Strongly Inhibited Spontaneous Emission of PbS Quantum Dots Covalently Bound to 3D Silicon Photonic Band Gap Crystals.

We present an optical study of the spontaneous emission of lead sulfide (PbS) nanocrystal quantum dots in 3D photonic band gap crystals made from silicon. The nanocrystals emit in the near-infrared range to be compatible with 3D silicon nanophotonics. The nanocrystals are covalently bound to polymer brush layers that are grafted from the Si-air interfaces inside the nanostructure by using surface-initiated atom transfer radical polymerization. The presence and position of the quantum dots were previously characterized by synchrotron X-ray fluorescence tomography. We report both continuous wave emission spectra and time-resolved, time-correlated single photon counting. In time-resolved measurements, we observe that the total emission rate greatly increases when the quantum dots are transferred from suspension to the silicon nanostructures, likely due to quenching (or increased nonradiative decay) that is tentatively attributed to the presence of Cu catalysts during the synthesis. In this regime, continuous wave emission spectra are known to be proportional to the radiative rate and thus to the local density of states. In spectra normalized to those taken on flat silicon outside the crystals, we observe a broad and deep stop band that we attribute to a 3D photonic band gap with a relative bandwidth of up to 26%. The shapes of the relative emission spectra match well with the theoretical density of states spectra calculated with plane-wave expansion. The observed inhibition is 4-30 times, similar to previously reported record inhibitions, yet for coincidental reasons. Our results are relevant to applications in photochemistry, sensing, photovoltaics, and efficient miniature light sources.

Sparse Group Penalties for bi-level variable selection.

Many data sets exhibit a natural group structure due to contextual similarities or high correlations of variables, such as lipid markers that are interrelated based on biochemical principles. Knowledge of such groupings can be used through bi-level selection methods to identify relevant feature groups and highlight their predictive members. One of the best known approaches of this kind combines the classical Least Absolute Shrinkage and Selection Operator (LASSO) with the Group LASSO, resulting in the Sparse Group LASSO. We propose the Sparse Group Penalty (SGP) framework, which allows for a flexible combination of different SGL-style shrinkage conditions. Analogous to SGL, we investigated the combination of the Smoothly Clipped Absolute Deviation (SCAD), the Minimax Concave Penalty (MCP) and the Exponential Penalty (EP) with their group versions, resulting in the Sparse Group SCAD, the Sparse Group MCP, and the novel Sparse Group EP (SGE). Those shrinkage operators provide refined control of the effect of group formation on the selection process through a tuning parameter. In simulation studies, SGPs were compared with other bi-level selection methods (Group Bridge, composite MCP, and Group Exponential LASSO) for variable and group selection evaluated with the Matthews correlation coefficient. We demonstrated the advantages of the new SGE in identifying parsimonious models, but also identified scenarios that highlight the limitations of the approach. The performance of the techniques was further investigated in a real-world use case for the selection of regulated lipids in a randomized clinical trial.

Obesity-related inflammatory protein signature in cardiovascular clinical outcomes: results from the Gutenberg Health Study.

OBJECTIVE: The objective of this study was to investigate whether an obesity-related inflammatory protein signature (OIPS) is associated with adverse cardiovascular events. METHODS: The Olink Target 96 Inflammation panel was performed in 6662 participants from the population-based Gutenberg Health Study (GHS). The OIPS was selected by a logistic regression model, and its association with cardiovascular outcomes was evaluated by Cox regression analysis. The GHS-derived OIPS was externally validated in the MyoVasc study. RESULTS: The identified OIPS entailed 21 proteins involved in chemokine activity, tumor necrosis factor (TNF) receptor binding, and growth factor receptor binding. The signature revealed a novel positive association of axis inhibition protein 1 with obesity. The OIPS was associated with increased risk of all-cause and cardiac deaths, major adverse cardiovascular events, and incident coronary artery disease, independent of clinical covariates and established risk instruments. A BMI-stratified analysis confirmed the association of OIPS with increased death in those with obesity and overweight and with increased risk for coronary artery disease in those with obesity. The association of OIPS with increased risk of all-cause and cardiac deaths was validated in the MyoVasc cohort. CONCLUSIONS: The OIPS showed a significant association with adverse clinical outcomes, particularly in those with overweight and obesity, and represents a promising tool for identifying patients at higher risk for worse cardiovascular outcomes.

