The Lancet

Introduction: Respiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited. Methods: We reviewed studies from 01/2002-11/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model. Results: Following exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions. Discussion: We highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.

Of the two influenza A virus (IAV) subtypes circulating endemically in humans, A/H3N2 and A/H1N1pdm09, A/H3N2 has historically been the dominant driver of disease burden in older adults. Based on an analysis of publicly available global surveillance data from 2015 to 2025 (>300,000 subtyped, age-stratified infections), we report a substantially increased contribution of A/H1N1pdm09 to influenza morbidity in older adults since approximately 2022. Birth cohort-stratified analyses suggest elevated A/H1N1pdm09 burden among individuals born before 1955-1959, consistent with erosion of pre-existing immunity originally generated by exposure to historical A/H1N1 strains. Pooled estimates across datasets and analytical approaches indicate the increase in A/H1N1pdm09 burden rises with earlier birth year, ranging from 1.22-fold (95% CI 1.08-1.37) for the 1955-1959 birth cohort to 3.10-fold (95% CI 2.58-3.72) for the 1930-1934 cohort. These findings point to a substantial rise in the overall influenza burden among the most vulnerable age groups, with implications for vaccine policy, clinical management, and public health planning.

Background. Infectious mononucleosis (IM) with hepatitis is associated with suppression of high-density lipoprotein cholesterol (HDL-C), but the magnitude, specificity, recovery kinetics, and long-term cardiovascular implications of this finding have not been systematically characterised. Methods. Using the TriNetX Global Collaborative Network (<190 million patients, 178 healthcare organisations), we conducted a retrospective real-world evidence study in 1,944 adults with IM and hepatitis. We compared HDL-C distributions at presentation across 14 propensity-score-matched (PSM) comparator cohorts spanning other infectious, metabolic, and immune-mediated conditions. Gaussian mixture modelling characterised the HDL distribution. Longitudinal HDL trajectory was assessed across six post-index time windows, with the number of patients contributing a measurement ranging from 318 (16-30 days) to 2,849 (1-3 years) per window. Long-term major adverse cardiovascular events (MACE) were analysed in PSM cohorts of IM patients with very low HDL ([&le;]20 mg/dL, n = 979 per arm after PSM) versus those without low HDL, over up to 20 years of follow-up, with COVID-19 (n = 83,888 per arm) and pharyngitis (n = 10,618 per arm) as comparators. Results. At presentation, mean HDL in IM hepatitis was 36.7 +/- 22.6 mg/dL (median 33 mg/dL), ~14-17 mg/dL lower compared to pre-illness values. Nearly one quarter (23.9%) had HDL [&le;]20 mg/dL and 43.9% had HDL [&le;]30 mg/dL. HDL suppression was equivalent to CMV hepatitis but substantially greater than pharyngitis and IM without hepatitis, supporting a hepatitis-driven mechanism. Gaussian mixture modelling identified a discrete suppressed subpopulation (mean 16 mg/dL, 41% of patients) absent in non-hepatitis controls. Recovery was rapid in most patients (mean HDL 50.0 mg/dL by 16-30 days) but prolonged among the severely suppressed ([&le;]20 mg/dL), who required 3-6 months to approach baseline. In PSM MACE analyses, IM patients with very low acute HDL had significantly higher long-term event rates for all outcomes (HR 1.92-2.47 versus IM without low HDL), a pattern mirrored in the COVID-19 cohort (HR 2.04-2.70) and, with attenuated effect size, in pharyngitis (HR 1.43-1.69). Conclusions. Very low HDL-C is a prevalent, hepatitis-driven finding in IM affecting approximately one quarter of patients. It identifies a subgroup at elevated long-term cardiovascular risk comparable to that observed after COVID-19. These findings warrant prospective evaluation of cardiovascular follow-up strategies for affected patients.

