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Aims Cardiovascular-Kidney-Metabolic (CKM) syndrome is an integrated context encompassing diabetes, obesity, cardiovascular, and chronic kidney diseases. The impact of CKM syndrome on cognitive impairment remained unclear. Methods This longitudinal, observational study used data from the China Health and Retirement Longitudinal Study waves 1 and 4 (2011 to 2018). In total, 8,833 participants were included for the analysis between baseline CKM and cognitive impairment, and 4,230 were included for the analysis between CKM transition and cognitive impairment. Baseline CKM were classified into 5 consecutive stages according to the AHA statement, and transitions in CKM stages were classified as improved, stable, or progressed based on the difference in states between 2011 and 2015. Logistic regressions were used to explore the associations between CKM stages, transitions and the risk of subsequent cognitive impairment. Result Compared with those in stage 0, the adjusted odds ratio [95% confidence intervals] (aOR [95% CI]) of incident cognitive impairment were 1.74 (1.00-3.18) for stage 1, 2.05 (1.17-3.81) for stage 2, 2.09 (1.27-3.66) for stage 3, and 3.91 (2.33-6.99) for stage 4, respectively. The odds ratios were higher among male and elder participants. In the transition analysis, the aOR (95% CI) was 0.44 (0.19-1.03) for improved group and 1.61 (1.01-2.59) for progressed group, compared with the those maintaining stable CKM stages. Conclusions Higher CKM stages are associated with incrementally elevated risk of cognitive impairment. Additionally, the progression of CKM stages corresponded with greater hazards of cognitive impairment, while stage reversion might be associated with reduced risk.

Background Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. Methods Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. Results Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45–0.59), and decreased HOMA-IR (β = − 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06–1.15), and decreased HOMA-B (β = − 0.04, SE = 0.01, P = 4.52 × 10 –5 ). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. Conclusions This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Sarcopenia is associated with cardiovascular diseases (CVDs). However, whether the changes in sarcopenia status affect CVD risk remained unclear. Additionally, how indoor fuel use impact the transitions process is less studied. The study prospectively examined the association of sarcopenia transitions with CVD risk, while exploring the effect of indoor fuel on these transitions. The prospective observational study used data from the China Health and Retirement Longitudinal Study (CHARLS) waves 1 to 4 (2011-2018). In total, 8739 participants with full data on sarcopenia and indoor fuel use were included for “indoor fuel use and sarcopenia transition” analysis, and 6385 participants without previous CVDs were included for “sarcopenia transition and CVD risk” analysis. Transition of sarcopenia was defined according to sarcopenia status at wave 1 (2011) and wave 2 (2013). Incident CVD included heart diseases, stroke and composite CVD. Information on indoor fuel were obtained at wave 1. Cox proportional hazards models were conducted to examine the effect of transition in sarcopenia on incident CVD. Logistic regression models were performed to investigate the impact of indoor fuel on these transitions. During a median of 7.0 years follow-up, 1233 incident CVDs were documented. Compared to stably normal participants, progressing from normal to possible or confirmed sarcopenia brought increased risk of incident CVD (hazard ratio (HR):1.42,95% confidence (CI):1.15-1.77). Conversely, recovering to normal state was associated with decreased risk (HR:0.72, 95% CI:0.55-0.95) for baseline possible sarcopenia individuals. Additionally, clean fuel use increased the odds of achieving a possible-to-normal transformation (odds ratio (OR):1.32, 95% CI: 1.06-1.64), while both solid cooking and heating fuel use were associated with higher risk of deterioration in sarcopenia status. Unfavorable transition in sarcopenia status is associated with higher CVD risk, while reversion from possible sarcopenia to normal could reduce the risk. Therefore, early intervention for sarcopenia is imperative for CVD prevention, and promoting clean fuel use is recommended. Not applicable

摘要 背景 以前的研究报道了饥荒暴露对代谢综合征(MetS)有影响。然而, 关于饥荒暴露、成年期肥胖和 MetS 风险之间的关系则较少研究。 方法 纳入上海市嘉定社区年龄 >40岁的8883名受试者。我们将饥荒暴露亚组定义为未暴露(1963‐1974)、胎儿暴露(1959‐1962)、儿童暴露(1949‐1958)和青春期暴露(1941‐1948)。 MetS根据 NCEP‐ATP III标准定义。 结果 与未暴露组相比, 胎儿、儿童和青春期暴露组的 MetS 风险增加, OR 和 95% CI 分别为 1.48 (1.23‐1.78)、1.89 (1.632.20) 和 2.34 (1.99‐ 2.74)。在校正性别、年龄、吸烟状况、饮酒状况、教育程度、体重指数(BMI)和体力活动后, 女性中观察到胎儿暴露组和儿童暴露组发生 MetS 的风险增加, OR 和 95%CI 分别为 1.42( 1.04‐1.94) 和 1.50 (1.02‐2.21)。在 BMI<23 kg/m2 的个体中, 饥荒暴露与 MetS 显着相关(整个队列中 BMI 类别与饥荒暴露之间的交互作用 P = 0.0002), 但存在性别差异(女性 P=0.0023, 男性P=0.4484)。在评估生命早期饥荒暴露和成年期肥胖对 MetS 的联合影响时, 我们观察到与没有饥荒暴露或成年肥胖的人相比, 成年肥胖和胎儿饥荒暴露的参与者有最高估计值(OR, 95%CI:17.52, 10.07‐ 30.48)。 结论 成年期肥胖显著加剧了早年营养不良个体(尤其是女性)发生 MetS 的风险。

