Wellcome Open Research

Autosomal dominant polycystic liver disease (ADPLD) commonly results from a pathogenic variant in one of 6 genes (GANAB, ALG8, LRP5, PRKCSH, SEC61B, SEC63). Pathogenic variants in these genes are also associated with kidney cysts, which rarely cause kidney failure, but the genes are included in cystic kidney panels. This study determined the population frequency of predicted pathogenic variants in the ADPLD genes in the general population. Variants for each gene were downloaded from gnomAD and annotated with ANNOVAR. The population frequencies were calculated from the number of people with "predicted pathogenic" variants in gnomAD v.2.1.1:loss-of-function structural and copy number; null; and rare, computationally-damaging missense changes that affected a conserved residue. Frequencies were also estimated from the number of gnomADv.4.1 variants assessed as Pathogenic or Likely pathogenic in ClinVar. Predicted pathogenic variants affected one in 95 people using our strategy and gnomAD v.2.1.1, and one in 151 with ClinVar assessments of gnomAD v.4.1 variants. LRP5 and ALG8 which are associated with a milder clinical phenotype, were the commonest affected genes with both strategies. Predicted pathogenic variants in ADPLD appear more frequent in admixed American (one in 100), Finnish (one in 107) and African/African American (one in 130) people (p all <0.0001 compared with Europeans (one in 197).Predicted pathogenic variants for ADPLD may be even more common because of additional unidentified causative genes. However not all ADPLD variants result in liver cysts, nor indeed cystic kidneys, because of incomplete penetrance and variable expressivity.

Background and hypothesis Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide including an estimated 30,000-70,000 in the United Kingdom (UK). Tolvaptan is the only disease-modifying therapy approved for rapidly progressing disease. Despite national guidance, prescribing rates were hypothesised to vary by kidney centre. Treatment may not always align with guidelines: some patients eligible for tolvaptan may not be initiated, while other patients initiated on tolvaptan may not meet eligibility criteria. This may have important consequences for healthcare costs and health-related quality of life. Methods The National Registry of Rare Kidney Diseases (RaDaR) collects longitudinal data from UK NHS kidney centres. This retrospective cohort study used routinely collected data (2016-2023) to examine tolvaptan prescribing across kidney centres. Kidney centre-level initiation patterns were described, assessed using mixed-effects logistic regression and visualised with funnel plots. Cost-effectiveness analyses combined observed prescribing practices under likely negotiated commercial discounts to estimate costs and quality-adjusted life year (QALY) consequences of prescribing at the national level. Results Our study included 3,609 people with ADPKD from 72 kidney centres. Patients eligible for tolvaptan who were not initiated accounted for 34.8% (292/839). Across centres, five (6.9%) initiated tolvaptan significantly more than expected among eligible participants, while one centre (1.4%) initiated significantly less. Nationally, this could result in up to {pound}53.7 million in lost savings (assuming a 60% medication price reduction) and result in up to 1,245 lost QALYs. Patients initiated on tolvaptan who were not eligible accounted for 26.1% (103/395). Only one centre had significantly fewer eligible patients than expected among initiated patients. Nationally, this could cost up to {pound}15.9 million (assuming a 60% medication price reduction). Conclusions There is evidence of variation in tolvaptan prescribing in the UK. A substantial proportion of patients eligible for tolvaptan were not initiated at the cohort-level, with evidence of variation between centres suggesting differences in treatment decision-making. A substantial proportion of patients initiated on tolvaptan were not eligible at the cohort-level, but there was limited evidence of variation between centres. Together, these findings raise questions regarding the potential consistency of clinical decision-making, equitable access to a sole disease-modifying therapy in a rare disease, alignment with national guidance, and effective use of healthcare resources.

Background Social contact surveys, which measure who-contacts-whom, are widely used to inform infectious disease transmission models and estimate the reproduction number (R), a key metric for assessing epidemic risk. Despite their widespread use, sample size calculations are not routinely performed. Aims To assess the impact of sample size on estimates of R and determine a practical target sample size for social contact surveys used in epidemic modelling. Methods We conducted a review of social contact surveys (2008-2025) to characterise current practice. We characterised the impact of survey size on epidemic metrics using two social contact surveys, the UK Social Contact Survey and POLYMOD (Europe) and two methods. For each dataset and approach, we generated repeated subsamples and calculated the resulting reproduction numbers, characterised their distributions and measured uncertainty. Results We identified 107 unique social contact surveys from 57 studies. Sample sizes ranged from 30 to more than 10,000 participants, with a median of 1,438. One quarter of surveys contained fewer than 1,000 participants. From our simulations, we find that sample sizes below 200 individuals can result in highly variability reproduction numbers. Increasing sample size increases precision, and the most meaningful gains are up to 1,300 individuals. Increasing sample sizes over 3,000 individuals leads to smaller gains. Conclusions A minimum sample size of approximately 1,200-1,300 participants appears sufficient for general-purpose use. These findings support the inclusion of sample size considerations in the design, reporting and interpretation of social contact surveys used for epidemic intelligence and public health decision-making.

