Search

Purpose: Vitamin D (VitD) is a pleiotropic hormone with effects on a multitude of systems and metabolic pathways. Consequently, the relevance of a sufficiently high VitD serum level becomes self-evident., Methods: A rapid immunofluorescence assay designed for the point-of-care measurement of serum VitD 3 solely was tested. Inter- and intra-assay validation, double testing and result comparison with a standardized laboratory method were performed., Results: An overall linear correlation of r = 0.89 (Pearson, 95% CI 0.88-0.92, p < 0.01) between the point of care and the conventional reference assay was registered. Accuracy and precision were of special interest at cut-points (10 ng/ml [mean deviation 1.7 ng/ml, SD 1.98 ng/ml, SE 0.16 ng/ml], 12 ng/ml [MD 0.41, SD 1.89, SE 0.19] and 30 ng/ml [MD - 1.11, SD 3.89, SE 0.35]). Only a slight deviation was detected between the two assays when using fresh (r = 0.91, 95% CI 0.86-0.94, p < 0.01) and frozen serum samples (r = 0.86, 0.82-0.89, p < 0.01). Results remained steady when samples were frozen several times. Inter- and intra-assay validation according to the CLSI protocol as well as multiuser testing showed stable results., Conclusion: This novel, innovative, and controlled study indicates that the evaluated rapid point of care VitD assay is reliable, accurate, and suited for clinical practice., (© 2021. The Author(s).)

Purpose: Low birth weight (BW) is associated with alterations of foveal shape development in childhood-leading to an increased retinal thickness of the fovea. The aim of the present study was to assess whether BW has a long-term effect on foveal retinal thickness (RT) and is still present in adulthood., Methods: In the German population-based Gutenberg Health Study (GHS), participants were examined with spectral-domain optical coherence tomography. The association between self-reported BW and RT in the foveolar and perifoveal locations was assessed. Multivariable linear regression analyses with adjustment for potential confounders and grading of foveal hypoplasia were performed., Results: Overall, RT measurements and self-reported BW were available for 2,539 participants (1300 female, mean age 54.5 ± 9.7 years). The absolute foveolar RT was 239.6 ± 25.8 µm, 232.2 ± 20.1 µm and 234.8 ± 21.0 µm, respectively, in the low (<2500 g), normal (2500-4000 g) and high (>4000 g) BW groups (P < 0.001). After adjustment for confounders, an association was observed between lower BW and increased foveolar thickness (B = -0.35 [95% confidence interval {CI}: -0.49; -0.20] µm/100 g; P < 0.001), whereas only a weak association with RT was observed with the nasal (P = 0.010), temporal (P = 0.011), and inferior (P = 0.021) quadrants in the 1 mm distance, with no association in the 2 mm distance to the fovea. Foveal hypoplasia grade 1 was more frequent in the low BW group (6.8%) compared to the normal (0.9%) and high BW group (1.2%)., Conclusions: This study provides evidence of an association between lower BW and increased foveolar thickness and foveal hypoplasia, indicating that prenatal growth may affect macular morphology, which in turn may persist until adulthood and predispose to retinal disease later in life.

Aims: Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce., Methods and Results: Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6-37.4%], 13.3% [12.6-13.9%], and 40.8% [39.9-41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19-1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11-2.05), P = 0.009]., Conclusion: Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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 (HR perSD ) 1.60, 95% CI 1.39-1.85; P < 0.0001) and all-cause mortality (HR perSD 1.36, 95% CI 1.25-1.47; P < 0.0001) in T2DM. No relationship between galectin-3 and cardiac function was found in euglycaemia, whereas NT-proBNP consistently related to reduced cardiac function. Prospective value of NT-proBNP on cardiovascular and all-cause mortality was higher. NT-proBNP was superior to galectin-3 to assess reduced systolic and diastolic function., (© 2021. The Author(s).)

