Evolution, Medicine, and Public Health

The basic reproduction number R0 confounds pathogen biology with adaptive human contact behavior. Earlier epidemiological--economic theory predicted a forward-looking behavioral contact response but could not test it in the absence of appropriate behavioral data. Using directly measured mobility as an observable proxy for contact, we (i) estimate the behavioral response function directly from data; (ii) show that the biology/behavior decomposition and hence the behavioral correction to R0 is not identified from an epidemic trajectory, the apparent constant-contact R0 being one endpoint of an observational-equivalence class that fits the factual curve identically yet diverges under counterfactual; and (iii) characterize that divergence ("what R0 deletes") as state-dependent, unimodal in counterfactual severity and vanishing when behavior saturates. We then show that, across US jurisdictions, the correction is empirically bounded because risk-responsiveness and behavioral non-saturation are confounded (r=-0.57, n=51): where behavior could compensate, it was already maximal, and where it was not maximal it did not respond. What R0 deletes is thus real and structurally characterizable yet empirically modest here, for reasons the framework itself supplies.

An epidemic's expected course is determined by the magnitude and timing of a typical person's infectiousness --- captured, in turn, by the basic reproduction number and the generation-time distribution. These fundamental, population-average quantities can mask individual-level variation that shapes how an epidemic actually unfolds: for example, individual variation in the magnitude of infectiousness (overdispersion) creates superspreading, a key feature of the SARS-CoV-1 and SARS-CoV-2 epidemics. However, the impact of individual variation in infectiousness timing is less well understood. Here, we demonstrate that individual infectiousness timing varies substantially and to different degrees across pathogens. For some common pathogens, including influenza, measles, and SARS-CoV-2, infectiousness is "bursty", or highly concentrated and variably-timed across individuals: for example, the window of appreciable infectiousness for SARS-CoV-2 may last for roughly a day, vs. the 9--12 days usually quoted. We show that bursty infectiousness creates superspreading without inherent superspreaders, makes epidemic timing more variable, amplifies the time-sensitivity of common interventions, and complicates inference of key epidemiological parameters. Together with the reproduction number, the generation-time distribution, and overdispersion, burstiness completes a family of basic parameters that govern how epidemics unfold.

Background. The 2018-2020 Ebola virus disease outbreak in the Democratic Republic of the Congo (DRC) was the country's largest, and the second largest globally, amid armed conflict and community mistrust. Transmission heterogeneity (superspreading) is recognised in Ebola epidemics, but empirical estimates of its extent and determinants remain scarce for DRC outbreaks. We quantified transmission heterogeneity and its determinants during this outbreak. Methods. In this retrospective observational study, we reconstructed transmission chains for confirmed and probable cases (Aug 1, 2018, to June 25, 2020) using routinely collected Ministry of Health and Medecins Sans Frontieres surveillance data. We modelled the offspring distribution with a Bayesian negative binomial framework, correcting for incomplete contact tracing, to estimate the effective reproduction number (Reff), dispersion parameter (k), and proportion of cases responsible for 80% of transmission (prop80), overall, by subgroup, and over time. Individual-level determinants were assessed with a regression extension, adjusting for covariates. Findings. Among 3481 cases, 2008 transmission events linked 2402 (69%) individuals into 415 chains (median size 3, range 2-102). Overall Reff was 1.00 (95% CI 0.92-1.08) with k 0.29 (0.26-0.32); 17.8% of cases generated 80% of transmission. Overdispersion stayed stable despite fluctuating Reff. Non-isolation (IRR 1.79), death outside a treatment centre (IRR 4.34), and unfollowed contact status (IRR up to 4.48) predicted more secondary cases; vaccination cut transmission by about 60%. Interpretation. Epidemiological investigations linked 67.7% (2356/3481) of cases into 415 transmission chains (median size 3, range 2-102); linkage to a known infector fell to 10% during the November 2018-February 2019 period of peak insecurity. Transmission was heterogeneous overall, with dispersion parameter k of 0.29 (0.26-0.32), such that 17.8% (16.8-18.9) of cases generated 80% of onward transmission confirming superspreading as a stable, structural feature of Ebola dynamics. Critically, k remained stable throughout the outbreak, including during periods of elevated Reff, indicating that transmission surges reflected intensification of the same underlying process rather than new superspreading contexts, and that Reff alone is an insufficient summary of epidemic potential. Regression analyses identified predominantly modifiable determinants: cases not isolated in an Ebola treatment centre (IRR 1.79 [1.54-2.06]) or who died outside one (IRR 4.34 [3.47-5.31]) generated substantially more secondary cases, as did those registered as contacts but not followed up (IRR 3.01 [2.39-3.70]) or unregistered altogether (IRR 4.48 [3.67-5.38]) relative to actively followed-up contacts. Vaccination reduced onward transmission by 60-64% (IRR 0.36-0.40). These findings indicate that transmission was shaped less by gaps in epidemiological knowledge than by the operational reach of contact tracing, isolation, and vaccination delivery, particularly during periods of insecurity.