Here we evaluated the performance of a previously published tiling PCR primer scheme by Ringlander et al. (2022) for whole-genome amplification of Hepatitis B virus (HBV) in combination with Oxford Nanopore sequencing. The primer set originally developed for Ion Torrent sequencing was adapted by removing platform-specific adapters and tested using clinical serum or plasma samples submitted for routine HBV genotyping and resistance testing. Two multiplexing strategies were compared: a single PCR pool containing all primers and a two-pool strategy with non-overlapping amplicons. Sequencing reads were processed using a Nanopore analysis pipeline, and genome coverage and amplicon performance were compared across samples spanning a wide Ct range and representing HBV genotypes A-E. Across all samples, the median genome coverage was approximately 50%, although recovery varied widely, ranging from complete failure to nearly full genomes. Combining all primers into a single PCR reaction, or separating overlapping amplicons into different reactions, had little overall impact on genome recovery, and no consistent differences between the two pooling strategies were observed. In contrast, amplification efficiency differed markedly between individual amplicons. Amplicons 1-5 generally produced higher sequencing depth, whereas amplicons 6-10 frequently showed low coverage and contributed to incomplete genome recovery. Genome coverage was strongly associated with Ct values, with higher coverage observed in samples with lower Ct values, while coverage was broadly similar across genotypes. These results demonstrate that the Ringlander et al. primer scheme can be adapted for multiplex PCR and Nanopore sequencing of HBV, but uneven amplicon performance limits consistent full-genome recovery and highlights the need for further optimization of HBV tiling PCR designs.

BackgroundDatasets related to infectious diseases are essential for public health decision-making, yet their reuse remains limited by persistent barriers to data sharing and integration. Achieving data that are Findable, Accessible, Interoperable, and Reusable (FAIR) is widely recognized as essential for accelerating scientific discovery and enabling coordinated responses to emerging threats, but the needs of the global pathogen data community have not been systematically characterized. AimThis study, conducted by the Pathogen Data Network (PDN), aims to identify infrastructural and educational priorities among stakeholders working with infectious disease-related data in order to guide community-responsive support for data sharing and interoperability. MethodsA cross-sectional stakeholder survey was disseminated to a well-defined expert population within PDN networks and via open professional channels. A total of 136 responses from researchers, healthcare professionals, bioinformaticians, and educators were analyzed descriptively to identify prioritized barriers, training needs, and preferred support mechanisms. ResultsRespondents consistently identified structural constraints as the primary impediments to effective data use, including limited funding (74%), data-aggregation challenges (68%), and a shortage of skilled personnel (52%). Respondents identified bioinformatics for infectious disease research (68%) as the highest priority for training, followed by guidance on using the integrated pathogen data and tools portal provided by the PDN, the Pathogens Portal (51%). The Pathogens Portal was also ranked as the most essential PDN resource (72%). Preferred training formats included virtual short courses (68%) and webinars (66%). Notably, while researchers emphasized technical subjects like machine learning, educators prioritized foundational case studies. ConclusionThese findings provide an evidence-based diagnostic of community needs and suggest that barriers to FAIR pathogen data are predominantly systemic rather than purely technological. The survey framework and openly available dataset offer a reusable template for assessing needs in other communities and regions. By aligning training, infrastructure development, and outreach with empirically identified priorities, organizations supporting infectious disease research can strengthen the interoperability and reuse of data and establish a benchmark for future community-driven improvements.

Background & AimsAntiviral therapies targeting hepatitis B virus (HBV) suppress viral replication, but rarely achieve functional cure. Understanding HBV-host cell interaction is crucial for developing novel therapeutic approaches. Here, we report host cell proteins associated with HBV virions and filamentous subviral particles (fSVPs) and characterize one of them, apolipoprotein C1 (ApoC1), mechanistically. MethodsHighly purified HBV virions and fSVPs were obtained by sequential use of several biophysical methods. Particles were analyzed by mass spectrometry and associated proteins were evaluated phenotypically using an HBV infection model. The top hit, ApoC1 was characterized in detail. ResultsAssociated with virions and fSVPs, we identified in addition to known chaperones such as HSP90AB1 and HSC70, several apolipoprotein-related factors. RNAi-based phenotypic validation identified strongest effects for ApoC1, likely due to two complementary effects. First, ApoC1 depletion reduced intracellular cholesterol level impairing HBV infection and SVP production, which was compensated by exogenous cholesterol substitution. Second, ApoC1 that is mainly enriched in high-density lipoprotein (HDL), associates with HBV virions and fSVPs and increases HBV infectivity. The same was found for hepatitis D virus (HDV), a satellite virus utilizing HBV envelopes. Supplementation of exogenous HDL enhanced infection most likely via scavenger receptor class B type 1 (SR-B1), the natural HDL receptor. Consistently, inhibition of SR-B1 suppressed HBV and HDV infection. ConclusionsWe established a method for obtaining highly purified HBV virions and fSVPs and identified the HDL component ApoC1 to associate with both particle types. ApoC1 promotes HBV and HDV infection most likely via SR-B1 facilitating viral entry.