Background Post-acute sequelae are well described following COVID-19 but may also occur after other respiratory infections and Aedes-borne infections. Evidence remains fragmented due to heterogeneity in study design, populations, and exposure, outcome, and follow-up definitions. Methods We synthesized and compared post-acute sequelae across influenza, RSV-ARI, dengue fever, chikungunya, Zika, and yellow fever. We searched five databases from inception to 25-08-2025 for articles quantifying risk, incidence, or rates of post-acute sequelae following these diseases. Eligible non-randomized observational studies assessed post-acute neurological, psychiatric, gastrointestinal, cardiovascular, respiratory, renal, musculoskeletal, autoimmune, or endocrine outcomes after confirmed infection. Risk of bias was assessed using ROBINS-E. Random-effects meta-analyses with restricted maximum likelihood estimation were conducted when comparable effect estimates were available (PROSPERO #CRD420251124994). Findings 51 studies were included, predominantly from high-income regions. Most were retrospective cohorts using ICD-coded diagnoses; prospective studies used laboratory-confirmed infections. Data sources, comparator groups, exposure definitions, outcome ascertainment, and follow-up periods varied substantially. Meta-analyses were feasible for RSV, influenza, and dengue fever. All RSV-ARI studies were pediatric and assessed infections during infancy, which were associated with higher pooled odds of physician-diagnosed asthma (OR:2.93 [95%CI: 2.12-4.06]). Influenza studies used COVID-19-positive comparators; pooled estimates showed lower risk for neurological (HR:0.82 [0.76-0.89]) and composite outcomes (RR:0.88 [0.82-0.95]), with other organ systems non-significant. Dengue fever studies spanned all ages and showed increased risks of anxiety (HR:1.34 [1.01-1.78]), dementia (HR:1.61 [1.10-2.35]), autoimmune (RR:1.39 [1.17-1.67]), cardiovascular (HR:1.51 [1.27-1.80]), psychiatric (HR:1.17 [1.07-1.28]), and any sequelae (HR:1.19 [1.13-1.25]) versus those without prior infection. Interpretations Post-acute sequelae contribute to overall disease burden following RSV-ARI and dengue fever. The evidence remains limited by heterogeneity in study design, exposure and outcome definitions, comparator selection, and follow-up duration. Greater standardization in study design and reporting is needed to improve comparability and strengthen causal inference.

Objectives To quantify the frequency of baseline control-group use in published long COVID prevalence studies and assess their key methodological features. Design Cross-sectional meta-epidemiological evaluation of published post-acute COVID-19 prevalence studies, supplemented by a corresponding-author survey. Setting Published studies identified through a systematic review by Hou et al. (2025) and supplementary data obtained through direct email contact with corresponding authors. Participants A total of 440 published long COVID prevalence studies. Main Outcome measures Presence and type of comparator group, reliance on solely self-reported outcomes, acknowledgment of lack of a control group among uncontrolled studies, and availability of additional comparator data through author survey. Results Among 440 studies, 372 (84.5%) reported no control group on their publication. Healthy or uninfected comparators were reported in 55 studies (12.5%) and other comparator types in 14 (3.2%); 1 study included both categories. Solely self-reported outcomes were used in 279 studies (63.4%). Among 372 uncontrolled studies, 244 (65.6%) did not explicitly acknowledge the absence of a baseline comparator as a limitation anywhere in text. Corresponding authors of 140 studies (31.8%) responded to the survey; among them, 126 (90.0%) reported no additional comparative data, while 14 (10.0%) mentioned some available comparative datasets (19 additional datasets). Almost all of that information (10/14, 17/19) had been already published in other articles not captured by the Hou et al. systematic review. Conclusions Most published long COVID prevalence studies lacked comparator groups and relied exclusively on self-reported outcomes without acknowledging this limitation. Direct author contact identified little additional comparator information. Much of the long COVID prevalence literature may therefore be poorly suited to estimating burden attributable specifically to SARS-CoV-2, underscoring the need for appropriately matched comparators and more objective outcome assessment. Registration The protocol was prospectively registered on the Open Science Framework (https://osf.io/f4hra).

ABSTRACT Background: Corticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19. Methods: We utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support. Results: This emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated). Conclusions: In this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.

