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To investigate the 5-year cumulative incidence and progression of myopic maculopathy in the general population in Germany and to analyze potential risk factors.The Gutenberg Health Study (GHS) is a population-based cohort study including 15 010 participants aged 35 to 74 years at baseline.A total of 494 eyes of 323 participants (mean age, 50.2 ± 9.2 years; median, -7.25 diopters [D] myopic refractive error) without myopic maculopathy at baseline and 34 eyes of 27 subjects (mean age, 56.7 ± 9.1 years; median, -8.75 D myopic refractive error) with myopic maculopathy met the inclusion conditions, phakic eyes with spherical equivalent ≤-6 D (baseline), and had gradable fundus photographs at baseline and 5-year follow-up.Myopic maculopathy incidence and progression were assessed by grading of fundus photographs according to a recent international photographic classification system (META-PM). Multivariable logistic regression analysis was used to assess risk factors for progression of myopic maculopathy.Estimates for incidence and progression of myopic maculopathy.The 5-year cumulative incidence of myopic maculopathy was 0.3% (95% confidence interval [CI], 0.02-1.99; n = 1). Progression occurred in 17 of 34 eyes (50%) with prior myopic maculopathy over 5 years with 4 changes in category. The most common types of progression were enlargement of diffuse and patchy chorioretinal atrophy; a new pathology was present in 8 eyes. Higher intraocular pressure (IOP) (odds ratio [OR], 1.62; 95% CI, 1.51-1.59; P = 0.035) was associated with progression of myopic maculopathy. Female gender (OR, 5.54; 95% CI, 0.93-32.92; P = 0.060) and higher myopic refractive error (OR, 1.62 per diopter; 95% CI, 0.99-1.49; P = 0.063) showed a tendency toward progression.Incidence of myopic maculopathy is rare in highly myopic eyes in the general population aged 35 to 74 years in Germany. Progression of myopic maculopathy in the German population occurred in 50% of highly myopic eyes. We presented population-based 5-year follow-up data on incidence and progression of myopic maculopathy in Europe.

Alpha fetoprotein (AFP) is the most widely used diagnostic and prognostic serum biomarker for hepatocellular carcinoma (HCC). Despite its wide clinical use, a systematic clinicopathologic study comparing AFP expression in HCC in situ with serum AFP concentrations has not yet been conducted. To analyze AFP expression in a large cohort of patients by immunohistochemistry, we employed a comprehensive tissue microarray with 871 different HCCs of overall 561 patients. AFP immunoreactivity was detected in only about 20% of HCC core biopsies, whereas 48.9% of the patients displayed increased serum values (12 ng/mL). Immunostaining of whole tumor slides revealed that lack of detectable immunoreactivity in core biopsies in a subgroup of patients with elevated AFP serum concentrations is due to heterogeneous intratumoral AFP expression. Serum AFP concentrations and AFP expression in situ were moderately correlated (Spearman's rank correlation coefficient .53, P = 1.2e - 13). High AFP expression detected in serum (227.3 ng/mL) or in situ predicted unfavorable prognosis and was associated with vascular invasion, higher tumor grade and macrotrabecular-massive tumor subtype. Multivariate and ROC curve analysis demonstrated that high AFP concentrations in serum is an independent prognostic parameter and represents the more robust prognostic predictor in comparison to AFP immunostaining of core biopsies. The previously published vessels encapsulating tumor clusters (VETC) pattern turned out as an additional, statistically independent prognostic parameter. AFP-positivity was associated with increased tumor cell apoptosis, but not with increased vascular densities. Additionally, AFP-positive tumors displayed increased proliferation rates, urea cycle dysregulation and signs of genomic instability, which may constitute the basis for their increased aggressiveness.

Hearing loss is the most common sensory impairment worldwide. It restricts patients in many aspects of their daily lives and can lead to social exclusion. Understanding this burden is a mandatory requirement for the care of those affected. Therefore, the aim of this study was to estimate the burden of hearing loss in a large German cohort.Cohort study.The Gutenberg Health Study is designed as a single-center, prospective, and observational cohort study and representative for the city of Mainz, Germany, with its district. Participants were interviewed concerning common otologic symptoms and tested by pure-tone audiometry. The primary outcome was hearing impairment stratified by age and sex. The prevalence of tinnitus was estimated for a subcohort to calculate disability-adjusted life years (DALYs). All results were weighted by the European Standard Population (ESP) 2013.A total of 5,024 participants (mean age: 61.2 years, 2,591 men and 2,433 women) were included in the study. Hearing impairment showed the following prevalence: 28.2% (95% confidence interval [CI], 26.9%-29.4%) mild impairment, 10.1% (95% CI, 9.3%-11.0%) moderate impairment, 2.3% (95% CI, 1.9%-2.7%) moderately severe impairment, 0.2% (95% CI, 0.1%-0.4%) severe impairment, 0% (95% CI, 0.0%-0.1%) profound impairment, and 0.1% (95% CI, 0.0%-0.2%) complete impairment. Weighted for the ESP 2013 (all ages), hearing impairment across all levels (with/without tinnitus) causes a total of 2,118.97 DALYs per 100,000.With 40.9% affected, the hearing loss represents a relevant burden of the German population. Understanding this will provide the basis for future guidelines on how to care for these patients.2 Laryngoscope, 132:1843-1849, 2022.

Background During the SARS-CoV-2 pandemic, preventive measures like physical distancing, wearing face masks, and hand hygiene have been widely applied to mitigate viral transmission. Beyond increasing vaccination coverage, preventive measures remain urgently needed. The aim of the present project was to assess the effect of protective behavior on SARS-CoV-2 infection risk in the population. Methods Data of the Gutenberg COVID-19 Study (GCS), a prospective cohort study with a representative population-based sample, were analyzed. SARS-CoV-2 infections were identified by sequential sampling of biomaterial, which was analyzed by RT-qPCR and two antibody immunoassays. Self-reported COVID-19 test results were additionally considered. Information on protective behavior including physical distancing, wearing face masks, and hand hygiene was collected via serial questionnaire-based assessments. To estimate adjusted prevalence ratios and hazard ratios, robust Poisson regression and Cox regression were applied. Results In total, 10,250 participants were enrolled (median age 56.9 [43.3/68.6] years, 50.8% females). Adherence to preventive measures was moderate for physical distancing (48.3%), while the use of face masks (91.5%) and the frequency of handwashing (75.0%) were high. Physical distancing appeared to be a protective factor with respect to SARS-CoV-2 infection risk independent of sociodemographic characteristics and individual pandemic-related behavior (prevalence ratio [PR] = 0.77, 95% confidence interval [CI] 0.62–0.96). A protective association between wearing face masks and SARS-CoV-2 transmission was identified (PR = 0.73, 95% CI 0.55–0.96). However, the protective effect declined after controlling for potential confounding factors (PR = 0.96, 95% CI 0.68–1.36). For handwashing, this investigation did not find a beneficial impact. The adherence to protective behavior was not affected by previous SARS-CoV-2 infection or immunization against COVID-19. Conclusion The present study suggests primarily a preventive impact of physical distancing of 1.5 m, but also of wearing face masks on SARS-CoV-2 infections, supporting their widespread implementation. The proper fit and use of face masks are crucial for effectively mitigating the spread of SARS-CoV-2 in the population.

