Plasma metabolomics identifies key metabolites and improves prediction of diabetic retinopathy: development and validation across multi-national cohorts.

PURPOSE: To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and evaluate their utility in predicting DR development and progression. DESIGN: Multicenter, multi-ethnic cohort study. PARTICIPANTS: This study included 17,675 participants with baseline pre-diabetes/diabetes, in accordance with the 2021 American Diabetes Association guideline, and free of baseline DR from the UK Biobank (UKB); and an additional 638 diabetic participants from the Guangzhou Diabetic Eye Study (GDES) for external validation. METHODS: Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort. Model assessments included the C-statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical utility in both cohorts. MAIN OUTCOME MEASURES: DR development, progression, and retinal microvascular damage. RESULTS: Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C-statistic: 0.802, 95% CI, 0.760-0.843 vs. 0.751, 95% CI, 0.706-0.796; P = 5.56×10-4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C-statistic: 0.807, 95% CI, 0.711-0.903 vs. 0.617, 95% CI, 0.494, 0.740; P = 1.68×10-4) and progression (C-statistic: 0.797, 95% CI, 0.712-0.882 vs. 0.665, 95% CI, 0.545-0.784; P = 0.003) in the external cohort. Improvements in NRIs, IDIs, and clinical utility were also evident in both cohorts (all P <0.05). In addition, lactate and citrate were associated to microvascular damage across macular and optic disc regions (all P <0.05). CONCLUSIONS: Metabolomic profiling has proven effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology.

A linear adjustment-based approach to posterior drift in transfer learning.

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.

Comparison of body composition measures assessed by bioelectrical impedance analysis versus dual-energy X-ray absorptiometry in the United Kingdom Biobank.

BACKGROUND: Bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) serves as common modalities for body composition assessment. This study was aimed to evaluate the agreement between BIA and DXA measures in UK Biobank. METHODS: UK Biobank participants with body fat mass (FM) and fat-free mass (FFM) estimates obtained through BIA (Tanita BC418MA) and DXA concurrently were included. Correlation between BIA and DXA-derived estimates were assessed with Lin's concordance correlation coefficients. Bland-Altman and Passing-Boblok analyses were performed to quantify the difference and agreement between BIA and DXA. Multivariable linear regression was used to identify predictors influencing the differences. Finally, prediction models were developed to calibrate BIA measures against DXA. RESULTS: The analysis included 34437 participants (female 51.4%, mean age 64.1 years at imaging assessment). BIA and DXA measurements were highly correlated (Lin's concordance correlation coefficient 0.94 for FM and 0.94 for FFM). BIA (Tanita BC418MA) underestimates FM overall by 1.84 kg (23.77 vs. 25.61, p < 0.01), and overestimated FFM overall by 2.56 kg (52.49 vs. 49.93, p < 0.01). The BIA-DXA differences were associated with FM, FFM, BMI and waist circumference. The developed prediction models showed overall good performance in calibrating BIA data. CONCLUSION: Our analysis exhibited strong correlation between BIA (Tanita BC418MA)- and DXA-derived body composition measures at a population level in UK Biobank. However, the BIA-DXA differences were observed at individual level and associated with individual anthropometric measures. Future studies may explore the use of prediction models to enhance the calibration of BIA measures for more accurate assessments in UK Biobank.

Associations of sugary beverage consumption with chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap syndrome: A prospective cohort study.