Background: Wearing facemasks and practising social distancing slow the spread of respiratory pathogens. However, in the event of a new pandemic emerging, the willingness of populations to voluntarily adopt these behaviours is unclear. Methods: A discrete choice experiment was conducted among 2,006 UK-based adults. Participants were presented with hypothetical scenarios describing the emergence of a respiratory virus pandemic and were asked to choose when they would wear facemasks and practise social distancing. A mixed multinomial logit model was used to jointly estimate how disease severity and prevalence, uncertainty in these quantities, and individual-level characteristics influence behavioural choices. Findings: Participants were averse to facemasks and social distancing in the absence of pandemic risk. For each ten-unit increase in severity (10 additional hospitalisations/1,000 infections), the odds of always wearing a facemask outside the home increased by 15.9% (95%CI: 14.3%, 17.5%), relative to rarely/never, and the odds of avoiding all people as much as possible increased by 16.4% (14.6%, 18.2%), relative to not avoiding anyone. Greater disease prevalence, uncertainty in disease severity or disease prevalence, a university education, prior COVID-19 vaccination and non-white ethnicity were also associated with choosing to always wear facemasks and avoid all people as much as possible. The probability of participants choosing to rarely/never wear facemasks varied from 13.4% (11.9%, 14.9%) in the lowest-risk scenario to 1.4% (1.2%, 1.7%) in the highest-risk scenario. Interpretation: Perceived risks of disease and associated uncertainty drive intention of UK adults to adapt their behaviour in a future pandemic.

Background Artemisinin derivatives are central to first-line treatment of both uncomplicated and severe Plasmodium falciparum malaria. Emerging artemisinin partial resistance in East Africa threatens to spread across the continent. Methods In two cross-sectional studies in Zambia in 2024, we genotyped the artemisinin resistance-associated gene Pfkelch13. In Kaoma, western Zambia, we evaluated the percentage of patients with day-3 parasite positivity following treatment with artemisinin-based combination therapy, and ex vivo parasite susceptibility to dihydroartemisinin (the active metabolite of artemisinin). We also assessed longitudinal changes in Pfkelch13 mutation prevalence in Kaoma using isolates collected from 2018 through 2026. Results We identified a novel mutation, Pfkelch13 A724E, in 52% (113 of 217) of isolates from Western Province, 51% (94 of 184) of isolates from North-Western Province, and 11.7% (229 of 1,949) of isolates country-wide. In Kaoma, 28% (21 of 75) of patients carrying Pfkelch13 A724E mutant parasites before treatment were parasite positive on day 3, compared with 0% (0 of 23) of patients with the wild-type allele (P=0.003). Within day-3 positive patients, the proportion of A724E mutant parasites increased significantly after treatment (P = 0.013). The prevalence of Pfkelch13 A724E in Kaoma increased steadily from 0% (95% confidence interval [CI], 0 to 22%) in 2018 to 79% (95% CI, 73 to 85%) in 2026. Conclusions A novel Pfkelch13 mutation conferring partial resistance to artemisinin is spreading in Zambia. Additional clinical evaluations are urgently needed in the region. (Funded by the Gates Foundation, INV-048316).

Background Coeliac disease affects approximately 1% of the global population and remains substantially underdiagnosed. Histopathological assessment of duodenal biopsies is the diagnostic gold standard but is subject to approximately 20% inter-observer disagreement. While machine learning approaches show promise, most prior work relies on black-box models with limited interpretability, restricting clinical adoption. Methods We present an interpretable pipeline that follows established histopathological criteria by extracting clinically meaningful morphological features from H&E-stained whole-slide images. Five sequential stages perform pre-processing, semantic segmentation of villi, crypts, intraepithelial lymphocytes (IELs) and enterocytes, crypt morphometry, villus length estimation via a novel polyline-based keypoint model, and coeliac disease classification using three quantitative features: IEL-to-enterocyte ratio, villus-to-crypt area ratio, and villus-length-to-crypt-depth ratio. Training and validation used data from four institutions; independent testing used 1,357 WSIs from two further institutions including one with a previously unseen scanner manufacturer, spanning five diagnostic categories: coeliac disease, normal mucosa, chronic inflammation, gastric metaplasia, and gastric heterotopia. Results Semantic segmentation achieved villus and crypt precision and recall of 87-90%. Villus length estimation correlated strongly with expert annotations (Pearson's r=0.85, mean relative error 13.5% post-calibration). All three morphological features significantly separated coeliac disease from all non-coeliac diagnostic groups across internal and external datasets (p<0.01 in all comparisons). On the test set the diagnostic classifier achieved accuracy 94.5%, PPV 92.9%, NPV 94.7%, and AUC 0.982. Conclusions This interpretable framework achieves strong multi-centre diagnostic performance while producing quantitative morphological outputs, villus length, crypt depth, and IEL-to-enterocyte ratios, that directly reflect established histopathological criteria, representing a meaningful step towards standardised AI-assisted coeliac disease diagnosis.

