Abstract Background The impacts of social isolation on diverse health conditions and how it contributes to health risks remain unclear. We aimed to investigate the associations of social isolation with 59 health conditions among older adults. Methods Participants from the UK Biobank without baseline diagnosis of the included diseases were selected. Social isolation was assessed with three questions. The 59 health conditions included all-cause mortality, 5 cause-specific mortalities, and 53 diseases. We used an instrumental variable from multivariable common factor GWAS in Mendelian randomization (MR) to explore causal links of social isolation with diseases. Omics analyses were conducted to assess the roles of Olink plasma proteins and metabolomics, and PERM was calculated to evaluate the influence of other factors. Results A total of 489,741 individuals [266,706 (54.5%) women; mean age 56.5 years (SD 8.1)] were included. During a median follow-up of 12.5 years, social isolation was uncorrelated with the majority of 59 health conditions. Significantly, it was associated with increased risks of all-cause [adjusted HR (aHR) 1.28, 95% CI 1.25–1.32], 5 cause-specific mortalities (aHR range, 1.18–1.38), and 11 specific diseases (aHR range, 1.08–1.17). Living alone was the strongest item of isolation in predicting mortality (aHR range, 1.18–1.45) and selected diseases. MR analyses offered little evidence to support a causal link between social isolation and these diseases. The proteins involved in these associations are predominantly related to “response to stimulus”. Proteomic signatures (PERM, 36%–49%), health behaviours (32%–59%), and socioeconomic factors (22%–42%) were the main explanatory factors linking social isolation to 8 health outcomes. Conclusions Social isolation is associated with elevated risks of 17 out of the 59 examined adverse health outcomes, predominantly mortality-related conditions; however, MR analyses indicate an absence of evidence supporting causality for these associations.

BACKGROUND:Identifying high-risk individuals for cardiovascular and all-cause mortality among individuals with cardiovascular-kidney-metabolic (CKM) syndrome stage 0-3 can guide the implementation of targeted interventions. This study aimed to evaluate the predictive value of plasma proteins for future cardiovascular and all-cause mortality. METHODS:This study included 39,007 participants from the UK Biobank (UKB) with CKM stage 0-3 and available proteomic data. Associations between plasma proteins and future risks of cardiovascular and all-cause mortality were assessed using Cox proportional hazards models. Key proteins were identified through an ensemble machine learning approach integrating support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost) algorithms. Subsequently, Cox models were applied to evaluate the incremental predictive value of these key proteins and their ability to enhance risk stratification for mortality outcomes. Furthermore, temporal trajectories of protein levels were examined in the years preceding death. RESULTS:During a median follow-up of 15.2 years, 505 participants died from cardiovascular causes and 3368 from any cause. 56 and 269 out of 2911 plasma proteins were significantly associated with cardiovascular and all-cause mortality, respectively (Bonferroni-adjusted P < 0.05). Incorporating seven and eight key proteins into conventional model significantly improved long-term predictive performance (C-statistics: 0.812 versus 0.782 for cardiovascular mortality; 0.772 versus 0.739 for all-cause mortality; both P < 0.001), and also provided incremental predictive value for 5- and 10-year mortality risks. Notably, participants died during follow-up exhibited markedly elevated certain protein levels over a decade before deaths, with progressively increasing trajectories over time. Stratification based on optimal predicted risk thresholds further revealed distinct cumulative mortality risks across groups. CONCLUSIONS:In individuals with CKM stage 0-3, plasma proteins combined with traditional risk factors may predict future cardiovascular and all-cause mortality.

Abstract Aims Insomnia increases the risk of cardiovascular diseases (CVDs), but whether insulin resistance (IR) or its related traits mediate the underlying associations is unclear. We conducted a two‐step two‐sample Mendelian randomization (MR) study to address these questions. Methods and Results We selected genetic variants of insomnia, IR, and its traits as instrumental variables, whereas summary‐level data of five CVDs served as the main outcomes, which were derived from previous genome‐wide association studies. In the MR analysis, genetically predicted insomnia symptoms were significantly associated with five CVD risks and six IR‐related traits after correcting for multiple tests, whereas genetically predicted IR and its related traits, such as T2DM, TG, and high‐density lipoprotein cholesterol (HDL‐C), were associated with four CVD risks. In the mediation analysis, we found strong evidence for the mediating effects of IR, TG, HDL‐C, and T2DM in the causal pathway from insomnia to four CVDs, except for atrial fibrillation. The multivariable MR analysis provided further evidence supporting the potential mediation effects of IR and its related traits in the causal pathway between insomnia and CVDs. Conclusions These results suggest that genetically predicted insomnia symptoms are associated with a higher risk of CVDs, with considerable mediation by IR and T2DM.

