The Lancet

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.

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.

Background. Vietnam's disease burden has shifted from communicable, maternal, neonatal, and nutritional (CMNN) causes to non-communicable diseases (NCDs), but the tempo, drivers, and regional positioning of this transition have not been jointly quantified. We characterised Vietnam's epidemiological transition 1990-2023 against ten Southeast-Asian (SEA) peers. Methods. Using Global Burden of Disease 2023 data, we computed joinpoint-regression AAPC with 95% CI (BIC-penalised, up to three break-points) for age-standardised DALY rates and cause-composition shares. We applied Das Gupta three-factor decomposition to 1990-2023 absolute DALY change (population-size, age-structure, age-specific-rate effects) and benchmarked Vietnam's NCD share against an SDI-conditional peer trajectory via leave-one-out quadratic regression. Premature mortality was quantified as WHO 30q70 under both broad NCD and strict SDG 3.4.1 definitions, using Chiang II life-table adjustment identically across all eleven countries. Findings. The CMNN age-standardised DALY rate fell from 13,295.9 to 4,022.1 per 100,000 (AAPC -4.63%/year; 95% CI -4.80 to -4.46); the NCD rate fell only from 21,688.2 to 19,282.8 (AAPC -0.37; -0.45 to -0.30). NCD share of total DALYs rose from 52.99% to 70.67% (+17.67 pp; AAPC +1.09). Vietnam ranked fourth of eleven SEA countries in 2023 (up from sixth in 1990) and sat 5.3% above the SDI-expected trajectory. Das Gupta decomposition attributed the +10.63 million NCD DALY increase to population growth (+6.26 M) and ageing (+6.08 M); rate change removed only 1.71 M. Premature NCD mortality fell from 25.02% to 21.80% (broad, 12.9% reduction) and from 22.17% to 19.50% (SDG 3.4.1, 12.0%; Vietnam sixth of eleven) - far short of the SDG 3.4 one-third-reduction target. Interpretation. Vietnam has entered a disability- and ageing-dominated NCD phase. Meeting SDG 3.4 by 2030 requires population-scale primary prevention sized to demographic momentum.

BackgroundTuberculosis (TB) and human immunodeficiency virus (HIV) are leading causes of infectious disease deaths, with disproportionate impact in low- and middle-income countries (LMICs). Despite well-established biological relationships between these diseases, there is limited information on how TB prevalence differs between people living with and without HIV. MethodsWe conducted a systematic review and meta-analysis of TB prevalence surveys conducted in LMICs and published during January 1st 1993-October 13th 2025 (PROSPERO CRD42024503853). We extracted bacteriologically-confirmed TB prevalence estimates stratified by participant HIV status. Surveys that offered HIV testing to all, sputum-collection-eligible, or TB-positive participants were included in the primary analysis. We applied Bayesian meta-regression to estimate pooled risk ratios (RR) of bacteriologically-confirmed TB prevalence among participants living with versus without HIV. Additionally, we estimated country-level and overall TB notification-to-prevalence (N:P) ratios by HIV status. FindingsOf 10,211 potentially relevant publications, 12 TB prevalence surveys--representing 264,530 participants within nine countries in Southern and Eastern Africa--were used in the primary analysis. Reported TB prevalence was higher among participants living with versus without HIV in 11/12 surveys, with an overall pooled RR of 3{middle dot}86 (95% credible interval: 2{middle dot}41-5{middle dot}53). N:P ratios were higher among participants living with HIV in all examined countries. The overall pooled N:P ratios were 1{middle dot}74 (0{middle dot}59-4{middle dot}56) and 0{middle dot}48 (0{middle dot}17-1{middle dot}20) among participants living with versus without HIV, respectively. InterpretationIn Southern and Eastern Africa, bacteriologically-confirmed TB prevalence is three- to six-times higher among people living with HIV. Comparison of prevalence and notification data suggest higher rates of TB diagnosis for people living with versus without HIV, but also indicates substantial delays in the detection of untreated TB cases for both populations. FundingWellcome Trust, UK National Institute for Health and Care Research, UK Foreign, Commonwealth and Development Office, NIH. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is limited systematic evidence on how the prevalence of TB disease differs between people living with HIV and without HIV. Multiple observational cohorts have described substantially elevated TB incidence among populations with HIV, but disease prevalence will also be affected by differences in mortality and treatment uptake rates. We searched PubMed from inception through January 21, 2026 using the search string ((HIV AND TB) OR HIV/TB) AND (prevalence AND (systematic review OR meta-analysis)) without any restrictions on language. We also reviewed investigators personal libraries. This search yielded 506 publications; however few of these included prevalence data. An analysis conducted in 2020 synthesized HIV status-stratified data from seven national TB prevalence surveys in Africa and found that HIV prevalence was lower among prevalent TB cases than among notified cases. This study did not include subnational surveys and did not distinguish between survey participants with self-reported or test-confirmed HIV status. Added value of this studyThis study synthesized TB prevalence data, stratified by participant HIV status, from national and subnational surveys conducted in LMICs and published between January 1st 1993 and October 13th, 2025. Collated data represented 681,402 survey participants across ten countries. All but one study were conducted in Southern and Eastern Africa. We limited our primary analysis to surveys that systematically tested participants for HIV and bacteriologically-confirmed TB. The prevalence of bacteriologically-confirmed TB was estimated to be three to six times higher than among people living with versus without HIV. Ratios of TB notifications to TB prevalence were higher for people living with HIV compared to people without HIV, suggesting higher rates of TB case detection (and likely shorter duration of disease) for people living with HIV and untreated TB than those without HIV. Implications of all available evidenceFew estimates of community-representative TB prevalence stratified by participant HIV status exist. These surveys have been concentrated in Southern and Eastern Africa, despite TB-HIV burden being distributed globally. Our findings highlight the elevated burden of TB among people living with HIV in these settings, as well as the limited data on the intersection of TB and HIV epidemiology in other world regions. Furthermore, our comparison of notification and prevalence data demonstrate substantial shortfalls in TB case detection, regardless of an individuals HIV status.

