Smoking Timing, Healthy Diet, and Risk of Incident CKD Among Smokers: Findings From UK Biobank.

RATIONALE & OBJECTIVE: While smoking is a recognized risk factor for chronic kidney disease (CKD), the relationship between the time smoking is initiated after awakening each day and CKD remains largely unstudied. This study examined the association between this timing and the risk of CKD, and the potential interactions of smoking timing with other risk factors for the occurrence of CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A total of 32,776 participants in the UK Biobank with complete data on the time from waking to the first cigarette and free of prevalent CKD were included. EXPOSURE: Time from waking to the first cigarette. OUTCOME: Incident CKD cases. ANALYTICAL APPROACH: Cox proportional hazards regression was used to investigate the associations between the time smoking is initiated each day and the risk of CKD. The potential interactions of smoking timing with risk factors in relationship to CKD risk were assessed on both multiplicative and additive scales. RESULTS: During a median follow-up of 12 years, 940 incident CKD cases occurred. Shorter durations of time from waking to the first cigarette were associated with a higher risk of incident CKD (P-trend=0.01). Compared to >120 minutes, the adjusted hazard ratio (HR) associated with smoking timing was 1.28 (95% CI: 0.92-1.80) for 61-120 minutes, 1.48 (95% CI: 1.11-1.96) for 30-60 minutes, 1.36 (95% CI: 1.01-1.88) for 5-15 minutes, and 1.70 (95% CI: 1.22-2.37) for <5 minutes, respectively. Furthermore, there was a significant additive interaction and multiplicative interactions between the timing of smoking and a healthy diet score (P for additive interaction=0.01, P for multiplicative interaction=0.004). LIMITATIONS: Generalizability; Possible residual confounding limiting causal inference. CONCLUSION: These findings reveal a significant association between the shorter time from waking to the first cigarette and a higher CKD risk. The magnitude of these associations were greater in the setting of an unhealthy diet.

Loneliness, social isolation and incident chronic kidney disease among patients with diabetes.

Background: Individuals with diabetes have a significantly higher risk of developing chronic kidney disease (CKD) and higher levels of social isolation and loneliness compared with those without diabetes. Recently, the American Heart Association highlighted the importance of considering social determinants of health (SDOH) in conjunction with traditional risk factors in patients with diabetes. Aims: To investigate the associations of loneliness and social isolation with incident CKD risk in patients with diabetes in the UK Biobank. Methods: A total of 18 972 patients with diabetes were included in this prospective study. Loneliness and Social Isolation Scales were created based on self-reported factors. An adjusted Cox proportional hazard model was used to investigate the associations of loneliness and social isolation with CKD risk among patients with diabetes. The relative importance in predicting CKD was also calculated alongside traditional risk factors. Results: During a median follow-up of 10.8 years, 1127 incident CKD cases were reported. A higher loneliness scale, but not social isolation, was significantly associated with a 25% higher risk of CKD, independent of traditional risk factors, among patients with diabetes. Among the individual loneliness factors, the sense of feeling lonely emerged as the primary contributing factor to the elevated risk of CKD. Compared with individuals not experiencing feelings of loneliness, those who felt lonely exhibited a 22% increased likelihood of developing CKD. In addition, feeling lonely demonstrated greater relative importance of predicting CKD compared with traditional risk factors such as body mass index, smoking, physical activity and diet. Conclusions: This study indicates the significant relationship between loneliness and CKD risk among patients with diabetes, highlighting the need to address SDOH in preventing CKD in this population.

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.

Analyzing greenhouse gas emissions and influencing factors of 247 actual wastewater treatment plants in China using emission factor and operational data integrated methods (ODIM).

