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Background Models with polygenic risk scores and clinical factors to predict risk of different cancers have been developed, but these models have been limited by the polygenic risk score–derivation methods and the incomplete selection of clinical variables. Methods We used UK Biobank to train the best polygenic risk scores for 8 cancers (bladder, breast, colorectal, kidney, lung, ovarian, pancreatic, and prostate cancers) and select relevant clinical variables from 733 baseline traits through extreme gradient boosting (XGBoost). Combining polygenic risk scores and clinical variables, we developed Cox proportional hazards models for risk prediction in these cancers. Results Our models achieved high prediction accuracy for 8 cancers, with areas under the curve ranging from 0.618 (95% confidence interval = 0.581 to 0.655) for ovarian cancer to 0.831 (95% confidence interval = 0.817 to 0.845) for lung cancer. Additionally, our models could identify individuals at a high risk for developing cancer. For example, the risk of breast cancer for individuals in the top 5% score quantile was nearly 13 times greater than for individuals in the lowest 10%. Furthermore, we observed a higher proportion of individuals with high polygenic risk scores in the early-onset group but a higher proportion of individuals at high clinical risk in the late-onset group. Conclusion Our models demonstrated the potential to predict cancer risk and identify high-risk individuals with great generalizability to different cancers. Our findings suggested that the polygenic risk score model is more predictive for the cancer risk of early-onset patients than for late-onset patients, while the clinical risk model is more predictive for late-onset patients. Meanwhile, combining polygenic risk scores and clinical risk factors has overall better predictive performance than using polygenic risk scores or clinical risk factors alone. [ABSTRACT FROM AUTHOR]

Objective. To explore the associations between metabolic syndrome (MetS) and its individual components and the risk of rheumatoid arthritis (RA). Methods. A total of 369,065 individuals were included in the present study based on the UK Biobank. Multivariable Cox proportional hazards regression models were applied to estimate the associations between MetS and its individual components and the risk of RA. Mediation analysis was performed to further assess the potential mediating role of C-reactive protein (CRP) in the relationship between MetS and RA. Results. During a median follow-up period of 12.04 years, a total of 4901 incident RA cases were documented. MetS (hazard ratio [HR] 1.22, 95% CI 1.14-1.30) and 4 of its 5 components (elevated waist circumference [WC; HR 1.21, 95% CI 1.12-1.32], elevated triglyceride [TG] level [HR 1.12, 95% CI 1.05-1.19], reduced high-density lipoprotein cholesterol [HDL-C] level [HR 1.31, 95% CI 1.23-1.39], and hyperglycemia [HR 1.15, 95% CI 1.05-1.25]) were associated with an increased risk of RA. In addition, the risk of RA increased as the number of diagnosed MetS components increased, with the highest risk in participants with all 5 components. Mediation analysis showed that CRP might mediate the association between MetS and RA, accounting for 9.27% of the total effect. Conclusion. These findings indicated positive associations between MetS and 4 of its components (WC, TG, HDL-C, and hypergly [ABSTRACT FROM AUTHOR]

Importance Knowledge gained from cohort studies has dramatically advanced both public and precision health. The All of Us Research Program seeks to enroll 1 million diverse participants who share multiple sources of data, providing unique opportunities for research. It is important to understand the phenomic profiles of its participants to conduct research in this cohort. Objectives More than 280 000 participants have shared their electronic health records (EHRs) in the All of Us Research Program. We aim to understand the phenomic profiles of this cohort through comparisons with those in the US general population and a well-established nation-wide cohort, UK Biobank, and to test whether association results of selected commonly studied diseases in the All of Us cohort were comparable to those in UK Biobank. Materials and Methods We included participants with EHRs in All of Us and participants with health records from UK Biobank. The estimates of prevalence of diseases in the US general population were obtained from the Global Burden of Diseases (GBD) study. We conducted phenome-wide association studies (PheWAS) of 9 commonly studied diseases in both cohorts. Results This study included 287 012 participants from the All of Us EHR cohort and 502 477 participants from the UK Biobank. A total of 314 diseases curated by the GBD were evaluated in All of Us , 80.9% (N  = 254) of which were more common in All of Us than in the US general population [prevalence ratio (PR) >1.1, P  <   2 × 10−5]. Among 2515 diseases and phenotypes evaluated in both All of Us and UK Biobank, 85.6% (N  = 2152) were more common in All of Us (PR >1.1, P  <   2 × 10−5). The Pearson correlation coefficients of effect sizes from PheWAS between All of Us and UK Biobank were 0.61, 0.50, 0.60, 0.57, 0.40, 0.53, 0.46, 0.47, and 0.24 for ischemic heart diseases, lung cancer, chronic obstructive pulmonary disease, dementia, colorectal cancer, lower back pain, multiple sclerosis, lupus, and cystic fibrosis, respectively. Discussion Despite the differences in prevalence of diseases in All of Us compared to the US general population or the UK Biobank, our study supports that All of Us can facilitate rapid investigation of a broad range of diseases. Conclusion Most diseases were more common in All of Us than in the general US population or the UK Biobank. Results of disease-disease association tests from All of Us are comparable to those estimated in another well-studied national cohort. [ABSTRACT FROM AUTHOR]

Background: While a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types. Method: We conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genomewide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran's Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted. Result: Our study uncovered the causal relationship between specific IgG Nglycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP. Conclusion: This study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management. [ABSTRACT FROM AUTHOR]

Healthy lifestyle might alleviate the socioeconomic inequities in health, but the extent of the joint and interactive effects of these two factors on dementia are unclear. This study aimed to detect the joint and interactive associations of socioeconomic status (SES) and lifestyle factors with incident dementia risk, and the underlying brain imaging alterations. Cox proportional hazards analysis was performed to test the joint and interactive associations. Partial correlation analysis was performed to reflect the brain imaging alterations. A total of 276,730 participants with a mean age of 55.9 (±8.0) years old from UK biobank were included. Over 8.5 (±2.6) years of follow-up, 3013 participants were diagnosed with dementia. Participants with high SES and most healthy lifestyle had a significantly lower risk of incident dementia (HR=0.19, 95% CI=0.14 to 0.26, P<2×10−16), Alzheimer's disease (AD, HR=0.19, 95% CI=0.13 to 0.29, P=8.94×10−15), and vascular dementia (HR=0.24, 95% CI=0.12 to 0.48, P=7.57×10−05) compared with participants with low SES and an unhealthy lifestyle. Significant interactions were found between SES and lifestyle on dementia (P=0.002) and AD (P=0.001) risks; the association between lifestyle and dementia was stronger among those of high SES. The combination of high SES and healthy lifestyle was positively associated with higher volumes in brain regions vulnerable to dementia-related atrophy. These findings suggest that SES and lifestyle significantly interact and influence dementia with its related brain structure phenotypes. [ABSTRACT FROM AUTHOR]

