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As an integral membrane protein, purification and characterization of phospho-N- acetylmuramyl- pentapeptide translocase MraY have proven difficult. Low yield and concerns of retaining stability and activity after detergent solubilization have hampered the structure-function analysis. The recently developed detergent-free styrene-maleic acid (SMA) co-polymer system offers an alternative approach that may overcome these disadvantages. In this study, we used the detergent free system to purify MraY from Bacillus subtilis. This allowed efficient extraction of MraY that was heterologously produced in Escherichia coli membranes into SMA-wrapped nanodiscs. The purified MraY embedded in these nanodiscs (SMA-MraY) was comparable to the micellar MraY extracted with a conventional detergent (DDM) with regard to the yield and the purity of the recombinant protein but required significantly less time. The predominantly alpha-helical secondary structure of the protein in SMA-wrapped nanodiscs was also more stable against heat denaturation compared to the micellar protein. Thus, this detergent-free system is amenable to extract MraY efficiently and effectively while maintaining the biophysical properties of the protein. However, the apparent activity of the SMA-MraY was reduced compared to that of the detergent-solubilized protein. The present data indicates that this is caused by a lower accessibility of the enzyme in SMA-wrapped nanodiscs towards its polyisoprenoid substrate.

Grasses form morphologically derived, four-celled stomata, where two dumbbell-shaped guard cells (GCs) are flanked by two lateral subsidiary cells (SCs). This innovative form enables rapid opening and closing kinetics and efficient plant-atmosphere gas exchange. The mobile bHLH transcription factor MUTE is required for SC formation in grasses. Yet whether and how MUTE also regulates GC development and whether MUTE mobility is required for SC recruitment is unclear. Here, we transgenically impaired BdMUTE mobility from GC to SC precursors in the emerging model grass Brachypodium distachyon. Our data indicate that reduced BdMUTE mobility severely affected the spatiotemporal coordination of GC and SC development. Furthermore, although BdMUTE has a cell-autonomous role in GC division orientation, complete dumbbell morphogenesis of GCs required SC recruitment. Finally, leaf-level gas exchange measurements showed that dosage-dependent complementation of the four-celled grass morphology was mirrored in a gradual physiological complementation of stomatal kinetics. Together, our work revealed a dual role of grass MUTE in regulating GC division orientation and SC recruitment, which in turn is required for GC morphogenesis and the rapid kinetics of grass stomata., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Esters are valuable aroma compounds and can be produced enzymatically by Baeyer-Villiger monooxygenases (BVMOs) from (aliphatic) ketone precursors. However, a genetically encoded biosensor system for the assessment of BVMO activity and the detection of reaction products is missing. In this work, we assembled a synthetic enzyme cascade - featuring an esterase, an alcohol dehydrogenase, and LuxAB - in the heterologous host Escherichia coli. Target esters are produced by a BVMO, subsequently cleaved, and the corresponding alcohol oxidized through the artificial pathway. Ultimately, aldehyde products are detected in vivo by LuxAB, a luciferase from Photorhabdus luminescens that emits bioluminescence upon the oxidation of aldehydes to the corresponding carboxylates. This biosensor system greatly accelerated the screening and selection of active BVMO variants from a focused library, omitting commonly used low-throughput chromatographic analysis. Engineered enzymes accepted linear aliphatic ketones such as 2-undecanone and 2-dodecanone and exhibited improved ester formation., (© 2024 Wiley‐VCH GmbH.)

Background: Obesity-related cardiometabolic comorbidity is common in major depressive disorder (MDD). However, sex differences and MDD recurrence may modify the MDD-obesity-link., Methods: Sex-specific associations of MDD recurrence (single [MDD S ] or recurrent episodes [MDD R ]) and obesity-related traits were analyzed in 4.100 adults (51.6% women) from a cross-sectional population-based cohort in Germany (SHIP-Trend-0). DSM-IV-based lifetime MDD diagnoses and MDD recurrence status were obtained through diagnostic interviews. Obesity-related outcomes included anthropometrics (weight, body mass index, waist- and hip-circumference, waist-to-hip ratio, waist-to-height ratio), bioelectrical impedance analysis of body fat mass and fat-free mass, and subcutaneous (SAT) and visceral adipose tissue (VAT) from abdominal magnetic resonance imaging. Sex-stratified linear regression models predicting obesity-related traits from MDD recurrence status were adjusted for age, education, and current depressive symptoms., Results: 790 participants (19.3%) fulfilled lifetime MDD criteria (23.8% women vs. 14.5% men, p<0.001). In women, MDD S was inversely associated with anthropometric indicators of general and central obesity, while MDD R was positively associated with all obesity-related traits, except waist-to-hip ratio and fat-free mass. In women, MDD R versus MDD S was associated with higher levels of obesity across all outcomes except fat-free mass. In men, MDD was positively associated with SAT regardless of MDD recurrence. Additionally, lifetime MDD was positively associated with VAT in men. Results remained significant in sensitivity analyses after exclusion of participants with current use of antidepressants., Conclusions: The MDD-obesity association is modified by MDD recurrence and sex independent of current depressive symptoms. Accounting for sex and MDD recurrence may identify individuals with MDD at increased cardiometabolic risk.

Background: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability., Methods and Results: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10 -8 ). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously ( SPPL2B and RFX6 )., Conclusions: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.

Stony corals, the engines and engineers of reef ecosystems, face unprecedented threats from anthropogenic environmental change. Corals are holobionts that comprise the cnidarian animal host and a diverse community of bacteria, archaea, viruses and eukaryotic microorganisms. Recent research shows that the bacterial microbiome has a pivotal role in coral biology. A healthy bacterial assemblage contributes to nutrient cycling and stress resilience, but pollution, overfishing and climate change can break down these symbiotic relationships, which results in disease, bleaching and, ultimately, coral death. Although progress has been made in characterizing the spatial-temporal diversity of bacteria, we are only beginning to appreciate their functional contribution. In this Review, we summarize the ecological and metabolic interactions between bacteria and other holobiont members, highlight the biotic and abiotic factors influencing the structure of bacterial communities and discuss the impact of climate change on these communities and their coral hosts. We emphasize how microbiome-based interventions can help to decipher key mechanisms underpinning coral health and promote reef resilience. Finally, we explore how recent technological developments may be harnessed to address some of the most pressing challenges in coral microbiology, providing a road map for future research in this field., (© 2024. Springer Nature Limited.)

