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Background: Clonal hematopoiesis of indeterminate potential (CHIP) can lead to adverse outcomes and may begin early in life. This study aimed to investigate the association between early-life events and CHIP. Methods: In total, 456,658 participants from U.K. Biobank without baseline hematologic malignancies were enrolled. Exposures included 17 early-life events, including reproductive, childhood adversity, and pre-adulthood development factors. CHIP was derived from whole-exome sequencing for mutations in 74 driver genes. Logistic regressions were used to estimate associations between early-life events and the presence of any CHIP or gene-specific CHIP mutations. Results: Overall, 17,513 (3.8%) individuals with any CHIP were identified, among which the most common subtype was DNMT3A (2.4%), followed by TET2 (0.6%) and ASXL1 (0.4%). Compared with participants without sexual abuse in childhood, those who experienced such abuse were positively associated with CHIP (OR 1.35, 95% CI 1.02-1.80), especially among ASXL1, JAK2, and TP53 mutations. Long-term/recurrent antibiotic use as a child or teenager was positively associated with CHIP (OR 1.11, 95% CI 1.02-1.21), especially among DNMT3A, ASXL1, and EP300 mutations. Sex-specific differences were observed, including sexual abuse associated with ASXL1-CHIP in males and JAK2/TP53-CHIP in females and long-term/recurrent antibiotic use associated with DNMT3A/EP300-CHIP in males and ASXL1-CHIP in females. Furthermore, we identified circulating proteomic biomarkers shared by six pairs of early-life factors and gene-specific CHIP mutations, including B2M for sexual abuse and JAK2-CHIP. Conclusions: Early-life factors, especially sexual abuse and long-term/recurrent antibiotic use, were positively associated with the presence of CHIP, particularly among specific gene mutations, offering potential targets for susceptibility and pathogenesis exploration.

Background&aims

In 2019, the EAT-Lancet Commission proposed a predominantly plant-based diet aimed at enhancing human health and supporting environmental sustainability. However, its relationship with sleep apnea has not been extensively studied. This study aimed to investigate the association between adherence to the EAT-Lancet diet and the risk of developing sleep apnea.

Methods

The analysis included 200,373 participants from the UK Biobank. Dietary intake was assessed according to a modified diet history approach, and an EAT-Lancet diet index (scored 0–42 points) was calculated. Cox proportional hazards regression models were conducted to investigate the relationship between the EAT-Lancet diet and the risk of sleep apnea, while causal mediation analyses were used to assess the mediating role of BMI in this association.

Results

Over a mean 11.6 years follow-up, 2924 cases of sleep apnea (17.1%) were recorded. Participants with the highest adherence to the EAT-Lancet diet had an 18% lower risk of sleep apnea (95% CI: 6%–28%) compared to those with the lowest adherence (P < 0.05). Furthermore, the relationship between the EAT-Lancet diet and sleep apnea risk was 26.4% (95% CI: 13.6%–44.8%) mediated by BMI.

Conclusion

These findings indicate that higher adherence to the EAT-Lancet diet is associated with a lower risk of developing sleep apnea, with BMI partially mediating this association.

Background: Exploring the association of clonal haematopoiesis of indeterminate potential (CHIP) with psychiatric disorders (PDs) may help to elucidate the biological mechanisms underlying PDs. The study aimed to identify the specific PD subtypes associated with CHIP and gene-specific CHIP for each PD subtype.

Methods: A total of 360,451 participants from UK Biobank without PDs at baseline, aged 40-69 years and recruited between 2005 and 2014, were included. CHIP status was determined from whole exome sequencing for mutations in 74 driver genes. Any CHIP (variant allele fraction (VAF) >= 2%), large CHIP (VAF >= 10%), and gene-specific CHIP were set as exposures. The primary outcomes were overall psychiatric disorder with 13 PD subtypes. Brain imaging-derived phenotypes (IDPs), derived from 40,000 individuals during follow-up, were further included.