Objectives Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (DM). The homeostatic model assessment of insulin resistance (HOMA-IR) provides an estimate for IR from fasting glucose and insulin serum concentrations. The aim of this study was to obtain a reference interval for HOMA-IR for a specific insulin immunoassay. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, single-center cohort study in Germany with 15,030 participants aged 35–74 years. Fasting glucose, insulin, and C-peptide were available in 10,340 participants. HOMA-IR was calculated in this group and three reference subgroups with increasingly more stringent inclusion criteria. Age- and sex-dependent distributions of HOMA-IR and reference intervals were obtained. In a substudy three insulin assays were compared and HOMA-IR estimated for each assay. Results Among the 10,340 participants analyzed there were 6,590 non-diabetic, 2,901 prediabetic, and 849 diabetic individuals. Median (interquartile range [IQR]) HOMA-IR was 1.54 (1.13/2.19), 2.00 (1.39/2.99), and 4.00 (2.52/6.51), respectively. The most stringently selected reference group consisted of 1,065 persons. Median (IQR) HOMA-IR was 1.09 (0.85/1.42) with no significant difference between men and women. The 97.5th percentile was 2.35. There was a non-significant trend towards higher values with older age. Comparison of three immunoassays for insulin showed an unsatisfactory correlation among the assays and systematic differences in calculated HOMA-IR. Conclusions We present HOMA-IR reference intervals for adults derived by more or less stringent selection criteria for the reference cohort. In addition we show that assay specific reference intervals for HOMA-IR are required.

ObjectiveLittle is known on optimal screening population for detecting new atrial fibrillation (AF) in the community. We describe characteristics and estimate cost-effectiveness for a single timepoint electrocardiographic screening.MethodsWe performed a 12-lead ECG in the German population-based Gutenberg Health Study between 2007 and 2012 (n=15 010), mean age 55±11 years, 51% men and collected more than 120 clinical and biomarker variables, including N-terminal pro B-type natriuretic peptide (Nt-proBNP), risk factors, disease symptoms and echocardiographic variables.ResultsOf 15 010 individuals, 466 (3.1%) had AF. New AF was found in 32 individuals, 0.2% of the total sample, 0.5% of individuals aged 65–74 years and predominantly men (86%). The classical risk factor burden was high in individuals with new AF. The median estimated stroke risk was 2.2%/year, while risk of developing heart failure was 21% over 10 years. In the 65–74 year age group, the cost per quality-adjusted life-year gained resulting from a single timepoint screening was €30 361. In simulations, the costs were highly sensitive to AF detection rates, proportion of treatment and type of oral anticoagulant. Prescreening by Nt-proBNP measurements was not cost-effective in the current setting.ConclusionsIn our middle-aged population cohort, we identified 0.2% new AF by single timepoint screening. There was a significant estimated risk of stroke and heart failure in these individuals. Cost-effectiveness for screening may be reached in individuals aged 65 years and older. The simple age cut-off is not improved by using Nt-proBNP as a biomarker to guide a screening programme.

Background: Intermittent fasting (IF) is defined as an eating pattern without calorie restrictions, alternating between periods of fasting and eating. In the past decades IF has not only become a popular weight-reducing diet but is thought to improve Quality of Life (QoL) and fatigue. However, very little evidence exists for the general population. Thus, we aimed to assess the impact of a 16-h fasting period per day over a three-month study period on QoL and especially fatigue in healthy people. Methods: We conducted a prospective cohort study including healthy subjects. All participants fasted 16 h for at least five days a week while maintaining their normal lifestyle. In the study, we analysed blood samples as well as QoL through standardized questionnaires (WHO-5 questionnaire, Short Form Health 36). Furthermore, we measured the degree of fatigue with the Fatigue Assessment Scale (FAS) and Fatigue Severity Scale (FSS) as well as compliance, activity records, and weight alterations. All endpoints were evaluated at baseline, after two weeks, four weeks, and three months of IF. Results: A total of 30 participants fasted for the entire study period. The results of the WHO-5 questionnaire (15.6 ± 4.6 vs. 18 ± 3.6, p < 0.0019) demonstrated a significant increase in QoL. For long-term QoL six out of eight domains measured by the Short Form Health 36 (SF-36) significantly improved (e.g., physical health: 92.3 ± 11.6 vs. 96.5 ± 6.3, p = 0.015; mental health: 75.5 ± 12.0 vs. 81.7 ± 9.0; p < 0.001 and body pain: 74.1 ± 31.8 vs. 89.5 ± 14.9; p = 0.008) after three months. Fatigue significantly decreased from 10.3 ± 3.2 to 8.4 ± 2.5; p = 0.002 for mental fatigue and from 12.6 ± 3.8 to 10.7 ± 3.3; p = 0.002 measured by the FAS. The mean FSS-Score at baseline was 3.5 ± 1.2 compared to 2.9 ± 1.1 (scale 1–7) after three months (p < 0.001). Notably, the proliferation marker IGF-1 was significantly reduced. No clinically significant changes in laboratory parameters were observed that would have endangered a participant’s safety. Conclusions: IF according to the 16:8 regime over a fasting period of three months significantly improved several aspects of the QoL and decreased fatigue in healthy people, while maintaining a good safety profile. The practicability of this diet was also demonstrated for shift workers and people with a high percentage of active labour. Apart from the improvement in QoL and fatigue, the significant reduction in IGF-1, which can act as an accelerator of tumour development and progression, might be an indicator of the potential benefits of IF for patients with cancer.

Aims To assess the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in the general population and to investigate the associated cardiovascular burden and clinical outcome. Methods and Results The study sample comprised 15,010 individuals aged 35–74 years of the population-based Gutenberg Health Study. Subjects were classified into euglycaemia, prediabetes and T2DM according to clinical and metabolic (HbA1c) information. The prevalence of prediabetes was 9.5% (n = 1415) and of T2DM 8.9% (n = 1316). Prediabetes and T2DM showed a significantly increased prevalence ratio (PR) for age, obesity, active smoking, dyslipidemia, and arterial hypertension compared to euglycaemia (for all, P prediabetes 1.20, 95% CI 1.07–1.35, P = 0.002) and represented as a risk factor for asymptomatic cardiovascular organ damage independent of traditional risk factors (PR 1.04, 95% CI 1.01–1.08, P = 0.025). Prediabetes was associated with a 1.5-fold increased 10-year risk for cardiovascular disease compared to euglycaemia. In Cox regression analysis, prediabetes (HR 2.10, 95% CI 1.76–2.51, P P P Conclusion Besides T2DM, also prediabetes inherits a significant cardiovascular burden, which translates into poor clinical outcome and indicates the need for new concepts regarding the prevention of cardiometabolic disorders.