BACKGROUND: The associations between specific types of sugary beverages and major chronic respiratory diseases remain relatively unexplored. OBJECTIVE: To investigate the associations of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and natural juices (NJs) with chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap syndrome (ACOS). METHODS: This prospective cohort study included 210,339 participants from the UK Biobank. Sugary beverage intake was measured in units (glasses/cans/cartons/250 ml) through 24-hour dietary questionnaires. Logistic regression and Cox proportional hazards models were used to analyze the prevalence and incidence, respectively. Quantile G-computation was employed to estimate the joint associations and relative contributions of the three types of sugary beverages. RESULTS: Over a median follow-up of 11.6 years, 3,491 participants developed COPD, 4,645 asthma, and 523 ACOS. In prevalence analysis, certain categories of SSB and NJ consumption were associated with increased asthma prevalence, while high ASB consumption (>2 units/day) was linked to higher risks of all three outcomes. In incidence analysis, high SSB consumption (>2 units/day) was associated with incident COPD [hazard ratio (HR) 95% confidence interval (CI): 1.53 (1.19, 1.98)] and asthma [HR (95% CI): 1.22 (0.98, 1.52)]. Dose‒response relationships were observed for ASB consumption with all three outcomes [continuous HR (95% CI): 1.98 (1.36, 2.87) for COPD; 1.65 (1.24, 2.20) for asthma; and 2.84 (1.20, 6.72) for ACOS]. Moderate NJ consumption (>0-1 unit/day) was inversely associated with COPD [HR (95% CI): 0.89 (0.82, 0.97)], particularly grapefruit and orange juice. Joint exposure to these beverages (per unit increase) was associated with COPD [HR (95% CI): 1.15 (1.02, 1.29)] and asthma [HR (95% CI): 1.16 (1.06, 1.27)], with ASBs having greater positive weights than SSBs. CONCLUSION: Consumption of SSBs and ASBs was associated with increased risks of COPD, asthma, and potentially ACOS, whereas moderate NJ consumption was associated with a reduced risk of COPD, depending on the juice type.

Associations between systemic inflammation indicators and nonalcoholic fatty liver disease: evidence from a prospective study.

Background: Although 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. Methods: After 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. Results: According 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<0.001), representing the strongest correlation among the tested relationships; lymphocyte count and the LMR showed an L-shaped correlation; monocyte count and neutrophil count showed a linear positive correlation (all P< 0.001); and the NLR, PLR, and SII showed a U-shaped correlation (all P<0.001). Conclusions: Multiple systemic inflammatory indicators are strongly associated with the development of NAFLD, and aggressive systemic inflammation management may have a favourable impact on reducing the burden of NAFLD; further randomized controlled studies are needed.

Association of neuroticism with incident dementia, neuroimaging outcomes, and cognitive function.

INTRODUCTION: Higher neuroticism might be associated with dementia risk. Here we investigated modification by genetic predisposition to dementia, mediation by mental health and vascular conditions, neuroimaging outcomes, and cognitive function. METHODS: Cox proportional-hazards models were used to assess the association between neuroticism score and incident dementia over up to 15 years in 1,74,164 participants. Cross-sectional analyses on dementia-related neuroimaging outcomes and cognitive function were conducted in 39,459 dementia-free participants. RESULTS: Higher neuroticism was associated with an 11% higher risk of incident dementia, especially vascular dementia (15% higher risk), regardless of genetic predisposition to dementia. Mental and vascular conditions mediated the association of neuroticism with all-cause dementia and vascular dementia. Neuroticism was associated with higher cerebrovascular pathology, lower gray matter volume, and worse function across multiple cognitive domains. DISCUSSION: Neuroticism could represent a risk factor for dementia, and vascular and mental health might drive these associations. HIGHLIGHTS: Neuroticism was associated with an increased risk of incident all-cause dementia, particularly vascular dementia. Associations were not modified by genetic predisposition to dementia. Associations were largely mediated by mental and vascular conditions. Neuroticism was associated with increased cerebrovascular pathology and lower gray matter volume. Neuroticism was associated with worse function across multiple cognitive domains.

Association between grip strength and walking pace with incidence of degenerative cervical myelopathy: a UK biobank observational study.

PURPOSE: This study investigates the association between handgrip strength, walking pace, and the incidence of degenerative cervical myelopathy (DCM) using the UK Biobank dataset. METHODS: We analyzed data from 364,716 UK Biobank participants without prior neurological conditions. Handgrip strength was measured with a dynamometer, and walking pace was self-reported. Cox proportional hazards models assessed hazard ratios (HRs) and 95% confidence intervals (CIs) for DCM development. RESULTS: The cohort, with an average age of 56.2 years (SD, 8.1) and 47.4% male, was followed for a median of 12.6 years. During this period, 3,993 participants (1.1%) developed DCM. A significant inverse correlation was found between handgrip strength and DCM incidence (P for trend < 0.001), with decreasing HRs for DCM across quartiles of increasing grip strength: HRs were 0.70 (95% CI: 0.64-0.76), 0.62 (95% CI: 0.57-0.68), and 0.59 (95% CI: 0.54-0.66) for the second, third, and fourth quartiles, respectively. Participants with average or brisk walking paces had a lower DCM risk (HR, 0.55; 95% CI: 0.50-0.61 and HR, 0.48; 95% CI: 0.43-0.54) compared to slow walkers. The greatest risk reduction was in those with both higher handgrip strength and faster pace (HR, 0.39; 95% CI: 0.34-0.44). CONCLUSIONS: Handgrip strength and walking pace are inversely associated with DCM incidence, suggesting their potential as cost-effective screening tools for identifying individuals at risk for DCM.