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<0.0001), higher age (OR = 2.54 per decade, p<0.0001), smoking (OR = 1.59, p<0.0001), hyperopia (OR = 1.05 per diopter, p<0.0001), thinner cornea (OR = 0.994 per μm, p<0.0001), higher IOP (OR = 1.02, p = 0.039), higher HDL-C-level (OR = 2.13, p<0.0001), higher LDL-C-level (OR = 1.21, p<0.0001), and intake of lipid modifying agents (OR = 1.26, p = 0.0001). Arcus was not associated with socio-economic status, BMI, arterial blood pressure, and HbA1c., Conclusions: Corneal arcus is a frequent alteration of the cornea in Germany and is associated with ocular parameters and systemic parameters of dyslipidemia., Competing Interests: Funding from commercial sources: Boehringer Ingelheim; PHILIPS Medical Systems, Allergan, Bayer Vital, Novartis, PlusOptix, and Heidelberg Engineering. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Coronavirus disease 19 (COVID-19)-associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome-microvascular thrombosis, stroke, and venous and pulmonary clots-are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven., Objectives: To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients., Methods: Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome-coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19., Results: We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA., Conclusions: COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19-associated coagulopathy., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: This study sought to investigate the prevalence and clinical outcome of left ventricular (LV) geometry in prediabetes and type 2 diabetes mellitus (T2DM) and the impact of glucose metabolism on the incidence of left ventricular hypertrophy (LVH)., Methods: 15,010 subjects (35-74 years) of the population-based Gutenberg Health Study were categorized into euglycemia, prediabetes, and T2DM according to clinical and metabolic (HbA1c) information. Clinical outcome was assessed via structured follow-up., Results: The study comprised 12,121 individuals with euglycemia (81.6%), 1415 with prediabetes (9.5%), and 1316 with T2DM (8.9%). Prevalence of LVH increased from euglycemia (10.2%) over prediabetes (17.8%) to T2DM (23.8%). Prediabetes and T2DM were associated with increased LV mass index (prediabetes: β1.3 (95% CI 0.78-1.81), p < 0.0001; T2DM: β2.37 (95% CI 1.81; 2.92), p < 0.0001) independent of age, sex, and cardiovascular risk factors (CVRF). The frequency of LVH was related to the presence of T2DM (prevalence ratio (PR)T2DM 1.2 (95% CI 1.06-1.35), p = 0.0038). T2DM was related to mortality independent of age, sex, and CVRF regardless of LVH (hazard ratio (HR)T2DM-LVH 2.67 (95% CI 1.94-3.66), p < 0.0001; HRT2DM-noLVH 1.59 (95% CI 1.29-1.96), p < 0.0001), prediabetes was only associated with outcome in individuals with LVH independent of age and sex (HRprediabetes-LVH 1.51 (95% CI 1.01-2.25), p = 0.045). Neither T2DM nor prediabetes were predictors of incident LVH after adjustment for clinical covariates., Conclusions: Prediabetes and T2DM promote alterations of cardiac geometry. T2DM and particularly the coprevalence of T2DM with LVH substantially reduce life expectancy. These findings highlight the need for new therapeutic and screening approaches to prevent and detect cardiometabolic diseases at an early stage.

Background: The PAGE-B score (Platelet Age GEnder-HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy., Methods: cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10-17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed., Results: Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2-17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient's lost earnings or productivity were 15.6-17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany., Conclusions: PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment., (© 2021. The Author(s).)

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 <0.0001) and women ( 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.

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., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Platelet indices have been associated with traditional cardiovascular risk factors, cardiovascular diseases and all-cause mortality. This study aimed to investigate the role of platelet count, mean platelet volume (MPV) and platelet-to-leukocyte ratio, including platelet-to-monocyte and platelet-to-lymphocyte ratio with cardiac function, heart failure (HF) phenotypes and clinical outcome, worsening of HF., Methods and Results: Univariate and multivariable linear and Cox regression analyses were used to investigate the associations between platelet indices, cardiac function and worsening of HF in 3250 subjects enrolled in the MyoVasc study. Higher MPV, lower platelet count, lower platelet-to-leukocyte and platelet-to-monocyte ratios have been associated with reduced left ventricular ejection fraction (beta estimate [β] MPV [fL]  = -0.05 [-0.09; -0.02], β platelet count (× 10 /L) 9  = 3.4 [1.2; 5.6], β platelet-to-leukocyte ratio  = 1.4 [1.1; 1.8], β platelet-to-monocyte ratio  = 28 [20; 36]) and increased E/E' ratio (β MPV [fL]  = 0.04 [0.003; 0.07], β platelet count (× 10 /L) 9  = -3.1 [-5.3; -0.92], β platelet-to-leukocyte ratio  = -0.83 [-1.2; -0.46], β platelet-to-monocyte ratio  = -20 [-28; -12]), independent of age and sex. Cox regression demonstrated an increased risk for worsening of HF in subjects with MPV > 75th percentile (hazard ratio [HR] = 1.47 [1.16; 1.87]), platelet count < 25th percentile (HR = 1.36 [1.07; 1.74]), platelet-to-leukocyte < 25th percentile (HR = 1.53 [1.20; 1.95]), platelet-to-monocyte < 25th percentile (HR = 1.38 [1.08; 1.77]) and platelet-to-lymphocyte > 75th percentile (HR = 1.50 [1.17; 1.93]) ratios, independent of potential confounders. MPV > 75th percentile and platelet count < 25th percentile were strongly related to outcome in HFpEF vs. HFrEF (P for difference = 0.040). Platelet-to-leukocyte ratios were associated with worse outcome in both HF phenotypes, without a significant difference between HFpEF and HFrEF., Conclusions: Platelet indices are linked with worse cardiac function and adverse clinical outcome, independent of subjects' underlying cardiovascular profile. This study emphasizes their important value to provide additional information on pathophysiology and risk stratification in HF syndrome., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass-related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox., (© 2021 by The American Society of Hematology.)