Objective The aim of this study was to develop and validate an automated, scalable framework to harmonise fragmented UK primary care prescription records into a research-ready dataset by mapping four diverse medical ontologies to a unified, historically comprehensive reference standard. Materials and Methods We used raw prescription records for consented participants in the UK Biobank, in which participants are uniquely characterized by multiple data modalities. Primary care data were preprocessed by selecting one drug code if multiple were recorded, cleaning codes to match reference presentations, expanding code granularity based on drug descriptions, and updating outdated codes to a single reference version. Harmonisation entailed mapping British National Formulary (BNF) and Read2 codes to dm+d, the universal NHS standard vocabulary for uniquely identifying and prescribing medicines. Harmonised dm+d records were then homogenised to a single concept granularity, the Virtual Medicinal Product (VMP). We validated our methods by creating medication profiles mapping contemporary drug prescribing patterns in 312 physical and mental health conditions. Results We preprocessed 57,659,844 records (100%) from 221,868 participants (100%). Of those, 48,950 records were dropped due to lack of drug code. 7,357,572 records (13%) used multiple ontologies. Most (76%) records were encoded in BNF and most had the code granularity expanded via the drug description (N=28,034,282; 49%). 41,244,315 records (72%) were harmonised to dm+d and 99.98% of these were converted to VMP as a homogeneous dataset. Across 312 diseases, we identified 23,352 disease-drug associations with 237 medications (represented as BNF subparagraphs) that survived statistical correction of which most resembled drug - indication pairs. Conclusion Our methodology converts highly fragmented and raw prescription records with inconsistent data quality into a streamlined, enriched dataset at a single reference, version, and granularity of information. Harmonised prescription records can be easily utilised by researchers to perform large-scale analyses in research.

Background: Sub-Saharan Africa (SSA) still experiences a high burden of micronutrient deficiencies. For monitoring of micronutrient status among young children in SSA, non-invasive alternatives to blood-based biomarkers are desirable. Handheld Raman spectrophotometry appears to offer this alternative to quantify intracellular stores of micronutrients. In rural Burkina Faso and Kenya, we validated the Cell-/SO-Check device (ZellCheck(R)) against conventional laboratory-based methods. Methods: For this validation study, we recruited children aged [&ge;]24 months attending routine clinics within the Health and Demographic Surveillance Systems (HDSS) in Siaya and Nouna. Anthropometric measurements and venous blood samples were taken. Plasma ferritin, soluble transferrin receptor (sTfR) and C-reactive protein (CRP) were measured by ELISA, and plasma zinc by atom absorption. The spectrometer was used to quantify zinc and iron. For continuous outcomes, we generated Bland Altman plots and calculated bias and limits of agreement (LoA). For binary outcomes, we produced Receiver Operator Characteristic (ROC) areas under the curve (AUC), and estimated sensitivity, specificity and predictive values. Results: We analysed data of 48 children from Burkina Faso and 54 children from Kenya (male: 53%; age range: 24-66 months). According to spectrophotometry, the proportions of iron deficiency and zinc deficiency were 16.7% and 25.5%, respectively. The median concentrations were for ferritin 24.0 {micro}g/L (range: 2.0-330.0), for sTfR 5.7 mg/L (2.8-51.0), and for zinc 9.9 {micro}mol/L (5.2-25.0). The corresponding bias for iron levels by spectrophotometry was 42.4 with LoA: -18.7, 103.6. The bias for zinc levels was 7.5 with LoA: -49.3, 64.2. For the classification of deficiency, the ROC-AUC, sensitivity, and specificity for spectrophotometry vs. biomarker-based diagnosis were for iron deficiency 0.62, 68% and 55%, respectively, and for zinc deficiency 0.55, 33% and 91%, respectively. Conclusions: The Cell-/SO-Check device may be used to rank children in population-based studies in SSA according to their zinc status, but not iron status. The method should not replace the standard laboratory measurements for clinical diagnoses of zinc and iron deficiencies.

