Immunoglobulin G (IgG) is recognized as a key regulator of metabolic dysfunction and fibrosis in adipose tissue, and its functional properties are tightly regulated by its glycosylation profile. However, the role of IgG glycosylation in adipose aging remains unclear. Here, we performed transcriptomic and glycoproteomic analyses of epididymal white adipose tissue (eWAT) from young and aged mice. RNA sequencing (RNA-seq) analysis revealed a significant downregulation of adipogenic genes in aged eWAT, accompanied by elevated expression levels of inflammatory and fibrotic markers, which were further validated by quantitative polymerase chain reaction (qPCR). N- and O-glycoproteomic analyses revealed widespread changes in glycosylation. Differentially glycosylated proteins are primarily localized to the extracellular space and participate in innate immune responses, transport and signal transduction, extracellular matrix (ECM)–receptor interaction pathways, and so on. Notably, IgG glycosylation levels were significantly increased in aged mice. Specifically, the N-fucosylation of IgG1, IgG2a, and IgG3 was elevated by 3.1-, 10.4-, and 3.2-fold, respectively, while only IgG2a showed increased O-fucosylation. These findings suggest that N-fucosylation is a common age-related modification across IgG subtypes. Using in vivo models, we further demonstrated that B-cell depletion-induced IgG reduction increased adipogenic and inflammatory gene expression, while the expression of fibrotic markers was suppressed. These effects were reversed upon repletion with either fucosylated or nonfucosylated IgG. Importantly, compared with nonfucosylated IgG, fucosylated IgG exacerbated inflammation and fibrosis but inhibited adipogenesis more strongly. Taken together, our results identify fucosylated IgG as a key mediator of adipose dysfunction during aging and suggest that modulating IgG fucosylation may offer therapeutic potential for age-related metabolic disorders.

To examine how distinct cardiovascular health (CVH) trajectories before age 50, estimated by Life’s Essential 8 (LE8), a composite measure comprising four behavioral and four biological components, relate to incident cardiovascular disease (CVD), all-cause mortality, and CVD-free survival in a Chinese population, from a predictive, preventive, and personalized medicine (PPPM) perspective. We included 39,305 CVD-free participants (77.3

Cardiorespiratory fitness(CRF)is defined as the ability of the circulatory,respiratory,and muscular systems to deliver oxygen during prolonged,sustained,and dynamic exercises of moderate to vigorous intensity[1].Previous studies have shown that,compared with traditional risk factors,such as hyperlipidemia,obesity,hypertension,and insulin resistance,CRF has not been routinely used in clinical practice,although it is a stronger predictor of cardiovascular disease(CVD)and all-cause mortality.Moreover,the associations between CRF and mortality risk are inverse,independent,and graded across age ranges,including individuals in their 70s and 80s,men,women,and all races.Higher CRF is associated with lower all-cause mortality and CVD risk[2].However,whether CRF ultimately influences all-cause mortality and life expectancy by mediating these chronic diseases and the causal relationship between CRF and longevity remain unclear.Therefore,it is crucial to investigate the association between CRF and all-cause mortality.Furthermore,previous studies did not consider the causal relationship between CRF and all-cause mortality.

To investigate the associations of baseline high-sensitivity C-reactive protein (hs-CRP), hs-CRP trajectories, and cumulative hs-CRP (CumCRP) exposure with the risk of incident heart failure (HF) in individuals with diabetes. We analyzed 18,269 patients with diabetes from the Kailuan Study who were free of HF and cancer at baseline (2006–2012). Baseline hs-CRP was categorized into quartiles (Q1-Q4), with a separate group for hs-CRP values > 20 mg/L. Repeated measurements were used to identify long-term trajectories via group-based trajectory modelling and calculate time-weighted cumulative hs-CRP after excluding participants with hs-CRP > 20 mg/L. Fine-Gray subdistribution hazard models were employed to estimate adjusted hazard ratios (HRs) for incident HF. Over a mean follow-up of 9.66 ± 2.85 years, 826 HF occurred. Compared with baseline hs-CRP quartile (Q1), the HRs for HF increased across higher quartiles and in the > 20 mg/L group were 1.22 (95