Benchmarking computational variant effect predictors by their ability to infer human traits.

BACKGROUND: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts. RESULTS: AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation. CONCLUSION: We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.

Reproductive factors, genetic susceptibility and risk of type 2 diabetes: A prospective cohort study.

AIM: To explore the relationships of multiple reproductive factors with type 2 diabetes mellitus (T2DM) risk and the joint effects of reproductive factors and genetic susceptibility. METHODS: We included 262,368 women without prevalent T2DM from the UK biobank. Cox proportional hazards regression models were employed to estimate the relationships of reproductive factors with T2DM risk and the joint effects of reproductive factors and genetic susceptibility. RESULTS: During a mean follow-up of 12.2 years, 8,996 T2DM cases were identified. Early menarche (<12 years, hazard ratio (HR) 1.08 [95 % confidence interval (CI) 1.02;1.13]), late menarche (≥15 years, HR 1.11 [1.04;1.17]), early menopause (<45 years, HR 1.20 [1.12;1.29]), short reproductive lifespan (<30 years, HR 1.25 [1.16;1.35]), hysterectomy (1.31, HR [1.23;1.40]), oophorectomy (HR 1.28 [1.20;1.36]), high parity (≥4, HR 1.25 [1.17;1.34]), early age at first live birth (<20 years, HR 1.23 [1.16;1.31]), miscarriage (HR 1.13 [1.07;1.19]), stillbirth (HR 1.14 [1.03;1.27]), and ever used hormonal replacement therapy (HR 1.19 [1.14;1.24]) were related to a higher T2DM risk, while ever used oral contraceptives (HR 0.93 [0.89;0.98]) was related to a lower T2DM risk. Furthermore, women with reproductive risk factors and high genetic risk had the highest T2DM risk compared to those with low genetic risk and without reproductive risk factors. CONCLUSION: Our findings show that multiple reproductive factors are related to T2DM risk, particularly in women with high genetic risk.

Age, sex, and APOE gene-specific associations between dynapenic obesity and dementia in a large cohort.

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 (<65 years, HR: 1.97, 95% CI: 1.55-2.50), and non-ε4-carrier (HR: 1.97, 95% CI: 1.60-2.44) (all P for interaction <0.05). In participants under 65 years and non-ε4-carrier, those with dynapenic obesity had the highest risk of dementia (HR: 2.63, 95% CI: 1.91-3.62), compared with the healthy group (P for second order interaction = 0.026). CONCLUSIONS: Dynapenic obesity is associated with increased risks of dementia, especially in participants under 65 years and non-ε4-carrier, suggesting the importance of managing dynapenic obesity in the prevention of cognition-related disorders.

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

STUDY OBJECTIVES: This study aimed to determine the associations between accelerometer-measured sleep durations and the risks of incident cardiovascular disease (CVD) and CVD-related mortality. METHODS: A total of 92,261 participants (mean age: 62.4±7.8 years, 56.4% female) were included in UK Biobank between 2013 and 2015. Average daily sleep durations were measured using wrist-worn accelerometers over a seven-day period. Sleep durations were categorized as <7 hours/day, 7-9 hours/day (reference), and >9 hours/day. The incidence of CVD and CVD-related mortality were ascertained by hospital records and death registries. RESULTS: During a median follow-up period of 7.0 years, a total of 13,167 participants developed CVD, and 1,079 participants died of CVD. Compared with a sleep duration 7-9 hours/day, an accelerometer-measured sleep duration <7 hours/day but not >9 hours/day was associated with higher risks of incident CVD (HR 1.06, 95% CI: 1.02-1.10), CVD-related mortality (HR 1.29, 95% CI: 1.14-1.47), coronary heart disease (HR 1.11, 95% CI: 1.03-1.19), myocardial infarction (HR 1.14, 95% CI: 1.03-1.27), heart failure (HR 1.20, 95% CI: 1.08-1.34), and atrial fibrillation (HR 1.15, 95% CI: 1.07-1.24). A curvilinear dose‒response pattern was observed between accelerometer-measured sleep durations and incident CVD (Poverall<0.001), with L-shaped associations found for incident CVD and CVD-related mortality. CONCLUSIONS: An accelerometer-measured sleep duration <7 hours/day but not >9 hours/day was associated with elevated risks of incident CVD and CVD-related mortality. Maintaining adequate sleep may help promote cardiovascular health.

