Associations of computer gaming with incident dementia, cognitive functions, and brain structure: a prospective cohort study and Mendelian randomization analysis.

BACKGROUND: Computer gaming has recently been suggested to be associated with benefits for cognition, but its impact on incident dementia remains uncertain. We aimed to investigate the observational associations of playing computer games with incident dementia, cognitive functions, and brain structural measures, and further explore the genetic associations between computer gaming and dementia. METHODS: We included 471,346 White British participants without dementia at baseline based on the UK Biobank, and followed them until November 2022. We estimated the risk of dementia using Cox proportional hazard models, and assessed the changes of cognitive functions and brain structural measures using logistic regression models and linear regression models. Mendelian randomization (MR) analyses were performed to examine the association between genetically determined computer gaming and dementia. RESULTS: High frequency of playing computer games was associated with decreased risk of incident dementia (HR, 0.81 [95% CI: 0.69, 0.94]). Individuals with high frequency of playing computer games had better performance in prospective memory (OR, 1.46 [1.26, 1.70]), reaction time (beta, -0.195 [-0.243, -0.147]), fluid intelligence (0.334 [0.286, 0.382]), numeric memory (0.107 [0.047, 0.166]), incorrect pairs matching (-0.253 [-0.302, -0.203]), and high volume of gray matter in hippocampus (0.078 [0.023, 0.134]). Genetically determined high frequency of playing computer games was associated with a low risk of dementia (OR, 0.37 [0.15, 0.91]). CONCLUSIONS: Computer gaming was associated with a decreased risk of dementia, favorable cognitive function, and better brain structure, suggesting that computer gaming could modulate cognitive function and may be a promising target for dementia prevention.

Lower plasma linoleic acids as a risk factor for gout: an integrated analysis of population-based cohort and genetic data.

Background: Gout is a nutrition-related, highly prevalent inflammatory arthritis with undesirable effects on the quality of life. The relationships between circulating fatty acids (FAs) and gout remain poorly understood. Method: We included 268 174 participants with plasma FAs measured using nuclear magnetic resonance at the baseline (2006-2010) from the UK Biobank, of which 15 194 participants had repeated measures of FAs between 2012 and 2013. Cox proportional hazards models were used to assess the association of the baseline and longitudinal changes in relative levels of plasma FAs (% total FAs) with incident gout. Mendelian randomization (MR) analyses were conducted to assess the potential causality of the examined association. Results: Over a median follow-up of 12.8 years, 5160 incident cases of gout occurred. Baseline polyunsaturated fatty acids (PUFAs), n-6 PUFAs, and linoleic acids (LAs) were inversely associated with incident gout (all P-trend values < 0.0001). Baseline monounsaturated fatty acids (MUFAs), n-3 PUFAs, and docosahexaenoic acids (DHAs) were positively associated with incident gout (all P-trend values < 0.0001). Longitudinal increments of n-6 PUFAs and LAs were associated with a lower risk of subsequent gout, whereas an increment of n-3 PUFAs was associated with a higher risk. In two-sample MR analyses, genetically determined higher levels of PUFAs, n-6 PUFAs, and LAs were associated with a decreased risk of gout (all P values < 0.05). Conclusions: Our findings consistently indicate a causal relationship of elevated levels of n-6 PUFAs, especially LAs, with a reduced risk of gout.

Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease.

