Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Altered iron homeostasis has long been implicated in Parkinson's Disease (PD), although the mechanisms have not been clear. Given the critical role of PD-related activating mutations in LRRK2 (leucine-rich repeat protein kinase 2) within membrane trafficking pathways we examined the impact of a homozygous mutant LRRK2G2019S on iron homeostasis within the RAW macrophage cell line with high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state with highly elevated levels of ferritin light chain and a reduction of ferritin heavy chain. LRRK2G2019S mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload there was a near complete block in the degradation of the ferritinophagy adaptor NCOA4. These conditions lead to an accumulation of phosphorylated Rab8 at the plasma membrane, which is selectively inhibited by LRRK type II kinase inhibitors. Iron overload then leads to increased oxidative stress and ferroptotic cell death. These data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.

PurposeAnti-vascular endothelial growth factor (anti-VEGF) therapy is the standard of care for neovascular age-related macular degeneration (AMD), yet many patients exhibit persistent retinal degeneration, fibrosis, and incomplete therapeutic response. The molecular pathways underlying this incomplete response remain poorly understood. We sought to identify VEGF-independent signaling pathways active in the vitreous of anti-VEGF-treated AMD patients. MethodsWe performed multiplex antibody-based proteomic profiling of 1,000 human proteins in vitreous samples from patients with neovascular AMD receiving anti-VEGF therapy (n=8) and comparative controls (n=6). Differential protein expression was assessed using one-way ANOVA, followed by gene ontology and pathway enrichment analyses. Drug-target relationships were evaluated to identify potential opportunities for therapeutic repositioning. ResultsWe identified 107 differentially expressed proteins (p<0.05), including key regulators of immune signaling, angiogenesis, and metabolism. Notably, multiple components of cytotoxic lymphocyte pathways were dysregulated, including IL-21R, SIGLEC-7, CTLA4, and IL-2-associated signaling. Enrichment analyses revealed significant activation of pathways related to T-cell activation, interleukin signaling, and leukocyte-mediated cytotoxicity. These immune signatures persisted despite suppression of VEGF signaling. Several clinically available immunomodulatory agents--including abatacept, sirolimus, and dupilumab--targeted pathways identified in this dataset. ConclusionsAnti-VEGF-treated neovascular AMD exhibits persistent cytotoxic immune signaling in the vitreous, suggesting that VEGF-independent immune mechanisms may contribute to ongoing retinal damage and incomplete therapeutic response. These findings provide a rationale for combination therapeutic strategies targeting both angiogenic and immune pathways in AMD.

Background & AimsClonal hematopoiesis of indeterminate potential (CHIP) has been linked to chronic liver disease progression, yet its role across the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD), from its initial development to end-stage complications, remains unclear. We aimed to comprehensively investigate the association of CHIP and its major subtypes with both the incidence and progression of MASLD. MethodsWe conducted a prospective cohort study of 353,218 UK Biobank participants, stratified into a healthy cohort free of MASLD at baseline (Cohort 1; n=230,270) and a prevalent MASLD cohort (Cohort 2; n=122,948). CHIP was ascertained from whole-exome sequencing data. We used multivariable Cox regression, competing risk models, and mediation analyses to assess the associations of CHIP (overall, by driver gene, and by clone size) with incident MASLD, cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. ResultsIn Cohort 1, CHIP was associated with an increased risk of incident MASLD (HR 1.25, 95% CI 1.08-1.44) and cirrhosis (HR 1.57, 95% CI 1.10-2.25). These associations were driven by non-DNMT3A mutations, particularly TET2, and showed a linear dose-response relationship with clone size. In Cohort 2, non-DNMT3A CHIP was associated with progression to cirrhosis (HR 1.82, 95% CI 1.28-2.58). The associations were more pronounced in males and in individuals without obesity or diabetes. C-reactive protein partially mediated the CHIP-MASLD association. ConclusionCHIP, driven predominantly by non-DNMT3A mutations (particularly TET2) is an independent risk factor for both the development and progression of MASLD. These findings position CHIP as a novel player in the pathophysiology of MASLD and suggest potential avenues for risk stratification and targeted anti-inflammatory intervention. Impact and ImplicationsThis large-scale, prospective study establishes clonal hematopoiesis of indeterminate potential (CHIP) as a novel and independent risk factor for the entire spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD), from its initial development to its progression to cirrhosis and liver-related death. For hepatologists and hematologists, these findings identify a genetically defined, high-risk subpopulation, particularly individuals with non-DNMT3A mutations, who may benefit from enhanced liver surveillance. The identification of systemic inflammation as a partial mediator of the CHIP-MASLD association suggests that anti-inflammatory therapies currently under development for liver disease could represent a targeted treatment strategy for this growing patient population.

