Association between alcohol consumption and sleep traits: observational and mendelian randomization studies in the UK biobank.

Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.

Social Isolation, Loneliness, and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes Mellitus.

RATIONALE & OBJECTIVE: Social disconnection has been associated with poor cardiometabolic health. This study sought to investigate the associations of social isolation and loneliness with diabetic microvascular complications (DMC) among individuals with type 2 diabetes mellitus (T2DM) and compare these associations to those related to traditional risk factors. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 24,297 UK Biobank participants with T2DM and no DMC at baseline. EXPOSURE: Social isolation and loneliness measured using self-reported questionnaires. OUTCOME: The incidence of DMC defined as a composite of diabetic kidney disease, diabetic retinopathy, or diabetic neuropathy. ANALYTICAL APPROACH: Multivariable cause-specific hazards regression. To compare the relative importance of social disconnection with other established factors, the R2 values of the Cox models were calculated. RESULTS: During a median follow-up of 12.6 years, 5,530 patients were documented to develop DMC (3,458 with diabetic kidney disease, 2,255 with diabetic retinopathy, and 1,146 with diabetic neuropathy). The highest level of social isolation was associated with an increased risk of any DMC component (most vs. least: HR: 1.13; 95% CI: 1.05-1.22), especially diabetic kidney disease (HR: 1.14, 95% CI: 1.04-1.25) and neuropathy (HR: 1.31, 95% CI: 1.11-1.53). Any level of loneliness was associated with an increased risk of any DMC component (HR: 1.12; 95% CI: 1.02-1.23) and diabetic kidney disease (HR: 1.16, 95% CI: 1.03-1.30). Social isolation and loneliness exhibited associations with DMC comparable to other conventional risk factors including smoking, blood pressure, and physical activity. LIMITATIONS: Limited generalizability related to the composition of participants in the UK Biobank Study. CONCLUSIONS: Social isolation and loneliness were independently associated with a higher risk of incident DMC among individuals with T2DM, with comparable importance to other traditional risk factors. These findings underscore social isolation and loneliness as novel and potentially modifiable risk factors for DMC.

Association between sleep duration and metabolic syndrome: linear and nonlinear Mendelian randomization analyses.

BACKGROUND: Observational studies have found that both short and long sleep duration are associated with increased risk of metabolic syndrome (MetS). This study aimed to examine the associations of genetically determined sleep durations with MetS and its five components (i.e., central obesity, high blood pressure, dyslipidemia, hypertriglyceridemia, and hyperglycemia) among a group of elderly population. METHODS: In 335,727 participants of White British from the UK Biobank, linear Mendelian randomization (MR) methods were first employed to examine the causal association of genetically predicted continuous sleep duration with MetS and its each component. Nonlinear MR analyses were performed to determine the nonlinearity of these associations. The causal associations of short and long sleep duration with MetS and its components were further assessed by using genetic variants that associated with short (≤ 6 h) and long sleep (≥ 9 h) durations. RESULTS: Linear MR analyses demonstrated that genetically predicted 1-h longer sleep duration was associated with a 13% lower risk of MetS, a 30% lower risk of central obesity, and a 26% lower risk of hyperglycemia. Non-linear MR analyses provided evidence for non-linear associations of genetically predicted sleep duration with MetS and its five components (all P values < 0.008). Genetically predicted short sleep duration was moderately associated with MetS and its four components, including central obesity, dyslipidemia, hypertriglyceridemia, and hyperglycemia (all P values < 0.002), whereas genetically long sleep duration was not associated with MetS and any of its components. CONCLUSIONS: Genetically predicted short sleep duration, but not genetically predicted long sleep duration, is a potentially causal risk factor for MetS.

Effects of glycemic traits on left ventricular structure and function: a mendelian randomization study.