Results: During a median follow-up of 13.6 years, 50,074 (13.9%) participants developed at least one PD. This prospective study demonstrated that CHIP and large CHIP were independently associated with a 15% (10%-20%) and 27% (18%-36%) increased risk of PDs. Among PD subtypes, CHIP and large CHIP were associated with hazard ratios (HR) of 1.12 (1.04-1.21) and 1.27 (1.11-1.44) for major depressive disorders, and 1.27 (1.20-1.35) and 1.21 (1.09-1.34) for substance use disorders, respectively. Gene-specific analyses revealed that risk for PDs was generally increased across CHIP driven by seven genes (DNMT3A, TET2, ASXL1, PPM1D, SRSF2, NF1, SF3B1) with the highest mutation frequency. Associations of gene-specific CHIP were also heterogeneous across PD subtypes. Furthermore, CHIP carries, especially DNMT3A-CHIP carries, had significant changes in 11 brain white matter (WM) tract IDPs.

Conclusions: CHIP was associated with elevated risk of psychiatric disorders, specifically major depressive disorders and substance use disorders, with gene-specific associations observed with changes in brain WM tracts. These findings revealed a potential biological association between CHIP and psychiatric disorders, offering new insights into disease mechanisms and possible therapeutic targets.

BACKGROUND: Circadian rhythms may influence metabolic dysfunction-associated steatotic liver disease (MASLD), but the impact of personal light exposure and rest-activity rhythms on MASLD risk remain unclear.

METHODS: The study utilized accelerometry data from both NHANES and UK Biobank cohorts. 24-hour rest-activity rhythm (24h-RAR) was assessed using nonparametric metrics, including activity level during the most active 10 hours (M10), activity level during the least active 5 hours (L5), relative amplitude (RA), M10 onset, and L5 onset. Light exposure was categorized into daytime and nighttime periods, with exposure durations recorded separately at different threshold levels. The primary outcome was MASLD, with secondary outcomes, including fibrosis and cirrhosis.

RESULTS: In the UK Biobank prospective analysis, each 0.1-unit and 1-unit increase in RA and M10 were associated with a 30% and 2% reduction of MASLD risk, respectively. In contrast, each 1-unit increase in L5 and delayed L5 onset were linked to an 8% and 21% increase of MASLD risk. Moreover, each additional hour of daylight exposure above 6000 lux was associated with 9% lower risk of MASLD, while each additional 30 minutes of nightlight exposure above 30 lux corresponded to a 22% higher risk of MASLD. Additionally, a favorable 24h-RAR profiles and adequate light exposure were associated with a lower risk of fibrosis and cirrhosis, as well as improved life expectancy among participants with MASLD. Similar associations were observed in the NHANES analysis.

CONCLUSION: Greater daytime light exposure, reduced nocturnal light exposure, and regulated rest-activity rhythms may protect against MASLD and prevent its progression to liver fibrosis and advanced liver disease.

Introduction and Objectives

Tobacco exposure during critical developmental windows may have lasting health effects, but its role in the development of chronic liver disease (CLD) remains unclear. This study aimed to examine the association between early-life tobacco exposure and CLD incidence in adulthood.

Materials and Methods

We included 429,603 participants without prior liver diseases from the UK Biobank. Information on in utero tobacco exposure and the age of smoking initiation was extracted, categorized as never-smokers, adulthood (≥18 y), adolescence (15–17 y), and childhood (5–14 y). Composite CLD and individual endpoints, including non-alcoholic fatty liver disease (NAFLD), fibrosis/cirrhosis, alcohol-related liver disease (ALD), viral hepatitis, and liver cancer, were ascertained through electronic health records.

Results

After covariate adjustment, in utero tobacco exposure was associated with a greater risk of incident CLD (HR 1.27; 95 % CI 1.21, 1.34). A significant dose-response association was observed between the age of smoking initiation and CLD risk; the HRs (95 % CIs) for smoking initiation in adulthood, adolescence, and childhood were 1.45 (1.36, 1.54), 1.48 (1.40, 1.57), and 1.81 (1.68, 1.96), respectively (P trend <0.001). The results were similar for NAFLD, fibrosis/cirrhosis, and ALD. Participants with both in utero tobacco exposure and smoking initiation in childhood had the highest CLD risk (HR 2.22; 95 % CI 1.98, 2.48). Among participants who started smoking in childhood or adolescence, the risk of CLD was substantially reduced in those with smoking cessation in midlife compared to those who continued smoking. The mediation analysis indicated that metabolic traits including obesity-related traits, lipid profile, and liver function partially explained the association between early-life tobacco exposure and CLD incidence.

Conclusions

In utero and childhood/adolescence exposure to tobacco smoke was associated with an increased risk of CLD later in life.