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

AIMS Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of noninvasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality. METHODS AND RESULTS In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N = 12,599) and fingertip peripheral arterial tonometry (N = 11,125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank

Purpose Low birth weight (BW) individuals have an increased risk for myopic refractive error. However, it is unclear which ocular geometric alterations lead to an increase in myopic refractive error. This study aims to evaluate the impact of ocular biometry in interaction with BW on refractive error. Methods Participants of the prospective, observational, population-based Gutenberg Health Study (GHS) with self-reported BW aged 40–80 years and objective refraction and optical biometry were included. Linear regression analyses were conducted to evaluate associations between spherical equivalent with corneal power, anterior chamber depth, lens thickness and axial length and its interaction with BW adjusted for age and sex. Low BW was defined as BW

Purpose: To investigate the incidence of retinal detachment in the German population and to assess potential risk factors. Methods: The Gutenberg Health Study is a population-based cohort study in Mainz, Germany, including subjects (n = 15,010) with an age range from 35 to 74 years at baseline examination. Study participants underwent a comprehensive ophthalmological examination including distant-corrected visual acuity, refraction and slit-lamp examination at baseline examination. A computer-assisted telephone interview was conducted after 2.5 and 5 years, and health events were recorded. The 5-year cumulative incidence of retinal detachment was computed for the study sample and stratified on age decades. Risk factors were analyzed using logistic regression including age, sex, spherical equivalent, pseudophakia and prior laser retinal therapy. Results: 13,416 participants (age 52.2 ± 10.7 years, 48.8% female) were included in this analysis. Twenty-eight subjects had a retinal detachment in one eye, no subject had a retinal detachment in both eyes. The 5-year cumulative incidence of retinal detachment was 0.21% (95% CI 0.14–0.31%), the incidence rate was 42/100,000 person-years. Risk factors were male sex (OR 4.16, p = 0.004), pseudophakia (OR 3.93, p = 0.045) and myopia (OR 1.31 per diopter myopia, p < 0.0001), but not prior retinal laser therapy or age. Conclusion: The incidence of retinal detachment in Germany at the age of 35–74 years is comparable to estimates from neighboring European countries. Risk factors are male sex, pseudophakia and myopia.

Objectives Following an exploratory approach, we examined cardiovascular disease risk factors at baseline and the 5-year incidence proportion of self-reported doctor-diagnosed cardiovascular diseases (CVD) in teachers and other occupational groups of the Gutenberg Health Study. Methods Study participants lived in the region of Mainz, Germany. Data from 6510 working participants without prevalent CVD at baseline (2007–2012) were analyzed. Participants were teachers (n = 215), other professionals from the health, social or educational (HSE) fields (n = 1061) or worked outside the HSE fields (n = 5234). For occupational comparisons, we estimated prevalence ratios (PR) for each CVD risk factor at baseline with robust Poisson regression analyses. We calculated crude CVD incidence rates based on the observed 5-year CVD cumulative incidence at follow-up and estimated age-weighted incidence proportions. All analyses were stratified by sex. Results Male non-HSE workers showed a higher prevalence of smoking and physical inactivity than male teachers (PR 2.26; 95%-CI: 1.06–4.82/PR 1.89; 95%-CI: 1.24–2.87). In contrast, non-HSE workers and other HSE professionals were less likely to have reported an unhealthy alcohol intake than teachers. Differences were attenuated after SES-adjustment. We did not detect occupational group-specific differences in CVD incidence. However, there were only two cases of CVD among the teachers. Conclusion Particularly male teachers showed a healthier lifestyle regarding physical inactivity and smoking. Nevertheless, occupational-medical care practitioners and researchers need to be aware of the relatively heightened prevalence of unhealthy alcohol intake in female and male teachers, and in absolute terms, the high hypertension prevalence in male teachers.

Purpose Age-related macular degeneration (AMD) is a major cause of visual impairment and blindness. This study evaluates the incidence and progression of AMD in a large German cohort. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany that includes 15,010 participants between 35 and 74 years of age. The baseline examination, including fundus photography, was conducted between 2007 and 2012, and the 5-year follow-up examination was performed between 2012 and 2017. AMD grading of fundus photographs was performed according to the Rotterdam Eye Study classification. The 5-year cumulative incidence and progression of AMD were calculated. Poisson regression analysis was conducted to investigate factors associated with the cumulative incidence and progression of AMD. Results Six-thousand-eight-hundred-eighty-eight participants (49.8%, n = 3427 female) were included in the analysis. AMD prevalence was 8.5% [95% CI: 7.9–9.2%] at baseline and 10.3% [95% CI: 9.6–11.1%] at follow-up. The cumulative 5-year-incidence was 2.0% [1.7–2.4%]. AMD progression within 5 years was seen in 18.1% [95% CI: 15.1–21.5%] of the participants. AMD incidence and AMD progression were associated with higher age, for each 10-year increase in age, the risk of AMD doubles (RR = 2.30), and the risk of progression of the disease is increased by 1.6. while AMD incidence also with pseudophakic status. Conclusions In summary, this population-based sample provides substantial epidemiologic data from a large German cohort, including data on progression and cumulative incidence of macular degeneration in younger age groups. AMD progression over 5 years is common in the German population, 18.1% of subjects with AMD showed progression in at least one eye in this time frame and is associated with higher age. Nevertheless, although usually defined to occur over the age of 50, in this cohort AMD occurred in 0.5% and AMD progression occurred in 5.4% of those already affected in the youngest age group before 50 years of age.

Low birth weight (LBW

Background Studies in immigrant youth have suggested differences in parenting patterns by immigration status. Knowledge of variation in recalled parenting pattern and its distinctive impact on mental health in adult immigrants, however, is limited. Therefore, the purpose of the current study was to investigate similarities and differences in recalled maternal and paternal rearing behavior and its association with depressiveness in adult 1st generation immigrants compared to non-immigrants. Methods Seven hundred and forty-three 1st generation immigrants (M = 57.4, SD = 10.1 years) and 6518 non-immigrants (M = 60.3, SD = 10.7 years) participated in a population-based study. Regarding countries of origin, the largest subgroups were immigrants from Eastern-Europe, Former-SU, and Arabic-Islamic countries. All participants completed the ultra-short version of The Recalled Parental Rearing Behavior-questionnaire and the PHQ-9 assessing depressiveness. Multiple linear regressions with depressiveness as outcome variable were analyzed separately for each facet of parental rearing behavior adjusting for socio-demographic and migration-related variables. Results In addition to differences in depressiveness and socioeconomic status, 1st generation immigrants recalled both their mothers and fathers as more controlling and overprotecting than non-immigrants. Parental emotional warmth was negatively associated with depressiveness across all groups. The relationship between parental control, respectively parental rejection and depressiveness, however, varied in direction and severity between the groups. Conclusion The results support the notion that parental warmth is a universal protective factor against depressiveness, whereas the impact of parental control on mental health might be more culturally influenced. Analyses point to the importance of considering the unique contribution of fathers’ rearing behavior on mental health, particularly in immigrant samples.