Background: Heart failure (HF) is a multifactorial syndrome with pathophysiological complexities still not fully understood. Higher mean platelet volume (MPV), a potential marker of platelet activation, and high concentrations of parathyroid hormone (PTH) have been implicated in the pathogenesis of HF. Aim: This study aims to investigate sex-specifically the association between PTH concentrations and platelet indices in phenotypes of HF. Methods and Results: PTH and platelet indices (MPV and platelet count) were available in 1,896 participants from the MyoVasc study in Mainz, Germany. Multivariable linear regression models, adjusted for age, sex, season, vitamin D status, cardiovascular risk factors, comorbidities, estimated glomerular filtration rate, and medication, were used to assess the associations between platelet indices and PTH. The results showed distinct sex-specific associations between PTH and platelet indices. A positive association between PTH and MPV was found in females with symptomatic HF with reduced ejection fraction (HFrEF) only [β = 0.60 (0.19; 1.00)]. Platelet count was inversely associated with PTH in male HFrEF individuals [β = -7.6 (-15; -0.30)] and in both males and females with HF with preserved ejection fraction (HFpEF). Conclusion: This study reports differential, sex-specific relationships between PTH and platelet indices in HF individuals independent of vitamin D status and clinical profile. Particularly in phenotypes of symptomatic HF, distinct associations were observed, suggesting a sex-specific mechanism involved in the interaction between PTH and platelets., Competing Interests: PW received research funding from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo Europe, Novartis, AstraZeneca, Evonik, Sanofi-Aventis, Bayer Vital, AstraZeneca, DiaSorin and Evonik and received nonfinancial support from DiaSorin and I.E.M. JH. JP reports personal fees from Bayer AG and Boehringer Ingelheim. S-OT has received personal fees from Philips Health Care for a lecture outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dahlen, Müller, Tröbs, Heidorn, Schulz, Arnold, Hermanns, Schwuchow-Thonke, Prochaska, Gori, ten Cate, Lackner, Münzel, Wild and Panova-Noeva.)

Several rapid antigen tests (RATs) for the detection of SARS-CoV-2 were evaluated recently. However, reliable performance data for laboratory-based, high-throughput antigen tests are lacking. Therefore and in response to a short-term shortage of PCR reagents, we evaluated DiaSorin's LIAISON SARS-CoV-2 antigen test in comparison to RT-qPCR, and concerning the application of screening non-COVID-19 patients on hospital admission. Applying the manufacturer-recommended cut-off of 200 arbitrary units (AU/mL) the specificity of the LIAISON Test was 100%, the overall analytical sensitivity 40.2%. Lowering the cut-off to 100 AU/mL increased the sensitivity to 49.7% and decreased the specificity to 98.3%. Confining the analysis to samples with an RT-qPCR result < 25 Ct resulted in a sensitivity of 91.2%. The quality of the LIAISON test is very similar to that of good RATs described in the literature with the advantage of high throughput and the disadvantage of relatively long analysis time. It passes the WHO quality criteria for rapid antigen tests and is characterized by particularly high specificity. The LIAISON test can therefore be used for the same applications as recommended for RATs by the WHO. Due to limited sensitivity, the LIAISON test should only be used for screening, if PCR-based assays are not available.

Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort. Methods and results: 15,010 participants (aged 35-74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit and resistance arteries was determined by flow-mediated dilation (FMD) of the brachial artery, reactive hyperemia index (RHI) using peripheral arterial tonometry, as well as by reflection index (RI) derived from digital photoplethysmography, respectively. Among all subjects, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Mean cumulative smoking exposure was 22.1 ± 18.1 pack-years in current smokers and mean years since quitting was 18.9 ± 12.7 in former smokers. In multivariable linear regression models adjusted for typical confounders, smoking status, pack-years of smoking, and years since quitting smoking were independently associated with RHI and RI, while no association was found for FMD. Overall, no clear dose-dependent associations were observed between variables, whereby higher exposure tended to be associated with pronounced resistance artery endothelial dysfunction. Conclusions: Cigarette smoking is associated with altered endothelial function of resistance, but not conduit arteries. The present results suggest that smoking-induced endothelial dysfunction in different circulatory beds may exhibit a differential picture., Competing Interests: TM and PW are PI's of the DZHK, Partner Site Rhine-Main, Mainz, Germany. PW and JP are funded by the Federal Ministry of Education and Research (BMBF 01EO1503). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hahad, Arnold, Prochaska, Panova-Noeva, Schulz, Lackner, Pfeiffer, Schmidtmann, Michal, Beutel, Wild, Keaney, Daiber and Münzel.)