CONTEXT: Younger women have a slower progressive loss of kidney function than age-matched men and the sex advantage diminishes after menopause, suggesting a role for female hormones in the development of kidney diseases. OBJECTIVE: To examine the relationships of numerous reproductive factors and exogenous hormone use with long-term risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in women. METHODS: A total of 260,108 women without prevalent CKD and ESRD were included. The relationships of various reproductive factors and exogenous hormone use with incident CKD and ESRD were assessed, with multivariable adjustment for potential confounders. RESULTS: During a median of ∼12.5 years of follow-up, 8,766 CKD and 554 ESRD cases were identified. Younger age at first live birth, hysterectomy or bilateral oophorectomy before 50 years old, menopausal before 45 years old, and menopausal hormone therapy (MHT) initiated before 50 years old was associated with a higher risk of CKD. The relationships of these factors with ESRD were generally consistent with those for CKD. Each 5-year increment in menopausal age was associated with an 11% lower risk of CKD (HR = 0.89; 95% CI: 0.87, 0.91) and a 13% lower risk of ESRD (HR = 0.87; 95% CI: 0.79, 0.95). Each 5-year delay in starting MHT was associated with a 13% lower risk of CKD (HR = 0.87; 95% CI: 0.84, 0.90) and a 15% lower risk of ESRD (HR = 0.85; 95% CI: 0.73, 0.99). CONCLUSION: Several reproductive characteristics reflecting shorter cumulative exposure to endogenous estrogen or premature exposure to exogenous hormones are associated with a greater risk of CKD and ESRD in women, supporting a potential role of female hormones in renal pathophysiology.

Lactobacillus rhamnosus GG alleviates radiation-induced intestinal injury by modulating intestinal immunity and remodeling gut microbiota.

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.

Dose-response relationship between physical activity and the morbidity and mortality of cardiovascular disease among individuals with diabetes: A meta-analysis of prospective cohort studies.

BACKGROUND: Diabetes, a chronic condition affecting various organs, is frequently associated with abnormal lipid metabolism, notably increased cholesterol and triglyceride levels. These lipid abnormalities are closely linked to the development and advancement of cardiovascular disease (CVD). Although regular physical activity (PA) has consistently shown benefits in reducing CVD risk in the general population, its precise influence on CVD risk among diabetic patients remains uncertain, particularly regarding dose-response relationships. OBJECTIVE: This study aimed to summarize the evidence from prospective studies on the association between PA and CVD morbidity and mortality in individuals with diabetes, and to explore the optimal levels for public health recommendation. METHODS: We systematically reviewed prospective cohort studies in PubMed, EMBASE, and Web of Science up to December 2022, with inclusion criteria specifying the studies published in English and included adult participants diagnosed with diabetes. A random-effects model was used to pool the relative risk (RR) with the corresponding 95% confidence interval (CI) comparing the highest with the lowest PA categories in each study for qualitative evaluation. In addition, linear and spline regression analyses were used to estimate dose-response associations. RESULTS: The meta-analysis included 12 prospective cohort studies, involving a total of 109,820 participants with diabetes. The combined results revealed that higher levels of PA were associated with a reduced risk of CVD. The RR of CVD for the highest compared with the lowest PA category was 0.62 (95% CI, 0.51-0.73). In addition, there were four studies describing leisure-time physical activity (LTPA) and the pooled RR was 0.68 (95% CI, 0.52-0.83) for the highest versus the lowest activity. The linear regression model revealed that each 10 MET-h/week of incrementally higher PA was associated with a 19.0% (95% CI, 11.6%-25.7%) and a 6.9% (95% CI, 4.5%-9.3%) reduction in CVD morbidity and mortality. Additionally, spline regression curves showed nonlinear relationships between PA levels and the risk of CVD and CVD mortality (both P-nonlinearity <0.001), with a limited reduction in CVD risk and some further reduction in CVD mortality above 20 MET-h per week of PA levels. CONCLUSIONS: For patients with diabetes, especially type 2 diabetes, there was a dose-response relationship between increased PA and reduced risk of CVD morbidity and mortality. The observed PA threshold is consistent with the recommended level for the general population. Gradually moving from inactivity to a guideline-recommended PA level could therefore significantly reduce the burden of CVD in patients with diabetes.

Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults.