Background: Childhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, including understudied physical health outcomes and bias due to unmeasured confounding. We address these limitations through a large-scale outcome-wide triangulation study. Methods: We performed two outcome-wide analyses (OWAs) in the UK Biobank. First, we examined the relationship between self-reported maltreatment exposure (number of maltreatment types, via Childhood Trauma Screener) and 414 outcomes in a sub-sample of 157,316 individuals using generalized linear models ("observational OWA"). Outcomes covered a broad range of health themes including health behaviors, cardiovascular disease, digestive health, socioeconomic status, and pain. Second, we examined the relationship between a polygenic risk score for maltreatment and 298 outcomes in a non-overlapping sample of 243,006 individuals ("genetic OWA"). We triangulated results across OWAs based on differing sources of bias. Results: Overall, 23.8% of the analytic sample for the observational OWA reported at least one maltreatment type. Of 298 outcomes examined in both OWAs, 25% were significant in both OWAs and concordant in the direction of association. Most of these were considered robust in the observational OWA according to sensitivity analyses and included outcomes such as marital separation (OR from observational OWA, ORo = 1.25 (95% CI: 1.21, 1.29); OR from genetic OWA, ORg = 1.06 (1.03, 1.08)), major diet changes due to illness (ORo = 1.27 (1.24, 1.29); ORg = 1.01 (1.00, 1.03)), certain intestinal diseases (ORo = 1.14 (1.10, 1.18); ORg = 1.03 (1.01, 1.06)), hearing difficulty with background noise (ORo = 1.11 (1.11, 1.12); ORg = 1.01 (1.00, 1.01)), knee arthrosis (ORo = 1.13 (1.09, 1.18); ORg = 1.03 (1.01, 1.05)), frequent sleeplessness (ORo = 1.21 (1.20, 1.23); ORg = 1.02 (1.01, 1.03)), and low household income (ORo = 1.28 (1.26, 1.31); ORg = 1.02 (1.01, 1.03)). Approximately 62% of results were significant in the observational OWA but not the genetic OWA, including numerous cardiovascular outcomes. Only 6 outcomes were significant in the genetic OWA and null in the observational OWA; these included diastolic blood pressure and glaucoma. No outcomes were statistically significant in opposite directions in the two analyses, and 11% were not significant in either OWA. Conclusions: Our findings underscore the far-reaching negative effects of childhood maltreatment in later life and the utility of an outcome-wide triangulation design with sensitivity analyses for improving causal inference. [ABSTRACT FROM AUTHOR]

Background: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF. Methods: We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes. Results: We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05]. Conclusions: We leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies. [ABSTRACT FROM AUTHOR]

Background: Patients with multiple conditions present a growing challenge for healthcare provision. Measures of multimorbidity may support clinical management, healthcare resource allocation and accounting for the health of participants in purpose-designed cohorts. The recently developed Cambridge Multimorbidity scores (CMS) have the potential to achieve these aims using primary care records, however, they have not yet been validated outside of their development cohort. Methods: The CMS, developed in the Clinical Research Practice Dataset (CPRD), were validated in UK Biobank participants whose data is not available in CPRD (the cohort used for CMS development) with available primary care records (n = 111,898). This required mapping of the 37 pre-existing conditions used in the CMS to the coding frameworks used by UK Biobank data providers. We used calibration plots and measures of discrimination to validate the CMS for two of the three outcomes used in the development study (death and primary care consultation rate) and explored variation by age and sex. We also examined the predictive ability of the CMS for the outcome of cancer diagnosis. The results were compared to an unweighted count score of the 37 pre-existing conditions. Results: For all three outcomes considered, the CMS were poorly calibrated in UK Biobank. We observed a similar discriminative ability for the outcome of primary care consultation rate to that reported in the development study (C-index: 0.67 (95%CI:0.66–0.68) for both, 5-year follow-up); however, we report lower discrimination for the outcome of death than the development study (0.69 (0.68–0.70) and 0.89 (0.88–0.90) respectively). Discrimination for cancer diagnosis was adequate (0.64 (0.63–0.65)). The CMS performs favourably to the unweighted count score for death, but not for the outcomes of primary care consultation rate or cancer diagnosis. Conclusions: In the UK Biobank, CMS discriminates reasonably for the outcomes of death, primary care consultation rate and cancer diagnosis and may be a valuable resource for clinicians, public health professionals and data scientists. However, recalibration will be required to make accurate predictions when cohort composition and risk levels differ substantially from the development cohort. The generated resources (including codelists for the conditions and code for CMS implementation in UK Biobank) are available online. [ABSTRACT FROM AUTHOR]

Objective: The occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers. Methods: A total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships. Results: After adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration <10 years or CRP<1.3mg/L or males, IMDs had no effect on incident ALS. Interpretation: Our study provides evidence that previous any IMDs and endocrine-system and the intestinal-system specific IMDs are associated with an increased risk of developing ALS in females, but not in males. [ABSTRACT FROM AUTHOR]

Caspase recruitment domain‐containing protein (CARD)9, CARD10, CARD11, and CARD14 all belong to the CARD‐coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD‐CC/BCL10/MALT1 (CBM) complexes leading to nuclear factor‐kappa‐B (NF‐κB) activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto‐inhibition compared with other CARD‐CC family proteins, with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto‐inhibition of other CARD‐CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, 11, and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF‐κB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease‐associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome‐based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety, and depression, which can occur as comorbidities. [ABSTRACT FROM AUTHOR]

Antipsychotics (APs) are among the most widely prescribed medications, and have been shown to cause cognitive decline. But previous studies on their effects on dementia risk are controversial and scarce. We aimed to examine the relationships of APs exposure with the risk of dementia. Data were obtained from a prospective cohort of 415,100 UK Biobank (UKB) participants. We investigated the effects of APs exposure and their various classes on dementia risk by using multivariable Cox proportional hazard models and further the dose-response effects of oral APs. After a mean follow-up of 8.64 years, 5235 (1.3 %) participants developed all-cause dementia (ACD), among whom 2313 (0.6 %) developed Alzheimer's disease (AD), and 1213 (0.3 %) developed vascular dementia (VaD). Exposure to any APs conferred increased risks of ACD (HR: 1.33, 95 % CI = 1.17–1.51, P < 0.001) and VaD (HR: 1.90, 95 % CI = 1.51–2.40, P < 0.001), but not AD (HR: 1.22, 95 % CI = 1.00–1.48, P = 0.051). Cumulative dose-response relationships of oral APs with the risks of ACD and VaD were observed (P for trend, P < 0.05). Our study is observational and does not show evidence of causality. Since there are relatively few cases of dementia in the UKB, APs exposure may be higher than estimated in our study. APs exposure increased the risk of developing dementia. Dose-response relationships were found between oral APs and dementia risk. Efforts to raise awareness of doctors and patients about this potential drug-related risk are critical to reducing APs use. • Exposure to any antipsychotics (APs) conferred increased risks of dementia. • Cumulative dose-response relationships between oral APs and dementia risk existed. • Both typical and atypical APs increased dementia risk with different effect sizes. • The results were robust across a range of sensitivity analyses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to examine the association of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gammaglutamyl-transferase (GGT), with type 2 diabetes (T2D) risk, particularly their dose-response relationship. Methods: This cross-sectional study enrolled participants aged >20 years old who underwent physical examination at our local hospital from November 2022 to May 2023. A generalized additive model (GAM) was fit to assess the doseresponse relationship between liver enzymes and T2D risk. Furthermore, data from the UK Biobank (n=217,533) and National Health and Nutrition Examination Survey (NHANES 2011-2018; n= 15,528) were analyzed to evaluate whether the dose-response relationship between liver enzymes and T2D differed by population differences. Results: A total of 14,100 participants were included (1,155 individuals with T2D and 12,945 individuals without diabetes) in the analysis. GAM revealed a nonlinear relationship between liver enzymes and T2D risk (Pnon-linear < 0.001). Specifically, T2D risk increased with increasing ALT and GGT levels (range, <50 IU/L) and then plateaued when ALT and GGT levels were >50 IU/L. Elevated AST within a certain range (range, <35 IU/L) decreased the risk of T2D, whereas mildly elevated AST (>35 IU/L) became a risk factor for T2D. The UK Biobank and NHANES data analysis also showed a similar non-linear pattern between liver enzymes and T2D incidence. Conclusion: Liver enzymes were non-linearly associated with T2D risk in different populations, including China, the UK, and the US. Elevated ALT and GGT levels, within a certain range, could increase T2D risk. More attention should be given to liver enzyme levels for early lifestyle intervention and early T2D prevention. Further studies are necessary to explore the mechanism of the nonlinear association between liver enzymes and T2D risk. [ABSTRACT FROM AUTHOR]