Background: Although the hemagglutination inhibition (HAI) titer remains the gold standard correlate of protection against influenza, it does not fully capture the broader antibody responses that contribute to immunity. Methods: We analyzed immune responses in paired pre-infection and convalescent sera from 306 RT-PCR-confirmed A/H3N2 infections from two household studies (2014-18) in Managua, Nicaragua. Antibody responses were measured by HAI and enzyme-linked immunosorbent assays (ELISAs) against full-length hemagglutinin (HA), the HA stalk, and neuraminidase (NA). Participants were classified as HAI responders ([&ge;]4-fold HAI rise), alternate responders (no HAI rise but [&ge;]4-fold boost in [&ge;]1 ELISA), or no-response individuals (no [&ge;]4-fold rise in any assay). We compared demographic, clinical, and pre-infection antibody characteristics across these groups. We also analyzed predictors of an NA response. Results: Overall, 77% of participants had HAI seroconversion or a 4-fold rise. Among the 23% HAI non-responders, 62% had alternate antibody responses. No-response individuals had the highest pre-infection HAI and full-length HA titers (p < 0.0001), the lowest viral loads, and the fewest fever or influenza like illness (ILI) symptoms (p < 0.01). An NA response was more common among symptomatic individuals (p = 0.0483) and those with low or high baseline NA titers. Conclusions: High baseline HAI titers can limit detectable 4-fold rises and are associated with milder illness. Evaluating additional immune responses may capture a more complete picture of the host response to infection, thereby improving surveillance and informing vaccine development. Keywords: Influenza A/H3N2; Hemagglutination inhibition (HAI); Neuraminidase antibodies; symptomatic vs asymptomatic infection; correlates of protection.

Background. Targeted Universal Tuberculosis Testing (TUTT) may increase tuberculosis (TB) case detection by including people who are not actively seeking TB care but are at high risk of the disease. Non-invasive tongue swab (TS) testing may facilitate TUTT. We evaluated two TS testing protocols in people with HIV (PWH) tested irrespective of TB symptoms. Methods. Study staff collected Copan FLOQSwab and Medline foam swab specimens, alongside urine and sputa, from PWH, most of whom were presenting for antiretroviral therapy initiation at primary healthcare clinics in KwaZulu-Natal, South Africa. FLOQSwabs were tested by sequence-specific magnetic capture (SSMaC) with qPCR (FLOQSwab-SSMaC). Foam swabs were tested by centrifuge-sedimentation and high-volume qPCR (foam-sedimentation). Urine lipoarabinomannan was detected using LF-LAM. The extended microbiological reference standard (eMRS) comprised any positive result on Xpert Ultra and/or liquid culture of sputum. Results. We enrolled 251 participants (median age 34 years, 56% female, 67% with self-reported TB symptoms). Participants had a median CD4 count of 347 cells/ul, and 16% (40/251) had prior TB. FLOQSwab-SSMaC was 43% sensitive (13/30) and 100% specific (131/131) relative to eMRS. Foam-sedimentation was 47% (9/29) sensitive and 100% (176/176) specific. Sensitivity increased to 52% (FLOQSwab-SSMaC) and 50% (foam-sedimentation) when sputum Xpert Ultra Trace positive results were excluded from eMRS. TS was more sensitive than urine LAM, and both sample types were more sensitive when CD4 counts were below 200. Discussion. TS testing detected about half of PWH with TB and outperformed urine LAM within this population, including among PWH with low CD4 counts.