ImportanceAge-related eye diseases, such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), are leading causes of irreversible vision loss globally. Chronic inflammation is a shared pathogenic pathway, but the role of systemic inflammatory drivers like clonal hematopoiesis of indeterminate potential (CHIP) is unknown. ObjectiveTo investigate the association of CHIP, including its major genetic subtypes and clone sizes, with the risk of four major age-related eye diseases. Design, Setting, and ParticipantsThis was a prospective cohort study conducted using data from the UK Biobank, a large-scale, population-based cohort. A total of 436,469 participants free of the four eye diseases at baseline were included in the analysis. Data were collected from 2006 to 2010, with follow-up extending to March 2022. ExposuresCHIP status was ascertained from whole-exome sequencing data, defined by the presence of a somatic driver mutation with a variant allele fraction of 2% or greater. Main Outcomes and MeasuresThe primary outcomes were incident cases of cataract, glaucoma, AMD, and DR, identified through linked electronic health records. Associations were assessed using multivariable Cox proportional hazards regression models. ResultsOf 436,469 participants (mean [SD] age, 56.4 [8.1] years; 54.5% women), 14,110 (3.2%) had CHIP. Over a median follow-up of 13.1 years, CHIP was significantly associated with an increased risk of incident cataract (Hazard Ratio [HR], 1.08; 95% CI, 1.03-1.14), AMD (HR, 1.12; 95% CI, 1.04-1.21), and DR (HR, 1.41; 95% CI, 1.20-1.64). No significant association was found with glaucoma (HR, 1.08; 95% CI, 0.99-1.17). The risk for AMD was primarily associated with smaller clones (VAF <10%), while the risk for DR was highest with non-DNMT3A mutations. Systemic inflammation, particularly neutrophil count, partially mediated the associations. Conclusions and RelevanceIn this study, CHIP was independently associated with a higher risk of developing cataract, AMD, and DR, but not glaucoma. These findings establish a link between hematopoietic somatic mutations and the pathogenesis of several major age-related eye diseases, suggesting that CHIP-driven inflammation is a potential target for risk stratification and prevention. Key PointsO_ST_ABSQuestionC_ST_ABSIs clonal hematopoiesis of indeterminate potential (CHIP) associated with the risk of major age-related eye diseases? FindingsIn this cohort study of 436,469 participants, CHIP was associated with an increased risk of incident cataract (HR, 1.08; 95% CI, 1.03-1.14), age-related macular degeneration (HR, 1.12; 95% CI, 1.04-1.21), and diabetic retinopathy (HR, 1.41; 95% CI, 1.20-1.64), but not glaucoma. MeaningThese findings identify CHIP as an independent, non-ocular risk factor for cataract, AMD, and diabetic retinopathy, suggesting that systemic inflammation driven by CHIP contributes to the pathogenesis of these conditions and may represent a novel target for preventive strategies.

Semaglutide has shown benefit in metabolic dysfunction-associated steatohepatitis (MASH), but real-world evidence across longitudinal liver phenotypes remains limited, particularly regarding how liver remodeling relates to weight loss and dose exposure. Using a de-identified federated electronic health record network spanning more than 29 million patients in the United States, including 489,785 semaglutide-treated adults, we analyzed 6,734 patients with baseline liver disease burden. We find that higher attained pre-landmark (0-2 years) semaglutide dose was associated with lower post-landmark (2-4 years) risk of steatohepatitis, alcoholic liver disease, and all-cause mortality, whereas greater pre-landmark weight loss was associated with lower post-landmark risk of steatohepatitis, steatotic liver disease, and hepatorenal syndrome, indicating distinct dose- and weight-linked patterns of long-term liver benefits. These associations were notable because semaglutide prescribing was generally lower during the post-landmark period, raising the possibility of durable benefit beyond peak exposure. Towards better understanding mechanistic bases for liver protection, we performed a complementary longitudinal study of 326 adults with paired noninvasive liver elastography measurements before and after treatment initiation. Median liver stiffness decreased from 4.85 [3.02 - 7.20] to 3.9 [2.6 - 5.8] kPa after semaglutide initiation (median change = -0.38 kPa; p<0.001), with 194 of 326 patients (59.5%) showing lower follow-up stiffness. A clinically meaningful reduction of at least 20% was observed in 133 of 326 patients (40.8%), and 69 of 326 (21.2%) shifted to a lower fibrosis stage by prespecified elastography thresholds. Larger improvements were also seen in patients with higher baseline stiffness (p<0.001); notably 80% of patients with cirrhosis-range baseline stiffness ([&ge;]12.5 kPa) achieved [&ge;]20% improvement versus 29.5% with minimal baseline disease (p <0.001). The proportion achieving at least 20% stiffness improvement was similar across weight-loss strata, including patients with no weight loss or weight gain and those with at least 10% weight loss (38.0% in each group), and liver stiffness change showed negligible correlation with changes in weight, BMI, HBA1c, alanine aminotransferase, or aspartate aminotransferase. To provide biological context, single cell RNA analyses demonstrated sparse overall hepatic GLP1R expression (0.0239%), with enrichment in non-parenchymal niches including cholangiocytes, intrahepatic cholangiocytes, liver sinusoidal endothelial cells, and hepatic stellate cells implicated in fibrogenesis and vascular remodeling. Together, this real-world evidence suggests diverse liver benefits for semaglutide beyond weight-loss with intricate dose response relationships.