Background Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep. Methods We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). Results Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to <2 hours vs <1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs <1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43). Conclusions Of the sleep characteristics studied, higher wakefulness after sleep onset—a measure of poor sleep quality—was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted. [ABSTRACT FROM AUTHOR]

Background: Few studies on the risk of incident major adverse cardiac and cerebrovascular events (MACCEs) in sarcopenia have been reported. The objective was to assess the association between presarcopenia and sarcopenia and a higher risk of MACCEs. Methods: This study on the UK Biobank prospective cohort, used data collected between 2006 and 2021. Community‐dwelling Caucasian participants aged 37 to 73 years were included if values for Handgrip Strength (HGS) and Skeletal Muscle Index (SMI) were available and if no history of MACCEs was reported. Exposure was assessed using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Muscle strength was measured using HGS, and muscle mass using the SMI. Presarcopenia was defined through the two definitions available in the literature, as low HGS with normal SMI and as normal HGS with low SMI, whereas sarcopenia was defined as low HGS with low SMI. The main outcome was to determine whether presarcopenia and/or sarcopenia were predictors of MACCEs (composite events). Results: A total of 406,411 included participants (women: 55.7%) were included. At baseline, there were 18,257 (4.7%) presarcopenics—subgroup n°1 (low HGS only), 7940 (2.1%) presarcopenics—subgroup n°2 (low SMI only), and 1124 (0.3%) sarcopenics. Over a median follow‐up of 12.1 years (IQR: [11.4; 12.8]), 28,300 participants (7.0%) were diagnosed with at least one event. Compared to NonSarc, presarcopenic (subgroups n°1 and n°2) and sarcopenic status were significantly associated with a higher risk of MACCEs (respectively fully adjusted HRs: HR = 1.25 [95% CI: 1.19; 1.31], HR = 1.33 [95% CI: 1.23; 1.45] and HR = 1.62 [95% CI: 1.34; 1.95]). Conclusions: In a community‐dwelling population, the risk of MACCEs was higher in both presarcopenic and sarcopenic participants. See related editorial by Mirzai and Tang in this issue. [ABSTRACT FROM AUTHOR]

Objectives Disorders of immune system may impact cardiovascular health; however, comprehensive study is lacking. We aimed to analyse the association of total and 20 individual immune-mediated diseases (IMDs) with risk of incident cardiovascular disease (CVD). Methods In this prospective cohort study, 414 495 participants (55.6% women; mean age 55.9 years) from UK Biobank with baseline assessment at 2006–10 were included. Among them, 21 784 participants had prevalent IMDs. Information on IMDs at baseline and incidence of CVDs during follow-up were recorded. Cox proportional hazard models were used to estimate the association between IMDs and CVDs risk. Results During the median follow-up of 12.1 years, there were 6506 cases of CVDs in participants with IMDs (29.9%) and 77 699 cases in those without IMDs (19.8%). After multivariable adjustment, participants with IMDs were significantly associated with an increased risk of total CVD [hazard ratio (HR) 1.57; 95% CI 1.52–1.61]. Among the 20 IMDs, 16 showed significant associations with CVD (all P  < 0.0025 after Bonferroni correction), with HR ranging from 1.34 (1.16–1.54) for celiac disease to 2.75 (2.10–3.61) for SLE. Participants with any IMD exposure had a higher risk of all individual CVD events, with HR ranging from 1.34 (1.14–1.58) for cerebral hemorrhage to 1.80 (1.54–2.11) for pericardium diseases. IMD duration <5, 5–10 and >10 years was associated with 55%, 59% and 56% increased risk of total CVD, respectively. Conclusion Total and individual IMDs were associated with an increased risk of overall CVDs. It is important to consider primary prevention of CVD in patients with IMD and dysregulation of immune system in the cardiovascular health. [ABSTRACT FROM AUTHOR]

• Higher C-reactive protein at baseline was associated with a reduced risk of Parkinson's disease. • No assication was identified between interleukin 6 level at baseline and risk of Parkinson's disease. • Significant and negative genetic correlation was identified between C-reactive protein level and risk of PD. • Higher polygenic risk score of C-reactive protein was associated with a lower risk of PD. Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79–0.90, P = 4.23E−07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: −0.14, P = 6.31E−05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = −0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB , HNF4A , PPM1G , ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Genetic factors, diet and inflammation are associated with the development of dementia. In this study, we aimed at evaluating the impact of the dietary inflammatory index (DII) scores and genetic susceptibility on the development of dementia. Methods: This prospective study involved 207,301 participants aged between 39 and 72 years from UK biobank. A web-based 24-h dietary questionnaire was collected at least once from participants between 2006 and 2012. The DII was calculated based on inflammatory effect score of nutrients. Individual AD-GRS (Alzheimer's disease genetic risk score) was calculated. Incident dementia was ascertained through hospital or death records. Results: Of all 207,301 participants, 468 incident cases of all-cause dementia (165 AD, 91 VD and 26 FTD) were reported during a follow-up period of 11.4 years. The participants in the highest quintile (Q) of DII scores reported a higher risk for all-cause dementia (Q5 vs. Q3, hazard ratio (HR) = 1.702; 95% CI: 1.285–2.255) and VD (Q5 vs. Q3, HR = 2.266, 95% CI: 1.133–4.531) compared to participants in the Q3. Besides, when compared with the Q1, there was a higher risk for AD in the subjects of Q5 (Q5 vs. Q1, HR = 1.590; 95% CI: 1.004–2.519). There was a non-linear relationship between DII score and all-cause incidence (P for non-linear = 0.038) by restricted cubic splines. Subgroup analysis found that the increased risk for all-cause dementia and AD was more pronounced in the elderly, women, and higher educated population. Cox regression models indicated that compared with the participants who had a low AD-GRS risk and in the lowest tertile of DII, participants had a high AD-GRS and the highest tertile of DII were associated with a higher risk of AD (HR = 1.757, 95% CI: 1.082–2.855, P = 0.023). Conclusions: The DII scores were independently associated with an augmented risk for all-cause dementia, AD and VD. Additionally, high AD-GRS with higher DII scores was significantly associated with a higher risk of AD. [ABSTRACT FROM AUTHOR]

