Leisure Sedentary Behavior, Physical Activities, and Cardiovascular Disease Among Individuals With Metabolic Dysfunction-Associated Fatty Liver Disease.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease is a significant risk factor for cardiovascular disease (CVD). This study assesses the association between leisure-time physical activity, sedentary behavior, and CVD risk among patients with metabolic dysfunction-associated fatty liver disease, considering genetic predisposition to CVD. METHODS: This cohort study included 157 794 participants with metabolic dysfunction-associated fatty liver disease from the UK Biobank who were free of CVD at baseline. The study measured leisure-time sedentary behaviors (watching TV, using a computer, and driving) and physical activities (walking for pleasure, light and heavy do-it-yourself activities, strenuous sports, and other exercises) in terms of frequency and duration over the 4 weeks before assessment. Both a Cox proportional hazard model and an isotemporal substitution model were utilized in the study to assess the association between leisure sedentary behavior, physical activities, and CVD risk. RESULTS: During a median 12.5 years of follow-up, 26 355 CVD cases were reported, including 19 746 coronary heart disease, 4836 stroke, and 7398 heart failure cases. High physical activity levels were linked to a significantly lower risk of CVD (21%), coronary heart disease (20%), stroke (15%), and heart failure (31%). In contrast, individuals with >6.5 h/d of sedentary behavior faced a 16% to 21% higher risk of these conditions compared with those with ≤3.5 h/d. Notably, replacing 30 minutes of inactivity with physical activity reduced CVD risks by 3% to 16%, particularly with strenuous sports. A significant interaction was observed between physical activity, sedentary behavior, and genetic predisposition in relation to stroke risk. CONCLUSIONS: Among patients with metabolic dysfunction-associated fatty liver disease, higher leisure-time physical activity levels correlate with reduced CVD risks, while increased sedentary behavior is linked to higher CVD risks. Replacing sedentary time with physical activity consistently shows benefits in reducing CVD outcomes, irrespective of genetic predisposition.

Accelerometer-measured physical activity, sedentary behavior, and incidence of macrovascular and microvascular events in individuals with type 2 diabetes mellitus and prediabetes.

BACKGROUND: Physical activity (PA) is considered beneficial for lowering cardiovascular risks following type 2 diabetes mellitus (T2DM) and prediabetes, but existing evidence relies mainly on self-reported measurements. We aimed to describe the intensity-specific dose-response associations of PA and sedentary behavior (SB) with macrovascular and microvascular events among individuals with T2DM and prediabetes. METHODS: This study included 11,474 individuals with T2DM and prediabetes from the UK Biobank. PA, including total PA, moderate-to-vigorous intensity PA (MVPA), light intensity PA (LPA), and SB, were measured by accelerometers over 7 days. MVPA was categorized according to the American Diabetes Association guideline-recommended level (at least 150 min/week), and total PA, LPA, and SB were grouped by tertiles. The outcomes were incidences of macrovascular events, microvascular events, heart failure (HF), and their combination (composite events). The events were ascertained using the ICD-10 codes on the hospital or death records. RESULTS: During a median follow-up of 6.8 years, 1680 cases were documented, including 969 macrovascular events, 839 microvascular events, and 284 incidents of HF. Accelerometer-measured PA, irrespective of intensity, was inversely associated with the risk of composite events and each outcome in the dose-response patterns. Regarding categorized PA, engagement in total PA (high vs. low) was associated with decreased risk of macrovascular events (hazard ratio (HR) = 0.80; 95% confidence interval (95%CI): 0.67-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.93), and HF (HR = 0.46; 95%CI: 0.32-0.66). Adherence to MVPA, but not LPA, above the guideline-recommended level (at least 150 min/week) was associated with reduced risk of macrovascular events (HR = 0.80; 95%CI: 0.68-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.92), and HF (HR = 0.65; 95%CI: 0.46-0.92). The minimum dose of MVPA for lowering the risk of composite events was approximately 59.0 min/week. More time spent in SB was associated with an increased risk of composite events (high vs. low, HR = 1.17; 95%CI: 1.02-1.35) and HF (high vs. low, HR = 1.54; 95%CI: 1.09-2.20). Replacement of 30 min of SB (HR = 0.73; 95%CI: 0.65-0.81) and LPA (HR = 0.74; 95%CI: 0.66-0.83) with MVPA dramatically reduced the risk of composite events. CONCLUSION: Adherence to a higher amount of accelerometer-measured PA, especially MVPA at least 59 min/week, is associated with reduced risks of macrovascular and microvascular events among individuals with T2DM and prediabetes. Replacement of SB and LPA with MVPA helped lower the risk of diabetic vascular events.