In response to China's policies on pollution control and carbon emission (CE) reductions, more stringent regulations have been implemented to evaluate CE in wastewater treatment facilities. In this study, we have analyzed CE from China's wastewater treatment plants (WWTPs) and influencing factor. Emission factor (EF) and operational data integrated methods (ODIM) were utilized to measure emissions, using data collected from 247 WWTPs over a 1-year period across seven regions in China. The average CE intensity was 0.45 kgCO2-eq/m3, affected by region, season, influent water quality, treatment processes, effluent discharge standards, and facilities. The scale effect was obvious only in the range of 2 × 105 m3/day. Underground WWTPs exhibited significantly higher CE compared to aboveground WWTPs. In summary, the assessment of CE in 247 actual WWTPs not only identifies emission reduction potential but also provides a scientific basis for formulating targeted emission reduction measures.

Enrichment methods of N-linked glycopeptides from human serum or plasma: A mini-review.

Human diseases often correlate with changes in protein glycosylation, which can be observed in serum or plasma samples. N-glycosylation, the most common form, can provide potential biomarkers for disease prognosis and diagnosis. However, glycoproteins constitute a relatively small proportion of the total proteins in human serum and plasma compared to the non-glycosylated protein albumin, which constitutes the majority. The detection of microheterogeneity and low glycan abundance presents a challenge. Mass spectrometry facilitates glycoproteomics research, yet it faces challenges due to interference from abundant plasma proteins. Therefore, methods have emerged to enrich N-glycans and N-linked glycopeptides using glycan affinity, chemical properties, stationary phase chemical coupling, bioorthogonal techniques, and other alternatives. This review focuses on N-glycans and N-glycopeptides enrichment in human serum or plasma, emphasizing methods and applications. Although not exhaustive, it aims to elucidate principles and showcase the utility and limitations of glycoproteome characterization.

Smoking timing, genetic susceptibility and the risk of incident type 2 diabetes: A cohort study from the UK Biobank.

AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.

Isotemporal Substitution Modeling on Sedentary Behaviors and Physical Activity With Mortality Among People With Different Diabetes Statuses: A Prospective Cohort Study From the National Health and Nutrition Examination Survey Analysis 2007-2018.

BACKGROUND: To assess the associations of replacing sedentary behavior with different types of physical activity with mortality among the US adults of varying diabetes statuses. METHODS: This prospective cohort study included 21,637 participants (mean age, 48.5 y) from the National Health and Nutrition Examination Survey 2007-2018. Physical activity including leisure-time moderate-vigorous-intensity activity (MVPA), walking/bicycling, worktime MVPA, and sedentary behavior. We conducted an isotemporal substitution analysis using Cox regression to estimate the associations between replacements and mortality risks. RESULTS: We found significant protective associations between replacing 30 minutes per day sedentary behavior with 3 types of physical activity and all-cause, cardiovascular disease (CVD) mortality risk (except worktime MVPA for CVD mortality) among total participants, with hazard ratio (HR; 95% confidence interval [CI]) ranging from 0.86 (0.77-0.95) to 0.96 (0.94-0.98). Among participants with diagnosed diabetes, replacing sedentary behavior with leisure-time MVPA was associated with a lower all-cause mortality risk (HR 0.81, 95% CI, 0.70-0.94), which was also observed in other subgroups, with HRs (95% CI) ranging from 0.87 (0.80-0.94) to 0.89 (0.81-0.99). Among those with prediabetes/undiagnosed diabetes, replacing sedentary behavior with walking/bicycling was associated with lower CVD mortality risk, and replacement to work-time MVPA was associated with lower all-cause and CVD mortality risk, with HRs (95% CI) ranging from 0.72 (0.63-0.83) to 0.96 (0.92-0.99). CONCLUSIONS: Replacing sedentary behaviors with 30 minutes per day leisure-time MVPA was associated with lower all-cause mortality, regardless of diabetes statuses. Among people with prediabetes/undiagnosed diabetes, walking/bicycling was additionally associated with lower CVD mortality, and worktime MVPA was associated with lower all-cause and CVD mortality.

Adherence to a healthy lifestyle including sleep and sedentary behaviors and risk of metabolic dysfunction-associated steatotic liver disease in Chinese adults.