Glomerular filtration rate (GFR) declines with age by approx. 1 ml/min/m 2 per year beginning in the third decade of life. At 70 years of age > 40 ml/min/m 2 of GFR will be lost. Thus, factors affecting loss of GFR have significant public health implications. Furthermore, the definition of chronic kidney disease based on GFR may not be appropriate for the elderly. We analyzed factors affecting absolute and relative change of eGFR over a 5 year period in 12,381 participants of the Gutenberg Health Study. We estimated GFR at baseline and after 5 years of follow-up by two different equations. Association with the decline of estimated GFR (eGFR) was assessed by multivariable regression analysis. We confirmed a median loss of eGFR per year of approx. 1 ml/min/m 2 . Aside from albuminuria systolic blood pressure was most strongly associated with faster decline of eGFR followed by echocardiographic evidence of left ventricular diastolic dysfunction and reduced ejection fraction. White blood cell count showed a moderate association with eGFR loss. Diastolic blood pressure, serum uric acid and serum albumin were associated with slower GFR decline in multivariable analysis. Sensitivity analysis with exclusion of individuals taking diuretics, antihypertensive, antidiabetic, or lipid lowering drugs confirmed these associations.

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., (© 2021 by The American Society of Hematology.)

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 < .001), obesity (β = 0.64; 95% CI, 0.25-1.0; P = .001), atrial fibrillation (β = 1.2; 95% CI, 0.69-1.6; P < .001), myocardial infarction (β = 1.5; 95% CI, 1.00-2.1; P < .001), and estimated glomerular filtration rate (β = -0.53; 95% CI, -0.73 to -0.32; per SD, P < .001) were independently associated with GLS in multivariable regression analysis. Global longitudinal strain was associated with the severity of HF as reflected by N-terminal prohormone B-type natriuretic protein (NT-proBNP) levels after additionally adjusting for cardiac structure and function (P < .001). During follow-up, GLS was associated with all-cause mortality (hazard ratio [HR] per SD, 1.55; 95% CI, 1.19-2.01; P < .001) and cardiac death (HR per SD, 2.32; 95% CI, 1.57-3.42; P < .001) independent of image quality, observer variability, clinical profile, HF medications, NYHA class, and cardiac structure and function. After further adjustment for the NT-proBNP level, GLS remained associated with cardiac death (HR per SD, 1.60; 95% CI, 1.07-2.41; P = .02) but not all-cause mortality (HR per SD, 1.26; 95% CI, 0.95-1.66; P = .11)., Conclusions and Relevance: In patients with chronic HF, GLS was associated with clinical and cardiac status, reflected neurohormonal activation, and was associated with cardiac mortality independent of clinical and cardiac status. These findings suggest that GLS may serve as a useful tool to improve risk stratification in patients with HF.

Purpose: This study investigates the relationship between diabetic retinopathy (DR) and birth weight (BW) in diabetic subjects sampled from the general population., Methods: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in participants aged from 35 to 74 years. Criteria for diabetes diagnosis were HbA1c ≥6.5% at study entry, a doctor-diagnosis of diabetes, or diabetes medication. The presence of DR was determined by evaluating fundus photographs. BW was assessed by self-reports. GHS participants were divided into three different BW groups (low: <2500 g; normal: 2500-4000 g; high:>4000 g). Logistic regression analysis was conducted as uni- and multivariable analysis with adjustment for age and sex. Effect mediators were separately investigated., Results: A total of 1,124 GHS participants (7.5% of the cohort) had diabetes at study entry. Of these, 402 subjects (35.8%) had gradable fundus photographs, reported BW data and were included into this study. Overall, 91/402 subjects (23%) had DR. With regard to BW groups, DR was descriptively more frequent in subjects with low (28.1% [95%-CI: 14.4-47.0%; n = 32]) and high BW (30.8% [95%-CI: 19.1-45.3%; n = 52]) compared to normal BW (20.8% [95%-CI: 16.5-25.7%; n = 318]). Both high and low BW were associated with DR in multivariable analysis (high: OR = 1.68, p = .037; low: OR = 1.81, p = .05). The BW effect was mediated by duration of diabetes in both BW groups and by arterial hypertension in the low BW group., Conclusion: Low and high BW in persons with diabetes is related to higher risk of diabetic retinopathy. Longer duration of diabetes and higher prevalence of arterial hypertension are factors in these subjects explaining the elevated risk.

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death., Materials and Methods: Patients ( n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data., Results: COVID-19 patients ( n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels., Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.

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., Competing Interests: None declared., (Thieme. All rights reserved.)