Background: Zoonotic infectious disease risk arises at human-animal-environment interfaces where pathogen spillover can occur. Rural communities living in biodiverse settings may experience frequent contact with wildlife and shared environments through livelihoods, food practices, and economic activities. Reducing spillover risk and strengthening pandemic prevention requires both structural and individual-level change. Community-based interventions that promote awareness, risk perception, self-efficacy, pro-environmental behaviour, and safe coexistence with wildlife may support prevention by shifting behavioural determinants of zoonotic disease risk. The Saan Suk intervention was co-developed with rural communities in Thailand using a Human-Centred Design approach and is grounded in the Health Belief Model and One Health principles. The intervention is intended to be feasible, acceptable, and deliverable through Thailands established Village Health Volunteer (VHV) system. Methods: This protocol describes a parallel-arm, cluster-randomised controlled superiority trial that will be conducted during July - October 2026, in Chanthaburi Province, Thailand. 24 villages will be equally randomised to the Saan Suk intervention or the current practice (control). In intervention villages, trained VHVs will deliver, once a week over four weeks, a multimodal One Health educational intervention designed to improve knowledge of zoonotic spillover, promote protective behaviours, reduce risky wildlife-related contacts, and support respectful coexistence with wildlife. Trained outcome assessment teams will conduct structured interviews with 42 adult participants per village, yielding a total sample size of 1,008 participants. The sample size was calculated for the primary outcome, accounting for clustering, with 90% power to detect a medium effect size (6 points on the 0-100 knowledge scale) at a significance level of 0.05, accounting for a design effect with an ICC of 0.028. The primary outcome is knowledge of zoonotic spillover, transmission pathways, risk factors, protective and risky behaviours, and safe coexistence with wildlife. Secondary outcomes include attitudes, self-efficacy, preventive and risky behaviours, and reported contacts with major local reservoir hosts. A structured questionnaire was developed, expert-reviewed, and piloted for the outcome assessment. Outcomes will be analysed using mixed-effects regression models with random effects for village and adjustment for relevant pre-specified confounders. Primary analyses will follow the intention-to-treat principle. Discussion: This trial will evaluate whether a co-designed, VHV-delivered One Health educational programme can improve knowledge of zoonotic disease prevention and behavioural determinants in rural communities living in close contact with wildlife and shared ecosystems. If effective and feasible, Saan Suk could inform integration into routine VHV training and community-based zoonotic disease and pandemic prevention strategies. Trial Registration: The Saan Suk trial is registered with the German Clinical Trials Register (DRKS). Registration ID: DRKS00038582; date of registration: 11 May 2026.

