Accurate dating of brittle fracturing and faulting is vital for a better understanding of continental deformation. The development of U-series and in situ U-Pb geochronology of carbonates opened new possibilities for tectonic and geodynamic reconstructions, since carbonate mineralization is common in many settings of brittle deformation. The SE Tibetan Plateau has experienced complex and multi-stages deformation histories and is still one of the most tectonically active and rapidly deforming regions of the continental crust. It represents an ideal natural laboratory for investigating intracontinental deformation processes in response to both Tethys Ocean closure and ongoing continental convergence-collision. This study provides fault-related calcite geochronological evidence to investigate the history of fault activity during brittle deformation in the SE Tibetan Plateau. Twenty-two fault-related carbonates from the Lijiang-Jianchuan, Heqing-Eryuan and Longpan-Qiaohou fault zones yielded U-series ages larger than 500 ka, which beyond its applicable timeframe ranges and their actual ages should be treated as >500 ka, with their older limits undefined. These samples then underwent LA-ICPMS in situ U-Pb dating. Nine samples, four of them containing multi-generational phases, yielded thirteen ages: 238.0 +/- 6.1, 186 +/- 34, 145 +/- 25, 130.8 +/- 9.0, 116.5 +/- 6.5, 109 +/- 45, 58 +/- 11, 51 +/- 22, 37.8 +/- 8.7, 33.29 +/- 0.70, 27.9 +/- 2.2, 13.0 +/- 5.8 and 8.2 +/- 2.4 Ma, respectively. The earliest fault-related calcite precipitated at 238 Ma, which might be related to the subduction stage of the Paleo-Tethys and the subsequent Songpan Ganze-Yidun Arc-Qiangtang convergence-collision process. The fault-related calcite vein with a U-Pb age of 186 Ma formed in association with movements between the Indochina and South China blocks influenced by the subduction of the Meso-Tethys Ocean, and the coeval accretion of Meso-Tethys oceanic plateau along the Bangong-Nujiang suture. Subsequently, the subduction of the Meso-Tethys Ocean during Early Cretaceous might have activated these fault zones during 145-109 Ma, resulting in the formation of fault-related cements and veins. More frequent fault movements occurred during 58-51, 38-28, and 13-8 Ma, most likely in response to the Cenozoic India-Eurasia collision and opening of the South China Sea. Our work documents the history of fault activity from 238 Ma to 8 Ma in response to brittle deformation in the SE Tibetan Plateau, which is well correlated with regional tectonics. This study demonstrates the effectiveness of carbonate geochronology in reconstructing long-term history of fault activity during the brittle deformation.

BackgroundNight shift work has been associated with adverse health outcomes. Whether night shift work is associated with cholelithiasis remains uncertain, and the roles of genetic risk and lifestyle factors in cholelithiasis risk are unclear.MethodsWe conducted a prospective analysis of 219,810 UK Biobank participants. Cox proportional hazards models were used to estimate the association between night shift work and incident cholelithiasis. Polygenic risk score analyses and causal mediation analyses were performed to investigate the roles of the genetic risk and lifestyle factors in cholelithiasis risk.ResultsCompared with day workers, the HR and 95% CI of cholelithiasis was 1.09 (1.01-1.17) for individuals with rarely/some night shifts and 1.18 (1.04-1.35) for those with usual/permanent night shifts. Additionally, those with a higher frequency of night shifts and a longer length of each night shift were associated with an increased risk of cholelithiasis. Notably, individuals with usual/permanent night shifts and high genetic risk exhibited the highest risk of cholelithiasis (HR: 1.48, 95% CI: 1.21-1.81). Mediation analysis indicated that a substantial portion (24.64%) of the association was mediated by BMI, followed by unhealthy alcohol intake (4.50%) and sedentary time (1.82%).ConclusionsNight shift work is associated with an increased risk of cholelithiasis, with this relationship being largely mediated by lifestyle factors. Reducing the frequency and length of night shifts may help mitigate the incidence of cholelithiasis among night shift workers, particularly for those with heightened genetic susceptibility.

