The Lancet

Introduction Acute lower respiratory tract disease (aLRTD) is a leading cause of hospitalisation and death, particularly in older adults and adults with comorbidities, with acute lower respiratory tract infection (aLRTI; pneumonia and non-pneumonic LRTI) being a major component. Non-pulmonary complications and functional decline after aLRTI are recognised, but their pathogen-specific burden is poorly described. We aimed to quantify renal, hepatic, thromboembolic and functional complications, and mortality, after aLRTI hospitalisation, by clinical phenotype and pathogen. Methods We conducted a cohort study of adults (>18 years) admitted with aLRTD to two hospitals in Bristol, UK (01 August 2022-31 July 2024). aLRTD was classified as pneumonia, non-pneumonic LRTI (NP-LRTI) or no diagnosis of aLRTI. Pathogens were identified from standard-of-care and research microbiology. Outcomes were acute kidney injury (AKI), acute liver dysfunction, venous thromboembolism (VTE), in-hospital falls, reduced mobility at discharge, increased care requirements, and 30-day and 1-year mortality. Analyses were descriptive. Results Among 246,797 adult admissions, 21,456 aLRTD hospitalisations were included: 10,239 (47.7%) pneumonia, 7,742 (36.1%) NP-LRTI and 3,475 (16.2%) with no evidence of aLRTI. Of 19,152 tested aLRTD admissions, 8,503 (44.4%) had a positive microbiological/virological test, yielding 9,204 pathogen detections; 1,194 (6.2%) had co-infections, and SARS-CoV-2 was most frequent, with influenza the second most common in pneumonia and NP-LRTI. Pneumonia had greater severity than NP-LRTI and no diagnosis of aLRTI (median length of stay 6 vs 4 vs 4 days; ICU admission 3.4% vs 0.7% vs 0.5%, respectively). Overall, 22.2% developed AKI, 6.1% acute liver dysfunction, 0.6% DVT and 2.4% PE; 1.8% had a fall, 11.5% reduced mobility, and 16.6% required increased care at discharge. 30-day and 1-year mortality were highest for pneumonia (14.0% and 32.0%, respectively). Pathogen-specific analyses showed longer stays and higher complications and mortality rates for SARS-CoV-2 and Streptococcus pneumoniae, and shorter stays with lower complication and mortality rates for influenza and Haemophilus influenzae. Conclusions Non-cardiovascular complications and functional decline after aLRTI were common, particularly in pneumonic and SARS-CoV-2 or pneumococcal disease. These findings support routine surveillance for renal, hepatic, thromboembolic events, early mobilisation and rehabilitation, and consideration of multi-system outcomes when evaluating public health and economic value of vaccines and therapies.

ObjectivesRespiratory Syncytial Virus (RSV) vaccine policies have varied globally since their approval in 2023. In the UK, policy has adapted in line with National evidence generation such that from Autumn 2026 at-risk persons [&ge;]65 years old will become eligible for vaccination. Immunosuppressed persons <65 years will still not be offered protection. The objective of this study is to investigate the relative burden of RSV infection by age and immunosuppressed status (IC). DesignRetrospective observational cohort study using routine healthcare data from North West London Integrated Care System. ParticipantsPatients with a confirmed diagnosis of a respiratory viral infection (RSV, Influenza A and B, SARS-CoV2) between October 2021 and July 2025. Main outcomes measuresPrevalence and severity of RSV infection in immunosuppressed persons <65 years old, and to provide a comparative analysis with Influenza and SARS-CoV2 in a sub-cohort tested using a 4-in-1 combined rapid PCR test. ResultsDuring the study period, 1226 patients were diagnosed with RSV of whom 596 (48.6%) were <65 years old. In 1091 patients with clinical data, 341 (31.3%) were IC. Fifty (9.9%) patients <65 years old had severe infection (ICU admission or death within 28 days of diagnosis), of whom 14 (28.0%) were IC. Proportionally, 16.7% of all RSV-associated deaths and 55.1% of all ICU RSV-admissions occurred in adult patients <65 years old. RSV accounted for 665 (10.1%) infections confirmed by 4-in-1 viral PCR testing. Eight-nine (13.4%), 172 (9.3%) and 448 (12.0%) patients with RSV, Influenza A and SARS-COV2 experienced severe infection, of whom 32 (36.0%), 82 (47.7%) and 156 (34.8%) were <65 years old respectively. Eight (25.0%), 20 (24.4%) and 52 (33.3%) of patients <65 years old with severe infection were IC. On adjusted analysis, having an immunosuppressive condition increased the odds of a severe SARS-CoV2 infection, OR (95% CI) 1.36 (1.08-1.71) but not a severe RSV or Influenza infection. ConclusionsSevere RSV infections occur in persons <65 years old, with a significant proportion of patients having an immunosuppressive condition. Urgent research is needed to investigate the potential benefit of extending the current UK RSV vaccine policy to protect younger immunosuppressed adults.

