Background:Despite extraordinary progress in global tobacco control and prevention, smoking, secondhand smoke (SHS) and chewing tobacco continue to profoundly impact public health, affecting males and females differently. Existing studies have not systematically characterized sex disparities in disease burden attributable to these three tobacco risks within a unified framework, nor have they quantified the contributions of demographic and exposure-related drivers to these disparities or projected their future trajectories. We aimed to assess patterns of sex disparity in smoking-, SHS-, and chewing tobacco-attributable disease burden from 1990 to 2023, decompose the drivers of these disparities, and project sex-specific burden to 2050 under alternative scenarios. Methods:We used data from the Global Burden of Disease Study (GBD) 2023, including sex-specific estimates of disability-adjusted life years (DALYs) and the age-standardized DALY rates (ASDR) attributable to smoking, SHS, and chewing tobacco. Sex disparities were examined across geographic, temporal, and age dimensions. Decomposition analysis was applied to quantify the contributions of population growth, population aging, change in risk exposure, and change in risk-deleted burden to sex-specific DALY changes between 1990 and 2023. Sex ratios were derived from ASDR and their 95% confidence intervals (CI) were estimated using the delta method. Future sex disparities were projected to 2050 under four counterfactual tobacco exposure scenarios. Findings:Over the past three decades, the tobacco-attributable disease burden among males has consistently exceeded that among females. In 2023, the overall smoking-attributable ASDR remained substantially higher in males than in females (3146.9 [95% uncertainty interval 2591.8-3703.8] vs. 507.8 [361.0-677.1] per 100,000). The all-cause ASDR attributable to SHS was slightly higher in males than in females (540.7 [434.3-672.9] vs. 506.6 [402.8-612.5] per 100,000). For chewing tobacco, the attributable burden was also markedly greater in males (95.3 [61.3-144.1] vs. 47.8 [25.4-78.5] per 100,000). Decomposition analysis showed that population growth and aging were the predominant drivers of increasing absolute DALYs in both sexes, with consistently larger effects among males, while change in risk exposure contributed differently to sex-specific burden trajectories across the three tobacco risks. Among GBD regions, the sex ratio of smoking-attributable ASDR of all causes was notably lowest in Australasia and high-income North America. The sex ratio of SHS-attributable all-cause ASDR increased from below 1.0 in 1990 to above 1.0 in 2023 across several GBD regions like high-income Asia Pacific and Andean Latin America. Globally, the sex ratio of overall ASDR attributable to chewing tobacco has remained stable, from 1990 (ratio: 1.9 95% CI 1.0-4.0) to 2023 (ratio: 2.0 95% CI 1.0-4.0). Among age groups, smoking-attributable DALY rates increased with age, peaking in the 75+ group in 2023, and the burden among males always exceeded that among females in all age brackets. Compared to the sex ratios of DALY rates attributable to smoking risk in the same regions, the fluctuations in disease burden attributable to SHS and chewing tobacco between sexes across age groups were less pronounced in 2023. Projections suggested that sex disparities would persist to 2050, with alternative tobacco control scenarios yielding divergent patterns of future burden. Interpretation:While smoking- and SHS-attributable ASDRs have declined and chewing tobacco-attributable ASDR has remained stable, sex disparities have varied by time, region, and life stage. These findings may inform the integration of sex-specific perspectives into tobacco control strategies, which could strengthen the implementation of the Framework Convention on Tobacco Control and help mitigate the future burden of tobacco use. Funding:National Science and Technology Innovation 2030, Noncommunicable Chronic Diseases-National Science and Technology Major Project.