The obesity paradox is common among older adults at risk for various diseases. Although this paradox has also been observed in the association between obesity and osteoporosis, the available evidence remains controversial. This study aimed to investigate the association between obesity and OP risk in an older population. A cross-sectional and prospective study was conducted using data from 177,734 participants in the UK Biobank. The association of body mass index (BMI), waist circumference (WC), and fat percentage with BMD was examined using Spearman correlation analysis with baseline BMD data. Cox proportional hazards regression analysis was used to investigate the association between obesity and OP risk. Restricted cubic spline (RCS) were used to assess the nonlinear associations of BMI, WC, and fat percentage with OP. Baseline cross-sectional analyses revealed a significant positive association between BMI, WC, and fat percentage with BMD in women, whereas this association was very weak in men. A total of 8,998 OP patients were identified during a median follow-up period of 13.7 years. Cox analyses showed that obesity as defined by BMI, WC, and fat percentage was associated with a 33

Unhealthy diets contribute to the onset and progression of chronic kidney disease (CKD), with poor dietary habits identified as significant lifestyle factors that elevate CKD risk. Data from the UK Biobank cohort, which included over 500,000 participants aged 40–69 from diverse regions of England, Wales, and Scotland, were analyzed. Participants, who completed at least one online 24-hour dietary recall assessment, were included in the study. The baseline for analysis was the first 24-hour dietary recall in 2011, with follow-up extending until the earliest occurrence of CKD diagnosis, death, or the end of the study period. A total of 207,268 British individuals who completed at least one online 24-hour dietary recall assessment were included in this study. Four healthy dietary pattern scores were evaluated: the Healthy Plant-based Diet Index (hPDI), the Healthy Eating Index (HEI)-2015, the Mediterranean Diet (MED) Score, and the Alternative Mediterranean Diet (AMED) Score. These scores assessed the association between dietary patterns and the incidence of CKD. Relative to the lowest dietary scores, the HR for CKD was 0.79 (95

Sleep disorders are considered a risk factor for aging and skeletal degeneration, but their impact on intervertebral disc degeneration (IDD) remains unclear. The aim of this study was to assess associations between sleep characteristics and IDD, and to identify potential causal relationships. Exposure factors included six unhealthy sleep characteristics: insomnia, short sleep duration (< 7 h), long sleep duration (≥ 9 h), evening chronotype, daytime sleepiness, and snoring. The primary outcomes included cervical disc degeneration (CDD) and lumbar disc degeneration (LDD). Firstly, we examined the associations between sleep characteristics and IDD risk in 368,348 participants from the UK Biobank using Cox proportional hazards model. Two-sample Mendelian randomization (MR) analyses were conducted to validate associations found in observational analyses, using genome-wide association data from the UK Biobank and FinnGen consortia. During a median follow-up time of 13.8 years, a total of 1,637 cases of CDD and 7,654 cases of LDD were identified. Observational analyses found that almost all unhealthy sleep characteristics were associated with an elevated risk of IDD, except snoring. Conversely, the risk of IDD decreased linearly with an increasing number of healthy sleep characteristics. MR analyses supported a causal association between genetically determined insomnia and increased risk of LDD (OR 1.25 [1.07–1.47]), and between short sleep duration and increased risk of both IDD phenotypes (OR 5.41 [1.95–15.01] for CDD; OR 3.48 [1.76–6.89] for LDD). However, long sleep duration was causally associated with a reduced risk of LDD (OR 0.13 [0.03–0.53]), which contrasts with the observational findings. We found associations between multiple sleep characteristics and IDD risk and confirmed that insomnia and short sleep duration increased IDD risk. Although more research is needed to confirm the underlying mechanisms, prioritizing interventions to improve sleep quality and ensure adequate sleep could help mitigate IDD.