IntroductionThere is increasing interest in the peripheral administration of vasopressors for two main reasons: (1) to expedite vasopressor initiation in patients with refractory shock and (2) to avoid the potential complications associated with central venous catheter placement. The current evidence on the use of peripheral vasopressor administration is primarily based on single-center observational studies. There are inconsistencies in the administration of peripheral vasopressors, including catheter gauge and location, monitoring practices, vasopressor concentrations, and duration of use. This has made it difficult for institutions to develop best practice guidelines. A randomized controlled trial is needed to address this knowledge gap. Methods and analysisThe Peripheral Use of Low-dose Vasopressors for Safety and Efficacy (PULSE) in the intensive care unit is a prospective, unblinded feasibility study. Eligible patients will be 18 years or older, have no existing central venous catheter or peripherally inserted central catheter and have the presence of shock requiring a minimum vasopressor dose of any of the following: norepinephrine 0.0625 mcg/kg/min, phenylephrine 0.625 mcg/kg/min, and epinephrine 0.0625 mcg/kg/min. Fifty patients will be randomized 1:1 into either the peripheral venous catheter or central venous catheter group. The primary outcome is feasibility, defined as (1) a recruitment rate of 4 participants per month, (2) a data capture rate of [&ge;]90%, and (3) a <50% conversion rate from peripheral to central access. The secondary outcomes include the safety of peripheral vasopressor use, alive and central-line-free days, the number of attempts needed to place a catheter, volume status, in-hospital mortality rate, ICU and hospital length of stay, and patient-centred important outcomes. ImplicationsThe data collected from this study will inform the design of a definitive randomized controlled trial to assess the safety and efficacy of protocol-driven peripheral vasopressor administration. Ethics and disseminationThis study received approval (6042888) from the Queens University Health Sciences/Affiliated Teaching Hospitals Research Ethics Boards. Results of this study will be presented at critical care conferences and submitted for publication. Trial registration numberNCT06920173 (https://clinicaltrials.gov/study/NCT06920173).

Globally, respiratory tract infections (RTI) are the main cause of morbidity, and in Low-middle-income countries (LMICs) RTI including pneumonia are a leading cause of morbidity and mortality in children <5 years. Diarrheal illness increases RTI risk in young children through micronutrient depletion, and immune stress, yet data on post-diarrhea RTI burden in LMICs are limited. We determined the prevalence and risk factors of RTI within three months following medically-attended diarrhea (MAD) in children aged 6-35 months enrolled in seven EFGH country sites in Asia, Africa and South America. The EFGH study prospectively enrolled children aged 6-35 months with MAD in selected health facilities during a 24-month period from 2022 to 2024 and followed them for three months. RTI was defined as cough or difficulty breathing and the presence of one of the following symptoms at any scheduled or unscheduled visit during follow-up: stridor; fast-breathing; oxygen saturation <90%; or chest indrawing. The period prevalence and 95% confidence intervals of RTI were calculated, and correlates of RTI were assessed using modified-Poisson regression. From June 2022 to August 2024, 9,476 children aged 6-35 months presenting with MAD in the EFGH study sites were screened: 9,116 (96.2%) included in the current study. Nearly half were female (46.7%), and median age was 15 months. Overall, 48.5% received all age-appropriate vaccines, and 87.6% received the pneumococcal vaccine, with significant variation across countries. Nearly one-quarter of children were stunted, 17.2% wasted, and 21.9% underweight. RTI occurred in 3.8% of children during the three-month follow-up, mostly within the first month. Higher prevalence of RTI occurred among children aged 12-23 months (8.7%), those undernourished (16.1%), unvaccinated (4.0%) or living in poor sanitation settings (4.1%). While children who received all age-appropriate or pneumococcal vaccinations had a lower crude prevalence of RTI, these associations were not statistically significant after adjusting for age, sex and study site. RTI was infrequently observed in the three months following MAD presentation, with significant variability by site and with the highest prevalence in Malawi. RTI risk was highest in 12-23-month-olds and among children with undernutrition, and those living in poor sanitation conditions.