INTRODUCTION:We aimed to explore the potential incremental cost-effectiveness of the PRODEMOS coach-supported mobile health intervention for primary prevention of dementia versus standard of care provided to people aged 55-75 years with low socio-economic status (SES) in the United Kingdom (UK), and any SES in China. METHODS:12-18-month PRODEMOS trial (ISRCTN15986016) efficacy outcomes on hypertension, obesity, hypercholesterolemia, physical inactivity and smoking were extrapolated to lifetime impact on dementia onset, myocardial infarction, stroke and death using a health-economic open-source simulation model. RESULTS:Simulated outcomes showed dementia cases were avoided (UK = -206 (-658 to 281), China = -140 (-456 to 205) per 100,000 persons) and disease-free time was gained for dementia, myocardial infarction and stroke (mean months per person UK = 0.4, 0.0 and 0.0; China = 0.2, 0.0 and 0.0 respectively). Assuming a maximum intervention duration of 10 years with a 10 % annual non-adherence rate, the incremental net health benefit in the UK (-0.190) and China (-0.009) indicated a potential lack cost-effectiveness. LIMITATIONS:Our method was limited by strong assumptions regarding causality and sustained effectiveness, lack of some country-specific input estimates, and the lack of probabilistic analysis. CONCLUSION:The PRODEMOS coach-supported mobile health intervention for the primary prevention of dementia, aimed at people aged 55 to 75 years with low SES in the UK and those of any SES in China, may potentially lack cost-effectiveness in both countries. However, lack of data required strong assumptions regarding causality and sustained effectiveness, which limited policy recommendations.

Chronic low-grade inflammation has been identified as the etiology of disease across the life span; however, the underlying genetic mechanism are poorly understood, and no genetic association study is performed. Here, we quantified chronic low-grade inflammation using the low-grade inflammation score (INFLA-score) and performed a genome-wide association study in a large European cohort of 217,984 individuals, involving 6,134,151 single nucleotide polymorphisms (SNPs). We identified 20,182 SNPs at 194 loci reaching genome-wide significance (p < 5 × 10-8), with the lead SNP rs429358 in apolipoprotein E (APOE) showing an extremely low p-value of 8.69 × 10-166. Gene analysis found 470 genes with p < 2.70 × 10-6 (0.05/18,519), among which phosphodiesterase 4B was most significant (p = 1.67 × 10-22). Among those, 15 SNPs were first reported, including GS1-259H13.10, AC068533.7, AL355490.1, and so on. Tissue expression analysis revealed significant links between genetic variants and chronic low-grade inflammation in spleen and whole blood. Our findings identify variants linked to chronic low-grade inflammation and related inflammatory and cellular regulation traits, and suggest a close association between chronic low-grade inflammation and the spleen.

Objective:Immunoglobulin G (IgG) N-glycosylation is associated with mild cognitive impairment through the regulation of inflammatory balance; however, the underlying mechanisms remain unclear. Methods:Our study utilized a post-genome-wide association studies (GWAS) method that integrated GWAS data for cognitive function with gene expression quantitative trait loci (eQTL), protein QTL (pQTL), and IgG N-glycan-QTL data. Results:Mendelian randomization (MR) analyses suggested bidirectional causalities between glycan peaks (GPs) and cognitive function, with GP7, GP12, and GP19 showing a causal effect on cognitive function, while cognitive function conversely showed a causal effect on GP1 and GP8. Two proteins and 10 genes were implicated in the regulation of IgG N-glycosylation. Furthermore, multivariable MR results suggested complex causalities between genes/proteins and IgG N-glycans, which jointly promote or independently affect cognitive function. Conclusion:Our study reveals a novel mechanism by which genes, proteins, and modified IgG N-glycans converge to pathologically affect cognitive function.