Background: Light-intensity physical activity (LPA) constitutes a substantial portion of daily activities; however, it is more challenging to record and measure accurately compared to moderate- to vigorous-intensity physical activity (MVPA). Consequently, the health benefits associated with LPA are frequently overlooked. Our study aimed to investigate the associations of LPA pattern including objectively measured LPA’s duration, proportion, and timing with risk of incident cardiovascular diseases (CVDs). Methods: With the UK Biobank, 83,658 participants free of CVD with valid accelerometry data were included between 2013 and 2015. Data on physical activity (PA) were collected using the Axivity AX3 wrist-based triaxial accelerometer worn for 1 week. LPA duration was estimated using machine learning models based on bouts data from wrist-worn accelerometers. The LPA proportion was calculated by dividing the amount of LPA by the sum of LPA and MVPA. LPA timing was determined using hierarchical clustering analysis based on the average duration of LPA within each time window across the 24-h cycle. CVDs of interest including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) were identified through the linkage to hospital admission records and death registers. Results: Over a median follow-up duration of 7.98 (interquartile range: 7.43 to 8.47) years, a total of 2,239 CVDs, including 1,014 CHDs, 352 strokes, 796 AFs, and 194 HFs, were recorded. An L-shaped relationship was found between LPA duration and the risk of HF. Compared to individuals in the lowest quartile, those in the second (hazard ratio [HR], 0.64; 95% confidence interval [CI]: 0.44, 0.93), third (HR, 0.56; 95% CI: 0.37, 0.84), and highest quartile (HR, 0.65; 95% CI: 0.43, 0.99) of daily LPA were associated with lower risks of HF. Higher LPA in the morning, midday, and evening was associated with a higher risk of HF, whereas higher LPA in the night showed an adverse impact on HF risk. These findings were not observed for CHD, stroke, and AF. Conclusions: Our findings highlighted that maintaining sufficient duration of LPA might be beneficial for HF as a compensatory PA strategy, but it is also essential to regulate the proportion and timing of LPA.

Background: A neuroimaging-derived biomarker termed the brain age is considered to capture the degree and diversity in the aging process of the brain, serving as a robust indicator of overall brain health. The impact of different levels of physical activity (PA) intensities on brain age is still not fully understood. This study aimed to investigate the associations between accelerometer-measured PA and brain age. Methods: A total of 16,972 eligible participants with both valid T1-weighted neuroimaging and accelerometer data from the UK Biobank was included. Brain age was estimated using an ensemble learning approach called Light Gradient-Boosting Machine (LightGBM). Over 1,400 image-derived phenotypes (IDPs) were initially chosen to undergo data-driven feature selection for brain age prediction. A measure of accelerated brain aging, the brain age gap (BAG) can be derived by subtracting the chronological age from the estimated brain age. A positive BAG indicates accelerated brain aging. PA was measured over a 7-day period using wrist-worn accelerometers, and time spent on light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), and moderate- to vigorous-intensity PA (MVPA) was extracted. The generalized additive model was applied to examine the nonlinear association between PA and BAG after adjusting for potential confounders. Results: The brain age estimated by LightGBM achieved an appreciable performance (r = 0.81, mean absolute error [MAE] = 3.65), which was further improved by age bias correction (r = 0.90, MAE = 3.03). We found that LPA (F = 2.47, P = 0.04), MPA (F = 6.49, P < 1 × 10−300), VPA (F = 4.92, P = 2.58 × 10−5), and MVPA (F = 6.45, P < 1 × 10−300) exhibited an approximate U-shaped relationship with BAG, demonstrating that both insufficient and excessive PA levels adversely impact brain aging. Furthermore, mediation analysis suggested that BAG partially mediated the associations between PA and cognitive functions as well as brain-related disorders. Conclusions: Our study revealed a U-shaped association between accelerometer-measured PA and BAG, highlighting that advanced brain health may be attainable through engaging in moderate amounts of objectively measured PA irrespectively of intensities.

Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.

