The Lancet

ImportanceRecent reports have highlighted an intense influenza activity related to the circulation of the influenza A(H3N2) subclade k variant. There is no data available on the impact of the emergence of H3N2 subclade k on the severity of the 2025-2026 epidemic or on the clinical phenotype of patients requiring admission to the intensive care unit (ICU). ObjectiveTo compare the clinical presentation, hospital mortality and virological characteristics of patients with laboratory-confirmed influenza infection included in French intensive care units during the 2025-2026 epidemic season with those of patients admitted during the 2024-2025 season. We also aimed at measuring the impact of the A(H3N2) subtype on hospital mortality during the 2025-2026 season. DesignProspective, multicenter, observational SEVARVIR cohort study including patients admitted during the 2024-2025 and 2025-2025 influenza seasons. SettingForty-two French ICUs ParticipantsAdult patients with laboratory-confirmed influenza infection Interventionsnone Main Outcomes and MeasuresThe primary outcome measure was in-hospital mortality. ResultsPatients admitted in intensive care units for influenza in 2024-2025 (n=360) and 2025-2026 (n=325) were included in the French nationwide prospective multicentre SEVARVIR study. There was no significant difference in day-28 mortality between the seasons (12.7%, n=45/355 vs 16.5% n=28/170; p=0.28). In the 2025-26 season, 49% had the A(H1N1) subtype and 51% the A(H3N2) subtype (k subclade: 77%). The univariable Cox analysis revealed that patients infected with A(H3N2) viruses were at greater risk of death over time. Multivariable Cox analysis revealed that during the 2025-2026 season, age (adjusted hazard ratio, aHR=1.05 [1.00;1.11]; p=0.046) and the clinical frailty scale (aHR=1.82 [1.26;2.72]; p=0.001) were associated with an increased risk of death. The A(H3N2) subtype was not associated with an increased risk of death (aHR=1.13 [0.32;4.51]; p=0.85). Phylogenetic analyses from our ICU cohort together with 300 contextual sequences from community-acquired influenza cases collected during the same period showed no clustering according to severity. Conclusions and RelevanceThis French national prospective observational study, found that the emergence of the influenza A(H3N2) subclade K was associated with an increased risk of death in univariable but not multivariable analysis, adjusting for host-related factors. Trial RegistrationNCT051625 Key PointsQuestion: What impact did the 2025-26 influenza epidemic and the A(H3N2) variant have on the mortality of patients admitted to intensive care units? Findings: In this prospective, nationwide cohort study of 685 patients admitted to intensive care units with severe influenza during the 2024-25 or 2025-26 seasons, no difference in hospital mortality was observed between the two seasons. Patients infected with the A(H3N2) virus, 77% of which corresponded to clade k, were at higher risk of death in univariable but not in multivariable analysis after adjusting for age and clinical frailty scale. Meaning: Patients in intensive care units with severe A(H3N2) infection during the 2025/2026 season were not at higher risk of death after adjusting for confounding variables.