BACKGROUND: Sedentary behavior has been demonstrated to be a modifiable factor for several chronic diseases, while coffee consumption is believed to be beneficial for health. However, the joint associations of daily sitting time and coffee consumption with mortality remains poorly understood. This study aimed to evaluate the independent and joint associations of daily sitting time and coffee intakes with mortality from all-cause and cardiovascular disease (CVD) among US adults. METHODS: An analysis of a prospective cohort from the 2007-2018 National Health and Nutrition Examination Survey of US adults (n = 10,639). Data on mortality were compiled from interview and physical examination data until December 31, 2019. Daily sitting time was self-reported. Coffee beverages were from the 24-hour diet recall interview. The main outcomes of the study were all-cause and cardiovascular disease mortality. The adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. RESULTS: Among 10,639 participants in the study cohort, there were 945 deaths, 284 of whom died of CVD during the follow-up period of up to 13 years. Multivariable models showed that sitting more than 8 h/d was associated with higher risks of all-cause (HR, 1.46; 95% CI, 1.17-1.81) and CVD (HR, 1.79; 95% CI, 1.21-2.66) mortality, compared with those sitting for less than 4 h/d. People with the highest quartile of coffee consumption were observed for the reduced risks of both all-cause (HR, 0.67; 95% CI, 0.54-0.84) and CVD (HR, 0.46; 95% CI, 0.30-0.69) mortality compared with non-coffee consumers. Notably, joint analyses firstly showed that non-coffee drinkers who sat six hours or more per day were 1.58 (95% CI, 1.25-1.99) times more likely to die of all causes than coffee drinkers sitting for less than six hours per day, indicating that the association of sedentary with increased mortality was only observed among adults with no coffee consumption but not among those who had coffee intake. CONCLUSIONS: This study identified that sedentary behavior for more than 6 h/d accompanied with non-coffee consumption, were strongly associated with the increased risk of mortality from all-cause and CVD.

Genetic Subtypes of Prediabetes, Healthy Lifestyle, and Risk of Type 2 Diabetes.

Prediabetes is a heterogenous metabolic state with various risks for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latino participants without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic White participants without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing various pathways related to T2D. Consensus clustering was performed in participants with prediabetes in HCHS/SOL (n = 3,677) and UKBB (n = 16,284) separately based on these pPRSs. Six clusters of individuals with prediabetes with distinctive patterns of pPRSs and corresponding metabolic traits were identified in the HCHS/SOL, five of which were confirmed in the UKBB. Although baseline glycemic traits were similar across clusters, individuals in cluster 5 and cluster 6 showed an elevated risk of T2D during follow-up compared with cluster 1 (risk ratios [RRs] 1.29 [95% CI 1.08, 1.53] and 1.34 [1.13, 1.60], respectively). Inverse associations between a healthy lifestyle score and risk of T2D were observed across different clusters, with a suggestively stronger association observed in cluster 5 compared with cluster 1. Among individuals with a healthy lifestyle, those in cluster 5 had a similar risk of T2D compared with those in cluster 1 (RR 1.03 [0.91, 1.18]). This study identified genetic subtypes of prediabetes that differed in risk of progression to T2D and in benefits from a healthy lifestyle.

Microvascular burden and long-term risk of stroke and dementia in type 2 diabetes mellitus.

OBJECTIVE: To examine the associations between microvascular disease (MVD) and risk of stroke, dementia, and their major subtypes among individuals with type 2 diabetes mellitus (T2DM). METHODS: We included 26,173 participants with T2DM from the UK Biobank who had no known stroke or dementia at baseline. MVD burden was reflected by the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidential intervals (CIs) of stroke and dementia associated with overall MVD burden and individual MVD. RESULTS: During a median follow-up of 11.5 years, 1103 incident stroke (964 ischemic and 269 hemorrhagic stroke) and 813 incident dementia (312 Alzheimer's disease and 304 vascular dementia) cases were identified. The risk of stroke, dementia, and their major subtypes all increased with an increasing number of MVD (all P-trend <0.001). The adjusted HRs (95 % CIs) comparing three with no MVD were 5.03 (3.16, 8.02) for all stroke, 4.57 (2.75, 7.59) for ischemic stroke, and 6.60 (2.65, 16.43) for hemorrhagic stroke. The corresponding estimates were 4.28 (2.33, 7.86) for all-cause dementia, 6.96 (3.02, 16.01) for Alzheimer's disease, and 3.81 (1.40, 10.42) for vascular dementia. Among the three MVD, chronic kidney disease showed the strongest associations with both stroke subtypes, while peripheral neuropathy was most strongly associated with both dementia subtypes. CONCLUSIONS: Risk of stroke, dementia, and their major subtypes increased with an increasing number of MVD. The associations of individual MVD with stroke and dementia varied substantially by types of MVD.