BackgroundThe mechanisms underpinning associations between sleep and psychiatric conditions are poorly understood, partly due to challenges with longitudinal sleep studies outside the laboratory. Children and young people with rare genetic conditions caused by micro-deletions or -duplications (Copy Number Variants or CNVs) have increased risk of disrupted sleep and poorer neurodevelopmental (ND) outcomes. The Sleep Detectives study aims to investigate this by tracking behavioural and neurophysiological signatures of sleep health in young people with ND risk or ND-CNVs. To optimally achieve this, we have worked with families with ND-CNVs and charity partners to co-design our tools, methods, study protocol, and materials. MethodWe established a Lived Experience Advisory Group (LEAP) with nine parents and 13 children and young people with ND-CNVs, alongside representatives of UK charities Max Appeal and Unique. Together, the research team and LEAP co-designed two in-person family workshops in which we collected feedback on the acceptability of sleep monitoring devices, the design of bespoke cognitive tasks, and overall study protocol. Informal interviews and surveys were conducted with LEAP members and researchers, to enable the team to reflect and learn from their Patient/Public Involvement (PPI) experiences. ResultsKey outputs included pre-workshop invitation and briefing materials and insights that iteratively refined the main study design, including the need for flexibility to increase accessibility, selection of sleep devices, customisation of cognitive tasks, and choice of language in documents. The PPI process was highly valued by LEAP members, workshop attendees, and the research team. One investigator described the PPI work as "reinvigorating my love of research by helping me focus on science that matters". Participating families also established peer support networks. ConclusionsInvolving families affected by ND-CNVs in co-designing the Sleep Detectives study maximised opportunities for acceptability, accessibility and scalability. The research team gained inspiration and deeper understanding of the impact of ND-CNVs on families. Families gained awareness about research, established connections with each other and peer support, and were enthusiastic about future research involvement. This experience empowered families to engage more deeply with the research process and helped the PPI work to be more impactful and inclusive. Plain English summaryChildren and young people with rare genetic conditions caused by small deletion or duplication of genetic material are more likely to experience sleep difficulties such as insomnia, restless sleep, and tiredness. They also show an increased likelihood of neurodevelopmental conditions such as learning disability and autism, and mental health issues such as anxiety. The Sleep Detectives team wanted to explore how these genetic conditions affect childrens sleep, cognition and psychiatric health. To make sure that the project design was well suited to the children and young people that would be invited to participate, the team worked closely with families to design the study. Parents and caregivers of affected children and young people were invited to join a Lived Experience Advisory Panel (LEAP), together with charity representatives and Sleep Detective researchers, to co-design two hands-on workshops, and advise on study design. Children and young people and parents/caregivers attending the workshops tried out and provided feedback on tools and devices that the research team were developing. They also advised on the arrangements and support families might need whilst taking part, and on the study protocol. This collaborative approach helped ensure the study design was optimally suited for the recruitment and participation of children and young people and their families. This report documents our public involvement work for the Sleep Detectives study, illustrating the difference the partnership between researchers and families has made to the project, and the wider benefits for all concerned.

Background India represents 18% of the global population yet remains underrepresented in health research. Moreover, existing national surveys miss critical variation across its 4,600 ethnolinguistic groups. We present a comprehensive phenotypic characterisation of 81 populations from the GenomeIndia project. Methods We analysed 67 sociodemographic, anthropometric, and blood biochemistry variables from 17,777 individuals sampled across 81 ethnolinguistic populations from India, examining population-level variation, disease reporting fractions, and age- and sex-specific life-course trends. Findings Ethnolinguistic identity predicted health outcomes independently of administrative state, improving phenotypic variance explained by an average of 7.4%. 95% of participants had at least one abnormal biochemical or anthropometric marker, driven by low HDL (52.2%) and elevated triglycerides (43.6%). Metabolic risk, however, was highly stratified: adjusted prevalence for low HDL ranged four-fold across ancestry groups from 17.2% to 67.7%. We also identified an "awareness gap"; only 17.6% of people with hypertension and 2.2% of people with dyslipidemia were aware of their condition. This awareness gap was higher in tribal populations, in which women did not show the higher HDL levels typically seen compared to men, pointing to distinct metabolic profiles and healthcare access barriers across India. Interpretation The Indian phenotypic landscape is highly structured along ethnolinguistic lines, where ancestry and environment both influence risk. The high systemic burden of abnormalities necessitates population-specific reference intervals. GenomeIndia provides a foundational map for precision public health, shifting the focus from state-level averages to population-specific risk profiles. Funding This work was funded by the Department of Biotechnology, Ministry of Science and Technology, Government of India.

SignificanceQuantifying lipid droplet (LD) remodeling in 3D hepatic organoids is often limited to endpoint staining or phototoxic live fluorescence imaging, thereby obscuring droplet-level kinetics. AimWe aimed to develop a label-free method to track LD dynamics in living hepatic organoids under different fatty-acid loads. ApproachTime-lapse 3D refractive-index tomograms were acquired using holotomography and analyzed with a depth-adaptive, multi-threshold segmentation pipeline to quantify LD number, volume, sphericity, and refractive-index-derived concentration and dry mass at single-droplet resolution. ResultsOleic acid and linoleic acid induced LD accumulation while preserving organoid integrity, whereas palmitic acid triggered rapid structural collapse. Despite increases in total LD burden under both oleic acid and linoleic acid, droplet-level dynamics diverged: oleic acid produced volume-dominated accumulation via enlargement of fewer LDs and increased size heterogeneity, whereas linoleic acid produced number-dominated accumulation via sustained increases in LD number, yielding a more uniform population of small droplets. ConclusionsLabel-free holotomography with depth-adaptive analysis enables non-invasive, longitudinal, and multi-scale quantification of LD dynamics in intact organoids and reveals fatty-acid- dependent temporal modes of lipid storage. Statement of DiscoveryWe developed a label-free, longitudinal 3D holotomography framework with depth-adaptive lipid droplet segmentation that quantifies single-droplet dynamics in living mouse hepatic organoids. Using this platform, we found that oleic acid and linoleic acid induce LD accumulation via distinct strategies--oleic acid via droplet enlargement and linoleic acid via sustained increases in droplet number--while palmitic acid rapidly compromises organoid integrity.