IntroductionAccess to Hepatitis C virus (HCV) testing and treatment remains low globally. HCV self-testing (HCVST) may facilitate diagnosis and cure. We analysed treatment uptake and outcomes following a positive HCVST result in three distinct African epidemic contexts. MethodsA multi-country cohort study nested within HCVST implementation programmes in Cameroon, Nigeria, and South Africa (May 2023-May 2024). Adults ([≥]18 years) with positive HCVST results were followed through confirmatory testing and care outcomes until last event. Co-primary outcomes were: (i) cascade progression, (treatment initiation and sustained virological response [SVR]); estimated using country-cascades; and (ii) cumulative incidence of disengagement from care, estimated using Bayesian competing-risks survival models. Analyses were conducted separately for South Africa and jointly for Cameroon-Nigeria due to structural differences in service organisation. Covariate associations were estimated as hazard ratios. Disease severity was assessed through fibrosis staging derived from AST-to-platelet ratio index (APRI). Results1,341 participants had positive HCVST results (117 in Cameroon, 226 in Nigeria, 998 in South Africa). Among laboratory confirmed HCV cases, treatment initiation and SVR were highest in Cameroon (Tx 98.6%, 71/72; SVR 96.4%, 53/55), followed by Nigeria (Tx 90.8%, 168/185; SVR 91.8%, 56/62), and low in South Africa (Tx 4.3%, 37/854; SVR 60.6%, 3/5). Crude disengagement was lowest in Nigeria (24.4%; 95% CrI 19.1%-30.3%), followed by Cameroon (52.4%; 95% CrI 44.4%-61.2%), and South Africa (77.9%; 95% CrI 76.2%-79.8%). By 24-weeks, disengagement was lower in specialist hospitals than community sites in Cameroon and Nigeria. In South Africa, the greatest predictor of disengagement was HIV positive status (HR 1.96; 95% CrI 1.71 to 2.23). Viraemia exceeded regional estimates (82.2%, 1102/1341), with liver scarring highest in Cameroon (fibrosis: 8.3%, cirrhosis: 6.9%) and lowest in South Africa (2.9% and 1.6%, respectively). ConclusionHCV self-testing enabled detection of HCV cases, including severe disease, but poorer progression in community settings suggests decentralised treatment pathways require strengthening to realise cure.

BackgroundViet Nam has one of the worlds most diverse hepatitis C virus (HCV) epidemics, dominated by genotype 6. Understanding pre-treatment resistance-associated substitutions (RASs) particularly in under-studied genotype 6 is essential to protect cure rates and guide national elimination strategies. We aimed to evaluate the landscape of viral diversity and baseline drug resistance in Vietnam. MethodsWe utilized whole-genome sequencing to analyze HCV isolates from a cohort of 1,649 patients enrolled in six clinical studies in Viet Nam between 2013 and 2023. The study assessed genotype and subtype distribution, associations with demographic and clinical variables, and prevalence of known and putative RASs in NS3, NS5A, and NS5B relevant to DAAs used in Viet Nam. FindingsPhylogenetic analysis revealed that genotype 6 was dominant (50.3%, 829/1,649). We observed distinct geographical and demographic partitioning: genotype 2 was concentrated in the south and associated with older age and HIV co-infection, while genotype 3 was clustered in the north among younger males. Clinically relevant RASs were detected in 37.9% (617/1,630) of patients, with the highest burden in NS5A region. Genotypes 2 and 3 displayed near-universal intrinsic resistance. Among genotype 6 infections, subtype 6a frequently carried L28F mutation (43.3%, 181/418), whereas subtype 6e remained largely susceptible. InterpretationViet Nam is characterized by a complex, genotype 6-predominant HCV epidemic with significant reservoirs of natural resistance. The high-level resistance mutations in genotypes 2 and 3 suggests that "pan-genotypic" regimens may face efficacy gaps, highlighting the need for subtype-level molecular surveillance to guide national treatment policies.

BackgroundIn 2004, South Africas public health system faced the dual challenge of rapidly scaling up antiretroviral therapy (ART) while reducing the cost of laboratory monitoring. At the time, conventional CD4 testing methods were expensive, labour-intensive, and impractical for sustaining a national testing network. This study aimed to assess the financial impact and cost savings associated with the implementation of the PanLeucogated CD4 (PLG/CD4) enumeration method between 2004 and 2024 in the public-sector in South Africa. MethodsA longitudinal cost analysis was conducted using annual test volumes and state tariffs for PLG/CD4 testing and the 4-colour CD3/CD4/CD8/CD45 T-cell enumeration reference method. Annual cost savings were calculated in United States Dollars (USD) by applying historical South African Rands (ZAR) to United States Dollars (USD) exchange rates. The state prices for tariff codes PLG/CD4 and the reference method were provided by calendar year in ZAR and converted to USD based on the prevailing exchange rate. The USD test prices were multiplied by annual test volumes. Cost savings were calculated by multiplying annual test volumes and the difference in test prices in USD (difference between PLG/CD4 and the reference method). ResultsThere were 50,745,848 PLG/CD4 tests performed over 20-years. The cost-per-test of PLG/CD4 was consistently lower than the reference method, ranging from $4,06 to $9,40, compared to $13,06 to $28,21. Cumulative national savings amounted to USD 626 million. The peak annual savings of $64,6 million occurred in 2011, coinciding with the height of ART enrolment. Cost savings persisted despite a doubling in the exchange rate over the study period. ConclusionThe PLG/CD4 implementation enabled cost-efficient, scalable, quality-assured CD4 testing as part of the national HIV response, reducing reliance on complex/costly technologies while improving coverage. These findings support the critical role of context-specific diagnostic innovation to strengthen health system resilience.