Interpretability of bi-level variable selection methods.

Variable selection is usually performed to increase interpretability, as sparser models are easier to understand than full models. However, a focus on sparsity is not always suitable, for example, when features are related due to contextual similarities or high correlations. Here, it may be more appropriate to identify groups and their predictive members, a task that can be accomplished with bi-level selection procedures. To investigate whether such techniques lead to increased interpretability, group exponential LASSO (GEL), sparse group LASSO (SGL), composite minimax concave penalty (cMCP), and least absolute shrinkage, and selection operator (LASSO) as reference methods were used to select predictors in time-to-event, regression, and classification tasks in bootstrap samples from a cohort of 1001 patients. Different groupings based on prior knowledge, correlation structure, and random assignment were compared in terms of selection relevance, group consistency, and collinearity tolerance. The results show that bi-level selection methods are superior to LASSO in all criteria. The cMCP demonstrated superiority in selection relevance, while SGL was convincing in group consistency. An all-round capacity was achieved by GEL: the approach jointly selected correlated and content-related predictors while maintaining high selection relevance. This method seems recommendable when variables are grouped, and interpretation is of primary interest.

Current and past depression as risk factors for incident type 2 diabetes mellitus and pre-diabetes in men and women: evidence from a longitudinal community cohort.

BACKGROUND: Depression is associated with an increased risk for type 2 diabetes mellitus. However, depression may take different courses, and it is not fully understood how these affect the development of diabetes. It is further to be determined whether sex modifies the association between depression and type 2 diabetes. METHODS: We analyzed data from the Gutenberg Health Study, a longitudinal and population-based cohort study (N = 15,010) in Germany. Depressive symptoms (measured by PHQ-9), history of depression, diabetes mellitus, and relevant covariates were assessed at baseline, and the outcomes of prediabetes and type 2 diabetes mellitus were evaluated 5 years later. Logistic regression was used to estimate odds ratios of incident prediabetes and type 2 diabetes mellitus, adjusting for potential confounders as identified in a Directed Acyclic Graph. RESULTS: In the confounder adjusted model, current depression (PHQ-9 ≥ 10 at baseline; OR = 1.79, 95% CI = 1.11 to 2.74, p = 0.011), and persistent depression had a statistically significant (OR = 2.44, 95% CI = 1.62 to 3.54, p = 0.005) effect on incident type 2 diabetes mellitus. A history of depression without current depression had no statistically significant effect on type 2 diabetes (OR = 1.00, 95% CI = 0.68 to 1.43, p = 0.999). The effect of depression on incident diabetes did not differ significantly between women (OR = 2.02; 95% CI = 1.32 to 3.09) and men (OR = 2.16; 95% CI = 1.41 to 3.31; p-value for interaction on the multiplicative scale p = 0.832 and on the additive scale p = 0.149). Depression did not have a significant effect on incident prediabetes. CONCLUSION: This study shows how the history and trajectory of depression shape the risk for diabetes. This raises interesting questions on the cumulative effects of depression trajectories on diabetes and body metabolism in general. Depression can negatively affect physical health, contributing to increased morbidity and mortality in people with mental disorders.

Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease.

The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile. Px-102 demonstrated the anticipated pharmacodynamic (PD) effects in healthy volunteers but caused a 2-fold increase in alanine aminotransferase (ALT) activity and changes in cholesterol levels. These data guided development of a high fat diet mouse model to screen FXR agonists based on ALT and cholesterol changes. Cilofexor was identified to elicit only minor changes in these parameters. The differing effects of cilofexor and Px-102 on ALT/cholesterol in the model could not be explained by potency or specificity, and we hypothesized that the relative contribution of intestinal and liver FXR activation may be responsible. Gene expression analysis from rodent studies revealed that cilofexor, but not Px-102, had a bias for FXR transcriptional activity in the intestine compared to the liver. Fluorescent imaging in hepatoma cells demonstrated similar subcellular localization for cilofexor and Px-102, but cilofexor was more rapidly washed out, consistent with a lower membrane residence time contributing to reduced hepatic transcriptional effects. Cilofexor demonstrated antisteatotic and antifibrotic efficacy in rodent models and antisteatotic efficacy in a monkey model, with the anticipated PD and a manageable safety profile in human phase I studies. Significance Statement FXR (farnesoid X receptor) agonists have shown promise in treating non-alcoholic steatohepatitis and other liver diseases in the clinic, but balancing efficacy with undesired side effects has been difficult. Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of few remaining FXR agonists in clinical development.