Associations of objective sleep duration and physical activity with risk of heart failure: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the independent and joint associations of accelerometer-derived sleep duration and physical activity (PA) in different intensities with the risk of incident heart failure (HF). METHODS: The study included 89,572 participants (mean age 62.2 ± 7.8 years, 42.8% male) from the UK Biobank. Sleep duration (short: <6 h/day; normal: 6-8 h/day; long: >8 h/day) and PA [total PA, light PA (LPA), moderate-to-vigorous PA (MVPA), vigorous PA (VPA)] were measured using accelerometers over 7 days. MVPA and VPA were categorized according to the World Health Organization's recommended levels, while LPA and total PA were categorized based on the median. HF cases were identified through hospital records or death registries. RESULTS: Over a 7-year follow-up period, 1324 participants (2.1%; incidence rate, 2.1 per 1000 person-years) developed HF. Short, but not long, sleep duration was linked to a 33% increased risk of HF [hazard ratio (HR) 1.33, 95% confidence interval (CI): 1.11-1.59]. This increased risk associated with short sleep could be mitigated by increasing PA, especially to the levels of recommended MVPA or VPA. In joint analyses, compared to participants meeting the recommended MVPA and with normal sleep duration, those not meeting the MVPA recommendation and with short sleep had the highest HF risk (HR 1.78, 95% CI: 1.42-2.25). CONCLUSIONS: Accelerometer-derived short, but not long, sleep duration was associated with a higher risk of incident HF. Engaging in sufficient PA, especially recommended MVPA or VPA, can partially mitigate this risk.

Immediate and long-term efficacy of transcranial direct current stimulation (tCDS) in obsessive-compulsive disorder, posttraumatic stress disorder and anxiety disorders: a systematic review and meta-analysis.

Currently, there is still debate over the effectiveness of transcranial direct current stimulation (tDCS) in treating obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD) and anxiety disorders (ADs). To investigate the immediate and long-term effectiveness of tDCS in these diseases, we conducted a systematic review and quantitative analysis of existing literature on the treatment of OCD, PTSD, and ADs with tDCS. Following the PRISMA guidelines, we searched seven electronic databases and systematically retrieved articles published from May 2012 to June 2024 that compared the effects of active tDCS with sham stimulation in the treatment of these disorders. We included primary outcome measures such as the change scores in disorder-specific and general anxiety symptoms before and after treatment, as well as secondary outcomes such as changes in disorder-specific and general anxiety symptoms at follow-up. We also assessed the impact of tDCS on depressive symptoms. Fifteen papers met the eligibility criteria. Overall, the results of meta-analysis indicated that tDCS had a high effect in improving specific symptoms (SMD = -0.73, 95% CI: -1.09 to -0.37) and general anxiety symptoms (SMD = -0.75; 95% CI: -1.23 to -0.26) in OCD, PTSD and ADs, with effects lasting up to 1 month and showing a moderate effect size. Furthermore, tDCS demonstrated immediate and significant alleviation of depressive symptoms in these diseases. This study concludes that tDCS can serve as a non-invasive brain stimulation technology for treating these disorders, and the therapeutic effects can be maintained for a period of time.

Dietary pattern modifies the risk of MASLD through metabolomic signature.

Background & Aims: The EAT-Lancet Commission in 2019 advocated a plant-centric diet for health and environmental benefits, but its relation to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to discover the metabolite profile linked to the EAT-Lancet diet and its association with MASLD risk, considering genetic predisposition. Methods: We analyzed data from 105,752 UK Biobank participants with detailed dietary and metabolomic information. We constructed an EAT-Lancet diet index and derived a corresponding metabolomic signature through elastic net regression. A weighted polygenic risk score for MASLD was computed from associated risk variants. The Cox proportional hazards model was employed to estimate hazard ratios (HRs) and 95% CIs for the risk of MASLD (defined as hospital admission or death). Results: During a median follow-up period of 11.6 years, 1,138 cases of MASLD were documented. Participants in the highest group for the EAT-Lancet diet index had a multivariable HR of 0.79 (95% CI 0.66-0.95) for MASLD compared to the lowest group. The diet's impact was unaffected by genetic predisposition to MASLD (p = 0.42). Moreover, a robust correlation was found between the metabolomic signature and the EAT-Lancet diet index (Pearson r = 0.29; p <0.0001). Participants in the highest group for the metabolomic signature had a multivariable HR of 0.46 (95% CI 0.37-0.58) for MASLD, in comparison to those in the lowest group. Conclusions: Higher intake of the EAT-Lancet diet and its associated metabolite signature are both linked to a reduced risk of MASLD, independently of traditional risk factors. Impact and implications: Our analysis leveraging the UK Biobank study showed higher adherence to the EAT-Lancet diet was associated with a reduced risk of metabolic dysfunction-associated steatotic liver disease (MASLD). We identified a unique metabolite signature comprising 81 metabolites associated with the EAT-Lancet diet, potentially underlying the diet's protective mechanism against MASLD. These findings suggest the EAT-Lancet diet may offer substantial protective benefits against MASLD.