We present new models and methods for the posterior drift problem where the regression function in the target domain is modelled as a linear adjustment, on an appropriate scale, of that in the source domain, and study the theoretical properties of our proposed estimators in the binary classification problem. The core idea of our model inherits the simplicity and the usefulness of generalized linear models and accelerated failure time models from the classical statistics literature. Our approach is shown to be flexible and applicable in a variety of statistical settings, and can be adopted for transfer learning problems in various domains including epidemiology, genetics and biomedicine. As concrete applications, we illustrate the power of our approach (i) through mortality prediction for British Asians by borrowing strength from similar data from the larger pool of British Caucasians, using the UK Biobank data, and (ii) in overcoming a spurious correlation present in the source domain of the Waterbirds dataset. [ABSTRACT FROM AUTHOR]

Background Grip strength has prognostic value for aging-related health outcomes. Whether the associations of grip strength with the risk of dementia and Alzheimer's disease (AD) vary by the genetic risk of AD and related dementias (ADD) is unknown. Methods This study included 148 659 older adults of white British ancestry (aged ≥60 years) participating in UK Biobank with no dementia, and self-reported poor health status at baseline. Polygenic risk scores (PRS) for ADD were calculated based on 64 genetic variants. Grip strength was measured by hand dynamometers. Results The hazard ratios (HR) of dementia (n  = 4 963) and AD (n  = 2 373) for high genetic risk of ADD were 2.36 (95% confidence interval [CI]: 2.15–2.59) and 3.00 (95% CI: 2.61–3.44), respectively, compared with low genetic risk. Compared with the bottom tertile of grip strength, the top tertile of grip strength had a hazard ratio (HR) of 0.69 (95% CI: 0.64–0.74) for incident dementia, and 0.74 (95% CI: 0.66–0.82) for incident AD, after adjustment for confounders and PRS for ADD. The risk of dementia and AD was lower with the top grip strength tertile within each level of genetic susceptibility to ADD. There was no evidence of multiplicative interaction between grip strength and genetic susceptibility to ADD for both dementia (p value:.241) and AD (p value:.314). Conclusions Older adults with higher PRS for ADD are at higher risk of developing dementia and AD. The risk of dementia and AD was lower in individuals with higher grip strength, regardless of their level of genetic susceptibility to ADD. [ABSTRACT FROM AUTHOR]

• Accelerometer-measured short but not long sleep is associated with an increased risk of incident type 2 diabetes among 88,000 participants from the UK Biobank. • Accelerometer-measured physical activity (PA) is inversely associated with the risk of incident type 2 diabetes. • Both moderate-to-vigorous PA and light-intensity PA potentially ameliorate the negative impact of short sleep duration on incident type 2 diabetes. The aim of the current study was to investigate the association of accelerometer-measured sleep duration and different intensities of physical activity (PA) with the risk of incident type 2 diabetes in a population-based prospective cohort study. Altogether, 88,000 participants (mean age = 62.2 ± 7.9 years, mean ± SD) were included from the UK Biobank. Sleep duration (short: <6 h/day; normal: 6–8 h/day; long: >8 h/day) and PA of different intensities were measured using a wrist-worn accelerometer over a 7-day period between 2013 and 2015. PA was classified according to the median or World Health Organization-recommendation: total volume of PA (high, low), moderate-to-vigorous PA (MVPA) (recommended, not recommended), and light-intensity PA (high, low). Incidence of type 2 diabetes was ascertained using hospital records or death registries. During a median follow-up of 7.0 years, 1615 incident type 2 diabetes cases were documented. Compared with normal sleep duration, short (hazard ratio (HR) = 1.21, 95% confidence interval (95%CI): 1.03–1.41) but not long sleep duration (HR = 1.01, 95%CI: 0.89–1.15) was associated with excessive type 2 diabetes risk. This increased risk among short sleepers seems to be protected against by PA. Compared with normal sleepers with high or recommended PA, short sleepers with low volume of PA (HR = 1.81, 95%CI: 1.46–2.25), not recommended (below the World Health Organization-recommended level of) MVPA (HR = 1.92, 95%CI: 1.55–2.36), or low light-intensity PA (HR = 1.49, 95%CI: 1.13–1.90) had a higher risk of type 2 diabetes, while short sleepers with a high volume of PA (HR = 1.14, 95%CI: 0.88–1.49), recommended MVPA (HR = 1.02, 95%CI: 0.71–1.48), or high light-intensity PA (HR = 1.14, 95%CI: 0.92–1.41) did not. Accelerometer-measured short but not long sleep duration was associated with a higher risk of incident type 2 diabetes. A higher level of PA, regardless of intensity, potentially ameliorates this excessive risk. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The genetic association of allergic rhinitis (AR) with other physiological systems throughout the human body remains unknown. Objective: The aim of this Mendelian randomization (MR) study was to explore the association of this respiratory disorder with multiple common sleep and neuropsychological disorders at the genetic level. Methods: Summary data for total AR and pollen AR were collected from the most updated FinnGen genome-wide association studies involving more than 340 000 European subjects. Summary data for 12 sleep and neuropsychological disorders (including snoring) were included from UK Biobank studies involving 63 392 to 462 933 European subjects. Three MR methods, including inverse-variance weighting (IVW), weighted median and MR–Egger, were used to determine the relationships between the exposures and outcomes. Several sensitivity analyses, including Cochran's Q, MR–Egger intercept, MR-PRESSO, "leave-one-out" test and funnel plot, were used to detect heterogeneity and horizontal pleiotropy. Results: IVW revealed that total and pollen AR were associated with an increased risk of snoring (odds ratio (OR) = 1.011, 95% confidence interval (CI) = 1.004∼1.019, P =.003; OR = 1.006, 95% CI = 1.001∼1.011, P =.014). Two other MR methods supported the results from the IVW analysis. No heterogeneity or horizontal pleiotropy was confirmed by sensitivity analyses. In addition, IVW did not reveal any association between AR and other included disorders. Conclusion: AR (specifically AR caused by pollen) might be an independent risk factor for snoring at the genetic level, which should be verified in the future. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at P interaction<5e−8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (P interaction=4e−8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P interaction=9.4e−7) and 0.20±0.06 mm Hg (P interaction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P =4e−273) and cis-DNA methylation quantitative trait loci variants (P =1e−300). Although the closest gene for rs117878928 is MTHFS , the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Background The 2018 (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are evidence-based lifestyle recommendations which aim to reduce the risk of cancer worldwide. Sociodemographic factors modulate lifestyle behaviours, and both cancer incidence and survival are socio-economically patterned. We investigated adherence to these recommendations and examined patterns of adherence across sociodemographic subgroups in the UK Biobank cohort. Methods We included 158 415 UK Biobank participants (mean age 56 years, 53% female). Total adherence scores were derived from dietary, physical activity and anthropometric data using the 2018 WCRF/AICR standardized scoring system. One-Way analysis of variance (ANOVA) was used to test for differences in total scores and in values for individual score components according to sociodemographic factors and Pearson's Χ 2 test to investigate associations between sociodemographic factors according to tertiles of adherence score. Results Mean total adherence score was 3.85 points (SD 1.05, range 0–7 points). Higher total scores were observed in females, and older (>57 years), Chinese or South Asian, and more educated participants. We found significant variations in adherence to individual recommendations by sociodemographic factors including education, Townsend deprivation index and ethnicity. Conclusions Identifying and understanding lifestyle and dietary patterns according to sociodemographic factors could help to guide public health strategies for the prevention of cancers and other non-communicable diseases. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease worldwide. At the same time, the relationship between air pollution and the likelihood of developing NAFLD has been a subject of debate due to conflicting findings in previous observational research. Our objective was to examine the potential correlation between air pollutant levels and the risk of NAFLD in the European population by employing a two-sample Mendelian randomization (MR) analysis. The UK Biobank Consortium provided the summary statistics for various air pollution indicators (PM2.5, PM2.5 absorbance, PM2.5–10, PM10, NO2, and NOx). Additionally, information on NAFLD was obtained from three studies, including one derivation set and two validation sets. Heterogeneity, pleiotropy, and sensitivity analyses were performed under different MR frameworks, and instrumental variables associated with confounders (such as education, smoking, alcohol, and BMI) were detected by tools. In the derivation set, causal relationships between PM2.5, NO2, and NAFLD were observed in univariable Mendelian randomization (UVMR) (Odds Ratio (OR) = 1.99, 95% confidence interval (95% CI) = [1.22–3.22], p = 0.005; OR = 2.08, 95% CI = [1.27–3.40], p = 0.004, respectively). After adjustment for air pollutants or alcohol intake frequency in multivariable Mendelian randomization (MVMR), the above genetic correlations disappeared. In validation sets, the null associations remained in UVMR. Our findings from MR analysis using genetic data did not provide evidence for a causal association between air pollution and NAFLD in the European population. The associations observed in epidemiological studies could be partly attributed to confounders. [ABSTRACT FROM AUTHOR]