Although several ancillary tests are available in limited laboratories, diagnosis of microphthalmia (MiT)/TFE family translocation renal cell carcinoma (tRCC) could be challenging due to diverse and overlapping tumor morphology and the lack of reliable biomarkers. GPNMB has been recently identified as a diagnostic marker for various renal neoplasms with FLCN/TSC/mTOR-TFE alterations. However, the sensitivity and specificity of GPNMB immunostain are suboptimal and the result interpretation in ambiguous cases could be difficult. To search additional biomarkers that could improve the screening sensitivity and predict genetic aberrations in FLCN/TSC/mTOR-TFE pathway in renal tumors, we performed bioinformatic analysis of publicly available cancer databases and found GPR143, a transmembrane protein regulated by MiT transcription factors, was highly expressed in a subset of renal cell carcinomas (RCCs). In two the Cancer Genome Atlas (TCGA) kidney cancer cohorts, RCCs with high levels of GPR143 expression were enriched for renal neoplasms with FLCN/TSC/mTOR-TFE alterations. Similar to GPNMB labeling, GPR143 immunostain was positive in the majority of tRCC cases and renal tumors with FLCN/TSC/mTOR alterations, suggesting that GPR143 could function as another surrogate marker for FLCN/TSC/mTOR-TFE alterations in certain renal tumors. Interestingly, despite the concordant GPR143 and GPNMB immunoreactivity in most renal neoplasms with FLCN/TSC/mTOR-TFE alterations, diffuse GPR143 immunostain was observed in some cases with negative or focal GPNMB labeling. Taken together, our results indicate GPR143 could serve as a useful adjunct marker to improve the sensitivity for screening renal tumors with FLCN/TSC/mTOR-TFE alterations.

Background & AimsMetabolic disorders such as dyslipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and diabetes are promoted by chronic pro-inflammatory and pro-oxidative states. Paraoxonase 1 (PON1), a liver-derived HDL-associated enzyme, plays an important antioxidant role by hydrolyzing oxidized lipids and protecting against oxidative stress- induced damage. Genetic variation in PON1, particularly in promoter and coding regions, modulates enzyme expression and activity, thereby influencing susceptibility to metabolic and cardiovascular diseases. This study investigated the genetic determinants of serum paraoxonase (PONase) activity and their relationship with dysmetabolic phenotypes. MethodsA genome-wide association study was conducted in 922 Portuguese individuals from the PREVADIAB2 cohort. Genetic variants and haplotypes related to PONase activity were analyzed, and associations with dysglycemia and liver fibrosis were evaluated in individuals aged over 55 years. ResultsWe identified two key PON1 variants as determinants of PONase activity: rs2057681 (in strong linkage disequilibrium with the non-synonymous Q192R variant) and rs854572 (located in the promoter region). Analysis of rs854572-rs2057681 haplotypes revealed that specific combinations differentially modulate PONase activity and confer risk or protection for dysglycemia and liver fibrosis, depending on the rs2057681 genotype context. Notably, although PONase activity was strongly associated with PON1 variants, it did not directly correlate with dysmetabolic phenotypes, suggesting that genetic context and haplotype structure, rather than enzyme activity alone, shape disease susceptibility. ConclusionsThese findings highlight the complex genetic architecture of PON1 and its role in metabolic disease risk, supporting the use of PON1 genetic information to uncover predisposition to dysmetabolic conditions. Our results provide insights into the interplay between PON1 genetics, enzyme function, and dysmetabolism, with implications for risk stratification in metabolic liver disease. Lay SummaryPON1 is a liver-derived gene that encodes an enzyme involved in protection against oxidative stress, a key contributor to metabolic liver disease and diabetes. In this study, we found that specific combinations of PON1 genetic variants are associated with abnormalities in blood glucose regulation and with markers of liver fibrosis. These associations were dependent on genetic configuration rather than enzyme activity alone, suggesting that PON1 genetic information may help identify individuals at higher risk of metabolic liver disease.