Relationship of microvascular complications and healthy lifestyle with all-cause and cardiovascular mortality in women compared with men with type 2 diabetes.

BACKGROUND: Sex differences exist in the prevalence of microvascular disease (MVD) and healthy-lifestyle adherence. Whether MVD and healthy lifestyles are associated with mortality risk similarly for women and men who have type 2 diabetes mellitus (T2DM) remains unknown. METHODS: The present study included 9992 women and 15,860 men with T2DM from the UK Biobank. MVDs included retinopathy, peripheral neuropathy, and chronic kidney disease. Healthy lifestyle factors consisted of ideal BMI, nonsmoking, healthy diet, regular exercise, and appropriate sleep duration. Sex-specific hazard ratios (HRs) of mortality associated with the MVDs or healthy lifestyles were calculated and women-to-men ratio of HRs (RHR) were further estimated, after multivariable adjustment for potential confounders. RESULTS: During a median of 12.7 years of follow-up, 4346 (1202 in women) all-cause and 1207 (254 in women) CVD deaths were recorded. The adjusted HRs (95% CI) of all-cause mortality for 1 additional increment of the MVDs were 1.71 (1.55, 1.88) for women and 1.48 (1.39, 1.57) for men, with an RHR of 1.16 (1.03, 1.30). The corresponding RHR was 1.36 (1.09, 1.69) for cardiovascular mortality. Adhering to a healthy lifestyle (≥4 vs. ≤1 lifestyle factor) was associated with an approximately 60%-70% lower risk of all-cause and cardiovascular mortality without sex differences (P-interaction >0.70). Furthermore, as compared with having no MVD and an unfavorable lifestyle, having ≥2 MVDs but a favorable lifestyle was not associated with a higher risk of all-cause mortality either in women (HR = 0.88; 95% CI: 0.49, 1.60) or in men (HR = 0.95; 95% CI: 0.64, 1.40), similarly when considering cardiovascular mortality. CONCLUSIONS: In T2DM, while MVDs are more strongly associated with mortality risk in women than in men, adhering to a favorable lifestyle is associated with a substantially lower risk of mortality and may eliminate the detrimental impact of MVDs in both sexes.

Microvascular disease, modifiable risk factor profiles and incident arrhythmias in type 2 diabetes.

BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.

Plant-based diets, mediating biomarkers, and mortality risk among adults with diabetes or prediabetes.

Background: A healthy eating pattern characterized by a higher intake of healthy plant foods has been associated with a lower risk of premature mortality, but whether this applies to individuals with varying glycemic status remains unclear. Methods: This study included 4621 participants with diabetes and 8061 participants with prediabetes from the US National Health and Nutrition Examination Survey (2007-2016). Using the dietary data assessed by two 24 h dietary recalls, a healthful plant-based diet index (hPDI) and an unhealthful plant-based diet index (uPDI) were created based on 15 food groups and were assessed for their relationships with mortality risk. Results: Over a median follow-up of 7.2 years, there were 1021 deaths in diabetes and 896 deaths in prediabetes. A higher hPDI (highest vs. lowest quartile) was associated with a 41% (HR = 0.59, 95% CI: 0.49-0.72; P-trend < 0.001) lower risk of all-cause mortality in diabetes and a 31% (HR = 0.69, 95% CI: 0.55-0.85; P-trend < 0.001) lower risk in prediabetes. A higher uPDI was associated with an 88% (HR = 1.88, 95% CI: 1.55-2.28; P-trend < 0.001) higher risk of mortality in diabetes and a 63% (HR = 1.63, 95% CI: 1.33-1.99; P-trend < 0.001) higher risk in prediabetes. Mediation analysis suggested that C-reactive protein and γ-glutamine transaminase explained 6.0% to 10.9% of the relationships between hPDI or uPDI and all-cause mortality among participants with diabetes. Conclusions: For adults with diabetes as well as those with prediabetes, adhering to a plant-based diet rich in healthier plant foods is associated with a lower mortality risk, whereas a diet that incorporates less healthy plant foods is associated with a higher mortality risk.