Objective: Fat distribution pattern could help determine cardiometabolic risk profile. This study aimed to evaluate the association of balance/ imbalance between visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), and liver fat (LF) with incident type 2 diabetes (T2D) and cardiovascular disease (CVD) in the UK Biobank prospective cohort study. Methods: Magnetic resonance images of 40 174 participants were analyzed for VAT, aSAT, and LF using AMRA® Researcher. To assess fat distribution patterns independent of body mass index (BMI), fat z-scores (z-VAT, z-aSAT, z-LF) were calculated. Participants without prevalent T2D/CVD (N = 35 138) were partitioned based on balance between (1) z-VAT and z-LF (z-scores = 0 as cut-points for high/low), (2) z-VAT and z-aSAT, and (3) z-LF and z-aSAT. Associations with T2D/CVD were investigated using Cox regression (crude and adjusted for sex, age, BMI, lifestyle, arterial hypertension, statin treatment). Results: T2D was significantly associated with z-LF (hazard ratio, [95% CI] 1.74 [1.52-1.98], P < .001) and z-VAT (1.70 [1.49-1.95], P < .001). Both remained significant after full adjustment. For z-scores balance, strongest associations with T2D were z-VAT > 0 and z-LF > 0 (4.61 [2.98-7.12]), z-VAT > 0 and z-aSAT < 0 (4.48 [2.85-7.06]), and z-LF > 0 and z-aSAT < 0 (2.69 [1.76-4.12]), all P < .001. CVD was most strongly associated with z-VAT (1.22 [1.16-1.28], P < .001) which remained significant after adjustment for sex, age, BMI, and lifestyle. For z-scores balance, strongest associations with CVD were z-VAT > 0 and z-LF < 0 (1.53 [1.34-1.76], P < .001) and z-VAT > 0 and z-aSAT < 0 (1.54 [1.34-1.76], P < .001). When adjusted for sex, age, and BMI, only z-VAT > 0 and z-LF < 0 remained significant. Conclusion: High VAT in relation to BMI (z-VAT > 0) was consistently linked to both T2D and CVD; z-LF > 0 was linked to T2D only. Skewed fat distribution patterns showed elevated risk for CVD (z-VAT > 0 and z-LF < 0 and z-VAT > 0 and z-aSAT < 0) and T2D (z-VAT > 0 and z-aSAT < 0). [ABSTRACT FROM AUTHOR]

Objective: To investigate the associations between dynapenic obesity and the risk of dementia, and the modifying effects of age, sex, and the APOE gene, using a large population-based cohort. Methods: 279,884 participants aged 55 and above from the UK Biobank were included. The participants were classified into four categories based on body mass index and hand grip strength: healthy, obesity, dynapenia, and dynapenic obesity. The incident dementia was identified based on linked hospital records and death register data. Cox proportional hazards regression models were used to estimate the associations, followed by age-, sex-, and apolipoprotein E (APOE) gene-stratified analyses. Results: During the median follow-up of 12.4 years, 5,170 (1.8%) participants developed dementia. Compared with the healthy group, participants with dynapenic obesity had 67% higher dementia risk (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.44–1.94). Compared with the healthy group, higher risks of dementia in participants with dynapenic obesity were respectively observed in male (HR: 2.03, 95% CI: 1.65–2.50), younger (

Background: The associations of age at diagnosis of breast cancer with incident myocardial infarction (MI) and heart failure (HF) remain unexamined. Addressing this problem could promote understanding of the cardiovascular impact of breast cancer. Methods: Data were obtained from the UK Biobank. Information on the diagnosis of breast cancer, MI, and HF was collected at baseline and follow-ups (median = 12.8 years). The propensity score matching method and Cox proportional hazards models were employed. Results: A total of 251,277 female participants (mean age: 56.8 ± 8.0 years), of whom 16,241 had breast cancer, were included. Among breast cancer participants, younger age at diagnosis (per 10-year decrease) was significantly associated with elevated risks of MI (hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.19–1.56, p

Irritable bowel syndrome (IBS) patients exhibit significantly lower levels of serum selenium (Se) compared to healthy controls. This study integrates a prospective cohort analysis and animal experiments to investigate Se deficiency as a potential risk factor for IBS. Using data from the UK Biobank, a longitudinal analysis was conducted to explore the associations between dietary Se intake and the risk of incident IBS. In animal study, C57BL/6 mice were fed diets with normal (0.2 ppm) or low (0.02 ppm) Se levels to assess the impacts of Se deficiency on IBS symptoms. Furthermore, we performed 16 S rRNA sequencing, untargeted colonic fecal metabolomics analysis, and colon transcriptome profiling to uncover the regulatory mechanisms underlying Se deficiency-induced IBS. The analysis of UK Biobank data revealed a significant correlation between low dietary Se levels and an increased incidence of IBS. In the experimental study, a low Se diet induced IBS symptoms, evidenced by elevated abdominal withdrawal reflex scores, colon inflammation, and severe pathological damage to the colon. Additionally, the low Se diet caused disturbances in gut microbiota, characterized by an increase in Faecalibaculum and Helicobacter, and a decrease in Bifidobacterium and Akkermansia. Combined colonic fecal metabolomics and colon transcriptome analysis indicated that Se deficiency might trigger IBS through disruptions in pathways related to ''bile excretion'', ''steroid hormone biosynthesis'', ''arachidonic acid metabolism'', and ''drug metabolism-cytochrome P450''. These findings underscore the significant adverse effects of Se deficiency on IBS and suggest that Se supplementation should be considered for IBS patients.