Background Having achieved the UNAIDS 95-95-95 targets, Eswatini faces a growing burden of non-communicable diseases which are major contributors to morbidity and mortality. Hypertension-associated cardiovascular disease (CVD) is rising among people living with HIV (PLHIV) as survival improves and metabolic risks - including those linked to dolutegravir (DTG) - increase. We projected CVD burden among PLHIV and HIV-negative adults (PLWHIV) through 2045 to inform integrated HIV-CVD planning. Methods EMOD-HIV, an agent-based model calibrated to Eswatini's epidemic, generated HIV prevalence trajectories. These were combined with age-standardized Global Burden of Disease CVD estimates and published relative risks (RRs) to produce HIV-stratified CVD projections. CVD burden trajectories were then projected through 2045 using a logistic generalized additive model with Monte Carlo uncertainty quantification. Five scenarios were evaluated to assess how different assumptions about RR of CVD among PLHIV versus PLWHIV affect projected burden: (1) CVD prevalence under a constant RR; (2) CVD mortality under a constant RR; (3) HTN-attributable CVD mortality under a constant RR; (4) HTN-attributable CVD mortality under a post-DTG RR increase following Eswatinis 2021 dolutegravir rollout; and (5) HTN-attributable CVD mortality under a gradual RR increase from 2010-2045 reflecting cumulative metabolic and demographic shifts. Results PLHIV consistently exhibited higher CVD burden than HIV-negative adults. Scenario 1: CVD prevalence was 11.0% (95% UI: 9.0-13.5%) among PLHIV versus 6.8% (6.0-7.8%) in 2025, stable through 2045. Scenario 2: CVD mortality rate was 0.60% (0.47-0.76%) versus 0.37% (0.31-0.45%) in 2025, declining modestly through 2045 with consistent excess. Scenario 3: HTN-attributable mortality was 73% (70-76%) versus 64% (61-66%) in women and 61% (58-64%) versus 58% (55-60%) in men, stable through 2045. Scenario 4: Following DTG rollout, mortality rose from 73% to 85% in women and 61% to 70% in men by 2022, remaining stable thereafter. Scenario 5: By 2045, mortality reached 85% (82-88%) in women and 67% (64-70%) in men with HIV, versus 60% (57 - 63%) and 55% (53 - 57%) in HIV-negative adults. Conclusions While excess CVD burden among PLHIV is projected to persist even under stable risk conditions, ART-related metabolic trajectories - particularly those linked to DTG - may drive substantial widening of this gap through 2045. HTN-attributable CVD mortality is particularly elevated among women with HIV. Strengthening integrated HIV-NCD services, including blood pressure screening, risk-based therapy, and sex-specific DTG counseling, will be essential to sustain long-term health gains.

Background Nipah virus (NiV) is a priority zoonotic pathogen causing high-fatality outbreaks. Early NiV outbreaks in Malaysia and Singapore had limited transmission beyond spillover events. However, since 2001, NiV outbreaks with person-to-person transmission have occurred in Bangladesh and India, driven by the NiV-Bangladesh genotype and NiV-India genotype. Our study aims to estimate the reproduction number, offspring dispersion, and serial interval governing NiV transmission in Bangladesh and India during 2001-2026. Methods We conducted a systematic review of NiV outbreak investigations in Bangladesh and India, searching PubMed, Embase, Web of Science, and grey literature through 28 February 2026. Case-level offspring counts from 27 eligible sources (323 cases across 67 outbreaks) were used as input to a hierarchical Bayesian negative binomial offspring distribution model. The serial interval was estimated by parametric distribution fitting to 137 transmission pairs. Country-stratified and sensitivity analyses were performed to evaluate the robustness of estimates. Results Pooling across 67 outbreaks, we estimated a median reproduction number of 0.46 (95% CrI: 0.28-0.73), an offspring dispersion parameter of 0.07 (0.05-0.10), and a serial interval of 13.3 days (95% CI: 12.8-13.8). Country-stratified median reproduction numbers were 0.48 (0.23-0.97) for India and 0.35 (0.19-0.59) for Bangladesh, and dispersion parameters were 0.04 (0.02-0.07) and 0.11 (0.06-0.18), respectively, indicating marked overdispersion in both settings. Conclusion NiV transmission is self-limiting on average and highly overdispersed, suggesting that a disproportionate share of onward transmission arises from a small number of cases. This epidemiological profile supports targeted containment measures, including contact tracing and quarantine, for effective NiV outbreak control.