Background Interpretation of genetic variants detected by sequencing of genomic DNA, which may cause splicing defects, regularly requires mRNA analysis. Usually, only bioinformatic testing is provided, because simple and non-invasive assay protocols are lacking. Furthermore, the detection of mis-splicing is often hampered by nonsense mediated mRNA decay (NMD). Methods Starting from a case of Pompe disease with two potential splicing variants an assay for the analysis of splice defects in general was developed. We analyzed the transcripts from the gene of interest by standard methods after short-term culture of the patient's lymphocytes in the presence and absence of a NMD inhibitor. Variant and wild type transcript expression were quantified by allele specific PCR in the patient and both parents and the expression ratio with/without NMD inhibition was calculated for each transcript. Results NMD detection in lymphocytes was optimized and evaluated by analyzing a naturally occurring NMD transcript. Several compounds inhibited NMD successfully, including potential therapeutic agents. Sample storage for up to 4 days at room temperature prior to lymphocyte isolation did not affect results. In a proof of concept we identified two candidate variants as severe splicing variants in a patient with Pompe disease, but the strategy can also be used to screen for any mis-spliced transcripts prone to NMD. Conclusions We developed a simple, non-invasive assay for the detection and characterization of potential splicing variants. This is essential, because early and near-term diagnosis and disease classification is required to facilitate therapy in many genetic diseases.

Background Environmental noise exposure has been associated with increased cardiovascular morbidity and mortality. Recently, noise annoyance was shown to induce atrial fibrillation, which was accompanied by significantly increased levels of midregional pro atrial natriuretic peptide (MR-proANP). Therefore, the aim of the present study was to analyze the association between noise annoyance, MR-proANP, incident cardiovascular events, and all-cause mortality. Methods Levels of MR-proANP were measured in the first 5000 participants of the population-based Gutenberg Health Study. Annoyance was assessed separately for aircraft, road traffic, railway, neighborhood, and industrial/construction noise during the day and sleep. Results In cross-sectional analyses, aircraft noise annoyance during day and sleep, industrial/construction noise annoyance during day, and railway noise annoyance during sleep were independently associated with increased levels of MR-proANP after multivariable adjustment. After a 5-year follow-up period, there were 43 cases of incident atrial fibrillation and 103 of incident cardiovascular disease (comprising atrial fibrillation, coronary artery disease, myocardial infarction, heart failure, or stroke). Moreover, there were 301 deaths after a mean follow-up of 7.42 ± 1.66 years. An odds ratio (OR) of 2.82 ([95% confidence interval (CI) 1.86; 4.35], p p = 0.0046) for incident cardiovascular disease per 1-standard deviation (SD) increase in MR-proANP levels were found. A 36% (hazard ratio: 1.36 [95% CI 1.19; 1.55], p Conclusions Noise annoyance may contribute to cardiovascular morbidity and mortality and is characterized by increased levels of MR-proANP. Graphic abstract

Background Iron deficiency is now accepted as an independent entity beyond anemia. Recently, a new functional definition of iron deficiency was proposed and proved strong efficacy in randomized cardiovascular clinical trials of intravenous iron supplementation. Here, we characterize the impact of iron deficiency on all-cause mortality in the non-anemic general population based on two distinct definitions. Methods The Gutenberg Health Study is a population-based, prospective, single-center cohort study. The 5000 individuals between 35 and 74 years underwent baseline and a planned follow-up visit at year 5. Tested definitions of iron deficiency were (1) functional iron deficiency—ferritin levels below 100 µg/l, or ferritin levels between 100 and 299 µg/l and transferrin saturation below 20%, and (2) absolute iron deficiency—ferritin below 30 µg/l. Results At baseline, a total of 54.5% of participants showed functional iron deficiency at a mean hemoglobin of 14.3 g/dl; while, the rate of absolute iron deficiency was 11.8%, at a mean hemoglobin level of 13.4 g/dl. At year 5, proportion of newly diagnosed subjects was 18.5% and 4.8%, respectively. Rate of all-cause mortality was 7.2% (n = 361); while, median follow-up was 10.1 years. After adjustment for hemoglobin and major cardiovascular risk factors, the hazard ratio with 95% confidence interval of the association of iron deficiency with mortality was 1.3 (1.0–1.6; p = 0.023) for the functional definition, and 1.9 (1.3–2.8; p = 0.002) for absolute iron deficiency. Conclusions Iron deficiency is very common in the apparently healthy general population and independently associated with all-cause mortality in the mid to long term. Graphic abstract

Aims In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Methods and results The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P Conclusion As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-No 2011-005305-73

In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a transplant database. Of the 339 potential liver transplant candidates, uEtG was negative in 86.4 %. Most patients were male (64.3 %), with an average age of 56.42 ± 10.1 years. In the multivariate analysis, mean corpuscular volume (p = 0.001), urinary creatinine (p = 0.001), gamma-glutamyl transferase (p = 0.001), and hemoglobin (p = 0.003) were significantly associated with a positive uEtG test result. The sensitivity of the ELISA screening test was 100 % for uEtG values 2000 µg/L, as confirmed by LC-MS/MS. uEtG is an effective parameter to reveal alcohol consumption by patients on the waiting list for LT. The sensitivity of the ELISA is excellent for uEtG values 2000 µg/L, for which LC-MS/MS confirmation could be omitted. In der deutschen Richtlinie für die Wartelistenführung und die Organvermittlung gem. § 16 Abs. 1 S. 1 Nrn. 2 u. 5 TPG wird eine durch Bestimmung von Ethylglucuronid im Urin (uEtG) nachweisliche, absolute Alkoholabstinenzzeit von mindestens 6 Monaten als Voraussetzung für eine Lebertransplantation (LT) bei einer ethyltoxischen Leberzirrhose gefordert. Zwischen Januar 2015 und Juni 2016 wurde an der Universitätsmedizin Mainz uEtG mindestens einmal bei 339 Patienten mit Leberzirrhose und Indikation für eine LT mittels ELISA Screening Test (cut off: 500 µg/l) gemessen. Bei Werten ≥ 500 µg/l erfolgte ein massenspektrometrischer Bestätigungstest. Die Daten wurden prospektiv in einer LT-Datenbank erhoben. Von den 339 potenziellen LT Kandidaten waren 86,4 % uEtG-negativ. Die meisten Patienten waren männlich (64,3 %) und durchschnittlich 56,42 ± 10,1 Jahre alt. In der multivariaten Analyse waren MCV (p = 0,001), Urin-Kreatinin (p = 0,001), Gamma-Glutamyltransferase (GGT) (p = 0,001) und Hämoglobin (Hb) (p = 0,003) signifikant mit einem positiven uEtG assoziiert. Die Sensitivität des ELISA Screeningtest war bei uEtG-Werten 2000 µg/l 100 %. In unserer Real-World-Kohorte konnte uEtG als valider und zuverlässiger Marker zum Nachweis eines Alkoholkonsums bei Patienten auf der Warteliste zur Lebertransplantation bestätigt werden. Zudem konnten wir zeigen, dass der ELISA-Screenintest bei uEtG-Werten 2000 µg/l eine exzellente Sensitivität hat und somit auf den massenspektrometrischen Bestätigungstest verzichtet werden kann.