Night shift work and cardiovascular diseases among employees in Germany: five-year follow-up of the Gutenberg Health Study.

OBJECTIVE: This study aimed to determine if there is an increased risk of incident cardiovascular diseases (CVD) resulting from cumulative night shift work in the German population-based Gutenberg Health Study (GHS). METHODS: We examined working participants of the GHS at baseline and after five years. Cumulative night shift work in the 10 years before baseline was assessed and categorized as low (1-220 nights ≙ up to 1 year), middle (221-660 nights ≙ 1-3 years), and high (>660 nights ≙ more than 3 years) night shift exposure. Hazard ratios (HR) were estimated for incident "quality-assured CVD events" using Cox proportional hazard models. RESULTS: At baseline, 1092 of 8167 working participants performed night shift work. During the follow-up, 202 incident cardiovascular events occurred. The crude incidence rates for CVD per 1000 person-years were 6.88 [95% confidence interval (CI) 4.80-9.55] for night shift workers and 5.19 (95% CI 4.44-6.04) for day workers. Cumulative incidence curves showed a higher cumulative incidence in workers exposed to night shift work compared to day workers after five years. The adjusted HR for incident CVD events were 1.26 (95% CI 0.68-2.33), 1.37 (95% CI 0.74-2.53) and 1.19 (95% CI 0.67-2.12) for employees in the low, middle and high night shift categories compared to employees without night shift work, respectively. CONCLUSIONS: The observed tendencies indicate that night shift work might be negatively associated with cardiovascular health. We expect the continued follow-up will clarify the long-term impact of night shift work.

Prevalence of Overweight and Obesity, Its Complications, and Progression in a 10-Year Follow-Up in the Gutenberg Health Study (GHS).

INTRODUCTION: Overweight and obesity lead to numerous complications and their treatment. The associated costs represent a health and sociopolitical burden. Therefore, the development of overweight and obesity is of great importance for health policy. METHODS: The Gutenberg Health Study (GHS), a population-based observational study of individuals aged 35-74 years in the city of Mainz and the district of Mainz-Bingen, examined current data on the prevalence and development of overweight and obesity and their association with concomitant diseases and medication use. RESULTS: Among men, 48.1% were overweight and 26.3% had obesity. Among women, these proportions were 32.1% and 24.1%, respectively. Elevated body mass index (BMI) was associated with numerous complications, particularly insulin resistance and type 2 diabetes, arterial hypertension, elevated triglycerides and low HDL cholesterol, and cardiovascular disease. Accordingly, medications to treat these conditions were used significantly more often in individuals with elevated BMI. During the 10-year observation period, mean weight increased in the population. Both men and women had a moderate but significant increase in BMI compared to men and women of the same age at baseline. Individual weight changes over the 10-year observation period, on the other hand, were age-dependent. In the two younger age decades, weight gain was observed, while in the oldest age decade, mean body weight decreased. CONCLUSION: These current data confirm that overweight and obesity are associated with relevant complications and that these complications lead to significant use of appropriate medications. The study also suggests that there is a significant trend toward increased prevalence of obesity (BMI ≥30) over the 10-year period.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Hydrogen-Tolerant La0.6Ca0.4Co0.2Fe0.8O3-d Oxygen Transport Membranes from Ultrasonic Spray Synthesis for Plasma-Assisted CO2 Conversion.

