Whether physical activity modifies the associations of sarcopenia and basic/instrumental activities of daily living (ADL/IADL) disability with mortality remains unclear. The study included 64,146 participants from three nationally representative cohorts: Health and Retirement Study (HRS), Survey of Health, Aging and Retirement in Europe (SHARE), and China Health and Retirement Longitudinal Study (CHARLS). In HRS, the greater risk of mortality associated with each dysfunction was more pronounced in inactive participants, with multi-variable-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) in Cox models of 3.88 (3.57-4.23) for sarcopenia, 1.82 (1.70-1.95) for ADL disability, and 1.95 (1.81-2.09) for IADL disability, while the corresponding HRs (95% CIs) were 3.32 (2.92-3.77), 1.39 (1.20-1.61), and 1.44 (1.26-1.65) in regularly active participants (all P for multiplicative interaction < 0.010). Consistent interaction patterns were observed in SHARE and CHARLS. This study revealed that regular activity meeting the WHO recommendations significantly mitigated the hazards of mortality associated with sarcopenia and ADL/IADL disability.

Unhealthy lifestyles are linked to epilepsy, but the underlying mechanisms involving metabolism and brain structure are unclear. This prospective study analyzed 130,530 UK Biobank participants with multimodal data including lifestyle factors, genotyping, metabolomics, and brain MRI. We examined associations between a composite healthy lifestyle score and incident epilepsy using Cox regression, stratified by polygenic risk score (PRS). We derived a metabolic signature using elastic net regression and identified causal metabolites using Mendelian randomization. Mediation analyses and structural equation modeling (SEM) were performed to elucidate the lifestyle-metabolite-brain-epilepsy axis. During 15.87 years of follow-up, a healthy lifestyle was associated with a lower risk of epilepsy (HR, 0.89; 95% CI: 0.84-0.95), even among individuals with high genetic risk. We identified 94 metabolites characterizing a healthy lifestyle, including specific lipid subclasses and inflammatory markers like GlycA. This metabolic signature was strongly associated with reduced epilepsy risk (HR, 0.75; 95% CI: 0.62-0.91) and mediated 20.51% of the protective effect of lifestyle. Furthermore, neuroimaging analysis revealed that a healthy lifestyle correlated with larger volumes in specific brain structures, such as the hippocampus. Specifically, hippocampal volume partially mediated the link between the metabolic signature and epilepsy. SEM revealed that lifestyle influences epilepsy through metabolic and structural brain alterations. A healthy lifestyle is a robust protective factor against epilepsy, even in genetically susceptible individuals. This protection is mechanistically linked to metabolic signature and brain structure, offering novel targets for prevention.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95

Optimization of HbA1c, blood pressure and cholesterol, referred to as the “ABCs”, is central to the management of diabetes. However, the age-specific associations of these factors with mortality in patients with diabetes remains unclear. In this prospective cohort study, 43,732 Chinese adults aged ≥ 40 years with diabetes were included from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Participants were stratified by age (< 55, 55-<65, 65-<75, ≥ 75 years). Cox proportional hazards regression and Fine-Gray competing risk models were employed to estimate the associations of HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) with all-cause, cardiovascular, and non-cardiovascular mortality across age groups. Relative importance and population attributable fractions (PAFs) were computed for each metabolic factor. During a median follow-up of 10.1 years, 3,975 deaths were documented. Age significantly modified the associations of HbA1c, SBP, and LDL-C with all mortality outcomes (all P for interaction < 0.05). Among participants aged < 75 years, HbA1c showed graded positive associations with all-cause, cardiovascular, and non-cardiovascular mortality. The SBP thresholds associated with increased mortality risk were 140 mmHg in those aged < 65 years and 160 mmHg in those aged 65–<75 years. Among those aged ≥ 75 years, however, the patterns of these associations differed markedly. Elevated mortality risk was observed only at HbA1c ≥ 9