Objective Sepsis is a heterogeneous syndrome characterized by substantial variation in infection source, organ dysfunction, and clinical outcomes, and a disproportionate burden in Africa. We aimed to derive and externally validate clinical subphenotypes among adults hospitalized with sepsis in Africa. Design We used latent class analysis with infection source and organ dysfunction as model inputs. We labeled classes post hoc according to their predominant clinical features. We evaluated associations between subphenotypes and 30-day mortality using multivariable logistic regression. Setting Hospitals in Uganda, Rwanda, Liberia, Tanzania, and Malawi. Patients We pooled data from three prospective cohorts of adults hospitalized with sepsis in Uganda, Rwanda, and Liberia for model derivation and independent cohorts from Tanzania and Malawi for external validation. Interventions None. Measurements and Main Results The derivation dataset included 467 adults with sepsis, of whom 128 (27.4%) died within 30 days of admission. Latent class analysis identified four subphenotypes: Class 1 (heterogeneous; n=227; 30.8% mortality), Class 2 (abdominal; n=141; 31.9%), Class 3 (pulmonary; n=68; 16.2%), and Class 4 (soft tissue; n=31; 6.5%). Mortality differed significantly across the four classes (p=0.003). Compared with Class 1, Classes 3 (aOR 0.22, 95% CI 0.10-0.47) and 4 (aOR 0.14, 95% CI 0.02-0.52) had lower odds of 30-day mortality. External validation in 316 adults demonstrated high classification certainty (entropy=0.78; mean maximum posterior probabilities, 0.89-0.92), with similar mortality patterns across corresponding subphenotypes. Conclusions Latent class analysis identified reproducible clinical sepsis subphenotypes defined by infection source and organ dysfunction with distinct mortality risks. These externally validated subphenotypes may improve risk stratification and inform subphenotype-based clinical trials and treatment strategies in Africa.

Importance Several influenza vaccine products are available for older adults, but evidence combining both their absolute effectiveness and head-to-head comparisons within the same large population remains scarce, limiting product-specific vaccination guidance for this high-risk group. Objective To estimate the relative and absolute effectiveness of influenza vaccines against influenza-related hospitalization and in-hospital mortality among older adults. Design, Setting, and Participants Nationwide cohort study using the French National Health Data System (SNDS), including all adults born in 1958 or earlier, living in metropolitan France, at the start of the 2023-2024 campaign. Relative effectiveness (rVE) was assessed using a landmark design with exposure fixed before epidemic onset. Absolute effectiveness (VE) was assessed using a sequential trial emulation with weekly matching of newly vaccinated individuals to yet unvaccinated controls. Follow-up ran from December 5, 2023 to April 19, 2024. Exposures Vaccination with a high-dose (Efluelda) or one of three standard-dose quadrivalent vaccines (Influvac, Fluarix, Vaxigrip), compared individually or by dosage category, and against no vaccination. Main Outcomes and Measures Hospitalization with a diagnosis of influenza and death during such hospitalization. Effectiveness was estimated as 1 minus the hazard ratio from weighted Cox models, with corresponding numbers needed to vaccinate to prevent one case. Results Among 13.8 million eligible individuals, 5.7 million (41%) were vaccinated at the beginning of follow-up. The high-dose vaccine showed greater rVE than standard-dose vaccines against hospitalization (27% [95%CI, 23 to 31%]) and in-hospital death (27% [95%CI,14 to 38%]). Absolute VE was 39% (95%CI, 38 to 41%) against hospitalization and 45% (95%CI, 40 to 49%) against in-hospital death, and was higher for the high-dose vaccine (50%) than standard-dose vaccines (36%) against hospitalization. This difference was most evident among adults 70 years and older, while overall effectiveness declined with age. Conclusions and Relevance In this study, influenza vaccination conferred moderate protection against severe outcomes in older adults, and high-dose vaccination was associated with significantly greater effectiveness than standard-dose vaccines, particularly among adults 70 years and older. These findings support product-level differentiation in vaccination strategy for this population.