Background and Aim: Body shape and anthropometrics are well-known risk factors for cardiovascular diseases (CVD) and mortality. Hand-grip strength (HGS) is also a meaningful marker of health and a promising predictor of CVD and mortality. There is a lack of studies that have systematically investigated associations between body shape and anthropometrics with HGS. In a population-based study, we investigated if anthropometric markers derived from 3D body scanning are related to HGS., Methods and Results: We used the data of 1,599 individuals aged 36 to 93 years, who participated in the Study of Health in Pomerania. A total of 87 anthropometric markers, determined by a 3D body scanner, were included in the analysis. Anthropometric measurements were standardized and used as exposure variables. HGS was measured with a hand dynamometer and used as outcome. Sex-stratified linear regression models adjusted for age and height were used to relate standardized anthropometrics and HGS. Anthropometric markers were ranked according to -log-p-values. In men, left and right forearm circumference, left arm length to neck (C7), left forearm length, and forearm-fingertip length were most strongly related to HGS. In women, right forearm circumference, forearm-fingertip length, shoulder breadth, left forearm circumference, and right wrist circumference showed the most significant associations with HGS. The final prediction models contained 13 anthropometric markers in males (R 2 =0.54) and eight anthropometric markers in females (R 2 =0.37)., Conclusions: The identified parameters may help estimate HGS in the clinical setting. However, studies in clinical settings are essential to validating our findings., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The direct electrochemical reduction of nicotinamide adenine dinucleotide (NAD + ) results in various products, complicating the regeneration of the crucial 1,4-NADH cofactor for enzymatic reactions. Previous research primarily focused on steady-state polarization to examine potential impacts on product selectivity. However, this study explores the influence of dynamic conditions on the selectivity of NAD + reduction products by comparing two dynamic profiles with steady-state conditions. Our findings reveal that the main products, including 1,4-NADH, several dimers, and ADP-ribose, remained consistent across all conditions. A minor by-product, 1,6-NADH, was also identified. The product distribution varied depending on the experimental conditions (steady state vs. dynamic) and the concentration of NAD + , with higher concentrations and overpotentials promoting dimerization. The optimal yield of 1,4-NADH was achieved under steady-state conditions with low overpotential and NAD + concentrations. While dynamic conditions enhanced the 1,4-NADH yield at shorter reaction times, they also resulted in a significant amount of unidentified products. Furthermore, this study assessed the potential of using pulsed electrochemical regeneration of 1,4-NADH with enoate reductase (XenB) for cyclohexenone reduction., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

Background and Aims: Childhood maltreatment (CM) is linked to self-reported liver disease in adulthood. However, specific diagnostic entities, e.g., metabolic dysfunction-associated steatotic liver disease (MASLD) as the most frequent chronic liver disease, and sex-differences have previously not been considered., Methods: Cross-sectional analyses were conducted in 4188 adults from a population-based cohort in Northeastern Germany after excluding individuals with excessive alcohol consumption, cirrhosis, or chronic viral hepatitis. CM-exposure was assessed using the Childhood Trauma Questionnaire (CTQ). Liver-related outcomes included serologic liver enzymes, fibrosis-4 score (FIB-4) and, in 1863 subjects who underwent magnetic resonance imaging examination, liver fat content. Sex-stratified linear regression and logistic regression models predicting liver-related outcomes and risk for MASLD, respectively, from overall CTQ scores were adjusted for age, school education, alcohol consumption, and waist circumference. Exploratory analyses investigated effects of CTQ-subscales on liver-related outcomes and risk for MASLD., Results: In both sexes, overall CM-exposure was associated with higher levels of serum aspartate aminotransferase and FIB-4 score. In men, effects were mainly driven by physical abuse, and in women by emotional neglect. Only in men, overall CM-exposure (β = 0.70, 95%-CI 0.26-1.13, p = 0.002) and four CTQ-subscales were associated with greater liver fat content, and physical abuse (aOR = 1.22, 95%-CI 1.02-1.46, p = 0.034) and physical neglect (aOR = 1.25, 95%-CI 1.04-1.49, p = 0.015) were associated with higher risk for MASLD., Conclusions: These results suggest sex differences in the association between CM and objective serum and imaging markers of MASLD in adulthood. For men especially, a history of CM-exposure may increase risk of developing MASLD in adulthood., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Increased diameters of the aorta are associated with increased mortality risk. In the present analyses, we assessed whether aortic diameters are associated with cardiovascular and all-cause mortality in community-dwelling individuals free of known cardiovascular disease (CVD)., Methods: MRI-derived vascular parameters of the thoracic and abdominal aorta from 2668 participants (median age = 53 years; 51.1% women) of the population-based SHIP-START-2 and SHIP-TREND-0 cohorts without CVD were analyzed. Age- and sex-adjusted, as well as multivariable-adjusted Cox-proportional hazard models, were used to estimate associations of diameters of six different aortic segments to mortality., Results: Over a median follow-up time of 10.6 years (IQR: 8.7; 12.4), a total of 188 participants (126 men and 62 women) died, of which 38 deaths were due to CVD. In unadjusted models, mortality rates were higher in participants with aortic diameters above the median compared to below the median for all investigated aortic sections (all log-rank p < 0.001). In multivariable-adjusted models, the diameters of the ascending thoracic aorta (HR = 1.34 95% CI: 1.04; 1.72, p = 0.022) and of the infrarenal aorta (HR = 3.75 95% CI: 1.06; 13.3, p = 0.040), modeled continuously, were associated with greater cardiovascular mortality. The diameter of the subphrenic aorta was associated with higher cardiovascular mortality only in the age and sex-adjusted model (HR = 3.65 95% CI: 1.01; 13.3, p = 0.049). None of the investigated aortic segments were associated with all-cause mortality., Conclusion: Non-indexed diameters of the ascending thoracic and infrarenal aorta were associated with higher cardiovascular mortality but not with all-cause mortality in a population sample free of clinically overt CVD at baseline., Clinical Relevance Statement: Increased aortic diameter is associated with cardiovascular mortality and can help to identify high-risk patients., Key Points: Increased aortic diameter is associated with mortality. Non-indexed diameters of the ascending and infrarenal aorta are associated with cardiovascular mortality but not all-cause mortality. Aortic diameter measurements support the estimate of cardiovascular mortality., (© 2024. The Author(s).)