La0.6Ca0.4Co1-xFexO3-d in its various compositions has proven to be an excellent CO2-resistant oxygen transport membrane that can be used in plasma-assisted CO2 conversion. With the goal of incorporating green hydrogen into the CO2 conversion process, this work takes a step further by investigating the compatibility of La0.6Ca0.4Co1-xFexO3-d membranes with hydrogen fed into the plasma. This will enable plasma-assisted conversion of the carbon monoxide produced in the CO2 reduction process into green fuels, like methanol. This requires the La0.6Ca0.4Co1-xFexO3-d membranes to be tolerant towards reducing conditions of hydrogen. The hydrogen tolerance of La0.6Ca0.4Co1-xFexO3-d (x = 0.8) was studied in detail. A faster and resource-efficient route based on ultrasonic spray synthesis was developed to synthesise the La0.6Ca0.4Co0.2Fe0.8O3-d membranes. The La0.6Ca0.4Co0.2Fe0.8O3-d membrane developed using ultrasonic spray synthesis showed similar performance in terms of its oxygen permeation when compared with the ones synthesised with conventional techniques, such as co-precipitation, sol-gel, etc., despite using 30% less cobalt.

Acute exposure to simulated nocturnal traffic noise and cardiovascular complications and sleep disturbance-results from a pooled analysis of human field studies.

OBJECTIVES: A series of human field studies demonstrated that acute exposure to simulated nocturnal traffic noise is associated with cardiovascular complications and sleep disturbance, including endothelial dysfunction, increased blood pressure, and impaired sleep quality. A pooled analysis of these results remains to be established and is of tremendous interest to consolidate scientific knowledge. METHODS: We analyzed data from four randomized crossover studies (published between 2013 to 2021 and conducted at the University Medical Center Mainz, Germany). A total of 275 subjects (40.4% women, mean age 43.03 years) were each exposed to one control scenario (regular background noise) and at least to one traffic noise scenario (60 aircraft or train noise events) in their homes during nighttime. After each night, the subjects visited the study center for comprehensive cardiovascular function assessment, including the measurement of endothelial function and hemodynamic and biochemical parameters, as well as sleep-related variables. RESULTS: The pooled analysis revealed a significantly impaired endothelial function when comparing the two different noise sequences (0-60 vs. 60-0 simulated noise events, mean difference in flow-mediated dilation -2.00%, 95% CI -2.32; -1.68, p < 0.0001). In concordance, mean arterial pressure was significantly increased after traffic noise exposure (mean difference 2.50 mmHg, 95% CI 0.54; 4.45, p = 0.013). Self-reported sleep quality, the restfulness of sleep, and feeling in the morning were significantly impaired after traffic noise exposure (all p < 0.0001). DISCUSSION: Acute exposure to simulated nocturnal traffic noise is associated with endothelial dysfunction, increased mean arterial pressure, and sleep disturbance.

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer: The CVSS Study.

Background The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. Methods and Results A total of 1002 CCSs (age range, 23-48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age- and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4-2.8) for HF stage A and 4.6 (95% CI, 4.1-5.1) for the composite of HF stage B to D in an age- and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (ß, -4.30 [95% CI, -5.70 to -2.80]), soft tissue sarcoma (ß, -1.60 [95% CI, -2.90 to -0.30]), and renal tumors (ß, -1.60 [95% CI, -2.80 to -0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. Conclusions The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.

Circulating microRNAs predict recurrence and death following venous thromboembolism.

BACKGROUND: Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating microRNAs (miRNAs) has yet to be explored in detail. OBJECTIVES: To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement. METHODS: Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses. RESULTS: A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HRSD, 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (ORSD for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis. CONCLUSION: Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.

Heart rate variability: reference values and role for clinical profile and mortality in individuals with heart failure.