INFLA score: a novel inflammatory marker for assessing cardiometabolic disease risk in obese individuals.

BACKGROUND: The low-grade inflammation score (INFLA-score) is a composite index that assesses chronic inflammatory status using multiple inflammatory markers. However, its correlation with cardiometabolic diseases (CMDs) in obese populations remains unclear. METHODS: We conducted a prospective cohort study involving 79,160 participants with obesity (BMI ≥ 30 kg/m2) from the UK Biobank. The INFLA-score was calculated based on high-sensitivity C-reactive protein, leukocyte count, platelet count and granulocyte/lymphocyte ratio. We employed Kaplan-Meier survival curves, multivariable Cox regression, restricted cubic splines and accelerated time-to-failure models to analyse the association between the INFLA-score and CMDs risk, including coronary heart disease (CAD), stroke and type 2 diabetes mellitus (T2DM). RESULTS: Over a median follow-up of 161.41 months, we recorded 14,903 CMDs events, comprising 7184 CAD cases, 1914 strokes and 7924 T2DM cases. Cox regression analysis revealed that each unit increase in the INFLA-score corresponded to a 1.5%, 1.1%, 1.2% and 2.4% increase CMDs risk (HR: 1.015, 95% CI 1.013-1.018), CAD risk (HR: 1.011, 95% CI 1.007-1.015), stroke risk (HR: 1.012, 95% CI 1.004-1.020) and T2DM risk (HR: 1.024, 95% CI 1.020-1.028), respectively. Restricted cubic spline analysis indicated a non-linear relationship between cumulative INFLA-score and CMDs risk (P = 0.044). Subgroup analysis revealed interactions between sex, age, history of lipid-lowering drug use, and INFLA-score regarding CMDs risk. Sensitivity analysis corroborated the main findings. CONCLUSION: Our findings strongly support the close association between INFLA-score and CMDs risk, particularly notable in women, those aged < 55, and individuals with a history of lipid-lowering drug use. These findings offer new insights into the role of inflammation in obesity-related CMDs, suggesting potential applications for prevention and identification of high-risk populations.

Association between frailty and gestational diabetes mellitus: a bidirectional and multivariable Mendelian randomization study.

Background: The causality between frailty and gestational diabetes mellitus (GDM) has not yet been fully explored. A potential bidirectional causality was also needed to be confirmed. Methods: A 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. Results: Frailty 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 ( ß , 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. Conclusion: Our 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.

Association of Mosaic Chromosomal Alterations and Genetic Factors with the Risk of Cirrhosis.

Background and Aims: Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA are structural somatic variants that indicate clonal hematopoiesis. This study aimed to investigate whether mCAs contribute to the risk of cirrhosis and modify the effect of a polygenic risk score (PRS) on cirrhosis risk prediction. Methods: mCA call sets of individuals with European ancestry were obtained from the UK Biobank. The PRS was constructed based on 12 susceptible single-nucleotide polymorphisms for cirrhosis. Cox proportional hazard models were applied to evaluate the associations between mCAs and cirrhosis risk. Results: Among 448,645 individuals with a median follow-up of 12.5 years, we identified 2,681 cases of cirrhosis, 1,775 cases of compensated cirrhosis, and 1,706 cases of decompensated cirrhosis. Compared to non-carriers, individuals with copy-neutral loss of heterozygosity mCAs had a significantly increased risk of cirrhosis (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.12-1.81). This risk was higher in patients with expanded cell fractions of mCAs (cell fractions ≥10% vs. cell fractions <10%), especially for the risk of decompensated cirrhosis (HR 2.03 [95% CI 1.09-3.78] vs. 1.14 [0.80-1.64]). In comparison to non-carriers of mCAs with low genetic risk, individuals with expanded copy-neutral loss of heterozygosity and high genetic risk showed the highest cirrhosis risk (HR 5.39 [95% CI 2.41-12.07]). Conclusions: The presence of mCAs is associated with increased susceptibility to cirrhosis risk and could be combined with PRS for personalized cirrhosis risk stratification.