Scaling HIV pre-exposure prophylaxis (PrEP) services in health systems will require collaboration and clear role distinction among professionals, and between specialist and primary care. This study examined how power dynamics shape efforts to expand PrEP care beyond specialised HIV clinics in Belgium. We conducted semi-structured interviews with 36 HIV clinic providers and two community-based organisation (CBO) representatives, and 16 online group discussions with general practitioners (GPs). We analysed data thematically, guided by the concepts of collaborative and competitive power to examine how providers negotiated expertise and role division in PrEP delivery across professional and organisational boundaries. We found that reimbursement regulations anchored PrEP initiation and follow-up within HIV clinics, embedding specialist jurisdiction in care pathways. HIV specialists reinforced this position by drawing on their recognised expertise in HIV medicine to justify clinical coordination and authority in determining standards of care. GPs emphasised accessibility and preventive care roles but made limited claims to PrEP provision, linked to misaligned organisational incentives, role blurring, limited training opportunities, and the historical concentration of HIV care in specialist services. CBOs facilitated access, enabling coordination between vulnerable communities and clinics while remaining weakly embedded in formal care structures. Findings show that expanding integrated PrEP services beyond specialised care is not only shaped by operational issues such as training and resources but also by the structural dynamics of regulations, institutional mandates, and professional jurisdictions that influence collaboration. Effective scale-up will require policies that align incentives, clarify responsibilities, and support collaboration across specialised, primary care, and community settings.

Males incur greater risk of tuberculosis (TB) than females, but the contribution of sex-associated immune differences remains unclear. We addressed this using sex-stratified transcriptomic analyses across four independent studies spanning active pulmonary TB, subclinical TB and latent infection, in peripheral blood, bronchoalveolar lavage (BAL) and by using the tuberculin skin test (TST) as a standardised in vivo antigenic challenge. In blood of active TB patients, expression of TNF- and type I interferon-regulated signatures, genome-wide gene expression, and performance of leading host-response biomarkers of TB were comparable between sexes. Similarly, blood transcriptomic biomarkers showed no meaningful sex-related differences for predicting asymptomatic or incident TB. In the TST of people with latent infection, bulk and single-cell RNA sequencing identified only limited differences, largely restricted to sex chromosome-linked transcripts, with no consistent evidence of dimorphism in immune-regulated pathways. Single-cell RNA sequencing of BAL samples identified reduced abundance of B cells in male TB patients, with gene expression differences again largely restricted to sex chromosome-linked transcripts. These findings suggest that canonical immune responses associated with TB are broadly similar between the sexes, and that increased TB risk among males more likely reflects differential exposure rather than intrinsic immunological susceptibility.

Objectives: We tested how multi-level socioeconomic disadvantage relates to biological aging and systemic inflammation in women and men from the population-based Canadian Longitudinal Study on Aging (CLSA). Methods: We examined cross-sectional data from 8,516 CLSA participants with baseline measures on systemic inflammatory biomarkers (C-reactive protein, interleukin-6, and tumoral necrosis factor-) and biological aging (metabolomic and six DNA methylation [DNAm] age estimates). Plasma samples underwent metabolomic profiling by Metabolon, Inc. Metabolomic age was estimated separately in males and females using sex-stratified models based on age-correlated metabolite levels. DNAm data generated using the Illumina Infinium MethylationEPIC v1.0 array were used to estimate DNAm age across six established models, including Horvath, Hannum, PhenoAge, GrimAge, GrimAge2, and DunedinPACE. We used log-transformed metabolite levels to calculate metabolomic age by sex. We linked education, income, material and social deprivation to biomarkers of systemic inflammation and biological aging stratified by sex using generalized linear models. Multivariable models were adjusted by age, major behavioral risk factors, and chronic conditions. Results: Participants were aged on average of 62.6 years of age, and approximately 50% were females. In multivariable linear adjusted models, we found that in comparison to those earning [&ge;]$100K a year, women earning less <$20K were on average 1.14 (95%CI: 0.46, 1.82) year older with respect to metabolomic age; those earning [&ge;]$20K & <$50K were on average 0.90 (95%CI: 0.26, 1.53) years older; and those earning [&ge;]$50K & <$100K were on average 0.70 (95%CI: 0.05, 1.34) years older. We did not observe this dose response among men. A similar dose-response association was observed for interleukin-6 in both men and women. Discussion: These findings suggest that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging.