The combined effects of metabolic status and genetic predisposition on healthy ageing remain unclear. We aimed to investigate the association of metabolic status and genetic predisposition with healthy ageing and life expectancy across obesity levels in the context of predictive, preventive, and personalized medicine (PPPM). Cox regression models were used to examine the relationships of metabolic status and polygenic risk score (PRS) with healthy ageing across obesity levels using data from the UK Biobank. Multistate life tables were used to evaluate life expectancy with and without major chronic diseases, cognitive dysfunction, physical impairment, and mental impairment. Compared with individuals with metabolically unhealthy obesity (MUO) and a low PRS for healthy ageing, those with metabolically healthy obesity (MHO) and a high PRS had a significantly increased likelihood of healthy ageing (hazard ratio [HR]: 1.10; 95

Objective:Previous studies link lower body mass index (BMI) with increased obsessive-compulsive disorder (OCD) risk, yet other body mass indicators may be more etioloically relevant. We dissected the causal association between body fat mass (FM) and OCD. Methods:Summary statistics from genome-wide association studies of European ancestry were utilized to conduct two-sample Mendelian randomization analysis. Heterogeneity, horizontal pleiotropy, and sensitivity analyses were performed to assess the robustness. Results:The inverse variance weighting method demonstrated that a genetically predicted decrease in FM was causally associated with an increased OCD risk [odds ratio ( OR) = 0.680, 95% confidence interval ( CI): 0.528-0.875, P = 0.003]. Similar estimates were obtained using the weighted median approach ( OR = 0.633, 95% CI: 0.438-0.915, P = 0.015). Each standard deviation increases in genetically predicted body fat percentage corresponded to a reduced OCD risk ( OR = 0.638, 95% CI: 0.455-0.896, P = 0.009). The sensitivity analysis confirmed the robustness of these findings with no outlier instrument variables identified. Conclusion:The negative causal association between FM and the risk of OCD suggests that the prevention or treatment of mental disorders should include not only the control of BMI but also fat distribution and body composition.

Gastrointestinal (GID) and cardiovascular diseases (CVD) often coexist, making integrated predictive, preventive, and personalised medicine (PPPM/3PM) management challenging. Although GIDs are established CVD risk factors, their bidirectional link remains unclear, hindering early risk stratification and tailored interventions. This bidirectional study enrolled 460,899/405,701 participants without baseline CVD/GID from the UK Biobank cohort. Associations of GID/CVD with CVD/GID incidence, and associations of comorbidities with all-cause mortality among GID/CVD patients, were estimated via time-dependent Cox regression models. During a median follow-up of 13.5/13.2 years, 70,435 CVD cases and 113,191 incident GID cases occurred. Patients with GID had an elevated risk of CVD (adjusted hazard ratio [aHR] = 1.33, 95

BACKGROUND:The study utilized the remnant cholesterol (RC) to high-density lipoprotein cholesterol (HDL-C) ratio as a lipidemia indicator. Assessing its long-term impact on cardiovascular disease (ASCVD) is crucial for primary prevention. METHODS:84,380 participants were enrolled in the prospective cohort. Participants were classified into low, medium, and high levels based on baseline RC/HDL-C levels at the 50th percentile and 90th percentile. Participants were followed until December 31, 2023. Calculate the incidence density of ASCVD for each group. The time-dependent Cox proportional hazards model was utilized to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for ASCVD risk among different groups. RESULTS:The study included 42,181, 33,739, and 8460 participants in the low, medium, and high levels respectively. A median follow-up of 16.92 years, 8397 ASCVD cases were identified. The 1000 person-years incidence density and 95% CIs for ASCVD were 5.86 (5.67, 6.05) in the low level, 6.92 (6.70, 7.15) in the medium level, and 8.85 (8.35, 9.39) in the high level. Compared to the low level, the Cox model showed that the HRs and 95% CIs for ASCVD were 1.09 (1.04, 1.14) and 1.23 (1.15, 1.32), respectively in medium and high levels. CONCLUSION:Higher RC/HDL-C level was significantly associated with an increased risk of ASCVD. Including the RC/HDL-C in lipid evaluation can reduce the onset of ASCVD. CLINICAL TRIAL REGISTRATION NUMBER:ChiCTR2000029767.