Optimal control of hemoglobin A1c (HbA1c), blood pressure, and cholesterol (ABC risk factors) is essential for reducing cardiovascular disease (CVD) risk in individuals with diabetes. However, age-specific contributions of these factors remain inadequately characterized. Using data from the China Cardiometabolic Disease and Cancer Cohort study, we assessed the associations between ABC risk factors and incident CVD among Chinese adults with diabetes, stratified by age groups of < 55, 55 to < 65, 65 to < 75, and ≥ 75 years. Cox proportional hazards models and population-attributable fractions (PAFs) were used to quantify the associations between ABC risk factors and incident CVD. During a median follow-up of 10.1 years, 4707 incident cases of CVD were documented. Higher levels of baseline HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) were significantly associated with increased CVD risk. Age modified these associations (P interaction < 0.05), with progressively attenuated hazard ratios (HRs) observed in older age groups. Compared with HbA1c < 7.0%, HbA1c ≥ 9.0% showed stronger CVD associations in adults aged < 55 years (HR = 2.42; 95% confidence interval [CI]: 1.98-2.97) than in those aged ≥ 75 years (HR = 1.50; 95% CI: 1.12-2.02), and SBP ≥ 140 mmHg and LDL-C ≥  4.1 mmol/L were significant only in younger groups. The leading contributor to PAFs for CVD was SBP (28.3%), followed by HbA1c (12.0%) and LDL-C (9.2%), with diminishing impacts across older groups. These results underscore the importance of age-specific management of ABC risk factors in diabetes care, with the benefit of stricter risk factor management in younger adults and the need for a more flexible approach in older populations.

ABSTRACT Background Metabolic diseases remain a fast‐growing global health burden. Besides other known factors, socioeconomic status (SES) has been recognized as a key determinant of metabolic health. This study aimed to investigate the association between SES and the prevalence of metabolic diseases in the Chinese population. Methods We analyzed data from a nationwide community‐based cross‐sectional study in China. SES was derived to a composite score (range 0–3) using three indicators (educational attainment, living conditions, and marital status), with higher scores indicating better SES. Chronic diseases were diagnosed through biochemical testing and clinical assessments. Logistic regression models were applied to estimate associations between SES scores and metabolic diseases. Results Among 201 532 participants, the lowest SES group had 87.1% higher odds of metabolic diseases than the highest SES group (odds ratio [OR] = 1.871, 95% confidence interval [CI]: 1.739, 2.016). One‐point decrease in SES score was associated with increased prevalence of hypertension (OR = 1.096, 95% CI: 1.080, 1.113) and obesity (OR = 1.112, 95% CI: 1.091, 1.134). In contrast, lower SES scores were linked to a reduced prevalence of dyslipidemia (OR = 0.931, 95% CI: 0.918, 0.945) and diabetes (OR = 0.974, 95% CI: 0.958, 0.990) after adjusting for covariates. We also observed that lower SES scores showed stronger associations with increased prevalence of obesity and hypertension in women but decreased risks of diabetes, dyslipidemia, and obesity in men. Conclusions Lower SES was associated with a higher prevalence of hypertension and obesity but a lower prevalence of dyslipidemia and diabetes, with significant gender differences.

Background Chronological age is central to cardiovascular risk assessment but may inadequately capture biological vascular aging. Carotid intima-media thickness (cIMT), a non-invasive marker of subclinical atherosclerosis, may provide additional insight into individualized cardiovascular risk. Methods In this prospective cohort study, We analyzed 31,311 UK Biobank participants with cIMT measurements. Vascular age and Δ-age were derived using multivariable models incorporating cIMT and conventional risk factors, and extreme Δ-age deciles were used to define early vascular aging (EVA) and supernormal vascular aging (SUPERNOVA). Associations with major adverse cardiovascular events (MACE) were assessed using Cox models, and incremental predictive value was evaluated using discrimination and reclassification metrics. Results During a median follow-up of 4.18 years, 682 MACE cases were recorded. After multivariable adjustment, EVA was associated with a twofold increase in MACE risk (HR 2.00, 95% CI 1.45–2.75), whereas SUPERNOVA demonstrated a significant protective effect (HR 0.70, 95% CI 0.54–0.91). Stratified analyses revealed that these associations were most pronounced in the high-risk group (Framingham Risk Score > 20%), where EVA further increased MACE risk (HR 2.69, 95% CI 1.72–4.20) and SUPERNOVA remained protective (HR 0.64, 95% CI 0.47–0.85). Incorporating these vascular aging phenotypes into traditional risk models significantly improved predictive performance, yielding a Net Reclassification Improvement (NRI) of 13.1% (95% CI 8.7–16.8). Conclusion cIMT-derived vascular age effectively stratifies extreme vascular aging phenotypes and is associated with future cardiovascular events. Incorporation of vascular age into conventional risk models provides incremental prognostic value beyond traditional risk scores.