Purpose: To identify the ocular biometric parameters associated with refractive outcomes in Chinese Primary angle closure glaucoma (PACG) patients receiving phacoemulsification and intraocular lens (IOL) implantation (PEI) surgery. Methods: 165 Chinese PACG patients receiving PEI and goniosynechialysis (GSL) and 53 cataract patients as controls only receiving PEI surgery were recruited. The prediction accuracy of IOL power calculation was assessed by the prediction error (PE), mean absolute error (MAE), median absolute error (MedAE), and proportions of eyes with a PE within {+/-} 0.25 diopters (D), {+/-} 0.50 D, {+/-} 0.75 D, and {+/-} 1.00 D. The association of different ocular biometric parameters with the PE of IOL calculation were evaluated. Results: The PACG patients had significantly higher absolute of PE as compared to the control subjects, especially the acute PACG patients. The axial length (AL), changes in aqueous depth pre- and post-surgery ({bigtriangleup}AD), and the ratio of {bigtriangleup}AD/AL were significantly associated with the PE in acute PACG patients. The association of {bigtriangleup}AD with the PE of IOL power calculation was found in PACG patients with AL [&ge;] 22 mm. Conclusions: This study revealed the association of AL and {bigtriangleup}AD with the PE of IOL calculation in Chinese PACG patients. Precisely predict the {bigtriangleup}AD is necessary for acute PACG patients, especially for those with AL [&ge;] 22 mm, to improve the refractive outcomes.

BackgroundPreterm birth is one of the most significant etiologies for neonatal morbidity and mortality. Preterm delivery is classified as iatrogenic preterm delivery and spontaneous preterm delivery. The role of placental pathology is studied. Materials and methodsWe have previously collected placental pathology data with maternal pregnancy and neonatal birth data, and we investigated the role of placental pathology in preterm delivery. Preterm delivery was categorized as late preterm (34-36 weeks), moderate preterm (32 to 33 weeks), and extreme preterm (less than 32 weeks). Neonatal, maternal, placental gross and histologic features, and laboratory parameters were compared across groups using chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables using various programs in R-package. ResultsTotally 3723 singleton placentas including 3307 term (88.8%) and 416 preterm placentas (11.2%) were examined with maternal pregnancy data and neonatal birth data. There were 614 placentas from patients with preeclampsia/pregnancy induced hypertension (PRE/PIH) (16.5%). Preterm delivery showed significantly lower fetal birth weight, placental weight, and fetal-placental ratio (all p<0.01). Maternal Black race was more prevalent in preterm groups (up to 50.8% in extreme preterm vs. 33.2% in term, p<0.01). Preterm delivery was statistically associated with PRE/PIH and maternal vascular malperfusion (MVM), maternal and fetal inflammatory response (MIR and FIR), and increased pre-delivery white blood count (WBC). Extreme preterm deliveries were markedly associated with intrauterine fetal death (27.5%, p<0.01) and MIR/FIR (56.7%, p<0.01). After excluding PRE/PIH patients, preterm delivery was statistically associated with MIR/FIR and increased WBC. ConclusionsDistinct clinicopathologic profiles exist across preterm subcategories, with MVM predominating in late/moderate preterm and severe pathologic features (including fetal demise and acute inflammation) in extreme preterm. These findings highlight heterogeneous etiologies of preterm delivery.

Wastewater surveillance (WWS) is established as a vital tool for monitoring polio and SARS-CoV-2 with potential to improve surveillance for many other infectious diseases. This study evaluated the feasibility of detecting measles virus (MeV) RNA in wastewater as part of a national WS preparedness trial in Brisbane, Australia, from March to June 2025. Composite and passive sampling methods were employed in parallel at three wastewater treatment plants serving populations between 230,000 and 584,000. Nucleic acids were extracted and analyzed using RT-qPCR targeting MeV N and M genes to distinguish wild-type and vaccine strains. MeV RNA were detected in both 24-hour composite and passive samples on May 26 to 27, 2025 from the largest catchment of 584,000 which also included an international airport. No measles cases were reported in this city or region within 4 weeks of the WS detections. These were confirmed as vaccine-derived measles virus (MeVV) strain via specific RT-qPCR assay. Extraction recoveries varied (11.5% to 70.5%), with passive sampling showing higher efficiency. This is the first report of use of passive samples for detection of MeV. These findings are consistent with other studies reporting WWS results of both MeVV genotype A and wild type genotype B and/or D. It demonstrates the potential for sensitive MeV WWS with rapid differentiation of MeVV from wild type MeV shedding, including in airport transport hubs and with different sample types. Use of WWS could strengthen measles surveillance by enabling rapid detection of MeV RNA and supporting outbreak preparedness and response. This requires optimised methods which are specific to or differentiate wild-type MeV from MeVV. Furthermore, the successful detection of MeV using passive sampling in this study highlights its potential for deployment in diverse global contexts which may include non-sewered settings.