BACKGROUND: Adverse ventricular structure and function is a key pathogenic mechanism of heart failure. Observational studies have shown that both insulin resistance (IR) and glycemic level are associated with adverse ventricular structure and function. However, whether IR and glycemic level are causally associated with cardiac structure and function remains unclear. METHODS: Genetic variants for IR, fasting insulin, HbA1c, and fasting glucose were selected based on published genome-wide association studies, which included 188,577, 108,557, 123,665, and 133,010 individuals of European ancestry, respectively. Outcome datasets for left ventricular (LV) parameters were obtained from UK Biobank Cardiovascular Magnetic Resonance sub-study (n = 16,923). Mendelian randomization (MR) analyses with the inverse-variance weighted (IVW) method were used for the primary analyses, while weighted median, MR-Egger, and MR-PRESSO were used for sensitivity analyses. Multivariable MR analyses were also conducted to examine the independent effects of glycemic traits on LV parameters. RESULTS: In the primary IVW MR analyses, per 1-standard deviation (SD) higher IR was significantly associated with lower LV end-diastolic volume (ß = - 0.31 ml, 95% confidence interval [CI] - 0.48 to - 0.14 ml; P = 4.20 × 10-4), lower LV end-systolic volume (ß = - 0.34 ml, 95% CI - 0.51 to - 0.16 ml; P = 1.43 × 10-4), and higher LV mass to end-diastolic volume ratio (ß = 0.50 g/ml, 95% CI 0.32 to 0.67 g/ml; P = 6.24 × 10-8) after Bonferroni adjustment. However, no associations of HbA1c and fasting glucose were observed with any LV parameters. Results from sensitivity analyses were consistent with the main findings, but with a slightly attenuated estimate. Multivariable MR analyses provided further evidence for an independent effect of IR on the adverse changes in LV parameters after controlling for HbA1c. CONCLUSIONS: Our study suggests that genetic liability to IR rather than those of glycemic levels are associated with adverse changes in LV structure and function, which may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.

Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank.

AIMS: Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. METHODS AND RESULTS: Genetic variants associated with continuous, short (≤6 h) and long (≥9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P < 0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P < 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD. CONCLUSION: This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long sleep duration is unlikely to be a causal risk factor for most CVDs.

Similarities and Differences in Psychology.

Addiction is marked by repeating a certain behavior while ignoring the potential physical or mental consequences. Non-substance addiction provides an ideal model for researching the emergence and development of addiction's basic mechanism. Comparative studies of substance and non-substance addiction are helpful to reveal the common basis of addiction development. This article explores this topic from a psychological angle, touching upon sensation seeking, inhibitory control, attentional bias, intertemporal choice and environment. A review of previous literature urges future research to propose a biopsychosocial model of addiction and consider addiction's effect on basic cognitive function alongside cognitive neuroscience technology.

Exposure to extinction-associated contextual tone during slow-wave sleep and wakefulness differentially modulates fear expression.

Recent research has used context cues (odor or auditory cues) to target memories during sleep and has demonstrated that they can enhance declarative and procedural memories. However, the effects of external cues re-presented during sleep on emotional memory are still not fully understood. In the present study, we conducted a Pavlovian fear conditioning/extinction paradigm and examined the effects of re-exposure to extinction memory associated contextual tones during slow-wave sleep (SWS) and wakefulness on fear expression. The participants underwent fear conditioning on the first day, during which colored squares served as the conditioned stimulus (CS) and a mild shock served as the unconditioned stimulus (US). The next day, they underwent extinction, during which the CSs were presented without the US but accompanied by a contextual tone (pink noise). Immediately after extinction, the participants were required to take a nap or remain awake and randomly assigned to six groups. Four of the groups were separately exposed to the associated tone (i.e. SWS-Tone group and Wake-Tone group) or an irrelevant tone (control tone, CtrT) (i.e. SWS-CtrT group and Wake-CtrT group), while the other two groups were not (i.e. SWS-No Tone group and Wake-No Tone group). Subsequently, the conditioned responses to the CSs were tested to evaluate the fear expression. All of the participants included in the final analysis showed successful levels of fear conditioning and extinction. During the recall test, the fear responses were significantly higher in the SWS-Tone group than that in the SWS-No Tone group or the SWS-CtrT group, while the Wake-Tone group exhibited more attenuated fear responses than either the Wake-No Tone group or Wake-CtrT group. Otherwise, re-exposure to auditory tones during SWS did not affect sleep profiles. These results suggest that distinct conditions during which re-exposure to an extinction memory associated contextual cue contributes to differential effects on fear expression.