Background Coccidioidomycosis is an emerging fungal disease across the arid Americas and a frequent cause of community-acquired pneumonia. Understanding where Coccidioides populations originate, how they move across space, and whether they are expanding is important for interpreting changing patterns of Valley fever and anticipating future infection risk. Methods We prospectively collected and whole-genome sequenced 186 Coccidioides-positive clinical isolates submitted to a national diagnostic laboratory, and included 126 previously sequenced genomes. We applied genomic clustering, time-calibrated phylogenetic reconstruction, ancestral area reconstruction, mating-type assignment, and demographic inference to identify major populations, infer dispersal patterns, assess evidence for recombination and clonality, and reconstruct historical population dynamics. Findings We analyzed 312 genomes (139 C. immitis; 173 C. posadasii) and identified three major genetic populations within each species. C. immitis included two California-centered populations and one Pacific Northwest population, whereas C. posadasii included two Arizona-centered populations and one Texas-centered population. The most recent common ancestor was estimated at approximately 127,000 years for C. immitis and 234,000 years for C. posadasii. Most populations were not fully monophyletic, consistent with retained ancestral variation and/or ongoing gene flow. Inferred dispersal was largely asymmetric, with most movement originating from California in C. immitis and from Arizona and Texas in C. posadasii. Most populations contained both mating types, but one C. immitis population and a Brazilian subgroup of C. posadasii were clonal. All populations showed recent demographic expansion. Interpretation The evolutionary history of Coccidioides is characterized by strong geographic structure, ongoing gene flow, and recent demographic expansion. These processes are likely to influence future patterns of Valley fever endemicity and supports the use of genomic surveillance to detect shifts in disease risk as environmental conditions change.

We aimed to assess the burden and correlates of late diagnosis of cervical cancer among women attending care at a public health facility in Coastal Kenya. A retrospective cross-sectional design was used. Data extracted from medical records of women already diagnosed with cervical cancer at Kilifi County Referral Hospital (KCRH) were used. Logistic regression was used to assess independent predictors of late diagnosis of cervical cancer. A total of 126 patients were included in this analysis. Out of the 126 participants, 67.5% (n=85) were 50 years and older with a mean age of 54 years. Among the 126 participants whose records were included in analysis, 73.0% (n=92; [95% CI: 64.3 - 80.5]) were diagnosed with late-stage cervical cancer. In multivariable analysis, none of the variables included in the model showed an association with the outcome. In conclusion, we found a high burden of late diagnosis of cervical cancer in this setting. Targeted interventions are warranted to reverse this trend.

Background: Travellers visiting friends and relatives (VFRs) experience a disproportionate burden of travel-associated infectious diseases, yet little is known about the complexity of pre-travel consultations required to support their care. We compared enquiries relating to VFR travellers and tourists received by the UK National Travel Health Network and Centre (NaTHNaC) specialist Advice Line to identify differences in traveller characteristics, destinations and clinical complexity. Methods: We conducted a retrospective observational study of enquiries to the NaTHNaC Advice Line between 1 January 2019 and 31 December 2025. Enquiries relating to VFR travellers and tourists were compared using descriptive statistics and appropriate statistical tests. Traveller demographics, travel characteristics, destinations and enquiry management were analysed. Results: Of 16,367 enquiries relating to specific travellers, 3,090 (18.9%) concerned VFR travellers and 7,237 (44.2%) concerned tourists. Compared with tourists, VFR travellers were younger (median age 24 vs 52 years, P<0.001), more likely to undertake long-stay (8.4% vs 1.8%, P<0.001) and last-minute travel (5.0% vs 1.1%, P<0.001), and more frequently travelled to the WHO African Region (56.6% vs 29.2%, P<0.001) and Eastern Mediterranean Region (12.7% vs 2.8%, P<0.001). Pregnancy was substantially more common among VFR travellers (11.6% vs 4.3%, P<0.001). Enquiries concerning VFR travellers were more likely to require a call-back (16.1% vs 13.8%, P=0.012) and escalation to a specialist doctor (13.1% vs 10.5%, P<0.001), indicating greater consultation complexity. General practice generated a higher proportion of VFR-related enquiries than tourist enquiries (69.5% vs 63.9%, P<0.001). Conclusions: VFR travellers generate disproportionately complex pre-travel consultations characterised by higher rates of specialist escalation, distinct travel patterns and travel to destinations associated with the greatest burden of imported infectious diseases. These findings highlight the importance of specialist travel medicine support for healthcare professionals managing VFR travellers and reinforce the need for equitable access to timely, high-quality pre-travel healthcare for this high-risk population.