BackgroundThe World Health Organization has developed several global template protocols for epidemiological investigations, including for household transmission investigations (HHTIs). These investigations facilitate rapid characterisation of novel or re-emerging respiratory pathogens and support evidence-based public health actions. Beyond technical readiness, community buy-in is central to the feasibility and acceptability of HHTIs. Research is needed to determine the perceived legitimacy among the community to inform local protocol adaptation and development of implementation plans that consider community attitudes and needs. MethodsIn 2025, we conducted a convenience survey of community members living in Victoria, Australia to explore: their understanding of emerging respiratory diseases; their willingness to take part in public health surveillance activities such as HHTIs; the acceptability of clinical and epidemiological data collection and respiratory/blood sample collection as main components of HHTIs, and; participant comfort towards including their companion animals in HHTIs. ResultsWe received 282 survey responses, of which 235 were included in the analysis dataset. Compared to the general Victorian population, our participants included a higher proportion of participants who reported being female, tertiary-educated, of Aboriginal and/or Torres Strait Islander heritage, born in Australia and speaking only English at home. Participants indicated overall high levels of comfort and acceptability towards participation in HHTIs, particularly in relation to clinical and epidemiological data collection, with lesser but still high levels of comfort with providing multiple respiratory specimens in a 14-day period. Participants were least comfortable with other specimens such as urine and blood. Involving companion animals in HHTIs was similarly acceptable as human-focused components. ConclusionsDespite our survey population being non-representative of the general Victorian population, our findings provide valuable descriptive insights into the acceptability of HHTIs in Victoria, Australia from which to benchmark future local and international surveys and community engagement activities.

We used 2492 whole genome sequences from Laos to investigate the molecular epidemiology of SARS-CoV-2 from 2021 through 2024, covering the major waves of COVID-19 disease in Laos including time periods of travel restrictions and after relaxation of travel across international borders. We identify successive waves of COVID-19 caused by shifts in the dominant lineage, beginning with the Alpha variant in April 2021 and continuing through the Delta and Omicron variants. We quantify a shift from a small number of viral introductions responsible for widespread transmission in early waves to a larger number of introductions for each variant after travel restrictions were lifted, and identify potential routes of introduction into the country. Our study underscores the importance of genomic surveillance to public health responses to characterize viral transmission dynamics during pandemics.

BackgroundTimely cancer diagnosis in children and adolescents is critical to improving outcomes, yet substantial variation in diagnostic intervals persists across cancer types and care settings. We aimed to quantify time to diagnosis and assess variations by patient, demographic, and system-level factors. MethodsWe conducted a retrospective population-based study of children and adolescents aged 0-19 years diagnosed with one of 12 common cancers between 2010 and 2022 in Quebec, Canada. The diagnostic interval was defined as the time from first cancer-related healthcare encounter to diagnosis. We calculated medians and interquartile ranges (IQR) overall and by cancer type and used multivariable quantile regression to identify factors associated with time to diagnosis at the 25th, 50th, and 75th percentiles. ResultsAmong 2,927 individuals with cancer, diagnostic intervals varied by cancer type and age. Median intervals were longest for carcinomas (100 days; IQR 33-192) and shortest for leukemias (8 days; IQR 3-44). Compared with children living in Montreal, living in regional areas and other large urban centres was associated with longer 50th and 75th percentiles of time to diagnosis for hepatic and central nervous system (CNS) tumours. Diagnostic intervals were shorter in the post-pandemic period (2020-2022) across several cancer sites, with CNS tumours showing reductions across all quantiles. InterpretationDiagnostic timeliness differed by cancer type, age, and rurality, but not by sex, material, or social deprivation. The shorter diagnostic intervals observed in the post-pandemic period suggest that pandemic-related changes in care pathways may have expedited diagnosis for some cancers.