Evaluation of Changes in Social Isolation and Loneliness with Incident Cardiovascular Events and Mortality.

BACKGROUND: It remains unknown how the patterns of change of social isolation and loneliness are associated with the onset of cardiovascular disease (CVD) and mortality. We aimed to investigate the longitudinal association of changes in social isolation and loneliness with incident CVD, all-cause mortality, CVD mortality and subsequent cardiac function. METHODS: This prospective cohort study included 18,258 participants aged 38-73 years who participated in visit 0 (2006-2010) and visit 1 (2012-2013) using UK Biobank (mean age 57.1, standard deviation [SD] 7.4; 48.7% males). Social isolation or loneliness was categorized into four patterns: never, transient, incident, and persistent. Incident CVD, all-cause and CVD mortality were ascertained through linkage data. Cardiac function was assessed by cardiovascular magnetic resonance imaging in a subsample (N = 5188; visit 2, since 2014). RESULTS: Over a median follow-up of 8.3 (interquartile range [IQR] 8.1-8.6) years, compared with never social isolation, persistent social isolation was associated with the higher risk of incident CVD (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.03-1.33), all-cause (1.42, 1.12-1.81) and CVD (1.53, 1.05-2.23) mortality. Likewise, persistent loneliness was strongly associated with the greater risk of incident CVD (1.13, 1.00-1.27), all-cause (1.28, 1.02-1.61) and CVD mortality (1.52, 1.06-2.18). CONCLUSIONS: Persistent social isolation and loneliness posed a substantially higher risk for incident CVD, all-cause and CVD mortality, and cardiac dysfunction than other patterns. Persistent social isolation and loneliness, along with an increasing cumulative score, are associated with lower cardiac function.

Childhood maltreatment, genetic risk, and subsequent risk of arrhythmias: a prospective cohort study.

Background: Emerging evidence has linked childhood maltreatment with cardiovascular disease risk; however, the association between childhood maltreatment and cardiac arrhythmias remains unclear. Moreover, any genetic predispositions to atrial fibrillation (AF), a common cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality, that modify such associations have been undocumented.Purpose: To examine the associations between childhood maltreatment and incident arrhythmias, and whether a genetic predisposition to arrhythmias modifies these associations.Methods: This prospective analysis included 151,741 participants from the UK Biobank (mean age 55.8 years, 43.4% male). Childhood maltreatment, including five types, was measured using the Childhood Trauma Screener (CTS). Incident arrhythmias (AF, ventricular arrhythmias [VA], and bradyarrhythmia [BA]) were documented through linked hospital admission and death registry. Weighted AF genetic risk score was calculated. Cox proportional hazard models were conducted to test for associations between childhood maltreatment and incident arrhythmias.Results: During a median follow-up of 12.21 years (interquartile range, 11.49-12.90 years), 6,588 AF, 2,093 BA, and 742 VA events occurred. Compared with the absence of childhood maltreatment, having 3-5 types of childhood maltreatment was associated with an increased risk of incident AF (HR, 1.23; 95%CI 1.09-1.37), VA (HR, 1.39; 95%CI 1.03-1.89), and BA (HR, 1.32; 95%CI 1.09-1.61) after adjusting demographic, socioeconomic and lifestyle factors. The associations between cumulative type of childhood maltreatment and the risk of AF (Poverall < .001; Pnonlinear = .674) and BA (Poverall = .007; Pnonlinear = .377) demonstrated a linear pattern. There was a gradient association between childhood maltreatment and AF risks across the intermediate and high genetic risk groups (both Ptrend < .05) but not within the low genetic risk group (Ptrend = .378), irrespective of non-significant interaction effect (Pinteraction = .204).Conclusion: Childhood maltreatment was associated with higher risks of incident arrhythmias, especially AF and BA. Genetic risk of AF did not modify these associations.

