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Plasma proteomics could enhance risk prediction for multiple diseases beyond conventional risk factors or polygenic scores (PS). To assess utility of proteomics for risk prediction of ischemic heart disease (IHD) compared with conventional risk factors and PS in Chinese and European populations. A nested case-cohort study measured plasma levels of 2923 proteins using Olink Explore panel in ~ 4000 Chinese adults (1976 incident IHD cases and 2001 sub-cohort controls). We used conventional and machine learning (Boruta) methods to develop proteomics-based prediction models of IHD, with discrimination assessed using area under the curve (AUC), C-statistics and net reclassification index (NRI). These were compared with conventional risk factors and PS in Chinese and in 37,187 Europeans. Overall, 446 proteins were associated with IHD (false discovery rate < 0.05) in Chinese after adjustment for conventional cardiovascular disease risk factors. Proteomic risk models alone yielded higher C-statistics for IHD than conventional risk factors or PS (0.855 [95%CI 0.841-0.868] vs. 0.845 [0.829-0.860] vs 0.553 [0.528-0.578], respectively). Addition of 446 proteins to PS improved C-statistics to 0.857 (0.843-0.871) and NRI by 109.1%; and addition to conventional risk factors improved C-statistics to 0.868 (0.854-0.882) and NRI by 86.9%. Boruta analysis identified 30 proteins accounting for ~ 90% of improvement in NRI for IHD conferred by all 2923 proteins. Similar proteomic panels yielded comparable improvements in risk prediction of IHD in Europeans. Plasma proteomics improved risk prediction of IHD beyond conventional risk factors and PS and could enhance precision medicine approaches for primary prevention of IHD., Competing Interests: Declarations. Conflict of interest: None of the authors have any conflicts of interest in relation to this report. Ethical approval: The China Kadoorie Biobank (CKB) complies with all required ethical standards for medical research on human subjects. Ethical approvals were obtained and been maintained by the relevant institutional ethical research committees in the UK and China. Consent to participate/publication: All participants provided written informed consent., (© 2024. The Author(s).)

Purpose: Poor posture has a negative impact on physical capability and is associated with changes in biomechanics and motor control. The purpose of this study was to assess the effect of corrective exercises on ground reaction forces (GRFs) in male student handball players with upper crossed syndrome (UCS) during throwing., Methods: Thirty male handball students with UCS participated in this single-blind randomized controlled trial (IRCT20200622047888N2; IR.HUMS.REC.1402.135). Fifteen received an 8-week corrective exercise intervention (exercise-intervention group [EG]), consisting of exercise targeting muscles involved in the UCS, and 15 served as the control group (CG). During handball throwing, GRF was measured by force plate. The forward head and rounded shoulder angles were measured with a photogrammetric method. All measurements were repeated 8 weeks later., Results: Significant interactions for virtually all parameters indicated that changes over 8 weeks differed between the CG and EG. A reduction in GRFs and a delayed occurrence of peak GRFs were observed in the EG, but not in the CG (P < .05). This was accompanied by a significant reduction in forward head (P < .03; effect size: 0.87; 95% confidence interval, -2.34 to 0.13), rounded shoulder (P < .05; effect size: 0.68; 95% confidence interval, 0.32 to 1.22) and thoracic kyphosis (P < .02; effect size: 0.64; 95% confidence interval, 0.54 to 1.25) angles in the EG (P < .05) with no significant change over 8 weeks in the CG., Conclusion: Corrective exercises targeting muscles directly involved in UCS induces functional and postural improvements in male student handball players with UCS.

PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions., Competing Interests: Declaration of competing interest GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. Other authors have no potential conflict of interest to declare. Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies., (Copyright © 2024. Published by Elsevier Inc.)