Microvascular Disease, Cardiovascular Health, and Risk of Coronary Heart Disease in Type 2 Diabetes: A UK Biobank Study.

CONTEXT: The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. OBJECTIVE: To investigate the role of MVD and CVHMs in the development of CHD among T2DM. DESIGN: We included 19,664 participants with T2DM from the UK Biobank who had data on CVH metrics (CVHMs) and were free of CHD during recruitment. CVHMs were defined based on five behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and three biological factors (glycemic control, hyperlipidemia, and hypertension). MVD was defined as the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. HR and 95% CI of CHD were estimated by multivariable Cox regression models. RESULTS: There were 3,252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each of the unfavorable CVHMs was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR=4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. CONCLUSIONS: Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such an association may be amplified by unfavorable CVHMs.

Physical activity and sleep pattern in relation to incident Parkinson's disease: a cohort study.

BACKGROUND: How physical activity (PA) and different sleep traits and overall sleep pattern interact in the development of Parkinson's disease (PD) remain unknown. OBJECTIVE: To prospectively investigate the joint associations of PA and sleep pattern with risk of PD. METHODS: Included were 339,666 PD-free participants from the UK Biobank. Baseline PA levels were grouped into low (< 600 MET-mins/week), medium (600 to < 3000 MET-mins/week) and high (≥ 3000 MET-mins/week) according to the instructions of the UK Biobank. Healthy sleep traits (chronotype, sleep duration, insomnia, snoring, and daytime sleepiness) were scored from 0 to 5 and were categorized into "ideal sleep pattern" (≥ 3 sleep scores) and "poor sleep pattern" (0-2 sleep scores). Hazard ratios (HRs) and 95% confidence intervals (CIs) of PD were estimated by Cox proportional hazards models. RESULTS: During a median of 11.8 years of follow-up, 1,966 PD events were identified. The PD risk was lower in participants with high PA (HR = 0.73; 95% CI: 0.64, 0.84), compared to those with low PA; and participants with ideal sleep pattern also had a lower risk of PD (HR = 0.78; 95% CI: 0.69, 0.87), compared to those with poor sleep pattern. When jointly investigating the combined effect, participants with both high PA and ideal sleep pattern had the lowest risk of incident PD (HR = 0.55; 95% CI: 0.44, 0.69), compared to those with low PA and poor sleep pattern; notably, participants with high PA but poor sleep pattern also gained benefit on PD risk reduction (HR = 0.74; 95% CI: 0.55, 0.99). CONCLUSIONS: Both high PA and ideal sleep pattern were independently associated with lower risk of developing PD, and those with both high PA level and ideal sleep pattern had the lowest risk. Our results suggest that improving PA levels and sleep quality may be promising intervention targets for the prevention of PD.

Secondhand Smoke Exposure and Risk of Dementia in Nonsmokers: A Population-Based Cohort Study.

BACKGROUND: Large population-based prospective studies are necessary to provide clarification on the associations of panoramic secondhand smoking burden, including prenatal and postnatal secondhand smoke (SHS) exposure, with the risk of developing dementia. METHODS: Our study comprised a sample of 353,756 dementia-free individuals from the UK Biobank who were nonsmokers had data on the exposure of maternal smoking as well as SHS exposure in daily life, which was quantified in terms of hours per week (h/week) and whether they lived with household smokers. Multivariable Cox regression models were utilized to analyze the independent and joint associations of maternal smoking and daily life SHS exposure with dementia risk. RESULTS: During a median follow-up of 11.8 years, 4,113 participants developed dementia. Compared with those who lived in the environment without smokers, multivariable-adjusted hazard ratios (HRs) (95% CIs) were 1.11 (1.02, 1.20) and 1.31 (1.13, 1.52) for those who exposed to SHS for >0 but ≤4 h/week and >4 h/week, respectively, and was 1.25 (1.13, 1.39) for those who lived with smokers in the household. A positive history of maternal smoking was associated with a modestly higher risk of dementia (HR = 1.07; 95% CI: 1.01, 1.15). Furthermore, compared with participants with neither history of maternal smoking nor exposure to SHS, a particularly higher risk of dementia was observed among those with both exposures (HR = 1.48; 95% CI: 1.18, 1.86). Additionally, the HR (95% CI) was 1.32 (1.10, 1.59) when comparing participants with a history of maternal smoking who lived with smokers in their households with those who had neither exposures. CONCLUSIONS: Having a history of maternal smoking, longer exposure to SHS, and living with smokers in the household were each associated with an increased risk of developing dementia. Individuals who were simultaneously exposed to maternal smoking and SHS or lived with household smokers had a particularly higher dementia risk.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of intracerebral hemorrhage.

