FACETS

Antimicrobial resistance (AMR) is an ever-increasing threat to population health. Industrial, environmental and societal factors are increasingly recognized as important contributors to AMR within communities. Here, we investigated the spatial distribution of AMR genes (ARGs) across Alberta, Canada and their association with socio-economic, immigration-related, and agro-industrial characteristics using municipal wastewater-based surveillance. We analyzed monthly wastewater metagenomes collected between March 2022 and March 2023 across eleven municipalities, representing 39% of Alberta's population. Integration with census data enabled multivariate analysis, revealing that municipal resistome profiles were strongly structured along income and immigration-related population gradients. ARGs spanning 14 resistance classes exhibited distinct distributional patterns across income and immigration gradients, including contrasting associations among beta-lactam, aminoglycoside, and macrolide-lincosamide-streptogramin ARGs, consistent with heterogeneous selection pressures across sub-populations. These findings demonstrate the capacity of longitudinal wastewater surveillance to identify persistent population-level resistome patterns and highlight the importance of incorporating sociodemographic context into AMR surveillance and mitigation strategies.

Objectives: To compare the effectiveness of povidone-iodine ear wash compared to no ear wash and oral cotrimoxazole compared to placebo given in addition to standard topical antibiotic treatment (ciprofloxacin drops) for chronic suppurative otitis media (CSOM) in Australian Aboriginal children. Methods: A randomised, parallel, 2 x 2 factorial design, assessor-blinded clinical trial in the remote Northern Territory of Australia. Aboriginal children with confirmed CSOM were eligible to be randomised into four treatment groups, allowing two primary treatment comparisons in a 2-in-1 trial approach. Participants received standard treatment (twice daily cleaning and topical ciprofloxacin drops) plus: i) either 16 weeks of pre-treatment povidone-iodine ear wash or no povidone-iodine ear wash; and ii) either 16 weeks of oral cotrimoxazole or placebo. Central randomisation with allocation concealment and triple-blinding of the oral antibiotic treatment arms was used. The relative risk (RR) and risk difference (RD) were estimated after adjustment for age, community, and the other intervention. The primary outcome was the proportion of children with any otorrhoea (clinical failure) after 16 weeks of treatment. Secondary outcomes included size of tympanic membrane (TM) perforation and amount of discharge, time to cessation of discharge, proportion of children with respiratory and other pathogens in ear discharge (at baseline and 16 weeks) and hearing levels (at 12 months). Findings: 280 children with CSOM were randomised and 270 had their primary outcome assessed. Clinical failure (presence of any ear discharge) after 16 weeks of treatment was 66/134 (49%) in the povidone-iodine group versus 69/136 (51%) in the no povidone-iodine group (RD= -1% (-12,11), p= 0.93) and 56/134 (42%) in the cotrimoxazole group versus 79/136 (58%) in the placebo group (RD=-16% (-28,-4), p=0.007). The amount of discharge, TM perforation size, the level of hearing impairment, and serious adverse events were not significantly different in both treatment comparisons. Anaerobic growth (24%), Pseudomonas aeruginosa (21%) and Haemophilus influenzae (17%) were the most common pathogens found in the ear discharge before treatment. Fungi or yeast (24%), Staphylococcus aureus (15%), and anaerobic growth (10%) were the common pathogens after 16 weeks of treatment, with no significant differences between groups. At 12 months post-randomisation, 55-60% of children had at least one discharging ear and there was no difference between treatment groups. Interpretation: Povidone-iodine ear washes did not contribute to better ear outcomes in this study. Cotrimoxazole for 16 weeks resulted in more children with clinical improvement to dry ears. Oral cotrimoxazole may play a role in reducing the burden of CSOM in populations with high rates of persistent disease.