Background High-risk subgroups among household contacts of persons with tuberculosis (TB) might benefit from additional interventions. However, the significance of an abnormal baseline chest radiograph (CXR) suggestive of TB, despite negative sputum microbiology, is uncertain. Methods Adults ([&ge;]18 years) with recent household TB exposure were enrolled at three South African sites (April 2021-September 2022). All participants underwent symptom screening, CXR, and sputum Xpert Ultra and MGIT culture. Pulmonary TB diagnosis was microbiologically-confirmed. Participants without prevalent TB were followed for symptomatic incident TB through 12 months. Multivariable logistic regression identified factors associated with abnormal CXR suggestive of TB. Poisson regression estimated adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95%CI). Results Baseline CXR were available for 795/846 (94.0%) participants without prevalent TB and were abnormal in 157/795 (19.7%); associated with older age (adjusted odds ratio, aOR=1.04, 95%CI 1.02-1.05); prior TB (aOR=6.39, 95%CI 4.18-9.78); and current smoking (aOR=1.61, 95%CI 1.00-2.62). Symptomatic incident TB developed in 8/795 (1.0%) participants, including 7/8 (87.5%) who were asymptomatic and 4/8 (50.0%) with abnormal CXR at baseline. TB incidence was higher in those with abnormal versus normal CXR (aIRR=4.11, 95%CI 1.29-13.09), but after median 12.1 (IQR 11.1-13.1) months follow-up, 153/157 (97.5%) had not progressed to incident TB. Conclusions Adult household contacts with CXR abnormalities, but without prevalent TB, had a four-fold higher incidence of TB within one year, compared to those with normal CXR. This additional risk warrants targeted preventive treatment and extended surveillance, but since most remained TB-free, therapeutic TB treatment is not justified.

Background: Mucosal immunity is critical for preventing poliovirus transmission. Despite evidence that infant immunisation protects against poliovirus infection into adulthood, the duration of vaccine-induced intestinal antibody responses remains poorly characterised. Methods: We evaluated poliovirus type-specific neutralising activity and immunoglobulin levels in stool and serum from children in Tanzania who completed routine poliovirus vaccine series (bivalent oral polio vaccine at birth, 6, 10, and 14-weeks, and inactivated polio vaccine at 14-weeks). The study included a longitudinal cohort with four visits over 6 months and a cross-sectional sample of children recruited 1 to 108-months after vaccine series completion. Potential modification by nutritional factors, gastrointestinal infections, and environmental enteropathy was explored. Findings: Among 103 longitudinal and 246 cross-sectional participants enrolled, 33% and 18% had positive poliovirus type-1 (PV1) stool neutralisation, and 66% and 56% had positive poliovirus type-3 (PV3) neutralisation 1 month after vaccination. All were seropositive for PV1 and PV3 across timepoints. Infants followed longitudinally who were stool neutralisation-positive at enrolment had no boost in neutralisation after vaccination, while those stool neutralisation-negative at enrolment experienced a weak boost at 1 month. Stool neutralisation half-life among longitudinal cohort infants was 3.4 months [95% CI 2.6-5.0] for PV1 and 1.7 months [1.4-2.3] for PV3. Moderate evidence suggested concurrent viral intestinal infections were associated with lower neutralisation responses (PV1 p=0.153; PV3 p=0.052). Interpretation: Intestinal antibody responses to poliovirus vaccination were short-lived. The impact of waning intestinal antibodies on transmission risk remains unclear and research is needed to identify vaccination strategies that induce durable mucosal immunity.