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management., Competing Interests: Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms., (© 2024. The Author(s).)

Dilated cardiomyopathy (DCM) is characterized by reduced left ventricular ejection fraction (LVEF) and left or biventricular dilatation. We evaluated sex-specific associations of circulating proteins and metabolites with structural and functional heart parameters in DCM. Plasma samples (297 men, 71 women) were analyzed for proteins using Olink assays (targeted analysis) or LC-MS/MS (untargeted analysis), and for metabolites using LC MS/MS (Biocrates AbsoluteIDQ p180 Kit). Associations of proteins (n = 571) or metabolites (n = 163) with LVEF, measured left ventricular end diastolic diameter (LVEDD measured ), and the dilation percentage of LVEDD from the norm (LVEDD acc. to HENRY ) were examined in combined and sex-specific regression models. To disclose protein-metabolite relations, correlation analyses were performed. Associations between proteins, metabolites and LVEF were restricted to men, while associations with LVEDD were absent in both sexes. Significant metabolites were validated in a second independent DCM cohort (93 men). Integrative analyses demonstrated close relations between altered proteins and metabolites involved in lipid metabolism, inflammation, and endothelial dysfunction with declining LVEF, with kynurenine as the most prominent finding. In DCM, the loss of cardiac function was reflected by circulating proteins and metabolites with sex-specific differences. Our integrative approach demonstrated that concurrently assessing specific proteins and metabolites might help us to gain insights into the alterations associated with DCM.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies., Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors., Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years., Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein., Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses., Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people., Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

We investigated the associations of low handgrip strength (HGS, i.e., a marker of muscular fitness) with liver fat content (LFC) and serum liver enzymes in a population-based setting. We used data from 2700 participants (51.7% women), aged 21-90 years, from two independent cohorts of the population-based Study of Health in Pomerania (SHIP-START-2 and SHIP-TREND-0). Cross-sectional, multivariable adjusted regression models were performed to examine the associations of HGS with LFC, measured by magnetic resonance imaging and serum liver enzymes. We found significant inverse associations of HGS with both LFC and serum liver enzymes. Specifically, a 10-kg lower HGS was associated with a 0.59% (95% confidence interval [CI]: 0.24-0.94; p = 0.001) higher LFC, a 0.051 µkatal/L (95% CI: 0.005-0.097; p = 0.031) higher gamma-glutamyltransferase (GGT) concentration and a 0.010 µkatal/L (95% CI: 0.001-0.020; p = 0.023) higher aspartate aminotransferase (AST) concentration. The adjusted odds-ratio for prevalent hepatic steatosis (defined by a MRI-PDFF ≥5.1%) per 10-kg lower HGS was 1.21 (95% CI: 1.04-1.40; p = 0.014). When considering only obese individuals, those with low HGS had a 1.58% (95% CI: 0.18-2.98; p = 0.027) higher mean LFC and higher chance of prevalent hepatic steatosis (adjusted OR 1.74, 95% CI: 1.15-2.62; p = 0.009) compared to individuals with high HGS. We found similar associations in individuals with overweight, but not in those with normal weight. Lower HGS was strongly associated with both higher LFC and higher serum GGT and AST concentrations. Future studies might clarify whether these findings reflect adverse effects of a sedentary lifestyle or aging on the liver., (© 2024 The Authors. European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82-0.84) and a balanced accuracy of 0.78 (95% CI 0.77-0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40-0.74). Quantitative PCR validated LEF1-AS1's adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management., (© 2024. The Author(s).)

Background: In cardiology, cardiac output (CO) is an important parameter for assessing cardiac function. While invasive thermodilution procedures are the gold standard for CO assessment, transthoracic Doppler echocardiography (TTE) has become the established method for routine CO assessment in daily clinical practice. However, a demand persists for non-invasive approaches, including oscillometric pulse wave analysis (PWA), to enhance the accuracy of CO estimation, reduce complications associated with invasive procedures, and facilitate its application in non-intensive care settings. Here, we aimed to compare the TTE and oscillometric PWA algorithm Antares for a non-invasive estimation of CO., Methods: Non-invasive CO data obtained by two-dimensional TTE were compared with those from an oscillometric blood pressure device (custo med GmbH, Ottobrunn, Germany) using the integrated algorithm Antares (Redwave Medical GmbH, Jena, Germany). In total, 59 patients undergoing elective cardiac catheterization for clinical reasons (71±10 years old, 76% males) were included. Agreement between both CO measures were assessed by Bland-Altman analysis, Student's t-test, and Pearson correlations., Results: The mean difference in CO was 0.04 ± 1.03 l/min (95% confidence interval for the mean difference: -0.23 to 0.30 l/min) for the overall group, with lower and upper limits of agreement at -1.98 and 2.05 l/min, respectively. There was no statistically significant difference in means between both CO measures (P = 0.785). Statistically significant correlations between TTE and Antares CO were observed in the entire cohort (r = 0.705, P<0.001) as well as in female (r = 0.802, P<0.001) and male patients (r = 0.669, P<0.001)., Conclusions: The oscillometric PWA algorithm Antares and established TTE for a non-invasive estimation of CO are highly correlated in male and female patients, with no statistically significant difference between both approaches. Future validation studies of the Antares CO are necessary before a clinical application can be considered., Competing Interests: A.S. has part‐time obligations in Redwave Medical GmbH. M.D. has received equipment for research projects from custo med GmbH and funding for research projects from Redwave Medical GmbH. S.R. has received equipment for research projects from custo med GmbH. S.E. has received equipment for research projects from custo med GmbH. J.B. has interest in Redwave Medical GmbH, and has received equipment and lecture fees from IEM GmbH, BPLab, SMT medical GmbH & Co., SOT Medical Systems and Tensiomed. All other authors have no conflict of interest to state. Redwave Medical GmbH is patent holder for pulse wave analysis in oscillometric pulse waves that are recorded during inflation and deflation of a cuff (patent no DE 10 2017 117 337 B4) and provided information about the algorithm requested by the authors. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Stäuber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aim: Growing body of evidence consistently link obesity and inflammation, Although the direction of the association is still unclear. We aimed to investigate longitudinal associations of body anthropometric, composition and fat distribution parameters with inflammatory markers and vice versa., Method and Results: We used data from 2464 individuals of the SHIP-TREND cohort with a median follow-up of 7 years. Linear regression models adjusted for confounders were used to analyze associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) at baseline with changes in inflammatory markers (C-reactive protein (CRP), white blood cell (WBC), fibrinogen) and vice versa. Higher level of anthropometric markers at baseline were associated with an increase in the change of inflammatory markers. A 13.5 cm higher waist circumference (WC), 16.0 kg body weight and 7.76 % relative fat mass (FM) at baseline was associated with a change in CRP of 0.52 mg/L (95 % confidence interval [CI]: 0.29 to 0.74), 0.51 mg/L (95 % CI: 0.29; 0.74) and 0.58 mg/L (95 % CI: 0.34; 0.82) respectively. Absolute FM showed the strongest association with changes in serum fibrinogen levels (β for 8.69 kg higher FM: 0.07 g/L; 95 % CI: 0.05; 0.09). Baseline inflammatory markers were only associated with changes in hip circumference., Conclusion: Our study indicates the importance of anthropometric, body composition and fat distribution markers as a risk factor for the development of inflammation. To prevent inflammatory-related complications, important is to take measures against the development of obesity., Competing Interests: Declaration of competing interest The authors do not have any disclosures to report., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10 -8 ) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10 -126 ) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10 -44 ) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10 -34 ). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research., (© 2024. The Author(s).)