Abstract Background: Remote clinical reviews have become an integral component of contemporary nursing practice across community and acute care settings. Nurses increasingly make autonomous clinical decisions using telephone, video, and online/digital systems, often with limited sensory information and under conditions of uncertainty. However, empirical understanding of how nurses make clinical decisions via remote reviews remains limited. Aim: To explore and understand how registered nurses (RNs) make clinical decisions about patient care via remote reviews. Methods: A convergent mixed-methods design was employed. Quantitative data (analytic quantitative sample N=53) were collected using validated questionnaires that measured decision-making processes, physician-nurse collaboration, decision-making stress, and perceived decision-making ability. Qualitative data (N=23) were generated through semi-structured interviews. Data collection took place between October 2024 and April 2025. Quantitative data were analysed using descriptive statistics, correlation, and multiple regression. Qualitative data were analysed using framework analysis. Integration was achieved through pillar-building and theory-driven synthesis and illustrated by joint display tables. Results: Most nurses demonstrated a flexible decision-making style, integrating analytical and intuitive reasoning. Both analytical and intuitive processes were positively associated with perceived decision-making ability. Physician-nurse collaboration emerged as a strong predictor of decision-making confidence, while decision-related stress was not a significant predictor. Qualitative findings identified three themes: characteristics of remote review; making adaptive decisions shaped by both internal and external constraints and enablers; and external influencing factors. The integrated findings informed a theory-informed ICE framework to illustrate how nurses make clinical decisions via remote reviews. Conclusion: Remote clinical decision-making is a dynamic cognitive-environmental process rather than a purely individual cognitive act. The ICE framework conceptualises this interaction, extending existing decision-making theories to digitally mediated care. Impact: Understanding remote decision-making supports training design, clinical governance, and the development of Artificial Intelligence-enhanced decision-support tools grounded in ecological bounded rationality. Patient or Public Contribution: Patient and public representatives contributed to stakeholder discussions that informed the development of the interview topic guide and the theoretical model. Patients or members of the public were not involved in recruitment, data collection, analysis, interpretation of findings, or preparation of the manuscript. Keywords: clinical decision-making, remote reviews, telehealth, nursing, mixed methods, ecological bounded rationality

Fracture nonunion remains a major cause of morbidity, yet patient-specific factors associated with impaired healing remain incompletely characterized. Anemia has been associated with adverse orthopaedic outcomes, but its relationship with fracture nonunion is poorly understood. We examined whether pre-fracture anemia, anemia burden, and clinically relevant anemia subtypes were associated with nonunion following tibial or femoral fractures. Using commercial and Medicare fee-for-service claims from 2016 through 2023, we identified adults aged 19 years or older with a tibial or femoral fracture, continuous enrollment during the preceding year and for at least six months after fracture, and no baseline cancer. Pre-fracture anemia was evaluated as any anemia, the number of distinct anemia diagnoses, and nutritional, hemolytic, aplastic, and other anemia subgroups. Nonunion occurring six to eighteen months after fracture was assessed using incidence rates and multivariable-adjusted hazard models. Among 326,673 adults, 149,704 had pre-fracture anemia and 176,969 did not. The crude incidence of nonunion was 42% higher among individuals with anemia than among those without anemia (incidence rate ratio, 1.42; 95% confidence interval, 1.32 to 1.53) and increased with greater anemia burden. After adjustment for demographic and clinical characteristics, including prior fractures at other anatomical sites, pre-fracture anemia remained associated with nonunion following tibial and femoral fractures, with hazard ratios of 1.83 (95% confidence interval, 1.54 to 2.18) and 1.38 (95% confidence interval, 1.26 to 1.50), respectively. Associations were also observed for nutritional and other anemias, whereas estimates for hemolytic and aplastic anemias were limited by few nonunion events. Within the femur, the association was strongest for distal fractures. These findings demonstrate that pre-fracture anemia is independently associated with nonunion. The increase in risk with greater anemia burden and findings across evaluable subgroups suggest that pre-fracture anemia may help identify patients at increased risk of impaired fracture healing.

Background: Plasma phosphorylated tau-217 (pTau-217) measurements for use in Alzheimer disease (AD) identification require thresholds to define positivity and there exist different approaches to operationally defining the boundary. We compared amyloid {beta} (AB) PET-anchored and distribution-based positivity cut-off values and explored how these mapped onto latent biomarker states. Methods: We analysed plasma pTau-217 measured in the Bio-Hermes-001 cohort (N = 990) using an immunoassay (Lilly) and mass spectrometry assay (University of Gothenburg). Gaussian mixture models were used to identify latent classes and thresholds were derived in two ways: achieving 90% specificity for AB PET positivity and exceeding the mean + 2SDs of the lowest latent class. We explore classes in reference to AB PET status and clinical diagnosis, as well as agreement between approaches using Cohen kappa for both assays. Results: In both assays, three latent biomarker classes were identified with monotonic increases in AD clinical diagnosis and AB PET positivity. PET-anchored thresholds showed lower specificity but higher sensitivity to amyloid positivity than distribution-based thresholds. Overall agreement between the approaches was acceptable (k = 0.678 for Lilly and 0.575 for University of Gothenburg), with disagreement concentrated in the intermediate latent class. Classes with the lowest and highest pTau-217 concentrations were classified consistently using both thresholds Discussion: The two thresholding approaches yielded similar classifications at both the negative and positive tail of the observed biomarker distribution, but classify intermediate concentrations differently. The boundary definition influenced pTau-217 positivity more than the analytical platform itself. Thresholding approaches may capture different pTau-217 biomarker states, therefore such methodological decisions should be grounded in the context of the intended application.