AIMS: To establish reference values and clinically relevant determinants for measures of heart rate variability (HRV) and to assess their relevance for clinical outcome prediction in individuals with heart failure. METHODS: Data from the MyoVasc study (NCT04064450; N = 3289), a prospective cohort on chronic heart failure with a highly standardized, 5 h examination, and Holter ECG recording were investigated. HRV markers were selected using a systematic literature screen and a data-driven approach. Reference values were determined from a healthy subsample. Clinical determinants of HRV were investigated via multivariable linear regression analyses, while their relationship with mortality was investigated by multivariable Cox regression analyses. RESULTS: Holter ECG recordings were available for analysis in 1001 study participants (mean age 64.5 ± 10.5 years; female sex 35.4%). While the most frequently reported HRV markers in literature were from time and frequency domains, the data-driven approach revealed predominantly non-linear HRV measures. Age, sex, dyslipidemia, family history of myocardial infarction or stroke, peripheral artery disease, and heart failure were strongly related to HRV in multivariable models. In a follow-up period of 6.5 years, acceleration capacity [HRperSD 1.53 (95% CI 1.21/1.93), p = 0.0004], deceleration capacity [HRperSD: 0.70 (95% CI 0.55/0.88), p = 0.002], and time lag [HRperSD 1.22 (95% CI 1.03/1.44), p = 0.018] were the strongest predictors of all-cause mortality in individuals with heart failure independently of cardiovascular risk factors, comorbidities, and medication. CONCLUSION: HRV markers are associated with the cardiovascular clinical profile and are strong and independent predictors of survival in heart failure. This underscores clinical relevance and interventional potential for individuals with heart failure. GOV IDENTIFIER: NCT04064450.

Clinical profile and outcome of isolated pulmonary embolism: a systematic review and meta-analysis.

Background: Isolated pulmonary embolism (PE) appears to be associated with a specific clinical profile and sequelae compared to deep vein thrombosis (DVT)-associated PE. The objective of this study was to identify clinical characteristics that discriminate both phenotypes, and to characterize their differences in clinical outcome. Methods: We performed a systematic review and meta-analysis of studies comparing PE phenotypes. A systematic search of the electronic databases PubMed and CENTRAL was conducted, from inception until January 27, 2023. Exclusion criteria were irrelevant content, inability to retrieve the article, language other than English or German, the article comprising a review or case study/series, and inappropriate study design. Data on risk factors, clinical characteristics and clinical endpoints were pooled using random-effects meta-analyses. Findings: Fifty studies with 435,768 PE patients were included. In low risk of bias studies, 30% [95% CI 19-42%, I 2 = 97%] of PE were isolated. The Factor V Leiden [OR: 0.47, 95% CI 0.37-0.58, I 2 = 0%] and prothrombin G20210A mutations [OR: 0.55, 95% CI 0.41-0.75, I 2 = 0%] were significantly less prevalent among patients with isolated PE. Female sex [OR: 1.30, 95% CI 1.17-1.45, I 2 = 79%], recent invasive surgery [OR: 1.31, 95% CI 1.23-1.41, I 2 = 65%], a history of myocardial infarction [OR: 2.07, 95% CI 1.85-2.32, I 2 = 0%], left-sided heart failure [OR: 1.70, 95% CI 1.37-2.10, I 2 = 76%], peripheral artery disease [OR: 1.36, 95% CI 1.31-1.42, I 2 = 0%] and diabetes mellitus [OR: 1.23, 95% CI 1.21-1.25, I 2 = 0%] were significantly more frequently represented among isolated PE patients. In a synthesis of clinical outcome data, the risk of recurrent VTE in isolated PE was half that of DVT-associated PE [RR: 0.55, 95% CI 0.44-0.69, I 2 = 0%], while the risk of arterial thrombosis was nearly 3-fold higher [RR: 2.93, 95% CI 1.43-6.02, I 2 = 0%]. Interpretation: Our findings suggest that isolated PE appears to be a specific entity that may signal a long-term risk of arterial thrombosis. Randomised controlled trials are necessary to establish whether alternative treatment regimens are beneficial for this patient subgroup. Funding: None.

Unsupervised clustering of venous thromboembolism patients by clinical features at presentation identifies novel endotypes that improve prognostic stratification.