Aim: To explore RSV knowledge and awareness, RSV vaccination perceptions and acceptability, and preferences for maternal vaccine delivery and communication amongst pregnant women and mothers of infants and toddlers in England. Methods: Between July and November 2024, semi-structured qualitative interviews were performed with 30 mothers (youngest child under 2 years), two of whom were pregnant with a subsequent child. The study was conducted as a follow-on to a UK Health Security Agency survey of attitudes towards RSV vaccination amongst pregnant and post-partum women in England. Findings: Although most mothers had heard of RSV, mothers with experience in health roles were more likely to understand the potential severity of RSV in infants. Likelihood of maternal RSV acceptance was reported as high, with most mothers considering RSV vaccination as beneficial in protecting infants. Most mothers preferred a hybrid approach to vaccine communication, with information available online (e.g. through the NHS website), via written sources (e.g. NHS produced leaflet), and through talking with midwives. For convenience, most mothers preferred the option of fitting vaccinations within the antenatal midwifery appointment schedule rather than going to general practice for a separate appointment. Conclusion: To support maternal RSV vaccination decision-making and access, women need vaccine information early in pregnancy; information provision through a range of different sources (i.e. online, paper, in-person); and vaccination delivery in a convenient location (i.e. as part of antenatal appointments).

Background: Oseltamivir is an antiviral medication for influenza that can reduce the duration of symptoms and may lower the risk of some complications. Recommendations for use of oseltamivir include in the outpatient setting for individuals at higher risk of developing influenza complications. Objectives: To describe oseltamivir initiation and treatment completion among influenza-positive outpatients and identify factors associated with each. Methods: In a U.S. outpatient household transmission study, index participants with laboratory-confirmed influenza provided up to 12 days of detailed information on medication use. We described oseltamivir initiation among index cases and treatment course completion of [&ge;] 10 doses among cases who initiated oseltamivir. We used unadjusted and adjusted logistic regression to identify factors associated with initiation and course completion. Results: Among 823 enrolled index cases, 324 (39%) initiated oseltamivir treatment. Of 406 persons at higher risk for influenza complications, 172 (42%) initiated treatment. Oseltamivir initiation was lowest among children aged 2 to < 5 years (19%) compared to all other age groups. Among 313 cases who initiated oseltamivir, 42% completed the recommended treatment course of [&ge;] 10 doses. Among 163 individuals at higher risk of influenza complications, 69 (42%) completed the recommended treatment course of [&ge;] 10 doses. Children < 2 years were significantly less likely to complete treatment compared to adults aged 18-50 years (aOR: 0.21, 95% CI: 0.04, 0.78, p= 0.030); reasons for discontinuation could not be determined. Conclusions: These findings reveal differences in oseltamivir treatment in an outpatient setting among groups at higher risk for influenza complications.

BackgroundIn England, the burden of respiratory infections varies by ethnicity, contributing to health inequalities, but the role of additional demographic factors remains underexplored. We quantified how differences in social mixing and demographic characteristics between ethnic groups cause inequalities in transmission dynamics. MethodsWe analysed the association between the ethnicity and the number of contacts of 12,484 participants in the 2024-2025 Reconnect social contact survey, using a negative binomial regression model. We simulated respiratory pathogen epidemics using a compartmental model stratified by age, ethnicity, and contact levels, at a national level and in major cities in England. FindingsAfter adjusting for demographic variables, participants of Black and Mixed ethnicities had more contacts than those of White ethnicity (rate ratios (RR): 1.18 [95% Credible Interval (CI): 1.11-1.26], and 1.31 [95% CI: 1.14-1.52]). Participants of Asian ethnicity had fewer contacts (RR: 0.85 [95% CI: 0.79-0.91]). In national-level simulations, individuals of White ethnicity had the lowest attack rates due to demographic differences and mixing patterns. Local demographic structures changed simulated dynamics: attack rates in individuals of Black and Mixed ethnicities were approximately double those of White ethnicity in Birmingham, but less than 60% higher in Liverpool. InterpretationDemographic characteristics and mixing patterns create inequalities in transmission dynamics between ethnicities, while local demographic characteristics and pathogen infectiousness change the expected relative burden. To ensure mitigation strategies are effective and equitable, their evaluation must explicitly account for inequalities arising from local context. FundingMedical Research Council, National Institute for Health and Care Research, Wellcome Trust Research in context Evidence before this studyWe searched PubMed for population-based studies quantifying differences in respiratory infections between ethnic groups, up to 1 April 2026, with no language restrictions. Keywords included: (respiratory pathogens OR influenza OR COVID-19) AND (ethnic* OR race) AND (inequ*) AND (compartmental model OR incidence rate ratio OR hazard ratio). We excluded studies that focused on non-respiratory pathogens (e.g. looking at consequences of COVID-19 on incidence of other pathogens). A population-based cohort study showed that influenza infection risk was higher in South Asian, Black, and Mixed ethnic groups compared to White ethnicity in England. Another population-based cohort study highlighted that during the first wave of COVID-19 in England, the South Asian, Black, and Mixed ethnic groups were more likely to test positive and to be hospitalised than the White ethnic group. Census data in England showed that the distributions of age, household size, household income and employment status differed between ethnic groups, and the recent Reconnect social contact surveys highlighted the impact of each demographic factor on the participants number of contacts. Added value of this studyOur study shows that social contact patterns, mixing, and demographic structure all lead to unequal infection risk between ethnic groups in respiratory pathogen epidemics. Using the largest available social contact survey in England, we show that both the average number of contacts and the proportion of high-contact individuals varied by ethnic group, even after adjusting for participants demographics. These differences, together with mixing patterns and age structure, led to lower expected incidence among individuals of White ethnicity than in all other ethnic groups in simulated outbreaks. The level of inequality between ethnic groups changed when we used different values of pathogen transmissibility. Finally, as ethnic composition and population structure differ between cities in England, our results show differences in expected inequalities at a local level. Implications of all the available evidenceInequalities in infection risk between ethnic groups are context- and pathogen-dependent. They arise from both local population structure and contact patterns. Detailed information on mixing between groups and population structure is needed to accurately measure group-specific infection risk. These findings indicate that public health interventions based only on national-level estimates conceal regional variation in risk and may ultimately increase inequalities. Public health interventions need to be tailored to local contexts to be equitable and effective. Finally, our findings provide a foundation for understanding the progression from infection-risk inequalities to disparities in disease presentation and clinical outcomes.