BackgroundThe associations between sugary beverages and genetic predisposition to depression risk remain unclear.AimsThis study aimed to investigate the associations of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs) and natural juices (NJs) with depression and to assess whether these associations were modified by genetic predisposition.MethodsWe used data from the UK Biobank of 180 599 individuals aged 39–72 years who were depression-free at baseline. Dietary intake of SSBs, ASBs and NJs was accessed by a 24-hour dietary recall between 2009 and 2012. The Polygenic Risk Score for depression was estimated and categorised as low (lowest tertile), intermediate (tertile 2) and high (highest tertile). Cox proportional hazard and substitution models were conducted to evaluate hazard ratios (HRs) and 95% CIs.ResultsOver the 12-year follow-up, 4915 individuals developed depression. Higher consumption (>2 units/day) of SSBs (HR: 1.26, 95% CI 1.12 to 1.43) and ASBs (HR: 1.40, 95% CI 1.23 to 1.60) were both associated with an increased risk of depression. However, moderate consumption (>0–1 units/day) of NJs was associated with a lower risk of depression (HR: 0.89, 95% CI 0.83 to 0.95). Furthermore, genetic predisposition did not modify these associations (p interaction>0.05). In substitution models, the HRs for depression risk were 0.94 (95% CI 0.89 to 0.99) and 0.89 (95% CI 0.85 to 0.94), respectively, when 1 unit/day of SSBs or ASBs was replaced by an equivalent intake of NJs.ConclusionsHigher consumption of SSBs and ASBs was associated with an increased risk of depression; in contrast, moderate consumption of NJs was inversely associated with a lower risk of depression. In theory, substituting SSBs and ASBs with NJs would suppose a reduction of depression risk.

ObjectivesThis study examined the relationship of cardiorespiratory fitness (CRF) in the transition from healthy status to first cardiometabolic disease, subsequent cardiometabolic multimorbidity and further to death.MethodsWe used data from the UK Biobank of 47 484 participants without cardiometabolic diseases at baseline. CRF was assessed via a 6 min incremental ramp cycle ergometer test and expressed in metabolic equivalent of tasks (METs, 1 MET=3.5 mL/kg/min). Cardiometabolic multimorbidity was defined as at least two diseases among diabetes, hypertension, coronary heart disease and stroke.ResultsOver 12.5 years median follow-up, 8123 participants developed first cardiometabolic disease, 1958 developed cardiometabolic multimorbidity and 2177 died. CRF was associated with different transition stages in cardiometabolic multimorbidity development. The HRs (95% CIs) per MET increase in CRF were 0.94 (0.93 to 0.95) and 0.97 (0.96 to 0.99) for transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity. Per MET increase in CRF was associated with reduced risk of transition from healthy baseline to death (HR: 0.97, 95% CI 0.95 to 0.99), but not for the transition from first cardiometabolic disease and cardiometabolic multimorbidity to death. When first cardiometabolic disease was divided into specific cardiometabolic diseases, there were comparable trends of CRF on the disease-specific transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity.ConclusionHigher CRF was associated with a lower risk of progression from a healthy state to first cardiometabolic disease and subsequently to cardiometabolic multimorbidity. These findings suggest that improving CRF is a potential strategy for preventing cardiometabolic multimorbidity development.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. NAFLD leads to liver fibrosis and hepatocellular carcinoma, and it also has systemic effects associated with metabolic diseases, cardiovascular diseases, chronic kidney disease, and malignant tumors. Therefore, it is important to diagnose NAFLD early to prevent these adverse effects.MethodsThe GSE89632 dataset was downloaded from the Gene Expression Omnibus database, and then the optimal genes were screened from the data cohort using lasso and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The ROC values of the optimal genes for the diagnosis of NAFLD were calculated. The relationship between optimal genes and immune cells was determined using the DECONVOLUTION algorithm CIBERSORT. Finally, the specificity and sensitivity of the diagnostic genes were verified by detecting the expression of the diagnostic genes in blood samples from 320 NAFLD patients and liver samples from 12 mice.ResultsThrough machine learning we identified FOSB, GPAT3, RGCC and RNF43 were the key diagnostic genes for NAFLD, and they were further demonstrated by a receiver operating characteristic curve analysis. We found that the combined diagnosis of the four genes identified NAFLD samples well from normal samples (AUC = 0.997). FOSB, GPAT3, RGCC and RNF43 were strongly associated with immune cell infiltration. We also experimentally examined the expression of these genes in NAFLD patients and NAFLD mice, and the results showed that these genes are highly specific and sensitive.ConclusionsData from both clinical and animal studies demonstrate the high sensitivity, specificity and safety of FOSB, GPAT3, RGCC and RNF43 for the diagnosis of NAFLD. The relationship between diagnostic key genes and immune cell infiltration may help to understand the development of NAFLD. The study was reviewed and approved by Ethics Committee of Tianjin Second People's Hospital in 2021 (ChiCTR1900024415).

