Clinical Infectious Diseases

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: 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.

Numerous factors may influence the optimal rollout of new gonococcal antibiotics. We compared eight rollout strategies using a gonorrhea transmission model and ranked strategies by the number of gonococcal infections and clinically useful antibiotic lifespan. Rankings were most sensitive to the starting ceftriaxone resistance prevalence and screening frequency.

Introduction Improved diagnostics are needed for people at risk of tuberculosis, especially adolescents. Tongue swab (TS) molecular testing has emerged as a promising strategy for tuberculosis diagnosis. We evaluated diagnostic accuracy and acceptability of Xpert MTB/RIF Ultra (Xpert) using TS samples for tuberculosis detection among adolescents. Methods We conducted a cross-sectional diagnostic accuracy study with consecutive recruitment in Vietnam. Adolescents aged 10-19 who were recommended to undergo investigation for tuberculosis and had not received tuberculosis treatment in the past years were eligible. Participants provided TS and sputum samples and completed a structured survey regarding sampling experiences. TS was tested on Xpert, with sputum tested on Xpert and liquid culture. We utilised a composite reference standard of a positive result on sputum Xpert or sputum culture to define disease status. Sensitivity, specificity, and diagnostic yield were calculated for TS Xpert. Results From July to December 2025, we enrolled 225 adolescents from Can Tho and An Giang provinces in southern Vietnam. Fewer than half (96/225, 43%) the participants exhibited a tuberculosis -like symptom, and the majority (157/225, 70%) were close contacts of a person recently diagnosed with tuberculosis. TS were collected from all adolescents, while 116 (52%) could provide mucopurulent sputum. Tuberculosis prevalence was relatively low (12/225, 5.3%). TS Xpert sensitivity (90% CI) and specificity (90% CI) were 58.3% (35.6, 78.0) and 99.5% (97.9, 99.9), respectively. Diagnostic yield among all diagnosed was 58.3% (7/12). TS sampling was highly acceptable to adolescents; the short time and simplicity of collecting TS were considered favourably. Conclusions The sensitivity and diagnostic yield of TS Xpert was relatively low among adolescents recommended for tuberculosis investigation, which includes asymptomatic individuals who may not provide high quality sputum. Specificity was excellent, and everyone could provide a TS. TS high acceptability indicates it remains a promising sample for diagnostic algorithms.

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.

BackgroundChlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis are curable sexually transmitted infections (STIs) associated with adverse birth outcomes. Most infections are asymptomatic. Whether antenatal STI screening improves birth outcomes remains uncertain. MethodsIn a randomized three-group trial in South Africa, pregnant women aged 18 years or older were assigned before 27 weeks gestation to: (1) screening and treatment for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis at enrollment, with tests-of-cure (One-Time Screening); (2) screening and treatment at enrollment, repeated at 30 to 34 weeks (Two-Time Screening); or (3) Standard-of-Care (Syndromic management). The primary outcome was a composite of preterm birth (<37 weeks gestation) or low birthweight (<2500 g), analyzed in the modified intention-to-treat population of participants with live births. Components of the composite outcome were evaluated individually as the main secondary outcomes. The study was registered with ClinicalTrials.gov, NCT04446611. FindingsOf 2247 enrolled participants, 1910 had live births. The composite outcome occurred in 22{middle dot}9% of the One-Time Screening group (risk ratio [RR] 0{middle dot}99; 95% confidence interval [CI] 0{middle dot}81-1{middle dot}21), 20{middle dot}6% of the Two-Time Screening group (RR 0{middle dot}89; 95% CI 0{middle dot}72-1{middle dot}09), compared with 23{middle dot}2% of the Standard-of-Care group. Preterm birth occurred in 18{middle dot}9% of the One-Time Screening group (RR 1{middle dot}00; 95% CI 0{middle dot}80-1{middle dot}26), 14{middle dot}5% of the Two-Time Screening group (RR 0{middle dot}77; 95% CI 0{middle dot}60-0{middle dot}99), and 18{middle dot}8% of the Standard-of-Care group. Low birthweight occurred in 14{middle dot}1% of the One-Time Screening group (RR 1{middle dot}10; 95% CI 0{middle dot}83-1{middle dot}46), 12{middle dot}9% of the Two-Time Screening group (RR 1{middle dot}01; 95% CI 0{middle dot}76-1{middle dot}35), and 12{middle dot}8% of the Standard-of-Care group. InterpretationNeither screening strategy for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis reduced the primary composite outcome of preterm birth or low birthweight, or low birthweight alone. The Two-Time antenatal STI screening strategy, however, reduced preterm birth by 23%.