Previous studies indicate that childhood maltreatment is associated with cardiovascular disease risk.Childhood maltreatment was associated with an increased risk of incident arrhythmias, particularly atrial fibrillation and bradyarrhythmia. Genetic predisposition to atrial fibrillation did not significantly modify these associations.Childhood maltreatment could be a new psychological risk factor for cardiac arrhythmias in later life. Inquiries into childhood maltreatment and subsequent referral to psychological services may be helpful.

Trajectories of social isolation and loneliness and the risk of incident type 2 diabetes mellitus across genetic risk score.

AIM: This study aimed to investigate the association of social isolation, loneliness, and their trajectory with the risk of developing type 2 diabetes mellitus (T2DM) across genetic risk. METHODS: We included 439,337 participants (mean age 56.3 ± 8.1 years) enrolled in the UK Biobank study who were followed up until May 31, 2021. Social isolation and loneliness were self-reported and were further categorized into never, transient, incident, and persistent patterns. RESULTS: During a median follow-up of 12.7 years, 15,258 incident T2DM cases were documented. Social isolation (versus no social isolation: hazard ratio (HR) 95 % confidence interval (CI) 1.04 [1.00;1.09]) and loneliness (versus no loneliness: 1.26 [1.19;1.34]) were associated with an increased T2DM risk, independent of the genetic risk for T2DM. The interactions existed between social isolation and loneliness (Pinteraction < 0.05); the increased T2DM risk associated with social isolation was only significant among participants without loneliness. In the longitudinal analysis, only persistent social isolation (versus never social isolation: 1.22 [1.02;1.45]) was associated with an increased T2DM risk, whereas incident loneliness (versus never loneliness: 1.95 [1.40;2.71]) and persistent loneliness (2.00 [1.31;3.04]) were associated with higher T2DM risks. CONCLUSION: Social isolation and loneliness, especially their persistent pattern, were independently associated with an increased incident T2DM risk, irrespective of an individual's genetic risk. Loneliness modified the association between social isolation and incident T2DM.

Association of Disrupted Delta Wave Activity During Sleep With Long-Term Cardiovascular Disease and Mortality.

BACKGROUND: Delta wave activity is a prominent feature of deep sleep, which is significantly associated with sleep quality. OBJECTIVES: The authors hypothesized that delta wave activity disruption during sleep could predict long-term cardiovascular disease (CVD) and CVD mortality risk. METHODS: The authors used a comprehensive power spectral entropy-based method to assess delta wave activity during sleep based on overnight polysomnograms in 4,058 participants in the SHHS (Sleep Heart Health Study) and 2,193 participants in the MrOS (Osteoporotic Fractures in Men Study) Sleep study. RESULTS: During 11.0 ± 2.8 years of follow-up in SHHS, 729 participants had incident CVD and 192 participants died due to CVD. During 15.5 ± 4.4 years of follow-up in MrOS, 547 participants had incident CVD, and 391 died due to CVD. In multivariable Cox regression models, lower delta wave entropy during sleep was associated with higher risk of coronary heart disease (SHHS: HR: 1.46; 95% CI: 1.02-2.06; P = 0.03; MrOS: HR: 1.79; 95% CI: 1.17-2.73; P < 0.01), CVD (SHHS: HR: 1.60; 95% CI: 1.21-2.11; P < 0.01; MrOS: HR: 1.43; 95% CI: 1.00-2.05; P = 0.05), and CVD mortality (SHHS: HR: 1.94; 95% CI: 1.18-3.18; P < 0.01; MrOS: HR: 1.66; 95% CI: 1.12-2.47; P = 0.01) after adjusting for covariates. The Shapley Additive Explanations method indicates that low delta wave entropy was more predictive of coronary heart disease, CVD, and CVD mortality risks than conventional sleep parameters. CONCLUSIONS: The results suggest that delta wave activity disruption during sleep may be a useful metric to identify those at increased risk for CVD and CVD mortality.

Is cognitive behavioral therapy for insomnia (CBTI) more cost-effective? New-perspective on economic evaluations: a systematic review and meta-analysis.