Introduction Aspiration events in hospitalized adults are common and linked to substantial morbidity, mortality, and healthcare burden. While antiemetics have been studied for aspiration prevention in specific settings, evidence for their broader preventive use in hospitalized adults is limited. We conducted a systematic review and meta-analysis to evaluate the effect of prophylactic scheduled antiemetics on aspiration events in adult inpatients. Methods: Ovid MEDLINE, Ovid Embase, CINAHL, and Cochrane Library (via Wiley) were searched in May 2025. We included randomized controlled trials (RCTs) and observational studies assessing prophylactic scheduled antiemetic use in hospitalized adults, with aspiration events as the primary outcome. Secondary outcomes were aspiration pneumonia, hospital length of stay, increased oxygen requirement, ICU admission, and mortality. Two investigators screened and independently extracted data in duplicate using standardized data collection forms. Extracted information included study characteristics, patient demographics and clinical characteristics, interventions, and outcomes. Results: Three RCTs met inclusion criteria (n = 515 patients; 237 antiemetic, 278 placebo). Pooled analysis of two RCTs demonstrated an 88% relative risk [RR] reduction of aspiration events; (2.8% [3/106] prophylactic antiemetic vs 27.9% [29/104] placebo; RR = 0.12, 95% confidence intervals [CI]: 0.02-0.73, p <0.0001, low certainty) in the antiemetic group. Pneumonia rates were also lower in the antiemetic group although they did not reach statistical significance (16.5% vs 32.4%; RR 0.44, 95% CI 0.15-1.28, P = 0.13, low certainty). ICU admission rates were lower in the antiemetic group (2.6% [2/76]) vs. placebo (23% [17/74]); RR = 0.11, 95% CI: 0.03-0.48, p=0.003, very low certainty). Mortality was similar between groups (35.0% vs 38.1%; RR 1.02, 95% CI: 0.84-1.24, P = 0.85, low certainty). No adverse events were reported among all studies. Conclusion: Prophylactic scheduled antiemetics were associated with a significant reduction in aspiration and ICU admission. There was a non-significant but favorable trend towards reduction of pneumonia among hospitalized adults. Larger, high-quality trials are needed to clarify their role in aspiration prevention.

Mpox has re-emerged as a public-health priority across Nigeria, and successive international public-health emergencies were declared in 2022 and 2024. Facility-level descriptions of admitted, clinically suspected cases from northeastern Nigeria remain sparse. We conducted a register-based descriptive study of all admissions to the infectious-diseases isolation ward of Modibbo Adama University Teaching Hospital, Yola, in which mpox was recorded as the working or a differential diagnosis between February 2022 and January 2025. Age, sex, month of admission, locality, recorded clinical impression, and outcome were abstracted and summarised, with proportions reported using Wilson 95% confidence intervals. Fifteen suspected mpox admissions were identified, representing 4.5% (95% confidence interval 2.8-7.4) of 330 isolation-ward admissions. The median age was 20 years (interquartile range 13-37; range 7-57); six patients (40.0%) were children under 18 years and 12 (80.0%) were male, giving a male-to-female ratio of 4:1. Admissions clustered in 2022 (9 of 15; 60.0%), with six in July 2022, including a probable household cluster of four children and adolescents aged 7-14 years from a single locality who presented within eight days of one another. Three deaths were recorded (case fatality 20.0%, 95% confidence interval 7.0-45.2), including one disseminated case complicated by acute respiratory distress syndrome. The demographic profile closely matches previously reported Adamawa State and national surveillance data, whereas the elevated case fatality reflects referral concentration and diagnostic uncertainty rather than true mpox-attributable mortality. Cases were clinically suspected rather than laboratory-confirmed, which is the principal limitation of this study. We recommend targeted strengthening of laboratory diagnosis at facility and sub-national level, including dual monkeypox-varicella testing algorithms, use of existing molecular platforms rather than new infrastructure, and mandatory recording of laboratory results within ward registers.

Importance: Pharmacological targeting of host mechanisms that limit sepsis-induced organ dysfunction represents a new therapeutic approach. Preclinical studies showed that low-dose epirubicin enhances tissue damage control and attenuates sepsis severity independently of pathogen burden, thereby promoting disease tolerance to infection. Yet epirubicin can cause myelotoxicity when used in cancer therapy. Objective: To investigate whether low-dose epirubicin can safely be administered to patients with sepsis and septic shock. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial conducted in five German University hospitals. Patients with sepsis, defined by Sepsis-3 criteria, were eligible within 48 hours after diagnosis. The first patient was enrolled on October 19, 2022, and the last follow-up was conducted on May 21, 2025. Interventions: Eligible patients were randomized in a 4:1 ratio to receive either placebo or low-dose epirubicin in addition to standard care. There were three consecutive phases. Patients in the epirubicin group received a single dose of epirubicin (either 3.75 mg/m2, 7.5 mg/m2 or 15 mg/m2, depending on study phase). Main Outcomes and Measures: The primary endpoint of the trial was the 14-day myelotoxicity. Secondary and explorative outcomes included 90-day mortality, the degree of organ dysfunction as assessed by SOFA score, PK/PD modelling and cytokine release. Results: Of 854 patients assessed for eligibility, 32 were randomized and 31 were included in the primary analysis population. Six participants received placebo, nine participants received 3.75 mg/m2, nine received 7.5 mg/m2 and eight individuals received 15 mg/m2 epirubicin, respectively. There was no myelotoxicity in any group. Mortality at 90 days and SOFA-scores were not significantly different between groups. Two of 39 SAEs in the epirubicin group were assessed by the investigators as possibly related to epirubicin, Conclusions and Relevance Among patients with sepsis and septic shock, low dose epirubicin was not associated with increased myelotoxicity.