INTRODUCTION:Gallstone diseases affect intestinal inflammation, bile flow, and gut microbiota, which in turn may increase the risk of inflammatory bowel disease (IBD). However, epidemiological studies exploring the associations between gallstone diseases and subsequent IBD risk have been limited. METHODS:This is a combined analysis of 3 prospective cohort studies (Nurses' Health Study, Nurses' Health Study II, and UK Biobank) and replicated in a case-control study (Chinese IBD Etiology Study). We evaluated the hazard ratios (HRs)/odds ratios (ORs) between gallstone diseases with IBD risk by Cox logistic regression or conditional logistic regression, adjusting for demographic characteristics, lifestyles, comorbidities, and medication usage. RESULTS:We identified 3,480 cases of IBD over 2,127,471 person-years of follow-up in the 3 cohort studies. The participants with gallstone disease had a 38% increase in the risk of IBD (HR 1.38, 95% confidence intervals [CI] 1.21-1.59), 68% increase in Crohn's disease (HR 1.68, 95% CI 1.38-2.06), and 24% increase in ulcerative colitis (HR 1.24, 95% CI 1.03-1.49). In Chinese IBD Etiology Study, we found even larger magnitude of effects between gallstone diseases and IBD risk (IBD: OR 3.03, 95% CI 2.32-3.97; Crohn's disease: OR 5.31; 95% CI 3.71-7.60; ulcerative colitis: OR 1.49; 95% CI 1.07-2.06). There were no major differences in the estimated associations between the presence of unremoved gallstones and prior cholecystectomy with IBD risk. DISCUSSION:Gallstone disease was linked to an increased risk of IBD and its subtypes, independent of traditional risk factors. Further research is needed to confirm these associations and clarify the underlying biological mechanisms.

Obesity-related glomerulopathy (ORG) represents an escalating public health with no effective treatments currently available. Abnormal lipid metabolism and lipid droplet deposition in the kidneys are key contributors to ORG. Cyanidin-3-glucoside (C3G) has shown potential in regulating lipid metabolism and may offer reno-protective effects; however, its therapeutic efficacy and underlying mechanisms in ORG remain unclear. An ORG mouse model was established, followed by an 8-week C3G intervention. The mice were divided into three groups: normal control (CT) group, ORG group, and C3G treatment group. Fecal 16S rRNA sequencing, metabolomics of feces-serum-kidney, and kidney single-cell RNA sequencing (scRNA-seq) were performed to investigate the effects and mechanisms of C3G. Compared to CT mice, ORG mice exhibited elevated serum CHO, TG, Cys-C, UACR, urinary Kim-1, and NAG levels, along with glomerular hypertrophy and tubular injury. These biochemical and pathological indicators improved following C3G treatment. Fecal 16S analysis revealed reduced gut microbiota diversity in ORG mice compared to CT mice, while C3G intervention increased gut microbiota diversity. Metabolic profiling of feces, serum, and kidney indicated reprogramming of glycerophospholipid metabolism in ORG mice, ameliorated by C3G treatment. Further analysis demonstrated that abnormal glycerophospholipid metabolites correlated with blood lipids, urinary protein, urinary tubular injury markers, and gut microbiota, specifically Lachnospiraceae and Blautia. Additionally, scRNA-seq analysis identified activation of the PPARγ/CD36 pathway in proximal tubule cells (PTCs) of ORG mice. C3G improved abnormal glycerophospholipid metabolism and alleviated injury in PTCs by inhibiting the PPARγ/CD36 pathway. C3G reduces lipid droplet accumulation in the PTCs of ORG mice by modulating the gut microbiota and inhibiting the PPARγ/CD36 pathway. These findings offer new insights and therapeutic targets for ORG.

Cenozoic alkali-rich porphyries are widely distributed in the junction zone between the Sanjiang Orogenic belt and the Yangtze Plate. They are of great significance for understanding the regional geodynamics, tectonic evolution, and metallogenesis. However, the origin of these porphyries remains controversial. In this study, new petrological, geochemical, and geochronological data are presented for Cenozoic syenite porphyry from the Beiya porphyry Au-polymetallic deposit in western Yunnan. Zircon U-Pb dating results show that the Beiya syenite porphyries formed around 36.3–35.0 Ma, coinciding with the magmatic peak in the Jinshajiang-Red River (JSJ-RR) alkali-rich porphyry belt. Geochemical analyses indicate that the Beiya porphyries have potassic characteristics and an arc-like geochemical affinity, with C-type adakite affinity, suggesting a post-collisional setting. The JSJ-RR fault zone is unlikely to be the primary mechanism responsible for the formation of this alkali-rich porphyry magmatism. Instead, the development of the Beiya alkali-rich porphyries is likely associated with the convective removal of the lower part of the overthickened lithospheric mantle and asthenospheric upwelling during the Eocene–Oligocene. Their magmas probably originated from the partial melting of Paleo–Mesoproterozoic garnet amphibolite facies rocks in the thickened lower continental crust, with the addition of shoshonitic mafic magmas produced by the partial melting of metasomatized lithospheric mantle triggered by asthenospheric upwelling. This study provides additional reliable evidence to further constrain the origin of Cenozoic alkali-rich porphyries in the JSJ-RR belt.