Background: Low relative fat free mass (FFM) is associated with a greater risk of chronic diseases and mortality. Unfortunately, FFM is currently not being measured regularly to allow for individuals therapy., Objective: One reason why FFM is not being used may be related to additional equipment and resources, thus we aimed to identify easily accessible anthropometric markers related with FFM., Materials and Methods: We analyzed data of 1,593 individuals (784 women; 49.2%, age range 28-88 years) enrolled in the population-based Study of Health in Pomerania (SHIP-TREND 1). Forty-seven anthropometric markers were derived from a 3D optical body-scanner. FFM was assessed by bioelectrical impedance analysis (FFM BIA ) or air displacement plethysmography (FFM ADP ). In sex-stratified linear regression models, FFM was regressed on anthropometric measurements adjusted for body height and age. Anthropometric markers were ranked according to the coefficient of determination (R 2 ) derived from these regression models., Results: Circumferences of high hip, belly, middle hip, waist and high waist showed the strongest inverse associations with FFM. These relations were stronger in females than in males. Associations of anthropometric markers with FFM APD were greater compared to FFM BIA ., Conclusion: Anthropometric measures were more strongly associated with FFM ADP compared to FFM BIA . Anthropometric markers like circumferences of the high or middle hip, belly or waist may be appropriate surrogates for FFM to aid in individualized therapy. Given that the identified markers are representative of visceral adipose tissue, the connection between whole body strength as surrogate for FFM and fat mass should be explored in more detail., (© 2024. The Author(s).)

Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process., (© 2024. The Author(s).)

Background: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen., Study Design: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed., Statistical Analysis Plan: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes., Discussion: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals., Trial Registration: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered)., (© 2024. The Author(s).)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk for cardiovascular disease. Our study investigates the contribution of NAFLD to changes in cardiac structure and function in a general population., Methods: One thousand ninety-six adults (49.3% female) from the Study of Health in Pomerania underwent magnetic resonance imaging including cardiac and liver imaging. The presence of NAFLD by proton density fat fraction was related to left cardiac structure and function. Results were adjusted for clinical confounders using multivariable linear regression model., Results: The prevalence for NAFLD was 35.9%. In adjusted multivariable linear regression models, NAFLD was positively associated with higher left ventricular mass index (β = 0.95; 95% confidence interval (CI): 0.45; 1.45), left ventricular concentricity (β = 0.043; 95% CI: 0.031; 0.056), left ventricular end-diastolic wall thickness (β = 0.29; 95% CI: 0.20; 0.38), left atrial end-diastolic volume index (β = 0.67; 95% CI: 0.01; 1.32) and inversely associated with left ventricular end-diastolic volume index (β = -0.78; 95% CI: -1.51; -0.05). When stratified by sex, we only found significant positive associations of NAFLD with left ventricular mass index, left atrial end-diastolic volume index, left ventricular cardiac output and an inverse association with global longitudinal strain in women. In contrast, men had an inverse association with left ventricular end-diastolic volume index and left ventricular stroke volume. Higher liver fat content was stronger associated with higher left ventricular mass index, left ventricular concentricity and left ventricular end-diastolic wall thickness., Conclusion: NAFLD is associated with cardiac remodelling in the general population showing sex specific patterns in cardiac structure and function., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Ceramides and cardiorespiratory (CR) fitness are both related to cardiovascular diseases. The associations of three blood plasma ceramides (C16:0, C22:0, and C24:0) with CR fitness in the population-based Study of Health in Pomerania (SHIP-START-1; n = 1,102; mean age 50.3 years, 51.5% women) are investigated. In addition, subgroup analysis according to age (2 peak) kg -1 and oxygen consumption at the anaerobic threshold (VO 2 @AT 1 ) as well as for the relation of C24:0/C16:0 with maximum workload (Wattmax kg -1 ). In contrast, age/sex subgroup specific inverse associations with Wattmax kg -1 are found in women <54 years for C22:0, while a positive association in men ≥54 years. Higher levels of C24:0 are associated with higher Wattmax kg -1 , except for women <54 years, where no significant association can be found. The findings suggest that the use of single ceramides as cardiovascular biomarkers may be inferior, compared to ceramide ratio C24:0/C16:0. Therefore C24:0/C16:0 ratio may be a more suitable and robust cardiovascular biomarker and should be preferred over single ceramides., (© 2024 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

Recently, the parameter internal work (IW) has been introduced as change in oxygen uptake (VO 2 ) between resting and unloading workload in cardiopulmonary exercise testing (CPET). The proportional IW (PIW) was defined as IW divided by VO 2 at peak exercise. A second option is to calculate the PIW based on the workload [PIW (Watt)] by considering the aerobic efficiency. The aim of our study was to investigate whether IW and PIW differ between patients with and without pulmonary hypertension and healthy controls. Our study population consisted of 580 patients and 354 healthy controls derived from the Study of Health in Pomerania. The PIW was slightly lower in patients (14.2%) than in healthy controls (14.9%; p = 0.030), but the PIW (Watt) was higher in patients (18.0%) than in the healthy controls (15.9%; p = 0.001). Such a difference was also observed, when considering only the submaximal workload up to the VAT (19.8% in patients and 15.1% in healthy controls; p < 0.001). Since the PIW (Watt) values were higher in patients with pulmonary hypertension, this marker may serve as a useful CPET parameter in clinical practice. In contrast to most of the currently used CPET parameters, the PIW does not require a maximal workload for the patient. Further studies are needed to validate the prognostic significance of the PIW., (© 2024. The Author(s).)