Abstract Background Estimates of the healthcare costs associated with influenza treatment are essential for cost-effectiveness analyses that inform preventative and treatment strategies such as vaccination and non-pharmaceutical interventions. Existing evidence varies across treatment settings, age groups, and countries and there is little data from low- and middle-income settings. Methods We conducted an umbrella review of systematic reviews and meta-analyses reporting direct admitted and non-admitted hospitalisation costs of seasonal influenza treatment in children, adults, and older people. We supplemented an evidence gap with a systematised review of studies reporting adult non-admitted treatment costs. Costs were extracted and adjusted to 2023 USD. We fitted a Bayesian mixed-effects model to estimate influenza treatment costs using national economic indicators, age group, and treatment setting as a priori predictors. We predicted admitted and non-admitted treatment costs for children, adults, and older people in 195 countries and territories. Results Seven reviews were included in the umbrella review, supplemented by 17 primary studies for adult non-admitted care. Extracted data points most frequently described admitted treatment costs and came from high-income countries. The best-fitting model used healthcare expenditure per capita to predict treatment costs, with country-level random effects. Estimated costs increased with healthcare expenditure per capita, were higher for admitted than non-admitted care, and were highest for adults and lowest for children. Conclusions This study provides novel estimates of influenza-associated healthcare costs across age groups and treatment settings by synthesising the available global evidence. By extrapolating to settings without data, our estimates can inform future economic evaluation studies of influenza interventions worldwide.

Seasonal influenza remains a major cause of morbidity and mortality worldwide. Although neuraminidase inhibitors improve outcomes, influenza-related deaths persist. We evaluated the impact of early aspirin (ASA) and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use on outcomes in adults hospitalized with influenza. This retrospective study included adults admitted to the University of Minnesota Medical Center from 2016 to 2018. Continuous variables were summarized as medians with interquartile ranges (IQRs) and categorical variables as counts and percentages. Group comparisons used Wilcoxon rank-sum, Chi-square, or Fishers exact tests. Analyses included case-control comparisons, assessments by vaccination status, and subgroup analyses by early ASA or NSAID use. Among 2,816 patients, 320 had laboratory-confirmed influenza, with vaccination less common among cases. Unvaccinated patients had higher rates of intensive care unit (ICU) admission (23.6% vs. 11.1%; P = 0.003) and ventilatory support (15.0% vs. 6.1%; P = 0.009). In vaccinated patients, early ASA use was associated with older age and higher in-hospital mortality, whereas early NSAID use was associated with no in-hospital deaths, better one- and three-year survival (P < 0.001), and fewer, though not statistically significant, cardiovascular complications. In unvaccinated patients, ASA use was associated with lower three-year survival (59.1% vs. 79.2%; P = 0.013), while NSAID use was associated with fewer ICU admissions and no cardiovascular or renal complications. In both vaccinated and unvaccinated adults hospitalized with influenza, early NSAID use was associated with improved survival and fewer complications, whereas ASA use was associated with worse outcomes.

Background In adults, cold-attributable mortality exceeds heat-attributable mortality roughly 17-fold. Child-specific evidence has begun to emerge only recently - a nationwide Brazilian case-crossover study located the minimum mortality temperature (MMT) for under-five deaths, and a 56-country survey-based analysis linked monthly temperature anomalies to under-five mortality - but no multi-country, climate-zone-resolved estimate of the childhood respiratory-infection MMT exists, and whether temperature variability is independently associated with childhood respiratory mortality at the global scale is unknown. We quantified both. Methods We combined Global Burden of Disease 2023 mortality estimates, lower respiratory infection (LRI) deaths at ages 0-19 years and asthma deaths at ages 0-24 years, 171 countries, 1990-2023 - with 0.5 deg monthly land temperature and diurnal temperature range (DTR) fields from C-LSAT/C-LDTR (1901-2023). Four exposure dimensions (annual mean, DTR, seasonal amplitude, interannual variability) entered two-way fixed-effects models with Driscoll-Kraay standard errors. A quadratic term in mean temperature located the MMT, with percentile confidence intervals from a 300-replication country-cluster bootstrap. Future-exposure leads, country-level detrending, and permutation tests assessed contemporaneous causality, applied to both the linear coefficients and the quadratic term generating the MMT; national pneumococcal conjugate vaccine (PCV3) coverage and ambient PM2.5 exposure series were added as time-varying mechanistic covariates. Results The childhood LRI MMT was 17.1 C (95% CI 14.7-19.8), the 36th percentile of the annual-temperature distribution; zone estimates were 24.7 C in tropical and 15.8 C in subtropical countries, with weak temperate and no subarctic identification. The quadratic term underpinning the MMT, however, failed both falsification checks - future temperatures reproduced the U-shape and country-level detrending erased it - so these MMT values describe a trend-level geographic pattern of the annual construct rather than a contemporaneous dose-response. Interannual temperature variability was positively associated with LRI (+0.278, 95% CI 0.102-0.454; p = 0.002) and asthma mortality (+0.836, 95% CI 0.447-1.226; p = 2.6 x 10^-5) per 1 C, but future-exposure models returned nearly identical significant coefficients and detrending erased significance, supporting only a trend-level association; adjustment for national PCV3 coverage and PM2.5 exposure left these estimates essentially unchanged. Annual mean temperature was likewise inversely associated with both outcomes at the trend level; DTR and seasonal amplitude showed no independent within-country effects. Conclusions This study provides the first multi-country, climate-zone-resolved geography of the optimal temperature for childhood respiratory survival, spanning 171 countries; because the underlying quadratic association is trend-level, the estimates are directional. The observed variability-mortality associations are trend-level signals rather than contemporaneous causal evidence; daily-scale, child-specific designs are required to determine whether short-term thermal variability affects paediatric respiratory mortality.