Objectives: To explore whether COVID-19 vaccination protects against hospital admission by preventing infections and severe disease. Methods: We leveraged the UK Biobank and studied associations of COVID-19 vaccination (BioNTech-BNT162b2 or Oxford-AstraZeneca-ChAdOx1) with hospitalizations from cardiovascular and other selected diseases (N = 393,544; median follow-up = 54 days among vaccinated individuals). Multivariable Cox, Poisson regression, propensity score matching, and inverse probability treatment weighting analyses were performed. We also performed adjustment using prescription-time distribution matching, and prior event rate ratio. Results: We observed that COVID-19 vaccination (at least one dose), compared with no vaccination, was associated with reduced short-term risks of hospitalizations from stroke (hazard ratio [HR] = 0.178, 95% confidence interval [CI]: 0.127-0.250, P = 1.50e-23), venous thromboembolism (HR = 0.426, CI: 0.270-0.673, P = 2.51e-4), dementia (HR = 0.114, CI: 0.060-0.216; P = 2.24e-11), non-COVID-19 pneumonia (HR = 0.108, CI: 0.080-0.145; P = 2.20e-49), coronary artery disease (HR = 0.563, CI: 0.416-0.762; P = 2.05e-4), chronic obstructive pulmonary disease (HR = 0.212, CI: 0.126-0.357; P = 4.92e-9), type 2 diabetes (HR = 0.216, CI: 0.096-0.486, P = 2.12e-4), heart failure (HR = 0.174, CI: 0.118-0.256, P = 1.34e-18), and renal failure (HR = 0.415, CI: 0.255-0.677, P = 4.19e-4), based on standard Cox regression models. Among the previously mentioned results, reduced hospitalizations for stroke, heart failure, non-COVID-19 pneumonia, and dementia were consistently observed across regression, propensity score matching/inverse probability treatment weighting, prescription-time distribution matching, and prior event rate ratio. The results for two-dose vaccination were similar. Conclusions: Taken together, this study provides further support to the safety and benefits of COVID-19 vaccination, and such benefits may extend beyond reduction of infection risk or severity per se. However, causal relationship cannot be concluded and further studies are required.

COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a considerable health risk. Nevertheless, its risk factors are not thoroughly comprehended, and the association between the reticulocyte count and MASLD remains uncertain. This study aimed to explore the relationship between reticulocyte count and MASLD.Methods: A total of 310,091 individuals from the UK Biobank were included in this cross-sectional study, and 7,316 individuals were included in this prospective study. The cross-sectional analysis categorized reticulocyte count into quartiles, considering the sample distribution. Logistic regression models examined the connection between reticulocyte count and MASLD. In the prospective analysis, Cox analysis was utilized to investigate the association.Results: Our study findings indicate a significant association between higher reticulocyte count and an elevated risk of MASLD in both the cross-sectional and prospective analyses. In the cross-sectional analysis, the adjusted odds ratios (ORs) of MASLD increased stepwise over reticulocyte count quartiles (quartile 2: OR 1.22, 95% CI 1.17–1.28, p < 0.001; quartile 3: OR 1.44; 95% CI 1.38–1.51, p < 0.001; quartile 4: OR 1.66, 95% CI 1.59–1.74, p < 0.001). The results of prospective analyses were similar.Conclusion: Increased reticulocyte count was independently associated with a higher risk of MASLD. This discovery offers new insights into the potential of reticulocytes as biomarkers for MASLD.

Background: Previous observational studies have indicated associations of physical activity (PA) and air pollution with mortality. A few studies have evaluated air pollution and PA interactions for health. Still, the trade-off between the harmful effects of air pollution exposure and the protective effects of PA remains controversial and unclear. Objective: This study aimed to investigate the joint association of air pollution and PA with mortality risks. Methods: This prospective cohort study included 322,092 participants from 2006 to 2010 and followed up to 2021 in the UK Biobank study. The concentrations of air pollutants (2006–2010), including particulate matter (PM) with diameters

Objectives: The association of the dietary inflammatory potential with cancer risk remains uncertain. We examined the relationship of the dietary inflammatory potential with risk of overall and site-specific cancers and explored its sex and age differences. Design: A community-based longitudinal study. Setting: Participants from the UK Biobank completed baseline surveys during 2006–2010 and were followed for up to 15 years to detect incident cancer. Participants: 170,899 cancer-free participants with dietary data available (mean age: 55.73 ± 7.95, 54.10% female). Measurements: At baseline, dietary intake was assessed with a 24-h dietary record for up to 5 times. The inflammatory diet index (IDI) was calculated to assess the dietary inflammatory potential as a weighted sum of 31 food groups (including 14 anti-inflammatory and 17 pro-inflammatory) based on plasma high-sensitivity C-reactive protein (hsCRP) levels, and tertiled as low (indicating low-inflammatory diet), moderate, and high IDI (as reference). Overall and site-specific cancers were ascertained via linkage to routine hospital admission, cancer registry, and death certificate data. Data were analyzed using Cox regression and Laplace regression. Results: During the follow-up (median 10.32 years, interquartile range: 9.95–11.14 years), 18,884 (11.05%) participants developed cancer. In multi-adjusted Cox regression, low IDI scores were associated with decreased risk of rectal cancer (hazard ratio [95% confidence interval, CI] 0.76 [0.61, 0.94]), thyroid cancer [0.45 (0.27, 0.74)], lung cancer [0.73 (0.61, 0.88)]. However, the association between IDI score and the risk of overall cancer was not significant. Laplace regression analysis showed that 10th percentile differences (95% CIs) of cancer onset time for participants with low IDI scores was prolonged by 1.29 (0.32, 2.27), 1.44 (0.58, 2.30), and 2.62 (0.98, 4.27) years for rectal cancer, thyroid cancer, and lung cancer, respectively, compared to those with high IDI scores. Stratified analysis revealed that low IDI scores were associated with a lower risk of rectal cancer (p interaction between IDI score and sex = 0.035) and lung cancer in males, but not in females, and with a reduced risk of thyroid cancer in females, but not in males. Moreover, low IDI scores were associated with a reduced risk of rectal cancer and lung cancer in the participants aged ≥60 years, but not in those

Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.

BackgroundStroke continues to be a leading cause of death and disability worldwide despite improvements in prevention and treatment. Traditional stroke risk calculators are biased and imprecise. Novel stroke predictors need to be identified. Recently, deep neural networks (DNNs) have been used to determine age from ECGs, otherwise known as the electrocardiographic-age (ECG-age), which predicts clinical outcomes. However, the relationship between ECG-age and stroke has not been well studied. We hypothesized that ECG-age is associated with incident stroke.MethodsIn this study, UK Biobank participants with available ECGs (from 2014 or later). ECG-age was estimated using a deep neural network (DNN) applied to raw ECG waveforms. We calculated the Δage (ECG-age minus chronological age) and classified individuals as having normal, accelerated, or decelerated aging if Δage was within, higher, or lower than the mean absolute error of the model, respectively. Multivariable Cox proportional hazards regression models adjusted for age, sex, and clinical factors were used to assess the association between Δage and incident stroke.ResultsThe study population included 67,757 UK Biobank participants (mean age 65 ± 8 years; 48.3% male). Every 10-year increase in Δage was associated with a 22% increase in incident stroke [HR, 1.22 (95% CI, 1.00–1.49)] in the multivariable-adjusted model. Accelerated aging was associated with a 42% increase in incident stroke [HR, 1.42 (95% CI, 1.12–1.80)] compared to normal aging. In addition, Δage was associated with prevalent stroke [OR, 1.28 (95% CI, 1.11–1.49)].ConclusionsDNN-estimated ECG-age was associated with incident and prevalent stroke in the UK Biobank. Further investigation is required to determine if ECG-age can be used as a reliable biomarker of stroke risk.