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.

Objectives: To identifiy risk factors for antimicrobial resistance (AMR) in seven pathogen-antimicrobial combinations in patients with cancer and cancer survivors. Methods: Using data from patients with recent or past cancer diagnostic codes in Oxfordshire, UK, we examined associations between 22 potential risk-factors and AMR in blood culture isolates, collected between 1-April-2015 and 31-March-2025. Results: Among 5,975 bacteraemias in 4,365 adults, we analysed 3,141 (52.6%) due to Enterobacterales and 620 (10.4%) due to Enterococcus faecalis/faecium in 2,752 patients. Fourteen risk-factors for antimicrobial-resistant bacteraemia were identified, varying across pathogen-antimicrobial combinations. Compared with no previous antimicrobial susceptibility test result, prior resistance to the same antibiotic in any culture in the last year was strongly associated with AMR across all pathogen-antimicrobial combinations (all p<=0.001). Prior antibiotic exposure and younger age were also positively associated with AMR in four and five combinations, respectively. Cancer type showed modest effects; lymphoid/haematopoietic malignancies were associated with higher odds (vs colorectal cancer) of trimethoprim-sulfamethoxazole-resistant Enterobacterales (aOR=2.07 95%CI 1.40-3.06) and vancomycin-resistant Enterococcus bacteraemia (aOR=6.68, 1.21-36.91). Conclusions: Previous resistance was the greatest risk factor for bacteraemia with AMR in cancer patients and survivors, with prior antibiotic exposure and age also contributing. Lymphoid/haematopoietic malignancies increased risk of resistance to specific antimicrobials. Keywords: antimicrobial resistance, bacteraemia, cancer, risk factors

Non-pharmaceutical interventions (NPIs) have been important for controlling SARS-CoV-2 transmission, particularly before and during initial vaccine rollout. During the pandemic, the US Centers for Disease Control and Prevention issued isolation and masking guidance in case of COVID-19-like illness, a positive SARS-CoV-2 test, or known exposure to SARS-CoV-2. However, the impact of this guidance on mitigating transmission in office workplaces is unclear. We used a network-based mathematical model to estimate the impact of this guidance on SARS-CoV-2 transmission among office workers and their communities. The model represented social contacts in the home, office, and community. We used data from the CorporateMix study to parametrize social contacts among office workers and calibrated the model to represent the COVID-19 epidemic in Georgia, USA from January 2021 through August 2022. In the reference scenario (58% adherence to guidance among office workers and the broader population), workplace transmission accounted for a small fraction of total infections. Reducing adherence among office workers to 0% increased workplace transmissions by 27.1% and increasing adherence to 75% reduced workplace transmission by 7.0%. Increasing adherence to 75% among office workers had minimal impact on symptomatic cases and deaths; increasing it among the broader population was more effective in reducing office worker cases and deaths. In our model, moderate adherence to recommended NPIs in workplaces was effective in reducing transmission, but increasing adherence had limited benefit given workplaces that have low contact intensity and hybrid work arrangements. These results underscore the public health benefits of community-wide adoption of recommended NPIs.