BackgroundHuman Mastadenovirus B (HAdV-B) causes ocular and respiratory infections and is capable of causing outbreaks in healthcare settings. HAdV-B114, a recombinant genotype only formally recognised in 2023, has been reported predominantly from Germany, the USA, China and Japan; genomic data from UK clinical settings remain limited. This study analysed 68 HAdV-B whole genomes from ocular and respiratory-associated samples collected at a Nottingham hospital across the pre- and post-COVID-19 restriction periods (2017-2023). MethodsClinical samples typed positive for HAdV-B by partial hexon Sanger sequencing were selected for whole-genome sequencing using a novel overlapping PCR amplicon strategy, sequenced on the Oxford Nanopore Technologies PromethION platform. Phylogenetic and pairwise difference analyses were used to characterise genotype composition and genomic relatedness. SimPlot and amino-acid comparison characterised divergence between sub-lineages. ResultsWhole-genome phylogenetics confirmed that two species B genotypes were detected in Nottingham University Hospitals between 2017-23: HAdV-B114 (n=56) and HAdV-B7 (n=12). HAdV-B114 was detected before and after COVID-19 restrictions, with an increase in 2022-2023, consistent with post-restriction expansion of a pre-existing lineage. Pairwise difference analysis identified 24 genomically identical B114 sequences; associated metadata argued against a single nosocomial transmission chain interpretation, with the pattern more consistent with repeated detection of a widely circulating community strain, with the possibility of localised onward transmission. Within the B114 clade, multiple monophyletic groups were identified by whole-genome phylogenetics. ConclusionsThis study adds whole-genome resolution to the existing UK HAdV-B114 data, demonstrates the utility of WGS for clinical adenovirus surveillance and shows the benefits of combining epidemiological data with genomic analysis.

Background: Seasonal influenza, commonly known as flu, is an acute respiratory, highly contagious illness caused by influenza viruses. A clear understanding of influenza seasonality is crucial for guiding prevention and treatment strategies, including decisions on vaccination timing to prevent outbreaks. While well documented in temperate regions, data on influenza epidemiology in tropical areas, particularly sub-Saharan Africa, remain limited. We described the types, subtypes and positivity rate of seasonal influenza in Uganda during 2019-2023. Methods: We abstracted data from the National Influenza database on positive seasonal influenza cases confirmed by Polymerase Chain Reaction. The cases were disaggregated by age group, sex, region, month and year of reporting. Using Microsoft excel, we calculated the influenza positivity rate and disaggregated it by strain, sex, age, region and time. Test positivity rate was computed as the number of positive cases as a percentage of the total samples tested. Results: Among 17,957 individuals tested, the overall positivity rate for seasonal influenza was 5% (936 cases). Positivity was higher among males compared to females (7% vs. 4%), with children aged 5-9 years having the highest positivity rate (16%), while individuals aged 50-54 years had the lowest (1%). The median positivity rate was 4%, with a range of 1-16%. Regionally, the central region reported a positivity rate of 5%, with rates across all regions ranging from 5% to 8%. Over time, there was a gradual decline in positivity rates, decreasing from 16.5% in 2019 to 5.3% in 2023. Seasonal influenza exhibited bimodal peaks, with the primary peak occurring between March and May and a secondary peak from October to December. Influenza A was the predominant strain, accounting for 70% of seasonal influenza cases (669/936). Among the Influenza A subtypes, H3N2 was most common, representing 63% of cases (425/669). Conclusions: The declining seasonal influenza positivity rates from 2019 to 2023 and the predominance of Influenza A and H3N2 highlight the need for sustained surveillance in Uganda. Given Influenza A's high genetic variability and potential for novel strain emergence, monitoring circulating strains, informing vaccine development, and implementing targeted interventions for high-risk groups and regions are critical to controlling and preventing outbreaks.