BackgroundLimited epidemiological evidence exists concerning the impact of healthy dietary patterns on reducing the risk of cholelithiasis. We aimed to examine the association of seven established dietary patterns with subsequent cholelithiasis risk and whether this association was modified by genetic risk.MethodsWe conducted a prospective cohort study from the UK Biobank, including 155,323 participants initially free of cholelithiasis and cholecystectomy. Dietary patterns were assessed using a validated food frequency questionnaire (Oxford WebQ), covering Mediterranean Diet Score (MED), alternate Mediterranean Diet Score(aMED), overall Plant-based Diet Index (PDI), healthy Plant-based Diet Index (hPDI), unhealthy Plant-based Diet Index (uPDI), Healthy Eating Index 2015 (HEI-2015) and EAT-lancet Score. Genetic risk was quantified and stratified by a polygenic risk score (PRS) incorporating 13 known cholelithiasis-associated loci. Cox proportional hazards regression was employed to estimate the association between dietary patterns, PRS, and cholelithiasis incidence, adjusting for potential confounders.ResultsDuring a median follow-up of 13.3 years, 5,056 cases of cholelithiasis were identified. After adjusting for potential confounders, adherence to aMED and HEI-2015 dietary patterns reduced cholelithiasis risk by 10% (HR: 0.90; 95%CI: 0.83–0.98) and 11% (HR: 0.89; 95%CI: 0.82–0.96), respectively. A significant decrease in cholelithiasis risk was observed across PRS quintiles, low PRS was associated with a 16% reduced risk (HR: 0.84; 95%CI: 0.77–0.92). Participants with both high dietary scores and low genetic risk had the lowest cholelithiasis risk, with an HR of 0.76 (95%CI: 0.64–0.91) for aMED and 0.73 (95%CI: 0.61–0.88) for HEI-2015.ConclusionHigher adherence to aMED and HEI-2015 might significantly decrease the risk of cholelithiasis, irrespective of genetic risk. Our results highlighted the potential of diet intervention for cholelithiasis prevention in the general population.

BackgroundLimited epidemiological evidence exists regarding the role of healthy eating patterns in reducing the risk of Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to investigate the association between adherence to four established healthy eating patterns and subsequent CD or UC risk, and further examined whether these associations are linked to anti-inflammatory mechanisms.MethodsWe conducted a prospective cohort study of 197,391 participants from the UK Biobank who completed at least one dietary questionnaire and were free from inflammatory bowel disease or cancer at baseline. Four dietary patterns were assessed, including Alternate Mediterranean Diet (AMED), Healthy Eating Index 2015 (HEI-2015), Healthful Plant-based Diet Index (HPDI), and EAT-Lancet. Cox proportional models with restricted cubic splines were applied to explore the associations. The potential role of low-grade inflammation in these associations was examined through mediation analysis.ResultsDuring 2,193,436 person-years follow-up, 260 CD and 601 UC cases were identified. Higher AMED and HEI-2015 scores were associated with a reduced risk of CD but no UC, with no evidence against nonlinearity. These associations remained consistent across multiple sensitive and subgroup analyses. For dietary components, the fruits and monounsaturated fatty acids: saturated fatty acids ratio in AMED, and total fruits, total protein foods and fatty acid in HEI-2015 were linked to a decreased CD risk. Both diets were also associated with lower plasma inflammation biomarkers. Mediation analysis indicated that 7.66% and 13.40% of the reductions in CD risk attributed to AMED and HEI-2015 diets, respectively, were mediated by low-grade inflammation scores.ConclusionsHigher adherence to AMED and HEI-2015 might significantly reduce CD risk, partly due to their anti-inflammatory properties.