BACKGROUND:Social isolation and loneliness, the rising social determinant of health, are prevalent in stroke survivors. We aimed to investigate whether social isolation and loneliness are associated with poor outcomes after stroke. METHODS:A total of 394,308 individuals (mean ± SD age, 55.9 ± 8.1 years, 55.7% female, 95.4% White) from the UK Biobank were included in this study. 7267 (1.8%) had a prevalent stroke at baseline, while the remaining 387,041 (98.2%) had no history of stroke. Stroke history was ascertained at baseline using both self-reported data and electronic health records. Social isolation and loneliness were assessed using self-reported questionnaires. Stroke history was defined by self-report and electronic health records. Post-stroke outcomes, including all-cause mortality, CVD mortality, all-cause dementia, CVD and depression, were identified by linking hospital records and death registries. RESULTS:During a median follow-up of 10.2 years, 2906 of the 7267 baseline stroke survivors experienced post-stroke outcomes. In fully adjusted models, social isolation was independently associated with higher risks of all-cause mortality (HR: 1.41, 95% CI: 1.20-1.64), CVD mortality (HR: 1.57, 1.26-1.96), and depression (HR: 1.35, 1.07-1.69). Loneliness was linked to increased risks of all-cause mortality (HR: 1.23, 1.01-1.50), CVD mortality (HR: 1.45, 1.11-1.87), all-cause dementia (HR: 1.67, 1.12-2.49), and depression (HR: 1.43, 1.09-1.88). These associations-particularly for all-cause mortality (Pinteraction = 0.006) and CVD mortality (Pinteraction = 0.042)-were more pronounced in stroke survivors than in those without stroke. Health behaviours mediated a substantial proportion of the associations for social isolation (32-55%) and loneliness (12-50%) with most outcomes. CONCLUSIONS:Social isolation and loneliness were associated with greater risks for developing premature death, CVD, dementia, and depression after stroke. The findings highlighted strengthening social connections to improve stroke prognosis.

Ovarian aging leads to infertility, endocrine dysregulation and increased chronic disease risk, yet there are currently no approved therapies to delay ovarian aging. Physical activity (PA) is a crucial lifestyle factor for human health and antiaging, but its effects and mechanisms on ovarian aging remain unclear. Here we show, through a cross-sectional analysis of 152,435 participants in the UK Biobank, that lower PA levels were observed among postmenopausal persons when compared to premenopausal persons, and this finding was supported by another cross-sectional study of 12,418 participants in the National Health and Nutrition Examination Survey. Animal studies in mice show that higher levels of PA can delay ovarian aging. In addition, PA significantly increased adiponectin levels in the ovary, and the protective effects of PA on ovarian aging were attenuated in adiponectin-deficient mice. The adiponectin receptor agonist AdipoRon delayed ovarian aging and extended reproductive lifespan in mice. Our findings elucidate the role and mechanisms of PA in delaying ovarian aging, highlighting potential therapeutic targets for extending the reproductive lifespan.

BACKGROUND:Isolated REM sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, including Parkinson's disease (PD). Conventional sleep staging assigns each epoch to a single dominant stage, potentially obscuring within-epoch probabilistic features and stage mixing. We aimed to characterize alternation of probabilistic sleep-stage patterns in iRBD and to examine their clinical and neurobiological correlations. METHODS:In this case-control study, 104 patients with iRBD, 28 patients with PD and RBD (PD + RBD), and 50 controls underwent video polysomnography. Sleep-stage uncertainty and mixing were quantified using the U-Sleep 2.0 model. Clinical measures included RBD symptom severity (RBDQ-HK), motor function (UPDRS-III), and cognition (MoCA). Nigrostriatal dopaminergic function was assessed with [18F]-DOPA PET in a subgroup consisting of 40 patients with iRBD. Within the iRBD group, associations between probabilistic sleep-stage metrics and mixing with clinical measures and PET metrics were assessed using Pearson correlations. RESULTS:Both iRBD and PD + RBD groups exhibited significantly increased sleep-stage uncertainty and mixing compared with controls. Within the iRBD group, REM uncertainty was positively correlated with RBD symptom severity (RBDQ-HK score, r = 0.364, p = 0.003) and motor symptoms (UPDRS-III score, r = 0.343, p = 0.005). N2 uncertainty was negatively correlated with global cognitive performance (MoCA score, r = -0.345, p = 0.005), particularly delayed recall (r = -0.402, p < 0.001). N2-REM mixing was positively correlated with RBD symptom severity (RBDQ-HK score, r = 0.449, p < 0.001) and negatively correlated with bilateral putaminal dopaminergic uptake on PET (left: r = -0.492, p = 0.019; right: r = -0.510, p = 0.019). CONCLUSIONS:Probabilistic sleep staging reveals clinically significant alterations in sleep-stage uncertainty and stage mixing in iRBD and may provide complementary electrophysiological markers of early α-synuclein-related neurodegeneration.