STUDY OBJECTIVES: To investigate the cost-effectiveness of cognitive behavioral therapy for insomnia (CBTI), with an additional focus on digital cognitive behavioral therapy for insomnia (dCBTI) in adults with insomnia. METHODS: We searched eight electronic databases for economic evaluations of CBTI: PubMed, Scopus, Web of Science, psycINFO, Cochrane, Library, CINAHL, ProQuest and National Health Service Economic Evaluation Database. Meta-analyses were performed to investigate the effects and costs between CBTI and control groups (no treatment, other treatments included hygiene education and treatment as usual). Subgroup analyses for dCBTI were conducted. RESULTS: Twelve randomized controlled trails studies between 2004 and 2023 were included in our systematic review and meta-analyses. The incremental cost-utility ratios and incremental cost-effectiveness ratios showed that the CBTI and dCBTI groups were more cost-effective than controls, from healthcare perspective and societal perspective, respectively. Compared to controls, CBTI demonstrated significantly better efficacy within 12 months. Healthcare costs were significantly higher in the CBTI groups compared to the controls within 6 months but there was no difference at 12 months. Additionally, dCBTI was associated with significantly lower presenteeism costs compared to controls at 6 months. CONCLUSIONS: Our findings suggest that CBTI is more cost-effective than other treatments or no treatment for adults with insomnia. It may bring more economic benefits in the long-term, especially in long-lasting efficacy and costs reduction. In addition, dCBTI is one of the cost-effective options for insomnia.

Joint association of physical activity and sleep duration with risk of all-cause and cause-specific mortality: a population-based cohort study using accelerometry.

AIMS: To investigate the joint association of accelerometer-measured physical activity (PA) and sleep duration with mortality risk. METHODS AND RESULTS: A 7-day accelerometer recording was performed on 92 221 participants (age 62.4 ± 7.8 years; 56.4% women) from the UK Biobank between February 2013 and December 2015. We divided sleep duration into three groups (short, normal, and long), total volume of PA into three levels according to tertiles (high, intermediate, low), and moderate-to-vigorous PA (MVPA) into two groups based on the World Health Organization guidelines. The mortality outcomes were prospectively collected through the death registry. Over a median follow-up of 7.0 years, 3080 adults died, of which 1074 died from cardiovascular disease (CVD) and 1871 from cancer. The associations of PA and sleep duration with mortality risk were all in a curvilinear dose-response pattern (Pnonlinearity <0.001). PA and sleep duration had additive and multiplicative interactions on mortality risk (Pinteraction <0.05). Compared with the participants with guideline-recommended MVPA and normal sleep duration, those without recommended MVPA but having short or long sleep duration were at a higher risk for all-cause mortality [short sleep: hazard ratio (HR) = 1.88; 95% confidence interval (CI), 1.61-2.20; long sleep: HR = 1.69; 95% CI, 1.49-1.90]. A higher volume of PA or recommended MVPA attenuated the detrimental effects of short or long sleep duration on all-cause and CVD mortality risks. CONCLUSION: MVPA meeting recommendations or a higher volume of PA at any intensity potentially diminished the adverse effects on all-cause and cause-specific mortality associated with short and long sleep duration.

All-cause and cause-specific mortality risks associated with accelerometer-measured short or long sleep duration were attenuated by physical activity (PA).Both accelerometer-measured short and long sleep duration were associated with higher risk for all-cause and CVD mortality.Either a higher volume of PA or moderate-to-vigorous PA reaching the WHO-recommended level, as was also measured with accelerometer, attenuated the excessive mortality risks associated with short or long sleep duration.

Causal associations of sleep traits with cancer incidence and mortality.