To minimise health disparities, equitable access to medical treatment is paramount. In a pioneering intervention, National Health Service Englands Hepatitis C virus (HCV) programme has implemented country-wide peer support to boost treatment access. Peer support workers (peers) are individuals with relevant lived experience, who promote testing and treatment in marginalised populations underserved by traditional health services. We evaluated the English peers intervention, exploiting its staggered rollout and rich surveillance data between June 2016 and May 2021. Peers increased HCV cases identified by 13{middle dot}9% (95% credible interval (95% CrI) [5{middle dot}3, 21{middle dot}7]), sustained viral responses by 8{middle dot}0% (95% CrI [-4{middle dot}4, 18{middle dot}6]), and drug services referrals by 8{middle dot}8% (95% CrI [-12{middle dot}5, 22{middle dot}6]). The interventions effectiveness was magnified during the first COVID-19 lockdown and individuals supported by peers typically belonged to populations with poor treatment access. Our findings indicate that peers can boost equity in treatment access on a national scale.

BackgroundThe Toto Bora trial tested whether a course of azithromycin reduced rates of re-hospitalization or death in the 6 months following hospitalization among Kenyan children. We hypothesized that azithromycin would reduce enteric bacteria and increase carriage of macrolide resistance in the subsequent 3 months. MethodsKenyan children (1-59 months) hospitalized and subsequently discharged for non-traumatic conditions provided fecal samples before and 3 months after randomization to a 5-day course of azithromycin or placebo. Quantitative PCR identified enteropathogens and AMR-conferring genes in fecal samples. Generalized estimating equations assessed the impact of the randomization arm on pathogen and resistance gene detection, accounting for baseline presence and site. ResultsAmong 1,393 baseline stools, 12.4% had at least one bacterial enteropathogen, 94.7% had at least one macrolide-resistance gene, and 92.6% had at least one beta-lactamase-resistance gene identified. At month 3, children randomized to azithromycin had a 6.1% higher likelihood of carrying a macrolide resistance gene compared to placebo (adjusted prevalence ratio [aPR], 1.06; 95% CI, 1.04-1.08; P<0.001). Specifically, azithromycin randomization was associated with a higher relative prevalence of erm(B) (aPR, 1.09 [95% CI, 1.04-1.15]; P=0.001), erm(C) (aPR, 1.23 [95% CI, 1.14-1.31]; P<0.001), msr(A) (aPR, 1.14 [95% CI, 1.04-1.25]; P=0.007), and msr(D) (aPR, 1.07 [95% CI, 1.03-1.11]; P=0.001). There was no difference in overall bacterial pathogen prevalence (18.9% vs 17.3%) between randomization arms, but a slightly lower proportion of children had Shigella after randomization in the azithromycin arm (3% vs. 5%, aPR, 0.79 [95% CI, 0.62, 1.01]; P=0.063). InterpretationAzithromycin at hospital discharge was associated with higher carriage of macrolide-resistance-conferring genes in the post-discharge period compared with placebo, without significant declines in enteric pathogen carriage other than modest changes to Shigella. The potential benefits and risks of empiric azithromycin need to be considered, as children are increasingly exposed to this broad-spectrum antibiotic.