The use of proteomics in human studies investigating stroke and myocardial infarction (MI) has been increasing, prompting a review of the literature. This revealed proteinaceous biomarkers of stroke from thrombi, brain tissue, cells, and particles, some of which cross the blood-brain barrier (BBB). Several proteins were also implicated in coronary artery disease (CAD), which often underlies MI, cholesterol transportation, and inflammation. Furthermore, the platelet proteome revealed itself as a potential therapeutic target, along with differentially expressed proteins associated with MI progression. Moreover, proteomic data enhanced the performance of conventional risk scores and causal protein discovery has improved interventions and drug development for patients with MI and other conditions. These findings suggest that proteomics holds much promise for future stroke and MI research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The current study aimed to evaluate the psychometric properties of the Difficulties in Emotion Regulation Scale-Short Form (DERS-SF) in Iran, including testing its measurement invariance across sexes, as well as community and student populations. Two samples were recruited: a community sample of 583 participants (58.7% female; M age = 33.55) and a university student sample of 409 participants (67.2% female; M age = 24.48). Besides the DERS-SF, participants completed a battery of instruments online, measuring mentalizing capacity and borderline personality features. Confirmatory factor analyses supported the tenability of the five-factor model, excluding the awareness subscale. Except for the awareness subscale, acceptable to excellent internal consistencies were found for the DERS-SF and its subscales. The awareness-excluded DERS-SF was significantly and strongly associated with relevant constructs (|r s | = .49 to .59). This study also found evidence for configural, metric, and scalar invariance of the DERS-SF across sexes and community and student populations. Our findings extended the evidence for the validity and reliability of the DERS-SF and its awareness-excluded version by administering it in Iranian samples and supporting its cross-cultural applicability.

Numerous tools assess death anxiety, but many have questionable psychometric properties. The Death Anxiety Beliefs and Behaviors Scale (DABBS) addresses these shortcomings, assessing death-related maladaptive affect, beliefs, and behaviors that could be foundational to fears associated with death. We translated the DABBS into Persian and examined its psychometric properties among Iranian adolescents (n = 598, M age = 14.80, range = 12-18 years old). Confirmatory factor analyses supported the intended three-factor structure that comprises death-related affect, beliefs, and behaviors. Furthermore, the DABBS demonstrated good internal consistency, as well as expected associations with other measures of death anxiety and psychopathology measures, except that the Behaviors subscale unexpectedly did not relate to theoretically relevant constructs. Our findings indicate that the DABBS affect and belief subscales have strong psychometric properties among Iranian adolescents. However, further research is needed to elucidate whether the overall DABBS score demonstrates improved validity when used with other populations.

Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²). Genetically-predicted body mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-to-hip ratio (WHR) are significantly (FDR < 0.05) associated with 399, 239, 436, and 283 proteins, respectively, with 80 proteins associated with all four and 275 with only one adiposity trait. WHR is associated with the most proteins (n = 90) after adjusting for other adiposity traits. These associations are largely replicated in Europeans (mean BMI = 27.4 kg/m²). Two-sample Mendelian randomisation (MR) analyses in East Asians using cis-protein quantitative trait locus (cis-pQTLs) identified in GWAS find 30/2 proteins significantly affect levels of BMI/WC, respectively, with 10 showing evidence of colocalisation, and seven (inter-alpha-trypsin inhibitor heavy chain H3, complement factor B, EGF-containing fibulin-like extracellular matrix protein 1, thioredoxin domain-containing protein 15, alpha-2-antiplasmin, fibronectin, mimecan) are replicated in separate MR using different cis-pQTLs identified in Europeans. These findings identified potential novel mechanisms and targets, to our knowledge, for improved treatment and prevention of obesity and associated diseases., (© 2024. The Author(s).)

Several large-scale studies have measured plasma levels of the proteome in individuals with cardiovascular diseases (CVDs) 1-7 . However, since the majority of such proteins are interrelated 2 , it is difficult for observational studies to distinguish which proteins are likely to be of etiological relevance. Here we evaluate whether plasma levels of 2,919 proteins measured in 52,164 UK Biobank participants are associated with incident myocardial infarction, ischemic stroke or heart failure. Of those proteins, 126 were associated with all three CVD outcomes and 118 were associated with at least one CVD in the China Kadoorie Biobank. Mendelian randomization and colocalization analyses indicated that genetically determined levels of 47 and 18 proteins, respectively, were associated with CVDs, including FGF5, PROCR and FURIN. While the majority of protein-CVD observational associations were noncausal, these three proteins showed evidence to support potential causality and are therefore promising targets for drug treatment for CVD outcomes., (© 2024. The Author(s).)

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations., (© 2024. The Author(s).)