Background: The World Health Organization has expanded its recommendations for prophylactic Ebola vaccination for at-risk populations. Durable vaccine-induced immunity is important for sustaining outbreak preparedness in regions with recurrent Ebola virus disease (EVD). We assessed five-year persistence of vaccine-induced immune responses in adults and children from the PREVAC trial. Methods: Two large randomised phase 2 trials (NCT02876328), in adults and children aged [&ge;]1 year, were conducted in four west African countries. Participants were randomly assigned to placebo or to one of three Ebola vaccine strategies: Ad26.ZEBOV followed by MVA-BN-Filo at 56 days; rVSV{Delta}G-ZEBOV-GP followed by placebo; or rVSV{Delta}G-ZEBOV-GP followed by a homologous booster dose at 56 days. After 12 months of follow-up, the primary results were published, participants unblinded to their vaccine assignment, and follow-up continued for 60 months. After Month 24, placebo group recipients were offered active vaccination. Anti Ebola virus glycoprotein Immunoglobulin G (IgG) concentrations were measured for 5 years. Findings: 1401 adults and 1401 children were initially randomized, and 1315 (93.9%) adults and 1322 (94.4%) children attended at least one long-term visit. Retention was high, with 95% followed beyond 1 year and 83% completion at 5-year follow-up. For the three vaccine strategies, antibody geometric mean concentrations (GMC) declined modestly between Months 12 and 24, followed by a stable plateau from Months 24 to 60. At Month 60, antibody GMC were higher in the rVSV-based groups (1099 and 1216 EU/ml for adults; 1982 and 2347 EU/ml for children) than in the Ad26.ZEBOV, MVA-BN-Filo group (252 adults and 645 EU/ml children). Antibody persistence at Month 60 was heterogeneous, varying by age, sex, country, and baseline IgG concentration. Interpretation: Licensed Ebola vaccines induced sustained antibody responses in adults and children for up to 5 years. While the protective antibody level is unknown, these data demonstrate long-lasting immune responses from currently employed vaccine strategies.

Background Human challenge trials provide a unique opportunity to quantify pathogen infectivity in terms of the probability of infection given an inoculated dose. However, between-pathogen comparisons are often distorted by individual heterogeneity in host susceptibility and by differences in background immunity across trial populations. We examined how dose-dependent infection risks differ across common respiratory viruses when such heterogeneity is explicitly incorporated. Methods We conducted a systematic review of human challenge trials for four respiratory viruses: respiratory syncytial virus (RSV), influenza virus, rhinovirus, and adenovirus. Using the extracted data, we fitted dose-response models under different distributional assumptions, allowing both continuous susceptibility variation and discrete immune fractions. We compared alternative heterogeneity models and evaluated pathogen-specific dose-response patterns using original and scaled dose metrics. Results All four viruses showed substantial heterogeneity in host susceptibility, and models assuming homogeneous susceptibility were unsupported. RSV and influenza were best described by models with a distinct immune or effectively non-susceptible subgroup, and the estimated immune proportions were approximately 40% and 25%, respectively. In contrast, rhinovirus and adenovirus were better explained by continuously distributed susceptibility, with little evidence of a fully immune subgroup. On a scaled dose axis, rhinovirus and adenovirus showed steeper increases in infection risk with dose than RSV and influenza. Conclusions The structure of susceptibility heterogeneity differs across common respiratory viruses, which in turn shapes dose-dependent infection risks. Incorporating this heterogeneity is essential for valid cross-pathogen comparison and for interpreting human challenge data in epidemiologic and public health contexts.