Increased literature support the pathogenetic role of dysfunctional energetic metabolism in the setup and progression of organ damage and failure. Genetic diseases often offer the possibility to investigate pathogenetic mechanisms. In particular, excessive cardiac damage is the most frequent cause of mortality in Fabry disease (FD), a genetic condition caused by deficient -galactosidase A (GLA) activity, leading to globotriaosylceramide (Gb3) accumulation. Beyond Gb3 storage, metabolic alterations and mitochondrial dysfunction, supported by in vitro evidence or studies in other tissues, may contribute to FD cardiomyopathy. This study investigated, for the first time, the mechanisms of mitochondrial involvement in FD, its role in determining cardiac manifestations, and its potential as a therapeutic target. We used a humanized FD mouse model (R301Q-Tg/GLA knockout), along with derived embryonic fibroblasts and neonatal and adult cardiomyocytes, to assess mitochondrial function across the lifespan. FD cells showed impaired mitophagy, reduced mitochondrial respiration, and increased reactive oxygen species production. Importantly, this mitochondrial dysfunction exacerbated the lysosomal deficit in FD cells, forming a vicious cycle. In cardiomyocytes, these alterations progressed with age, leading to the accumulation of dysfunctional mitochondria, energetic failure, and, in adult hearts, terminal mitochondrial damage and apoptosis. These events ultimately result in cardiac remodeling and dysfunction, including hypertrophy and diastolic impairment. Indeed, L-arginine supplementation, which promotes NO/PGC-1-dependent mitochondrial rescue, prevented the development of cardiac abnormalities in FD mice. Our findings identify early mitochondrial dysfunction as a key driver of FD cardiomyopathy and support mitochondrial targeting, including L-arginine supplementation, as a promising adjuvant therapeutic strategy. The mechanistic link between lysosomal dysfunction, altered mitochondrial turnover, and energetic collapse emerges as a key targetable pathway in organ damage, extending beyond FD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/718770v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@2a5c4borg.highwire.dtl.DTLVardef@1117767org.highwire.dtl.DTLVardef@1b634c5org.highwire.dtl.DTLVardef@1429b6c_HPS_FORMAT_FIGEXP M_FIG C_FIG Cardiac manifestations vs mitochondrial alterations in Fabry disease: the visible tip and the hidden base of the icebergCardiac manifestations in hR301Q Tg/KO mice become evident from 9 months of age. However, mitochondrial homeostasis is perturbed much earlier (neonatal to young stages), with impaired mitophagy, reduced mitochondrial respiration and membrane potential, increased ROS production and PGC-1 downregulation. At later stages, from 6 months of age, mitochondrial dysfunction progresses and begins to impact cellular energetics, as indicated by reduced ETC expression and the onset of energetic deficit (ATP reduction). The resulting energetic collapse, together with progressive mitochondrial leakage, leads to cardiomyocyte hypertrophy, apoptosis, and dysfunction, which become detectable from 9 months of age, when clinical signs emerge. These findings support a mechanistic model in which 1) lysosomal incompetence due to GLA deficit is the initiating event inducing impairment of mitophagy; 2) Unsuccessful mitophagy, induces downregulation of PGC-1a-dependent mitogenesis; 3) exhausted mitochondria accumulate, inducing energetic collapse (able to exacerbate lysosomal dysfunction and further perturb mitophagy in a vitious cycle); 4) ultimate mitochondrial leakage induces Cytochrome C release and apoptosis activation. This cascade of molecular events is responsible for clinical manifestations, and mitochondrial targeting prevents cardiac organ damage. Significance statementFabry disease is a rare genetic disorder in which cardiac complications are a major cause of death, yet underlying mechanisms remain unclear. Here, we identify mitochondrial dysfunction as an early pathogenic event associated with impaired mitophagy, whereby defective mitochondrial quality control both results from and exacerbates lysosomal dysfunction, creating a self-reinforcing cycle that drives disease progression. Using a humanized model, we demonstrate that mitochondrial dysfunction is a key determinant of cardiac phenotype in vivo, driving energetic failure, oxidative stress, and cardiac damage. Importantly, L-arginine treatment restores mitochondrial function and prevents cardiac abnormalities. Our findings define a broadly relevant pathogenic axis linking lysosomal dysfunction, mitophagy failure, and mitochondrial impairment, that lead to impaired energetic metabolism and consequent cardiac hypertrophy, independently from GB3 accumulation. The implications of our study go beyond Fabry disease and support the therapeutic targeting of cellular energy homeostasis to prevent and treat organ damage and failure in chronic diseases. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org

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

Abstract Importance Stigma and discrimination against transgender and gender-diverse people are prevalent across many settings and may contribute to substantial health disparities. Objective To synthesize global evidence on the prevalence of stigma, discrimination, and resilience among transgender (trans) and gender-diverse adults. Data Sources A systematic search was conducted in PubMed, Embase, CINAHL, Cochrane Central, LILACS, and PsycInfo for articles published between January 1, 2010 and January 2, 2023. This database search was supplemented by grey literature and secondary reference searches. Article Selection Studies were eligible if they presented primary quantitative data on prevalence of stigma, discrimination, and/or resilience among trans and gender-diverse adults (aged 18 and over), with no restrictions on study design, language, or geographic region. Data Extraction and Synthesis Two independent reviewers extracted data using standardized forms, with discrepancies resolved by consensus. The JBI Critical Appraisal Checklist for Prevalence Articles was used to assess risk of bias. Random effects meta-analysis was conducted for dichotomous prevalence measures using inverse variance weighting and logit transformation; non-dichotomous prevalence data were summarized descriptively. Main Outcomes and Measures Outcomes included prevalence estimates for various forms of stigma (anticipated, perceived, internalized, and experienced), discrimination in legal/institutional settings (housing, healthcare, employment, police/prison), and resilience. Results A total of 97 articles, with data from 72,158 unique trans and gender-diverse participants across 26 countries, met inclusion criteria. Studies showed moderate levels of anticipated stigma, perceived stigma, and internalized stigma. Meta-analyses of 36 studies provided pooled estimates of discrimination prevalence across multiple domains: 21.4% in housing (e.g., eviction, rental denial), 24.6% in healthcare (e.g., denial of care, mistreatment), 32.8% in employment (e.g., hiring bias, workplace harassment), and 39.1% in police/prison settings (e.g., profiling, mistreatment). High heterogeneity was observed across studies, reflecting regional and methodological differences. Resilience scores ranged from moderate to high, indicating variation within trans and gender-diverse communities. Conclusions and Relevance This systematic review and meta-analysis found that stigma and discrimination against trans and gender-diverse adults are pervasive globally. Variation in stigma and discrimination across settings and regions underscores the need for targeted interventions and policy reforms. Funding World Health Organization through a grant from the Elton John AIDS Foundation and the Bill and Melinda Gates Foundation.