BackgroundThe causality between frailty and gestational diabetes mellitus (GDM) has not yet been fully explored. A potential bidirectional causality was also needed to be confirmed.MethodsA bidirectional two-sample Mendelian randomization (MR) was conducted, with frailty-related data was collected from UK Biobank and TwinGen and GDM-related data was collected from the FinnGen consortium. We performed univariable and multivariable-adjusted MR with adjustments for body mass index (BMI). Several methodologies of MR were conducted to confirm the robustness of results.ResultsFrailty was significantly associated with elevated risks of GDM (OR, 3.563; 95% CI, 1.737 to 7.309; P< 0.001) and GDM was also significantly associated with elevated risks of frailty (β, 0.087; 95% CI, 0.040 to 0.133; P< 0.001). There is no evidence demonstrating the existence of horizontal pleiotropy and heterogeneity. This association was robust after adjustments for BMI. The sensitivity analyses with Weighted median, Maximum likelihood, Penalised weighted median, MR Egger and MR PRESSO methods indicated consistent results.ConclusionOur study provides evidence of the bidirectional causal association between frailty and GDM from genetic perspectives, signaling that the identification and assessment of frailty should become a standard strategy during the early stages and care of gestational diabetes.

BackgroundAlthough inflammation has been linked to nonalcoholic fatty liver disease (NAFLD), most studies have focused only on a single indicator, leading to inconsistent results. Therefore, a large prospective study that includes a variety of well-documented single and composite indicators of inflammation is needed. This study aimed to thoroughly investigate the potential associations between different systemic inflammatory indicators and NAFLD in the UK Biobank cohort.MethodsAfter excluding ineligible participants, 378,139 individuals were included in the study. Associations between systemic inflammatory indicators and hepatic steatosis were assessed using multivariate logistic regression. The relationships between systemic inflammatory indicators and nonalcoholic fatty liver disease were analysed using Cox proportional hazards models, and nonlinear associations were investigated using restricted cubic splines.ResultsAccording to the cross-sectional analysis, systemic inflammatory indicators significantly correlated with hepatic steatosis. Over a median follow-up of 13.9 years, 4,145 individuals developed NAFLD. After sufficient adjustment for confounding factors, CRP levels were found to be nonlinearly positively associated with NAFLD risk (P

BackgroundMultiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. While previous studies have indicated that albumin, the primary protein in human plasma, may exert influence on the inflammatory process and confer beneficial effects in neurodegenerative disorders, its role in the context of MS has been underexplored. Here, we aimed to explore the link between albumin and the risk of MS.MethodsEmploying data from the UK Biobank, we investigated the association between baseline levels of serum and urine albumin and the risk of MS using Cox proportional hazards regression analysis.ResultsA higher baseline level of serum albumin was associated with a lower risk of incident MS (HR=0.94, 95% CI: 0.91–0.98, P=7.66E-04). Subgroup analysis revealed a more pronounced effect in females, as well as participants with younger ages, less smoking and deficient levels of vitamin D. Conversely, no association was identified between baseline microalbuminuria level and risk of incident MS.ConclusionHigher serum albumin level at baseline is linked to a reduced risk of MS. These results contribute to an enhanced understanding of albumin’s role in MS, propose the potential use of albumin as a biomarker for MS, and have implications for the design of therapeutic interventions targeting albumin in clinical trials.

BackgroundHeart failure (HF) risk is greater in rural versus urban regions in the United States (US), potentially due to differences in healthcare coverage and access. Whether this excess risk applies to countries with universal healthcare is unclear and the underlying biological mechanisms are unknown. In the prospective United Kingdom (UK) Biobank, we investigated urban–rural regional differences in HF risk and the mechanistic role of biological aging.MethodsMultivariable Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to residential urban–rural region and a Biological Health Score (BHS) that reflects biological aging from environmental, social, or dietary stressors. We estimated the proportion of the total effect of urban–rural region on HF mediated through BHS.ResultsAmong 417,441 European participants, 10,332 incident HF cases were diagnosed during the follow-up. Compared to participants in large urban regions of Scotland, those in England/Wales had significantly increased HF risk (smaller urban: HR = 1.83, 95%CI: 1.64–2.03; suburban: HR = 1.77, 95%CI: 1.56–2.01; very rural: HR = 1.61, 95%CI: 1.39–1.85). Additionally, we found a dose–response relationship between increased biological aging and HF risk (HRper 1 SD increase = 1.14 (95%CI: 1.12–1.17). Increased biological aging mediated a notable 6.6% (p

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Abstract Background The relation between incident cardiovascular disease (CVD) and sugar might not only depend on the quantity consumed but also on its source. This study aims to assess the association between various sources of dietary sugars and CVD incidence in the prospective population-based UK Biobank cohort. Methods A total of 176,352 participants from the UK Biobank with at least one web-based dietary questionnaire (Oxford WebQ) for assessment of sugar intake were included in this study. Mean follow-up lasted 10.9 years (standard deviation 2.0), with 12,355 incident cases of CVD. To determine the association of free sugar (FS) and intrinsic sugar intake with incident CVD, hazard ratios (HR) were calculated using Cox proportional hazard regression models. FS intake from beverages and beverage subtypes, i.e., soda/fruit drinks, juice, milk-based drinks, and tea/coffee, as well as from solid foods and solids subtypes, i.e., treats, cereals, toppings, and sauces, was included as penalised cubic splines. Results FS intake showed a J-shaped relationship with CVD risk, reaching the lowest HR (HR-nadir) at 9 %E, while intrinsic sugars displayed a non-linear descending association, with the HR-nadir at 14 %E. FS in beverages demonstrated a significant linear relationship with CVD with the HR-nadir at 3 %E, while FS in solids exhibited a significant non-linear U-shaped relationship with the HR-nadir at 7 %E. Within the beverage subtypes, soda/fruit drinks displayed a linear relationship, as did to a lesser extent FS in milk-based drinks and tea/coffee. Juice, however, showed a significant U-shaped relationship with CVD risk. Among solid foods subtypes, FS in treats had a J-shaped relation with the HR-nadir at 5 %E, and FS in cereals showed a linear association. In comparison, FS in toppings and sauces exhibited a U-shaped pattern with HR-nadir at 3 %E and 0.5 %E, respectively. All major results remained similar in various sensitivity analyses and were more robust for ischemic heart disease compared to stroke. Conclusions Only some sources of FS exhibit a robust positive association with CVD incidence. Public health efforts aiming at the reduction of CVD risk should prioritise the reduction of sugary beverages with an emphasis on soda/fruit drinks.

