (DWMH, 16%), which showed less association with SBP ( β  = 0.14, 95% CI = 0.05-0.24) and global cognition ( β  = -0.12, 95%CI = -0.21 to -0.03). Regarding different cognitive domains, PVH most strongly mediated effects of SBP on nonverbal memory (94%) and executive function (81%)., Conclusion: Our results indicate that PVH may predispose to cognitive impairment associated with hypertension, especially in the domains of nonverbal memory and executive function., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Physical and social neighbourhood characteristics can vary according to the neighbourhood socio-economic status (SES) and influence residents' perceptions, behaviours and health outcomes both positively and negatively. Neighbourhood SES has been shown to be predictive of mental health, which is relevant for healthy ageing and prevention of dementia or depression. Positive affectivity (PA) is an established indicator of mental health and might indicate a positive emotional response to neighbourhood characteristics. In this study, we focussed on the association of neighbourhood SES with PA among older residents in Germany and considered social integration and environmental perceptions in this association., Methods: We used questionnaire-based data of the ongoing population-based Heinz Nixdorf Recall Study for our cross-sectional analysis, complemented by secondary data on social welfare rates in the neighbourhood of residents' address. PA was assessed using the Positive and Negative Affect Schedule (PANAS) in 2016. Linear regression models were performed to estimate the associations and adjusted for socio-demographic variables., Results: Higher social welfare rates were associated with lower PA scores. The strongest negative association from the crude model (b = -1.916, 95%-CI [-2.997, -0.835]) was reduced after controlling for socio-demographic variables (b = -1.429, 95%-CI [-2.511, -0.346]). Social integration factors (b = -1.199, 95%-CI [-2.276, -0.121]) and perceived environmental factors (b = -0.875, 95%-CI [-1.971, 0.221]) additionally diminished the association of social welfare rates with PA in the full model (b = -0.945, 95%-CI [-2.037, 0.147])., Conclusion: Our results suggest that neighbourhoods have an influence on the occurrence and the extent of PA. Public health interventions that address socio-economic disadvantage in the neighbourhood environment could be an effective and far-reaching way to reduce the risk of depression and depressive symptoms due to low PA in older residents., (© 2022. The Author(s).)