1.Etiological diagnosis of lower respiratory tract infections (LRTIs) relies on sputum or bronchoalveolar lavage (BAL), which may be difficult to obtain or invasive. Exhaled breath aerosol (XBA) sampling offers a non-invasive alternative for pathogen detection. We evaluated the performance of the AveloMask, a face mask-based device designed to capture XBAs for molecular testing. In this prospective paired-sample study, hospitalized adults with pneumonia at three hospitals in Switzerland and Georgia provided an XBA sample using the AveloMask and a lower respiratory tract (LRT) specimen (sputum or BAL). XBA samples were analyzed by multiplex PCR using the Roche LightMix(R) panel and LRT samples were tested using the BioFire(R) FilmArray(R) Pneumonia Panel. Concordance between XBA and LRT samples was assessed using positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement (OPA). Ninety-three participants were enrolled and 63 participants provided paired samples. AveloMask sampling identified the dominant pathogen (lowest Ct value in the LRT sample) in 40/47 LRT-positive cases (85.1%). Across all targets, PPA was 61% (95%CI, 50-72%), NPA was 100% (95%CI, 99-100%), and OPA was 95% (95% CI, 92-96%). PPA was higher for bacteria than for viruses and lower PPA was largely driven by reduced detection of low-abundance or co-infecting pathogens. In a subset analysis, AveloMask results showed substantial overlap with standard-of-care testing and could have supported antimicrobial de-escalation. Breath aerosol sampling using the AveloMask enabled non-invasive molecular detection of LRT pathogens in pneumonia cases and may complement conventional standard-of-care testing, particularly when sputum is unavailable.

Background Tuberculosis (TB) remains a critical public health challenge, with two-thirds of the global TB burden in ten Asian countries. Social vulnerabilities, comorbidities, health inequity, multi-dimensional poverty, malnutrition, and barriers to healthcare access continue to fuel TB epidemic. Inability to detect asymptomatic and sub-clinical TB, combined with passive approach in service delivery and overreliance on smear microscopy, leads to delayed diagnosis, a substantial burden of undetected cases, and continuing TB transmission in the communities. In such a context, the introduction and scale-up of active case-finding approaches - including community-based TB screening using highly sensitive screening tools and novel rapid diagnostics - becomes a strategic priority to interrupt transmission. The growing availability of multiple screening and diagnostic options makes evidence-based decision-making increasingly complex. Methods To estimate the potential epidemiological impact and cost implications of scaling up TB diagnostics and community-based screening in ten high-burden Asian countries, we constructed a mathematical model and evaluated multiple intervention scenarios. We then assessed and compared four service delivery models: 1) digital ultraportable chest x-ray (UPCXR) & Xpert/Truenat in community, 2) digital UPCXR in community and Xpert/Truenat at health facilities, 3) digital UPCXR in community and near point of care (nPOC) at health facilities, 4) nPOC in community & Xpert/Truenat at health facilities - for total investment required and projected health benefits for their cost-effectiveness. Results and conclusions The modelling study indicated that strengthening health facility capacity (with enhanced TB screening, expanded molecular diagnostics, reduced loss to follow-up, private sector standard of care, leading to increased treatment coverage & quality of active disease treatment and reduced post-treatment relapse, scale-up of TB preventive treatment (TPT), and provision of nutritional support to 80% of TB patients and their household contacts) can significantly reduce TB incidence and mortality; however, community-wide mass screening remains essential to achieving TB elimination targets . Targeted screening of vulnerable populations demonstrated greater cost-effectiveness than untargeted screening approaches. Achieving the End TB goals will ultimately require an effective TB vaccine with high population-level coverage. AI-enabled digital UPCXR-based screening combined with Xpert/Truenat testing at the community level demonstrated maximum epidemiological impact potential, while the most cost-efficient model is Digital UPCXR in the community combined with nPOC testing at health facilities. An investment of USD 12.7 billion over the next five years in community-level implementation of digital UPCXR and molecular diagnostics could avert an additional 9.8 million TB cases and 1.9 million deaths across ten Asian countries over a ten-year horizon.

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.