Background Individuals experiencing or at risk of homelessness face substantial barriers to preventive eye care that are poorly addressed by standard service models. Interdisciplinary optometry-social work collaboration offers a rights-based approach to improving engagement and continuity of care. Methods A convergent mixed-methods study was conducted between February and August 2024 at a multidisciplinary community centre. Clients experiencing or at risk of homelessness received integrated optometry and social work assessment and were prioritised as high, medium, or low based on combined clinical and social risk. Social work follow-up was guided by the Triple Mandate and W-Questions framework. Quantitative data were summarised using mean (SD), median [IQR], or n (%). Qualitative case notes were analysed using content analysis with inductive coding and secondary review for consistency. Results A total of 165 clients had priority categories coded (high: 68; medium: 47; low: 154). Demographic data were available for 132 clients (60% male; mean age 49.5 years [SD 16]); 27% had not completed high school, 89% reported weekly income below AUD 1000, and 28% had vision impairment. Two hundred forty-five case-note entries were consolidated into 146 unique records. SMS (46%) and phone calls (38%) were the most documented contact methods, although only 21% of calls were answered; missed calls (13%) and disconnected numbers (7%) were common. Multi-modal contact was more frequently documented for higher-priority clients. Appointment assistance was the most recorded facilitator (71%), while rights-based supports, including interpreter and transport assistance, were infrequently documented (<=5%). Qualitative analysis identified unstable communication, reliance on informal supports, and service fragmentation as key influences on recall outcomes. Conclusion This study supports an interdisciplinary, rights-based optometry-social work model to address barriers to preventive eye care among people experiencing or at risk of homelessness. Embedding structured handovers and tiered recall processes within community-based services may strengthen continuity and accountability for high-priority clients. Future implementation should evaluate outcomes related to equity of reach, service integration, and sustained engagement in care.

Introduction: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) has become less effective at preventing malaria due to rising parasite resistance. IPTp with dihydroartemisinin-piperaquine (DP) alone or in combination with SP (DP+SP) dramatically lowers the risk of malaria in pregnancy compared to SP but is associated with lower birthweight and early life wasting. We estimated the effect of IPTp-DP, DP+SP, and SP on infant growth outcomes and assessed possible treatment mechanisms through a causal mediation analysis. Methods: We used infant follow-up data (N=761) from a trial (NCT04336189) that randomized pregnant women to receive monthly IPTp-DP, SP, or DP+SP. We compared weight-for-length (WLZ) and length-for-age (LAZ) z-scores between treatment arms. We assessed possible mediation through pregnancy, birth, and infancy factors using interventional indirect effect models. Results: Compared to IPTp-SP, IPTp-DP+SP decreased mean WLZ by 0.18 [95% confidence interval (CI) -0.03, 0.39] between 1-3 months and 0.28 (95% CI 0.07, 0.49) between 4-6 months, with the largest differences among primigravidae. Lower risk of active placental malaria in IPTp-DP+SP helped reduce differences in mean WLZ vs IPTp-SP (+0.06, 95% CI 0.02, 0.10). The IPTp-DP+SP arm had up to 0.28 lower mean LAZ between 7-13 months compared to IPTp-DP, particularly among children who were wasted between 0-6 months; low birthweight had a persistent, mediating effect on linear growth. Conclusion: Adverse birth outcomes contributed to early growth faltering among children born to mothers receiving IPTp-DP+SP vs IPTp-SP, but the prevention of placental malaria partially counteracted the negative effects of IPTp-DP+SP on ponderal growth.

Objectives: In Latin America, up-to-date information to monitor UNAIDS 95-95-95 HIV targets in key populations, such as men who have sex with men, is limited. Elsewhere, structural homophobia restricts access to ART. Conceptual frameworks suggest that intersecting forms of violence and discrimination may negatively influence HIV care outcomes through psychosocial and structural pathways, although empirical evidence remains limited. The study aimed to assess whether sexual orientation outness and recent homophobic violence are associated with not being on ART among Latin American MSM living with HIV. Methods: This cross-sectional study is a secondary analysis of data from LAMIS-2018, including 7,609 MSM aged 18+ with an HIV diagnosis [&ge;]1 year prior from 18 Latin American countries. Participants self-reported ART status, sociodemographic characteristics, homophobic violence, and sexual orientation outness. Bivariate and multivariate logistic regressions identified those factors associated with not being on ART. Results: Nine percent of MSM with HIV were not on ART, 18% reported low sexual orientation outness, and 27% experienced homophobic violence, especially in Andean and Central American countries. Not being on ART was associated with recent homophobic violence (aPR=1.25), low outness (aPR=1.22), unemployment (aPR=1.27), and residence in the Andean subregion (aPR=1.87), Mexico (aPR=1.28), or the Southern Cone (aPR=1.45) versus Brazil. Protective factors included being older (25-39: aPR=0.72; >39: aPR=0.49), living in large cities (aPR=0.72), having a stable partner (aPR=0.78), and university education (aPR=0.74). Conclusions: Recent homophobic violence and low sexual orientation outness were associated with not being on ART among MSM in Latin America. While access varies across countries, structural factors such as stigma and violence may limit engagement in care. Addressing these barriers alongside strengthening health systems may be key to improving ART uptake and advancing progress toward the 95-95-95 targets.