Genetic variants affecting mitochondrial function provide further insights for kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. METHODS: We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. RESULTS: Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. CONCLUSIONS: We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

Fish oil supplementation and risk of incident systemic lupus erythematosus: a large population-based prospective study.

BACKGROUND: Although fish oil has been considered to have an anti-inflammatory effect and has been proven to play a beneficial role in the incidence of numerous diseases, the association between fish oil supplementation and the risk of systemic lupus erythematosus (SLE) is still unknown. This study aimed at evaluating the correlation between fish oil use and incident SLE in a large population-based prospective cohort. METHODS: 390,277 participants without SLE at baseline from the UK Biobank were enrolled. Fish oil use was ascertained through a touchscreen questionnaire at baseline. The incidence of SLE was identified by the International Classification of Diseases version 10 code in medical records or self-report. Cox proportional hazard models were employed to estimate the association between fish oil use and SLE risk. RESULTS: Fish oil users accounted for 31.47% of participants. During a median follow-up duration of 11.57 years, 141 participants without fish oil use (4.56/100 000 person-years) and 68 participants with fish oil use (4.78/100 000 person-years) developed SLE. In four models with adjustments for different amounts of confounders, there was no significant difference in the risk of SLE between fish oil users and fish oil non-users (all p-values > 0.05). In subgroup analyses, we found that fish oil supplementation was associated with a lower risk of SLE among females with ultraviolet radiation ≥ 3 h/day (hazard ratio: 0.63, 95% confidence interval: 0.40-0.98), which turned insignificant after further adjustment for female-related factors and sun protection measures. CONCLUSIONS: No significant association between fish oil use and overall incident SLE was observed, except in females exposed to prolonged ultraviolet radiation. Subgroup analysis suggested that females exposed to prolonged ultraviolet radiation might benefit from fish oil supplementation in terms of preventing SLE, but it needs to be confirmed in further studies.

Association of MAFLD and MASLD with all-cause and cause-specific dementia: a prospective cohort study.

BACKGROUND: Liver disease and dementia are both highly prevalent and share common pathological mechanisms. We aimed to investigate the associations between metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of all-cause and cause-specific dementia. METHODS: We conducted a prospective study with 403,506 participants from the UK Biobank. Outcomes included all-cause dementia, Alzheimer's disease, and vascular dementia. Multivariable Cox proportional hazards models were used for analyses. RESULTS: 155,068 (38.4%) participants had MAFLD, and 111,938 (27.7%) had MASLD at baseline. During a median follow-up of 13.7 years, 5,732 participants developed dementia (2,355 Alzheimer's disease and 1,274 vascular dementia). MAFLD was associated with an increased risk of vascular dementia (HR 1.32 [95% CI 1.18-1.48]) but a reduced risk of Alzheimer's disease (0.92 [0.84-1.0]). Differing risks emerged among MAFLD subtypes, with the diabetes subtype increasing risk of all-cause dementia (1.8 [1.65-1.96]), vascular dementia (2.95 [2.53-3.45]) and Alzheimer's disease (1.46 [1.26-1.69]), the lean metabolic disorder subtype only increasing vascular dementia risk (2.01 [1.25-3.22]), whereas the overweight/obesity subtype decreasing risk of Alzheimer's disease (0.83 [0.75-0.91]) and all-cause dementia (0.9 [0.84-0.95]). MASLD was associated with an increased risk of vascular dementia (1.24 [1.1-1.39]) but not Alzheimer's disease (1.0 [0.91-1.09]). The effect of MAFLD on vascular dementia was consistent regardless of MASLD presence, whereas associations with Alzheimer's disease were only present in those without MASLD (0.78 [0.67-0.91]). CONCLUSIONS: MAFLD and MASLD are associated with an increased risk of vascular dementia, with subtype-specific variations observed in dementia risks. Further research is needed to refine MAFLD and SLD subtyping and explore the underlying mechanisms contributing to dementia risk.

