The CRISPR Journal

Background: Ribavirin is a guanosine analogue with clinical antiviral activity against a range of RNA viruses including hepatitis C virus (HCV), respiratory syncytial virus and Lassa virus. Several potential mechanisms of action have been proposed, but there is limited data supporting them clinically. Methods: We studied 196 HCV-infected participants from a trial of short-course directly antiviral therapy (STOPHCV-1) which included a factorial randomisation to ribavirin versus no ribavirin. Deep sequencing of the HCV genome was performed on samples with detectable viremia from three time-points: baseline (n = 191), day 3 of treatment (n = 25) and post-treatment failure (n = 47). Results: Ribavirin exposure significantly increased total mutational load at treatment failure (P = 0.0065) and enriched classical ribavirin-associated transitions, including G->A (P = 0.026) and C[->]U (P = 0.004), along with other key changes including A->G (P = 0.005), U->C (P = 0.023), C->G (P = 0.010), and U->A (P = 0.026). The resulting mutational signature was broad, not dominated by G-related changes. Region-specific analyses demonstrated this increase was broadly distributed across the viral genome, without strong evidence for protection of specific regions. Non-synonymous to synonymous mutation ratios (dN/dS) rose at day 3 (P = 5.5e-5) before declining at failure (P = 8.5e-7), with trends toward higher dN/dS in the ribavirin group at day 3 (P = 0.06). Conclusions: Ribavirin acts as a potent in vivo mutagen, driving viral populations toward genome-wide diversity rather than selecting a few highly fit drug-resistant clones. These findings support an error-catastrophe model.

PurposeAntibodies to Epstein-Barr virus (EBV) proteins can predict nasopharyngeal carcinoma (NPC) risk. We previously defined a prototype EBNA1 protein panel and multiplex immunoblot assay that distinguishes NPC risk several years pre-diagnosis. Assay throughput and specificity are critical to effectively implement a population-level screening program. Here, we developed a strip test assay - EBNA1 SeroStrip-HT - with an objective to increase throughput and maximize specificity. Experimental DesignEBNA1 full-length (FL) and glycine-alanine repeat deletion mutants (dGAr) were purified from insect and mammalian cells to screen serum IgA/IgG from prospective cohorts in Singapore and Shanghai, China, with known time intervals to NPC diagnosis. Twenty pre-diagnostic sera within 4 years to diagnosis were compared to 96 healthy controls using a nested case-control study design. ResultsIgA to mammalian-derived EBNA1 dGAr achieved 85.0% sensitivity and 94.8% specificity (AUC, 0.939) for NPC status. IgA to insect-derived EBNA1 dGAr showed the same sensitivity (85.0%) and similar specificity (93.8%) (AUC, 0.941). IgA to insect-derived EBNA1 FL had a higher 90% sensitivity, but lower 91.7% specificity (AUC, 0.940). Combining EBNA1 FL and dGAr results showed that subjects positive for both proteins had a 243.67 odds ratio for NPC incidence compared to double-negative scores. ConclusionThis study demonstrated the efficacy of EBNA1 SeroStrip-HT for NPC risk assessment and stratification in high- and intermediate-risk populations, yielding high accuracy and a 12-fold increased throughput over the prototype. The insect system was appropriate for large-scale production of purified EBNA1. Larger, geographically diverse cohorts are warranted to confirm these results, especially in low-incidence populations.

Objective Cerebral palsy (CP) affects approximately 1 million Americans and 18 million individuals worldwide, yet contemporary US epidemiologic data remains limited. We aimed to use Cerebral Palsy Research Network (CPRN) clinical registry to describe demographics and clinical characteristics of individuals with CP across the US and determine associations with gross motor function and genetic etiology. Methods Registry subjects were included if they had clinician-confirmed CP and prospectively entered data for Gross Motor Function Classification System (GMFCS) Level, gestational age, genetic etiology, CP distribution, and tone/movement types. Logistic regression was used to determine which of these variables plus race, sex, ethnicity, and age were associated with GMFCS level and genetic etiology. Results A total of 9,756 children and adults with CP from 22 CPRN sites met inclusion criteria. Participants were predominantly White (73.0%), male (57.3%), non-Hispanic (87.8%), and younger than 18 years (73.7%). Most were classified as GMFCS levels I-III (55.6%), born preterm (52.8%), had spasticity (83.8%), and had quadriplegia (41.9%); 12.2% were identified as having a genetic etiology. Tone/movement types, CP distribution, and gestational age were significantly associated with both GMFCS level and genetic etiology (p<0.001). Compared to White individuals, Black individuals were more likely to have greater gross motor impairment (p<0.001). Conclusion In this large US cohort, clinical and demographic factors, including race, were associated with gross motor function and genetic etiology in CP. These findings highlight persistent disparities and demonstrate the value of a national clinical registry for informing prognostication, quality improvement efforts, and targeted genetic testing strategies.