OBJECTIVE: Various lifestyle factors including smoking, alcohol, physical activity, sedentary behavior, diet quality, sleep behavior, and overweight have been related to metabolic dysfunction-associated steatotic liver disease (MASLD); however, their joint impact on risk of MASLD is not well known. We prospectively investigated the association between a combination of lifestyle factors and risk of MASLD. METHODS: This prospective cohort study included 13,303 participants (mean age: 39.1 ± 11.3 years, female: 60.1%) in China. A novel healthy lifestyle score was created combining seven healthy factors: not smoking, no alcohol intake, regular physical activity, short sedentary time, healthy diet, healthy sleep, and healthy weight. Incident MASLD cases were ascertained annually by liver ultrasound and cardiometabolic risk factors. Multivariable Cox proportional hazards regression models were used to estimate the association of healthy lifestyle score with risk of MASLD. RESULTS: Within 48,036 person-years of follow-up, 2823 participants developed MASLD. After adjusting for age, sex, education, occupation, household income, personal and family history of disease, and total energy intake, compared with participants with 0-2 healthy lifestyle factors, the multivariable hazard ratios (95% confidence interval) of MASLD were 0.81 (0.73, 0.89), 0.67 (0.61, 0.75), and 0.55 (0.49, 0.62) for healthy lifestyle score of 3, 4, and 5-7, respectively (P for trend <0.0001). Such associations were consistent across subgroup and sensitivity analyses. CONCLUSION: Our results indicate that a higher healthy lifestyle score is associated with a lower risk of MASLD.

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.

Degree of joint risk factor control and hazard of mortality in diabetes patients: a matched cohort study in UK Biobank.

BACKGROUND: Diabetes patients are at higher risk for mortality than the general population; however, little is known about whether the excess mortality risk associated with diabetes could be mitigated or nullified via controlling for risk factors. METHODS: We included 18,535 diabetes patients and 91,745 matched individuals without diabetes without baseline cancer or cardiovascular disease (CVD), followed up from 2006 to 2021. The main exposure was the number of optimized risk factors including glycated hemoglobin < 53 mmol/mole, systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, no albuminuria, non-current smoking and low-density lipoprotein cholesterol (LDL-C) < 2.5 mmol/L. We used Cox proportional hazards models to explore the association of the degree of risk factor control with all-cause mortality, cancer mortality, CVD mortality and other mortality. RESULTS: Each additional risk factor control was associated with a 16, 10, 21 and 15% lower risk of all-cause mortality, cancer mortality, CVD mortality and other mortality, respectively. Optimal risk factors control (controlling 5 risk factors) was associated with a 50% (HR 0.50, 95% CI 0.41-0.62), 74% (HR 0.26, 95% CI 0.16-0.43) and 38% (HR 0.62, 95% CI 0.44-0.87) lower risk of all-cause mortality, CVD mortality and other mortality, respectively. Diabetes patients with 4, 3 and 5 or more controlled risk factors, respectively, showed no excess risk of all-cause mortality, cancer mortality and CVD mortality compared to matched non-diabetes patients. CONCLUSIONS: The results from this study indicate that optimal risk factor control may eliminate diabetes-related excess risk of all-cause mortality, CVD mortality and other mortality.