Daytime light exposure is essential for health, primarily by synchronizing tissue and cellular-level clocks with the external light/dark cycle. Insufficient exposure may disrupt circadian alignment and contribute to adverse outcomes, including cancer. Given the high prevalence of gastrointestinal cancer, we conducted a prospective cohort study of 89,069 participants with objectively measured daytime light intensity and duration. Cox proportional hazards models were used to evaluate associations with gastrointestinal cancer incidence and mortality. Over a median follow-up of 8.8 years (804,111 person-years), 1692 gastrointestinal cancer cases were recorded, of which 891 were fatal. Higher mean levels of daytime light (≥ 1916 lux between 7:30-20:30, based on the 80% cut-off) were associated with lower risk of gastrointestinal cancer incidence (Hazard Ratio [HR]: 0.87, 95% confidence interval [CI]: 0.76-0.99, p = 0.04) and mortality (HR = 0.76, 95% CI: 0.63-0.93, p = 0.008), particularly for pancreatic cancer incidence (HR = 0.58, 95% CI: 0.40-0.85, p = 0.005) and mortality (HR = 0.47, 95% CI: 0.30-0.73, p = 0.001). Daytime light exposure ≥ 2.4 h (≥ 5000 lux between 7:30 and 20:30, which is often used as a chronotherapeutic threshold) was associated with a lower risk of pancreatic cancer incidence and mortality. Predictive ability of daytime light metrics exceeded that of sleep quality, diet, depression, and alcohol consumption. Higher daytime light exposure was associated with lower risks of gastrointestinal cancer incidence and mortality, especially for pancreatic cancer, indicating a potential protective effect that warrants further investigation in prevention and prognostic contexts.

Background Insomnia disorder is a prevalent, chronic, and recurrent sleep disorder associated with substantial mental, physical, and socioeconomic burden. Individuals with subthreshold insomnia are at increased risk of progression to insomnia disorder, yet scalable preventive interventions for this high-risk population remain limited. This multicenter randomized controlled trial (RCT) is designed to evaluate whether a smartphone-delivered emotional memory control intervention based on the Think/No-Think paradigm can reduce insomnia severity and prevent incident insomnia disorder in adults with subthreshold insomnia. Methods This community-based, three-arm, parallel RCT will recruit 750 adults aged 18–65 years with subthreshold insomnia, defined as insomnia symptoms below the diagnostic threshold for insomnia disorder and an Insomnia Severity Index score of 8–14. Participants will be randomly assigned in a 1:1:1 ratio to a suppress-negative group, a suppress-neutral group, or a waitlist control group. The intervention will be delivered through a smartphone mini-program over 2 weeks and will consist of two consecutive 6-day training phases based on the autobiographical Think/No-Think paradigm. The waitlist control group will receive no active training during Weeks 1–2 and will be offered the intervention after the 6-month follow-up. Primary outcomes are the change of insomnia severity and incidence of insomnia disorder assessed by clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Assessments will be conducted at baseline, immediately and 1 month after intervention, and at 3, 6, 12, and 24 months after intervention. Outcomes will be analyzed on an intention-to-treat basis using mixed-effects models for repeated measures and survival models. Discussion This trial will evaluate whether a digital emotional memory control intervention can reduce insomnia symptoms and prevent progression to insomnia disorder. If effective, it may provide a scalable, low-cost, and mechanism-informed strategy for community-level insomnia prevention. Trial registration: Chinese Clinical Trial Registry, ChiCTR2600116389. Registered on January 9, 2026.