Objectives: Although HIV incidence has declined in some settings, the overall global burden of sexually transmitted infections remains a major public health concern. In the context of the World Health Organization's call for people-centred STI prevention and care, identifying the shared geographic pattern of multiple STIs using data-driven analysis may help detect vulnerable areas and inform integrated prevention strategies. Methods: We analysed country-level incidence counts from the Global Burden of Disease 2023 study for 204 countries and territories over 1990-2023. A Bayesian shared-component spatiotemporal model was fitted, decomposing each disease's log-rate into a shared spatial component (scaled intrinsic conditional autoregressive prior), disease-specific spatial deviations, disease-specific first-order random walk temporal effects, and five socioeconomic covariates, with a negative binomial likelihood to accommodate overdispersion. The shared spatial score - the posterior mean of the shared spatial component - was used as a continuous index of STI co-occurrence burden. Posterior exceedance probabilities quantified directional stability. External validity was assessed via Spearman correlation with the Socio-demographic Index and generalised estimating equation regression of HIV/AIDS mortality on the shared score. Results: The shared spatial score exhibited marked geographic heterogeneity. The five highest-scoring countries were Eswatini (2.25), Lesotho (2.13), Malawi (1.90), Mozambique (1.89), and South Africa (1.85), all in southern Africa. Fifty-seven countries had high directional stability (posterior exceedance probability >0.95), concentrated in sub-Saharan Africa and the Caribbean. The score correlated negatively with SDI (Spearman rho = -0.619, p = 6.4 x 10^-23) and positively with HIV/AIDS mortality (incidence rate ratio = 14.64 per standard deviation, 95% CI: 11.90-18.01). Prior sensitivity analysis confirmed near-perfect ranking stability (rho >= 0.9999). Conclusions: STI co-occurrence is geographically concentrated, with the highest shared burden in sub-Saharan Africa and persistently elevated shared spatial signals also observed in parts of mainland Southeast Asia and the Caribbean. The shared spatial score provides a data-driven tool for prioritising integrated STI screening and prevention resources across countries.

Controlled human infection models (CHIMs) are increasingly used in infectious disease research to study pathogen dynamics and evaluate interventions under controlled conditions. However, these studies are resource-intensive and involve ethical and safety constraints, making efficient study design critical. Dose-finding is a key early component in CHIMs, where the aim is to identify a challenge dose that achieves a target infection probability. Traditional rule-based designs are commonly used but can be inefficient, motivating the use of model-based adaptive approaches such as the Bayesian Continual Reassessment Method (CRM). Although CRM has been extensively studied and widely adopted in Phase I oncology trials for identifying the maximum tolerated dose of therapeutics, its application in CHIM settings remains limited, particularly when the endpoint of interest is infection. This tutorial provides step-by-step guidance for implementing a Bayesian CRM in dose-finding CHIMs, using an oropharyngeal Neisseria gonorrhoeae challenge as a motivating case study. The framework outlines key design components, including dose-grid specification, dose-response model, prior elicitation, Bayesian updating, decision rules, and stopping criteria, with particular emphasis on a clinically interpretable parameterisation. Trial operating characteristics are evaluated through simulation studies under multiple dose-response scenarios and prior-predictive analyses, and compared with a commonly used '3+3' type rule-based design. This work highlights the advantages of Bayesian model-based designs for dose-finding in CHIMs over classic rule-based designs and provides a structured, reproducible framework for implementing CRM, supporting their application in future CHIM studies.