Assessing the impact of type 2 diabetes on mortality and life expectancy according to the number of risk factor targets achieved: an observational study.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of premature death. Whether multifactorial risk factor modification could attenuate T2D-related excess risk of death is unclear. We aimed to examine the association of risk factor target achievement with mortality and life expectancy among patients with T2D, compared with individuals without diabetes. METHODS: In this longitudinal cohort study, we included 316 995 participants (14 162 with T2D and 302 833 without T2D) free from cardiovascular disease (CVD) or cancer at baseline between 2006 and 2010 from the UK Biobank. Participants with T2D were categorised according to the number of risk factors within target range (non-smoking, being physically active, healthy diet, guideline-recommended levels of glycated haemoglobin, body mass index, blood pressure, and total cholesterol). Survival models were applied to calculate hazard ratios (HRs) for mortality and predict life expectancy differences. RESULTS: Over a median follow-up of 13.8 (IQR 13.1-14.4) years, deaths occurred among 2105 (14.9%) participants with T2D and 18 505 (6.1%) participants without T2D. Compared with participants without T2D (death rate per 1000 person-years 4.51 [95% CI 4.44 to 4.57]), the risk of all-cause mortality among those with T2D decreased stepwise with an increasing number of risk factors within target range (0-1 risk factor target achieved: absolute rate difference per 1000 person-years 7.34 [4.91 to 9.78], HR 2.70 [2.25 to 3.25]; 6-7 risk factors target achieved: absolute rate difference per 1000 person-years 0.68 [-0.62 to 1.99], HR 1.16 [0.93 to 1.43]). A similar pattern was observed for CVD and cancer mortality. The association between risk factors target achievement and all-cause mortality was more prominent among participants younger than 60 years than those 60 years or older (P for interaction = 0.012). At age 50 years, participants with T2D who had 0-1 and 6-7 risk factors within target range had an average 7.67 (95% CI 6.15 to 9.19) and 0.99 (-0.59 to 2.56) reduced years of life expectancy, respectively, compared with those without T2D. CONCLUSIONS: Individuals with T2D who achieved multiple risk factor targets had no significant excess mortality risk or reduction in life expectancy than those without diabetes. Early interventions aiming to promote risk factor modification could translate into improved long-term survival for patients with T2D.

Prognostic model revealing pyroptosis-related signatures in oral squamous cell carcinoma based on bioinformatics analysis.

One of the most common oral carcinomas is oral squamous cell carcinoma (OSCC), bringing a heavy burden to global health. Although progresses have been made in the intervention of OSCC, 5 years survival of patients suffering from OSCC is poor like before regarding to the high invasiveness of OSCC, which causes metastasis and recurrence of the tumor. The relationship between pyroptosis and OSCC remains to be further investigated as pyroptosis in carcinomas has gained much attention. Herein, the key pyroptosis-related genes were identified according to The Cancer Genome Atlas (TCGA) dataset. Additionally, a prognostic model was constructed based upon three key genes (CTLA4, CD5, and IL12RB2) through least absolute shrinkage and selection operator (LASSO) analyses, as well as univariate and multivariate COX regression in OSCC. It was discovered that the high expression of these three genes was associated with the low-risk group. We also identified LAIR2 as a hub gene, whose expression negatively correlated with the risk score and the different immune cell infiltration. Finally, we proved that these three genes were independent prognostic factors linked to overall survival (OS), and reliable consequences could be predicted by this model. Our study revealed the relationship between pyroptosis and OSCC, providing insights into new treatment targets for preventing and treating OSCC.

Body composition, lifestyle, and depression: a prospective study in the UK biobank.

BACKGROUND: Obesity has been related to depression and adhering healthy lifestyle was beneficial to lower the risk of depression; however, little is known about the relationship between body composition and fat distribution with depression risk and the influence of body composition and fat distribution on the association of lifestyle and depression. Therefore, we aimed to investigate whether body composition and fat distribution were associated with the adverse events of depression and the relationship between lifestyle and depression. METHODS: We included 330,131 participants without depression at baseline in the UK Biobank (mean age, 56.9 years; 53.83% females). The assessment of depression was sourced from health outcomes across self-report, primary care, hospital inpatient data, and death data. Body composition was determined by bioelectrical impedance. Seven lifestyles (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, healthy sleep pattern, and appropriate social connection) were used to generate a lifestyle score. RESULTS: During a median of 11.7 years of follow-up, 7576 incident depression occurred. All the body composition measures were positively associated with depression risk, with the Hazard ratios (HR) for the uppermost tertile (T3) versus the lowest tertile (T1) ranging from 1.26 (95% CI: 1.15-1.39) for trunk fat-free mass (TFFM) to 1.78 (1.62-1.97) for leg fat percentage (LFP). In addition, we found significant interactions between fat mass-related indices, especially leg fat mass (LFM) (p = 1.65 × 10-9), and lifestyle score on the risk of depression, for which the beneficial associations of a healthy lifestyle with the risk of depression were more evident among participants with low body fat measurement. CONCLUSIONS: High levels of body composition measures were associated with an increased depression risk. Adverse body composition measures may weaken the link between a healthy lifestyle and a reduced risk of depression.