Abstract Objectives: Skeletal degeneration is influenced by genetics, environment and lifestyle, but the role of sleep in its development remains uncertain. This study investigates the association between sleep and the risk of degenerative skeletal disorders, aiming to identify the impact of specific sleep characteristics on skeletal disorder phenotypes. Methods: The observational study utilized health data from 387,822 UK Biobank participants. Cox proportional risk regression estimated the association between sleep and degenerative skeletal disorders. Two-sample MR analyses validated the bidirectional causal relationships based on genetic associations summary data of sleep characteristics from UK Biobank and skeletal disorders from FinnGen as well as meta GWAS, using inverse-variance weighted (IVW), MR-PRESSO, weighed median and MR-Egger. Results: In observational study, 37 pairs of exposure-disease risk associations were identified between six sleep characteristics and eight degenerative skeletal phenotypes. The risk of degenerative skeletal disorders was increased with unhealthy sleep characteristics. MR analysis confirmed four robust causality associations: short sleep duration with overall OA (OR=2.88, 95%CI: 1.63-5.07), knee OA (OR=2.50, 95%CI: 1.33-4.68), and LDD (OR=2.97, 95%CI: 1.63-5.41), and long sleep duration with LDD (OR=0.13, 95%CI: 0.03-0.53). Four positive associations were considered potentially causal, including insomnia with LDD and spondylosis, early chronotype with overall OA, and short sleep duration with CDD. Conclusions and Relevance: Large prospective observational and MR studies suggest a causal effect of sleep on spine and peripheral joint degeneration, emphasizing the value of sleep management in ameliorating joint degeneration.

Background: Night shift work has been linked to various adverse health outcomes, but its relationship with incident cholelithiasis remains unclear. This study aims to investigate the association between night shift work and the risk of cholelithiasis, assess the potential modifying effects of genetic susceptibility, and explore the mediating roles of lifestyle factors. Methods: A total of 219,810 subjects who were either in paid employment or self-employed were included in the UK Biobank. Information on current and lifetime employment were collected. Genetic risk was quantified and stratified by a polygenic risk score (PRS) incorporating 13 known cholelithiasis-associated loci. We used Cox proportional hazard models to investigate associations between night shift work and risk of cholelithiasis. Lifestyle factors measured at baseline were explored as potential mediators. Results: During a median follow-up of 13.76 years, 6450 incidents of cholelithiasis were documented. Compared with day workers, the hazard ratio (HR) and 95% confidence interval (CI) of cholelithiasis was 1.09 (1.01, 1.17) for individuals with rarely/some night shifts and 1.18 (1.04, 1.35) for those with usual/permanent night shifts. Among the 62,558 participants who had reports on lifetime experience of night shift work, those with a higher frequency of night shifts and a longer length of each night shift were associated with an increased risk of cholelithiasis. Notably, individuals with usual/permanent night shifts and high genetic risk exhibited the highest risk of cholelithiasis (HR: 1.48, 95% CI: 1.21, 1.81), with day workers at low genetic risk serving as the reference. Mediation analysis indicated that a substantial portion (24.6%) of the association was mediated by BMI, followed by unhealthy alcohol intake (4.5%) and sedentary time (1.8%). Conclusions: Night shift work is associated with an increased risk of cholelithiasis, with this relationship being largely mediated by lifestyle factors. These findings suggest that reducing the frequency and duration of night shifts may help mitigate the incidence of cholelithiasis among night shift workers, particularly for those with heightened genetic susceptibility. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Natural Science Foundation of Gansu Province (23JRRA0956); Medical Innovation and Development Project of Lanzhou University (lzuyxcx-2022-157); The Startup Fund for the 100 Top Talents Program, SYSU (392012); Research Supporting Start-up Fund for Associate Researcher of SAHSYSU (ZSQYRSSFAR0004). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each participant provided a written informed consent before data collection. The UK Biobank obtained ethics approval from the National Research Ethics Committee (REC ID: 16/NW/0274). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UK Biobank is an open access resource, and the study website https://www.ukbiobank.ac.uk/ has information on available data and access procedures. Data sets used for the analysis will be made available under reasonable requests.

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.