Antimicrobial resistance (AMR) is a growing global public health threat that complicates the treatment and control of bacterial infections. Shigella spp., a leading cause of bacterial diarrhea worldwide, has increasingly exhibited resistance to multiple antimicrobial agents that are commonly recommended therapy for severe shigellosis. Although conventional antimicrobial susceptibility testing (AST) remains the reference standard, it is time-consuming and provides limited insight into the genetic mechanisms underlying resistance. Whole-genome sequencing (WGS) has emerged as a complementary approach for AMR detection by enabling direct identification of resistance genetic determinants encoded in bacterial genomes. Machine learning (ML) methods applied to genomic features such as k-mers have shown promise for predicting resistance phenotypes from WGS data; however, applications to Shigella remain limited. In this study, we developed and evaluated an interpretable ML framework for predicting ciprofloxacin resistance using k-mer features derived from WGS data of 1,424 Shigella isolates collected in Ontario, Canada, between 2018 and 2025. K-mers were extracted from known gene targets associated with ciprofloxacin resistance, including chromosomal quinoline resistance-determining regions (QRDRs: gyrA and parC) and plasmid-mediated determinants (qnr). Supervised ML approaches were trained and compared. We evaluated the influence of k-mer lengths (k=11, 15, 21 and 31) on predictive performance and model interpretability; and compared models based on chromosomal determinants alone and models incorporating both chromosomal and plasmid-mediated determinants. Randon Forest classifier achieved the most consistent performance across models. Inclusion of plasmid-mediated determinants improved predictive accuracy relative to chromosomal-only models. Although differences across k-mer lengths were modest, k = 11 produced the highest area under the receiver operating characteristic curve (AUC) and the lowest Brier score. SHAP analyses localized high-impact features within QRDRs of gyrA and parC, supporting biological interpretability. These findings demonstrate that biologically-informed k-mer-based ML models can accurately and transparently predict ciprofloxacin resistance in Shigella, supporting their potential integration into genomic AMR surveillance and digital public health frameworks. Author summaryIn this study, we used genome sequencing data to develop machine learning models that predict ciprofloxacin resistance for Shigella directly from bacterial DNA. We focused on small DNA fragments (k-mers) derived from known resistance genes and mutations. Among the approaches tested, a Random Forest model showed the most consistent performance. Combining chromosomal mutations with plasmid-mediated resistance genes improved prediction accuracy and helped identify key genetic regions associated with resistance. These findings demonstrate that machine learning applied to genomic data can accurately and interpretable predict antibiotic resistance, supporting its potential use in genomic surveillance and public health monitoring.

ObjectivesEpidural spinal cord stimulation (SCS) is an emerging therapy for motor rehabilitation following spinal cord injury (SCI) and other motor disorders. Conventionally, SCS leads are placed along the dorsal spinal cord (SCSD), where stimulation activates large diameter afferent fibers, which indirectly activate motoneurons through reflex pathways. This leads to broad activation of flexor and extensor muscles and limited fine-tuned control of motor output. Targeting the ventral spinal cord (SCSV) may enable more direct activation of motoneuron pools, potentially improving the specificity of muscle activation; however, there is currently no established method to place leads ventrally. To address this, we evaluated the feasibility of four modified percutaneous implantation techniques to target the ventrolateral thoracolumbar spinal cord. Materials and methodsPercutaneous SCSV implantation was performed in three human cadaver torso specimens under fluoroscopic guidance. The following approaches were evaluated: sacral hiatus, transforaminal, interlaminar contralateral, and interlaminar ipsilateral. The leads in the latter 3 approaches were inserted between L1 and L5. Eighteen implants were attempted, with nine leads retained for analysis. Lead and electrode position were assessed using computed tomography (CT) with three-dimensional reconstruction, along with anatomical dissection to verify lead and electrode placement within the epidural space. ResultsSuccessful ventral epidural lead placement was achieved using all four implantation approaches. The sacral hiatus (16/16 electrodes) and transforaminal (8/8 electrodes) approaches resulted in exclusively ventrolateral placement. The interlaminar contralateral approach led to 27/32 electrodes positioned ventrolaterally and 5/32 dorsally. The interlaminar ipsilateral implantation approach led to 14/32 electrodes positioned ventrolaterally and 18/32 positioned ventromedially. ConclusionsThese findings demonstrate that ventral epidural SCS lead placement can be achieved using modified percutaneous implant techniques. The four approaches outlined here provide a clinically feasible pathway to SCSV and establishes a foundation for future clinical studies investigating SCSV for motor rehabilitation following SCI.