Identification of a Group of Therapeutic Targets and Prognostic Biomarker for Triple Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Mining differentially expressed genes of TNBC is helpful to explore new therapeutic targets. This study aimed to investigate diagnostic biomarker genes in TNBC compared to normal tissue. Additionally, we explored the functions and prognostic value of these key genes as well as potential targeted drugs that could affect these genes. METHODS: Differential gene expression analysis was conducted using the R software with data from the Gene Expression Omnibus (GEO) database. Then, the identified differentially expressed genes (DEGs) were used to construct a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software. The mRNA expression levels of key genes were analyzed using the UALCAN database with data from The Cancer Genome Atlas (TCGA). Enrichment and survival analyses were performed using R software. In addition, potential compounds showing sensitivity to key genes were identified by gene set cancer analysis (GSCA). RESULTS: Compared with normal tissues, a total of 203 DEGs were upregulated in TNBC. These DEGs participated in various biological processes including nuclear division, microtubule binding, cell cycle, and the p53 signaling pathway. Through the PPI network analysis, ten key genes were identified, among which four genes showed significant correlation with poor progression-free interval (PFI) in patients with TNBC. Moreover, the four survival-related genes were found to act as sensitive therapeutic targets. CONCLUSION: The identified four key genes were considered new biomarkers for diagnosis and prognosis and also potential therapeutic targets for TNBC.

Degree of Risk Factor Control and Incident Cardiovascular Diseases in Patients With Hypertension.

OBJECTIVE: To investigate whether joint risk factor control could reduce the excess risk of cardiovascular disease (CVD) in patients with hypertension. PATIENTS AND METHODS: A total of 75,293 patients with diagnosed hypertension from the UK Biobank study were included, matched with 256,619 nonhypertensive controls, and followed up until May 31, 2021. Seven risk factors were measured to define joint risk factor control, including blood pressure, body mass index, low-density lipoprotein cholesterol, hemoglobin A1c, albuminuria, smoking, and physical activity. RESULTS: Among hypertensive patients, 14% to 24% lower risks of CVD outcomes were associated with each additional risk factor control. In the Cox proportional hazards models, adjusted hazard ratios for patients with 6 or more risk factor controls compared with patients having 2 or less risk factor controls were 0.49 (95% CI, 0.45 to 0.55) for CVD, 0.51 (95% CI, 0.45 to 0.57) for coronary heart disease, 0.48 (95% CI, 0.38 to 0.60) for stroke, and 0.34 (95% CI, 0.26 to 0.44) for CVD mortality. The excess risks of CVD outcomes in patients with hypertension were diminished to nonsignificant or even lower compared with controls if achieving 6 or more risk factor controls. Men experienced stronger protective associations of joint risk factor control on risks of CVD than women (P<.001 for interaction). CONCLUSION: The joint risk factor control is associated with lower risks of CVD, and a high degree of risk factor control may considerably attenuate the excess risk of CVD among patients with hypertension.

Improvement of Social Isolation and Loneliness and Excess Mortality Risk in People With Obesity.