Previous observational studies have reported associations between brain imaging-derived phenotypes (IDPs) and intracerebral hemorrhage (ICH), but the causality between them remains uncertain. We aimed to investigate the potential causal relationship between IDPs and ICH by a two-sample Mendelian randomization (MR) study. We selected genetic instruments for 363 IDPs from a genome-wide association study (GWASs) based on the UK Biobank (n = 33,224). Summary-level data on ICH was derived from a European-descent GWAS with 1,545 cases and 1,481 controls. Inverse variance weighted MR method was applied in the main analysis to investigate the associations between IDPs and ICH. Reverse MR analyses were performed for significant IDPs to examine the reverse causation for the identified associations. Among the 363 IDPs, isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule was identified to be associated with the risk of ICH (OR per 1-SD increase, 4.62 [95% CI, 2.18-9.81], P = 6.63 × 10-5). In addition, the reverse MR analysis indicated that ICH had no effect on ISOVF in the anterior limb of the left internal capsule (beta, 0.010 [95% CI, -0.010-0.030], P = 0.33). MR-Egger regression analysis showed no directional pleiotropy for the association between ISOVF and ICH, and sensitivity analyses with different MR models further confirmed these findings. ISOVF in the anterior limb of the left internal capsule might be a potential causal mediator of ICH, which may provide predictive guidance for the prevention of ICH. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA1c variability: A post hoc analysis of the ACCORD trial.

AIMS: To assess the impact of long-term visit-to-visit variability in HbA1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control. METHODS: Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA1c was defined as the coefficient of variation (CV) across HbA1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy. RESULTS: During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA1c-CV, but increased the risk among those with the highest HbA1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA1c variability. CONCLUSIONS: The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA1c during the treatment process, suggesting the significance of dynamic monitoring of HbA1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA1c variability.

Variant of the lactase LCT gene explains association between milk intake and incident type 2 diabetes.

Cow's milk is frequently included in the human diet, but the relationship between milk intake and type 2 diabetes (T2D) remains controversial. Here, using data from the Hispanic Community Health Study/Study of Latinos, we show that in both sexes, higher milk intake is associated with lower risk of T2D in lactase non-persistent (LNP) individuals (determined by a variant of the lactase LCT gene, single nucleotide polymorphism rs4988235 ) but not in lactase persistent individuals. We validate this finding in the UK Biobank. Further analyses reveal that among LNP individuals, higher milk intake is associated with alterations in gut microbiota (for example, enriched Bifidobacterium and reduced Prevotella) and circulating metabolites (for example, increased indolepropionate and reduced branched-chain amino acid metabolites). Many of these metabolites are related to the identified milk-associated bacteria and partially mediate the association between milk intake and T2D in LNP individuals. Our study demonstrates a protective association between milk intake and T2D among LNP individuals and a potential involvement of gut microbiota and blood metabolites in this association.

General or Central Obesity and Mortality Among US Hispanic and Latino Adults.

