Clinical Infectious Diseases

Background Nirsevimab has been widely administered in the United States since 2023 to protect infants and young children from severe disease caused by respiratory syncytial virus (RSV). Although early post-licensure studies have shown high effectiveness against medically attended RSV infection, uncertainty remains about the durability of protection, effectiveness beyond the first RSV season, and the extent to which changing RSV seasonality influences real-world effectiveness. Objective To estimate the effectiveness of nirsevimab against medically attended RSV infection across three consecutive RSV seasons and to examine how effectiveness varies by season and time since immunization. Methods We conducted a test-negative case-control study utilizing electronic health records of infants and young children tested for RSV by polymerase chain reaction in outpatient and inpatient settings within the Yale New Haven Health System between October 1, 2023, and March 1, 2026. Effectiveness of nirsevimab was estimated using multivariable logistic regression, adjusting for age, weekly RSV activity, pre-existing risk factors, and other potential confounders. Variation in effectiveness was examined by season, encounter setting, and time since immunization up to 24 months. Results Overall, 17,755 infants and young children were tested for RSV infection, of whom 2,388 (13.4%) were cases and 15,367 (86.6%) were controls. The overall effectiveness of nirsevimab was 67.3% (95% confidence interval [CI]: 59.8, 73.3%) against all medically-attended RSV infections, 60.2% (95% CI: 49.6, 68.5%) against RSV-associated outpatient visits, and 88.9% (95% CI: 82.3, 93.0%) against RSV-associated hospitalization. Effectiveness against medically attended RSV infection declined across seasons, from 76.7% (95% CI: 60.5, 86.3%) in 2023/24 to 54.4% (95% CI: 33.0, 68.9%) in 2025/26. Lower season-specific effectiveness in later seasons corresponded with progressively delayed RSV activity over. Protection against RSV-associated hospitalization declined with increasing time since immunization, from 92.5% (95% credible interval [CrI]: 85.9, 96.4%) at 1 month, to 77.2% (95% CrI: 60.4, 87.6%) at 6 months, and 39.9% (95% CrI: 2.4, 63.3%) at 12 months post-immunization, after which effectiveness plateaued. Conclusions Nirsevimab remained effective against RSV-associated hospitalization through 6 to 12 months after immunization. Delayed RSV activity was associated with lower effectiveness, highlighting the importance of aligning administration with local RSV circulation.

Introduction: Plasma metagenomic next-generation sequencing (mNGS) may detect pathogens in solid organ transplant (SOT) recipients, but optimal patient selection and result interpretation remain uncertain. Methods: Physicians reviewed SOT recipients with first-instance clinical plasma mNGS testing (Karius, Inc.) and determined consensus microbiological diagnoses, clinical impact of results, diagnostic yield, and clinical outcome. mNGS results were compared to microbiological diagnoses. A HIPAA-compliant large language model (GPT-4) was used to analyze electronic medical record (EMR) data and predict risk of infection with atypical bacteria, invasive fungi, mycobacteria, or parasites (collectively: pre-specified organisms of presumed significance, POPS) and identify patients who had positive-impact mNGS testing. Results: Of 145 SOT recipients, 119 (82.1%) had positive tests, 42 (29.0%) had [&ge;] 1 POPS organism, and 27 (19.1%) had [&ge;] 1 organism causing positive clinical impact. Positive impact was highly correlated with POPS status, with 24 (88.9%) of 27 positive-impact organisms categorized as POPS (P<0.001). GPT-4 scores accurately identified patients with POPS diagnoses (AUC 0.86), and assigned higher scores to patients with positive test impact (P=0.001). mNGS testing had highest sensitivity for atypical bacteria (82.4% sensitivity) and lower sensitivity for Aspergillus spp (53.3% sensitivity). Detection of greater numbers of organisms by mNGS was associated with increased mortality risk (odds ratio 1.32 per organism detected). Discussion: Plasma mNGS is a valuable clinical tool in SOT recipients. Positive clinical impact is associated with detection of atypical bacteria, fungi, mycobacteria, or parasites. GPT-4 analysis of EMR data identifies patients at risk of infection from these organisms and most likely to benefit from mNGS testing.