To explore the correlation and causality between multidimensional sleep traits and pan-cancer incidence and mortality among patients with cancer. The multivariable Cox regression, linear and nonlinear Mendelian randomization (MR), and survival curve analyses were conducted to assess the impacts of chronotype, sleep duration, and insomnia symptoms on pan-cancer risk (N = 326,417 from United Kingdom Biobank) and mortality (N = 23,956 from United Kingdom Biobank). In the Cox regression, we observed a linear and J-shaped association of sleep duration with pan-cancer incidence and mortality among cancer patients respectively. In addition, there was a positive association of insomnia with pan-cancer incidence (HR, 1.03, 95% CI: 1.00-1.06, p = 0.035), all-cause mortality (HR, 1.17, 95% CI: 1.06-1.30, p = 0.002) and cancer mortality among cancer patients (HR, 1.25, 95% CI: 1.11-1.41, p < 0.001). In the linear MR, there was supporting evidence of positive associations between long sleep duration and pan-cancer incidence (OR, 1.41, 95% CI: 1.08-1.84, p = 0.012), and there was a positive association between long sleep duration and all-cause mortality in cancer patients (OR, 5.56, 95% CI: 3.15-9.82, p = 3.42E-09). Meanwhile, a strong association between insomnia and all-cause mortality in cancer patients (OR, 1.41, 95% CI: 1.27-1.56, p = 4.96E-11) was observed in the linear MR. These results suggest that long sleep duration and insomnia play important roles in pan-cancer risk and mortality among cancer patients. In addition to short sleep duration and insomnia, our findings highlight the effect of long sleep duration in cancer prevention and prognosis.

Social isolation, loneliness and subsequent risk of major adverse cardiovascular events among individuals with type 2 diabetes mellitus.

Background: Individuals with type 2 diabetes mellitus (T2DM) are more vulnerable to social disconnection compared with the general population; however, there are few relevant studies investigating this issue. Aims: To investigate whether social isolation or loneliness may be associated with subsequent risk of developing major adverse cardiovascular events, whether these associations vary according to fatal and non-fatal outcomes and how behavioural, psychological and physiological factors mediate these associations. Methods: This longitudinal analysis included data from 19 360 individuals with T2DM at baseline (2006-2010) from the UK Biobank. Social isolation and loneliness were measured using self-report questionnaires. The study outcomes included the first events of myocardial infarction (MI) or stroke (n=2273) and all-cause (n=2820) or cardiovascular disease-related mortality through linked hospital data or death registries. Results: Over a median follow-up of 12.4 years (interquartile range (IQR): 11.6-13.3 years), participants who were more socially isolated (most social isolation vs least social isolation) experienced increased risks for all-cause (hazard ratio (HR) : 1.33, 95% confidence interval (CI): 1.19 to 1.47) and cardiovascular disease (HR: 1.36, 95% CI: 1.17 to 1.59) mortality but not first MI or stroke. Loneliness (yes vs no) was associated with a greater risk for a composite of incident MI or stroke (HR: 1.37, 95% CI: 1.19 to 1.57) but not mortality. Social isolation was associated with fatal MI and stroke, whereas loneliness was associated with non-fatal MI and stroke. The significant associations of social isolation and loneliness with outcomes were mainly mediated by behavioural factors (mediating proportion: 17.8%-28.2% and 17.6%-17.8%, respectively). Conclusions: Among individuals with T2DM, social isolation and loneliness are associated with a greater risk of developing major adverse cardiovascular events, with differences in both risks stratified according to fatal and non-fatal events and underlying mediating factors.

Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study.

BACKGROUND: Social isolation and loneliness have emerged as important risk factors for cardiovascular diseases, particularly during the coronavirus disease pandemic. However, it is unclear whether social isolation and loneliness had independent and joint associations with incident heart failure (HF). OBJECTIVES: This study sought to examine the association of social isolation, loneliness, and their combination with incident HF. METHODS: The UK Biobank study is a population-based cohort study. Social isolation and loneliness were assessed using self-reported questionnaires. HF cases were identified by linking hospital records and death registries. The weighted polygenic risk score associated with HF was calculated. RESULTS: Among the 464,773 participants (mean age: 56.5 ± 8.1 years, 45.3% male), 12,898 incident HF cases were documented during a median follow-up of 12.3 years. Social isolation (most vs least: adjusted HR: 1.17; 95% CI:1.11-1.23) and loneliness (yes vs no: adjusted HR: 1.19; 95% CI: 1.11-1.27) were significantly associated with an increased risk of incident HF. The association between an elevated risk of HF and social isolation was modified by loneliness (Pinteraction = 0.034). A gradient of association between social isolation and the risk of incident HF was found only among individuals without loneliness (Ptrend < 0.001), but not among those with loneliness (Ptrend = 0.829). These associations were independent of the genetic risk of HF. CONCLUSIONS: Social isolation and loneliness were independently associated with a higher likelihood of incident HF regardless of genetic risk. The association between social isolation and incident HF was potentially modified by loneliness status.