ObjectiveStudies of nutritional status and host responses during severe and critical illness have focused predominantly on obesity; in contrast, the relationship between undernutrition, host responses, and clinical outcomes in adults hospitalized with severe infection remains poorly defined. We sought to determine whether severe undernutrition is associated with distinct host responses and clinical outcomes in adults hospitalized with severe infection. DesignProspective cohort study. SettingTwo public referral hospitals in Uganda. PatientsNon-pregnant adults ([&ge;]18 yr) hospitalized with severe, undifferentiated infection. InterventionsNone. Measurements and Main ResultsWe analyzed clinical data and serum Olink proteomic data from 432 participants (median age, 45 yr [IQR, 31-57 yr]; 44% male). Overall, 213 participants (49%) met prespecified criteria for undernutrition, including 52 (12%) with severe undernutrition. Clinically, severe undernutrition was associated with HIV coinfection, microbiologically diagnosed tuberculosis, greater physiological instability, and higher mortality. After adjustment for age, sex, illness duration, study site, and HIV, malaria, and tuberculosis coinfection, severe undernutrition was associated with higher expression of proteins involved in pro-inflammatory immune signaling, endothelial and vascular remodeling, hypoxia and oxidative stress responses, and extracellular matrix remodeling, together with lower expression of proteins linked to growth signaling, anticoagulant regulation, and lipid homeostasis. ConclusionsSevere undernutrition is associated with a distinct high-risk clinical phenotype and biologic signature in adults hospitalized with severe infection. These findings suggest that undernutrition may potentiate key domains of sepsis pathobiology, with implications for strengthening nutritional support and informing host-directed treatment strategies in low- and middle-income countries where malnutrition is common. Key PointsO_ST_ABSQuestionC_ST_ABSHow does undernutrition influence immune, metabolic, and endothelial responses to severe infection in adults? FindingsIn this multicenter cohort study of 432 adults hospitalized with severe infection in Uganda, severe undernutrition was associated with greater physiologic instability, higher mortality, and a distinct proteomic host-response profile. Adults with severe undernutrition exhibited a proteomic signature characterized by pro-inflammatory immune signaling, endothelial and extracellular matrix remodeling, and hypoxia and oxidative stress responses, together with lower expression of proteins involved in growth signaling, anticoagulant regulation, and lipid homeostasis. MeaningSevere undernutrition is associated with a distinct high-risk clinical and biologic phenotype during severe infection, with implications for nutritional support, risk stratification, and host-directed therapeutic strategies, particularly in low- and middle-income countries.

Typhoid fever remains a significant public health challenge in low- and middle-income countries. In 2018, The World Health Organization recommended a single dose typhoid conjugate vaccine (TCV) for routine immunization in endemic settings; however, evidence guiding booster doses remains limited. Homologous TCV booster doses have demonstrated immune boosting. This study assessed the immunogenicity and safety of a heterologous booster using a Vi capsular polysaccharide-CRM197 TCV (Vi-CRM) administered 5-6 years after primary vaccination with a Vi capsular polysaccharide tetanus toxoid TCV (Vi-TT) in children. Children previously enrolled in a Phase 2 trial were recruited. Participants who had received TCV at 9-11 or 15-23 months were given a Vi-CRM booster at 6-7 years of age (Booster-TCV group), and controls received their first TCV dose at the same age (1st-TCV group). Serum anti-Vi IgG concentrations were measured at baseline and 28 days post-vaccination. Solicited and unsolicited adverse events (AEs) and serious adverse events (SAEs) were recorded. Among 147 children enrolled, 87 received a second and 60 received a first TCV dose. Baseline anti-Vi IgG geometric mean titers (GMT) were higher in the Booster-TCV group (21.5 EU/mL; 95% CI: 17.2-26.8) than in the 1st-TCV group (5.5 EU/mL; 95% CI: 4.5-6.7). At day 28, GMTs rose markedly in both groups: 5140.0 EU/mL (95% CI: 4302.0-6141.3) in the Booster-TCV group and 2084.8 EU/mL (95% CI: 1724.4-2520.5) in the 1st-TCV group. Local reactions and systemic AEs were mild. No SAEs were observed. Vi-TT-induced immunity persisted for at least 5-6 years, and a heterologous booster triggered a strong immune response with universal seroconversion. These findings support heterologous prime-boost strategies to maintain protection in school-age children and inform optimization of TCV schedules in endemic regions.