Abstract Background Timely diagnosis of tuberculosis and drug resistance remains a cornerstone of effective disease control. Multiplex open molecular platforms capable of simultaneously detecting Mycobacterium tuberculosis complex (MTBc), non-tuberculous mycobacteria (NTM), and resistance to first-line anti-tuberculosis drugs could streamline diagnostic pathways. Methods We conducted a laboratory-based evaluation of two multiplex real-time PCR assays (MTBc/NTM R-Gene and MTB-RIF/INH R-Gene) using 300 well-characterized samples, including 150 MTBc-positive culture isolates (including rifampicin-resistant, isoniazid-resistant, and drug-susceptible strains) and 150 MTBc-negative samples (50 NTM isolates and 100 mycobacteria-negative specimens). Composite reference standards included culture, MPT64 antigen testing, and line probe assay corroborated by phenotypic drug susceptibility testing for resistance profiling, with NTM speciation performed using a dedicated line probe assay. DNA extraction was performed using the QIAamp DNA Mini Kit (QIAGEN, Germany), followed by amplification on a real-time PCR platform according to manufacturer instructions. The diagnostic performance was assessed against composite reference standards. Results The analytical performance for detecting MTBc demonstrated 100% sensitivity and specificity (150/150). NTM detection showed 70.0% sensitivity (35/50) and a specificity of 100%, highlighting limitations in coverage of NTM species. Rifampicin resistance was detected with a sensitivity of 96.0% (48/50) and specificity of 100%, whereas isoniazid resistance detection was 100% sensitive and specific (50/50). Agreement with established reference standards was high ({kappa}=0.76-1.00) within this analytical context. Interpretation This analytical validation demonstrates that multiplex open real-time PCR assays can accurately and simultaneously detect MTBc, NTM, and rifampicin and isoniazid resistance using culture isolates. While these platforms offer potential advantages in flexibility and expanded resistance profiling, additional studies on clinical diagnostic accuracy, cost-effectiveness analyses, and operational feasibility are required to determine their practical utility and programmatic impact in high-burden settings

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.

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.

Objectives: To evaluate whether on-site molecular point-of-care testing (POCT) for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) is associated with reduced antibiotic overtreatment for presumed sexually transmitted infections (STIs) among adults living with HIV in rural Uganda. Methods: We conducted a single-site quasi-experimental pre-post intervention study at Kumi Hospital, comparing syndromic management (April-August 2024) with CT/NG POCT-guided management (September 2024-January 2025). Adults living with HIV presenting with symptoms suggestive of an STI were included. Overtreatment in the pre-intervention phase was estimated by comparing antibiotic prescribing with the expected number of CT/NG infections based on positivity observed during the intervention phase. Results: A total of 404 participants were included (203 pre-intervention, 201 intervention). During the intervention phase, CT and/or NG were detected in 14 individuals (7.0%). Median test turnaround time was 95 minutes, enabling same-day treatment in 93% of positive cases. Antibiotic prescribing decreased from 99.0% to 11.4% following POCT implementation (P < 0.001), corresponding to an absolute reduction of 87.6 percentage points. Estimated overtreatment declined from 30.0% to 5.0% for NG and from 74.9% to 6.0% for CT (both P < 0.001). Conclusions: Implementation of CT/NG POCT in routine HIV care was associated with a marked reduction in antibiotic prescribing and estimated overtreatment for presumed STIs. These findings support the potential of POCT-guided, aetiology-based STI management to reduce unnecessary antimicrobial exposure in settings where syndromic management remains standard practice.

BackgroundTuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, and treatment failure contributes to ongoing transmission, drug resistance, and poor clinical outcomes. Artificial intelligence and machine learning approaches have attracted growing interest for predicting tuberculosis treatment outcomes, but the literature is heterogeneous and lacks a comprehensive synthesis. MethodsWe conducted a systematic review and meta-analysis of studies that developed or validated machine learning models to predict TB treatment failure. We searched PubMed/MEDLINE and Embase from January 2000 to October 2025. Studies were eligible if they developed, validated, or implemented an artificial intelligence or machine learning model for the prediction of TB treatment failure or a closely related poor outcome in patients receiving anti-TB treatment. Risk of bias was assessed using the Prediction model Risk Of Bias Assessment Tool. Random-effects meta-analysis was performed to pool area under the curve values, with subgroup analyses and meta-regression to explore heterogeneity. ResultsThirty-four studies were included in the systematic review, of which 19 reported area under the curve values suitable for meta-analysis (total participants, 100,790). Studies were published between 2014 and 2025, with 91% published from 2019 onward. Tree-based methods were the most common algorithm family (52.9%), and multimodal models integrating three or more data types were used in 41.2% of studies. The pooled area under the curve was 0.836 (95% confidence interval 0.799-0.868), with substantial heterogeneity (I{superscript 2} = 97.9%). In subgroup analyses, studies including HIV-positive participants showed lower discrimination (pooled area under the curve 0.748) compared to those excluding them (0.924). Only eight studies (23.5%) performed external validation, and only one study (2.9%) was rated as low risk of bias overall, primarily due to methodological concerns in the analysis domain. Eggers test suggested publication bias (p = 0.024). Major evidence gaps included underrepresentation of high-burden countries, HIV-affected populations, social determinants, pediatric TB, and extrapulmonary disease. ConclusionsMachine learning models for predicting TB treatment failure show promising discrimination but are not yet ready for routine clinical implementation. Performance varies substantially across populations and settings, and methodological limitations, including inadequate validation, poor calibration assessment, and high risk of bias, limit confidence in current estimates. Future research should prioritize rigorous external validation, calibration assessment, and development in underrepresented populations, particularly HIV-affected and high-burden settings. Author SummaryTB kills over a million people annually. While curable, treatment failure remains common and drives ongoing transmission and drug resistance. Researchers increasingly use artificial intelligence and machine learning to predict which patients will fail treatment, but it is unclear if these models are ready for clinical use. We reviewed 34 studies including nearly 1.1 million participants from 22 countries. On average, models correctly distinguished patients who would fail treatment from those who would not 84% of the time, a performance generally considered good. However, this average hid enormous variation. Models developed in populations including HIV-positive people performed substantially worse, suggesting prediction is harder with HIV co-infection. Worryingly, only one study used high-quality methods; 97% had serious flaws in handling missing data, checking calibration, or testing in new populations. Only eight studies validated their models in different settings. To conclude, we found that machine learning is promising in predicting TB treatment failure, but it is not ready for clinical use. Researchers should prioritize validation in high-burden settings, include social determinants, and improve methodological rigor before these tools can help patients.

Target trial emulation (TTE) offers a principled way to estimate treatment effects using real-world observational data, but analyses of time-varying treatment strategies remain vulnerable to immortal time bias. The clone-censor-weight (CCW) approach is increasingly used to address this problem, yet key aspects of its causal interpretation and implementation remain unclear. In this work, we emulate a target trial using electronic health records (EHRs) to compare completion of a 3-dose 9-valent human papillomavirus vaccination (HPV) series within 12 months versus remaining partially vaccinated among vaccine initiators. We link CCW to the classic potential outcome framework in causal inference, evaluate the role of different weighting mechanisms, and account for within-subject correlation induced by cloning using cluster-robust variance estimation. Our study provides practical guidance for applying CCW in real-world comparative effectiveness studies to address immortal time bias and supports more rigorous and interpretable treatment effect estimation in TTE.

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.

The A(H1N1)pdm09 virus remains a major global health threat. This study examined the burden of ICU admission, mortality, and associated predictors among patients with A(H1N1)pdm09 pneumonia in a leading center for infectious diseases in Vietnam. Information on demographic, clinical, and laboratory characteristics, and outcomes was retrieved from medical records of adults admitted with influenza A(H1N1)pdm09 during 2009-2019. Among 729 cases, 21.7% (158/729) developed pneumonia. Among 158 pneumonia cases, 36.7% (58/158) developed moderate-to-severe acute respiratory distress syndrome (ARDS), and 15.2% (24/158) received invasive ventilation. ICU admission and mortality rates were 48.7% (77/158, 95%CI 41.1-56.5%) and 8.2% (13/158, 95%CI 4.9-13.6%), respectively. Predictors of ICU admission included being >60 years old (adjusted OR [AOR] 13.864, 95%CI 2.185-87.956, P=0.005), comorbidities (AOR 6.527, 95%CI 1.710-24.915, P=0.006), AST (AOR 1.013, 95%CI 1.001-1.025, P=0.029), and moderate-to-severe ARDS (AOR 14.027, 95%CI 4.220-46.627, P<0.001). Predictors of mortality were invasive ventilation (AOR 55.355, 95%CI 1.486-2062.375, P=0.030) and double-dose oseltamivir or combination therapy (AOR 32.625, 95%CI 1.594-667.661, P=0.024). In conclusion, mortality is not rare in A(H1N1)pdm09 infection. Monitoring of older patients and those with comorbidities, liver enzyme elevation, or moderate-to-severe ARDS is essential for the timely detection of complications requiring intensive care.