Background: Child maltreatment (CM) is linked to obesity in adulthood. However, sex-differences and direct measurements of body fat have previously been insufficiently considered in this context., Objective: To assess sex-specific associations of CM with anthropometric markers of overweight/obesity and direct measures of body fat., Participants and Setting: Analyses were conducted in 4006 adults from a population-based cohort in Northeastern Germany (SHIP-TREND-0)., Methods: CM was assessed using the Childhood Trauma Questionnaire (CTQ). Obesity-related traits included anthropometric indicators (i.e., height, weight, body mass index [BMI], waist [WC] and hip circumference [HC], waist-to-hip ratio [WHR], waist-to-height ratio [WHtR]), fat mass (FM) and fat-free mass (FFM) derived from bioelectrical impedance analysis (BIA), and subcutaneous (SAT) and visceral adipose tissue (VAT) ascertained using magnetic resonance imaging (MRI). Sex-stratified linear regression models predicting obesity-related traits from total CTQ scores were adjusted for age and education. Exploratory analyses investigated effects of CTQ subscales on obesity-related traits., Results: In men, CM was positively associated with WHtR (β = 0.04; p = .030) and VAT (β = 0.02; p = .031) and inversely with body height (β = -0.05; p = .010). In women, CM-exposure was positively associated with body weight (β = 0.07; p = .018), BMI (β = 0.03; p = .013), WC (β = 0.07; p = .005), HC (β = 0.05; p = .046), WHR (β = 0.03; p = .015), WHtR (β = 0.04; p = .006), FM (β = 0.04; p = .006), and SAT (β = 0.06; p = .041). In both sexes, effects were mainly driven by exposure to emotional and physical abuse., Conclusions: Results suggest that associations between CM-exposure and obesity-related traits in adulthood are primarily present in women. This may have implications for sex-specific obesity-related cardiometabolic risk after CM., Competing Interests: Declaration of competing interest HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and the metabolic syndrome.We aim to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania(SHIP) in Germany., Materials and Methods: 77% of a population-based sample of 4308 participants between 20 and 79 years was followed for 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline thyroxine(fT4) and thyrotropin(TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index(PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index(BMI)., Results: Compared with the 1st PTFQI quartile, Incidence Rate Ratios (IRR) for diabetes were 1.54(95% CI 0.97 to 2.46), 1.55(0.94 to 2.57), and 1.97(1.27 to 3.10) for the upper quartiles (p-trend=0.004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64(1.05 to 2.59) for the 4th vs the 1st quartile (p-trend=0.043)., Conclusions: An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7-year follow-up. Direct effects of baseline LVMI on brain morphometry at follow-up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m 2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow-up independent from hypertension and blood pressure. Exposure-outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow-up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Protein engineering is essential for altering the substrate scope, catalytic activity and selectivity of enzymes for applications in biocatalysis. However, traditional approaches, such as directed evolution and rational design, encounter the challenge in dealing with the experimental screening process of a large protein mutation space. Machine learning methods allow the approximation of protein fitness landscapes and the identification of catalytic patterns using limited experimental data, thus providing a new avenue to guide protein engineering campaigns. In this concept article, we review machine learning models that have been developed to assess enzyme-substrate-catalysis performance relationships aiming to improve enzymes through data-driven protein engineering. Furthermore, we prospect the future development of this field to provide additional strategies and tools for achieving desired activities and selectivities., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Enzyme-catalyzed late-stage functionalization (LSF), such as methylation of drug molecules and lead structures, enables direct access to more potent active pharmaceutical ingredients (API). S-adenosyl-l-methionine-dependent methyltransferases (MTs) can play a key role in the development of new APIs, as they catalyze the chemo- and regioselective methylation of O-, N-, S- and C-atoms, being superior to traditional chemical routes. To identify suitable MTs, we developed a continuous fluorescence-based, high-throughput assay for SAM-dependent methyltransferases, which facilitates screening using E. coli cell lysates. This assay involves two enzymatic steps for the conversion of S-adenosyl-l-homocysteine into H 2 S to result in a selective fluorescence readout via reduction of an azidocoumarin sulfide probe. Investigation of two O-MTs and an N-MT confirmed that this assay is suitable for the determination of methyltransferase activity in E. coli cell lysates., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Obesity is a global health concern and risk factor for cardiovascular disease. The assessment of central blood pressure (cBP) has been shown to improve prediction of cardiovascular events. However, few studies have investigated the impact of obesity on cBP in adults, and invasive data on this issue are lacking. This study aimed to evaluate cBP differences between patients with and without obesity, identify cBP determinants, and evaluate the accuracy of the algorithm Antares for non-invasive cBP estimation., Methods: A total of 190 patients (25% female; 39% with BMI ≥30kg/m2; age: 67±12 years) undergoing elective cardiac catheterization were included. cBP was measured invasively and simultaneously estimated non-invasively using the custo screen 400 device with integrated Antares algorithm., Results: No significant cBP differences were found between obese and non-obese patients. However, females, especially those with obesity, had higher systolic cBP compared to males (P<0.05). Multiple regression analysis showed that brachial mean arterial pressure, pulse pressure, BMI, and heart rate predicted cBP significantly (adjusted R2 = 0.82, P<0.001). Estimated cBP correlated strongly with invasive cBP for systolic, mean arterial, and diastolic cBP (r = 0.74-0.93, P<0.001) and demonstrated excellent accuracy (mean difference <5 and SD <8 mmHg)., Conclusions: This study discovered no significant difference in cBP between obese and non-obese patients. However, it revealed higher cBP values in women, especially those with obesity, which requires further investigation. Additionally, the study highlights Antares' effectiveness in non-invasively determining cBP in obese individuals. This could improve the diagnosis and treatment of hypertension in this special patient population., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Alexander Stäuber has part‐time obligations in Redwave Medical GmbH. Marcus Dörr has received equipment for research projects from custo med GmbH and funding for research projects from Redwave Medical GmbH. Stefan Richter has received equipment for research projects from custo med GmbH. Siegfried Eckert has received equipment for research projects from custo med GmbH. Johannes Baulmann has interest in Redwave Medical GmbH, and has received equipment and lecture fees from IEM GmbH, BPLab, SMT medical GmbH & Co., SOT Medical Systems and Tensiomed. All other authors have no conflict of interest to state. Redwave Medical GmbH is patent holder for pulse wave analysis in oscillometric pulse waves that are recorded during inflation and deflation of a cuff (patent no DE 10 2017 117 337 B4) and provided information about the algorithm requested by the authors. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Stäuber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Small studies and observations suggested that exercise training may improve peak oxygen consumption (peakVO 2 ) in patients with advanced heart failure and left ventricular assist device (LVAD). We investigated whether in this patient group a supervised exercise training can improve exercise capacity., Methods and Results: In this multicentre, prospective, randomized, controlled trial, patients with stable heart failure and LVAD were randomly assigned (2:1) to 12 weeks of supervised exercise training or usual care, with 12 weeks of follow-up. The primary endpoint was the change in peakVO 2 after 12 weeks (51 patients provided a power of 90% with an expected group difference in peakVO 2 of 3 ml/kg/min). Secondary endpoints included changes in submaximal exercise capacity and quality of life. Among 64 patients enrolled (97% male, mean age 56 years), 54 were included in the analysis. Mean difference in the change of peakVO 2 after 12 weeks was 0.826 ml/min/kg (95% confidence interval [CI] -0.37, 2.03; p = 0.183). There was a positive effect of exercise training on 6-min walk distance with a mean increase in the intervention group by 43.4 m (95% CI 16.9, 69.9; p = 0.0024), and on the Kansas City Cardiomyopathy Questionnaire physical domain score (mean 14.3, 95% CI 3.7, 24.9; p = 0.0124), both after 12 weeks. The overall adherence was high (71%), and there were no differences in adverse events between groups., Conclusion: In patients with advanced heart failure and LVAD, 12 weeks of exercise training did not improve peakVO 2 but demonstrated positive effects on submaximal exercise capacity and physical quality of life., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: The biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) has predictive value for identifying individuals at risk for cardiovascular disease (CVD). However, it is not widely used for screening in the general population, potentially due to financial and operational reasons. This study aims to develop a deep-learning model as an efficient means to reliably identify individuals at risk for CVD by predicting serum levels of NT-proBNP from the ECG., Methods: A deep convolutional neural network was developed using the population-based cohort study Hamburg City Health Study (HCHS, n=8,253, 50.9 % women). External validation was performed in two independent population-based cohorts (SHIP-START, n=3,002, 52.1 % women, and SHIP-TREND, n=3,819, 51.2 % women). Assessment of model performance was conducted using Pearson correlation (R) and area under the receiver operating characteristics curve (AUROC)., Results: NT-proBNP was predictable from the ECG (R, 0.566 [HCHS], 0.642 [SHIP-START-0], 0.655 [SHIP-TREND-0]). Across cohorts, predicted NT-proBNP (pNT-proBNP) showed good discriminatory ability for prevalent and incident heart failure (HF) (baseline: AUROC 0.795 [HCHS], 0.816 [SHIP-START-0], 0.783 [SHIP-TREND-0]; first follow-up: 0.669 [SHIP-START-1, 5 years], 0.689 [SHIP-TREND-1, 7.3 years]), comparable to the discriminatory value of measured NT-proBNP. pNT-proBNP also demonstrated comparable results for other incident CVD, including atrial fibrillation, stroke, myocardial infarction, and cardiovascular death., Conclusions: Deep learning ECG algorithms can predict NT-proBNP concentrations with high diagnostic and predictive value for HF and other major CVD and may be used in the community to identify individuals at risk. Long-standing experience with NT-proBNP can increase acceptance of such deep learning models in clinical practice., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Recent studies have highlighted the role of low-grade systemic inflammation in linking periodontitis to cardiovascular disease (CVD) outcomes, but many aspects remain unclear. This study examines the independent and reciprocal associations of periodontitis and low-grade systemic inflammation with all-cause and CVD mortality in a large-scale cohort., Methods: A total of 3047 participants from the prospective, population-based Study of Health in Pomerania (SHIP-START) were followed for a period of 13.0 ± 2.4 years. For the association between various inflammation/periodontitis measures and mortality, hazard ratios (HRs) were obtained from covariate-adjusted Cox proportional hazards models. Interactions were analysed in joint models: on the multiplicative scale, HRs were reported and on the additive scale, relative excess risks due to interaction (RERI) were calculated. Subject and variable-specific interval records were used to account for time-varying exposures and covariates., Results: During the observation period, 380 (12.5%) individuals died from CVD (n = 125) or other causes (n = 255). All markers of periodontitis and inflammation showed apparent associations with all-cause mortality (HRs per SD-increase: mean PPD: 1.068 (95% confidence interval (CI): 0.988-1.155), mean CAL: 1.205 (95% CI: 1.097-1.323), missing teeth: 1.180 (95% CI: 1.065-1.307), periodontitis score: 1.394 (95% CI: 1.202-1.616), leukocytes: 1.264 (95% CI: 1.163-1.374), fibrinogen: 1.120 (95% CI: 1.030-1.218), CRP: 1.231 (95% CI: 1.109-1.366), inflammation score: 1.358 (95% CI: 1.210-1.523)). For CVD mortality, all PPD related variables showed significant associations. Interaction modelling revealed some variation with respect to mortality type and exposure combinations. On the additive scale, RERIs for periodontitis score and inflammation score implied 18.9% and 27.8% excess mortality risk for all-cause and CVD mortality, respectively. On the multiplicative scale, the HRs for interaction were marginal., Conclusions: Both periodontitis and inflammation were significantly associated with all-cause mortality and CVD mortality. On the additive scale, a substantial excess risk was observed due to the interaction of periodontitis and inflammation, suggesting that the greatest treatment benefit may be achieved in patients with both periodontitis and high systemic inflammation. As periodontal therapy has been reported to also reduce systemic inflammation, the possibility of a reduction in CVD mortality risk by anti-inflammatory treatments, including periodontal interventions, seems worthy of further investigation., (© 2023. The Author(s).)