Clonal haematopoiesis of indeterminate potential (CHIP) and low vitamin D are recognised as independent risk factors for type 2 diabetes mellitus (T2DM); however, their joint effects on T2DM incidence remain unclear. We hypothesised that CHIP mutations and vitamin D deficiency may be jointly associated with the risk of T2DM. This study included 405,095 participants from the UK Biobank without T2DM at baseline. CHIP was identified through whole-exome sequencing of peripheral blood samples, and vitamin D was categorised into quartiles. All the participants' variables were tested at baseline. Cox regression was used to evaluate the joint effects of CHIP and vitamin D on incident T2DM. The mean age of the participants was 56.4 ± 8.1 years, and 54.0% were female. After a median follow-up of 12.9 years, 24,724 (6.1%) participants developed T2DM. Multivariable analyses revealed that higher vitamin D quartiles were associated with a lower risk of incident T2DM (HR [95% CI]: 0.89 [0.86-0.92], 0.78 [0.75-0.81], and 0.70 [0.67-0.73] for the 2nd, 3rd, and 4th quartiles vs. Q1, respectively), with similar associations observed in participants with and without CHIP, and no evidence of interaction. In contrast, the presence of CHIP was not clearly associated with incident T2DM after adjustment (HR 1.03 [0.97-1.09]). These findings suggest that vitamin D is associated with type 2 diabetes risk, independent of clonal haematopoiesis, and may help to contextualise risk heterogeneity among individuals with and without CHIP. 

Background Mosaic loss of chromosome Y (mLOY) has been linked to several cardiovascular diseases, but its association with peripheral artery disease (PAD) remains unclear. We examined the relationship between mLOY and symptomatic PAD.

Methods This longitudinal study included 217 047 men without prevalent PAD. mLOY was identified using the Mosaic Chromosomal Alterations pipeline. Incident symptomatic PAD was ascertained using International Classification of Diseases, Tenth Revision (ICD-10), and Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 codes. Cox regression was used to evaluate the association between mLOY and PAD. We also performed exploratory mediation analyses of immune-inflammatory biomarkers, examined the joint association of mLOY and smoking, and assessed the contribution of mLOY to sex-related PAD disparities.

Results During a median follow-up of 13.6 years, 4910 men developed symptomatic PAD. mLOY was associated with a higher risk of symptomatic PAD (hazard ratio [HR], 1.25 [95% CI, 1.17-1.33]; P<0.001), with the strongest association observed for expanded mLOY (mosaic cell fraction >= 10%) (HR, 1.35 [95% CI, 1.24-1.47]; P<0.001). Exploratory analyses suggested that several immune-inflammatory biomarkers were statistically related to the mLOY-PAD association. Additive-scale interactions were observed between mLOY and former or current smoking. Compared with nonsmokers without mLOY, current smokers carrying mLOY had the highest PAD risk (HR, 4.69). Compared with matched women, men with mLOY had an approximate to 1.74-fold higher PAD risk.

Conclusions mLOY was associated with symptomatic PAD, independently of other risk factors. These findings provide biologically informative evidence linking mLOY to symptomatic PAD and highlight smoking cessation as an important public-health priority in men.

Delirium is a common neuropsychiatric syndrome among hospitalized patients and has been linked to disturbances in sleep and circadian regulation. We conducted a network meta-analysis of randomized controlled trials evaluating sleep-modulating pharmacological interventions for delirium prevention. PubMed, Embase, and Web of Science were searched through August 2025. Thirty-three trials involving 5045 patients were included. In the random-effects model, melatonin and melatonin receptor agonists were associated with a lower risk of delirium compared with non-active control conditions (RR = 0.77, 95% CI: 0.64-0.92). Evidence from suvorexant trials was also associated with a lower delirium risk (RR = 0.51, 95% CI: 0.27-0.95), whereas midazolam-based benzodiazepine evidence did not demonstrate a statistically significant reduction in delirium risk (RR =1.64, 95% CI: 0.81-3.31). Subgroup analyses suggested that the association for melatonin-based interventions was more evident in non-ICU and surgical populations. The certainty of evidence ranged from low to moderate. Melatonin-based interventions and suvorexant were associated with lower delirium incidence; however, evidence directly comparing different active interventions remains limited, and findings should be interpreted cautiously given the agent-specific evidence base. Further direct comparative trials are needed to clarify the effectiveness and safety of sleep-modulating pharmacological interventions for delirium prevention.