Background: Isoniazid resistance is the most common form of drug-resistant tuberculosis (TB) globally. However, WHO-recommended molecular tests available to most TB patients worldwide detect rifampin resistance only, risking under-treatment of isoniazid-resistant, rifampin-susceptible TB (HR-TB) and subsequent emergence of rifampin resistance. Methods: This prospective study (2020-2024) aimed to collect and archive sputum specimens from all adults diagnosed with rifampin-susceptible pulmonary TB in Ho Chi Minh City, Vietnam. Cases were participants who developed rifampin-resistant recurrence; controls had rifampin-susceptible recurrence or no recurrence. Whole-genome sequencing of paired isolates distinguished acquired rifampin resistance from reinfection. The effect of pre-existing isoniazid resistance on rifampin resistance acquisition was estimated using inverse probability of treatment weighting, and the projected epidemiological impact of routine HR-TB testing was modelled. Results: 42,843 people were diagnosed with TB during the study period, from whom we archived 33,843 sputum samples. We enrolled 1,241 participants, 873 (70.4%) of whom had analysable data. 51/873 (5.8%) acquired rifampin resistance, of whom 49/51 (96.1%) had undetected isoniazid resistance. The weighted risk of acquired rifampin resistance was 2.98% (95% CI 2.08-4.50) with undetected isoniazid resistance, versus 0.03% (0.00-0.08) without (risk ratio105.42 (33.43-309.69)). Modelling projected that universal HR-TB diagnosis and treatment would reduce RR-TB incidence by 46% (35-61) over 10 years in Vietnam, with reductions of 26% (12-43) projected even where HR-TB prevalence was as low as 5%. Conclusions: Undetected, under-treated HR-TB confers a 100 fold increased risk of acquiring rifampin resistance. Routine isoniazid susceptibility testing combined with effective HR-TB treatment could substantially reduce the burden of RR-TB.

Background: Mortality rates have declined across most high-income countries for decades, but recent evidence suggests a slowdown in improvements or a shift to increasing mortality, particularly among working-age populations. The international distribution and drivers of these trends remain incompletely understood. Methods: Mortality trends during 2012-2019 were analysed using all-cause and cause-specific data from 30 countries. Trends were estimated via linear regression. K-means clustering with Dynamic Time Warping identified countries and ICD-10 chapters with similar temporal trajectories. Results: Trends varied substantially by nation. While Japan, Switzerland, and the Republic of Korea maintained consistent declines in all-cause mortality rates, increases were concentrated in the United States, Canada, and the United Kingdom, most prominently in persons aged 30-59 years. However, cause-specific analysis showed that rising mortality was not confined to these countries: most countries exhibited increases in at least one ICD-10 chapter, with several European countries showing increases across multiple chapters. Across countries, a small set of causes recurred among increasing trends, including external causes (self-harm, drug poisoning) at younger ages and chronic conditions (cardiovascular and liver diseases, specific cancers) in mid-life. Notably, ill-defined causes of death consistently appeared among the increasing causes across countries and age groups. Conclusions: Mortality increases in the 2010s were geographically more widespread than previously recognized. The recurrent rise in mortality from ill-defined causes suggests that an important component of mortality change remains poorly characterized. These findings indicate that stalled health progress is a systemic challenge across many high-income societies.

Background: The ongoing Bundibugyo virus disease (BDBV) outbreak in Central Africa highlights the absence of approved vaccines specifically targeting BDBV. Whether licensed Zaire ebolavirus (EBOV) vaccines induce cross-reactive immunity against BDBV remains largely unknown. Methods: We performed an immunogenicity analysis using serum samples from participants enrolled in the PREVAC randomized clinical trial evaluating licensed Ebola vaccine strategies in West Africa. Samples collected at day 28 (D28) and month 3 (M3) following vaccination with rVSV{Delta}G-ZEBOV-GP or Ad26.ZEBOV/MVA-BN-Filo were assessed using a multiplex Luminex assay against glycoproteins from multiple filoviruses, including EBOV Kikwit, EBOV Mayinga, BDBV, Sudan virus, Reston virus, and Marburg virus. Results: A total of 179 samples were analysed. Detectable cross-reactive antibody responses against BDBV were observed across vaccine groups, timepoints, and age categories. However, BDBV responses remained substantially lower than homologous EBOV responses. In rVSV recipients, median BDBV responses (net MFI) reached 282 (IQR 164-644) at D28 compared with 1788 (832-3311) against the homologous Kikwit antigen. Similar patterns were observed following rVSV booster vaccination and Ad26.ZEBOV/MVA-BN-Filo vaccination. The heterologous Ad26/MVA regimen demonstrated increasing BDBV responses between D28 and M3. Conclusions: Licensed EBOV vaccines induced detectable but quantitatively reduced cross-reactive antibody responses against BDBV. Although no direct assessment of vaccine efficacy against BDBV disease was possible, these findings support the plausibility of partial heterologous immunity following EBOV vaccination. In the absence of approved BDBV-specific vaccines, these data support the urgent evaluation of currently available Ebola vaccines during BDBV outbreaks and reinforce the importance of developing broadly protective pan-filovirus vaccines.