Associations of Insomnia With Insulin Resistance Traits: A Cross-sectional and Mendelian Randomization Study.

CONTEXT: Insomnia is associated with insulin resistance (IR) in observational studies; however, whether insomnia is causally associated with IR remains unestablished. OBJECTIVE: This study aims to estimate the causal associations of insomnia with IR and its related traits. METHODS: In primary analyses, multivariable regression (MVR) and 1-sample Mendelian randomization (1SMR) analyses were performed to estimate the associations of insomnia with IR (triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol [TG/HDL-C] ratio) and its related traits (glucose level, TG, and HDL-C) in the UK Biobank. Thereafter, 2-sample MR (2SMR) analyses were used to validate the findings from primary analyses. Finally, the potential mediating effects of IR on the pathway of insomnia giving rise to type 2 diabetes (T2D) were examined using a 2-step MR design. RESULTS: Across the MVR, 1SMR, and their sensitivity analyses, we found consistent evidence suggesting that more frequent insomnia symptoms were significantly associated with higher values of triglyceride-glucose index (MVR, ß = 0.024, P < 2.00E-16; 1SMR, ß = 0.343, P < 2.00E-16), TG/HDL-C ratio (MVR, ß = 0.016, P = 1.75E-13; 1SMR, ß = 0.445, P < 2.00E-16), and TG level (MVR, ß = 0.019 log mg/dL, P < 2.00E-16, 1SMR: ß = 0.289 log mg/dL, P < 2.00E-16) after Bonferroni adjustment. Similar evidence was obtained by using 2SMR, and mediation analysis suggested that about one-quarter (25.21%) of the association between insomnia symptoms and T2D was mediated by IR. CONCLUSIONS: This study provides robust evidence supporting that more frequent insomnia symptoms are associated with IR and its related traits across different angles. These findings indicate that insomnia symptoms can be served as a promising target to improve IR and prevent subsequent T2D.

Joint Associations of Device-Measured Sleep Duration and Efficiency With All-Cause and Cause-Specific Mortality: A Prospective Cohort Study of 90 398 UK Biobank Participants.

BACKGROUND: Both sleep duration and efficiency are essential for health outcomes. However, few studies have considered the effects of both sleep duration and efficiency on predicting the risks of mortality. This study investigated the independent and joint associations of accelerometer-measured sleep duration and efficiency with all-cause and cause-specific mortality. METHODS: The UK Biobank is a cohort study of over 500 000 individuals recruited between 2006 and 2010. This study included participants wearing wrist accelerometers for 7 consecutive days between February 2013 and December 2015. Mortality was ascertained by the national death registries. RESULTS: Of the 90 398 participants (age, 62.4 [7.8] years, 43.5% male) who were included, 2 685 deaths were reported within a median follow-up duration of 6.4 years. Both accelerometer-measured short (adjusted hazard ratios, 1.27; 95% confidence interval [CI]: 1.11-1.45) and long sleep duration (adjusted hazard ratios, 1.16; 95% CI: 1.06-1.28) were positively associated with the risks of all-cause mortality. Lower sleep efficiency was associated with an increased risk of all-cause and cause-specific mortality. Significant interaction existed between accelerometer-measured sleep duration and efficiency for the risk of all-cause mortality (Pinteraction = .001), participants with long sleep duration and lower sleep efficiency had a double mortality risk compared with those with higher sleep efficiency and normal sleep duration (adjusted hazard ratios = 2.11; 95% CI: 1.44-3.09). CONCLUSIONS: Accelerometer-measured short/long sleep duration and lower sleep efficiency were associated with increased risks of mortality. Sleep efficiency modified the effects of long sleep duration on survival.