Aim: General ICU severity scores predict hospital mortality across heterogeneous populations, not recovery within one diagnosis. We described favourable discharge across the range of APACHE IVa-predicted hospital mortality after cardiac arrest, and tested whether any bedside subgroup fell below a pre-specified benchmark. Methods: Observational cohort of 3,641 first ICU admissions in 161 eICU hospitals with a cardiac-arrest diagnosis documented within 24 hours. The exposure was APACHE IVa-predicted hospital mortality; the outcome was favourable discharge (home or rehabilitation), a functional-outcome proxy. Fourteen bedside subgroups were pre-specified; the benchmark required an upper 95% bound below 5%. Results: Favourable discharge occurred in 1,039 (28.5%), falling from 78.9% in the lowest predicted-mortality decile to 4.1% in the highest (trend z, -27.2; P < 0.001). Among 2,139 patients with predicted mortality at or above 50%, 301 (14.1%; 95% CI, 12.6 to 15.6) had a favourable discharge; among 281 at or above 90%, 9 (3.2%) did. No subgroup had an upper 95% bound below 5%; the lowest was 8 of 264 (3.0%; 95% CI, 1.3 to 5.9). At a more permissive 10% benchmark, two qualified. Among 1,961 not obeying commands, 263 (13.4%) had a favourable discharge. Discrimination did not differ detectably between unfavourable functional outcome (AUROC 0.789) and in-hospital death (0.774; P = 0.078). Conclusion: Favourable discharge declined as predicted mortality rose but remained observable at the highest risk levels, and no pre-specified subgroup was bounded below 5%. A general ICU mortality estimate is not on its own evidence that a favourable outcome is absent.

Background: The 2025/26 influenza season included A(H3N2) subclade K predominance with A(H1N1)pdm09 co-circulation and subsequent prolonged influenza B activity. The Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) in the context of genetic and antigenic relatedness to circulating viruses. Methods: We estimated VE by test-negative design among outpatients with medically-attended acute respiratory illness between November and April. We characterized case viruses by whole genome sequencing and hemagglutination inhibition assay. Results: Among 2809/9047 (31%) influenza-positive specimens, 82% (2306/2809) were influenza A with 18% (504/2809) influenza B. Of subtyped influenza A, 85% (1848/2169) were A(H3N2). We sequenced 59% (1099/1848) of A(H3N2) viruses, with 87% (956/1099) subclade K, antigenically-mismatched to subclade J.2 vaccine. VE against A(H3N2) and subclade K was 38% (95% confidence interval: 27%-47%) and 33% (19%-45%). We sequenced 69% (222/323) of A(H1N1)pdm09 viruses, virtually all (n=218) clade 5a.2a.1, including subclades D.3.1 (21%; n=47) and D.3.1.1 (77%; n=171), antigenically-matched to subclade D vaccine. VE against A(H1N1)pdm09, subclades D.3.1 and D.3.1.1 was 28% (4%-47%), -21% (-144%-40%) and 44% (14%-64%). We sequenced 82% (413/504) of influenza B viruses, all B/Victoria, including antigenically-mismatched subclade C.3 (18%; n=74) with D197N gain-of-glycosylation, and antigenically-matched subclade C.5 (82%; n=339) relative to subclade C vaccine. VE against influenza B, subclades C.3 and C.5 was 55% (41%-66%), 10% (-60%-49%) and 68% (51%-79%). Conclusions: The 2025/26 influenza vaccine reduced the risk of A(H3N2), A(H1N1)pdm09 and B/Victoria by over one-third, one-quarter and one-half, respectively. Laboratory-based indicators of vaccine match remain uncertain proxies for actual vaccine protection, reinforcing importance of annual epidemiological monitoring of VE.