BACKGROUND:Childhood obesity is a pressing global public health challenge requiring scalable prevention strategies. This study evaluated a tiered school-family-clinic intervention for obesity prevention among primary schoolchildren in China. METHODS:This cluster randomized controlled trial enrolled 1,627 third-grade students (intervention: n = 838; control: n = 789) from six primary schools in Ningbo, China. Intervention intensity was tailored to baseline weight status. In intervention schools, children without overweight or obesity received OptiChild, comprising health education and school weight-management policies. Children with overweight or obesity received SCIENT, adding teacher-led structured physical activity and individualized family dietary guidance from clinical nutritionists, supported by mobile health tools. Control schools maintained standard curricula. The primary outcome was change in body mass index (BMI). Secondary outcomes included BMI Z score, body fat distribution, blood pressure, and health behaviors. FINDINGS:After one academic year, BMI gain was attenuated in the intervention vs. control group (+0.02 vs. +0.24 kg/m2; mean difference [MD] -0.25; p = 0.006). Overweight/obesity prevalence declined from 24.8% to 18.9% in intervention schools vs. 23.6%-21.0% in controls (p = 0.015). OptiChild slowed BMI increase (+0.08 vs. +0.25 kg/m2; MD -0.19; p = 0.048) in children without baseline overweight and reduced incident overweight/obesity by 68% (1.1% vs. 3.5%; p = 0.007). SCIENT reduced BMI (-0.19 vs. +0.21 kg/m2; MD -0.38; p < 0.001). Both interventions improved health behaviors, with no adverse events reported. CONCLUSIONS:A tiered school-family-clinic intervention effectively mitigated BMI gain and reduced obesity prevalence, with promising implications for broader public health adoption. FUNDING:Major Science and Technology Projects for Health of Zhejiang Province.

Background/Objectives: Biliary atresia (BA) is the most common etiology for pediatric liver transplantation (LT). However, whether a previous Kasai hepatoportoenterostomy (KP) and its timing influence the outcomes of BA patients who undergo LT remains controversial. Methods: Pediatric patients with BA who underwent LT at Beijing Friendship Hospital, Capital Medical University, between June 2013 and November 2022 were recruited. The patients were divided into non-KP, early-KP (before 90 days of life), and late-KP subgroups. The clinical data were compared among the groups. A nomogram to predict the 1-, 3-, and 5-year graft survival probabilities based on a multivariate Cox model was constructed and validated. Results: Among the 475 BA patients, the no-KP group accounted for 31.8%, the early KP for 60.4%, and the late KP for 7.8%, respectively. The incidences of LT complications were comparable among the groups. From the multivariate Cox analyses, an intensive care unit (ICU) stay and bleeding were identified as the independent risk factors for postoperative patient survival, and the LT type, graft type, vascular complications, and biliary complications were those for graft survival. A nomogram for graft survival was constructed, with a C-index of 0.82, and areas under the curves (AUCs) of 0.829, 0.824, and 0.824 for the 1-, 3-, and 5-year survival nomograms, respectively. The calibration and decision curve analysis (DCA) curves showed good discrimination ability and clinical applicability. A risk classification system was further developed, and the Kaplan-Meier curves demonstrated high discrimination between the high- and low-risk groups (p < 0.0001). Conclusions: A previous KP has no impact on patients or graft survival after LT in BA patients. The established nomogram may be helpful for counseling BA patients about their clinical prognosis after LT.