Importance: The Hispanic and Latino population is the second largest ethnic group in the US, but associations of obesity parameters with mortality in this population remain unclear. Objective: To investigate the associations of general and central obesity with mortality among US Hispanic and Latino adults. Design, Setting, and Participants: The Hispanic Community Health Study/Study of Latinos is an ongoing, multicenter, population-based cohort study with a multistage probability sampling method performed in Hispanic and Latino adults aged 18 to 74 years with a baseline between January 1, 2008, and December 31, 2011. Active follow-up for this analyses extended from baseline through February 17, 2022. All analyses accounted for complex survey design (ie, stratification and clustering) and sampling weights to generate estimates representing the noninstitutionalized, 18- to 74-year-old Hispanic or Latino populations from selected communities. Exposures: Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), body fat percentage, waist circumference (WC), and waist to hip ratio (WHR). Main Outcome and Measure: Deaths were ascertained via death certificates, the National Death Index, and active follow-up. Results: Of 15 773 adults (mean [SE] age, 40.9 [0.3] years; 52.8% female), 686 deaths occurred during a median (IQR) follow-up of 10.0 (9.9-10.2) years. When adjusting for sociodemographic, lifestyle, and family history covariates, hazard ratios (HRs) for mortality were 1.55 (95% CI, 1.08-2.22) for a BMI of 35.0 or greater vs 18.5 to 24.9, 1.22 (95% CI, 0.92-1.64) for the highest vs lowest body fat percentage groups (defined according to sex-, age-, and Hispanic or Latino background-specific BMI distribution), 1.35 (95% CI, 0.98-1.85) for WC greater than 102 cm (men) or 88 cm (women) vs 94 cm (men) or 80 cm (women) or less, and 1.91 (95% CI, 1.28-2.86) for WHR of 0.90 (men) or 0.85 (women) or greater vs less than 0.90 (men) or 0.85 (women). Only WHR was associated with mortality with additional adjustment for major comorbidities (HR, 1.75; 95% CI, 1.17-2.62). The association of WHR with mortality was stronger among women compared with men (P = .03 for interaction), and the association between BMI and mortality was stronger among men (P = .02 for interaction). The positive association between severe obesity (BMI ≥ 35.0) and mortality was observed only among adults with WHR of 0.90 (men) or 0.85 (women) or greater but not among those with WHR below 0.90 (men) or 0.85 (women) (P = .005 for interaction) who had greater hip circumference. Conclusions and Relevance: In this cohort of US Hispanic and Latino adults, WHR was independently associated with higher all-cause mortality regardless of BMI and prevalent comorbidities. These findings suggest that prioritizing clinical screening and intervention for WHR in this population may be an important public health strategy, with sex-specific strategies potentially being needed.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Association of phthalate exposure with all-cause mortality across renal function status: The U.S. National Health and Nutrition Examination Survey, 2005-2018.

BACKGROUND: Wide phthalate exposure has been associated with both declines in renal function and an elevated risk of mortality. Whether phthalate-associated risk of premature mortality differs by renal function status remains unclear. METHODS: This study included 9605 adults from the U.S. National Health and Nutrition Examination Survey. Urinary concentrations of 11 phthalate metabolites were assessed using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. According to estimated glomerular filtration rate (eGFR), participants were grouped as having normal or modestly declined renal functions, or chronic kidney disease (CKD). Multivariable Cox regression models estimated all-cause mortality associated with phthalate exposure, overall and by renal function status. RESULTS: Overall, Mono-n-butyl phthalate (MnBP), Mono-benzyl phthalate (MBzP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and Mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) were associated with an elevated risk of mortality (P-trend across tertile <0.05). Moreover, significant interactions were observed between eGFR and MEHHP, MEOHP, MECPP, DEHP in the whole population (P for interactions <0.05). After stratification by renal function, total Di (2-ethylhexyl) phthalate (DEHP) was additionally found to be associated with mortality risk in the CKD group (HR = 1.12; 95% CI: 1.01, 1.25). Co-exposure to the 11 phthalate metabolites was associated with a higher risk of all-cause mortality in the CKD (HR = 1.47; 95% CI: 1.18, 1.84) and modestly declined renal function group (HR = 1.25; 95% CI: 1.09, 1.44). CONCLUSIONS: The associations between phthalate exposure and risk of all-cause mortality were primarily observed in CKD patients, reinforcing the need for monitoring phthalate exposure in this patient population.