Background Vascular alterations induced by antineoplastic treatment might be considered as a possible underlying mechanism of increased cardiovascular sequelae in childhood cancer survivors (CCSs). We aimed to evaluate arterial stiffness among long-term CCSs and to compare the data against a population-based sample. Methods and Results Arterial stiffness was assessed by digital photoplethysmography (stiffness index; m/s) among 1002 participants of the CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study, diagnosed with neoplasia (1980-1990) before an age of 15 years. A population-based sample from the GHS (Gutenberg Health Study) (n=5252) was investigated for comparison. All subjects underwent a comprehensive, standardized clinical examination in the same study center. CCSs had higher stiffness index (β=0.66 m/s; 95% CI, 0.51-0.80 m/s) in multivariable linear regression analysis after adjustment for cardiovascular risk factors compared with the population sample of comparable age range. Stiffer vessels were found among CCSs also in absence of arterial hypertension (β=0.66; 95% CI, 0.50-0.81) or history of chemotherapy/radiotherapy (β=0.56; 95% CI, 0.16-0.96) in fully adjusted models. Moreover, stiffness index differed by tumor entity, with highest values in bone and renal tumors. Almost 5.2-fold higher prevalence of stiffness index values exceeding age-specific, population-based reference limits was observed among CCSs compared with GHS participants. Conclusions This is the first study demonstrating increased arterial stiffness among long-term CCSs. The data suggest that vascular compliance might differ in survivors of childhood cancer from the established development concept for arterial stiffness in the population; cancer growth and antineoplastic treatment might be relevant determinants of the pathobiological features. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02181049.

To evaluate the cost-saving of a specialized, eHealth-based management service (CS) in comparison to regular medical care (RMC) for the management of patients receiving oral anticoagulation (OAC) therapy. Costs of hospitalization were derived via diagnosis-related groups which comprise diagnoses (ICD-10) and operation and procedure classification system (OPS), which resulted in OAC-related (i.e. bleeding/ thromboembolic events) and non-OAC-related costs for both cohorts. Cost for anticoagulation management comprised INR-testing, personnel, and technical support. In total, 705 patients were managed by CS and 1490 patients received RMC. The number of hospital stays was significantly lower in the CS cohort compared to RMC (CS: 23.4/100 py; RMC: 68.7/100 py); with the most pronounced difference in OAC-related admissions (CS: 2.8/100 py; RMC: 13.3/100 py). Total costs for anticoagulation management amounted to 101 EUR/py in RMC and 311 EUR/py in CS, whereas hospitalization costs were 3261 [IQR 2857-3689] EUR/py in RMC and 683 [504-874] EUR/py in CS. This resulted in an overall cost saving 2368 EUR/py favoring the CS. The lower frequency of adverse events in anticoagulated patients managed by the telemedicine-based CS compared to RMC translated into a substantial cost-saving, despite higher costs for the specialized management of patients.Trial registration: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

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.

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., (© 2020 S. Karger AG, Basel.)

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<2500 g and normal BW between 2500-4000 g., Results: Overall, 5123 participants were included. Linear regression showed an interaction of axial length (B = 0.009/100 g, p = 0.002) with BW on spherical equivalent while corneal power, anterior chamber depth and lens thickness revealed no interaction with BW on refractive error. Furthermore, linear regression analysis revealed, that axial length explains 58% of variance of spherical equivalent in low BW subjects, and 54% in normal BW subjects. In contrast, corneal power explained 1% of variance of spherical equivalent in both groups., Conclusions: Our results indicate that axial length variation explains the majority of variance in refractive error, while steeper corneal shape has no conclusive effects on refractive error. Low BW is not linked to effects of steeper corneal shape on myopic refractive error, while the effect of axial length on myopia is fractionally enlarged in those subjects., (Copyright © 2020 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.)

Essentials Prekallikrein (PK) deficiency is a recessive trait with isolated aPTT prolongation. KLKB1 c.451dupT is common in Nigerians (7/600 alleles) and absent in a European group (0/600). To date, all genotyped PK-deficient patients of African ancestry were homozygous for 451dupT. Diagnostics of isolated aPTT prolongation in African descendants should include PK testing. ABSTRACT: Background Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Africans according to gnomAD (allele frequency 1.43%). Patients/Methods The most common African (c.451dupT) and European (c.1643G>A, p.Cys548Tyr) PK deficiency causing KLKB1 variants were analyzed in two population-based collectives of 300 Nigerian and 300 German subjects. Genome databases were evaluated for variant frequencies and ethnicity of the subjects. The geographic origin of PK-deficient cases due to 451dupT was assessed. Results Two of five patients with PK deficiency caused by homozygous 451dupT were African, one African American, one from Oman, and one of unknown origin. The frequency of 451dupT was 1.17% in the Nigerian collective (7/600 alleles); none had Cys548Tyr. Subjects with 451dupT were found among different Nigerian ethnicities. Both variants were absent in the European collective. Database research was compatible with these findings, even though mainly data of African Americans (451dupT: 1.12%-1.78%) was accessible. A relevant number of non-American Africans are included only in the 1000Genomes collective: 451dupT frequency was 1.29% in native Africans and 1.56% in African Caribbeans. Conclusions This study underlines the higher prevalence of PK deficiency among people with African descent compared to Europeans. In order to avoid delay of necessary surgical procedures in patients of African origin, diagnostic algorithms for isolated, unexplained, activated partial thromboplastin time prolongation in these subjects should include PK deficiency screening., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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 < 0.0001) for incident atrial fibrillation and an OR of 1.49 ([95% CI 1.13; 1.96], 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 < 0.0001) higher risk of death was found per 1-SD increase in MR-proANP levels., Conclusions: Noise annoyance may contribute to cardiovascular morbidity and mortality and is characterized by increased levels of MR-proANP.