Co-expression of a pair of interdependent regulators coding genes ovmZ and ovmW awakens the production of angucyclinones antibiotics in Streptomyces neyagawaensis.

BACKGROUND: Microbial genome sequencing and analysis revealed the presence of abundant silent secondary metabolites biosynthetic gene clusters (BGCs) in streptomycetes. Activating these BGCs has great significance for discovering new compounds and novel biosynthetic pathways. RESULTS: In this study, we found that ovmZ and ovmW homologs, a pair of interdependent transcriptional regulators coding genes, are widespread in actinobacteria and closely associated with the biosynthesis of secondary metabolites. Through co-overexpression of native ovmZ and ovmW in Streptomyces neyagawaensis NRRL B-3092, a silent type II polyketide synthase (PKS) gene cluster was activated to produce gephyromycin A, tetrangomycin and fridamycin E with the yields of 22.3 ± 8.0 mg/L, 4.8 ± 0.5 mg/L and 20.3 ± 4.1 mg/L respectively in the recombinant strain of S.ne/pZnWn. However, expression of either ovmZ or ovmW failed to activate this gene cluster. Interestingly, overexpression of the heterologous ovmZ and ovmW pair from oviedomycin BGC of S. ansochromogenes 7100 also led to awakening of this silent angucyclinone BGC in S. neyagawaensis. CONCLUSION: A silent angucyclinone BGC was activated by overexpressing both ovmZ and ovmW in S. neyagawaensis. Due to the wide distribution of ovmZ and ovmW in the BGCs of actinobacteria, co-overexpression of ovmZ and ovmW could be a strategy for activating silent BGCs, thus stimulating the biosynthesis of secondary metabolites.

The Whole Genome DNA Methylation Signatures of Hindlimb Muscles in Chinese Alligators during Hibernation and Active Periods.

Many ectotherms hibernate to increase their chances of survival during harsh winter conditions. The role of DNA methylation in regulating gene expression related to hibernation in ectotherms remains unclear. Here, we employed whole-genome bisulfite sequencing (WGBS) technology to construct a comprehensive genome-wide DNA methylation landscape of the hindlimb muscles in the Chinese alligator during hibernation and active periods. The results indicated that methylation modifications were most abundant at CG sites, identifying 9447 differentially methylated regions (DMRs) and 2329 differentially methylated genes (DMGs). KEGG pathway enrichment analysis of the DMGs revealed significant enrichment in major pathways such as the neurotrophin signaling pathway, the MAPK signaling pathway, the GnRH signaling pathway, the biosynthesis of amino acids, and the regulation of the actin cytoskeleton, which are closely related to lipid metabolism, energy metabolism, and amino acid metabolism. Among these, 412 differentially methylated genes were located in promoter regions, including genes related to energy metabolism such as ATP5F1C, ATP5MD, PDK3, ANGPTL1, and ANGPTL2, and genes related to ubiquitin-proteasome degradation such as FBXO28, FBXO43, KLHL40, and PSMD5. These findings suggest that methylation in promoter regions may play a significant role in regulating the adaptive hibernation mechanisms in the Chinese alligator. This study contributes to a further understanding of the epigenetic mechanisms behind the hibernation of the Chinese alligator.

Associations of Accelerometer-measured Sleep Duration with Incident Cardiovascular Disease and Cardiovascular Mortality.