Abstract Introduction: Proximal humerus fractures account for approximately 5-6% of all adult fractures and are primarily managed nonoperatively. Healing is conventionally monitored with radiographs, with radiopaque callus formation indicating healing. Visible radiographic callus appears weeks after biological union begins. Ultrasound provides a dynamic, radiation-free, and cost-effective method that can detect early callus formation before x-ray visibility. Although ultrasound has demonstrated utility for fracture healing in the clavicle and humeral shaft, its role in proximal humerus fractures remains unclear. Methods: This single-centre prospective study will be conducted in two phases. The pilot phase will measure inter-rater reliability for ultrasound detection of early callus formation at 2 and 4 weeks post-injury. Ten patients with proximal humerus fractures treated nonoperatively will undergo standardized anterior and lateral scans. Each patient will generate four saved images (short- and long-axis views), producing forty anonymized images independently reviewed by two raters. The prospective cohort phase will recruit approximately thirty additional patients. Results: Reliability will be quantified using Cohens kappa. A power calculation will be performed after pilot analysis. Results from the prospective cohort phase will help determine the association and predictive value of early ultrasound-detected bridging callus for radiographic and clinical union at three and six months. Patient reported outcome measures will be assessed using the Quick Disabilities of Arm, Shoulder and Hand (QuickDASH) questionnaire. Discussion: This study will develop and validate a standardized ultrasound protocol for assessing early fracture healing in proximal humerus fractures. By establishing both inter-rater reliability and predictive value, the findings may support ultrasound as a reproducible, radiation-free adjunct to conventional imaging and enable earlier identification of union status.

Background: Bacteraemia is associated with poor outcomes but the diagnostic gold standard, peripheral blood culture, takes up to 24 hours to become clinically actionable, hampering early management decisions in suspected infection. Single predictors and existing sepsis risk scores discriminate poorly, and few multivariable bacteraemia models have been adequately validated in UK populations. Methods: We developed a logistic regression model, using backwards AIC based selection of predefined candidate predictors routinely available within hours of hospital attendance, in a retrospective cohort of 33,874 hospital encounters at University College London Hospitals (UCLH) between 2019 and 2024. Continuous predictors were modelled using restricted cubic splines and missing data handled using multiple imputation. Model performance was assessed via internal external cross validation and prediction instability analysis, before temporal validation in held-out 2024 UCLH data and external validation in 53,669 hospital encounters from the Infections in Oxfordshire Research Database (IORD). Results: Bacteraemia occurred in 5.2% of UCLH and 8.9% of IORD encounters, respectively. Twenty predictors were retained, spanning demographics, comorbidities, vital signs and blood tests. Discrimination was stable across development time periods (pooled c-statistic 0.82, 95%CI 0.81 to 0.84) and was maintained in temporal (0.83, 0.79 to 0.87) and external validation (0.83, 0.82 to 0.83), with excellent calibration in external validation (calibration slope 1.08 (1.05 to 1.11); calibration-in-the-large 0.01 (-0.02 to 0.04)). The model outperformed single predictors, established risk scores, and a reconstructed comparator model, and showed superior net benefit in decision curve analysis. Performance was consistent across age, sex, ethnicity and socioeconomic subgroups but degraded when blood cultures were sampled more than six hours after attendance and varied by likely infection site. Conclusions: This model accurately predicts bacteraemia using routinely collected data available within hours of hospital attendance, with performance maintained in a large, independent external validation cohort. It offers a generalisable, clinically interpretable tool to support early decision-making in suspected infection, pending further work to establish optimal implementation thresholds.

Objectives Despite their higher risk of stroke and known inequities in post-stroke outcomes, research amongst minoritised ethnic communities who have experienced stroke is scarce. This study aimed to explore the experiences of Black people in England and identify implications for supported self-management. Methods Between December 2023 and June 2024 qualitative interviews were conducted with 20 Black people living with stroke in England. Interviews were conducted in-person or online, depending on participants preferences. Data were analysed iteratively using reflexive thematic analysis. Results Three themes were developed: (1) My world after stroke capturing emotional and social identity-related impacts and adjustments; (2) My support: Family, Community and Peers, encapsulating different facets of support and the relational nature of self-management; and (3) Supported self-management as a negotiated partnership with healthcare professionals, highlighting the varied nature and outcomes of patient-professional interactions and their social embeddedness, including underlying power and historical racial dynamics. Conclusions Our study confirms the need for closer examination of how supported self-management can be provided to different populations. The post-stroke experiences of the Black people who participated in our study were inextricably shaped by their specific familial, social and cultural settings. Their adaptation to and management of the physical and emotional aspects of their condition was enacted across family systems, community and peer networks as well as healthcare services, with varying outcomes. In addition, their interactions and engagement with healthcare professionals were influenced by a broader historical context of discrimination and racism. Our study reveals the importance of delivering supported self-management to Black people living with stroke which responds to their specific social contexts and intersectional identities and which also strives to reduce power imbalances and address historical discrimination, thereby ensuring cultural safety in service provision. Overlooking these aspects risks undermining self-management and underserving those who already face significant health inequities.