摘要 背景 甘油三酯血糖(TyG)指数与亚临床动脉粥样硬化密切相关。然而，肥胖者和非肥胖者之间的联系仍然没有定论。 方法 这项前瞻性研究在5751名基线颈动脉内膜中层厚度(CIMT)正常的成年人中进行。根据TyG指数将人群分为四组，计算公式为:Ln(空腹甘油三酯[mg/dL]×空腹血糖[mg/dL]/2)。超声检查获得CIMT的相关信息。升高的CIMT定义为随访时IMT值大于0.9 mm。用多变量Logistic回归模型估计TyG指数与CIMT升高之间关联的优势比(OR)和95%置信区间(CI)。 结果 经过平均4.3年 的随访，有722例(12.6%)患者进展为CIMT升高。与TyG指数的第二个四分位数相比，在校正了潜在的混杂因素后，第一和第四个四分位数都具有更高的CIMT升高风险。在总人口中，第一和第四个四分位数的OR值分别为1.29(95%CI，1.00~1.66)和1.42(95%CI，1.11~1.83)。限制立方样条法显示TyG指数与非肥胖者和非肥胖者的CIMT升高呈近似的U型相关(P<0.05)，但在一般肥胖者或腹型肥胖者中不存在。 结论 仅在非肥胖的中国成年人中，TyG指数与CIMT升高呈U型相关。

摘要 目的 在发展中国家，关于教育对糖尿病风险的影响的证据很少。我们的目的是在中国的一个大人群样本中探索教育和糖尿病之间的联系，并确定可能的中介因素。 材料和方法 通过问卷调查，收集有关文化程度和生活方式因素的信息。糖尿病的诊断是通过自我报告和生化测量进行的。我们构建了结构方程模型量化了各变量的中介效应。 结果 与受教育程度最低的男性相比，受过大学教育的男性患糖尿病风险较高(优势比OR:1.19, 95%可信区间(95%CI):1.12~1.27)，而受过大学教育的女性患糖尿病风险较低(OR:0.77, 95%CI:0.73~0.82)。肥胖在两性中均是最强的中介因素(中介比例:男性11.6%，女性23.9%)，肥胖与教育呈正相关(β[SE]0.0387[0.0037])，与女性中负相关(β[SE]‐0.0824[0.0030])。所有行为因素加在一起，可以解释12.4%的男性和33.3%的女性患糖尿病的额外风险。 结论 在中国普通人群中，男性受教育程度与糖尿病之间存在正相关，而女性则为负相关。肥胖是糖尿病风险教育差异的主要中介因素，在女性中的中介作用更强。

Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue‐specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization and multi‐traits colocalization, combining the latest genetics data of gene expression (eQTLGen and GTEx) and proteomics (4746 proteins from five studies). We then evaluated associations of these potential genetic targets with mortality risk and life expectancy in the UK Biobank cohort. We performed in vitro cellular senescence experiments to confirm their effects. Fourteen plasma proteins and nine transcripts in whole blood had independent causal effects on longevity, where a cascading effect of both the tissue‐specific transcripts and plasma proteins of LPA, PDAP1, DNAJA4, and TMEM106B showed negative effects on longevity. PDAP1 (PDGFA‐associated protein 1) with the strongest genetic evidence might reduce lifespan by modifying sex hormones, adiposity, and epigenetic aging acceleration. In the prospective cohort, blood PDAP1 levels were significantly associated with higher all‐cause mortality and more years of loss. In vitro, cellular senescence is accompanied by upregulation of PDAP1 expression. Exogenous PDAP1 stimulation accelerates cellular senescence while the deficiency of PDAP1 attenuates replicative senescence. This study facilitates the discovery of potential drug targets and provides a broader understanding of the biological processes of longevity, where PDAP1 emerged as a star for modifying human lifespan. Integration of multi‐omics analyses reveals PDAP1 as one of the key regulators of longevity and aging. Mendelian randomization, colocalization, prospective studies, and in vitro experiments highlight PDAP1's effects on mortality, lifespan, and cellular senescence.