Importance: Doxycycline post-exposure prophylaxis (doxyPEP) is recommended to prevent bacterial sexually-transmitted infections (bSTIs) among certain men who have sex with men and transgender women. Impacts on bSTI transmission are unknown. Objective: To quantify the impact of doxyPEP implementation on bSTI risk, distinguishing indirect and direct protection. Design: Longitudinal cohort study, January 2022 to June 2025, with a nested test-negative design study among individuals potentially eligible to receive doxyPEP. Setting: Kaiser Permanente Southern California healthcare system. Participants: Individuals aged 16-59 years, including: 'at-risk males' assigned male sex at birth, who were living with HIV or who recently received HIV pre- or post-exposure prophylaxis; other males; and females. The nested test-negative design study included at-risk males who received bSTI testing after doxyPEP implementation. Exposures: Oral doxyPEP prescription dispense, defined as a 30+ dose supply of 200mg doxycycline absent accompanying bSTI diagnoses. Main outcomes and measures: Incident laboratory-confirmed gonorrhea, chlamydia, and syphilis. We quantified indirect effects as incidence rate ratios comparing observed to expected incidence of each bSTI, absent doxyPEP implementation, among doxyPEP non-recipients. We quantified direct effects among recipients via the adjusted odds ratio of recent doxyPEP dispenses among individuals testing positive or negative for each bSTI. Results: Analyses included 30,185 at-risk males, among whom 2,713 (9.0%) received 1+ doxyPEP fill; 1,212,854 other males; and 1,321,363 females. Among all at-risk males, overall doxycycline consumption increased 2.31-fold (95% confidence interval: 1.99-2.64; absolute increase by 18,953 [16,052-21,048] defined daily doses per 1,000 person-years) after doxyPEP implementation, without accompanying changes in consumption among other males or females. Resulting indirect protection was associated with 41.4% (95% confidence interval: 33.0-48.8%) and 29.0% (13.4-41.8%) lower-than-expected incidence of chlamydia and syphilis, respectively, among at-risk males who did not receive doxyPEP. We observed no indirect effect against gonorrhea among at-risk males, and no indirect effect against any bSTI among other males or females. Among 22,937 at-risk males in the nested test-negative design study, direct protection from doxyPEP was associated with 66.8% (47.6-78.7%) and 50.1% (2.1-74.2%) further reductions in chlamydia and syphilis risk, respectively, and no reduction in gonorrhea risk. Among doxyPEP recipients, one case of chlamydia and one case of syphilis was prevented for every 2,785 (1,553-5,491) and 20,001 (5,725-182,569) doses dispensed, respectively. Conclusions and relevance: DoxyPEP implementation conferred indirect as well as direct protection against chlamydia and syphilis among at-risk males. However, substantial volumes of antibiotic use were needed to realize this benefit. Tailoring doxyPEP guidance to circumstances associated with the greatest bSTI risk may be warranted to minimize unnecessary antibiotic use.

Background Tuberculosis remains the leading infectious cause of death worldwide. In the WHO African region, declining incidence has coincided with antiretroviral therapy (ART) scale-up, though whether this reflects reduced progression to disease or reduced transmission is unclear. We evaluated how ART and symptom status influence within-household Mycobacterium tuberculosis complex (MTBC) transmission risk. Methods We conducted a case-contact household study in rural South Africa, enrolling index adults with bacteriologically-confirmed pulmonary tuberculosis. MTBC immunoreactivity was measured in all child household contacts (aged 2-14 years) as a proxy measure of within-household transmission. We assessed the influence of index person ART status and symptom status, and explored effect-measure modification of the association between index person HIV status and transmission risk by sex. Results Among 755 child contacts of 296 index persons, effective ART was not associated with within-household MTBC transmission risk (risk ratio [RR], 1.07; 95% CI, 0.66-1.74). Among PLHIV engaged in ART care, WHO TB four-symptom screen (WHO4SS) status was not associated with transmission risk (RR, 0.80; 95% CI, 0.43-1.47), although absence of reported cough reduced risk (RR, 0.61; 95% CI, 0.38-0.96). A pronounced interaction between sex and HIV status was observed: HIV-negative women had the highest within-household MTBC transmission risk (30.5% vs. 14.3% in women with HIV) whereas risks were similar between HIV-positive and HIV-negative men. Conclusions We found no evidence that effective ART or WHO4SS status influenced within-household MTBC transmission risk, though confidence intervals were wide. Absence of reported cough was associated with lower risk, and transmission risk was highest among child contacts of HIV-negative women. These findings suggest reported cough is a useful marker of transmission risk and that routine tuberculosis screening within ART care may reduce transmission from PLHIV; intensified efforts are nonetheless needed to achieve earlier tuberculosis detection in HIV-negative individuals.