Background Coeliac disease (CD) diagnosis on duodenal biopsies is limited by interobserver variability. We have previously demonstrated pathologist-level performance with our artificial intelligence (AI) model for the histopathological diagnosis of adult CD, but not in paediatric practice. As paediatric CD screening programmes expand internationally, accurate and scalable diagnostic tools are needed. We investigated whether an AI model trained exclusively on adult whole-slide images (WSIs) can generalise to paediatric CD diagnosis across independent centres. Methods A training and validation dataset of 9,958 WSIs from 8,421 adult patients (961 CD) from five centres was used to develop an ensemble of multiple-instance learning models using features from a foundation model. Testing was performed on 708 consecutive paediatric patients (86 CD) from two centres (Edinburgh and Southampton) not included in training. Model calibration was assessed, and probability outputs were grouped into clinically interpretable categories. Findings In adult cross-validation, the AI model achieved an area under the receiver operating characteristic curve (AUC) of 98.7%, sensitivity of 84.9%, specificity of 99.0%, and negative predictive value (NPV) of 98.1%. On testing (paediatric) datasets, performance remained high (AUC 98.8%, sensitivity 80.2%, specificity 98.4%, NPV 97.3%). Restricting analysis to predictions outside the intermediate-probability range (predicted CD probability <10% or [&ge;]65%; 85.3% of cases) improved sensitivity to 100% and specificity to 98.7%. No misclassifications were observed among high-confidence predictions (<2% or [&ge;]85%; 66.0% of cases). The expected calibration error was 0.03. Performance improved significantly when biopsies from both duodenal sites (bulb [D1] and descending [D2/3]) were considered. Interpretation Our AI model, trained on adult biopsies, generalises to paediatric CD diagnosis across centres and scanner platforms. Well-calibrated probability outputs provide clinically interpretable measures of diagnostic confidence and could support safe identification of CD-negative biopsies within defined thresholds. These findings demonstrate the feasibility of applying adult-derived AI models in paediatric populations and reinforce the importance of multi-site (D1 & D2) biopsy sampling.

Background Large-for-gestational-age (LGA) and macrosomic newborns are at increased risk of adverse perinatal outcomes, including death, yet the burden of neonatal mortality associated with these conditions in low- and middle-income countries (LMICs), where ongoing nutritional and epidemiological transitions suggest their prevalence will rise, remains poorly quantified. In this study, we quantify the neonatal mortality risk associated with LGA and macrosomia from 16 subnational birth cohorts in low- and middle-income countries between 2000 and 2017. Methods and findings This is an individual-participant meta-analysis to estimate neonatal mortality rates (NMRs) and relative risks among LGA infants (>90th and >97th percentile birth weight-for-gestational-age using INTERGROWTH-21st) versus appropriate-for-gestational-age (AGA, 10th-90th percentile) infants. Macrosomic ([&ge;]4000 g and [&ge;]4500 g) neonates were compared with those weighing 2500 g-3999g. Missing birth weights were imputed using recalibration and multiple imputation methods. We used random effects meta-analysis to pool relative risks. Median prevalences of LGA >90th and >97th percentile were 5.3% (interquartile range 3.6-8.2) and 2.6% (IQR 1.3-4.5), respectively; macrosomia ([&ge;]4000 g and [&ge;]4500 g) prevalences were 1.0% (IQR 0.3-3.1) and 0.06% (IQR 0.0, 0.30), respectively. Mortality was highest among preterm plus LGA infants (61.3 per 1000). LGA infants in the >90th percentile had over twofold increased mortality compared with appropriate-for-gestational-age infants (RR: 2.46; 95% CI: 1.86-3.25), while >97th percentile infants had a higher risk (RR: 3.77; 95% CI: 2.50-5.69). Term LGA >97th percentile infants also showed elevated mortality (RR: 3.14; 95% CI: 1.58-6.22). For LGA >97th percentile, the risk was higher in the early neonatal period (RR: 2.71; 95% CI: 1.92-3.82) than late (RR: 1.69; 95% CI: 1.22-2.34). There was no overall association between macrosomia ([&ge;]4000 g) and neonatal mortality. Population attributable fractions were 7.2% for LGA >90th percentile and 0.4% for macrosomia ([&ge;]4000 g). Conclusions Neonatal mortality risks were elevated among LGA infants in low- and middle-income countries, particularly at extreme values (>97th percentile) and during the early neonatal period. Macrosomia showed weaker, less robust associations. Although LGA prevalence is currently low ([~]5%) and contributes less to neonatal mortality than small newborns, ongoing nutritional and epidemiological transitions suggest increasing prevalence. This highlights the need for strengthened surveillance, monitoring, and improved delivery planning to ensure that no population is left behind.