Background England's population is ageing rapidly, with those aged 80 years and older projected to increase 85% by 2047. Aging populations may change the dynamics of future pandemics, since older individuals face higher risks of severe outcomes and require a disproportionate share of early vaccine supply, for certain respiratory infections, despite having fewer social contacts. The net pandemic-risk implications of these competing effects cannot be resolved without dynamic transmission modelling. Methods We used an age-structured stochastic SARS-CoV-2 transmission model, previously calibrated to the real-time COVID-19 epidemic across seven NHS regions of England. Running the fitted model under the ONS principal population projection for 2047 as a counterfactual, we held all non-pharmaceutical interventions fixed and scaled vaccine supply to overall population growth. Nine counterfactual scenarios spanned three vaccine deployment strategies and three ONS migration assumptions. Findings The basic reproduction number remained largely unchanged by the projected age distribution. However, under the central counterfactual scenario, cumulative hospital admissions in the first two years of the pandemic were 674,004 - a 40.3% increase over the historic baseline - and hospital deaths increased by 49.4%, disproportionate to the 13.9% total population increase. Trajectories were similar before the Delta variant emerged but diverged thereafter, as a larger elderly cohort delayed vaccine protection in younger, higher-contact groups. Projected burden was robust to migration assumptions (664,451--689,833 admissions). Vaccine deployment strategy had substantially greater influence, with admissions ranging from 625,859 (optimistic age-scaled deployment) to 1,193,883 (non-scaled). Interpretations Population ageing will disproportionately amplify England's pandemic burden, driven primarily by the interaction between a growing elderly cohort and fixed age-ordered vaccine allocation, rather than by population growth alone. This vulnerability is largely independent of future migration uncertainty but is strongly modifiable through demographically-adaptive vaccine deployment planning developed before, not during, the next pandemic.

Importance: Acute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated. Objective: To test the a priori hypothesis that preventive acetazolamide achieves a 20% greater relative risk reduction (RRR) of AMS in female vs male lowlanders ascending to 3600 m. Design: Randomized, double-blind, placebo-controlled, parallel-group trial conducted from March 2024 to August 2025; participants, outcome assessors, and statistician were blinded until analysis was complete. Setting: Baseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic. Participants: Healthy female and male low-altitude residents (age 18-44 years, BMI 18-30 kg/m2, residence <1000 m); females were premenopausal, eumenorrheic, and not using hormonal contraception. Exclusion criteria included pre-existing disease, regular medication, pregnancy, anaemia, and altitude sojourn >2500 m within 4 weeks. Intervention: Acetazolamide 125 mg or matching placebo twice daily, from 24 hours before ascent and throughout the 2-day, 2-night stay at 3600 m. Main Outcomes and Measures: Primary outcome was the between-sex difference in RRR of AMS, defined as a 2018 revised Lake Louise Score of 3 or higher including headache. Secondary outcomes included absolute risk reduction (ARR) and drug tolerability. Results: Of 303 randomized participants (180 females, 123 males; mean [SD] age, 23 [4] years), AMS incidence under placebo (n=155) was 34% (females 42% vs males 23%; P=.02) and under acetazolamide (n=148) was 24% (females 30% vs males 14%; P=.02). Overall RRR was 31% (95% CI, 0% to 52%) and ARR was 10% (95% CI, 0% to 22%). Sex-stratified RRR was 27% (95% CI, -9% to 52%) in females and 42% (95% CI, -28% to 74%) in males; between-sex RRR difference, -15% (95% CI, -65% to 57%). Females had a 4.8-fold higher risk of moderate-to-severe drug-related side effects than males. Conclusions and Relevance: Preventive acetazolamide reduced overall AMS incidence at 3600 m, but the pre-specified 20% greater RRR in females (trial powered at 90%) was not observed. The nearly 5-fold higher risk of moderate-to-severe side effects in females warrants further investigation of sex-specific dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT06499727

Objective: To test the hypothesis that selected SIRS and SOFA criteria measured at ICU admission have divergent associations with (1) the development of new culture-confirmed infections and (2) early empiric broad-spectrum antibiotic receipt in critically ill patients with cirrhosis. Design: Retrospective, observational study using electronic health record (EHR) data. Setting: Both community and academic ICUs within a five-hospital health system between July 2017 and December 2025. Subjects: Adult patients >18 years of age diagnosed with cirrhosis admitted to the ICU within 96 hours of hospital admission. Patients transferred from outside facilities and those with positive cultures collected >24 hours before ICU admission were excluded. Interventions: None. Measurements: Multivariable logistic regression tested the association of the most aberrant values in nine SIRS/SOFA vital sign and laboratory parameters measured during the 24 hours prior to ICU admission with (1) the development a newly positive culture collected during the 24 hours before through the 96 hours after ICU admission and (2) receipt of broad-spectrum antibiotics during the 24 hours before through the 24 hours after ICU admission. Main Results: The presence of hyperthermia, hypothermia, hypoxia, or hypotension at ICU admission was associated with both culture positivity and antibiotic receipt. The presence of leukocytosis was associated with antibiotic receipt but not culture positivity. Among patients in the 21.6% of encounters with newly positive cultures, normothermia and normal WBC were common (respectively present in 97.2% and 77.5% of encounters) and associated with antibiotic omission at ICU admission despite the subsequent development culture positivity. Conclusions: Traditional physiologic markers of infection are often absent in critically ill patients with cirrhosis who develop new culture-confirmed infections at ICU admission, possibly contributing to delayed antibiotics. There may be opportunities to improve antibiotic delivery and stewardship at ICU admission in this high-risk population.