BackgroundUnited Kingdom Standards for Microbiology Investigations limits the pre-analytical delay of blood cultures to a maximum of four-hours between collection and incubation. Compliance with this delay standard is a measure of the ability of a microbiology service to support the management of sepsis which is a life-threatening complication of infection. A positive blood culture confirms the infection and an early result is critical to the effective management of the condition. Delayed results lead to the prolongation of empiric broad spectrum antimicrobial therapy which is considered a causal factor in the emergence of antimicrobial resistance. This retrospective observational study documents compliance with the standard by microbiology services in England in 2022/23. The impact of laboratory centralisation on the ability of microbiology services to comply with this standard is examined. MethodsFreedom of Information requests were submitted to 116 National Health Service Trusts/administrative units in England requesting retrospective audit data showing compliance with the recommended pre-analytical delay standard. Data relating to service configuration and cost were also requested. ResultsResponses were received from 89 Trusts (76.7%) managing 146 hospitals. Overall, the rate of compliance was low, with only four hospitals (2.7%) showing full compliance and 31.5% showing >80% compliance. ConclusionsPoor rates of compliance with the PAD standard are a concern as prompt attention to blood cultures improves patient outcomes from sepsis and supports antimicrobial stewardship. Laboratory centralisation has resulted in withdrawal of staff and facilities from some hospitals with insufficient investment in others, leading to a demonstrable inability of many hospitals to comply with this standard. Compliance will require investment in microbiology services. The financial implications of the improvements proposed should be evaluated in the context of overall health care and community benefits.

BackgroundLong COVID affects millions worldwide, yet the long-term trajectory of healthcare costs remains poorly characterized. Prior studies with limited follow-up have documented elevated but stable excess costs, leaving uncertainty about whether the economic burden attenuates or persists over time. MethodsWe conducted a retrospective cohort study using electronic health record data from 12 hospitals and 20 community health centers (January 2018 through December 2024). Adults with documented SARS-CoV-2 infection were classified as having Long COVID using a validated precision phenotyping algorithm or as controls without Long COVID. We used two-part generalized estimating equation models to estimate adjusted quarterly healthcare costs over 20 quarters, decomposed costs into visit frequency and cost-per-visit components, and conducted subgroup and sensitivity analyses accounting for differential mortality. ResultsAmong 143,544 adults (27,986 with Long COVID; 115,558 controls), the adjusted excess quarterly cost for Long COVID widened progressively rather than attenuating, increasing from $79 (95% CI, $48-$118) at baseline to $236 (95% CI, $176-$287) at quarter 19 - a threefold increase in the cost differential. Long COVID was associated with 20% higher odds of any healthcare utilization (OR, 1.20; 95% CI, 1.18-1.23) and 30% higher costs when care was accessed (cost ratio, 1.30; 95% CI, 1.25-1.35). Visit frequency diverged over time, reaching 44% higher utilization by quarter 19, while cost-per-visit premiums remained stable. Excess costs concentrated in the upper distribution tail (99th percentile difference: $8,482). The widening trajectory was consistent across subgroups defined by hospitalization status, sex, and comorbidity burden. Cumulative 5-year excess costs were $7,124 per Long COVID patient after mortality adjustment. ConclusionsContrary to assumptions of post-acute recovery, Long COVID is associated with progressively widening healthcare costs over five years, driven primarily by increasing utilization rather than care intensity, suggesting an evolving chronic disease burden with substantial and growing economic implications.