BACKGROUNDPatients with inflammatory bowel disease (IBD) are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. IBD is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction. METHODSA chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA-seq, co-immunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing. RESULTSChronic DSS colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide (LPS) translocation, bone marrow chimera experiments demonstrated that hematopoietic TLR4 signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified guanylate-binding protein 2b (GBP2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of LPS-TLR4 signaling. Upon LPS stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 and FIS1 to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling, and cardiac dysfunction. CONCLUSIONSThese findings establish the LPS-TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with IBD. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIPatients with inflammatory bowel disease have an increased risk of cardiovascular dysfunction that cannot be fully explained by traditional cardiovascular risk factors. C_LIO_LIGut microbiota dysbiosis and chronic innate immune activation are hallmarks of inflammatory bowel disease, but their direct contribution to cardiac remodeling remains unclear. C_LI What New Information Does This Article Contribute?O_LIChronic colitis-associated gut microbiota dysbiosis induces systemic immune cell metabolic and mitochondrial reprogramming that is sufficient to drive cardiomyocyte hypertrophy and cardiac dysfunction. C_LIO_LIHematopoietic Toll-like receptor 4 signaling links colitis associated gut microbiota to immune metabolic dysfunction and cardiac impairment, establishing a causal gut-immune-heart axis. C_LIO_LIGuanylate-binding protein 2b (GBP2b/GBP1) is identified as a critical downstream effector that promotes mitochondrial fission, oxidative stress, immune cell cardiac infiltration, and exosome-mediated cardiac remodeling. C_LI

Background: Vaccination coverage estimates and case-based surveillance have limitations in evaluating immunization programs. Serosurveillance offers a complementary approach by directly measuring population immunity. We assessed whether serologic analyses across multiple antigens (i.e., measles, diphtheria, tetanus) could provide additional insights into vaccination program performance. Methods: We conducted a matched case-control study among children aged 2- to 10-years-old (n=1286) in Zambia using specimens from the 2016 ZAMPHIA survey. Using previously generated data on measles serostatus, measles seronegative children (i.e., cases) were matched to measles seropositive children (i.e., controls) on sex, age, HIV infection status, and province. Samples were tested for tetanus and diphtheria antitoxin IgG antibodies using commercial enzyme immunoassays. We estimated the odds of tetanus and diphtheria seropositivity by measles serostatus using conditional logistic regression and examined age-specific antibody dynamics. Results: Measles seronegative children had 1.7-fold increased odds (95% credible interval [CrI]: 1.3-2.1) of being tetanus seronegative compared to measles seropositive children. Diphtheria serostatus had no significant association with measles serostatus (odds ratio: 1.3; 95% CrI: 0.9-1.7). Tetanus seroprevalence declined monotonically with age. However, diphtheria seroprevalence initially declined through 5 years of age, then increased again beginning at 6 years of age despite the lack of vaccine booster doses given after the primary series in infancy, potentially from asymptomatic or subclinical infections. Conclusions: Serologic analyses revealed measles serostatus was positively associated with tetanus serostatus (where seropositivity arises only via vaccination and not infection), suggesting children who are measles seronegative are more likely to have missed DTP vaccination. We additionally found that measles serostatus was not associated with diphtheria serostatus, suggesting that antibody responses to diphtheria continue to boost beyond infancy when DTP vaccination is given. Our findings support consideration of DTP booster doses in Zambia to address waning tetanus immunity and further investigation of potential diphtheria carriage and transmission.