The amino acids arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are related to nitric oxide (NO) metabolism and potential markers of two different disease entities: cardiovascular disease such as atherosclerosis and systemic inflammation in critically ill patients with sepsis. Although very different in their pathophysiological genesis, both entities involve the functional integrity of blood vessels. In this context, large population-based data associating NO metabolites with proinflammatory markers, e.g., white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), and fibrinogen, or cytokines are sparse. We investigated the association of Arg, ADMA and SDMA with WBC, hsCRP, and fibrinogen in 3556 participants of the Study of Health in Pomerania (SHIP)-TREND study. Furthermore, in a subcohort of 456 subjects, 31 inflammatory markers and cytokines were analyzed. We identified Arg and SDMA to be positively associated with hsCRP (β coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (β 5.23 × 10 -3 , SE 4.75 × 10 -4 and 0.083, 0.031, respectively). ADMA was not associated with WBC, hsCRP, or fibrinogen. Furthermore, in the subcohort, Arg was inversely related to a proliferation-inducing ligand (APRIL). SDMA was positively associated with osteocalcin, tumor necrosis factor receptor 1 and 2, and soluble cluster of differentiation 30. Our findings provide new insights into the involvement of Arg, ADMA, and SDMA in subclinical inflammation in the general population.

Aims: Sphingosine-1-phosphate (S1P) is a signaling lipid, which is involved in several cellular processes including cell growth, proliferation, migration and apoptosis. The associations of serum S1P levels with cardiac geometry and function are still not clear. We investigated the associations of S1P with cardiac structure and systolic function in a population-based sample., Methods and Results: We performed cross-sectional analyses of 858 subjects (467 men; 54.4%), aged 22 to 81 years, from a sub-sample of the population-based Study of Health in Pomerania (SHIP-TREND-0). We analyzed the associations of serum S1P with structural and systolic function left ventricular (LV) and left atrial (LA) parameters as determined by magnetic resonance imaging (MRI) using sex-stratified multivariable-adjusted linear regression models. In men, MRI data showed that a 1 µmol/L lower S1P concentration was associated with an 18.1 mL (95% confidence interval [CI] 3.66-32.6; p = 0.014) larger LV end-diastolic volume (LVEDV), a 0.46 mm (95% CI 0.04-0.89; p = 0.034) greater LV wall thickness (LVWT) and a 16.3 g (95% CI 6.55-26.1; p = 0.001) higher LV mass (LVM). S1P was also associated with a 13.3 mL/beat (95% CI 4.49-22.1; p = 0.003) greater LV stroke volume (LVSV), an 18.7 cJ (95% CI 6.43-30.9; p = 0.003) greater LV stroke work (LVSW) and a 12.6 mL (95% CI 1.03-24.3; p = 0.033) larger LA end-diastolic volume (LAEDV). We did not find any significant associations in women., Conclusions: In this population-based sample, lower levels of S1P were associated with higher LV wall thickness and mass, larger LV and LA chamber sizes and greater stroke volume and work of the LV in men, but not in women. Our results indicate that lower levels of S1P were associated with parameters related with cardiac geometry and systolic function in men, but not in women., (© 2023. The Author(s).)

Purpose: Cardiopulmonary exercise testing usually requires a maximal exhaustive effort by the patient and is time consuming. The purpose of this study was to assess whether the cost to initiate exercise termed "proportional internal work" (PIW) was related to cardiovascular disease (CVD) risk factors, ventilatory parameters, and mortality., Methods: We used data from population-based Study of Health in Pomerania. A total of 2829 (49.5% female) study participants with a median age of 52 (42-62) yr were included. Standardized questionnaires were used to assess CV risk factors. The cardiopulmonary exercise testing was performed using a modified Jones protocol. Regression models adjusted for sex and age were used to relate PIW with CVD risk factors and ventilatory parameters. The PIW was calculated by the following formula: (Oxygen uptake at rest - Oxygen uptake without load)/V˙ o2peak ) × 100. Cox regression analysis was used to relate PIW and all-cause mortality., Results: We identified a nonlinear association between PIW and percent predicted V˙ o2peak . Women had a 2.96 (95% CI, 2.61-3.32) greater PIW than men. With each year of age and every point in body mass index, the PWI increased by 0.04 (95% CI, 0.03-0.05) and 0.16 (95% CI, 0.12-0.20), respectively. After adjustment for age, sex, smoking, and body mass index, a 1-point greater PIW was associated with a 5% higher risk to die (HR = 1.05; 95% CI, 1.01-1.07)., Conclusions: The PIW is a new cardiopulmonary exercise testing parameter related to CVD risk and all-cause mortality. Future studies should assess the prognostic relevance of PIW for CVD prevention., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) leads to increased morbidity and mortality. The underlying causes of CKD are often similar to those of atherosclerosis. We investigated whether carotid atherosclerotic parameters are associated with renal function decline., Methods: Within the population-based Study of Health in Pomerania (SHIP), Germany, 2904 subjects were observed over 14 years. The carotid intima-media thickness (cIMT) as well as carotid plaques were measured by standardized B-mode ultrasound protocol. CKD is defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and albuminuria as urinary albumin-creatinine ratio (ACR) ≥30 mg/g. eGFR was calculated by the full age spectrum (FAS) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Mixed models were applied to associate carotid parameters with change in renal function longitudinally and adjusted for confounding., Results: The age range of the study sample was 25-86 years with a median of 54 years at baseline. In longitudinal analyses, subjects with high cIMT and the presence of plaques at baseline showed a greater decrease in eGFR (cIMT: FAS-eGFR: P < .001, CKD-EPI-eGFR: P < .001; plaques: FAS-eGFR: P < .001, CKD-EPI-eGFR: n.s.) as well as an increased risk of developing CKD during the follow-up (cIMT: FAS-eGFR: P = .001, CKD-EPI-eGFR: P = .04; plaques: FAS-eGFR: P = .008, CKD-EPI-eGFR: P = .001). There was no association between atherosclerotic parameters and the risk of developing albuminuria., Conclusions: cIMT and carotid plaques are associated with renal function decline as well as CKD in a population-based sample. Furthermore, the FAS equation adapts best to this study population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Telemedicine has been shown to improve the outcome of heart failure (HF) patients in addition to medical and device therapy. We investigate the effectiveness of a comprehensive telehealth programme in patients with recent hospitalisation for HF on subsequent HF hospitalisations and mortality compared to usual care in a real-world setting. The telehealth programme consists of daily remote telemonitoring of HF signs/symptoms and regular individualised telecoaching sessions. Between January 2018 and September 2020, 119,715 patients of a German health insurer were hospitalised for HF and were eligible for participation in the programme. Finally, 6065 HF patients at high risk for re-hospitalisation were enroled. Participants were retrospectively compared to a propensity score matched usual care group (n = 6065). Median follow-up was 442 days (IQR 309-681). Data from the health insurer was used to evaluate outcomes. After one year, the number of hospitalisations for HF (17.9 vs. 21.8 per 100 patient years, p < 0.001), all-cause hospitalisations (129.0 vs. 133.2 per 100 patient years, p = 0.015), and the respective days spent in hospital (2.0 vs. 2.6 days per year, p < 0.001, and 12.0 vs. 13.4, p < 0.001, respectively) were significantly lower in the telehealth than in the usual care group. Moreover, participation in the telehealth programme was related to a significant reduction in all-cause mortality compared to usual care (5.8 vs. 11.0 %, p < 0.001). In a real-life setting of ambulatory HF patients at high risk for re-hospitalisation, participation in a comprehensive telehealth programme was related to a reduction of HF hospitalisations and all-cause mortality compared to usual care., (© 2023. Springer Nature Limited.)