Importance: Individuals with obesity experience markedly higher levels of social isolation and loneliness than those without obesity, but little is known about whether improvement of social isolation or loneliness might attenuate obesity-related excess risk of mortality. Objective: To investigate whether improvement of social isolation or loneliness is associated with lower obesity-related excess risk of mortality. Design, Setting, and Participants: This cohort study included individuals without cancer or cardiovascular disease (CVD) at baseline from the UK Biobank with follow-up beginning in March 2006 and ending in November 2021. Main Outcomes and Measures: All-cause, cancer-related, and CVD-related mortality were estimated. Results: A total of 398 972 participants were included in this study (mean [SD] age, 55.85 [8.08] years; 220 469 [55.26%] women; 13 734 [3.44%] Asian, 14 179 [3.55%] multiracial, and 363 685 [91.16%] White participants). Overall, 93 357 (23.40%) had obesity, and 305 615 (76.60%) did not. During a median (IQR) follow-up of 12.73 (12.01-13.43) years, a total of 22 872 incident deaths were recorded. Compared with participants with obesity with an index of 2 or greater for social isolation, the multivariable adjusted hazard ratios (HRs) for all-cause mortality were 0.85 (95% CI, 0.79-0.91) and 0.74 (95% CI, 0.69-0.80) for participants with obesity and a social isolation index of 1 and 0, respectively (P for trend < .001); compared with participants with obesity and an index of 2 for loneliness, the HRs and 0.97 (95% CI, 0.89-1.06) and 0.86 (95% CI, 0.79-0.94) for participants with obesity and a loneliness index of 1 and 0, respectively (P for trend < .001). As the index of social isolation and loneliness went from highest to lowest, the HR for all-cause mortality decreased by 36% and 9%, respectively, in people with obesity compared with people without obesity using the multivariable model. Social isolation was ranked higher than loneliness, depression, anxiety, and lifestyle-related risk factors including alcohol, physical activity, and healthy diet for estimating the risks of all-cause mortality, cancer-related mortality, and CVD-related mortality. Conclusions and Relevance: In this cohort study of UK Biobank participants, a lower index of social isolation or loneliness was associated with a decreased risk of all-cause mortality among people with obesity, and improvement of social isolation and loneliness attenuated obesity-related excess risk of all-cause mortality.

Risk factor control and incident cardiovascular disease in patients with diabetes: Sex-specific relations.

AIM: Women with diabetes are at higher risk of cardiovascular diseases (CVD) than men with diabetes; however, the sex difference in the association between the degree of risk factor control and the risk of CVD in patients with diabetes is unclear. METHODS: In total, 17 260 participants diagnosed with diabetes from the UK Biobank were included and matched with 86 300 non-diabetes controls based on age, sex and assessment centre. The main exposure was the number of risk factors within the target range, including glycated haemoglobin level <53 mol/mol (7%), blood pressure <140/90 mm/Hg, low-density lipoprotein cholesterol <100 mg/dl, non-current smoking and absence of microalbuminuria. RESULTS: During a median follow-up of 13.3 years, a total of 3338 incident CVD cases, including 2807 ischaemic heart disease and 793 strokes, were documented. A more stringent control of risk factors was significantly associated with a lower risk of incident CVD, and such an association was significantly stronger in women than men. Compared with non-diabetes participants, the diabetes-related risk of CVD appeared to be eliminated if more than three risk factors were well controlled among women and men with diabetes. Moreover, clinical biomarkers (e.g. glycated haemoglobin and blood pressure) showed greater relative importance than other factors in women, whereas socio-economic and psychological factors (e.g. education and depression) exhibited similar relative importance to clinical biomarkers in men with diabetes. CONCLUSION: Our findings highlighted the importance of raising awareness of sex differences in the management of CVD risk factors among patients with diabetes.

Associations of healthy aging index and all-cause and cause-specific mortality: a prospective cohort study of UK Biobank participants.