The World Health Organization (WHO) validated Sri Lanka had eliminated lymphatic filariasis as a public health problem in 2016, the second country in Southeast Asia to attain this status. However, post-validation surveillance has identified sporadic cases of brugian filariasis. The reemergence of Brugia malayi infections in Sri Lanka warrants urgent investigations. Recent studies have shown that the parasite responsible for the reemergence is a novel zoonotic Brugia sp. maintained among dogs that is closely related but distinct to the human-infecting B. malayi species. The current study employed morphological and morphometric assessments, revealing that this novel zoonotic Brugia sp. is within the B. malayi morphological range. Molecular characterization of three genomic regions, the nuclear genomic region SLXI, the non-coding region HhaI, and the mitochondrial genomic region COXI confirmed it as a genetic variant more closely related to B. malayi than to B. pahangi. Phylogenetic analysis further indicated it as a distinct genomic variant, closely related to a B. malayi-like parasite reported from India. Notably, that same parasite was identified in infected humans, animals, and potential vector mosquitoes. This, together with the detection of both human and animal blood within the same brugian infective mosquitoes, and delineating the canine origin of the parasites in human infections, provides compelling evidence supporting zoonotic transmission of this parasite. To our knowledge, this is the first report demonstrating the presence of the same brugian parasite in humans, domestic animals, and potentially infective mosquitoes in Sri Lanka, supported by multi-genomic evidence. The recent identification of multiple potential mosquito vector species suggests that this parasite may have undergone adaptive changes, facilitating its ability to overcome the species barrier. These findings substantiate the long-held hypothesis of zoonotic transmission of the reemerged brugian parasite, highlighting significant implications for ongoing surveillance and control strategies.

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.

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 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.

Estimating dengue force of infection (FOI) is essential for understanding transmission dynamics and targeting intervention programmes, yet surveillance data in endemic settings required for estimations are often incomplete, with varying formats. We developed a Bayesian hierarchical catalytic model that jointly fits age-stratified case data, aggregate case data, and seroprevalence surveys within a single framework, incorporating external covariates to improve parameter identifiability. Synthetic validation showed that covariates alone recovered accurate FOI point estimates even when most districts contributed only aggregate data, but did so with poorly calibrated uncertainty; anchoring the model with a single seroprevalence survey was necessary to bring credible interval coverage close to nominal. Applied to 128 districts across Java and Bali, Indonesia (2016-2024), the model revealed substantial spatial heterogeneity in FOI and reporting rates. Many districts in Java exceeded the WHO-suggested seroprevalence threshold for vaccine introduction, yet were classified as low-priority when using reported incidence as prioritisation criterion, particularly in areas with weak surveillance. Model-based seroprevalence estimation, integrating multiple data sources, offers a more consistent basis for identifying high-priority districts for vaccine introduction, and is less susceptible to surveillance bias than reported incidence.

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.