The Graded Incomplete Letters Test (GILT): a rapid test to detect cortical visual loss, with UK Biobank implementation.

Impairments of object recognition are core features of neurodegenerative syndromes, in particular posterior cortical atrophy (PCA; the 'visual-variant Alzheimer's disease'). These impairments arise from damage to higher-level cortical visual regions and are often missed or misattributed to common ophthalmological conditions. Consequently, diagnosis can be delayed for years with considerable implications for patients. We report a new test for the rapid measurement of cortical visual loss - the Graded Incomplete Letters Test (GILT). The GILT is an optimised psychophysical variation of a test used to diagnose cortical visual impairment, which measures thresholds for recognising letters under levels of increasing visual degradation (decreasing "completeness") in a similar fashion to ophthalmic tests. The GILT was administered to UK Biobank participants (total n=2,359) and participants with neurodegenerative conditions characterised by initial cortical visual (PCA, n=18) or memory loss (typical Alzheimer's disease, n=9). UK Biobank participants, including both typical adults and those with ophthalmological conditions, were able to recognise letters under low levels of completeness. In contrast, participants with PCA consistently made errors with only modest decreases in completeness. GILT sensitivity to PCA was 83.3% for participants reaching the 80% accuracy cut-off, increasing to 88.9% using alternative cut-offs (60% or 100% accuracy). Specificity values were consistently over 94% when compared to UK Biobank participants without or with documented visual conditions, regardless of accuracy cut-off. These first-release UK Biobank and clinical verification data suggest the GILT has utility in both rapidly detecting visual perceptual losses following posterior cortical damage and differentiating perceptual losses from common eye-related conditions.

Antioxidant insights: investigating the protective role of oxidative balance in inflammatory bowel disease.

Background: Limited studies have investigated the relationship between systemic oxidative stress and inflammatory bowel disease (IBD). The purpose of this study was to explore the relationship between oxidative balance score (OBS) and IBD. Methods: We included 175,808 participants from the UK Biobank database from 2006 to 2010. OBS scores were calculated based on 22 lifestyle and dietary factors. Multiple variable Cox proportional regression models, as well as gender stratification and subgroup analysis, were utilized to investigate the relationship between OBS and IBD. Results: There is a significant negative correlation between OBS and the occurrence of IBD, ulcerative colitis (UC), and Crohn's disease (CD). Additionally, OBS is significantly negatively correlated with intestinal obstruction in CD patients. Gender stratified analysis suggest a significant correlation between OBS and CD in female patients, particularly pronounced in those under 60 years old. Sensitivity analysis indicates a significant negative correlation between lifestyle-related OBS and diet-related OBS with the occurrence of CD in females, diet-related OBS is negatively correlated with CD in males. Conclusion: OBS showed a significant negative correlation with IBD, especially in female CD patients. This study underscores the importance of antioxidant diet and lifestyle, which may provide a greater advantage for female CD patients.

The Role of Diet in Multiple Sclerosis Onset: A Prospective Study Using UK Biobank.

Multiple sclerosis (MS) is a debilitating autoimmune condition primarily affecting young adults, and its rise is evident globally. Despite this, its precise etiology remains elusive. Both genetic and environmental factors contribute to MS susceptibility; however, the link between diet and MS lacks substantial evidence due to limited large-scale studies. We exploited the UK Biobank resources to explore the nexus between diet, lifestyle, and MS risk. The dietary and lifestyle habits of MS incident cases, derived from a general food frequency questionnaire (FFQ) completed by all participants at study enrollment, were compared to those of subjects who did not develop MS during the follow-up. Our findings suggest the protective role of moderate oily fish consumption and weekly alcohol intake. Furthermore, by analyzing food intake data obtained through 24 h recall, completed by a subset of participants, we found a protective, though non-significant, trend of an increased adherence to the Mediterranean diet (MD). These findings, derived from the analysis of the UK Biobank and representing an unprecedented approach for this inquiry, warrant further exploration and integration in future research.