BackgroundIn England, individuals with chronic liver disease (CLD) are among those with the lowest seasonal influenza vaccine uptake despite being at elevated risk of severe influenza. We examined the relationship between CLD severity and aetiology, and influenza vaccine uptake in England. MethodsA retrospective cohort study of adults (18-115 years) using Clinical Practice Research Datalink Aurum primary care data was conducted for five seasons (2019/20-2023/24). Poisson regression was used to estimate rates of uptake by CLD severity (clinical diagnoses categorised as low, moderate, or severe) and aetiology (alcohol-related, viral-related, and diagnoses in the Green Book guidelines). FindingsThere were 182,174-277,470 with CLD per cohort. Among those who were additionally age-eligible for vaccination, uptake was 71{middle dot}1-79{middle dot}7% compared to 30{middle dot}9-40{middle dot}5% in those not additionally age-eligible. Among individuals below age eligibility without other comorbidities, severity was associated with higher uptake (incidence rate ratio [IRR] moderate 1{middle dot}80, 95% CI 1{middle dot}69-1{middle dot}90; severe 1{middle dot}95, 95% CI 1{middle dot}84-2{middle dot}08 in 2023/24); there was no effect in those with at least one additional comorbidity (moderate 1{middle dot}05, 95% CI 0{middle dot}99-1{middle dot}10; severe 1{middle dot}05, 95% CI 1{middle dot}01-1{middle dot}09). Alcohol- and viral-related aetiology were also associated with increased uptake in those not additionally age-eligible. Among individuals meeting age eligibility without additional comorbidities, severity was associated with a reduced uptake (moderate 0{middle dot}81, 95% CI 0{middle dot}73-0{middle dot}90; severe 0{middle dot}79, 95% CI 0{middle dot}74-0{middle dot}85), with attenuation in those with additional comorbidities (moderate 0{middle dot}99, 95% CI 0{middle dot}94-1{middle dot}04; severe 0{middle dot}91, 95% CI 0{middle dot}89-0{middle dot}94). InterpretationCLD severity and aetiology were important determinants of uptake in the absence of additional indications for influenza vaccination. Future research should prioritise understanding facilitators and barriers to vaccine uptake in individuals with CLD, particularly for those at highest risk of severe infection. FundingNIHR Health Protection Research Unit in Vaccines and Immunisation (NIHR200929/NIHR207408). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to June 2025 using the terms "chronic liver disease", "cirrhosis", "hepatitis", "influenza vaccination", "seasonal influenza", and "vaccine uptake". Previous research, including national data from England, has shown that people with chronic liver disease tend to have lower seasonal influenza vaccine uptake than individuals with other medical comorbidities which qualify for vaccination such as diabetes, chronic kidney disease or immunosuppression. The reasons for low influenza vaccine uptake in people with chronic liver disease are not well understood, and it is therefore difficult for vaccination providers, principally primary care services in England, to tailor interventions aimed to increase uptake. Qualitative research involving individuals aged less than 65 years living in England with clinical risk comorbidities, most commonly diabetes, found that chronic disease management pathways inconsistently provided information about the importance of influenza vaccination as part of chronic disease management. Individuals with long-term conditions reported low perceived risk of influenza infection and limited awareness of vaccine benefits as important reasons for non-uptake. We hypothesised that the severity and aetiology of chronic liver disease may be important determinants of uptake. Added value of this studyWe conducted a population-based study to examine how chronic liver disease severity and aetiology influence seasonal influenza vaccine uptake in adults in England. Using primary care electronic health record data from five consecutive influenza seasons (2019/20-2023/24), we found that more severe chronic liver disease was associated with a substantial increase in vaccine uptake in those without additional indications for seasonal influenza vaccination (age-based eligibility or other qualifying clinical risk comorbidities). Alcohol- and viral-related aetiology were also associated with increased uptake in those who were not additionally age-eligible for vaccination. In contrast, severity, alcohol- and viral-related underlying aetiology were associated with a modest reduction in uptake for individuals with chronic liver disease who also qualified for vaccination due to age. Implications of all the available evidenceDespite clear clinical vulnerability to infection and a substantially elevated risk of morbidity and mortality following infection, a large proportion of adults with chronic liver disease, particularly those aged under 65 years, remain unvaccinated against seasonal influenza each year. This study suggests that chronic liver disease severity and underlying aetiology are important determinants of uptake in individuals not meeting age-based vaccine eligibility, particularly in those without additional clinical risk comorbidities. This could be because of differing perceptions of influenza risk, or due to varying degrees of interaction with healthcare specialists as part of chronic disease management. In individuals who met age-based vaccination eligibility, the negative effect of severity on influenza vaccine uptake may reflect greater barriers to accessing vaccination services by those with more complex health needs, or competing medical priorities for long-term condition management during consultations. To inform targeted vaccination strategies, future research should aim to understand the specific facilitators and barriers to influenza vaccination experienced by individuals with chronic liver disease. This should include perspectives of individuals with different disease severity, across different age groups, in those with and without additional co-morbidities.