BackgroundCarrier screening for inherited genetic disorders can reduce the burden of conditions that lead to childhood morbidity and mortality, including thalassaemia, cystic fibrosis, and spinal muscular atrophy. To be successful, national carrier screening programs should aim to maximise uptake, which may depend on population preferences for screening characteristics. In this study, we aimed to determine how expanded carrier screening in Singapore should be designed based on operational factors including suggested copayments, wait times, and disorders included in screening panels. MethodsWe elicited stated preferences for the design of a hypothetical national carrier screening program with seven attributes from 500 Singaporeans of reproductive age (18 to 54). A discrete choice experiment was applied using 30 choice tasks with 3 alternatives per task, divided between 3 blocks. The mixed multinomial logit model was used to estimate willingness-to-pay for each attribute level. Predicted uptake for three plausible screening programs was assessed, with copayment amounts from $0 to $1,200 in increments of $30. Impact on the annual national budget was calculated as a function of 25,000 expected eligible couples per year. All costs were reported in 2026 SGD. ResultsRespondents showed the strongest preferences for cost, followed by the number of diseases included in the panel, then wait times, with limited impact of remaining attributes. With no copayments, predicted uptake ranged from 85% [95% CI: 83% to 87%] to 90% [88% to 92%] for the basic and utility-maximising screening programs, respectively. This declined to 61% [56% to 66%] and 69% [65% to 73%] and, respectively, at a copayment of $1,200 per test. The model predicted higher uptake if a selection of screening alternatives were available, compared to a single program. The budget impact was highly dependent on population eligibility, copayments, and couples decision-making processes, but was unlikely to exceed $22.5m [$19.0m to $26.6m] per year unless expanded beyond married couples. ConclusionsThere was high predicted demand for carrier screening even as copayments increased. Successful strategies to improve uptake may include reducing copays and wait times, increasing the number of screening options available to prospective parents, and increasing program eligibility beyond pre-conception married couples.

Background: The enterotype concept proposed that gut microbiomes cluster into discrete types, but subsequent critiques demonstrated that such clustering depends on methodological choices, that the number of clusters is not fixed, and that faecal samples cannot capture spatial heterogeneity along the gastrointestinal tract. The stomach remains particularly understudied, and no systematic classification exists for gastric microbial community types. Methods: We assembled a multi-cohort dataset of 566 gastric mucosal samples spanning healthy controls to gastric cancer, with both Helicobacter pylori (HP)-negative and HP-positive individuals. Critically, we applied the key methodological lessons of the enterotype debate: we used a variational autoencoder (VAE) for dimensionality reduction to learn a continuous latent representation without forcing discrete structure, determined the optimal number of clusters using the Silhouette index (an absolute validation measure) across K=2 to K=10 rather than arbitrarily selecting a cluster number, and performed transparent evaluation of multiple clustering solutions. This VAE-plus-silhouette workflow directly addresses the critiques leveled against the original enterotype analysis. Results: Four gastotypes were identified, with K=4 achieving the highest mean silhouette score, indicating good cluster cohesion and separation. Two gastotypes (Variovorax-type and Trabulsiella-type) were significantly enriched in HP-positive samples, while two gastotypes (Bacteroides-type and Streptococcus-type) were significantly enriched in HP-negative samples. Random Forest and Gradient Boosting achieved excellent baseline performance for predicting HP infection (AUC = 0.990 and 0.993). Conclusions: The VAE-plus-silhouette workflow provides a robust, data-driven approach for identifying gastotypes without forcing discrete structure or arbitrarily fixing cluster numbers. Using this framework, we identified four gastotypes with significantly different HP infection rates. Variovorax-type and Trabulsiella-type showed strong HP-positive enrichment, while Bacteroides-type and Streptococcus-type showed strong HP-negative enrichment. These findings demonstrate that methodological advances from the enterotype controversy can be successfully transferred to the stomach, offering a reproducible taxonomy for stratifying HP infection status with potential clinical utility.