Background There is growing interest in tuberculosis (TB) community screening and detection of asymptomatic TB (aTB). We explored how setting and screening approach influence the relationship between reported symptoms and underlying disease severity and infectiousness. Methods We compared markers of TB severity and infectiousness (computer-aided detection [CAD, CAD4TBv5] scores derived from chest radiographs and trace vs exceeding trace Xpert MTB/RIF Ultra results) among people diagnosed with aTB or symptomatic TB (sTB) through a community survey, and those diagnosed with aTB or sTB in clinics in the same South African community. We evaluated how variation in screening algorithms influence the relative severity of community-diagnosed aTB vs sTB, and estimated the TB prevalence and severity among people not eligible for testing in the survey (CAD score <25 and no reported symptoms). Results People with clinic-diagnosed sTB had higher CAD scores and a greater proportion of Xpert results exceeding trace than those with community-diagnosed sTB, whereas differences between community-diagnosed aTB and sTB were minimal. Under a hypothetical community universal Xpert testing strategy, people detected with sTB may have more severe disease on average than people detected with aTB. In contrast, restricting testing to people with CAD scores [&ge;]50 and/or reported symptoms would have resulted in higher CAD scores among those diagnosed with aTB than sTB. Conclusions Screening algorithm design and context influence the spectrum of TB disease detected. Community screening approaches where testing is based on symptoms and/or a threshold CAD score may identify aTB that is on average more severe than sTB.

In newborns seen a median of 11 days after birth, 97/1699 (5.7%) had conjunctivitis, including 13/97 (13.4%) with Chlamydia trachomatis or Neisseria gonorrhoeae detected. Among all babies, we estimated that 6.6% (95% confidence interval 3.8-9.9%) would have C. trachomatis or N. gonorrhoeae detected, of which 87.0% (74.8-93.8%) would be asymptomatic.

Background: Reactivation of herpes simplex viruses (HSV) can occur in the early post-allogeneic hematopoietic cell transplant (aHCT) period despite antiviral prophylaxis. Few studies have assessed HSV infection in the modern era, in which acyclovir/valacyclovir is recommended for up to 1 year post aHCT. We evaluated the incidence and management of breakthrough HSV during the first 100 days post-aHCT over two decades. Methods: Patients who received their first aHCT at Fred Hutchinson Cancer Center between 2002-2022 were reviewed for breakthrough HSV infection within the first 100 days on prophylaxis (acyclovir 800 mg or valacyclovir 500 mg twice daily). Cases were identified via culture, polymerase chain reaction, and/or direct fluorescent antibody testing; clinical records were reviewed for symptoms, outcomes, and prophylaxis/treatment regimens. Refractory/resistant (R/R) infections were defined according to consensus guidelines. Results: We reviewed data from 4,357 aHCT recipients aged [&ge;]18 years, among whom 3,749 (86%) were HSV seropositive and 23 developed breakthrough HSV infection (observed probability = 0.6%). Among those who had an infection, the median time from transplant to first positive test was 46 days (IQR: 24.0-69.5). Oral and genital mucosa were the most common sites of infection. In total, 11 of 23 (47.8%) patients with breakthrough HSV developed R/R infection. Conclusions: Breakthrough HSV infections are rare in the first 100 days after aHCT among patients receiving antiviral prophylaxis. Refractory/resistant infections were uncommon but represented almost half of breakthrough cases. Our findings highlight the sustained effectiveness of universal prophylaxis in the early post-transplant period.

Importance Tuberculosis preventive therapy is central to reducing tuberculosis, and foreign-born individuals account for most US tuberculosis cases. Current US Preventive Services Task Force guidance recommends testing and treating all foreign-born individuals regardless of age or time since immigration, yet the risks of disease progression and of treatment-related harm are not uniform across these groups. Objective To evaluate the cost-effectiveness and health outcomes of tuberculosis infection treatment strategies among immigrants from high-burden settings, stratified by age and time since immigration. Design Decision analytical model using individual-level microsimulation (Markov model) over a 30-year horizon, with deterministic and probabilistic (second-order Monte Carlo) sensitivity analyses. Costs and outcomes were discounted at 3%. Setting US federally funded tuberculosis clinic care (healthcare-sector perspective), using observed data from the Boston Medical Center/Boston Public Health Commission tuberculosis clinic and published literature. Participants A simulated cohort of 10000 IGRA-positive, foreign-born adults from high tuberculosis incidence settings (excluding immunosuppressed individuals), modeled as recent or remote (immigrated 25 years earlier) immigrants at ages 35 and 65 years. Interventions Rifampin daily for 4 months, isoniazid daily for 9 months, or no preventive therapy. Main Outcomes and Measures Costs, disability-adjusted life-years (DALYs), incident tuberculosis cases and deaths, treatment completion, and incremental cost-effectiveness ratios (ICERs), with the proportion of simulations in which each strategy was optimal at a willingness-to-pay threshold of $50000 per DALY averted. Results Among recent immigrants, rifampin was the dominant strategy at ages 35 and 65 years (optimal in 88.5% and 93.9% of simulations), yielding the fewest tuberculosis cases (119.44 and 82.31 per 10 000) and the highest treatment completion (71.4% and 67.7%). Among remote immigrants, rifampin remained the dominant strategy (optimal in 53.41% of simulations), followed by no treatment. In older remote immigrants, no treatment was optimal in 94.7% of simulations. ICERs for treatment vs no treatment were unfavorable ($193 600 and $412 857 per DALY averted for rifampin and isoniazid, respectively, at age 65). Conclusions and Relevance In this decision analytical model, rifampin was cost-effective for recent immigrants, whereas no treatment was optimal for older remote immigrants. Age and time since immigration may help risk-stratify tuberculosis infection treatment and reduce unnecessary treatment in lower-risk populations.