ABSTRACT Background The study aimed to investigate whether the associations of accelerometer‐measured physical activity (PA) and sedentary behaviour (SB) with incident chronic kidney disease (CKD) vary based on different levels of hand grip strength, identifying the modifying role of grip strength in these associations. Methods The study included 87 487 adults from the UK Biobank. PA and SB were quantified using accelerometers over 7‐day period, while grip strength was assessed using a hand dynamometer. CKD events were ascertained through hospital records or death registries. Results Participants had a mean age of 62.3 years, with 57.2% (50 062) identifying as female and 97% as White. Over a median follow‐up of 7.0 years, the total incidence rate of CKD was 4.7 per 1000 person‐years. Participants who performed higher volumes of PA were more likely to be younger; have better control of body weight, blood glucose and blood pressure; and have fewer major comorbidities (p < 0.001). Total PA, moderate‐to‐vigorous intensity PA (MVPA), and light intensity PA (LPA), were inversely associated with CKD risk in a dose–response manner (all poverall < 0.050). In contrast, SB was associated with a higher risk of CKD (poverall < 0.001). Hand grip strength significantly modified the relationship between PA, SB, and CKD risk (pinteraction < 0.10). The associations of total PA (HR, 0.70; 95% CI, 0.59–0.84), MVPA (HR, 0.75; 95% CI, 0.65–0.88), LPA (HR, 0.81; 95% CI, 0.69–0.94), and SB (HR, 1.43; 95% CI, 1.21–1.69) with CKD risk were more remarkable among individuals with lower hand grip strength. Of note, physical inactivity ranked higher in relative strength for predicting CKD than hypertension, diabetes, and obesity. Conclusions Hand grip strength could significantly modify the associations of accelerometer‐measured PA and SB with the risk of CKD. Regardless of intensity, PA consistently correlates with reduced risk of CKD, while SB is associated with increased risk, especially among individuals with lower grip strength. Notably, physical inactivity was found to be as predictive of CKD as traditional risk factors, highlighting the importance of promoting PA, especially among those with lower grip strength.

OBJECTIVE:To evaluate the risk of cardiovascular adverse events associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer (NSCLC). DESIGN:Systematic review and network meta-analysis. DATA SOURCES:PubMed, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and three clinical trial registries, from inception to 20 November 2024. STUDY SELECTION:Randomised controlled trials comparing EGFR tyrosine kinase inhibitor monotherapy with placebo or other treatments in patients with EGFR-mutated NSCLC. DATA EXTRACTION AND SYNTHESIS:Pairs of reviewers extracted data and assessed risk of bias. A random effects network meta-analysis using a frequentist approach compared adverse drug reactions across different treatments. Certainty of evidence was evaluated using the confidence in network meta-analysis approach. Pairwise meta-analyses were done to compare the three generations of EGFR tyrosine kinase inhibitors. RESULTS:The network meta-analysis comprised 89 randomised controlled trials involving 29 813 participants, mean follow-up 2.18 years. Compared with placebo, both first generation (odds ratio 1.51, 95% confidence interval 1.01 to 2.26; high certainty; pooled incidence 3.2%) and third generation EGFR tyrosine kinase inhibitors (2.18, 1.46 to 3.27; high certainty; 9.5%) were associated with increased risks of cardiac adverse events. Among third generation inhibitors, osimertinib (2.53, 1.53 to 4.19; high certainty; 8.9%) and lazertinib (2.84, 1.17 to 6.91; moderate certainty; 2.7%) were associated with cardiac adverse events. Combined therapies, such as antiangiogenesis with erlotinib or gefitinib, were associated with vascular adverse events (high certainty), whereas antiangiogenesis with osimertinib was associated with cardiovascular adverse events (moderate to high certainty). Also, the risk of arrhythmias was significantly higher with third generation inhibitors (3.26, 1.83 to 5.81; high certainty; 7.3%), such as osimertinib alone (3.35, 1.75 to 6.40; high certainty; 6.2%) and in combination with antiangiogenesis. Almonertinib was associated with vascular toxicity. In pairwise meta-analysis, third generation inhibitors were associated with higher risks of any grade and grade ≥3 cardiovascular adverse events compared with first generation inhibitors. CONCLUSIONS:In patients with EGFR-mutated NSCLC, first and third generation EGFR tyrosine kinase inhibitors, as well as combination therapies with antiangiogenesis, were associated with increased risks of cardiovascular adverse events. Risks were significantly higher with third generation compared with first generation inhibitors. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42023433003.