Objective We aimed to prospective investigate the association between cardiometabolic diseases (CMDs) with dementia, and to examine whether genetic factors and CMDs jointly contribute to the incidence of dementia. Methods We used data from the UK biobank of 204,646 adults aged 37-73 free of dementia at baseline. Genetic risk for dementia including APOE ε4 status and polygenic risk score (PRS) categorized as low, intermediate, and high. CMDs including ischemic heart disease (IHD), stroke, and type 2 diabetes (T2D) were confirmed by touchscreen questionnaires, medical examinations, and hospital inpatient records. Results Over the follow-up (median: 12.5 years), 5,750 participants developed dementia. The HRs (95% CI) of those with APOE ε4 carriers and high PRS were 3.16 (3.00-3.33) and 1.50 (1.41-1.60), respectively. The risk of dementia was 70% higher among those with CMDs (HR: 1.70; 95% CI: 1.60-1.82). In joint effect analyses, compared to no CMDs and APOE ε4 non-carriers, the HRs (95% CIs) of dementia were 3.53 (3.31-3.76)/2.06 (1.89-2.23) in participants with only APOE ε4 carriers and CMDs, and 5.06 (4.64-5.53) for those with APOE ε4 carriers plus CMDs. Compared to no CMDs and low PRS, the HRs (95% CIs) of dementia were 1.29 (1.19-1.40)/1.60 (1.48-1.73) in participants with only intermediate and high PRS, and 2.00 (1.79-2.23)/2.63 (2.38-2.92) for those with intermediate, and high PRS plus CMDs. Moreover, there were significant additive and multiplication interactions between CMDs and APOE ε4 carriers of dementia, but only multiplication interaction was observed for PRS. Conclusions CMDs were associated with higher risk of dementia regardless of genetic risk for dementia.

Alzheimer's disease (AD) remains a global health challenge. Previous studies have reported linkages between AD and multiple behavioural risk exposures, however, the underlying biological mechanisms and crucial genes of gene expression patterns driven by behavioural risks on the onset or progression of AD remains ambiguous. In this study, we performed an integrated analysis on the influence of behavioural risks including smoking, excessive alcohol consumption, physical inactivity, and non-healthy dietary pattern on AD with a comprehensive strategy. Our results demonstrated that multiple behavioural risk exposures could independently or collectively influence diverse hierarchical levels of gene expression patterns through multiple biological mechanisms such as Wnt, mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB, phosphatidylinositol 3-kinase (PI3K)-Akt, and insulin (INS) signalling pathways-mediated pathological processes, thereby prodromally or intermediately impacting AD. Our study provided insights into understanding the association of behavioural risk exposures with AD and informative support for further studies.

Depression is the consequence of both environment and genes working together. Genetic factors increase depression risk, but it is unclear whether this association can be offset by time spent in outdoor light. The study was undertaken to investigate the optimal time spent in outdoor light for lowering the risk of depression and the joint association of time spent in outdoor light and depression genetic risk. In UK Biobank, 380,976 depression-free individuals were included in this study. Polygenic risk score (PRS) was categorized into three groups in terms of tertiles. Time spent in outdoor light on a typical day in summer or winter originated from the questionnaire survey. Depression was defined as hospital admission. The potential dose-response relationship between time spent in outdoor light and depression risk was shown by a restricted cubic spline. Data were analyzed using Cox regressions and Laplace regression. After the median follow-up of 12.6 years, 13,636 individuals suffered from depression in the end. A nonlinear (J-shaped relationship) trend was observed between time spent in outdoor light and depression risk. On average, 1.5 h/day of outdoor light was related to the minimum risk of depression. Individuals below and above this optimal time both had elevated depression risk (below, HR = 1.09, 95% CI: 1.02–1.16; above, HR = 1.13, 95% CI: 1.07–1.20), and the time to incident depression were both shortened by 0.46 years (50th percentile differences [PD] = −0.46, 95% CI: −0.78, −0.14) and 0.63 years (50th PD = −0.63, 95% CI: −0.90, −0.35) years, respectively. In a comparison of individuals with the lowest tertile of PRS and average 1.5 h/day outdoor light, the HRs and 95% CIs of depression were 1.36 (1.21–1.53) and 1.43 (1.29–1.58) in those with the highest tertile of PRS and below/above this reference value, respectively. Significant multiplicative interactions were observed between intermediate genetic risks and longer time spent in outdoor light. We found that an average of 1.5 h/day spent in outdoor light was associated with a lower depression risk whatever the degree of depression genetic predisposition. Moderate time spent in outdoor light may contribute to a decreased depression risk even among people with a higher genetic risk of depression.