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

Background Urogenital schistosomiasis (UGS), caused by Schistosoma haematobium (S. haematobium), disproportionately affects women in sub-Saharan Africa and can lead to haematuria, anaemia, and urinary tract morbidity. Data on the prevalence in women of reproductive age remains limited in contrast to infection among school-aged children in Kenya. This study assessed the prevalence of UGS and its socioeconomic determinants among women in Kilifi County, Kenya. Methods: Urine samples (20-50 mL) were collected from each participant over three consecutive days. Day-one samples were tested for haematuria, proteinuria, nitrites, leukocytes, and pregnancy using dipsticks. On the other hand, 10 mL of urine was examined for S. haematobium eggs via urine filtration on all three days. Results: A total of 599 women aged 15-50 years were enrolled, with complete data available for 336. The mean age was 33 years; 57.7% were <35 years. Most participants were from rural Magarini Sub-county (63%) and engaged in crop farming (62.5%). Primary education was the highest level attained by 59.8% of participants. Frequent contact with stagnant water was reported by 92%. The overall prevalence of S. haematobium infection was 13.7% (95% CI: 10.2-17.8), higher in Magarini (14.9%) than in Rabai (12.0%), though not statistically significant. Younger age, primary education, and frequent water contact were associated with higher infection rates; however, after adjustment for covariates, haematuria showed the strongest independent association with infection. Women with haematuria were 25.2 times more likely to be infected (OR: 25.24, 95% CI: 7.07-82.63, p < 0.001); multivariate analysis confirmed haematuria as the sole significant predictor (OR: 20.83, 95% CI: 5.45-79.57, p < 0.001). Conclusion: UGS prevalence among women in Kilifi County is substantial, with variation between sub-counties. Haematuria demonstrated the strongest independent association with infection and may serve as a simple, non-invasive diagnostic marker. These findings underscore the pressing need for the integration of UGS screening into the reproductive health services and targeted interventions. Authors Summary UGS, caused by the parasitic worm Schistosoma haematobium, is a neglected tropical disease and remains a major public health problem in sub-Saharan Africa. Although control programmes in Kenya primarily target school-aged children, women of reproductive age are frequently exposed through daily water contact and may develop chronic urinary and reproductive health complications. However, data on the infection burden among adult women are limited. In this study, we assessed the prevalence of urogenital schistosomiasis and associated risk factors among women aged 15-50 years in Kilifi County, Kenya. Urine samples were collected over three consecutive days and examined for parasite eggs and indicators of urinary tract disease. We found that urogenital schistosomiasis affected more than one in ten women in the rural sub-counties where the study was conducted. Haematuria was strongly associated with infection and remained the most reliable predictor after accounting for other social and behavioural factors. These findings demonstrate that UGS is an under-recognised health issue among women and highlight the potential value of simple urine-based screening tools. Integrating UGS screening into existing reproductive health services could improve early detection and contribute to more inclusive disease control strategies.