White matter tracts (WMTs), which mediate information transmission in the brain, are closely associated with the pathogenesis of psychiatric disorders, yet the causality of their associations remain unclear. Thus, we employed two-sample bidirectional Mendelian randomization to explore the causality between WMTs and 10 psychiatric disorders. We found that one standard deviation changes of WMTs metrics modified risks for 8 psychiatric disorders by 2·2% to 71·4%. For example, increased fornix/stria terminalis radial diffusivities elevated PTSD risk by 8.3%, while heightened mode anisotropy reduced Tourette syndrome risk by 71.4%. Reversely, alcohol use disorder increased the risk of WMTs abnormalities. Our study provides novel insights into the potential causality between WMTs and psychiatric disorders, indicating that alterations of WMTs may serve as biomarkers for psychiatric disorders.

Previous research has shown that transcutaneous auricular vagus nerve stimulation (tVNS) promotes declarative fear extinction, but its neural mechanisms in this process are still unclear. This study aimed to explore tVNS's impacts on physiological (skin conductance response [SCR]) and neural (event-related potentials, ERP) fear-related responses. Forty healthy participants were randomly assigned to the tVNS or Sham group. During a fear-conditioned memory paradigm, electroencephalograph (EEG) and SCR were measured. We analyzed SCR amplitude, ERP components, EEG signal spectral analysis, and the correlation between SCR and EEG metrics. Results showed that compared with the Sham group, the tVNS group had a remarkable decrease in SCR amplitudes for conditioned stimuli (CS+) during retrieval and recall, suggesting reduced sympathetic arousal. ERP analysis revealed a notable decline in late positive potential (LPP) (400-800 ms) amplitudes for CS+ in the tVNS group during these phases, indicating weakened neural reactivity. A significant group-by-phase interaction showed that tVNS effectively suppressed immediate and sustained fear responses, maintaining lower fear-related physiological and neural activity levels. These findings suggest that tVNS modulates neural circuits involved in fear processing, clarifies the mechanisms underlying fear extinction, and highlights its therapeutic potential for fear-related disorders.

OBJECTIVE:To investigate the causal association between insomnia and chronic kidney disease (CKD) and to explore the underlying protein pathways. METHODS:In primary analyses, multivariate regression and 1-sample mendelian randomization (1SMR) analyses were performed to estimate the associations between insomnia and CKD in the UK Biobank cohort. The study was conducted from March 13, 2006, to November 12, 2021. Thereafter, a 2-sample MR (2SMR) analysis was used to validate the findings from primary analyses. Finally, proteome-wide MR analysis was conducted to pinpoint CKD-associated blood proteins, supplemented by the colocalization analysis. In addition, the potential mediation effects of blood proteins on the pathway of insomnia giving rise to CKD were explored through a 2-step MR design. RESULTS:Across the multivariate regression, 1SMR, and their sensitivity analyses, we found consistent evidence suggesting that more frequent insomnia was associated with a higher risk of CKD (multivariate regression: hazard ratio, 1.21 [95% CI, 1.17 to 1.25; P<.001]; 1SMR: odds ratio, 1.35 [95% CI, 1.02 to 1.79; P=.04]). Consistent evidence was obtained by using 2SMR (odds ratio,1.06; 95% CI, 1.02 to 1.11; P=.009). Genetically predicted 124 circulating proteins were associated with CKD in proteome-wide MR analysis. ENPP5 is a promising novel target that mediates the association between insomnia and CKD. CONCLUSION:More frequent insomnia is causally associated with increased risk of CKD, and ENPP5 as a potential blood protein mediates the association between insomnia and CKD. These findings indicate that addressing insomnia could serve as a viable and valid intervention to mitigate CKD risk.

Studies have demonstrated the association between black carbon (BC) particles and elevated risk of cardiovascular disease. However, the mechanisms underlying this relationship remain unclear. This study aims to investigate the effects of BC exposure on gene expressions in mice myocardium. Mice were divided into 3 groups (phosphate buffer saline (PBS) group, C50 group (50 μg BC) and C100 group (100 μg BC)). RNA sequencing was employed to conduct transcriptome analysis on myocardium samples. The expression levels of candidate genes were verified by qRT-PCR. Western Blot and Immunohistochemistry techniques were utilized to evaluate the expression of heat shock protein 70 (Hsp70). BC exposure can cause an increase in the level of cardiac L-1β and IL-6. Transcriptome analysis revealed 1027 differentially expressed genes (DEGs) in the C100 group compared with the PBS group. Gene Ontology (GO) enrichment analysis demonstrated that these DEGs were primarily enriched in misfolded protein binding, respiratory chain and ATP metabolic process. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated significant enrichment of DEGs in pathways mainly related to prion disease, oxidative phosphorylation and reactive oxygen species. HSPA1A and HSPA1B, as Hsp70 family genes, were enriched in GO term of misfolded protein binding and prion disease pathway. Moreover, the expression of cardiac Hsp70 was significantly decreased in both BC groups and showed a negative association with pro-inflammatory factors expression. BC exposure has been shown to cause inflammatory injury and may induce protein misfolding. Notably, Hsp70 was a potential cardioprotective factor and target for BC pollution-related effects.