In this study, we aimed to identify the most important and sex-specific social, psychological, behavioral and somatic predictors of recurrent depressive symptoms. Data was obtained at two measurement points within five years by the Gutenberg Health Study (GHS). Out of N = 12,061 individuals, a sample of 877 (age 52.3 ± 9.9) who reported clinically relevant depressive symptoms at baseline was analyzed. Univariate analyses and multiple logistic regression analyses were conducted. Almost half of participants depressed at baseline also reported depressive symptoms five years later. Sex-stratified multivariate analyses revealed that solely social support remained a significant protective predictor against recurrence of depression in men (OR = 0.93; CI95% = 0.87–0.99), whereas in women smoking (OR = 1.97; CI95% = 1.23–3.22), and Type D personality (OR = 1.65; CI95% = 1.10–2.49) were significant risk factors. However, when analyzing the entire sample, no interaction effect between sex and each predictor turned out to be significant. Only social support was retained as an overall predictive factor. As depressive symptoms recur, depressive vulnerability is established involving personality, health behavior and social factors. Although no significant sex-specific interactions were observed, sex-stratified analyses point out different patterns for relevant predictors of recurrent depressive symptoms in men and women.

Data of the EMPA-REG OUTCOME study have demonstrated a beneficial effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on cardiovascular outcome in patients with type 2 diabetes. The reduction in cardiovascular mortality and hospitalization due to heart failure might be in part explained by the direct effects of empagliflozin on cardiac diastolic function. The EmDia trial investigates the short-term effects of empagliflozin compared to placebo on the left ventricular E/E' ratio as a surrogate of left ventricular diastolic function.EmDia is a single-center, randomized, double-blind, two-arm, placebo-controlled, parallel group study of phase IV. Individuals with diabetes mellitus type 2 (T2DM) are randomized 1:1 to receive empagliflozin 10 mg per day or a placebo for 12 weeks. The main inclusion criteria are diagnosed as T2DM with stable glucose-lowering and/or dietary treatment, elevated HbA1c level (6.5-10.0% if receiving glucose-lowering therapy, or 6.5-9.0% if drug-naïve), and diastolic cardiac dysfunction with left ventricular E/E'≥8. The primary end point is the difference of the change in the E/E' ratio by treatment groups after 12 weeks. Secondary end points include assessment of the effect of empagliflozin on left ventricular systolic function, measures of vascular structure and function, as well as humoral cardiovascular biomarkers (i.e. brain natriuretic peptide, troponin, C-reactive protein). In addition, the multidimensional biodatabase enables explorative analyses of molecular biomarkers to gain insights into possible mechanisms of the effects of empagliflozin on human health in a systems medicine-oriented, multiomics approach.By evaluating the short-term effect of empagliflozin with a comprehensive biobanking program, the EmDia Study offers an opportunity to primarily assess the effects on diastolic function but also to examine effects on clinical and molecular cardiovascular traits.ClinicalTrials.gov; NCT02932436. Registration date, 2016/10/13.

The prevalence of liver disease, and especially of advanced liver fibrosis, in the German population is poorly defined. The aim of the study was to explore liver enzymes and surrogate scores of hepatic steatosis and advanced hepatic fibrosis in a population-based cohort study in Germany. In the cross-sectional population-based Gutenberg Health study, data of 14,950 participants enrolled between 2007 and 2012 were captured and analyzed. The distribution of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), fatty liver index (FLI), and Fibrosis-4 (FIB-4) score, as well as the underlying risk factors, were assessed by regression models. Elevated liver enzymes in this population-based sample were seen in 19.9% for ALT, 12.8% for AST, and 14% for GGT. Risk factors for liver disease included alcohol use and the presence of the metabolic syndrome, which were both risk factors associated with increased liver enzymes. The FLI suggested that 37.5% of the population exhibited hepatic steatosis and 1.1% of patients exhibited a FIB-4 above the upper cutoff, while 19.2% were in the intermediate range. Interestingly, advanced fibrosis was significantly more frequent in men compared with women (FIB-4: 1.5% vs. 0.6% [P 0.0001]; NFS: 3.6% vs. 1.9% [P 0.0001]). In addition, age was a relevant risk factor for exhibiting a noninvasive surrogate score suggestive of advanced fibrosis in the current study population. Conclusion: Elevated liver enzymes were seen in almost a fifth of the German population. At the population-based level, the prevalence of advanced fibrosis was estimated at 1% in Germany.

PURPOSE Changes in peripheral corneal thickness are described in various corneal diseases such as corneal ectasia. However, few data exist describing the increase in corneal thickness from central to peripheral and reporting the normal distribution of corneal thickness in rings around the corneal centre. The aim of this study was to report these cornea characteristics and investigate associated factors in a population-based setting. METHODS The Gutenberg Health Study is a prospective, population-based study examining participants in a 5-year follow-up (age range 40-80 years) using Scheimpflug imaging. Corneal thickness was assessed in each participant at the apex, as well as in the corneal centre (thinnest corneal thickness) and in rings with 2, 4, 6, 8 and 10 mm diameter around the corneal centre, and the increase in corneal thickness towards the periphery. The relationship between corneal thickness at these locations and possible associated factors was determined using linear regression models. For this purpose, general and ocular parameters were included. RESULTS A total of 9729 participants were included in the present analysis (4874 women, age 59.2 ± 10.8 years). Multivariable analysis showed a correlation between the increase in corneal thickness in the circles from 0 to 10 mm (diameter) and the following parameters: age (B = -0.24 µm per year, p