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins., Competing Interests: Michael Lenz, Andreas Schulz, Thomas Koeck, Steffen Rapp, Markus Nagler, Lisa Eggebrecht, Vincent Ten Cate, Karl J. Lackner, Thomas Münzel and Miguel A. Andrade-Navarro declare no conflict of interest. Madeleine Sauer and Kirsten Leineweber are employees of Bayer AG. Marina Panova-Noeva, Jürgen H. Prochaska, and Philipp S. Wild received funding from the Center for Thrombosis and Hemostasis Mainz. Philipp S. Wild reports grants from Bayer AG and from the German Federal Ministry of Education and Research, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants from Philips Medical Systems, grants and personal fees from Sanofi-Aventis, grants and personal fees from Bayer Vital, grants from Daiichi Sankyo Europe, personal fees from Bayer Health Care, personal fees from Astra Zeneca, personal fees and non-financial support from Diasorin and non-financial support from I.E.M., outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Psychosomatic medicine in the Gutenberg Health Study (GHS) - research questions, measurement instruments, selected results Goal: Main questions from the Gutenberg Health Study (GHS) related to psychosomatic medicine are presented: (1) Prevalence and incidence of mental illnesses, (2) Sex-specific risk- and protective factors for mental health, (3) Interplay between psychological and somatic diseases and (4) methodical-psychometric developments. Methods: The GHS is an ongoing, prospective and interdisciplinary cohort study in Mainz. The comprehensive examinations include psychological characteristics and clinical and laboratory tests. 15010 respondents were selected in the baseline study from 2007 until 2012 and re-examined after 2.5 years and 5 years. Results: Of the first 5000 respondents in the baseline study 413 women (8.7 %) and 276 men (5.8 %) indicated depressive symptoms (PHQ-9 > = 10). After five years, half of the participants with depressive symptoms at baseline also indicated depressive symptoms five years later. Risk factors for men were a lack of social support, for women smoking and Type D personality. The proportion of new cases of depression at follow-up was 4.4 %. Risk factors were symptoms of anxiety, Type D, smoking and comorbid cancer. Protective were age and social support. Findings on the association of physical and mental disorders and their behavioral and biological links (atherosclerosis, inflammation) are presented. Conclusions: Prospective assessment of biological, psychological and social parameters offers the possibility to study their interplay in the development of mental and somatic illnesses.

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.

Purpose: To determine the frequency of cataract surgery in Germany and to evaluate its impact on visual function in an adult population., Methods: The population-based Gutenberg Health Study was conducted in Germany with its baseline examination between 2007 and 2012 and a 5-year follow-up examiantion. An ophthalmological examination including slit-lamp examination, ocular biometry, and Scheimpflug imaging was carried out. Overall and age-specific frequencies of unilateral and bilateral cataract surgery within 5 years were computed including the 95% confidential intervals [95%-CI]. Association analyses were conducted to determine social and ocular associated factors using multivariable logistic regression analysis. Vision-related quality of life was assessed using NEI VFQ-25., Results: A total of 10,544 people aged 35 to 74 years were bilateral phakic at baseline and had information on lens status at the 5-year examination. Of these, 168 had unilateral cataract surgery (1.6% [1.4-1.9%]), and 448 had bilateral cataract surgery (4.2% [3.9-4.7%]) in the following 5 years. The frequency of cataract surgery increased with age: 45-54-year-old subjects had twice as often cataract surgery (in at least on eye: OR = 2.32) than at age 35-44 years. The frequency further strongly increases with age (55-64 years: OR = 10.5; 65-74 years: OR = 43.8, p < 0.001). Subjects with glaucoma were more likely to have cataract surgery (OR = 2.52, p < 0.001). Visual function increased when undergoing bilateral cataract surgery., Conclusions: The frequency of cataract surgery is low at younger ages and increases up to 26% at age 70-74 years. Persons with glaucoma are more likely to undergo cataract surgery at population-based level in Germany.

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 platelet-related 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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. This study aims to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, N=5000 subjects from the population-based Gutenberg Health Study were analysed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factors trigger in platelet poor plasma. Lag time, endogenous thrombin potential, and peak height were derived from the thrombin generation curve. Sex-specific multivariable linear regression analysis adjusted for age, cardiovascular risk factors, cardiovascular diseases and therapy, was used to assess clinical determinants of thrombin generation. Cox regression models adjusted for age, sex, cardiovascular risk factors and vitamin K antagonists investigated the association between thrombin generation parameters and total mortality. Lag time was positively associated with obesity and dyslipidaemia for both sexes (p<0.0001). Obesity was also positively associated with endogenous thrombin potential in both sexes (p<0.0001) and peak height in males (1 pM tissue factor, p=0.0048) and females (p<0.0001). Cox regression models showed an increased mortality in individuals with lag time (1 pM tissue factor, hazard ratio=1.46, [95% CI: 1.07; 2.00], p=0.018) and endogenous thrombin potential (5 pM tissue factor, hazard ratio = 1.50, [1.06; 2.13], p=0.023) above the 95th percentile of the reference group, independent of the cardiovascular risk profile. This large-scale study demonstrates traditional cardiovascular risk factors, particularly obesity, as relevant determinants of thrombin generation. Lag time and endogenous thrombin potential were found as potentially relevant predictors of increased total mortality, which deserves further investigation.