AIMS:This study aimed to investigate the association between Chinese visceral adiposity index (CVAI) and heart failure (HF) risk in diabetic individuals and to evaluate the predictive capability of CVAI compared to other obesity metrics. MATERIALS AND METHODS:A prospective cohort study (Kailuan Study) spanning 2006 to 2022 involved 12 243 diabetic patients. Participants were stratified into CVAI quartiles (Q1: <96.13, n = 3060; Q2: 96.13 to <121.25, n = 3061; Q3: 121.25 to <146.85, n = 3061; Q4: ≥146.85, n = 3061). The relationship between CVAI and HF occurrence was assessed using the Kaplan-Meier analysis and Cox regression models, supplemented by sensitivity analyses. Restricted cubic splines were used to evaluate potential nonlinear associations. Subgroup analyses examined the influence of sociodemographic factors and health behaviours. Receiver operating characteristic (ROC) analysis compared CVAI with other obesity indices. Statistical significance was set at p < 0.05. RESULTS:Over a median follow-up of 15 years, 861 new HF cases were recorded. HF incidence rose with increasing CVAI quartiles (Q1-Q4: 3.05-7.20/1000 person-years; p < 0.05). Adjusted HRs (95% CI) for HF in Q2-Q4 compared to Q1 were 1.32 (1.06-1.65), 1.41 (1.13-1.75) and 1.91 (1.55-2.35) (Ptrend < 0.01). Age significantly modified the CVAI-HF relationship (≥60 years: HR = 2.06, 1.60-2.64; Pinteraction <0.01). CVAI exhibited a linear correlation with HF (Pnonlinear = 0.75) and demonstrated superior ROC-predictive accuracy compared to other indices (p < 0.01). CONCLUSION:CVAI is independently associated with HF risk, especially in elderly patients, supporting its utility for visceral fat-related risk stratification.

Background:Modifiable risk factors have been linked to 45% of dementia cases. Mobile health (mHealth) interventions targeting lifestyle-related risk factors with remote coaching have the potential to reach underserved high-risk populations globally. To date, little is known about the implementation of such interventions in China. Methods:Fifty semi-structured interviews were conducted with 14 participants and 11 health coaches involved in the PRODEMOS trial. This trial investigated whether a coach-supported mHealth application intervention can reduce dementia risk in people aged 55-75 years with multiple risk factors. Interviews were conducted three months and 12-18 months into the intervention, focusing on implementation outcomes among Chinese participants using thematic analysis. Results:Participants found the PRODEMOS app easy to use and remote coaching convenient, although coach responses were sometimes perceived as slow due to not logging into the mHealth platform simultaneously, thus delaying text chat communication. The intervention's appropriateness was shaped by its effectiveness in enhancing health awareness and meeting participants' needs. Feasibility depended on integration into daily routines, participant progress, partner support, coach attention, smartphone literacy, and time availability. Challenges for the coaches included remote motivational interviewing and sustained participant-coach engagement, influenced by participant-coach relationships, social environment, and the COVID-19 pandemic. Participants generally adhered to goals, but fidelity varied. Integration into primary care was endorsed. Conclusions:This first qualitative study of the Chinese arm of the PRODEMOS intervention demonstrates that it is an acceptable and implementable approach for promoting lifestyle changes in individuals at increased risk of dementia. While coaching is crucial for sustained engagement, it presents challenges when delivered remotely. Despite significant variability in participants' adherence, positive feedback underscores its potential for integration into primary care and large-scale implementation, provided issues with coaching and engagement are addressed. These findings offer valuable insights for practitioners and policymakers seeking to incorporate mHealth solutions into public health strategies for dementia prevention. Registration:PRODEMOS: ISRCTN15986016.