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

Background: Children born prematurely (before 37 weeks) or admitted to the neonatal unit (NNU) are at increased risk of adverse long-term physical health outcomes. It is also recognised that there is an association with later academic performance and special educational needs, however it is not clear whether these broad risk factors could be used as stand-alone heuristics to identify children who may benefit from additional support in educational settings. We aimed to examine the associations between neonatal unit (NNU) admission and educational attainment in mid-childhood. Methods and Findings: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012) were linked to national educational outcomes (Department for Education, United Kingdom). Multivariable regression models adjusted for maternal, child, and socioeconomic factors were used to evaluate associations between (i) all NNU admissions, (ii) at term NNU admissions >48 hours, (iii) preterm birth without ongoing physical health needs, and educational outcomes at ages 5-11 years. Children who required any NNU care were more likely not to meet expected educational standards across multiple ages and domains in early and mid-childhood: age 5 early year foundation (aOR 1.64, 95% CI 1.19-2.27, p=0.003), phonics at age 6 (aOR 2.43, 95% CI 1.72-3.57, p<0.001), and at age 7 (here assessments were divided into multiple domains): reading (aOR 1.67, 95% CI 1.18-2.38, p=0.004), writing (aOR 1.72, 95% CI 1.25-2.38, p<0.001), mathematics (aOR 1.56, 95% CI 1.09-2.22, p=0.020), and science (aOR 1.85, 95% CI 1.22-2.78, p=0.003). Similar patterns were observed among both at term-born infants who stayed >48hrs in NNU (phonics assessment at age 6 aOR 2.26, 95% CI 1.51-3.36, p<0.001) and in children born preterm without long-term physical health sequelae (phonics assessment at age 6 aOR 3.07, 95% CI 1.96-4.81, p<0.001). These associations were robust to adjustment for demographic, perinatal, and socio-economic factors. By age 11, differences in academic attainment were attenuated and no longer clearly distinguishable across all exposure groups. However, there was an increased likelihood of special educational needs (SEN) at age 11 associated with any NNU admission (aOR 1.78, 95% CI 1.15-2.73, p=0.009), at term NNU admission for >48hrs (aOR 1.88, 95% CI 1.19-3.00, p=0.007), and children born preterm without long-term physical health sequelae (aOR 1.50, 95% CI 1.00-2.25, p=0.049). Predictive performance of any NNU admission for SEN at age 11 was moderate (AUC 0.70, 95% CI: 1.14-2.65, p=0.010), with balanced sensitivity and specificity and high negative predictive value. Conclusions: NNU admission, for both term and preterm infants, is associated with poorer educational outcomes and an increased likelihood of special educational needs in mid-childhood.

Background Post-infection conditions (PICs), such as Long Covid, are associated with heterogeneous, fluctuating symptoms that profoundly affect daily functioning. Despite moderate-certainty evidence from the NIHR-funded LISTEN trial (COV-LT2-0009) that personalised self management support improves outcomes and may reduce societal and economic impacts of Long Covid, many people living with PICs still receive condition-specific services, generic advice, or stand-alone digital tools that do not address their complex needs. Aim To map care approaches in general practice and synthesise UK evidence for PIC management. Design and setting Scoping review and online survey. Method A two-phase study was conducted: (1) a scoping review of UK evidence on PIC management in general practice; and (2) a supplementary online survey of practitioners working in UK general practice to provide contextual insights. Results The scoping review identified 32 studies focused on Long Covid. One study included a comparator group (ME/CFS). Study populations were predominantly white ethnicity and female. Evidence for non-Covid PICs in UK general practice was largely absent. The supplementary survey (n=46) provided preliminary practice-level insights. Healthcare practitioners reported varied PIC presentations, diagnostic uncertainty, limited referral pathways, inequitable access, and low confidence in managing PICs. Conclusion Evidence informing PIC management in UK general practice remains predominantly Long Covid-focused and may not reflect the range of PICs encountered in practice. While survey findings are preliminary and require confirmation in larger samples, they highlight uncertainty around PIC management. Further research is needed to evaluate whether existing Long Covid pathways should be expanded or complemented by broader PIC models. Keywords general practice; Long Covid; self-management; post-viral syndromes

Objective: There is a bidirectional relationship between emotional distress and pain. However, this relationship is understudied in people with HIV in low-resource settings. This study sought to describe the temporal relationship between emotional distress and pain in people with HIV. Design: Longitudinal observational study. Methods: Participants with virally suppressed HIV, reporting either no pain or persistent pain at baseline, provided weekly remote ratings of distress, worst pain, and average pain using 0-10 visual analogue scales. Within-individual fluctuations in distress and pain were visualised over time. Group-level correlations were determined using Spearman's correlation tests. Cumulative link mixed models assessed whether distress and pain each predicted the other in the following week. Results: 72 participants provided responses over 49 weeks. The participants had a median (IQR) age of 43 (37-51) years, 63% (n=45) were unemployed and most were females (n=51;71%). Distress and pain fluctuated concurrently within individuals: distress was positively correlated with worst pain ({rho}=0.66, 95% CI= 0.60-0.72, p<0.001) and average pain ({rho}=0.70, 95% CI=0.64-0.75, p<0.001) intensity within the same week. Worst pain (OR=1.42, 95% CI=1.17-1.71, p<0.001) and average pain (OR=1.43, 95% CI=1.20-1.71, p<0.001) intensity both predicted distress in the next week. Distress predicted worst pain intensity (OR=1.25, 95% CI=1.07-1.46, p=0.023) but not average pain intensity (OR=1.19, 95% CI=1.01-1.40, p=0.152) in the next week. Conclusions: The temporal relationship between distress and worst pain intensity was bidirectional, whereas distress did not temporally predict average pain intensity. Both pain and emotional distress should receive attention from HIV research and clinical care in low-resource settings.