STUDY OBJECTIVES: This study aimed to determine the associations between accelerometer-measured sleep durations and the risks of incident cardiovascular disease (CVD) and CVD-related mortality. METHODS: A total of 92,261 participants (mean age: 62.4±7.8 years, 56.4% female) were included in UK Biobank between 2013 and 2015. Average daily sleep durations were measured using wrist-worn accelerometers over a seven-day period. Sleep durations were categorized as <7 hours/day, 7-9 hours/day (reference), and >9 hours/day. The incidence of CVD and CVD-related mortality were ascertained by hospital records and death registries. RESULTS: During a median follow-up period of 7.0 years, a total of 13,167 participants developed CVD, and 1,079 participants died of CVD. Compared with a sleep duration 7-9 hours/day, an accelerometer-measured sleep duration <7 hours/day but not >9 hours/day was associated with higher risks of incident CVD (HR 1.06, 95% CI: 1.02-1.10), CVD-related mortality (HR 1.29, 95% CI: 1.14-1.47), coronary heart disease (HR 1.11, 95% CI: 1.03-1.19), myocardial infarction (HR 1.14, 95% CI: 1.03-1.27), heart failure (HR 1.20, 95% CI: 1.08-1.34), and atrial fibrillation (HR 1.15, 95% CI: 1.07-1.24). A curvilinear dose‒response pattern was observed between accelerometer-measured sleep durations and incident CVD (Poverall<0.001), with L-shaped associations found for incident CVD and CVD-related mortality. CONCLUSIONS: An accelerometer-measured sleep duration <7 hours/day but not >9 hours/day was associated with elevated risks of incident CVD and CVD-related mortality. Maintaining adequate sleep may help promote cardiovascular 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 (DMCs) among individuals with type 2 diabetes mellitus (T2DM) and compare these associations versus 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 DMCs at baseline. EXPOSURE: Social isolation and loneliness were measured using self-reported questionnaires. OUTCOME: The incidence of DMCs 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 experience DMCs (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 DMCs comparable to those of 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 DMCs 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 DMCs. PLAIN-LANGUAGE SUMMARY: Social isolation and loneliness are important social determinants that are associated with adverse cardiometabolic health. Individuals with diabetes are particularly vulnerable to social isolation and loneliness. However, the relationship of social isolation or loneliness with diabetic microvascular complications (DMCs) remains unclear. Our study used the UK Biobank study data to investigate the associations of social isolation and loneliness with the development of DMCs. We found that social isolation and loneliness were independently associated with a higher risk of incident DMCs. Remarkably, their association with DMCs was comparable to those of other lifestyle factors such as smoking, blood pressure, and physical activity. These findings collectively imply that social isolation and loneliness are 2 important potentially modifiable risk factors for DMCs among individuals with type 2 diabetes mellitus.

Visuospatial dysfunction predicts dementia-first phenoconversion in isolated REM sleep behaviour disorder.

OBJECTIVE: While isolated rapid eye movement sleep behaviour disorder (iRBD) is known as a prodrome of α-synucleinopathies, the prediction for its future phenoconversion to parkinsonism-first or dementia-first subtype remains a challenge. This study aimed to investigate whether visuospatial dysfunction predicts dementia-first phenoconversion in iRBD. METHODS: Patients with iRBD and control subjects were enrolled in this prospective cohort study. Baseline neuropsychological assessment included the Unified Parkinson's Disease Rating Scale part III, Montreal Cognitive Assessment (MoCA), Rey-Osterrieth complex figure (ROCF), Colour Trails test (CTT), Farnsworth-Munsell 100-hue test and Digit Span test. The anterior and posterior subscores of MoCA as well as their modified versions were explored. A composite score derived from ROCF and CTT was also explored. Regular follow-up was conducted to determine the phenoconversion status of iRBD patients. RESULTS: The study included 175 iRBD patients and 98 controls. During a mean follow-up of 5.1 years, 25.7% of patients experienced phenoconversion. Most of the neuropsychological tests could differentiate dementia-first but not parkinsonism-first convertors from non-convertors. The modified posterior subscore of MoCA, by integrating the Alternating Trail Making and Clock Drawing components into original the posterior subscore, which mainly reflects visuospatial function, was the strongest predictor for dementia-first phenoconversion (adjusted HR 5.48, 95% CI 1.67 to 17.98). CONCLUSION: Visuospatial dysfunction, as reflected mainly by the modified posterior subscore of MoCA, is a predictive factor for dementia-first phenoconversion in iRBD, suggesting its potential for being a biomarker for clinical prognostic prediction and potential neuroprotective trials aiming to delay or prevent dementia.

Multidimensional water level and water quality response to severe drought in Xingyun Lake.