Background Previous studies reported that famine exposure had an effect on metabolic syndrome (MetS). However, there is an inadequacy of study regarding the association between famine exposure, adulthood general obesity, and the risk of MetS. Methods A total of 8883 subjects aged ≥40 years from Jiading community in Shanghai were included. We defined famine exposure subgroups as nonexposed (1963–1974), fetal exposed (1959–1962), childhood exposed (1949–1958), and adolescence exposed (1941–1948). MetS was defined based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP‐ATP III) criteria. Results Compared with the nonexposed group, the risks of MetS were increased in the fetal‐, childhood‐, and adolescence‐exposed groups with odds ratios (OR) and 95% confidence intervals (CI) of 1.48 (1.23–1.78), 1.89 (1.63–2.20), and 2.34 (1.99–2.74), respectively. After adjusting for sex, age, smoking status, drinking status, education, body mass index (BMI), and physical activity, the increased risk of MetS related to the fetal‐exposed and childhood‐exposed groups with OR and 95% CI of 1.42 (1.04–1.94) and 1.50 (1.02–2.21), respectively, were observed only in women. Famine exposure was significantly associated with MetS among individuals with a BMI < 23 kg/m2 (p for interaction between BMI categories and famine exposure = 0.0002 in the whole cohort), while there existed a gender difference (p = 0.0023 in females, p = 0.4484 in males). When evaluating the joint effects of the combination of famine exposure in early life and general obesity in adulthood on MetS, we observed the highest estimate in participants with both adulthood general obesity and fetal famine exposure (OR 17.52; 95% CI, 10.07–30.48) compared with those without famine exposure nor adulthood obesity. Conclusions Obesity in adulthood significantly further aggravated the risk of MetS in individuals who experienced early life undernutrition, especially in females. 摘要 背景 以前的研究报道了饥荒暴露对代谢综合征(MetS)有影响。然而, 关于饥荒暴露、成年期肥胖和 MetS 风险之间的关系则较少研究。 方法 纳入上海市嘉定社区年龄 >40岁的8883名受试者。我们将饥荒暴露亚组定义为未暴露(1963‐1974)、胎儿暴露(1959‐1962)、儿童暴露(1949‐1958)和青春期暴露(1941‐1948)。 MetS根据 NCEP‐ATP III标准定义。 结果 与未暴露组相比, 胎儿、儿童和青春期暴露组的 MetS 风险增加, OR 和 95% CI 分别为 1.48 (1.23‐1.78)、1.89 (1.632.20) 和 2.34 (1.99‐ 2.74)。在校正性别、年龄、吸烟状况、饮酒状况、教育程度、体重指数(BMI)和体力活动后, 女性中观察到胎儿暴露组和儿童暴露组发生 MetS 的风险增加, OR 和 95%CI 分别为 1.42( 1.04‐1.94) 和 1.50 (1.02‐2.21)。在 BMI<23 kg/m2 的个体中, 饥荒暴露与 MetS 显着相关(整个队列中 BMI 类别与饥荒暴露之间的交互作用 P = 0.0002), 但存在性别差异(女性 P=0.0023, 男性P=0.4484)。在评估生命早期饥荒暴露和成年期肥胖对 MetS 的联合影响时, 我们观察到与没有饥荒暴露或成年肥胖的人相比, 成年肥胖和胎儿饥荒暴露的参与者有最高估计值(OR, 95%CI:17.52, 10.07‐ 30.48)。 结论 成年期肥胖显著加剧了早年营养不良个体(尤其是女性)发生 MetS 的风险。 Highlights In a community‐dwelling Chinese population, famine exposure in early life, especially during the fetal and childhood stages, has an association with an increased risk of metabolic syndrome (MetS) in later life, but the above findings only applied to females, not males. Compared to nonexposed and nonobese participants, those with both fetal famine exposure and adulthood general obesity had a higher risk of MetS of more than 17‐folds. The coexistence of malnutrition in early life and adulthood overweight/obesity had an association with a higher risk of MetS.

Malnutrition in early life increases the risk of osteoporosis, but the association of early-life undernutrition combined with adulthood obesity patterns with low-energy fracture remains unknown. This study included 5323 community-dwelling subjects aged ≥40 years from China. Early-life famine exposure was identified based on the participants' birth dates. General obesity was assessed using the body mass index (BMI), and abdominal obesity was evaluated with the waist-to-hip ratio (WHR). Low-energy fracture was defined as fracture occurring after the age of 40 typically caused by falls from standing height or lower. Compared to the nonexposed group, the group with fetal, childhood, and adolescence famine exposure was associated with an increased risk of fracture in women with odds ratios (ORs) and 95% confidence intervals (CIs) of 3.55 (1.57-8.05), 3.90 (1.57-9.71), and 3.53 (1.05-11.88), respectively, but not in men. Significant interactions were observed between fetal famine exposure and general obesity with fracture among women ( P for interaction = 0.0008). Furthermore, compared with the groups with normal BMI and WHR, the group of women who underwent fetal famine exposure and had both general and abdominal obesity had the highest risk of fracture (OR, 95% CI: 3.32, 1.17-9.40). These results indicate that early-life famine exposure interacts with adulthood general obesity and significantly increases the risk of low-energy fracture later in life in women.