BACKGROUND: Individuals with acute venous thromboembolism (VTE) constitute a heterogeneous group of patients with diverse clinical characteristics and outcome. OBJECTIVES: To identify endotypes of individuals with acute VTE based on clinical characteristics at presentation through unsupervised cluster analysis and to evaluate their molecular proteomic profile and clinical outcome. METHODS: Data from 591 individuals from the Genotyping and Molecular phenotyping of Venous thromboembolism (GMP-VTE) project were explored. Hierarchical clustering was applied to 58 variables to define VTE endotypes. Clinical characteristics, three-year incidence of thromboembolic events or death, and acute-phase plasma proteomics were assessed. RESULTS: Four endotypes were identified, exhibiting different patterns of clinical characteristics and clinical course. Endotype 1 (n = 300), comprising older individuals with comorbidities, had the highest incidence of thromboembolic events or death (HR [95 % CI]: 3.76 [1.96-7.19]), followed by endotype 4 (n = 127) (HR [95 % CI]: 2.55 [1.26-5.16]), characterised by men with history of VTE and provoking risk factors, and endotype 3 (n = 57) (HR [95 % CI]: 1.57 [0.63-3.87]), composed of young women with provoking risk factors, vs. reference endotype 2 (n = 107). The reference endotype was constituted by individuals diagnosed with PE without comorbidities, who had the lowest incidence of the investigated endpoint. Differentially expressed proteins associated with the endotypes were related to distinct biological processes, supporting differences in molecular pathophysiology. The endotypes had superior prognostic ability compared to existing risk stratifications such as provoked vs unprovoked VTE and D-dimer levels. CONCLUSION: Four endotypes of VTE were identified by unsupervised phenotype-based clustering that diverge in clinical outcome and plasmatic protein signature. This approach might support the future development of individualized treatment in VTE.

Tinnitus Prevalence in the Adult Population-Results from the Gutenberg Health Study.

Background and Objectives: Tinnitus is a common symptom in medical practice, although data on its prevalence vary. As the underlying pathophysiological mechanism is still not fully understood, hearing loss is thought to be an important risk factor for the occurrence of tinnitus. The aim of this study was to assess tinnitus prevalence in a large German cohort and to determine its dependence on hearing impairment. Materials and Methods: The Gutenberg Health Study (GHS) is a population-based cohort study and representative for the population of Mainz and its district. Participants were asked whether they suffer from tinnitus and how much they are burdened by it. Extensive audiological examinations using bone- and air-conduction were also performed. Results: 4942 participants (mean age: 61.0, 2550 men and 2392 women) were included in the study. The overall prevalence of tinnitus was 26.1%. Men were affected significantly more often than women. The prevalence of tinnitus increased with age, peaking at ages 75 to 79 years. Considering only annoying tinnitus, the prevalence was 9.8%. Logistic regression showed that participants with severe to complete hearing loss (>65 dB) were more likely to have tinnitus. Conclusions: Tinnitus is a common symptom, and given demographic changes, its prevalence is expected to increase.

DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking. RESULTS: A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10-11) and biological processes "skeletal system development" (q = 1.89 × 10-23). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10-6) and atherosclerosis (p = 4.9 × 10-4). CONCLUSION: This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.

The association of depressive symptoms and body weight change in midlife - Results from the Gutenberg Health Study in Germany.

BACKGROUND: The present study aimed to investigate how depressive symptoms affect bodyweight change (gain and loss), and how this association is intertwined with other psychosocial and biomedical factors in the adult general population. METHODS: In a population-based, prospective, observational single-center cohort study in the Rhine-Main-Region, Germany (Gutenberg Health Study GHS) with N = 12,220 participants, we analyzed baseline and five year follow-up data with logistic regressions separately for bodyweight gain and loss (vs. stable bodyweight). RESULTS: Overall, 19.8 % of participants gained bodyweight of at least 5 %. More female participants were affected than male participants (23.3 % vs. 16.6 %). Regarding weight loss, overall, 12.4 % lost >5 % of bodyweight; participants were more often female than male (13.0 % vs. 11.8 %). Depressive symptoms at baseline were associated with weight gain (OR = 1.03, 95 % CI = 1.02-1.05). In models controlling for psychosocial and biomedical factors, female gender, younger age, lower socioeconomic status and smoking cessation were associated with weight gain. In weight loss, there was no overall significant effect of depressive symptoms (OR = 1.01 [0.99; 1.03]). Weight loss was associated with female gender, diabetes, less physical activity, and higher BMI at baseline. Only in women, smoking and cancer were associated with weight loss. LIMITATIONS: Depressive symptoms were assessed via self-report. Voluntary weight loss cannot be determined. CONCLUSIONS: Significant weight change frequently occurs in middle to old adulthood resulting from a complex interplay of psychosocial and biomedical factors. Associations with age, gender, somatic illness and health behavior (e.g. smoking cessation) provide important information for the prevention of unfavorable weight change.