Ovarian cancer is a major female reproductive health issue with heterogeneous biological features on its subtypes, which may require different therapeutic strategies. Glucagon-like peptide-1 receptor (GLP-1R) agonists were reported to be beneficial for ovarian cancer, but the causal effects and mechanisms on its heterogeneous subtypes remain unclear. We used genetic variants robustly associated with gene expression, protein level, splicing event, and DNA methylation of GLP-1R in six endocrine-related tissues (N ≤ 35,431) as genetic instruments to proxy the effect of GLP-1R agonism. To increase power, we conducted a meta-analysis of genome-wide association studies of ovarian cancer (29,066 cases, 461,542 controls), and identified 12 genome-wide associated variants, including two previously unreported variants: rs77247401 (MIR1208) and rs56159231 (PLEKHM1). Here we show that gene expression of GLP-1R in pancreas is associated with a reduced risk of overall ovarian cancer risk odds ratio ([OR] = 0.94, 95

Urbanization intensifies aging challenges, positioning cities to address non-communicable diseases like diabetes through age-friendly planning, policies, and health interventions. This study used data from the 2018–2020 CHARLS, along with city characteristics from the China City Statistical Yearbook and Google Earth Engine. Principal component analysis and the entropy method were employed to construct a comprehensive picture of age-friendliness, encompassing five domains: health service and social security, housing conditions, community atmosphere, economic development, and ecological environment. Multilevel logistic regression models were then applied to analyze the relationship between age-friendly environments and the incidence of diabetes among older adults in China. The results indicate that a higher level of community atmosphere was associated with a lower risk of developing diagnosed diabetes within two years. The findings highlight the need to enhance home and community services, integrate smart technologies, and diversify elderly care solutions to mitigate diabetes risk among older adults.

Integrated genomic evidence on shared genetic architecture between obesity and psychiatric disorders remains limited. This work utilized multi-level genomic analytic approaches to identify pleiotropic loci, variants, and genes between 14 adiposity traits and 7 psychiatric disorders, including genetic correlation and bidirectional causality as well as gene expression, functional pathway, and druggability, using genome-wide association study data from up to 806,834 individuals of European descent. Based on 67 genetically correlated trait pairs established between the two groups, we identified 17 causal shared genes across 26 tissues, which were enriched in neurodevelopment, neuronal function, cellular transport, and developmental biology. Of these, NEGR1, CTNNB1, TAOK2, and RTN4RL1 were located in the druggable genome, and CTNNB1 and NT5C2 were clinically actionable. Mendelian randomization further supported extensive bidirectional causal associations. These findings provide robust evidence for a shared genetic etiology between adiposity and psychiatric disorders, underscoring mechanistic links and prioritizing actionable targets for comorbidity intervention.

Little has been found regarding the lifetime cumulative effect of reproductive factors on chronic kidney disease (CKD), and how this relationship varies with cardiovascular health (CVH) remains unexplored. This study aimed to assess the relationships of lifetime cumulative estrogen exposure reflected by reproductive factors, and LE8 CVH status with incident CKD among postmenopausal women. The study included 33,700 postmenopausal participants from the China Cardiometabolic Disease and Cancer Cohort (4 C) Study, enrolled between 2011 and 2012 with follow-up assessments conducted between 2014 and 2016 (median follow-up: 3.1 years). Lifetime cumulative estrogen exposure due to reproductive factors was evaluated through reproductive lifespan (RLS), endogenous estrogen exposure (EEE), and total estrogen exposure (TEE). Health behaviors information in Life’s Essential 8 (LE8) was collected by questionnaire and laboratory examination. The risk of CKD was analyzed with Cox proportional hazards models. Shorter lifetime cumulative estrogen exposure was associated with an increased risk of CKD (RLS, HR: 1.42, 95