BackgroundAn upsurge in Streptococcus pyogenes infections 2022-2023 highlighted potential benefits of point-of-care tests (POCT) to support clinical pathways, prevent outbreaks, and optimise antibiotic use. ObjectivesWe conducted a pilot research study in a west London paediatric emergency department (ED) to determine whether a molecular POCT had potential to alter management in children who were also having a conventional throat swab taken for culture. MethodsChildren <16 years presenting to ED who had a throat swab requested by a clinician were invited to have a second swab taken for research purposes only. Clinical management was unaffected by the research swab result, which was processed using a molecular POCT that was not approved for use in the host NHS Trust. ResultsPrevalence of streptococcal infection was low during the study (May 2023-June 2025); swab positivity in symptomatic children was 12.8% (6/47). Overall, 38/49 (77.6%) participants who had throat swabs received antibiotics. Of those children recommended to receive antibiotics, 29/38 (76.3%) had a negative POCT. Mean time to reporting of positive throat swab culture results was 3.67 days (range 3-5 days) leading to occasional delay in treatment, although POCT identified positive results within minutes. ConclusionAntibiotic use was frequent and could be avoided or stopped by use of a rule out POCT in over three-quarters of children in the ED, if suspicion of S. pyogenes is the main driver for prescribing. POCT were easy to process and produced immediate results compared with culture, in theory enabling timely decision-making and avoiding treatment delay.

BackgroundScrub typhus is a major yet neglected vector-borne disease in Thailand, where it has been nationally notifiable for over two decades. However, long-term changes in its epidemiology, including reporting rates, transmission intensity, disease severity, and seasonal patterns, have not been comprehensively characterised at the national level. MethodologyWe analysed 22 years of national surveillance data for scrub typhus in Thailand (2003-2024) using a latent process model that jointly fits reported cases with published nationwide seroprevalence data and antibody kinetics to estimate reporting rates and underlying transmission dynamics across all 77 provinces of Thailand. FindingsOver the 22-year study period, 143096 cases and 119 deaths were reported nationally. Estimated reporting proportion broadly mirrored transmission intensity, being higher in high-burden regions and lower elsewhere. A synchronous decline in detection was observed across all regions during the COVID-19 pandemic, followed by rapid rebound by 2024. After accounting for these reporting dynamics, the force of infection was highest in the northern provinces but also substantial in the northeast and south, with upward trends in some provinces. Susceptibility among older adults aged 65 and above increased progressively over the study period, reversing the pattern observed two decades earlier. Case-fatality in the 25-35-year reference group was low and declined from 0.14% (95% Credible Interval [CrI]: 0.06-0.29%) to 0.06% (95% CrI: 0.02-0.12%), but relative case-fatality remained consistently highest among adults above 65 across all periods. Three geographically distinct seasonal patterns were identified, all stable over time. ConclusionOver two decades, scrub typhus transmission in Thailand has been shown to extend well beyond its traditionally recognised northern focus, with substantial burden in previously underappreciated regions, while the demographic profile of those most affected has shifted progressively toward older adults. These findings support the need for regionally tailored surveillance, age-targeted clinical preparedness, and sustained investment in understanding the ecological drivers of transmission. Key messagesScrub typhus is a common but neglected cause of fever in Thailand, where it has been reported through the national surveillance system for over two decades. However, trends in reported cases can be misleading because they reflect not only true changes in transmission but also variation in diagnosis and reporting over time and across regions. We developed a model that combines surveillance data with seroprevalence surveys and antibody kinetics to separate true changes in transmission from variation in reporting, allowing us to estimate how transmission intensity, disease severity, and seasonal patterns have evolved from 2003 to 2024 across all 77 provinces. We found that substantial transmission occurs not only in the well-studied northern provinces but also in the northeast and south, where the disease has received less attention. Susceptibility has progressively shifted toward older adults, who also face the highest case-fatality, while three distinct seasonal patterns vary by region but have remained stable over time. These findings suggest that scrub typhus control in Thailand requires a shift from a predominantly northern focus toward regionally tailored strategies that account for local transmission timing, an ageing at-risk population, and the ecological drivers that sustain transmission in each setting.