Several observational studies have suggested that proton-pump inhibitor (PPI) use might increase diabetes risk, but the mechanism remains unclear. This study aimed to investigate the effects of PPI use on gut microbiota and bile acids (BAs) profiles, and to explore whether these changes could mediate the association of PPIs use with fasting blood glucose (FBG) levels and insulin resistance (IR) in Chinese population. A cross-sectional study was conducted in Shenzhen, China, from April to August 2021, enrolled 200 eligible patients from the local hospital. Participants completed a questionnaire and provided blood and stool samples. Gut microbiome was measured by16S rRNA gene sequencing, and bile acids were quantified by UPLC-MS/MS. Insulin resistance (IR) was assessed using the Homeostasis Model Assessment 2 (HOMA2-IR). PPI use was positively associated with higher levels of FBG and HOMA2-IR after controlling for possible confounders. PPI users exhibited a decreased Firmicutes and an increase in Bacteroidetes phylum, alongside higher levels of glycoursodeoxycholic acid (GUDCA) and taurochenodeoxycholic acid (TCDCA). Higher abundances of Bacteroidetes and Fusobacterium as well as higher levels of TCDCA in PPI users were positively associated with elevated FBG or HOMA2-IR. Mediation analyses indicated that the elevated levels of FBG and HOMA2-IR with PPI use were partially mediated by the alterations in gut microbiota and specific BAs (i.e., Fusobacterium genera and TCDCA). Long-term PPI use may increase FBG and HOMA2-IR levels, and alterations in gut microbiota and BAs profiles may partially explain this association.

Background and Aims The long-term impact of maternal smoking during pregnancy [MSDP] on the risk of Crohn's disease [CD] and ulcerative colitis [UC] in adult offspring remains uncertain. The present study aimed to investigate the individual and combined effects of early life exposure [MSDP], offspring personal behaviour [smoking], and genetic risk on the development of CD and UC in adult offspring.Methods We conducted a prospective cohort study using UK Biobank data, including 334 083 participants recruited between 2006 and 2010, with follow-up until December 31, 2021. Multivariable Cox regression models were used to evaluate the associations of genetic factors, maternal and personal smoking, and their combination with CD and UC.Results Participants exposed to MSDP had an 18% increased risk of CD compared to those without MSDP (hazard ratio [HR] = 1.18, 95% confidence interval [CI] = 1.01-1.39). However, no significant association was found between MSDP and UC risk [HR = 1.03, 95% CI = 0.92-1.16]. Personal smoking increased the risk of CD and UC, and had a numerically amplified effect with MSDP. Participants with high genetic risk and MSDP had a 2.01-fold [95% CI = 1.53-2.65] and a 2.45-fold [95% CI = 2.00-2.99] increased risk of CD and UC, respectively, compared to participants without MSDP and with low genetic risk.Conclusions Our prospective cohort study provides evidence that MSDP increases the risk of CD in adult offspring, whereas no evidence supports their causal association. Additionally, smoking and genetic susceptibility had a numerically amplified effect with MSDP on CD and UC, but the interaction lacked statistical significance.

BACKGROUND:The associations between 1-carbon metabolism (OCM) nutrients (methionine, folate, vitamin B-6, and vitamin B-12) and Alzheimer disease (AD) remains inconclusive. OBJECTIVES:This study aimed to investigate the association of dietary OCM nutrients with subsequent risk of AD and further assess whether participants with high genetic risk for AD might benefit from dietary OCM nutrients. METHODS:We analyzed data from 192,214 participants who completed at least one 24-h dietary questionnaire and had no previous history of AD based on the UK Biobank. Nutrients intake was calculated using McCance and Widdowson's The Composition of Food and USDA's Food and Nutrient Database for Dietary Studies. Cox proportional models with restricted cubic splines were applied to explore the associations. RESULTS:Over a median follow-up of 13.35 y, 959 cases of AD (41 early-onset cases and 918 late-onset cases) were identified. Compared with those in the low-intake OCM group (quartile 1), participants in the high-intake OCM group (quartile 4) had reduced risk of developing AD. The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for methionine, folate, vitamin B-6, and vitamin B-12 intake were 0.66 (0.54, 0.80), 0.71 (0.58, 0.87), 0.71 (0.59, 0.87), and 0.77 (0.64, 0.93), respectively. Similar associations were observed in late-onset AD. In early-onset AD, high methionine and vitamin B-12 intake were associated with 70% (HR: 0.30; 95% CI: 0.10, 0.86) and 71% (HR: 0.29; 95% CI: 0.09, 0.96) reduction in risk, respectively. Participants with low genetic risk and high OCM nutrients intake had >75% reduced AD risk compared with high-risk, low-intake participants. CONCLUSIONS:In this prospective cohort study, we found that higher intake of OCM nutrients is associated with reduced risk of AD. Participants with high genetic risk of AD are more likely to benefit from dietary OCM nutrients intake.