BACKGROUND:Albuminuria from low-grade to clinically elevated range confers cardiorenal risks. OBJECTIVES:The authors aimed to investigate the differential roles of lifestyle/metabolic factors in the association of fine-categorized and continuously measured urinary albumin-to-creatinine ratio (UACR) levels with cardiorenal outcomes. METHODS:A total of 82,509 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study were included, with a median follow-up of 3.0 years. Outcomes included incident cardiovascular disease (CVD), incident CKD, their composite, along with surrogate markers. Lifestyle factors included tobacco use, alcohol use, diet, physical activity and sleep. Metabolic factors included diabetes, hypertension, abdominal obesity, and elevated low-density lipoprotein cholesterol. Cox proportional hazard models were used to calculate hazard ratios. RESULTS:Compared to the lowest UACR, participants with mildly elevated UACR (≥10 to <30 mg/g) had a 39% higher risk of composite cardiorenal outcomes (multivariable-adjusted HR: 1.39, 95% CI: 1.29-1.50), whereas those with clinically elevated UACR (≥30 mg/g) had over double the risk (HR: 2.29, 95% CI: 2.12-2.47). A nonlinear J-shaped association was observed between continuous UACR and cardiorenal outcomes (Pnonlinearity = 0.0009), with UACR ≥10 mg/g already conferring risks, a pattern also reflected by the deterioration of PREVENT score and estimated glomerular filtration rate. Optimal lifestyle and metabolic status generally attenuated CVD risk related to low-grade albuminuria, while improvement of the latter additionally decreased CVD and cardiorenal risk, even in clinically elevated albuminuria (additive Pinteraction <0.0001). Hypertension showed the largest relative contribution to cardiorenal risk, particularly in UACR <30 mg/g. CONCLUSIONS:Our findings highlighted low-grade albuminuria as a key preventive window for cardiorenal outcomes requiring both aspects of modifiable risk factors, and the cardiovascular benefits of metabolic improvement in established albuminuria.

Birthweight readily measurable marker of fetal growth that may influence health across the lifespan. We aimed to investigate the potential causal association between birthweight and healthy aging and to identify the mediating roles of subsequent socioeconomic, behavioral, functional, and disease-related factors to inform life-course strategies to promote healthy aging and reduce health inequities. We performed two-sample Mendelian randomization analyses in European-ancestry participants to estimate the effect of birthweight (n = 298,142–423,683) on two robust, composite healthy aging phenotypes (genetically independent phenotype of aging (aging-GIP) and multivariate aging-related genetic factor (mvAge)) and six individual aging phenotypes, including healthspan, resilience, parental lifespan, self-rated health, phenotypic age deceleration, and 90th percentile self-longevity (n = 34,710–1,958,774), and screened for 100 candidate mediators (n = 14,267–1,812,017) using a two-step mediation analysis. Genetically determined each 1-SD higher birthweight was associated with higher aging-GIP (β [95

AIMS:To investigate the associations of general and central obesity with premature mortality in a Chinese population. MATERIALS AND METHODS:A total of 162 776 participants from the China Cardiometabolic Disease and Cancer Cohort Study were included in the current analysis. General and central obesity were assessed using body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Premature mortality was defined as all-cause mortality occurring before the age of 75 years, including cardiovascular disease (CVD)-related and non-CVD-related premature mortality. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS:During a median follow-up of 10.1 years, 5477 (3.36%) premature deaths were documented. Compared with normal weight (18.5 to <24 kg/m2), those with general obesity (BMI ≥28 kg/m2) were associated with elevated risk of CVD-related premature mortality (HR: 1.53; 95% CI: 1.30-1.82). Central obesity (WHR ≥0.95 for men or ≥0.90 for women) was associated with increased risks of all-cause (HR: 1.20; 95% CI: 1.11-1.31), CVD-related (HR: 1.51; 95% CI: 1.29-1.77) and non-CVD-related premature mortality (HR: 1.11; 95% CI: 1.01-1.22). These associations persisted after mutual adjustment for BMI and WHR. A significant interaction between BMI and WHR on the risk of premature mortality was observed (p for interaction = 0.028). Individuals with normal weight but central obesity exhibited the highest risk of all-cause premature death (HR: 1.21; 95% CI: 1.06-1.37), whereas the highest risk of CVD-related mortality was observed in those with both general and central obesity (HR: 1.89; 95% CI: 1.50-2.39). CONCLUSIONS:The combination of normal weight and central obesity significantly increases premature mortality risk, emphasizing the importance of integrating WHR into obesity assessments to improve risk stratification and prevention strategies among Chinese adults.