Association of accelerometer-derived circadian abnormalities and genetic risk with incidence of atrial fibrillation.

Evidence suggests potential links between circadian rhythm and atrial fibrillation (AF). However, whether circadian disruption can predict the onset of AF in the general population remains largely unknown. We aim to investigate the association of accelerometer-measured circadian rest-activity rhythm (CRAR, the most prominent circadian rhythm in humans) with the risk of AF, and examine joint associations and potential interactions of CRAR and genetic susceptibility with AF incidence. We include 62,927 white British participants of UK Biobank without AF at baseline. CRAR characteristics, including amplitude (strength), acrophase (timing of peak activity), pseudo-F (robustness), and mesor (height), are derived by applying an extended cosine model. Genetic risk is assessed with polygenic risk scores. The outcome is the incidence of AF. During a median follow-up of 6.16 years, 1920 participants developed AF. Low amplitude [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.25-1.58], delayed acrophase (HR: 1.24, 95% CI: 1.10-1.39), and low mesor (HR: 1.36, 95% CI: 1.21-1.52), but not low pseudo-F, are significantly associated with a higher risk of AF. No significant interactions between CRAR characteristics and genetic risk are observed. Joint association analyses reveal that participants with unfavourable CRAR characteristics and high genetic risk yield the highest risk of incident AF. These associations are robust after controlling for multiple testing and in a series of sensitivity analyses. Accelerometer-measured CRAR abnormalities, characterized by decreased strength and height, and later timing of peak activity of circadian rhythm, are associated with a higher risk of AF in the general population.

Association between accelerometer-measured amplitude of rest-activity rhythm and future health risk: a prospective cohort study of the UK Biobank.

BACKGROUND: The health effects of rest-activity rhythm are of major interest to public health, but its associations with health outcomes remain elusive. We aimed to examine the associations between accelerometer-measured rest-activity rhythm amplitude and health risks among the general UK population. METHODS: We did a prospective cohort analysis of UK Biobank participants aged 43-79 years with valid wrist-worn accelerometer data. Low rest-activity rhythm amplitude was defined as the first quintile of relative amplitude; all other quintiles were classified as high rest-activity rhythm amplitude. Outcomes of interest were defined using International Classification of Diseases 10th Revision codes and consisted of incident cancer and cardiovascular, infectious, respiratory, and digestive diseases, and all-cause and disease-specific (cardiovascular, cancer, and respiratory) mortality. Participants with a current diagnosis of any outcome of interest were excluded. We assessed the associations between decreased rest-activity rhythm amplitude and outcomes using Cox proportional hazards models. FINDINGS: Between June 1, 2013, and Dec 23, 2015, 103 682 participants with available raw accelerometer data were enrolled. 92 614 participants (52 219 [56·4%] women and 40 395 [42·6%] men) with a median age of 64 years (IQR 56-69) were recruited. Median follow-up was 6·4 years (IQR 5·8-6·9). Decreased rest-activity rhythm amplitude was significantly associated with increased incidence of cardiovascular diseases (adjusted hazard ratio 1·11 [95% CI 1·05-1·16]), cancer (1·08 [1·01-1·16]), infectious diseases (1·31 [1·22-1·41]), respiratory diseases (1·26 [1·19-1·34]), and digestive diseases (1·08 [1·03-1·14]), as well as all-cause mortality (1·54 [1·40-1·70]) and disease-specific mortality (1·73 [1·34-2·22] for cardiovascular diseases, 1·32 [1·13-1·55] for cancer, and 1·62 [1·25-2·09] for respiratory diseases). Most of these associations were not modified by age older than 65 years or sex. Among 16 accelerometer-measured rest-activity parameters, low rest-activity rhythm amplitude had the strongest or second- strongest associations with nine health outcomes. INTERPRETATION: Our results suggest that low rest-activity rhythm amplitude might contribute to major health outcomes and provide further evidence to promote risk-modifying strategies associated with rest-activity rhythm to improve health and longevity. FUNDING: National Natural Science Foundation of China and China Postdoctoral Science Foundation.