The healthy aging index (HAI) has been recently developed as a surrogate measure of biological age. However, to what extent the HAI is associated with all-cause and cause-specific mortality and whether this association differs in younger and older adults remains unknown. We aimed to quantify the association between the HAI and mortality in a population of UK adults. In the prospective cohort study, data are obtained from the UK Biobank. Five HAI components (systolic blood pressure, reaction time, cystatin C, serum glucose, forced vital capacity) were scored 0 (healthiest), 1, and 2 (unhealthiest) according to sex-specific tertiles or clinically relevant cut-points and summed to construct the HAI (range 0-10). Cox proportional hazard regression models were used to estimate the associations of the HAI with the risk of all-cause and cause-specific mortality. 387,794 middle-aged and older participants were followed up for a median of 8.9 years (IQR 8.3-9.5). A total of 14,112 all-cause deaths were documented. After adjustments, each 1-point increase in the HAI was related to a higher risk of all-cause mortality (hazards ratio [HR], 1.17; 95%CI, 1.15-1.18). Such association was stronger among adults younger than 60 years (1.19, 1.17-1.21) than that among those 60 years and older (1.15, 1.14-1.17) (P interaction < 0.001). For each unit increment of the HAI, the multivariate-adjusted HRs for risk of death were 1.28 (1.25-1.31) for cardiovascular diseases, 1.09 (1.07-1.10) for cancer, 1.36 (1.29-1.44) for digestive disease, 1.42 (1.35-1.48) for respiratory disease, 1.42 (1.33-1.51) for infectious diseases, and 1.15 (1.09-1.21) for neurodegenerative disease, respectively. Our findings indicate that the HAI is positively associated with all-cause and cause-specific mortality independent of chronological age. Our results further underscore the importance of effective early-life interventions to slow aging and prevent premature death.

Identifying Potential Causal Effects of Telomere Length on Health Outcomes: A Phenome-Wide Investigation and Mendelian Randomization Study.

BACKGROUND: Telomere length has been linked to various health outcomes. To comprehensively investigate the causal effects of telomere length throughout the human disease spectrum, we conducted a phenome-wide Mendelian randomization study (MR-PheWAS) and a systematic review of MR studies. METHODS: We conducted a PheWAS to screen for associations between telomere length and 1 035 phenotypes in the UK Biobank (n = 408 354). The exposure of interest was the genetic risk score (GRS) of telomere length. Observed associations passing multiple testing corrections were assessed for causality by 2-sample MR analysis. A systematic review of MR studies on telomere length was performed to harmonize the published evidence and complement our findings. RESULTS: Of the 1 035 phenotypes tested, PheWAS identified 29 and 78 associations of telomere length GRS at a Bonferroni- and false discovery rate-corrected threshold; 24 and 66 distinct health outcomes were causal in the following principal MR analysis. The replication MR using data from the FinnGen study provided evidence of causal effects of genetically instrumented telomere length on 28 out of 66 outcomes, including decreased risks of 5 diseases in respiratory diseases, digestive diseases, and myocardial infarction, and increased risks of 23 diseases, mainly comprised neoplasms, diseases of the genitourinary system, and essential hypertension. A systematic review of 53 MR studies found evidence to support 16 out of the 66 outcomes. CONCLUSIONS: This large-scale MR-PheWAS identified a wide range of health outcomes that were possibly affected by telomere length, and suggested that susceptibility to telomere length may vary across disease categories.

Deciphering resveratrol's role in modulating pathological pain: From molecular mechanisms to clinical relevance.

Pathological pain, a multifaceted and debilitating ailment originating from injury or post-injury inflammation of the somatosensory system, poses a global health challenge. Despite its ubiquity, reliable therapeutic strategies remain elusive. To solve this problem, resveratrol, a naturally occurring nonflavonoid polyphenol, has emerged as a potential beacon of hope owing to its anti-inflammatory, antioxidant, and immunomodulatory capabilities. These properties potentially position resveratrol as an efficacious candidate for the management of pathological pain. This concise review summaries current experimental and clinical findings to underscore the therapeutic potential of resveratrol in pathological pain, casting light on the complex underlying pathophysiology. Our exploration suggests that resveratrol may exert its analgesic effect by the modulating pivotal signaling pathways, including PI3K/Akt/mTOR, TNFR1/NF-κB, MAPKs, and Nrf2. Moreover, resveratrol appears to attenuate spinal microglia activation, regulate primary receptors in dorsal root sensory neurons, inhibit pertinent voltage-gated ion channels, and curb the expression of inflammatory mediators and oxidative stress responses. The objective of this review is to encapsulate the pharmacological activity of resveratrol, including its probable signaling pathways, pharmacokinetics, and toxicology pertinent to the treatment of pathological pain. Hopefully, we aim to map out promising trajectories for the development of resveratrol as a potential analgesic.