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.

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 < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group., 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: To determine the prevalence of myopic maculopathy in the general population in Germany and to analyse potential associations with ocular and systemic factors., Design: The Gutenberg Health Study is a population-based study, including 15 010 participants aged 35-74 years., Methods: Myopic maculopathy was graded in phakic eyes with spherical equivalent ≤-6 D by assessing fundus photographs according to a recent international photographic classification system (META-PM). 801 eyes of 519 participants (mean age 51.0±0.77 years) met the conditions and had gradable fundus photographs. Age-specific prevalence estimates were computed. Multivariable logistic regression analysis was used to assess associated factors with myopic maculopathy., Results: Myopic maculopathy was present in 10.3% (95% CI 7.9 to 13.3) study participants. The prevalence was 8.6% (95% CI 6.1% to 11.9%) in the 397 right eyes and 8.7% (95% CI 6.2% to 12.0%) in the 404 left eyes. The most common type of pathology was diffuse atrophy (8.1%), followed by patchy atrophy (1.3%) and macular atrophy (0.5%); plus lesions were present in 3% (right eyes). Age (OR 1.07 per year, 95% CI 1.03 to 1.11, p<0.001), higher myopic refractive error (p<0.001), and male gender (p=0.02) were associated with myopic maculopathy, while cardiovascular risk factors and socioeconomic factors were not., Conclusions: The prevalence of myopic maculopathy in the German population was 0.5%, and 10% in high myopic participants, aged 35-74 years. These population-based data are the first in Europe. Myopic maculopathy was related to severity of myopic refractive error and age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the retinal nerve fiber layer profile measured by optical coherence tomography and its relation to refractive error and axial length., Methods: The Gutenberg Health Study is a population-based study in Mainz, Germany. At the five-year follow-up examination, participants underwent optical coherence tomography, objective refraction and biometry. Peripapillary retinal nerve fiber layer (pRNFL) was segmented using proprietary software. The pRNFL profiles were compared between different refraction groups and the angle between the maxima, i.e., the peaks of pRNFL thickness in the upper and lower hemisphere (angle between the maxima of pRNFL thickness [AMR]) was computed. Multivariable linear regression analysis was carried out to determine associations of pRNFL profile (AMR) including age, sex, optic disc size, and axial length in model 1 and spherical equivalent in model 2., Results: A total of 5387 participants were included. AMR was 145.3° ± 23.4° in right eyes and 151.8° ± 26.7° in left eyes and the pRNFL profile was significant different in the upper hemisphere. The AMR decreased with increasing axial length by -5.86°/mm (95% confidence interval [CI]: [-6.44; -5.29], P < 0.001), female sex (-7.61°; 95% CI: [-8.71; -6.51], P < 0.001) and increased with higher age (0.08°/year; 95% CI: [0.03; 0.14], P = 0.002) and larger optic disc size (2.29°/mm 2 ; 95% CI: [1.18; 3.41], P < 0.001). In phakic eyes, AMR increased with hyperopic refractive error by 2.60°/diopters (dpt) (95% CI: [2.33; 2.88], P < 0.001)., Conclusions: The pRNFL profiles are related to individual ocular and systemic parameters., Translational Relevance: Biometric parameters should be considered when pRNFL profiles are interpreted in diagnostics, i.e., in glaucoma., Competing Interests: Disclosure: F.M. Wagner, None; E.M. Hoffmann, None; S. Nickels, None; A. Fiess, None; T. Münzel, None; P.S. Wild, Federal Ministry of Education and Research (BMBF 01EO1503) (F); M.E. Beutel, None; I. Schmidtmann, None; K.J. Lackner, None; N. Pfeiffer, Novartis, Ivantis, Santen, Thea, Boehringer Ingelheim Deutschland GmbH & Co. KG, Alcon, Sanoculis (F); A.K.-G. Schuster, Stiftung Auge (R), Deutsche Ophthalmologische Gesellschaft, Berufsverband der Augenärzte Deutschland e.V., Allergan, Heidelberg Engineering, Novartis, Bayer Vital (F), (Copyright 2020 The Authors.)