Use of galectin-3 for assessing cardiac function in prediabetes and type 2 diabetes mellitus (T2DM) needs to be established. Within the Gutenberg Health Study cohort (N = 15,010, 35–74 years) patient characteristics were investigated regarding galectin-3 levels. Prognostic value of galectin-3 compared to NT-proBNP concerning cardiac function and mortality was assessed in individuals with euglycaemia, prediabetes and T2DM in 5 years follow-up. Higher galectin-3 levels related to older age, female sex and higher prevalence for prediabetes, T2DM, cardiovascular risk factors and comorbidities. Galectin-3 cross-sectionally was related to impaired systolic (β − 0.36, 95% CI − 0.63/− 0.09; P = 0.008) and diastolic function (β 0.014, 95% CI 0.001/0.03; P = 0.031) in T2DM and reduced systolic function in prediabetes (β − 0.34, 95% CI − 0.53/− 0.15; P = 0.00045). Galectin-3 prospectively related to systolic (β − 0.656, 95% CI − 1.07/− 0.24; P = 0.0021) and diastolic dysfunction (β 0.0179, 95% CI 0.0001/0.036; P = 0.049), cardiovascular (hazard ratio per standard deviation of galectin-3 (HRperSD) 1.60, 95% CI 1.39–1.85; P

Background Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex‐specific relations between domains of physical activity (PA; commuting, domestic, and leisure‐time PA, including active sport and occupational PA) with AS were investigated. Methods and Results Stiffness index by digital photoplethysmography was investigated in 12 650 subjects from the GHS (Gutenberg Health Study). Self‐reported PA was evaluated by the “Short Questionnaire to Assess Health‐Enhancing Physical Activity” and reported as activity score peer week, being a combined measure of duration, frequency, and intensity of PA. Multivariable linear regression analysis demonstrated strong beneficial effects of repetitive activities, such as active commuting or leisure‐time PA–related walking on AS in men, but not in women. Lower AS associated with endurance training was also found among men and premenopausal women. In contrast, intense occupational PA was related to stiffer vessels in men ( P P =0.0021) in a fully adjusted model. Combination of both, performing endurance training and having stiffness index values below median, resulted in the best survival. In contrast, subjects with elevated stiffness index at baseline without any endurance activities demonstrated the worst survival. Conclusions In this population representative sample, a differential impact of domains of self‐reported PA on AS was demonstrated. Our data strengthen the importance of regular endurance PA to induce a reduction of AS, which, in turn, may improve cardiovascular prognosis. We also report deleterious effects of intense occupational PA on stiffness index, a finding that needs further confirmation by larger prospective trials.

COPD is an established predictor of clinical outcome in patients with chronic heart failure (HF). However, little evidence is available about the predictive value of FEVIs pulmonary function related to the progression of chronic HF?The MyoVasc study (ClinicalTrials.gov Identifier: NCT04064450) is a prospective cohort study of HF. Information on pulmonary and cardiac functional and structural status was obtained by body plethysmography and echocardiography. The primary study end point was worsening of HF.Overall 2,998 participants (age range, 35-84 years) with available FEVFEVClinicalTrials.gov; No.: NCT04064450; URL: www.clinicaltrials.gov.

Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease. Data from the prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF). Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (E/E′: β − 0.24 [− 0.36/− 0.12]; P

Background: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.Methods: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation–validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.Results: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.Conclusions: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.)

In contrast to overanticoagulation, evidence on risk factors and outcome of subtherapeutic oral anticoagulation (OAC) with vitamin K-antagonists (VKAs) under optimum care is limited. We investigated the clinical phenotype, anticoagulation control, and clinical outcome of 760 VKA patients who received OAC therapy by a specialized coagulation service in the thrombEVAL study (NCT01809015). During 281,934 treatment days, 278 patients experience ≥ 1 episode of subtherapeutic anticoagulation control and had lower quality of OAC therapy compared to 482 patients without subtherapeutic international normalized ratio: 67.6%, interquartile range (IQR) 54.9%/76.8% versus 81.0%, IQR 68.5%/90.4%; p

Choroidal thickness is associated with several cardiovascular parameters in case–control studies including patients with manifest disease. So far, it was unclear whether underlying cardiovascular risk factors or the continuum of heart failure may lead to alterations of the choroid. Therefore, our hypothesis was to test in a population-based study, whether choroidal thickness is associated with cardiovascular risk factors and heart disease. A population-based cross-sectional study was carried out in Germany. A comprehensive medical examination including assessment of cardiovascular risk factors, echocardiography and ophthalmological examinations with spectral-domain optical coherence tomography of the choroid was performed. Subfoveal choroidal thickness as well as left ventricular ejection fraction (LVEF) and a surrogate marker for left ventricular end-diastolic pressure (E/e’) were measured. Linear regression analyses were carried out to determine the relationship between subfoveal choroidal thickness and age, sex, body mass index, systolic blood pressure, dyslipidemia, HbA1c level, hematocrit, estimated glomerular filtration rate (eGFR), LVEF, E/e’ and left ventricular mass index adjusted for ocular parameters. 1.742 subjects (48% females) with a mean age 59.3 ± 10.6 years were included in this study. Mean subfoveal thickness was 252 ± 77 µm (right eyes) and 255 ± 77 µm (left eyes). Unadjusted linear regression analysis revealed that subfoveal choroidal thickness is associated with sex, age, systolic blood pressure, hematocrit, eGFR, left ventricular end-diastolic pressure, left ventricular mass index (all p

Background Higher, but also lower resting heart rate (HR), has been associated with increased cardiovascular events and mortality. Little is known about the interplay between HR, cardiovascular risk factors, concomitant diseases, vascular (endothelial) function, neurohormonal biomarkers, and all-cause mortality in the general population. Thus, we aimed to investigate these relationships in a population-based cohort. Methods 15,010 individuals (aged 35–74 at enrolment in 2007–2012) from the Gutenberg Health Study were analyzed. Multivariable regression modeling was used to assess the relation between the variables and conditional density plots were generated for cardiovascular risk factors, diseases, and mortality to show their dependence on HR. Results There were 714 deaths in the total sample at 7.67 ± 1.68 years of follow-up. The prevalence of diabetes mellitus, arterial hypertension, coronary and peripheral artery disease, chronic heart failure, and previous myocardial infarction exhibited a J-shaped association with HR. Mortality showed a similar relation with a nadir of 64 beats per minute (bpm) in the total sample. Each 10 bpm HR reduction in HR 64 subjects (Hazard Ratio 1.29; 95% confidence interval 1.19–1.41 per 10 bpm increase in HR). Results found for vascular and neurohormonal biomarkers exhibited a differential picture in subjects with a HR below and above the nadir. Discussion These results indicate that in addition to a higher HR, a lower HR is associated with increased mortality. Electronic supplementary material The online version of this article (10.1007/s00392-019-01466-2) contains supplementary material, which is available to authorized users.