Furin is an important proteolytic enzyme, converting several proteins from inactive precursors to their active forms. Recently, proteo-genomic analyses in European and East Asian populations suggested a causal association of furin with ischaemic heart disease, and there is growing interest in its role in cardiovascular disease (CVD) aetiology. In this narrative review, we present a critical appraisal of evidence from population studies to assess furin's role in CVD risk and potential as a drug target for CVD. Whilst most observational studies report positive associations between furin expression and CVD risk, some studies report opposing effects, which may reflect the complex biological roles of furin and its substrates. Genetic variation in FURIN is also associated with CVD and its risk factors. We found no evidence of current clinical development of furin as a drug target for CVD, although several phase 1 and 2 clinical trials of furin inhibitors as a type of cancer immunotherapy have been completed. The growing field of proteo-genomics in large-scale population studies may inform the future development of furin and other potential drug targets to improve the treatment and prevention of CVD.

Context: Postprandial lipemia (PPL) is associated with increased risk of endothelial dysfunction (ED), a precursor of atherosclerotic cardiovascular disease (ASCVD). The effects of low-carbohydrate, high-fat (LCHF) diets on ASCVD risk are uncertain; therefore, gaining a greater understanding of LCHF meals on PPL may provide valuable insights., Objective: The current systematic review investigated the effects of single LCHF meal consumption on PPL and markers of ED., Data Sources: CINAHL Plus, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for key terms related to endothelial function, cardiovascular disease, glycemia, lipemia, and the postprandial state with no restriction on date., Data Extraction: Full-text articles were independently screened by 2 reviewers, of which 16 studies were eligible to be included in the current review. All trials reported a minimum analysis of postprandial triglycerides (PPTG) following consumption of an LCHF meal (<26% of energy as carbohydrate). Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement., Data Analysis: Single-meal macronutrient composition was found to play a key role in determining postprandial lipid and lipoprotein responses up to 8 hours post-meal. Consumption of LCHF meals increased PPTG and may contribute to ED via reduced flow-mediated dilation and increased oxidative stress; however, energy and macronutrient composition varied considerably between studies., Conclusion: Consumption of an LCHF meal had a negative impact on PPL based on some, but not all, single-meal studies; therefore, the contribution of LCHF meals to cardiometabolic health outcomes remains unclear. Further research is needed on specific categories of LCHF diets to establish a causal relationship between postprandial modulation of lipids/lipoproteins and impaired vascular endothelial function., Systematic Review Registration: PROSPERO registration no. CRD 42023398774., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Objective: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D)., Research Design and Methods: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D., Results: Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D., Conclusions: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D., (© 2024 by the American Diabetes Association.)