BackgroundChikungunya virus (CHIKV) is an Aedes transmitted arbovirus. Demographic changes coupled with the expanding footprint of the mosquito from climate change have the potential to shift the global burden from the virus. MethodsHere we use projections of human demography and Aedes mosquitoes distribution to estimate baseline and future burden from CHIKV under different climate change scenarios in 178 countries. We then estimate the potential of vaccines to mitigate the growing burden. FindingsWe found that under RCP2.6 (an optimistic climate change scenario), the global population at risk from CHIKV will increase by 30.2% to 5.4 billion individuals. We estimated a 35% increase in annual infections, 49% increase in cases and a 128% increase in deaths. A similar impact was found under the more pessimistic RCP8.5 climate change scenario. In Europe and the Americas, the growing presence of Aedes will drive the growing case burden, with increases in human population size being key elsewhere. Ageing populations will result in major increases in the number of CHIKV-related deaths in all continents outside Africa. Vaccinating 50% of individuals aged 12y+ with a vaccine providing 70% protection against disease and 40% protection against infection would avert 29% of cases and 31% of deaths. InterpretationThese findings highlight how climate change will expand the footprint of CHIKV circulation, while demographic changes will lead to substantially increased case burden in affected countries. Vaccines will be critical to minimising this changing global burden. FundingCEPI

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.

BackgroundMulti-system impacts of long COVID remain unknown. We compared multi-system deficits between people with long COVID and controls. MethodsA case-control study recruited from the Avon Longitudinal Study of Parents and Children and TwinsUK population cohorts. Cases (141) had long COVID (evidence of COVID-19 infection and persistent symptoms [&ge;]4 weeks post infection); controls (280) included people making a full recovery in <4 weeks, people self-reporting long COVID like symptoms but without wild-type SARS-CoV-2 virus antibodies, and people without symptoms or history of COVID-19 infection. Participants underwent multi-system MRI, (cardiac, brain, lung, kidney), measurement of blood pressure and autonomic function, tests of exercise performance, spirometry, renal function, strength and physical capability. System-specific deficits were summed to a total potential score of 27. FindingsParticipants attended clinic between 2021-23. Overall deficit score in cases was 0.22 (95% CI -0.44,0.88) units greater than controls, adjusted for age, sex, ethnicity, cohort membership and relatedness. This estimate was little changed (0.32 (-0.34, 0.98)) when additionally adjusted for educational status, index of multiple deprivation, physical activity, smoking and co-morbidity. Restricting cases to those reporting at least fatigue (46) increased the excess deficit score to 0.81 (-0.19,1.81) units in the minimally adjusted model. A difference was only observed in the vascular domain, largely attributable to elevated blood pressure, showing a 1.76 (1.04,2.97) multivariable adjusted odds ratio excess in cases, and 3.04 (1.36,6.80) when restricted to cases with fatigue. InterpretationPeople with community-based long COVID should be reassured that there is not marked residual deficit across multiple systems. However, blood pressure measurement and control should be included in clinical follow-up. FundingJointly funded by the National Institute for Health and Care Research and UK Research and Innovation (CONVALESCENCE, COV-LT-0009, MC_PC_20051).