The purpose of the study was (1) to determine the prevalence of somatic symptoms in men and women in the general population and (2) to identify the contributions of psychosocial factors and somatic disease on symptom reporting. A total of 7,925 participants aged 40 to 80 years underwent medical and psychological assessments, based on the PHQ-15 (Patient Health Questionnaire). We excluded 3 items in order to avoid confounding findings: 2 items overlapping with the depression measure (PHQ-9) and the menstruation complaints item which biases sex comparisons. Pain complaints (arms, legs, joints, back pain) affected the majority of men and women, and somatic symptom reporting increased with age. When confounding has been reduced, psychosocial factors (lack of social support, adverse life events, loneliness, depression, generalized anxiety, panic, social phobia) have remained the strongest predictors of somatic symptoms. As shown by the interaction between sex and depression, depression plays a smaller role for somatic symptom reporting in women vs. men. Findings highlight the complex psychosocial and somatic contributions to somatic symptom reporting.

The electrocardiographic pattern of early repolarization (ER) is related to increased cardiac mortality in the general population. The pathophysiological basis of ER is largely unknown. We investigated the association of echocardiographic structural and functional parameters of the left ventricle with the presence of ER in the community. The presence of ER (ER+) was assessed in 13,878 participants (mean age 54.6 years, 51.1% women) of the Gutenberg Health Study and related to left ventricular structure and function derived from standard echocardiography. The prevalence of ER was 5.0% (694/13,878), with higher prevalence in men than women (6.6% vs. 3.5%, p

Objectives:The Tower of London (TOL) test has probably become the most often used task to assess planning ability in clinical and experimental settings. Since its implementation, efforts were made to provide a task version with adequate psychometric properties, but extensive normative data are not publicly available until now. The computerized TOL-Freiburg Version (TOL-F) was developed based on theory-grounded task analyses, and its psychometric adequacy has been repeatedly demonstrated in several studies but often with small and selective samples.Method:In the present study, we now report reliability estimates and normative data for the TOL-F stratified for age, sex, and education from a large population-representative sample collected in the Gutenberg Health Study in Mainz, Germany (n=7703; 40–80 years).Results:The present data confirm previously reported adequate indices of reliability (>.70) of the TOL-F. We also provide normative data for the TOL-F stratified for age (5-year intervals), sex, and education (lowvs. high education).Conclusions:Together, its adequate reliability and the representative age-, sex-, and education-fair normative data render the computerized TOL-F a suitable diagnostic instrument to assess planning ability. (JINS, 2019,25, 520–529)

IMPORTANCE: Global longitudinal strain (GLS) is an emerging echocardiographic biomarker of cardiac function in heart failure (HF). Evidence from large-scale studies comprehensively investigating GLS for its association with clinical phenotypes and mortality in asymptomatic and symptomatic chronic HF is limited. OBJECTIVE: To assess the factors associated with GLS and its prognostic value in patients with chronic HF. DESIGN, SETTING, AND PARTICIPANTS: The observational, prospective MyoVasc cohort study enrolled 3289 individuals with asymptomatic to symptomatic HF between January 17, 2013, and April 27, 2018. The median follow-up was 3.2 years (interquartile range, 2.0-4.0 years). Participants with stages A to D HF according to American Heart Association (AHA) criteria were examined at a dedicated study center. Echocardiography was performed with GLS measurement by independent reviewers. Data were analyzed from September 2, 2019, to January 15, 2020. MAIN OUTCOMES AND MEASURES: All-cause and cardiac mortality were recorded by structured follow-up and validated via death certificates. RESULTS: In the study sample, data on GLS were available on 2440 individuals, of whom 2186 (mean [SD] age, 65.0 [10.5] years; 1418 [64.9%] men) were classified as having AHA HF stages A to D. Mean (SD) GLS worsened across AHA stages from stage A (n = 434; −19.44 [3.15%]) to stage B (n = 629; −18.01 [3.46%]) to stages C/D (n = 1123; −15.52 [4.64%]). Age (β = −0.27; 95% CI, −0.47 to −0.067; per decade, P = .009), female sex (β = −1.2; 95% CI, −1.6 to −0.77; per decade, P

Purpose We aimed to determine the prevalence of corneal arcus and to identify associated factors in the general population of Germany. Methods The Gutenberg Health Study (GHS) is a population-based cohort study in Germany, which includes an ophthalmological assessment. Refraction, distance-corrected visual acuity, non-contact tonometry and anterior segment imaging were performed for the five-year follow-up examination. Anterior segment photographs were graded for the presence of corneal arcus. Prevalence estimates were computed, and multivariable logistic regression analysis was applied to determine associated factors for corneal arcus including sex, age, spherical equivalent, central corneal thickness, intraocular pressure (IOP), socio-economic status, smoking, BMI, systolic and diastolic arterial blood pressure, HbA1c, HDL-C, LDL-C, triglyceride, and lipid modifying agents. Results A total of 9,850 right and 9,745 left eyes of 9,858 subjects (59.2±10.8 years), 49.0% females were included in this cross-sectional analysis. 21.1% of men (95%-CI: 20.0%– 22.3%) had a corneal arcus in at least one eye, and 16.9% (95%-CI: 15.9%– 18.0%) of women. In multivariable analyses, the presence of corneal arcus was associated with male gender (OR = 0.54 for female, p Conclusions Corneal arcus is a frequent alteration of the cornea in Germany and is associated with ocular parameters and systemic parameters of dyslipidemia.

Depression has been associated with increased inflammation. However, only few large-scale, prospective studies have evaluated whether inflammation leads to new cases of depression and whether this association can be found in men and women. Longitudinal data of N = 10,357 adult participants with no evidence of depression at baseline (based on Patient Health Questionnaire (PHQ-9), lifetime diagnoses, and current antidepressant medication) were evaluated for depression 5 years later. Multivariate logistic regression models were used to predict the onset of depression based on C-reactive protein (CRP) and white blood cell count (WBC). We used interaction terms and separate analyses in men and women to investigate gender-dependent associations. Based on both markers, inflammation was predictive of new cases of depression 5 years later, even when adjusting for sociodemographic, physical health, health behavior variables, and baseline depression symptoms. As established by interaction terms and separate analyses, inflammatory markers were predictive of depression in men, but not in women. Additional predictors of new onset of depression were younger age, loneliness, smoking (only in men), cancer and less alcohol consumption (only in women). The study indicates gender differences in the etiology of depressive disorders within the community, with a greater role of physical factors in men.

Zusammenfassung

Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.

