Journal of Virology

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.

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.

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.

Introduction Globally and in Africa, HIV mortality is reported to have decreased over the years. Cameroon's national mortality rate was 1.7% in 2023, and there exist regional disparities and underreporting. We assessed the mortality and associated factors among People Living with HIV(PLHIV) initiated into HIV care from January 2021 to December 2023 at the Bamenda regional hospital (BRH) Methods A retrospective cohort study was conducted from June 2024 to December 2024 at the BRH. Using a non-probabilistic consecutive sampling technique, 331 newly initiated participants on ART were included. Data was collected from medical records using a questionnaire and analyzed using R software version 4.3.1. A multivariable Cox regression model included variables that showed statistical significance and assessed their relationship with mortality while adjusting for potential confounders. Significant predictors of mortality were identified. Results The mean age of participants was 41.6 {+/-} 11.7 years, and females constituted 57.7%. Opportunistic diseases were present in 19.0% of cases, with tuberculosis (8.2%) being the most common. Key comorbidities included hypertension (8.8%), diabetes (3.9%), and hepatitis B (3.0%). Blood tests showed elevated liver enzymes (ALAT/ASAT: 41.7{+/-}23.6 U/L) and high blood sugar (144.4{+/-}7.4 mg/dL). In contrast, kidney function (Creatinine: 0.9{+/-}0.2 mg/dL) and immune cell counts (Lymphocytes: 1.8{+/-}0.7 x103/L) appeared normal overall. A cumulative mortality rate of 7.6% over three years (approximately 2.5% per year) was observed. Male sex (AHR=7.83, 95% CI:1.44-42.5, p=0.017), opportunistic diseases (AHR=5.66, 95% CI:1.71-18.7, p=0.004), comorbidities (AHR=6.04, 95% CI:2.02-18.1, p=0.001), Abnormal ALAT/ASAT (p=0.005), and WHO clinical stage III (AHR: 1.1, 95%CI: 1.01 -1.5, p < 0.001), were identified as predictors of mortality. Whereas, BMI and ART adherence showed no significance. Conclusion Mortality among PLHIV in this study was associated with advanced disease, opportunistic diseases, commorbidities and abnormal laboratory findings. Strengthening early diagnosis, management of opportunistic infections, and monitoring of clinical and laboratory indicators may help reduce mortality in this population.

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.

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.

During the 2025-26 respiratory virus season, changes to COVID-19 vaccine eligibility, recommendations, and communication may have made vaccination follow-through especially challenging. Under-vaccination may reflect not only lack of willingness, but also breakdowns between willingness and uptake. We analyzed data from 3,390 adults in the CHASING COVID Cohort who completed assessments in August 2025 and March 2026 to examine gaps between vaccine willingness and subsequent influenza and COVID-19 vaccination. Vaccine willingness was defined using prior-season vaccination and stated intention to vaccinate during the 2025-26 respiratory virus season. In August 2025, 73% of participants were influenza vaccine willing and 68% were COVID-19 vaccine willing. Among vaccine-willing participants, 17% and 39% were unvaccinated for influenza and COVID-19, respectively, by March 2026. Absence of prior-season vaccination was the strongest predictor of not vaccinating for influenza and COVID-19, respectively (aRR [95% CI]: 4.04 [3.44-4.74]; 3.01 [2.72-3.34]). Non-vaccination was also associated with food insecurity (1.99 [1.66-2.37]; 1.47 [1.33-1.63]), any healthcare barrier (1.89 [1.57-2.28]; 1.51 [1.36-1.67]), and being not at all confident in vaccine safety (2.95 [2.15-4.05]; 2.21 [1.88-2.59]). Trajectory analyses suggested willingness-uptake gaps reflected incomplete follow-through on intentions and discontinuation among some prior vaccinators. Commonly reported reasons among vaccine-willing non-vaccinators included difficulty finding a convenient time, place, or appointment and, for COVID-19, lack of healthcare provider recommendation. Findings among non-vaccinated adults with prior or stated openness to vaccinate highlight missed opportunities and suggest avenues to improve coverage through strategies that reinforce vaccine confidence, reduce access and logistical barriers, and make vaccination easier to complete.