Objective: High-fat diets cause obesity in male mice; however, the underlying mechanisms remain controversial. Here, three contrasting ideas were assessed: hedonic overdrive, reverse causality, and passive overconsumption models., Methods: A total of 12 groups of 20 individually housed 12-week-old C57BL/6 male mice were exposed to 12 high-fat diets with varying fat content from 40% to 80% (by calories), protein content from 5% to 30%, and carbohydrate content from 8.4% to 40%. Body weight and food intake were monitored for 30 days after 7 days at baseline on a standard low-fat diet., Results: After exposure to the diets, energy intake increased first, and body weight followed later. Intake then declined. The peak energy intake was dependent on both dietary protein and carbohydrate, but not the dietary fat and energy density, whereas the rate of decrease in intake was only related to dietary protein. On high-fat diets, the weight of food intake declined, but despite this average reduction of 14.4 g in food intake, they consumed, on average, 357 kJ more energy than at baseline., Conclusions: The hedonic overdrive model fit the data best. The other two models were not supported., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Aims: Reduced muscle mass and reduced strength are frequently associated with both alterations in blood lipids and poorer cardiometabolic outcomes in epidemiological studies; however, a causal association cannot be determined from such observations. Two-sample Mendelian randomization (MR) was applied to assess the association of genetically determined appendicular lean mass (ALM) and handgrip strength (HGS) with serum lipid particle diameter., Methods and Results: Mendelian randomization was implemented using summary-level data from the largest genome-wide association studies on ALM ( n = 450 243), HGS ( n = 223 315), and lipoprotein [low-density lipoprotein (LDL), very LDL (VLDL), and high-density lipoprotein (HDL)] particle diameters ( n = 115 078). Inverse variance-weighted (IVW) method was used to calculate the causal estimates. Weighted median-based method, MR-Egger, and leave-one-out method were applied as sensitivity analysis. Greater ALM had a statistically significant positive effect on HDL particle diameter (MR-Egger: β = 0.055, SE = 0.031, P = 0.081; IVW: β = 0.068, SE = 0.014, P < 0.001) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: β = -0.114, SE = 0.039, P = 0.003; IVW: β = -0.081, SE = 0.017, P < 0.001). Similarly, greater HGS had a statistically significant positive effect on HDL particle diameter (MR-Egger: β = 0.433, SE = 0.184, P = 0.019; IVW: β = 0.121, SE = 0.052, P = 0.021) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: β = -0.416, SE = 0.163, P = 0.011; IVW: β = -0.122, SE = 0.046, P = 0.009). There was no statistically significant effect of either ALM or HGS on LDL particle diameter., Conclusion: There were potentially causal associations between both increasing ALM and HGS and increasing HDL particle size and decreasing VLDL particle size. These causal associations may offer possibilities for interventions aimed at improving cardiovascular disease risk profile., Competing Interests: Conflict of interest: R.K. has received payments from Abbott for the creation of educational media content, as well as speaker fees. All other authors declare that they have no relevant conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Dietary nitrates are thought to confer several cardiometabolic health benefits, including improvements in blood pressure and the plasma lipid profile. However, existing data from Iran is conflicting and there is a dearth of literature focusing on non-adult populations. A total of 988 adolescent girls were recruited from schools in different areas of Mashhad and Sabzevar, Iran. Dietary nitrate intake was assessed using a food frequency questionnaire and participants were categorized into quartiles based on this. Differences in participant characteristics between quartiles were assessed using one-way ANOVA and associations between total nitrate intake, nitrate intake from vegetables and cardiometabolic risk markers (blood lipid profile, fasting blood glucose, systolic and diastolic blood pressure) were assessed using linear regression. Nitrate intake from vegetables was positively correlated with triglycerides, even after adjusting for several variables (β = 0.086, 95% CI = 0.002-0.097; P = 0.043). Total nitrate intake was also significantly positively associated with serum triglycerides (β = 0.097, 95% CI = 0.010-0.084; P = 0.012); however, this relationship disappeared after adjusting for several variables. Significant interaction effects were observed between total nitrate intake, nitrate intake from vegetables, and vitamin C upon triglycerides (P < 0.01). No significant relationships were found between total nitrate intake, nitrate intake from vegetables, and other cardiometabolic risk markers. Our findings suggest there may be neutral or possibly detrimental cardiovascular effects of dietary nitrate and/or vitamin C intake which are not in agreement with contemporary literature and warrant further investigation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Context: Nonalcoholic fatty liver disease (NAFLD) is prevalent in 25-30% of British and European populations, representing a potential global public health crisis. Marine omega-3 (n-3) polyunsaturated fatty acids offer well-evidenced benefits to NAFLD biomarkers; however, the effect of plant-based n-3 has not been evaluated with a systematic review and meta-analysis., Objective: The review aimed to systematically evaluate the effect of plant-based n-3 supplementation on NAFLD surrogate biomarkers and parameters., Data Sources: Medline (EBSCO), PubMed, CINAHL (EBSCO), Cochrane Central Register of Controlled Trials, the International Clinical Trials Registry Platform, and Google Scholar databases were searched to identify randomized controlled trials published between January 1970 and March 2022 evaluating the impact of plant-based n-3 interventions on diagnosed NAFLD. The review followed the PRISMA checklist and is PROSPERO registered (CRD42021251980)., Data Extraction: A random-effects model and generic inverse variance methods synthesized quantitative data, followed by a leave-one-out method for sensitivity analysis. We identified 986 articles; after the application of selection criteria, six studies remained with 362 patients with NAFLD., Results: The meta-analysis showed that plant-based n-3 fatty acid supplementation significantly reduced alanine aminotransferase (ALT) (mean difference: 8.04 IU/L; 95% confidence interval: 14.70, 1.38; I2 = 48.61%) and plasma/serum triglycerides (44.51 mg/dL; 95% confidence interval: -76.93, -12.08; I2 = 69.93%), alongside body-composition markers in patients with NAFLD (P < 0.05)., Conclusion: Plant-based n-3 fatty acid supplementation improves ALT enzyme biomarkers, triglycerides, body mass index, waist circumference, and weight loss when combined with lifestyle interventions to increase physical activity and a calorie-controlled diet. Further research is needed to identify the most effective plant-based n-3 sources in larger numbers of patients with NAFLD over longer study durations., Systematic Review Registration: PROSPERO registration no. CRD42021251980., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute.)