Introduction: Podocyte injury is central to the pathogenesis of most glomerulonephritides (GN) and causes segmental glomerulosclerotic lesions that predict progression in IgA Nephropathy (IgAN). Recent advances in high-resolution microscopy and AI-assisted image analysis have enabled detailed quantification of podocyte foot process (FP) morphology. However, whether nanoscale podocyte morphometrics can predict disease progression or treatment response in GN has not been investigated. Aim: To evaluate whether nanoscale podocyte morphometric parameters predict clinical characteristics, disease progression, and treatment response in GN, with a focus on IgAN. Method: Podocyte morphometrics were analyzed in kidney biopsies from patients with GN using high-resolution microscopy and the deep learning-based tool Automatic Morphometric Analysis of Podocytes (AMAP). Four morphometric parameters were quantified: slit diaphragm length (SDL), FP area, FP circularity and FP perimeter. These parameters were correlated with clinical characteristics, conventional electron microscopy (EM) findings and longitudinal follow-up data. Results: The study included 37 patients with GN from Danderyd University Hospital (Stockholm, Sweden), with IgAN representing the largest diagnostic subgroup (n = 19). The median follow-up for the cohort was 3.0 years. SDL correlated significantly with urine albumin-to-creatinine ratio (uACR; p = 0.021), whereas conventional EM measurements did not (p = 0.22). Within the IgAN subgroup, lower SDL was associated with a steeper decline in eGFR, higher FP area with increased long-term proteinuria, and higher FP circularity with improvement in uACR during the first year. The association between lower SDL and eGFR decline remained as a trend in IgAN patients not treated with corticosteroids (p = 0.068) but was absent in the treatment group (p = 0.59). Conclusion: In this proof-of-concept study, nanoscale podocyte morphometrics demonstrated greater sensitivity than conventional EM in quantifying podocyte injury and predicting progression in IgAN. These findings suggest that high-resolution morphometrics may improve risk stratification in IgAN but require validation in larger, independent cohorts before clinical implementation.

Background: Digital health tools are increasingly promoted for strengthening health information systems in low- and middle-income countries, yet routine maternal and child health (MCH) data in tribal primary health centres (PHCs) in India remains underutilised for local decision-making. Top-down digital tools often fail in low-resource settings because they are designed without meaningful input from end-users. Co-creation approaches for digital health in tribal and indigenous settings are largely unexplored. Methods: We conducted an action research study in three tribal PHCs under the Integrated Tribal Development Agency (ITDA), Rampachodavaram, Andhra Pradesh, India. We applied the Three Co's Framework (Co-Define, Co-Design, Co-Refine) to co-create data science solutions for MCH decision-making with five medical officers, 24 auxiliary nurse midwives, and 36 accredited social health activists across two action research cycles (August 2023 to August 2024). Co-creation involved collaborative indicator definition, data modelling, data quality validation, health facility catchment area construction, spatial analysis, and interactive dashboard development. Keller's Data Science Framework was employed using R to structure the analytical pipeline, and Data.org's Data Maturity Assessment (DMA) was used to assess organisational data maturity pre- and post-intervention. Findings: During Co-Define, co-creators identified a fundamental mismatch between system outputs (aggregate statistics for upward reporting) and their operational need for individual-level, geographically disaggregated, prospective information. Co-Design produced five interconnected data science solutions: (1) 42 co-defined MCH indicators grounded in clinical workflows; (2) a data model linking individuals, health services, providers, and facilities; (3) a data quality framework using the pointblank R package; (4) health facility catchment area boundaries constructed from scratch using medical officers' local knowledge, enabling spatial analysis that revealed significant clustering of ANC coverage and anaemia prevalence; and (5) an R Shiny dashboard integrating these solutions into an offline-capable interface with lifecycle-organised views and village-level navigation. The DMA showed moderate improvement in organisational data maturity from 5.04 to 5.75 out of 10, with the largest gain in Analysis (+1.90). Co-Refine continued beyond the formal study period, with two transferred medical officers maintaining analytical engagement from new postings. Interpretation: The Three Co's Framework, combined with a data science approach, provided a structured yet flexible method for co-creating locally relevant data science solutions in a tribal setting. The framework's explicit separation of problem definition from solution design was particularly valuable in a context where "the problem" is typically defined externally. Co-creation in tribal digital health settings is feasible and produces solutions that address locally articulated needs.

Objectives Concerns about COVID-19 were a key driver of infection-prevention behaviour during the pandemic. The aim of this study was to gain an in-depth longitudinal understanding of the type and frequency of concerns experienced throughout the first two years of the COVID-19 pandemic. Design Content analysis of qualitative descriptions provided in a prospective longitudinal online survey as part of the COVID-19 UK Public Experiences (COPE) Study. Method At baseline (March/April 2020), when the UK entered its first national lockdown, 11,113 adults completed the COPE survey. Follow-up surveys were conducted at 3, 12, 18 and 24 months. Participants were recruited via the HealthWise Wales research registry and social media. Baseline surveys collected demographic and health data, and all waves included an open-ended question about COVID-19 concerns. Content analysis was used to identify the type and frequency of concerns at each time point. Results A total of 41,564 open-text responses were coded into six categories: personal harm (n=16,353), harm to others (n=11,464), social/economic impact (n=6,433), preventing transmission (n=4,843), government/media (n=1,048), and general concerns (n=1,423). The proportion of respondents reporting any concern declined from 75.3% at baseline to 65.8% at 24 months. Over time, concerns about personal harm increased (baseline 41.8% vs. 24-months 52.7%) whereas concerns about harm to others decreased (baseline 48.5% vs. 24-months 28.6%). Concerns about harm were also expressed in relation to clinical vulnerability, lack of trust in government/media, and perceived lack of adherence by others. These were balanced against concerns about wider social and economic impacts of restrictions. Conclusions Public concerns about COVID-19 evolved substantially over the first two years of the pandemic, reflecting changing perceptions of risk and responsibility. Monitoring concerns longitudinally is vital to help guide effective communication and behavioural interventions during future pandemics.