BACKGROUND:The cardioprotective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA)-based therapies in nondiabetic individuals with overweight or obesity remain underexplored. This meta-analysis evaluates their impact on cardiovascular events and metabolic parameters in this population. METHODS:A meta-analysis was conducted using PubMed, Embase, Cochrane, and Web of Science databases from inception to June 18, 2024. Eligible studies were randomized controlled trials (RCTs) enrolling nondiabetic adults with overweight or obesity. These studies compared GLP-1RA-based therapies with placebo and reported cardiovascular events and metabolic parameters. RESULTS:A total of 29 RCTs involving 9 GLP-1RA-based drugs and 37 348 eligible participants were included. Compared to placebo, GLP-1RA-based therapies significantly reduced the risk of total cardiovascular events (relative risk: 0.81, 95% confidence interval [CI]: [0.76, 0.87]), major adverse cardiovascular events (0.80, [0.72, 0.89]), myocardial infarction (0.72, [0.61, 0.85]), and all-cause mortality (0.81, [0.71, 0.93]). No significant differences were observed in cardiovascular death or stroke. Additionally, GLP-1RA-based therapies were associated with significant reductions in some cardiometabolic parameters. Among GLP-1RA-based therapies, orfroglipron demonstrated strong benefits in reducing systolic blood pressure (mean difference: -7.10 mmHg, 95% CI: [-11.00, -2.70]). Tirzepatide induced the greatest reduction in body mass index (-6.50 kg/m2, [-7.90, -5.10]) and hemoglobin A1c concentrations (-0.39%, [-0.52, -0.26]). Retatrutide and semaglutide were most effective in improving lipid profiles and reducing C-reactive protein levels (-1.20 mg/dL, [-1.80, -0.63]), respectively. CONCLUSIONS:In nondiabetic individuals with overweight or obesity, GLP-1RA-based therapies significantly reduce cardiovascular events and improve cardiometabolic parameters. These findings underscore the potential for individualized GLP-1RA-based therapies targeting cardiovascular risk factors.

Context Emerging studies have revealed associations between dietary medium-chain fatty acids (MCFAs) and glucose homeostasis. However, the relationship between serum MCFAs and the incidence of diabetes, and potential interactions with genetic predisposition, remains unclear in prospective cohort studies.Objective This work aimed to investigate associations and genetic susceptibility between serum MCFAs and diabetes risk.Methods We investigated baseline serum MCFAs (n = 5) in a nested case-control study comprising incident diabetes cases (n = 1707) and matched normoglycemic control individuals (n = 1707) from the China Cardiometabolic Disease and Cancer Cohort Study. Associations between MCFAs and type 2 diabetes mellitus (T2DM) were examined, both overall and stratified by diabetes genetic susceptibility. Genetic risk scores (GRS) were calculated based on 86 T2DM-associated genetic variants.Results In the fully adjusted conditional logistic regression model, serum octanoic acid and nonanoic acid exhibited inverse dose-response relationships with diabetes risk, showing odds ratios (95% CI) of 0.90 (0.82-0.98) and 0.84 (0.74-0.95), respectively. Subgroup analysis demonstrated that inverse associations between MCFAs and incident diabetes were more pronounced among individuals with physical inactivity (Pinteraction = .042, .034, and .037, for octanoic, nonanoic and decanoic acid, respectively). Moreover, inverse associations of octanoic acid with diabetes risk were notably enhanced among individuals with high genetic risk compared to those with low genetic risk. Statistically significant interactions were observed between octanoic acid and GRS on T2DM risk (Pinteraction = .003).Conclusion These findings provide evidence supporting inverse associations between serum MCFAs and T2DM risk, and reveal potential interplay between genetic susceptibility and circulating octanoic acid in modulating diabetes risk.

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity.

Diabetic kidney disease (DKD) remains one of the most serious complications of type 2 diabetes, significantly impacting patients' morbidity and mortality. Microalbuminuria (mALB), a clinically validated biomarker, plays a key indicator for both early diagnosis and predicting the progression of DKD. However, existing point-of-care testing methods for albumin detection often suffer from limited sensitivity and operational complexity. To overcome these challenges, we developed and evaluated a fully printed, photonic crystal-integrated microarray-assisted point-of-care platform specifically designed for the rapid and precise detection of mALB. The system employs polymer latex microspheres, selected for their optical compatibility with detection fluorophores, as signal-enhancing carriers. By exploiting the photonic bandgap and photon localization effects inherent in photonic crystal structures, the platform significantly amplifies fluorescence signals in immunoassays, thereby substantially enhancing detection sensitivity and resolution. A detection method based on a double-antibody sandwich immunoassay was employed, enabling specific antigen-antibody binding and accurate quantification. Validation using clinical urine samples demonstrated the diagnostic efficiency of the platform. The full analysis can be executed in under 10 min, demonstrating a robust linear association between the fluorescence level and the mALB content.. The platform achieved a detection limit of 19.5 pg mL-1 and an accuracy of up to 92.9%. Further validation with 70 clinical urine samples confirmed that the platform exhibited a good diagnostic performance, demonstrating high sensitivity, specificity, and operational stability. In summary, this photonic crystal microarray-based point-of-care system offers a sensitive, accurate, and time-efficient solution for early DKD diagnosis and long-term disease monitoring. Its convenience and portability render it ideal for frequent assessments and long-term patient care, possibly enhancing results and decreasing medical expenses.