Background: The 2024-25 influenza season was the most severe in the United States (US) since 2017-18, with co-circulation of both influenza A virus subtypes (H1N1 and H3N2). Influenza vaccine effectiveness (VE) has varied by season, setting, and patient characteristics. Methods: Using electronic healthcare encounter data from eight US states, we evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalizations and emergency department or urgent care (ED/UC) encounters from October 2024-April 2025 among children aged 6 months-17 years and adults aged 18+ years. Using a test-negative, case-control design, we compared the odds of influenza vaccination between acute respiratory illness (ARI) encounters with a positive (cases) versus negative (controls) test for influenza by molecular assay, adjusting for confounders. Results: Analyses included 108,618 encounters (5,764 hospitalizations and 102,854 ED/UC encounters) among children and 309,483 encounters (76,072 hospitalizations and 233,411 ED/UC encounters) among adults. Among children across care settings, 17.0% (6,097/35,765) of cases versus 29.4% (21,449/72,853) of controls were vaccinated. Among adults, 28.2% (21,832/77,477) of cases versus 44.2% (102,560/232,006) of controls were vaccinated. VE was 51% (95% confidence interval [95% CI]: 41-60%) against influenza-associated hospitalizations and 54% (95% CI: 52-55%) against influenza-associated ED/UC encounters among children. VE was 43% (95% CI: 41-46%) against influenza-associated hospitalizations and 49% (95% CI: 47-50%) against influenza-associated ED/UC encounters among adults. Conclusions: Influenza vaccination provided protection against influenza-associated hospitalizations and ED/UC encounters among children and adults in the US during the severe 2024-25 influenza season. These findings support influenza vaccination as an important tool to reduce influenza-associated disease.

BackgroundOlder age is widely considered a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC), typically attributed to immunosenescence and inflammaging. However, whether this association reflects intrinsic biological ageing or accumulated comorbidity burden remains unclear, with implications for clinical risk stratification. MethodsWe conducted a retrospective cohort study using the Precision PASC Research Cohort (P2RC) from Mass General Brigham, comprising 133,792 COVID-19 patients from 12 hospitals and 20 community health centres in Massachusetts (March 2020-May 2024). PASC was ascertained using a validated computational phenotyping algorithm. We used generalised estimating equations with cluster-robust variance to model PASC risk, causal mediation analysis to decompose age effects through comorbidity burden and acute severity, and specification curve analysis across 768 analytical specifications to assess robustness. FindingsAfter adjustment for comorbidity burden, each decade of age was associated with 6% lower odds of PASC (OR 0.94; 95% CI 0.93-0.95). Causal mediation analysis revealed that comorbidities accounted for 145% of the total age effect, indicating inconsistent mediation wherein ages direct protective effect was masked by its indirect harm through chronic disease accumulation. This protection was age-dependent: adults younger than 65 years retained robust resilience independent of comorbidities (ADE:-0.0042, p<0.001), whereas adults 65 years and older showed complete loss of this protection (ADE: +0.0020, p=0.14). InterpretationLong COVID susceptibility is driven by physiological reserve rather than chronological age until approximately age 65, beyond which age-related protective mechanisms become exhausted. Risk stratification should prioritise comorbidity burden over birth year in younger adults. FundingNational Institute of Allergy and Infectious Diseases (NIAID).

BackgroundDeath certificates record both an underlying cause and contributing conditions, yet mortality statistics predominantly report only the underlying cause. We quantify this "hidden burden" across all ICD-10 conditions in Australian mortality data using the multiple-to-underlying ratio (MUR): total death certificate mentions divided by underlying cause deaths. MethodsWe analysed Australian Bureau of Statistics Causes of Death 2023 data (N = 187,268 registered deaths) to compute the ratio for all ICD-10 conditions. Three pre-registered confirmatory hypotheses tested sex differences in hypertension and mental health ratios, and geographic variation by preventability, with Holm-Bonferroni correction. ResultsDeath certificates recorded an average of 3.5 causes per decedent, meaning the underlying cause captures only [~]29% of recorded morbidity. Of 663 conditions with [&ge;]10 underlying cause deaths, the ratio ranged from 1.0 (external causes) to 281.1, with a median of 2.5. Among conditions with stable estimates ([&ge;]50 underlying deaths), the highest ratio was 94.3 (complications of medical care). Age explained only 10.9% of ratio variation (R2 = 0.109), and no top-ranked conditions were identified as primarily age-driven, suggesting the ratio ranking is robust to age confounding. However, external validation using US CDC data showed age standardisation materially changed absolute ratio values for 6 of 8 cause groups (divergence 16-34%), with the direction varying by condition rather than following a simple age-concentration pattern. Males showed consistently higher ratios, most strikingly for mental health disorders (62% higher); a counterfactual analysis estimated suicide coding rules explain only 6-15% of this sex difference. Three pre-registered hypotheses were null after correction; H1 and H3 (sex differences) were underpowered (n = 4, n = 8 pairs) with large effect sizes (r = 0.77-0.80), while H2 (geographic variation) showed a clear null. ConclusionsThe hidden burden of mortality in Australia is substantial and unevenly distributed, with symptom codes, mental health conditions, and hypertension most undercounted. The ratio provides a transparent framework for identifying conditions whose health impact is systematically understated by conventional mortality reporting.