Purpose The purpose of this study was to investigate the association between intraocular pressure (IOP) and ocular geometry. Methods The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Study participants underwent a comprehensive ophthalmologic examination including noncontact tonometry, objective refraction, optical biometry, and Scheimpflug imaging of the anterior segment at the first 5-year follow-up examination (in 2012–2017). Multivariable linear regression analysis was carried out to determine associations of IOP and geometric parameter of the human phakic eye, namely central corneal thickness (CCT), corneal curvature, anterior chamber depth (ACD), lens thickness, and axial length. In addition, the relationship of IOP and the anterior chamber angle (ACA) width was analyzed. Results There were 6640 participants with phakia (age 57.3 ± 10.2 years, 49.1% women) that were included in this cross-sectional analysis. Mean IOP was 14.8 ± 2.9 mm Hg in the right eyes and 14.9 ± 2.9 mm Hg in the left eyes. IOP increased with higher CCT, greater posterior segment length, higher age (all P < 0.001), thicker lens (P = 0.003), and female sex (P = 0.05), whereas the ACD was not associated with higher IOP. The IOP increased with a narrower ACA in univariable analysis (P < 0.001), but not in adjusted analysis in subjects with an open angle. Conclusions IOP values are related to ocular geometry, as shown in this population-based study on Caucasian subjects. Thus, knowledge of the architecture of the eye is an important factor when measuring IOP. Longitudinal evaluation will analyze whether some of these parameters are also risk factors for the development of glaucoma.

Objective Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality. Methods Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study (n = 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality. Results Multivariable linear regression analysis identified smoking (β 0.095 [0.054–0.136]) as a positive determinant for total TFPI activity, while diabetes (β –0.072 [–0.134 to –0.009]), obesity (β –0.063 [–0.101 to –0.024]), and history of coronary artery disease (CAD) were negatively associated with total TFPI activity, independent of age, sex, and the remaining cardiovascular risk factors. After adjustment for lipoprotein levels, the association between total TFPI activity levels and obesity and CAD was lost. The analysis additionally revealed a strong positive association between total TFPI activity levels and low-density lipoprotein (β 0.221 [0.204–0.237]). The Cox regression models revealed that a higher total TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (hazard ratio = 2.58 [95% confidence interval: 1.49–4.47]), independent of age, sex, and cardiovascular risk profile. Conclusion In the Gutenberg Health Study population-based cohort, the highest percentage of total TFPI correlated with an increased mortality risk. While elevated TFPI may reflect endothelial cell activation, the associations between total TFPI activity and obesity and CAD, points to additional mechanistic interactions.

Objectives: Addressing the lack of population-based data, the purpose of this representative study was to assess sex- and age-specific associations of maternal and paternal rearing behavior with depressiveness and anxiety controlling for sociodemographic and somatic variables. Methods: 8,175 subjects participating in a population-based study completed standardized questionnaires measuring Recalled Parental Rearing Behavior and distress. Results: Women recalled their fathers as more controlling and warmer, and their mothers as more rejecting than men. Comparisons between age groups (≤ 60 vs. > 60 years) revealed that younger participants recalled more parental control and emotional warmth. In addition to sociodemographic and somatic risk factors, paternal rejection and maternal control were associated with depressiveness and anxiety both for women and men (OR 1.58-1.96; OR 1.37-1.66). Maternal warmth was negatively related to distress (OR 0.66-0.69). Conclusions: Findings suggested sex- and age-specific differences in recalled maternal and paternal rearing behavior. The current results highlighted the important role of recalled parental rearing behavior besides sociodemographic factors and somatic diseases for the occurrence of depression and anxiety symptoms across the age groups.

Objective: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Escherichia coli augmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain–containing adapter-inducing interferon-β) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model. Conclusions: Collectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.

Background Coronary heart disease is a leading cause of mortality worldwide. Iron deficiency, a frequent comorbidity of coronary heart disease, causes an increased expression of transferrin receptor and soluble transferrin receptor levels (sTfR) levels, while iron repletion returns sTfR levels to the normal physiological range. Recently, sTfR levels were proposed as a potential new marker of iron metabolism in cardiovascular diseases. Therefore, we aimed to evaluate the prognostic value of circulating sTfR levels in a large cohort of patients with coronary heart disease. Methods and Results The disease cohort comprised 3423 subjects who had angiographically documented coronary heart disease and who participated in the AtheroGene study. Serum levels of sTfR were determined at baseline using an automated immunoassay (Roche Cobas Integra 400). Two main outcomes were considered: a combined end point of myocardial infarction and cardiovascular death and cardiovascular death alone. During a median follow‐up of 4.0 years, 10.3% of the patients experienced an end point. In Cox regression analyses for sTfR levels, the hazard ratio (HR) for future cardiovascular death and/or myocardial infarction was 1.27 (95% CI, 1.11–1.44, P P =0.02) after additional adjustment for body mass index, smoking status, hypertension, diabetes mellitus, dyslipidemia, C‐reactive protein, and surrogates of cardiac function, size of myocardial necrosis (hs‐Tnl), and hemoglobin levels. Conclusions In this large cohort study, sTfR levels were strongly associated with future myocardial infarction and cardiovascular death. This implicates a role for sTfR in secondary cardiovascular risk prediction.

Background Heart failure (HF) is a poly-aetiological syndrome with large heterogeneity regarding clinical presentation, pathophysiology, clinical outcome and response to therapy. The MyoVasc study (NCT04064450) is an epidemiological cohort study investigating the development and progression of HF. Methods The primary objective of the study is (a) to improve the understanding of the pathomechanisms of HF across the full spectrum of clinical presentation, (b) to investigate the current clinical classifications of HF, and (c) to identify and characterize homogeneous subgroups regarding disease development using a systems-oriented approach. Worsening of HF, that is, the composite of transition from asymptomatic to symptomatic HF, hospitalization due to HF, or cardiac death, was defined as the primary endpoint of the study. During a six-year follow-up period, all study participants receive a highly standardized, biannual five-hour examination in a dedicated study centre, including detailed cardiovascular phenotyping and biobanking of various biomaterials. Annual follow-up examinations are conducted by computer-assisted telephone interviews recording comprehensively the participants´ health status, including subsequent validation and adjudication of adverse events. Results In total, 3289 study participants (age range: 35 to 84 years; female sex: 36.8%) including the full range of HF stages were enrolled from 2013 to 2018. Approximately half of the subjects (n=1741) presented at baseline with symptomatic HF (i.e. HF stage C/D). Among these, HF with preserved ejection fraction was the most frequent phenotype. Conclusions By providing a large-scale, multi-dimensional biodatabase with sequential, comprehensive medical-technical (sub)clinical phenotyping and multi-omics characterization (i.e. genome, transcriptome, proteome, lipidome, metabolome and exposome), the MyoVasc study will help to advance our knowledge about the heterogeneous HF syndrome by a systems-oriented biomedicine approach. Trial registration ClinicalTrials.gov; NCT04064450.