Abstract Background Diabetic individuals often encounter various sleep-related challenges. Although the association between sleep duration and atrial fibrillation (AF) have been explored, the association of other sleep traits with the incidence of AF remains unclear. A comprehensive understanding of these traits is essential for a more accurate assessment of sleep conditions in patients with diabetes and the development of novel AF prevention strategies. Methods This study involved 23,785 patients with diabetes without any pre-existing cardiovascular disease, drawn from the UK Biobank. Sleep behaviour traits examined encompassed sleep duration, chronotype, insomnia, snoring and daytime sleepiness. Sleep duration was categorised into three groups: low (≤ 5 h), proper (6–8 h) and long (≥ 9 h). We assessed associations using multivariate Cox proportional risk regression models. Furthermore, four poor sleep behaviours were constructed to evaluate their impact on the risk of new-onset AF. Results Over a mean follow-up period of 166 months, 2221 (9.3%) new cases of AF were identified. Short (hazard ratio (HR), 1.28; 95% confidence interval (CI) 1.10–1.50) and long sleep durations (HR 1.16; 95% CI 1.03–1.32) consistently exhibited an elevated risk of AF compared to optimal sleep duration. Early chronotype, infrequent insomnia and daytime sleepiness were associated with 11% (HR 0.89; 95% CI 0.82–0.97), 15% (HR 0.85; 95% CI 0.77–0.95) and 12% (HR 0.88; 95% CI 0.81–0.96) reduced risk of new-onset AF, respectively. However, no significant association was found between snoring and the incidence of AF (HR 0.99; 95% CI 0.91–1.07). Conclusions In diabetic populations, sleep duration, chronotype, insomnia and daytime sleepiness are strongly associated with AF incidence. An optimal sleep duration of 6–8 h presents the lowest AF risk compared to short or long sleep duration. Additionally, poor sleep patterns present a greater risk of new-onset AF in women than in men.

Abstract 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 (

Abstract Background We aimed to quantify the association of handgrip strength and self‐reported walking pace with incident Parkinson's disease (PD) in the general population. Methods A total of 419 572 participants (54.1% females, mean age: 56.1 years [SD, 8.2]) without prior PD were included from UK Biobank. Handgrip strength was assessed by dynamometer. Walking pace was self‐reported as slow, average or brisk. The study outcome was incident PD, determined by self‐report data, hospital admission records or death records. Results The mean handgrip strength was 23.5 (SD, 6.3) and 39.6 (SD, 8.9) kg for females and males, respectively. A total of 33 645 (8.0%), 221 682 (52.8%) and 164 245 (39.2%) participants reported slow, average and brisk walking pace, respectively. Over a median follow‐up duration of 12.5 years, 2152 participants developed incident PD. When handgrip strength was assessed as sex‐specific tertiles, compared with those in the third tertile, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) of incident PD for participants in the second and first tertiles were 1.23 (1.09–1.39) and 1.60 (1.42–1.79), respectively. Compared with brisk walking pace, average (HR, 1.33; 95% CI: 1.20–1.47) or slow (HR, 1.84; 95% CI: 1.57–2.15) walking pace was associated with a higher risk of incident PD. A lower grip strength (Tertiles 1 and 2) and an average/slow walking pace accounted for 23.8% and 19.9% of PD cases, respectively. When handgrip strength and walking pace were considered together, the highest risk of incident PD was observed in participants with both lowest handgrip strength and slow walking pace (HR, 2.89; 95% CI: 2.30–3.64). Genetic risks of PD did not significantly modify the relation of handgrip strength (P for interaction = 0.371) or walking pace (P for interaction = 0.082) with new‐onset PD. Conclusions Low handgrip strength and slow walking pace were significantly associated with a higher risk of incident PD, regardless of the individuals' genetic risk profile.

Abstract Background Paracetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer. Methods This prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up. Results During a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06–1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up. Conclusion The regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol.

Abstract Background There is increasing evidence for the role of environmental factors and exposure to the natural environment on a wide range of health outcomes. Whether exposure to green space, blue space, and the natural environment (GBN) is associated with risk of psychiatric disorders in middle-aged and older adults has not been prospectively examined. Methods Longitudinal data from the UK biobank was used. At the study baseline (2006–2010), 363,047 participants (women: 53.4%; mean age 56.7 ± 8.1 years) who had not been previously diagnosed with any psychiatric disorder were included. Follow-up was achieved by collecting records from hospitals and death registers. Measurements of green and blue space modeled from land use data and natural environment from Land Cover Map were assigned to the residential address for each participant. Cox proportional hazard models with adjustment for potential confounders were used to explore the longitudinal associations between GBN and any psychiatric disorder and then by specific psychiatric disorders (dementia, substance abuse, psychotic disorder, depression, and anxiety) in middle-aged and older adults. Results During an average follow-up of 11.5 ± 2.8 years, 49,865 individuals were diagnosed with psychiatric disorders. Compared with the first tertile (lowest) of exposure, blue space at 300 m buffer [hazard ratio (HR): 0.973, 95% confidence interval (CI): 0.952–0.994] and natural environment at 300 m buffer (HR: 0.970, 95% CI: 0.948–0.992) and at 1000 m buffer (HR: 0.975, 95% CI: 0.952–0.999) in the third tertile (highest) were significantly associated with lower risk of incident psychiatric disorders, respectively. The risk of incident dementia was statistically decreased when exposed to the third tertile (highest) of green space and natural environment at 1000 m buffer. The third tertile (highest) of green space at 300 m and 1000 m buffer and natural environment at 300 m and 1000 m buffer was associated with a reduction of 30.0%, 31.8%, 21.7%, and 30.3% in the risk of developing a psychotic disorder, respectively. Subgroup analysis suggested that the elderly, men, and those living with some comorbid conditions may derive greater benefits associated with exposure to GBN. Conclusions This study suggests that GBN has significant benefits for lowering the risk of psychiatric disorders in middle-aged and older adults. Future studies are warranted to validate these findings and to understand the potential mechanistic pathways underpinning these novel findings.

Abstract Objective The association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank. Methods A prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan–Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk. Results A total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12–1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5–1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1–1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05–1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02–1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3–1.4). Conclusion MetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

Abstract Background Long-term exposure to air pollution has been found to contribute to the development of cognitive decline. Our study aimed to assess the association between various air pollutants and cognitive impairment and dementia. Additionally, explore the modification effects of lifestyle and genetic predisposition. Methods The exposure levels to various air pollutants, including particulate matter (PM) with diameters ≤ 2.5 (PM2.5), ≤ 10 (PM10), and between 2.5 and 10 μm (PM2.5−10) and nitrogen oxides (NO and NO2) were identified. An air pollution score (APS) was calculated to evaluate the combined exposure to these five air pollutants. A genetic risk estimate and healthy lifestyle score (HLS) were also generated. The Cox regression model adjusted by potential confounders was adopted to access the association between pollution exposure and cognitive decline, and several sensitivity analyses were additionally conducted to test the robustness. Results The combined exposure to air pollutants was associated with an increased risk of incident cognitive decline. Compared with the low exposure group, the hazard ratio (HR) and 95% confidence interval (CI) for all-cause dementia, Alzheimer’s dementia, vascular dementia, and mild cognitive impairment (MCI) in those exposed to the highest levels of air pollutants were respectively 1.07 (95% CI: 1.04 to 1.09), 1.08 (95% CI: 1.04 to 1.12), 1.07 (95% CI: 1.02 to 1.13), and 1.19 (95% CI: 1.12 to 1.27). However, the modification effects from genetic predisposition were not widely observed, while on the contrary for the healthy lifestyle. Our findings were proven to be reliable and robust based on the results of sensitivity analyses. Conclusions Exposure to air pollution was found to be a significant contributing factor to cognitive impairment and dementia, and this association was not easily modified by an individual’s genetic predisposition. However, adopting a healthy lifestyle may help to manage the risk of cognitive decline related to air pollution.