BackgroundMpox-related ophthalmic disease (MPOXROD) ranges from mild conjunctivitis to sight-threatening keratitis, however, data based on systematic ophthalmological assessment are scarce. We aimed to characterise the prevalence, features, and temporal evolution of MPOXROD during a clade Ib mpox outbreak. MethodsWe conducted MBOTE-EYE, a prospective ophthalmological sub-study, nested within a clinical characterisation cohort in Kamituga, South-Kivu, Democratic Republic of the Congo. All hospitalised patients with mpox confirmed by PCR in the prior 48 hours were eligible. Participants underwent comprehensive ophthalmological examination at enrolment, discharge, and days 29 and 59 post-diagnosis. Conjunctival swabs were collected for monkeypox virus PCR testing. MPOXROD was defined as conjunctivitis, scleritis, keratitis, uveitis, or optic nerve involvement. Risk factors were assessed using mixed-effects Poisson regression. FindingsBetween 28 October 2024 and 30 June 2025, 310 participants were enrolled (median age 14 years, IQR 2.5-25.0; 53.5% female, n=166/310). At enrolment, conjunctivitis was present in 36.1% (95% CI 31.0-41.6%, n=112/310), keratitis in 7.7% (95% CI 5.3-11.3%), and anterior uveitis in 0.6% (95% CI 0.2-2.3%). Overall, 43.2% (95% CI 37.8-48.8%) developed MPOXROD during follow-up, most often bilaterally. Visual acuity <8/10 occurred in 22.9% (95% CI 17.6-29.2%, n=24/310), and persistent blindness in 0.9% (95% CI 0.24-5.5%, n=2/225), due to ulcerative keratitis. Periorbital lesions (adjusted risk ratio [aRR] 2.82, 95% CI 1.40-5.69) and severe malnutrition (aRR 5.06, 2.25-11.38) were independently associated with MPOXROD. Conjunctival swabs with PCR Ct values < 25 occurred exclusively in participants with active MPOXROD. InterpretationOphthalmic involvement in clade Ib mpox is common and frequently bilateral, with a substantial burden of keratitis and risk of vision loss, particularly in young children and severely malnourished individuals. These findings highlight the need for systematic eye examinations in mpox care and provide critical evidence to inform future trials of targeted ophthalmic therapies. FundingNone of the funders had a role in study design, analysis, interpretation, or writing.

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related death in sub-Saharan Africa (SSA). Differentiating primary HCC from metastatic liver tumors remains a significant diagnostic challenge. Understanding the prevalence and clinical predictors of HCC is crucial for improving diagnosis and patient care. This study examined the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and HCC, and clinical predictors of HCC. MethodsWe used immunohistochemical markers on archived liver tumor biopsies and analyzed the data using descriptive and logistic regression analysis. ResultsAmong 58 liver carcinoma cases, 37.9% had HCC, and 62% had metastatic liver carcinoma (MLC). HCC was most common (61.5%) among middle-aged adults (50-59 years). HCC was more frequent in males (47.2%) than in females (22.7%). Over half of the patients (51.7%) tested positive for HBV. HCC was more prevalent in HBV-positive patients than HBV-negative ones (43.3% vs 32.1%). Hepatic fibrosis was identified in 27.6% of cases. HCC was more common in patients with fibrosis (56.2%) than in those without (31%). HCV infection was rare (6.9%) in this study. In multivariable logistic regression analysis, none of the examined predictors reached statistical significance (P>0.05). Patients aged 50-59 years, males, those with HBV infection, and hepatic fibrosis showed higher odds of HCC. Hepatocyte Paraffin-1 (Hep Par-1) demonstrated 97% specificity and a 95% positive predictive value (PPV) for differentiating HCC from MLC. The combined marker pattern of Hep Par-1 positive and AE1/AE3 negative was highly predictive of HCC (100% specificity, 100% PPV, and 93.2% diagnostic accuracy). ConclusionsOur findings indicate that while the assessed risk factors tend to show directional association with HCC, as expected, larger studies are needed to determine their independent effects. The combined Hep Par-1 AE1/AE3 immunophenotype is more accurate than either marker alone. Therefore, this combined test is a valuable diagnostic tool for confirming HCC in resource-limited settings.