ObjectivesWe determined the frequency of sexually transmitted infection (STI) testing among people accessing sexual health services (SHS) in England. MethodsWe assessed STI testing frequency in face-to-face and online SHSs in England using data from the GUMCAD STI surveillance system. We quantified different combinations of tests (e.g. single chlamydia test or full STI screen), number of tests completed in 2024 and test positivity by sociodemographic and behavioural characteristics, as well as clinical setting and outcomes. ResultsOverall, there were 2,222,028 attendances at SHS in England in 2024 that involved tests for chlamydia, gonorrhoea, syphilis and/or HIV. Most of these attendances involved tests for all four of these STIs. Most people accessing SHS in England tested once (80.1%), and a small minority (1.9%) tested at least quarterly (4+ times). Some groups had a comparably larger proportion of quarterly testers; these included gay, bisexual, and other men who have sex with men (GBMSM) (6.7%), London residents (3.6%), online testers (2.5%), people using HIV-PrEP (13%), and people with 5+ partners in the previous 3 months (10.6%). Only 10.5% of GBMSM reporting higher-risk sexual behaviours tested quarterly despite recommendations for quarterly testing in this group. ConclusionsThe majority of those who tested for STIs in England in 2024 only tested once. The minority who tested at least quarterly had a higher proportion of GBMSM, people using HIV-PrEP, London residents and people reporting higher risk behaviours. Quarterly testing often appears to be aligned with current testing recommendations in England; however, we also observed that only a low proportion of behaviourally high-risk GBMSM and HIV-PrEP users are meeting these recommendations. It is important to acknowledge groups with lower or higher testing frequency when developing interventions and updating guidelines related to STI testing. WHAT IS ALREADY KNOWN ON THIS TOPICThe effectiveness of asymptomatic testing for chlamydia and gonorrhoea in gay, bisexual and other men who have sex with men (GBMSM), and the potential impact of the consequent increased antibiotic use on rising antimicrobial resistance and individual harm has recently been questioned. Testing and treatment remains a key pillar of STI prevention and management; despite this, there is limited evidence of STI testing frequency within sexual services (SHS) on a national level. WHAT THIS STUDY ADDSThis analysis shows that the majority of people attending SHSs in England in 2024 tested once, and only a small proportion of behaviourally high-risk people tested frequently. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYAwareness of groups that are behaviourally high risk but testing infrequently is important to guide interventions and messaging regarding STI testing. The low levels of frequent testing, even among those who would be recommended quarterly testing under UK guidelines, provides important context for wider discussion around asymptomatic STI screening.

Wearable-derived physiological features have been associated with disease risk, but most current studies focus on single conditions, limiting understanding of cross-disease patterns. This study adopts a trans-diagnostic approach to examine whether wearable data capture shared and condition-specific physiological signatures across multiple chronic conditions spanning physical and mental health, and then evaluates the utility of these features for disease classification. A total of 9,301 patients with at least 21 days of consecutive FitBit data from the All of Us Controlled Tier Dataset version 8 were analyzed. Disease subcohorts included cardiovascular disease (CVD), diabetes, obstructive sleep apnea (OSA), major depressive disorder (MDD), anxiety, bipolar disorder, and attention-deficit/ hyperactivity disorder (ADHD), chosen based on prevalence and relevance. Logistic regression and XGBoost models were fitted for each disease subcohort versus the control cohort. We found that compared to using just baseline demographic and lifestyle features, incorporating wearable-derived features enabled improved classification performance in all subcohorts for both models, except for ADHD where improvement was mainly observed for ROC-AUC in logistic regression model likely due to the smaller sample size in ADHD subcohort. The largest performance gains were observed in MDD (increase in ROC-AUC of 0.077 for Logistic regression, 0.071 for XGBoost; p < 0.001) and anxiety (increase in ROC-AUC of 0.077 for logistic regression, 0.108 for XGBoost; p < 0.001). This study provides one of the first comprehensive transdiagnostic evaluations of wearable-derived features for disease classification, highlighting their potential to enhance risk stratification in the real-world setting as a practical complement to clinical assessments and providing a foundation to explore more fine-grained wearable data. Author summaryWearable devices such as fitness trackers and smartwatches are becoming increasingly popular and affordable, providing continuous measurements of heart rate, physical activity, and sleep. Alongside the growing digitization of health records, this creates new opportunities for large-scale, real-world health studies. In this study, we analyzed wearable-derived physiological patterns across a range of chronic conditions spanning both physical and mental health to better understand how these signals relate to disease risk. We found that incorporating wearable-derived heart rate, activity and sleep features improved disease risk classification across several conditions, with particularly strong gains for major depressive disorder and anxiety. By examining how individual features contributed to model predictions, we also identified meaningful associations between physiological signals and disease risk. For example, both duration and day-to-day variation of deep and rapid eye movement (REM) sleep were associated with increased risk in certain conditions. Our study supports the development of real-time, automated tools to assess disease risk alongside clinical care.