Background and Aims The optimal treatment for first episodes and first recurrences of Clostridioides difficile infections (CDI) is unknown and there is emerging evidence for pulse and taper (P-T) regimens. Therefore, we sought to estimate the relative efficacy of treatment options. Methods MEDLINE and CENTRAL were searched from database inception to May 21, 2025 and unpublished conference abstracts were searched from recent infectious disease conferences. RCTs on the treatment of first episodes or first recurrences of CDI comparing fixed-dose or P-T regimens of fidaxomicin or vancomycin were included. The primary and secondary outcomes were 40- and 56-day CDI recurrence, respectively. A random-effects network meta-analysis on the risk ratio (RR) scale was conducted using a standard regimen (10-14 days) of vancomycin as the comparator. Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results 8 RCTs were included comprising a total of 2181 patients. For 40-day recurrence, fidaxomicin P-T had the highest probability of ranking best (RR=0.10, 95%Confidence Interval [95%CI]=0.10-0.49, SUCRA=1.00), followed by vancomycin P-T (RR=0.49, 95%CI=0.32-0.76, SUCRA=0.61), fixed-dose fidaxomicin (RR=0.61, 95%CI=0.49-0.76, SUCRA=0.39), and, finally, fixed-dose of vancomycin (SUCRA=0.00). The treatments ranked in the same order for 56-day recurrence, though only 3 RCTs reported on this timepoint. Conclusion Vancomycin P-T, fidaxomicin P-T, and fixed-dose fidaxomicin were all superior to a fixed-dose vancomycin. Head-to-head comparative effectiveness RCTs are needed to quantify their relative effect sizes of and impact on long-term prevention of recurrent CDI.

Background: Opioid use disorder (OUD) is heritable, yet most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic architecture of OUD in non-European populations underexplored. Methods: We conducted GWAS of OUD across three ancestries using electronic health records and genomic data from 52,357 All of Us Research Program participants (8,912 cases; 43,445 matched opioid-exposed controls; 48.5% female). Participants were stratified into European (EUR), African (AFR), and Admixed American (AMR) ancestry groups for logistic regression GWAS, with independent replication in the Million Veteran Program. We then applied the deep-learning model AlphaGenome to predict the tissue-specific transcriptomic and splicing consequences of top risk variants across 13 reward-pathway brain regions. Results: We identified and replicated a novel DDX6 risk locus, alongside established OPRM1 and FURIN signals. AlphaGenome predicted the DDX6 regulatory allele downregulates the stress-resistance gene FOXR1 in the nucleus accumbens, while the protective OPRM1 variant (rs1799971) upregulates OPRM1 expression across reward networks. Other signals of interest included IL6R and SHISA9 (EUR); GHR (AFR); and ASTN2 (AMR). Conclusions: This study identifies DDX6 as a novel OUD risk locus, replicates associations with OPRM1 and FURIN, and highlights biologically plausible ancestry-specific signals in AFR and AMR populations. We also replicated top variants in an independent population. Finally, integrating GWAS with deep-learning annotations provides specific, localized biological hypotheses to guide future experimental validation and targeted therapeutics.

Background The 2022-2023 global mpox outbreak highlighted the critical need for robust genomic surveillance capabilities to track mpox virus (MPXV) evolution and transmission dynamics. Methods Building upon our established SARS-CoV-2 sequencing infrastructure, we implemented a Molecular Loop probe-based long-read sequencing approach using Pacific Biosciences Sequel II technology for comprehensive MPXV genomic surveillance across the United States (US). From August 2024 to June 2025, we generated 326 high-quality whole genome sequences from residual mpox-positive clinical specimens collected by Labcorp across all 10 US Department of Health and Human Services regions. Results Our analysis identified two samples containing clade Ib MPXV in January and June 2025 and captured shifting trends in clade IIb diversity, with 13 distinct lineages observed. We also identified multiple instances of large (~1.6-17.6kb) deletions proximal to the inverted terminal repeats in clade IIb genomes. APOBEC3 mutation analysis indicated substantial evidence of human-to-human transmission among both clades. Further, we observed significantly higher APOBEC3-associated SNPs per kilobase (P<0.001) in clade IIb genomic variable regions relative to their central conserved region. Our assay exhibited strong reproducibility across biological replicates from individual patients and accuracy was confirmed via parallel sequencing of select specimens by US Centers for Disease Control and Prevention (CDC) using metagenomic sequencing. We also demonstrated via custom simulation that our assay discriminates all known MPXV clades and lineages, including those we have not observed in the US. Conclusions Our integrated nationwide surveillance system facilitates real-time genomic tracking of outbreak evolution, with demonstrated capacity across SARS-CoV-2 and MPXV, positioning this platform for rapid deployment during future pathogen emergence.