BACKGROUND:No effective treatment is available to delay or reverse the onset and progression of Alzheimer's dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility. METHODS:We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated using nine signaling questions tailored to identify potential biases based on the STROBE-MR guidelines. RESULTS:A total of 125 eligible publications were examined, including 106 AD-related MR studies reporting 674 records and 28 cognition-related MR studies reporting 141 records. We identified 185 unique causal risk factors for AD and 49 for cognitive status. More than half of the MR studies reporting AD or cognitive status outcomes exhibited poor methodological quality, with a high risk of bias observed in 59% of the AD-related studies and 64% of the cognitive-related studies. CONCLUSIONS:This systematic review summarized modifiable factors and omics signatures, providing a database of MR studies on AD and related cognitive status. The evaluation of bias risk in MR studies serves to raise awareness and improve overall quality. A critical appraisal checklist for assessing the risk of bias may pave the way for the development of a standardized tool. SYSTEMATIC REVIEW REGISTRATION:The review protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023213990.

AIMS:To examine the isotemporal substitution association of replacing moderate-to-vigorous physical activity (MVPA) with other behaviors on the prevalence of chronic kidney disease (CKD) among Chinese adults with type 2 diabetes mellitus (T2DM). METHODS:This study included 5421 adults with T2DM from the National Metabolic Management Centre Ningbo Branch. Data on physical activity, sedentary behavior, and sleep were collected using a standardized questionnaire through face-to-face interviews. Isotemporal substitution models were employed to evaluate the associations of reallocating time from other behaviors to MVPA with the risk of CKD. RESULTS:Substitution of 30 min per day of sleeping or sitting with MVPA was associated with a lower CKD prevalence (OR: 0.87 for sleep substitution; 0.90 for sitting substitution). Among individuals with inadequate MVPA levels (less than 150 min per week), the association of replacing 30 min of sleeping, sitting, or low-intensity physical activity with MVPA was particularly strong, cutting the risk of CKD by more than 60%. Stratified analysis among participants with inadequate MVPA revealed that the association of reallocating time to MVPA with lower CKD prevalence were predominantly observed among men, individuals with prolonged sleep duration (sleep duration more than 7.5 h per day), and those with better glycemic control (HbA1c levels below 7%). CONCLUSIONS:This study revealed that replacing sleep or sedentary time with MVPA was associated with a lower prevalence of CKD among Chinese adults with T2DM, especially those with low MVPA. Incorporating MVPA into daily routines is potentially beneficial for improving renal health in people with T2DM.

Suboptimal health status (SHS) is a reversible predisease stage and represents a key “window of opportunity” for predictive, preventive, and personalized medicine (3PM/PPPM). However, current screening methods still rely mainly on subjective questionnaires and lack objective, interpretable, and actionable tools for timely intervention. We aimed to develop an exploratory prototype system that combines multiomic signals with explainable artificial intelligence to apply 3PM in young adults. Transcriptomic, metabolomic, and gut microbiome data from 30 SHS patients and 35 healthy controls were analyzed. Seven machine learning algorithms were compared, with elastic net selected for its balance of accuracy, stability, and interpretability. Calibration and decision curve analyses were performed to test robustness and clinical utility. Shapley additive explanations (SHAP) were applied for both global and individual interpretations. The multiomic elastic net prototype achieved high and stable discrimination (accuracy 0.941, ROC-AUC 0.999), with strong calibration and net benefit. Beyond statistical performance, the system identified biologically plausible and modifiable molecular targets—such as reduced vitamin K and elevated glycerophosphocholine—that are directly amenable to preventive strategies. SHAP further provided individual-level profiles, revealing the specific biological drivers of SHS risk for each participant and offering a template for personalized recommendations. This study proposes an innovative 3PM-guided prototype system for predicting suboptimal health status on the basis of multiomics data. We suggest embedding this tool into preventive healthcare to enable early risk prediction, applying personalized interventions to delay or reverse the progression of SHS, and providing individualized follow-up to support long-term health management. From a public health perspective, this approach may substantially reduce the future burden of chronic diseases by addressing risks at a reversible stage.