Objectives: The aim of this study was to evaluate the individual and combined effects of maternal smoking during pregnancy (MSDP) and personal smoking on mortality and life expectancy. Study design: A prospective cohort study based on the UK Biobank, with a median follow-up of 12.47 years. Methods: This study employed multivariate Cox regression to determine the relative risks of mortality from all causes and specific diseases according to maternal and/or personal smoking status and pack-years of smoking (0, 1-20, 21-30, >30). Additionally, this study estimated the additive interaction between the two exposures. Life table analyses were performed using the estimated age-specific mortality rates to forecast life expectancy. Results: Results indicated that MSDP elevated the risk of all-cause mortality (HR = 1.12, 95% CI: 1.09-1.15) and mortality due to neoplasms (HR = 1.10, 95% CI: 1.06-1.12), circulatory (HR = 1.13, 95% CI: 1.06-1.19), respiratory (HR = 1.27, 95% CI: 1.16-1.40) and digestive system diseases (HR = 1.22, 95% CI: 1.08-1.38). Notably, both multiplicative and additive interactions were observed between maternal and personal smoking, with Relative Excess Risk due to Interaction (RERI) values for mortality from all causes, neoplasms, circulatory, and respiratory diseases being 0.21, 0.22, 0.16, and 0.76, respectively. This study also found a trend towards shorter gained life expectancy when maternal smoking and increasing pack-years of personal smoking were combined. Conclusions: In this cohort study of UK Biobank, MSDP was associated with an increased risk of all-cause mortality and reduced life expectancy, suggesting that quitting smoking during pregnancy might have health and longevity benefits for both generations.

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.

BACKGROUND:Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD:This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS:During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION:Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

BACKGROUND:Type 2 diabetes is associated with a variety of complications, including micro- and macrovascular complications, neurological manifestations and poor wound healing. Adhering to a Mediterranean Diet (MED) is generally considered an effective intervention in individuals at risk for type 2 diabetes mellitus (T2DM). However, little is known about its effect with respect to the different specific manifestations of T2DM. This prompted us to explore the effect of MED on the three most significant microvascular complications of T2DM: diabetic retinopathy (DR), diabetic kidney disease (DKD), and vascular diabetic neuropathies (DN). METHODS:We examined the association between the MED and the incidence of these microvascular complications in a prospective cohort of 33,441 participants with hyperglycemia free of microvascular complications at baseline, identified in the UK Biobank. For each individual, we calculated the Alternate Mediterranean Diet (AMED) score, which yields a semi-continuous measure of the extent to which an individual's diet can be considered as MED. We used Cox proportional hazard models to analyze hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographics, lifestyle factors, medical histories and cardiovascular risk factors. RESULTS:Over a median of 12.3 years of follow-up, 3,392 cases of microvascular complications occurred, including 1,084 cases of diabetic retinopathy (DR), 2,184 cases of diabetic kidney disease (DKD), and 632 cases of diabetic neuropathies (DN), with some patients having 2 or 3 microvascular complications simultaneously. After adjusting for confounders, we observed that higher AMED scores offer protection against DKD among participants with hyperglycemia (comparing the highest AMED scores to the lowest yielded an HR of 0.79 [95% CIs: 0.67, 0.94]). Additionally, the protective effect of AMED against DKD was more evident in the hyperglycemic participants with T2DM (HR, 0.64; 95% CI: 0.50, 0.83). No such effect, however, was seen for DR or DN. CONCLUSIONS:In this prospective cohort study, we have demonstrated that higher adherence to a MED is associated with a reduced risk of DKD among individuals with hyperglycemia. Our study emphasizes the necessity for continued research focusing on the benefits of the MED. Such efforts including the ongoing clinical trial will offer further insights into the role of MED in the clinical management of DKD.