Rationale. Guidelines disagree on antibacterial treatment for adults with community-acquired pneumonia and a positive respiratory viral test, particularly hospitalized patients and outpatients with comorbidities. Objectives. To estimate associations between antibacterial treatment selected for community-acquired pneumonia and outcomes in adults with virus-positive, imaging-evaluated nonsevere pneumonia. Methods. We conducted a retrospective multicenter study using Epic Cosmos data from 2016-2025. Hospitalized patients treated empirically by 24 hours were compared by continuation during hours 24-48; outpatients were compared by prescription at emergency-department discharge. Analyses were stratified by guideline-defined comorbidity and used propensity-score overlap weighting with source-cluster bootstrap confidence intervals. Exploratory analyses assessed respiratory virus, antiviral treatment, antibacterial class, and outpatient timing. Measurements and Main Results. The cohort included 376,320 adults: 275,604 inpatients and 100,716 outpatients. Inpatients who continued treatment had higher 30-day adverse-event risk without guideline comorbidity (adjusted risk difference, 1.70 percentage points; 95% confidence interval, 0.80-2.39) and with guideline comorbidity (2.56; 1.88-3.14), and longer post-landmark stay (adjusted mean ratios, 1.14 and 1.08). Exploratory class-specific analyses showed the largest adverse-event and mortality associations with broad therapy targeting resistant staphylococci or Pseudomonas; macrolide-containing and other atypical coverage showed no consistent adverse signal. Outpatient prescribing was associated with lower risks, but care-transition and residual confounding remained. Conclusions. Continued inpatient therapy after the empiric period showed no evidence of benefit and was associated with worse observed outcomes. Outpatient associations favored prescribing but remained vulnerable to care-transition and residual confounding.

Introduction: Tuberculosis (TB) care is typically organised around biomedical and public health priorities, including diagnosis, infection control, treatment adherence, and prevention of transmission. Although qualitative research has described the burden of TB, lived experience is often treated as descriptive rather than as knowledge that can inform care. We examined how Aboriginal people in remote northern Australia experienced TB, and what these experiences reveal about how TB care can be strengthened in practice. Methods: We conducted an inductive qualitative study involving in-depth interviews with Aboriginal people with lived experience of TB. Interviews were supported by Aboriginal community health workers. Data were analysed using reflexive thematic analysis, with Aboriginal contributors involved in interpretive workshops to refine themes and guide culturally safe representation. Results: Twenty-one Aboriginal people contributed across 13 interviews. Three interrelated themes described the TB journey. Illness often challenged dominant biomedical expectations: symptoms were commonly normalised, which fear, ambivalence, and endurance were shaped by experiences of compromised health and cumulative loss. Distance from family, community, and Country was experienced as both protection and sacrifice; separation was endured to protect others but carried substantial costs, particularly when its purpose and duration were unclear. Recovery involved rebuilding strength, connection, and identity. Clear explanation, continuity, and opportunities for choice supported engagement in care, while survivors and community health workers provided important sources of trust, support, and shared responsibility. Conclusion: Lived experience is practice-relevant knowledge for TB programmes. Care should minimise avoidable harms of separation, support continuity and choice, and recognise survivors, Aboriginal health workers, and communities as partners in the design and delivery of care.

Public genomic repositories can support antimicrobial resistance (AMR) surveillance, but unequal sampling can bias interpretation. We characterised AMR determinants, multicountry genomic cluster overlap and surveillance gaps across Africa using an NCBI Pathogen Detection snapshot retrieved on 24 August 2026 for 55 African Union member states. Records were validated and deduplicated by BioSample, and complete AMRFinderPlus calls were summarised across five United Nations M49 subregions and eight overlapping regional economic communities (RECs). Country-pair cluster overlap was assessed using the Jaccard index, while project-based and composition-standardised sensitivity analyses evaluated repository bias. The dataset contained 86,829 unique BioSamples from 51 states; South Africa, Malawi and Kenya contributed 55.8%. Complete extended-spectrum {beta}-lactamase calls were detected in 21,513 isolates and carbapenemase calls in 4,642. blaCTX-M-15 dominated the ESBL profile, while NDM and OXA types predominated. Seventy clusters contained carbapenemase-positive isolates from at least two countries. A shared REC covered all participating countries in 38 clusters, while 32 crossed REC boundaries. Normalised country-pair overlap was low, with a maximum Jaccard index of 9.5%. Project balancing reduced the Northern African carbapenemase estimate from 32.3% to 17.9% and the Eastern African ESBL estimate from 36.9% to 12.5%. Public repositories identify determinants and clusters for investigation but do not estimate prevalence or transmission. AMR surveillance should combine national confirmation, regional institution-led investigation where countries share an REC, and continent-wide coordination through Africa CDC for cross-REC signals, supported by representative One Health sampling, standardised metadata and sustained African sequencing capacity.