Purpose: Pathogenic variants in NFIX cause Marshall-Smith syndrome and Malan syndrome (MALNS). We identified a severe subtype of MALNS characterized by adolescent-onset musculoskeletal deterioration and investigated functional consequences of underlying variants. Methods: Clinical data were collected from seven individuals with pathogenic NFIX variants. Wild-type and mutated recombinant NFIX DNA-binding domains (DBDs) were evaluated using biochemical, structural, and DNA-binding assays. Results: Six individuals carrying R116W, R116P, K125E, or G147E NFIX substitutions developed progressive muscle wasting, markedly reduced body mass index, and rapidly progressive scoliosis after the typical childhood features of MALNS; two died from disease-related complications. A seventh individual with R116G did not develop this severe phenotype. Functional studies on recombinant NFIX DBDs showed complete or near-complete loss of DNA-binding activity for R116W, R116P, K125E, and G147E despite preserved protein folding, consistent with disrupted DNA recognition and a potential dominant-negative mechanism. In contrast, R116G exhibited a 7.7{degrees}C decrease in thermal stability, which may support haploinsufficiency mediated by protein degradation. Conclusion: Specific NFIX missense variants define a severe subtype of MALNS associated with progressive musculoskeletal deterioration. In vitro functional studies support variant-specific disruption of DNA binding, providing a mechanistic basis of genotype-phenotype correlations and informing prognosis, clinical surveillance, and therapy development.

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.

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.

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.

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.

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: 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.

Patients and caregivers seek informational and emotional support throughout medical care, especially when interpreting unfamiliar laboratory test results. Although resources such as patient portals and online health communities (OHCs) help address questions, gaps remain. The emergence of large language models (LLMs) offers the potential to be a complementary source of support to assist patients and caregivers in understanding and using their test results. The objective of our study is to empirically compare LLM responses to patients online questions containing their laboratory test results to responses written by peers in an OHC. We compared the 519 peer replies to 122 laboratory test-related posts from an OHC to 488 responses generated from four LLMs using mixed computational and qualitative methods. LLMs frequently provided clear explanations of medical terminology and structured interpretations of numeric results but were longer and less readable. Peers offered more personalized, context-specific emotional support. Overall, LLMs have the potential to complement peer responses in OHCs, but require greater emotional depth, reasoning transparency, and alignment with community norms.

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

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.

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.

Purpose: Nonresponse to routinely collected patient-reported outcome measures (PROMs) threatens the representativeness of aggregated data. We characterized patient-, provider-, and clinic-level factors associated with PROMIS Global-10 nonresponse in routine radiation oncology care. Methods: In this retrospective cohort study, all adults seen at five Mass General Brigham radiation oncology clinics over one year were included. The primary outcome was patient-level nonresponse, defined as never completing the portal-administered Global-10 versus completing it at least once. Using iterative mixed-effects logistic regression, we modeled patient-, provider-, and clinic-level factors. Results: Among 12,214 patients, 71 providers, and five clinics, patient- and appointment-level response rates were 35.4% and 10.9%, with patient-level response ranging nearly fivefold across clinics (12.8% to 66.2%). In Model 1, male sex, lower education, not working, and recent surgery had higher odds of nonresponse, and longer time since diagnosis lower odds. After provider- and clinic-level factors were added, patient sex, education, and employment became nonsignificant, whereas recent surgery (adjusted odds ratio [aOR] 1.97) and longer time since diagnosis (aOR 0.46 for >12 months) persisted. A provider's historical collection rate was protective but attenuated at the clinic level. There, a later program launch (aOR 0.29) and higher historical collection rate (aOR 0.79) correlated with lower nonresponse, whereas academic versus community setting did not. Conclusions: Nonresponse to routinely collected PROMs is a multilevel phenomenon driven substantially by clinic-level implementation factors, not patient characteristics alone. Because response rate is only a proxy for representativeness, PROMs programs and PRO-based performance measures should prioritize representative collection over volume.