Background: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking., Methods: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality., Results: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6)., Conclusions: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen., Methods: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients' global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed., Discussion: This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care., Trial Registration: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT 4 based on the risk of cardiovascular disease and mortality., Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT 4 , and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT 4 , thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576., Findings: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT 4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT 4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT 4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT 4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality., Interpretation: There was a J-shaped association of FT 4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT 4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT 4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes., Funding: None., Competing Interests: Declaration of interests TIMK reports personal fees from IBSA, Meck, Berlin-Chemie, and Quidel; is an unpaid co-chair of the American Thyroid Association guidelines on thyroid and pregnancy. BBY reports grants from National Health and Medical Research Council, Fremantle Hospital Medical Research Foundation, and Ada Bartholomew Medical Research Trust. NR reports a grant from the Swiss National Science Foundation. SR reports a grant for an investigator-initiated trial by Merck; manufacturer of levothyroxine and speaker fees from Merck, Abbott Pharmaceuticals, IBSA (makers of levothyroxine). JWJ reports research grants from or was a speaker (with or without lecture fees) at (Continuing Medical Education accredited) meetings sponsored or supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare, Johnson and Johnson, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. DCB reports research grants from the National institutes of Health. DF reports a research grant from DFG SFB TR 296 LOCOTACT. RGJW reports a research grant from the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: Various cross-sectional studies have observed an association between high circulating concentrations of the adipokine chemerin and an unfavorable metabolic profile. However, the prognostic value of chemerin for the risk of associated diseases and mortality was examined only in a few studies mostly using small and highly selected patient populations. We aimed to analyze the association between plasma chemerin concentrations and all-cause as well as cause-specific mortality in the general population., Study Design and Methods: From the Study of Health in Pomerania (SHIP), participants of two independent cohorts (SHIP-START-1 [n = 3037], SHIP-TREND-0 [n = 4193]) were followed up for 15 and 9 years (median), respectively. The association between plasma chemerin and all-cause mortality was analyzed using multivariable Cox proportional hazard regression models. Additionally, cause-specific hazards for cardiovascular disease (CVD) and cancer mortality were modeled considering competing events., Results: A total number of 507 and 208 deaths occurred during follow-up in SHIP-START-1 and SHIP-TREND-0, respectively. Multivariable regression analyses revealed a significant association between high plasma chemerin concentrations and greater overall mortality that was independent of major confounders. Each 30 ng/mL increase in chemerin was associated with a 17% higher risk of all-cause mortality (95%-confidence interval: 1.10-1.26). Cause-specific analyses further showed that the chemerin concentration was significantly associated with cancer mortality but not with CVD mortality., Conclusion: The present study detected a positive association between plasma chemerin concentrations and all-cause mortality in a large population-based study sample. Cause-specific analyses have shown that chemerin is likely to play a decisive role in cancer-related deaths. However, a direct association with cardiovascular mortality could not be established., (© 2023. The Author(s).)

Background and Aim: The associations of body composition markers derived from different modalities with inflammatory markers are unclear. The aim of this study was to determine associations of the body composition markers from different modalities with inflammatory markers in a population-based study., Methods and Results: We analyzed data from 4048 participants (2081 women, 51.4%) aged 20-84 years. Linear regression models adjusted for confounding were used to analyze the association of classic anthropometry markers, absolute and relative fat mass, absolute fat-free mass (FFM), and body cell mass (BCM) assessed by bioelectrical impedance analysis, subcutaneous, visceral, and liver fat from magnetic resonance imaging (MRI), with markers of inflammation. We found positive associations of classic anthropometry markers, total body fat, subcutaneous, visceral, and liver fat, with all inflammatory markers. Waist circumference (WC) showed the strongest association with high-sensitivity C-reactive protein (hsCRP) (β: 1.39; 95% confidence interval [CI]: 1.22 to 1.56) and white blood cell (WBC) (0.39; 0.29 to 0.48), whereas visceral fat showed the strongest association with ferritin (41.9; 34.7 to 49.0). Relative body fat was strongly associated with hsCRP (1.39; 1.20 to 1.58), fibrinogen (0.29; 0.27 to 0.32), and WBC (0.35; 0.25 to 0.46). Conversely, we found inverse associations of body height, FFM, and BCM with hsCRP, fibrinogen, and WBC., Conclusions: Our study indicates the importance of WC as an easily measured marker for early inflammation. MRI-assessed markers of central obesity seem to be most strongly related to ferritin., Competing Interests: Declaration of competing interest The authors do not have any disclosures to report., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population., Materials & Methods: Cross-sectional data from 1,106 individuals aged 30-90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers., Results: Spleen volume was positively associated with RBC ( β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = -16.3; 95% CI = -20.5 to -12.1) and WBC (β = -0.25; 95% CI = -0.37 to -0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = -0.17; 95% CI = -0.24 to -0.09), HDL-C (β = -0.08; 95% CI = -0.10 to -0.05), and LDL-C (β = -0.12; 95% CI = -0.17 to -0.06). There was no significant association of spleen volume with triglycerides., Conclusion: Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 The Author(s). Published by Upsala Medical Society.)