BackgroundInfluenza A(H1N1)pdm09 and A(H3N2) viruses predominated during the 2024-25 U.S. influenza season. We estimated influenza vaccine effectiveness (VE) in the United States against mild-to-moderate outpatient influenza illness by influenza type and subtype in the 2024-25 season. MethodsWe enrolled outpatients aged [&ge;]8 months with acute respiratory illness symptoms including cough in 7 states. Upper respiratory specimens were tested for influenza type/subtype by reverse-transcriptase polymerase chain reaction (RT-PCR). Influenza VE was estimated with a test-negative design comparing odds of testing positive for influenza among vaccinated versus unvaccinated participants controlling for age, study site, underlying health status, and month of illness onset. We also estimated VE of current season vaccination among adults stratified by prior season vaccination status. ResultsAmong 6,793 enrolled patients, 2,016 (30%) tested positive for influenza including 961 A(H3N2), 770 A(H1N1)pdm09, and 183 B/Victoria. Overall vaccine effectiveness against any influenza illness was 33% (95% Confidence Interval [CI]: 24 to 41): 27% (95% CI: 14 to 39) against influenza A(H3N2), 37% (95% CI: 24 to 48) against A(H1N1)pdm09, and 40% (95% CI: 12 to 59) against B/Victoria. VE did not differ based on whether or not participants had received influenza vaccine the previous season. ConclusionsInfluenza vaccination during the 2024-25 season protected against circulating influenza viruses, reducing the risk of outpatient medically attended influenza overall by approximately one-third among people who were vaccinated. Key PointsInfluenza vaccine reduced the risk of outpatient acute respiratory illness due to laboratory-confirmed influenza during the 2024-25 season by a third.

FluSurvey is a participatory surveillance system used to monitor trends in influenza and other respiratory viruses through weekly symptom surveys among the UK population. We aimed to characterise the wider impact of "influenza-like illnesses" (ILI) among FluSurvey participants and assess correlations of ILI with other established influenza surveillance systems. We included data reported by FluSurvey participants over the 2023-24 and 2024-25 winter seasons. Using weekly symptoms surveys, we derived ILI episodes and estimated the proportion reporting healthcare service use, medication use, impact on daily life, absenteeism and use of tests. We applied existing methodologies (omitting first report and weighting to the age-sex structure of England) and assessed cross-correlations of weekly FluSurvey ILI rates with the national surveillance of GP ILI consultations, influenza hospital admissions, and influenza PCR test positivity at time lags of up to +/- 2 weeks. There were 3057 participants over two winter seasons (N2023-24=2540, 63% female, mean age 60 years; N2024-25=2273, 64% female, mean age 61 years). Of 1868 ILI episodes, only a minority contacted healthcare services (14%, most frequently visiting the GP). A large proportion of episodes reported medication use (89%), impact on daily life (75%) and missing school or work (47%). Notable differences in testing behaviour were apparent by season, with fewer reporting use of tests in 2024-25. FluSurvey ILI rates were strongly correlated with other influenza surveillance, predominantly leading GP ILI consultations (max r=0.73), coinciding with influenza hospital admissions (max r=0.88) and lagging influenza test positivity (max r=0.88). The majority of ILI reported to FluSurvey do not contact healthcare due to symptoms but experienced wider impacts on daily life. FluSurvey ILI corresponds well with other national influenza surveillance and provides broader context on community illness, supplementing the monitoring of influenza activity for public health response.

Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.

Background/ObjectivesThe trajectory of influenza hospitalization burden from pre-pandemic baseline through post-pandemic recovery remains poorly characterized at the national level. This study characterized phase-stratified burden and seasonal structure, quantified racial and ethnic disparities, and assessed whether post-pandemic seasons represent anomalous departures from pre-pandemic expectations. MethodsSixteen seasons of FluSurv-NET surveillance data (2009-2010 through 2024-2025; 509 observation weeks) were analyzed across pre-pandemic, disruption, and recovery phases using OLS regression with effect-size estimation, bootstrapped age-adjusted rate ratios, seasonal-trend decomposition (STL), Prophet time-series forecasting, and Isolation Forest anomaly detection. ResultsMean peak weekly hospitalization rate nearly doubled from pre-pandemic to recovery (5.1 to 11.1 per 100,000), cumulative seasonal burden increased from 46.3 to 87.0 per 100,000, and median peak timing advanced from MMWR week 9 to week 50. STL decomposition revealed a marked shift from weak pre-pandemic seasonality (Fs = 0.14) to substantially stronger annual regularity (Fs = 0.98) across three recovery seasons, with threefold amplitude increase. Non-Hispanic Black persons had rate ratios of 1.72, 2.16, and 1.99 relative to White persons across phases; American Indian and Alaska Native persons showed the highest disruption-phase ratio (2.24, 95% CI 1.90-3.53), based on two contributing seasons. A flat-growth Prophet model detected first exceedance in February 2020, outperforming a linear-growth specification on held-out validation. Isolation Forest identified 2017-2018, 2023-2024, and 2024-2025 as robust anomalies across all contamination thresholds. ConclusionsPost-pandemic influenza recovery is characterized by intensified and restructured seasonality, persistent racial and ethnic disparities, and anomalous burden exceeding pre-pandemic projections, identified independently by time-series forecasting and unsupervised anomaly detection.

People who inject drugs (PWID) and people who use drugs (PWUD) bear a disproportionate burden of hepatitis C virus (HCV) infection globally. In South Africa, HCV testing and treatment remain limited outside externally funded projects. This study investigated the implementation feasibility of assisted HCV self-testing (HCVST) among PWID and PWUD in Johannesburg. Between 12th May 2023 and 28th March 2024, participants were recruited to an implementation study across mobile harm reduction sites and a central clinic. Participants performed self-tests using either oral-fluid or blood-based HCV antibody rapid tests. Reactive results were followed by on-site venous sampling for confirmatory RNA testing and referral for direct-acting antiviral (DAA) therapy at a centralized facility. We describe HCV case-detection, care cascade progression, and behavioral risk factors associated with HCV reactivity using logistic regression. Of 1,566 participants tested, 998 (63.7%) were HCV reactive. The median age was 31 years (IQR 28-35); 82.2% were male and 77.1% identified as PWID. Ever injecting drugs (OR 35.6, 95% CI 23.6-56.0), frequent injecting ([&ge;] daily: OR 36.7, 95% CI 25.1-55.3), and recent needle sharing (OR 7.3, 95% CI 5.8-9.3) were the strongest predictors of HCV reactivity. Histories of incarceration were also independently associated with HCV reactivity (OR 3.2, 95% CI 2.6-4.0). Despite high self-testing acceptability, progression through the care cascade was limited: among 854 RNA-confirmed infections, only 147 (17.2%) were prioritized for treatment, with three participants achieiving sustained virologic response. Thematic analysis identified fear of needles, poor venous access, and structural barriers, notably centralized treatment delivery, as key impediments to linkage. This study showed a high burden of HCV among PWID and PWUD in Johannesburg and demonstrates that assisted HCVST is acceptable. Centralized treatment models severely constrained linkage to care. Simplified delivery of treatment is critical in transforming diagnosis into cure.