Drought stress has a significant impact on the quality and quantity of lake water. Understanding this impact is crucial for preventing water security risks and pollution recovery. However, there is a lack of systemic understanding of how drought affects water quality and quantity, and how they change in multiple dimensions. This manuscript established a synthesized methodology with the principles to judge the applicability and three steps of application to detect the change in water quality and water level under severe drought in Xingyun Lake, China. Results show that (1) The water level and water quality of Xingyun Lake have a synchronous and evident response to drought during 2009-2014. The rainfall during 2008-2015 declined by 22.9 % to normal, and the inundated area and lake water depth in 2012 decreased by 10.50 % from 2002 to 1.38 m to the average depth, respectively. The pollution index climbed above 1.21 after 2008, fluctuating around 1.42. (2) Under drought, the water quality indicators significantly changed in the terms of the overall feature, trend, eigenvalue, and morphological characteristics. The water quality indicators of Set2008-2015 are significantly different from set2000-2007 and not in the groups of set1994-2000. The morphological characteristics of water quality indicators in set2008-2015 differs significantly from that in set2000-2007 shown by the minimum, maximum, median, quartiles, and extreme values. (3) Although NH3-N showed no significant change, the water quality deteriorated in the physical, chemical, and biological aspects. The TP, IMN, and BOD5 changed more evidently than DO and NH3-N. (4) Water quality grade and indicator concentration deteriorated significantly and sharply under severe drought and are threatened deeply by TP and TN. The synthesized methodology is scientifically constructed and canbe employed in the characteristics cognition of water quality and water level to severe drought in and out of this research. And the intervention time and various regulating measures for pollution degradation and water quality recovery canbe constructed based on the multi-dimensional analysis of water quality change under drought evolution.

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.

Life's Essential 8 and risks of cardiovascular morbidity and mortality among individuals with type 2 diabetes: A cohort study.

BACKGROUND: The association of cardiovascular health levels, as measured by the Life's Essential 8 score, with cardiovascular disease (CVD) incidence and mortality among individuals with type 2 diabetes (T2D) has not been fully elucidated. METHODS: This cohort study included 15,118 participants with T2D from the UK Biobank who were free of CVD and cancer at baseline. The cardiovascular health of participants was evaluated using the Life's Essential 8 score, categorizing their health levels into low, moderate, and high based on this assessment. RESULTS: During a median follow-up period of 13.0 years, we observed a total of 4421 cases of CVD, comprising 3467 cases of coronary heart disease (CHD), 811 cases of stroke, 1465 cases of heart failure (HF), and 523 cases of CVD mortality. Compared to participants with low cardiovascular health, those with high cardiovascular health had a 52 %, 50 %, 47 %, 67 %, and 51 % lower risk of CVD, CHD, stroke, HF, and CVD mortality, respectively. Among the components of the Life's Essential 8 score, body mass index showed the highest population attributable risk of 12.1 %. Similar findings were observed in joint analyses of cardiovascular health and diabetes severity status. CONCLUSIONS: This study emphasizes the importance of maintaining good cardiovascular health among individuals with T2D to reduce their risk of CVD incidence and mortality.

Circadian rhythm dysfunction and psychopathology in the offspring of parents with bipolar disorder: a high-risk study in the Chinese population.

Background: Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder. Nevertheless, some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited. Aims: To examine the prevalence rates of sleep and circadian dysfunctions, mental disorders and their symptoms in the offspring of parents with (O-BD) and without bipolar disorder (O-control). Methods: The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area, China. The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders, and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, respectively. Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring. Results: Adjusting for age, sex and region of recruitment, there was a significantly higher risk of delayed sleep phase symptoms (9.55% vs 2.58%, adjusted OR: 4.04) in O-BD than in O-control. O-BD had a nearly fivefold higher risk of mood disorders (11.70% vs 3.47%, adjusted OR: 4.68) and social anxiety (6.28% vs 1.49%, adjusted OR: 4.70), a fourfold higher risk of depressive disorders (11.17% vs 3.47%, adjusted OR: 3.99) and a threefold higher risk of mood symptoms (20.74% vs 10.40%, adjusted OR: 2.59) than O-control. Subgroup analysis revealed that O-BD children (aged under 12 years) had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control, while there was a nearly 4-fold higher risk of delayed sleep phase symptoms, a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents (aged 12 years and over). Conclusions: There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterparts, confirming the central role of circadian rhythm dysfunction in bipolar disorder. The findings of the specific age-related and stage-related developmental patterns of psychopathologies and circadian dysfunction in children and adolescent offspring of parents with bipolar disorder paved the way to develop specific and early clinical intervention and prevention strategies. Trial registration number: NCT03656302.