Childhood socioeconomic position (SEP) can have lifelong effects on health. Many studies have used adult height as a surrogate marker for early-life conditions. In this study, we derived the non-genetic component of height, calculated as the residual from sex-specific standardized height regressed on genetically predicted height, as a surrogate for childhood SEP, using data from the Hispanic Community Healthy Study/Study of Latinos (2008-2011). A positive residual would indicate favorable early-life conditions promoting growth, while a negative residual indicates early-life adversity that may stunt the development. The height residual was associated with early-life variables such as parental education, year of birth, US nativity and age at first migration to the US (50 states/DC), supporting the validity of height residual as a surrogate for early-life conditions. Furthermore, a height residual was positively associated with better cardiovascular health (CVH) and cognitive function among middle-aged and older adults. Interestingly, among <35 years old, the height residual was negatively associated with the "Lifes Essential 8" clinical CVH scores. These results suggest the non-genetic component of height as a surrogate for childhood environment, with predictive value for CVH and cognitive function.

BackgroundAccelerometer-derived behavioral phenotype captures multidimensional aspects of human behavior extending well beyond physical activity, encompassing light exposure, step counts, physical activity patterns, sleep, and circadian rhythms. Whether these five domains constitute a unified behavioral architecture underlying cancer risk and whether circadian organization and light exposure confer incremental predictive value beyond movement volume alone remains to be comprehensively established. MethodsWe conducted an accelerometer-wide association study (AWAS) encompassing the complete accelerometer-derived behavioral exposome across five behavioral domains in UK Biobank participants with valid wrist accelerometry data. Incident solid cancers were designated as the primary endpoint, with prespecified site-specific solid cancers and hematological malignancy as secondary outcomes. Cox proportional hazards models with age as the timescale were used. The minimal covariate set served as the primary reporting tier, followed by sensitivity analyses additionally adjusting for adiposity/metabolic factors, independent activity patterns, shift work history, and accelerometry measurement quality. Nominal statistical significance was defined as two-sided P < 0.05 ResultsAmong 89,080 participants, 6,598 incident solid cancer events were observed over a median follow-up of 8.39 years. In the minimally adjusted model, the pan-solid-tumor association atlas was dominated by signals from activity volume, inactivity fragmentation, and circadian rhythm. Higher overall acceleration (HR per SD: 0.91, 95% CI: 0.89-0.94) and higher daily step counts (HR: 0.93, 95% CI: 0.90-0.95) were independently associated with reduced solid cancer risk, while inactivity fragmentation metrics were consistently linked to higher risk. Notably, circadian rhythms, most prominently cosinor mesor (Midline Estimating Statistic of Rhythm under cosinor model), emerged as leading inverse risk signals, underscoring the independent contribution of circadian behavioral architecture. Site-specific analyses revealed pronounced heterogeneity across tumor sites. Lung cancer exhibited a robust inverse activity-risk gradient, while breast cancer showed reproducible associations with MVPA. Most strikingly, nocturnal light exposure demonstrated a tumor-site-specific association confined to pancreatic cancer, a signal absent across all other sites examined. Associations for uterine cancer were predominantly inactivity-related and substantially attenuated following adjustment for adiposity and metabolic factors. ConclusionsAcross five accelerometer-derived behavioral domains, solid cancers as a whole were most consistently associated with a high-movement, low-fragmentation, and circadian-coherent behavioral profile. While site-specific heterogeneity exists, the broad cancer risk landscape is dominated by movement volume, inactivity fragmentation, and circadian rhythmicity. Light exposure, although more localized in its contribution, demonstrates a potentially novel and specific association with pancreatic cancer risk. These findings support a five-domain behavioral exposome framework for cancer epidemiology and, importantly, position circadian rhythm integrity and nocturnal light exposure as critically understudied dimensions warranting dedicated mechanistic investigation.

Background: Dengue is rapidly emerging in parts of Europe. How households value vector control attributes, and whether inferences depend on decision models or message framing, is unclear. Methods: We conducted a split-ballot online experiment among adults in Italy and France, as well as a hotspot subsample from Marche, Italy. National samples included 1,505 respondents in Italy and 1,501 in France; 183 respondents were recruited in Marche. Participants were randomised to a discrete choice experiment (random utility maximisation) or a regret-based choice experiment (random regret minimisation) and to one of three pre-task messages (control, loss aversion, community values). Each respondent completed 12 choice tasks comparing two dengue control programmes and an opt-out. We estimated mixed logit and mixed random-regret models with random parameters and treatment effects. Results: Across frameworks, nearby cases and high mosquito prevalence were the dominant drivers of programme uptake, whereas cost and operational burden were secondary. In pooled analyses, loss-aversion messaging increased the weight on high mosquito prevalence in both models (from 0.483 to 0.547 in the utility model; from 0.478 to 0.557 in the regret model). Cost effects were small nationally but larger in the hotspot subsample. Conclusions: Risk salience dominates preferences for dengue vector control in these European settings. Random utility and random regret models yield consistent rankings of attributes but differ in behavioural interpretation and some secondary effects; messaging effects were modest and context dependent.