Purpose: This study investigates the prevalence of manifest strabismus and its subtypes in adulthood and analyzes the risk factors and its impact on vision-related quality of life (VRQoL)., Design: The Gutenberg Health Study (GHS) is a population-based, observational cohort study. A cross-sectional analysis of the baseline examination was conducted., Participants: Participants aged 35 to 74 years were included (n = 15  010)., Methods: All participants were examined with a comprehensive ophthalmologic and general examination including the Hirschberg corneal reflex test to detect manifest strabismus. The following risk factors were analyzed: age, sex, socioeconomic status, birth weight, maternal age at birth, anisometropia, astigmatism, spherical equivalent, low visual acuity in the worse seeing eye (≥1.3 logMAR), and cardiovascular factors, and included in multivariable logistic regression analysis. Lifetime period prevalence and point prevalence of manifest strabismus were computed, and VRQoL was compared between participants with and without strabismus., Main Outcome Measure: Strabismus prevalence., Results: A total of 14  700 participants (age, 55.0±11.1 years; 49.5% were female) were included in this analysis. The weighted prevalence of ever having strabismus was 2.9% (2.6%-3.2%), and the point prevalence for concomitant strabismus was 2.5% (2.3%-2.8%). Esotropia was twice as frequent as exotropia, and 2 participants had paralytic strabismus. Concomitant strabismus was associated with age 65 to 69 years (odds ratio [OR], 0.13 [0.05-0.39], P < 0.001); age 70 to 74 years (OR, 0.14 [0.05-0.4], P < 0.001); anisometropia (>1.0 diopters [D]: OR, 3.61 [2.32-5.62], P < 0.001; >2.0 D: OR, 6.93 [4.23-11.35], P < 0.001); astigmatism (≥1.0 D: OR, 2.09 [1.42-3.08], P < 0.001; ≥2.0 D: OR, 3.74 [2.35-5.97], P < 0.001); spherical equivalent (per diopter: OR, 1.43 [1.33-1.53], P < 0.001); and low visual acuity in the worse seeing eye (≥1.3 logMAR: OR, 21.7 [11.2-42.0], P < 0.001). VRQoL was lower in participants with strabismus compared with participants without strabismus in adjusted analysis (B = -5.96, P < 0.001)., Conclusions: Strabismus is a frequent chronic eye condition that is associated with a lower VRQoL. Individuals with anisometropia, astigmatism, and hyperopia are more likely to have strabismus. In addition, low visual acuity in the worse eye was linked to strabismus prevalence., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Low birth weight (LBW; < 2,500 g) has been identified as a risk factor for adverse mental health outcomes over the life span. However, little is known about the association of LBW and suicidal ideation in middle and late adulthood. We investigated N = 8,278 participants of a representative community cohort: 3,849 men (46.5%) and 4,429 women (53.5%) (35-74 years of age). We assessed standardized measures of mental distress, sociodemographics, health behavior, and somatic factors (based on an extensive medical assessment). Controlling for these confounders, we examined the relationship of birth weight and suicidal ideation in logistic regression models. As men and women differ with regard to their susceptibility to suicidal ideation and behavior, we tested sex-dependent effects. LBW was reported by 458 participants (5.5%). In men, LBW was associated with a higher likelihood of reporting suicidal ideation (OR 2.92, 95% CI 1.58-5.12). In women, there was no such relationship. The findings underscore the interrelatedness of the physical and psychological domain, the role of early adversity in suicidal ideation, and they identify a vulnerable group whose numbers are expected to grow. They also indicate other risk factors for suicidal ideation in the community (mental distress, lack of social support, and health risk behavior).

Purpose: Retinal vein occlusion (RVO) is the second most common retinal vascular disease and a major cause of visual impairment. In this study, we aimed to observe whether RVO cases have different antibody profiles as a new potential risk factor and whether a conversion of retinal vein occlusion (RVO) to neovascular glaucoma (NVG), one of the major complications, is occurring within a 5-year timeframe., Methods: We performed a nested case-control study (1 : 4) within the Gutenberg Health Study (GHS), a population-based, prospective cohort study in the Rhine-Main Region of Germany including 15,010 participants. RVO subjects ( n  = 59) were identified by grading of fundus photographs. Optic nerves of RVO subjects and age- and sex-matched controls ( n  = 229) at baseline and their follow-up examination after 5 years were analyzed for glaucomatous alterations. Of all RVO subjects and controls, serum autoantibody profiles were measured using in-house manufactured antigen-antibody microarrays., Results: Of the 59 RVO patients, 3 patients (5%) showed glaucomatous optic disc alterations at baseline, whereas no new glaucoma case was detected at 5-year follow-up. Four of the autoantibodies measured (against dermcidin, neurotrophin-3, superoxide dismutase 1, and signal recognition particle 14 kDa protein) were significantly increased in the serum of RVO patients ( p < 0.001). Multivariable conditional logistic regression analysis showed that 3 of these 4 antibodies were independent of cardiovascular risk factors., Conclusions: We found several autoantibodies associated with RVO, targeting proteins and structures possibly involved in RVO pathogenesis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Katharina Bell et al.)