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.

Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

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.

Effects of cognitive behavioural therapy and bright light therapy for insomnia in youths with eveningness: study protocol for a randomised controlled trial.

BACKGROUND: Insomnia and eveningness are common and often comorbid conditions in youths. While cognitive behavioural therapy for insomnia (CBT-I) has been suggested as a promising intervention, it remains unclear whether it is sufficient to also address circadian issues in youths. In addition, despite that light has been shown to be effective in phase-shifting one's circadian rhythm, there has been limited data on the effects of bright light therapy and its combination with CBT-I on sleep and circadian outcomes in youths. The current protocol outlines a randomised controlled trial that examines the efficacy of CBT-I and CBT-I plus bright light therapy (BLT) in reducing insomnia severity, improving mood symptoms and daytime functioning (e.g. sleepiness, fatigue, cognitive function), and improving subjective and objective sleep and circadian measures compared to a waitlist control group. METHODS: We will carry out a randomised controlled trial (RCT) with 150 youths aged 12-24 who meet the criteria of insomnia and eveningness. Participants will be randomised into one of three groups: CBT-I with bright light therapy, CBT-I with placebo light, and waitlist control. Six sessions of CBT-I will be delivered in a group format, while participants will be currently asked to use a portable light device for 30 min daily immediately after awakening throughout the intervention period for bright light therapy. The CBT-I with light therapy group will receive bright constant green light (506 lx) while the CBT-I with placebo light group will receive the modified light device with the LEDs emitting less than 10 lx. All participants will be assessed at baseline and post-treatment, while the two active treatment groups will be additionally followed up at 1 month and 6 months post-intervention. The primary outcome will be insomnia severity, as measured by the Insomnia Severity Index. Secondary outcomes include self-reported mood, circadian, daytime functioning, and quality of life measures, as well as sleep parameters derived from actigraphy and sleep diary and neurocognitive assessments. Objective measures of the circadian phase using dim-light melatonin onset assessment and sleep parameters using polysomnography will also be included as the secondary outcomes. DISCUSSION: This study will be the first RCT to directly compare the effects of CBT-I and BLT in youths with insomnia and eveningness. Findings from the study will provide evidence to inform the clinical management of insomnia problems and eveningness in youths. TRIAL REGISTRATION: ClinicalTrials.gov NCT04256915. Registered on 5 February 2020.

Birth weight, ideal cardiovascular health metrics in adulthood, and incident cardiovascular disease.

BACKGROUND: Prenatal and postnatal factors may have joint effects on cardiovascular health, and we aimed to assess the joint association of birth weight and ideal cardiovascular health metrics (ICVHMs) prospectively in adulthood with incident cardiovascular disease (CVD). METHODS: In the UK Biobank, 227,833 participants with data on ICVHM components and birth weight and without CVD at baseline were included. The ICVHMs included smoking, body mass index, physical activity, diet information, total cholesterol, blood pressure, and hemoglobin A1c. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) in men and women. RESULTS: Over a median follow-up period of 13.0 years (2,831,236 person-years), we documented 17,477 patients with incident CVD. Compared with participants with birth weights of 2.5-4.0 kg, the HRs (95% CIs) of CVD among those with low birth weights was 1.08 (1.00-1.16) in men and 1.23 (1.16-1.31) in women. The association between having a birth weight <2.5 kg and CVD risk in men was more prominent for those aged <50 years than for those of older age ( P for interaction = 0.026). Lower birth weight and non-ideal cardiovascular health metrics were jointly related to an increased risk of CVD. Participants with birth weights <2.5 kg and ICVHMs score 0-1 had the highest risk of incident CVD (HR [95% CI]: 3.93 [3.01-5.13] in men; 4.24 [3.33-5.40] in women). The joint effect (HR [95% CI]: 1.36 [1.17-1.58]) could be decomposed into 24.7% (95% CI: 15.0%-34.4%) for a lower birth weight, 64.7% (95% CI: 56.7%-72.6%) for a lower ICVHM score, and 10.6% (95% CI: 2.7%-18.6%) for their additive interaction in women. CONCLUSIONS: Birth weight and ICVHMs were jointly related to CVD risk. Attaining a normal birth weight and ideal ICVHMs may reduce the risk of CVD, and a simultaneous improvement of both prenatal and postnatal factors could further prevent additional cases in women.

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.