BackgroundFamily-based HIV index case testing identifies family members with unknown HIV status and links them to care. Data are limited in southern Ethiopia. MethodsA facility-based cross-sectional study was conducted among 377 adults on antiretroviral therapy (ART) in Wolaita Zone, Southern Ethiopia, from November 2022 to May 2023. Participants were selected using systematic random sampling. Data were collected via interviewer-administered semi-structured questionnaire. Multivariable logistic regression identified factors associated with index case family testing. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were calculated, and statistical significance was declared at p < 0.05. ResultsThe proportion of index case family testing for HIV was 84.9% (95% CI: 81.2- 88.6). In multivariable analysis, urban residence (AOR = 2.8; 95% CI: 1.16-6.75), duration on ART greater than 12 months (AOR = 13.0; 95% CI: 4.6-36.9), disclosure of HIV status to family members (AOR = 5.6; 95% CI: 1.9-16.5), discussion of HIV status with family members (AOR = 6.6; 95% CI: 1.9-23.2), and being counselled by health professionals to bring families for testing (AOR = 6.3; 95% CI: 2.1-19.0) were significantly associated with index case family testing. ConclusionThe prevalence of family-based HIV index case testing in Wolaita Zone was 84.9%, below the national 95% target. Health professionals should strengthen counselling on ART adherence, status disclosure, family discussion, and active referral to improve testing uptake among family members of people living with HIV.

Study questionWhat are the characteristics and treatment outcomes of women who undertook planned egg freezing (PEF) in Australia and New Zealand between 2009 and 2023? Summary answerThere has been an average yearly increase in the uptake of PEF of 35%, with most women undergoing a single PEF procedure in their mid-thirties. Given ten years follow-up a little over one in four women return, with nearly half of those using donor sperm and one-third achieving a live birth. What is known alreadyPEF, where women freeze their eggs as a strategy to preserve fertility, has increased dramatically in high income countries in the last decade. Despite the rapid uptake of PEF, there remains limited information to guide women, clinicians and policy makers regarding the characteristics of women undertaking this procedure and treatment outcomes. Study design, size, durationA retrospective population-based cohort study of all women who undertook PEF in Australia and New Zealand between 2009 and 2023, including their subsequent return to thaw their eggs and treatment outcomes. Where women returned to utilise their eggs, all subsequent embryo transfer procedures were linked enabling calculation of live birth rates per woman. Participants/materials, setting, methods20,209 women who undertook PEF in Australia and New Zealand between 2009 and 2023 including 1,657 women who returned to thaw their eggs. Main results and the role of chanceThere has been a huge increase in uptake of PEF, from 55 women in 2009 to 4,919 in 2023. Women who freeze their eggs are typically aged 34-38 years (interquartile range) and nulliparous (98.6%). For women with at least 10 years follow-up (i.e. undertook PEF in 2009-13; N=514), 27.9% returned and thawed their frozen eggs (average time to return: 4.9 years). This reduced to 22.1% in those with at least 5 years follow-up (i.e. undertook PEF in 2009-2018; N=4,288). Of those who used their frozen eggs, 47% used donor sperm. After at least two years follow up, 33.9% had a live birth, rising over time to 37.8% for eggs thawed between 2019-2021. Limitations, reasons for cautionIn the timeframe 2009-2019 we did not have information on whether egg freezing occurred because of a cancer diagnosis, a cohort we wished to exclude from the study. As a result, for this timeframe we weighted observations by the probability that egg freezing occurred due to cancer, with the prediction model developed on the years 2020-2023. Wider implications of the findingsThis study provides recent and comprehensive data on PEF to guide prospective patients and clinicians and inform policy. The exponential growth in PEF in Australia and New Zealand mirrors trends in other high-income countries, suggesting a doubling time of 2-3 years. Study findings highlight the need for setting realistic expectations about the likelihood of returning to use frozen eggs and live birth rates. Study funding/competing interest(s)2020-2025 MRFF Emerging Priorities and Consumer Driven Research initiative: EPCD000014