BackgroundDefinition and staging rationale of cardiovascular-kidney-metabolic syndrome were developed. The utility of cardiovascular-kidney-metabolic construct in risk stratification and target strategies of health and behavior modifications needs to be addressed. The study aims to investigate the individual and combined associations of cardiovascular-kidney-metabolic stage and cardiovascular health (CVH) by Life's Essential 8 (LE 8) with incident cardiovascular events (CVD), and determine the distribution and contribution of domain-specific CVH across cardiovascular-kidney-metabolic stages.MethodsThe study included 100,727 individuals in the China Cardiovascular Disease and Cancer Cohort with complete data on cardiovascular-kidney-metabolic factors and LE 8 metrics, with a median follow-up of 10.1 years. Cardiovascular-kidney-metabolic stages and CVH metrics (nicotine exposure, diet, physical activity, sleep, body mass index, blood lipids, blood pressure, blood glucose) were defined according to Presidential Advisory from the American Heart Association. Incident CVD events including cardiovascular death, myocardial infarction, and stroke were validated. The Fine-Gray hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of CKM stages or CVH status associated with CVD.ResultsCompared with cardiovascular-kidney-metabolic stage 0, the adjusted competing HRs and 95% CIs of CVD events were 1.20 (0.95-1.51), 2.45 (1.97-3.04), 4.43 (3.53-5.58), and 5.95 (4.75-7.45) from stage 1 to stage 4, respectively. Optimal CVH status and each optimal CVH metric presented a significantly decreased risk of CVD events. Variation was observed in the association between cardiovascular-kidney-metabolic stage and CVD events with different CVH status or numbers of optimal CVH metrics. Compared with those in stage 0, Participants in stage 1 or 2 with optimal CVH no longer had elevated risks for incident CVD events. Suboptimal health factor contributed larger population attributable fractions to CVD events in cardiovascular-kidney-metabolic stage 0-2 (51.2%) than in stage 3-4 (25.2%), whereas suboptimal health behavior exhibited larger contribution in advanced stages (13.1% in stage 0-2 and 18.2% in stage 3-4).ConclusionsThe study indicated that cardiovascular-kidney-metabolic stage was associated with cardiovascular events, and optimal cardiovascular health could attenuate this risk. Health factor contributed predominantly at the early-stage, whereas health behavior exhibited consistent and slightly increased contribution along the spectrum. These findings support the utility of cardiovascular-kidney-metabolic construct and highlight the importance of target health improvement based on LE 8 framework.

AIM:To investigate whether interleukin-17A (IL-17A) gets involved in the mechanisms of inflammation-related retinal pigment epithelium (RPE) cells injury and its significance in age-related macular degeneration (AMD). MRTHODS:A sodium iodate (NaIO3) mouse model as well as IL-17A -/- mice were established. The effects of inflammatory cytokines in RPE cells and retinal microglia before and after NaIO3 modeling in vivo and in vitro, were investigated using immunofluorescence, immunoprotein blotting, and quantitative real-time fluorescence polymerase chain reaction (qRT-PCR), respectively. Interventions using recombinant IL-17A protein (rIL-17A) or IL-17A neutralizing antibody (IL-17A NAb) were used to observe the subsequent differences in fundus, fundus photography and optical coherence tomography (OCT), cell viability, and expression of oxidative stress-related markers before and after modeling, and to screen for key signaling pathways. RESULTS:In the scenario of NaIO3 stimulation, RPE cells obviously tended to degenerate. Simultaneously proliferation and activation of retinal microglia was confirmed in NaIO3-stimulated mice, whereas such effects induced by NaIO3 were significantly ameliorated with IL-17A NAb intervention or in IL-17A -/- mice. In addition, IL-17A promoted the proliferation and activation of microglia as well as oxidative damage and the secretion of inflammatory cytokines alongside NaIO3-induced damage in RPE cells in vivo and ex vivo. Meanwhile, the extracellular signal-regulated kinase (ERK) signaling pathway was shown to be participated in the regulation of NaIO3-induced RPE cells injury mediated by IL-17A in vivo and ex vivo, as IL-17A-induced inflammatory cytokines release in the NaIO3 model was alleviated after blocking the ERK pathway. CONCLUSION:IL-17A probably promotes the NaIO3-induced RPE cells injury through exacerbating inflammation in terms of retinal microglia activation and inflammatory cytokines release via ERK signaling pathway. Inhibition of IL-17A may be a new potential target for dry AMD treatment.