BACKGROUND:Mental disorders have become a global health challenge particularly among ageing populations, while physical activity holds substantial promise as an accessible and non-pharmacological intervention. Tracking daily steps is a simple and popular way of physical activity, but its impact on mental health remains unclear. This study aims to examine the association between accelerometer-measured step count and intensity with the risk of multiple mental disorders in the ageing adults. METHODS:This prospective cohort study included 83,578 middle-aged and elderly participants from the UK Biobank, with a median follow-up of 6.94 years. Step count and intensity were measured using accelerometers. Mental disorder incidence was determined through hospital records and death registries, encompassing depressive disorders, sleep disorders, dementia, and eight other conditions. RESULTS:An inverse dose-response relationship was observed between daily step count and intensity with the risk of mental disorders. Risk reduction plateaued at approximately 10,000, 4800, and 6500 steps for total, purposeful, and incidental steps, respectively. Higher-intensity steps provided additional benefits when sufficient step counts were achieved. Mediation analyses, incorporating physical, behavioral, neuroimaging (8.0 % of all indirect effects, p = 0.037), and blood profile (20.7 %, p = 0.003) and multi-omic biomarkers (blood proteins, 26.1 %, p < 0.001; NMR metabolites, 8.6 %, p < 0.001), identified lipid metabolism, inflammation, and brain structural changes as key mechanisms underlying the protective effects of daily steps on mental health. CONCLUSION:These findings suggest that setting daily step goals could be a promising public health strategy for promotion of mental health especially in the ageing population.

Heart failure, which is often the final stage of various cardiovascular diseases, remains a major cause of mortality, challenging the efficacy of current therapeutic advancements. Contemporary pharmacological treatments for heart failure aim to mitigate neurohormonal activation, alleviate volume overload, and provide inotropic support, particularly under conditions of hemodynamic instability. Despite these efforts and advancements in medications and medical technology, the mortality rates associated with heart failure continue to be alarmingly high. Recent research has increasingly focused on disruptions in cardiac energy metabolism and their contributions to the development of heart failure. These metabolic disturbances are closely associated with the circadian clock, which is a critical regulator of cardiac energy balance and essential for maintaining heart function. In this review, we summarize how the circadian clock influences cardiac energy homeostasis and how its disruption can lead to detrimental changes in various metabolic pathways in the heart, potentially precipitating heart failure. Furthermore, we propose preventive and therapeutic strategies that focus on correcting the imbalances in myocardial energy metabolism regulated by circadian rhythms. These strategies may present promising avenues for improving the treatment and management of heart failure.

BackgroundSocial isolation and loneliness, two independent constructs of social disengagement, are becoming increasingly recognized factors for dementia risk.ObjectiveWe aimed to investigate whether these two constructs also associate with dementia risk in individuals with type 2 diabetes mellitus (T2DM), which is becoming more prevalent.MethodsThe longitudinal study included 24,986 participants (mean age: 60.0 ± 6.9 years, median follow-up: 12.0 years) with T2DM at baseline from the UK Biobank. Social isolation and loneliness were assessed using self-reported questionnaires. Genetic risk factors for dementia including polygenic risk score (PRS) and APOE genotype were extracted. We identified incident dementia cases by linking hospital records and death registries.ResultsSocial isolation (most versus least: hazard ratio, HR: 1.46 [95% confidence intervals, CI: 1.22-1.75]) and loneliness (yes versus no: 1.56 [1.25-1.95]) were associated with an increased risk of incident dementia after adjusting for demographic factors; however, such associations attenuated when further adjusting for health behaviors, psychological factors, or diabetes-related characteristics. The social isolation-dementia association was predominantly attributable to health behaviors (48% for the most social isolation), while the loneliness-dementia association was largely explained by psychological factors (46%). Significant modification effects of dementia genetic risk were observed in these associations.ConclusionsSocial isolation and loneliness were associated with a greater risk for incident dementia among T2DM individuals, with differential explanatory factors. The genetic risk for dementia modified these associations. The findings underscore the importance of strengthening social connections to mitigate diabetes-related dementia risk.