Background: Monoclonal antibodies have emerged as a prophylactic strategy to prevent symptomatic SARS-CoV-2 infection in immunocompromised individuals. However, the evolutionary and clinical implications of breakthrough infections under this regime remain unclear. Methods: A male in their 80s with a haematological/oncological diagnosis received a 2000 mg intravenous infusion of sotrovimab in March 2023 and was diagnosed with COVID-19 by RT-qPCR from a nasopharyngeal swab in August 2023. Weekly samples (n=24) were collected through February 2024 (171 days). All samples underwent whole-genome sequencing, with select mutations subjected to functional assessment. Findings: Sequencing identified the GE.1 lineage at all timepoints. An intra-host recombination event in ORF1ab (positions 8942-12458) was detected prior to 23 weeks post-detection, followed by a 14-fold increase in viral load (7.42e+06 to 1.00e+08 RNA copies/mL) and a marked shift in the viral population. E340D, a sotrovimab resistance mutation, was detected at low abundance (46%) within the first week post-infection, fluctuated over time, and was nearly fixed by week 15 (107 days) post-detection. We assessed five spike mutations - V36M, S98F, and V213G in the N-terminal domain, Y505P in the receptor-binding domain, and P681Q near the S1/S2 cleavage site - and additionally evaluated the impact of E340D. V36M conferred the highest infectivity across all cell lines, with the most significant effect in low-TMPRSS2 cells. While all mutations showed enhanced infectivity with the addition of E340D, the effect was most pronounced in mutations with lower baseline infectivity. The addition of E340D significantly decreased relative neutralizing titres for V36M, S98F, and V213G, enabling escape from neutralizing antibodies in XBB-responsive individuals, illustrating an enhanced phenotypic advantage. Patient neutralizing activity was absent pre-sotrovimab, and sotrovimab-induced neutralization was further compromised by selection of E340D. Interpretation: Sotrovimab pre-exposure prophylaxis in an immunocompromised patient did not prevent SARS-CoV-2 infection, and selected for resistant mutation E340D, with unexpected fitness consequences across non-receptor binding domain spike regions.

We present FootNet, a 453-image multi-view smartphone foot dataset for binary foot segmentation, with expertannotated masks across six anatomical views (dorsal, medial, and plantar, both left and right). We benchmark four segmentation models under a controlled protocol: U-Net with a MobileNetV2 encoder achieves the best performance (IoU 0.9268, Dice 0.9608, 95 % CI [0.9209, 0.9320]); DeepLabV3 with MobileNetV3-Large scores IoU 0.8984 (Dice 0.9449); UNet++ with MobileNetV2 scores IoU 0.8913 (Dice 0.9391); and SAM ViT-B with oracle boundingbox prompt scores IoU 0.9219 on the matched 191-image subset. Bonferroni-corrected Wilcoxon signed-rank tests (k = 6 comparisons) show U-Net significantly outperforms DeepLab (p < 0.001, r = 0.638) and SAM ViT-B with oracle boundingbox (p = 0.005, r = 0.202); UNet++ does not significantly differ from DeepLab (p = 0.062). Connected-component postprocessing yields negligible benefit (mean {triangleup}IoU = +0.0003, 12 of 453 images improved). The extended dataset is available upon request

Stochastic epidemic models are a cornerstone of infectious disease epidemiology and are often used to study intervention scenarios. However, large run-to-run variability can make intervention effects difficult to estimate precisely. We revisit the epidemic Sellke construction, which assigns each individual an infection threshold for the cumulative infection hazard such that, conditional on the thresholds, the epidemic trajectory becomes deterministic. This enables coupling of simulations with and without an intervention, yielding low-variance effect estimates even when outcomes such as final size or peak incidence vary widely between runs. We develop an exact, event-driven implementation that maintains infection and recovery events in priority queues. Cumulative infection-hazard updates require O(log N) time per event, yielding overall complexity O(Elog N) for E events in a population of size N. The implementation achieves computational performance comparable to the classical Gillespie algorithm while naturally accommodating non-Markovian infectious periods and complex infectiousness profiles. We illustrate the approach using distance-dependent spread of avian influenza between poultry farms in the Netherlands and a multilayer population with households, schools, and workplaces. In both examples, coupling enables efficient within-run comparisons of intervention scenarios across stochastic realisations.