Background: Dementia, mainly Alzheimer’s disease (AD) and vascular dementia (VaD), remains a global health challenge. Previous studies have demonstrated the benefits of acupuncture therapy (AT) in improving dementia. Nevertheless, the therapeutic targets and integrated biological mechanisms involved remain ambiguous. Objective: To identify therapeutic targets and biological mechanisms of AT in treating dementia by integrated analysis strategy. Methods: By the identification of differentially expressed genes (DEGs) of AD, VaD, and molecular targets of AT active components, the acupuncture therapeutic targets associated with the biological response to AD and VaD were extracted. Therapeutic targets-based functional enrichment analysis was conducted, and multiple networks were constructed. AT-therapeutic crucial targets were captured by weighted gene co-expression network analysis (WGCNA). The interactions between crucial targets with AT active components were verified by molecular docking. Results: Our results demonstrated that 132 and 76 acupuncture therapeutic targets were associated with AD and VaD. AT-therapeutic crucial targets including 58 for AD and 24 for VaD were captured by WGCNA, with 11 in shared, including NMU, GRP, TAC1, ADRA1D, and SST. In addition, 35 and 14 signaling pathways were significantly enriched by functional enrichment analysis, with 6 mutual pathways including neuroactive ligand-receptor interaction, GABAergic synapse, calcium signaling pathway, cAMP signaling pathway, chemokine signaling pathway, and inflammatory mediator regulation of TRP channels. Conclusion: The improvement of AD and VaD by AT was associated with modulation of synaptic function, immunity, inflammation, and apoptosis. Our study clarified the therapeutic targets of AT on dementia, providing valuable clues for complementing and combining pharmacotherapy.

OBJECTIVE to examine the association between different patterns of impaired lung function with the incident risk of dementia and magnetic resonance imaging (MRI)-based brain structural features. METHODS in UK Biobank, a total of 308,534 dementia-free participants with valid lung function measures (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) were included. Association was assessed using Cox proportional hazards regression model. Furthermore, the association between impaired lung function and brain MRI biomarkers related to cognitive function was analysed among 30,159 participants. RESULTS during a median follow-up of 12.6 years, 3,607 incident all-cause dementia cases were recorded. Restrictive impairment (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.27-1.60) and obstructive impairment (HR, 1.28; 95% CI, 1.15-1.42) were associated with higher risk of all-cause dementia. The restricted cubic splines indicated FEV1% predicted and FVC % predicted had reversed J-shaped associations with dementia. Participants with impaired lung function have higher risks of all-cause dementia across all apolipoprotein E (APOE) risk categories, whereas associations were stronger among those of low APOE risk (P for interaction = 0.034). In addition, restrictive and obstructive impairment were linked to lower total (β: -0.075, SE: 0.021, Pfdr = 0.002; β: -0.033, SE: 0.017, Pfdr = 0.069) and frontoparietal grey matter volumes, higher white matter hyperintensity, poorer white matter integrity, lower hippocampus (β: -0.066, SE: 0.024, Pfdr = 0.017; β: -0.051, SE: 0.019, Pfdr = 0.019) and other subcortical volumes. CONCLUSIONS participants with restrictive and obstructive impairments had a higher risk of dementia. Brain MRI indices further supported adverse effects and provided insight into potential pathophysiology biomarkers.