Quantitative measures for tracking functional health have generally been lacking. Intrinsic capacity (IC) has been proposed as an appropriate measure, but its metrics have been derived in small datasets and sparse longitudinal data. Using harmonized measures of cognition, locomotion, sensory function, vitality, and psychological well-being from 501,615 UK Biobank participants and followed for a median of 15.5 years, we derived domain-specific and composite IC scores. We examined associations with incident disease, cause-specific mortality, multimorbidity, lifestyle and socioeconomic factors, and multi-omic profiles from Olink proteomics, NMR metabolomics, clinical biochemistry, and blood-cell traits. We found that composite IC declined non-linearly with age, and within-person decline was steeper than the cross-sectional age measures. Participants with greater baseline morbidity, those who subsequently developed incident disease, and those who died earlier in follow-up showed lower IC trajectories across adulthood. The IC domains were only modestly correlated with one another, supporting multidimensionality, yet higher overall IC was associated with lower risk of most diseases examined. The dominant IC domain varied by endpoint, with cognition informative for dementia, sensory function for hearing loss, psychological capacity for depression, locomotion for osteoarthritis, and vitality for cardiometabolic outcomes. IC was also associated cross-sectionally with physical activity, insomnia, smoking, medication burden, and socioeconomic disadvantage. More proteins were found predictive for vitality, and enrichment converged on immune/inflammatory and metabolic pathways. Blood-based surrogates recapitulated part of the phenotypic signal, particularly for vitality. Overall, this IC framework captures longitudinal health trajectories and broad disease vulnerability in a large middle- to older-aged cohort and supports IC as a clinically meaningful, multidomain phenotype of aging and identifies blood-based correlates that may facilitate at-scale future monitoring of aging-related function declines.

BackgroundThe rapid growth of the worlds urban population has contributed to the expansion of informal urban settlements in many cities across the world. In these settings, lack of safe sanitation combined with high population density and poverty contributes to heightened health risks for often vulnerable populations. The aim of this study was to evaluate the effect of a shared, onsite sanitation intervention on the nutritional status of children in Maputo, Mozambique. MethodsThe Maputo Sanitation (MapSan) trial was a controlled before-and-after study to evaluate the effect of a shared, onsite sanitation intervention on child health in Maputo, Mozambique. Here, we report the effects on childhood stunting, wasting and underweight, and height-for-age, weight-for-height and weight-for-age z-scores. Children were enrolled aged 1-48 months at baseline and outcomes were measured before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. The primary analysis was intention-to-treat. The trial was registered at ClinicalTrials.gov, number NCT02362932. ResultsWe enrolled 757 and 852 children in the intervention and control groups respectively. There was no evidence for an effect of the intervention on any outcome at 12 or 24 months of follow-up except for wasting where there was very weak evidence for an effect (adjusted prevalence ratio: 0.497; 95% CI: 0.22-1.11; p=0.09). In two exploratory analyses - one including only those children born into compounds post-intervention and a second excluding children in control compounds which had independently improved their sanitation facilities during follow-up - we found that stunting increased in the intervention group whilst wasting decreased. ConclusionsThis study contributes to the growing evidence on the role of sanitation in shaping child health outcomes in informal urban settlements. We found no evidence for an effect on stunting and weak evidence for an effect on wasting. More research is needed to understand how sanitation can reduce childhood undernutrition in complex urban environments.

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.

Background. Young sexual and gender minorities of color face compound health risks shaped by interlocking systems of racism, cisgenderism, and class inequality. Spatial health research documents that place shapes health, but existing methods cannot specify the mechanisms through which spatial configurations produce different health outcomes for differently positioned people. This gap prevents targeted intervention. ObjectiveTo develop and pilot test the Spatial Intersectionality Health Framework (SIHF), which specifies three mechanisms through which space produces intersectional health inequities: Layered (multiple oppressive systems activating simultaneously), Positional (the same space producing different health pathways by intersectional position), and Conditional (nominally protective spaces carrying hidden costs for specific positions). We also introduce and validate Intersectional Geographically-Explicit Ecological Momentary Assessment (IGEMA) as the methodology operationalizing SIHF across three data levels. MethodsThe GeoSense study enrolled 32 young sexual and gender minorities of color (ages 18-29) in New York City. IGEMA was implemented across three integrated levels: (1) GPS mobility tracking via participants personal smartphones, linked to census tract structural exposure indices across n=19 participants; (2) ecological momentary assessment of intersectional discrimination with multilevel modeling of mood, stress, and sleep outcomes; and (3) map-guided qualitative interviews with SIHF mechanism coding and intercoder reliability assessment across 92 coded records from 18 participants. This study was conducted as the pilot for NIH R01HL169503. ResultsAll three SIHF mechanisms were empirically detectable. A compound structural gendered racism index outperformed every single-axis alternative in predicting daily mood (b=-0.048, p=.001) and stress (b=0.121, p<.001). The Positional mechanism accounted for 71% of coded harm experiences. Intercoder reliability for mechanism assignment reached kappa=0.824 at Stage 2 reconciliation. Daily intersectional discrimination predicted greater sleep disturbance (b=1.308, p=.004). ConclusionsSIHF and IGEMA together provide an empirically testable framework for specifying how space produces intersectional health inequities. Mechanism specification, not spatial location alone, is the condition for designing research and intervention that reaches the source of harm for multiply marginalized populations.

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

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.

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.

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.