Clesrovimab and nirsevimab are long-acting monoclonal antibodies used to prevent respiratory syncytial virus (RSV) disease in infants, but waning protection in the first year of life is incompletely characterised. We applied a published Bayesian inference framework to clesrovimab and pooled nirsevimab trial data to estimate time-varying efficacy against medically attended RSV lower respiratory tract infection (LRTI) and RSV-associated hospitalisation, accounting for differences in placebo-arm event timing between trials. Estimated clesrovimab efficacy declined from 60.7% (95% CrI: 46.3-72.6) shortly after dosing to 38.3% (8.6-52.9) at six months against medically attended RSV LRTI, and from 87.1% (71.2-96.2) to 49.6% (10.4-70.7) against RSV-associated hospitalisation. For nirsevimab, corresponding estimates declined from 86.9% (75.4-95.0) to 53.8% (27.4-69.7) against LRTI, and from 77.5% (52.6-91.8) to 49.7% (15.7-68.3) against hospitalisation. After accounting for differences in RSV exposure timing and LRTI endpoint definitions between trials, we found no evidence of a difference in efficacy or waning between clesrovimab and nirsevimab.

Background Community-based tuberculosis screening can identify asymptomatic tuberculosis, but microbiological confirmation has been sputum-dependent. We evaluated the diagnostic performance, yield, and operational characteristics of centralized qPCR testing of community-collected tongue swabs (TS). Methods We conducted a cross-sectional study among household contacts (HHCs; [&ge;]18 years) of individuals receiving treatment for pulmonary TB in South Africa. During household visits, health workers collected TS specimens and, where possible, sputum, which was tested in participants' homes using Xpert MTB/RIF Ultra. TSs were transported non-refrigerated in molecular transport medium to a distant central laboratory for manual qPCR assay. The primary outcome was diagnostic performance of TS qPCR compared with sputum Xpert Ultra using paired results. Secondary outcomes were diagnostic yield by TS and operational indicators of the centralized testing workflow. Findings 909 HHCs were enrolled; median age 39 years (IQR 28-55), 532 (58.5%) were asymptomatic, 617 (67.9%) were sputum scarce. TS were collected from 901/909 (99.1%) and sputum from 292/909 (32.1%) participants. Among 271 paired TS-sputum results, TS qPCR sensitivity was 60.9% (95% CI 38.5-80.3), specificity 95.2% (91.7-97.5), and overall agreement 92.3% (88.5-95.0). Yield increased from 1.8% (95% CI 1.0-2.8) with symptom-restricted sputum testing to 3.2% (2.1-4.5) with symptom-agnostic sputum testing and 5.9% (4.5-7.7) when TS testing was implemented among sputum-scarce individuals, identifying 25 additional HHCs with positive molecular test results (86.2% increase). Operational indicators demonstrated successful implementation, with 2.3% specimen loss and valid molecular results for 93.8% who provided a TS. Interpretation Despite lower per-test sensitivity than sputum testing, TS may provide a scalable strategy for expanding microbiological screening beyond sputum-dependent pathways, thereby substantially increasing tuberculosis detection among HHCs. Funding U.S. NIH; Australian Department of Foreign Affairs and Trade; UK Foreign, Commonwealth and Development Office

Introduction: Enteric infections caused by Shigella and Campylobacter species are associated with acute diarrhea as well as enteric dysfunction leading to chronic malnutrition and poor child development. However, interventional studies to reduce exposure to these pathogens have been ineffective, and evidence that identifies putative sources and species transmission dynamics between humans, animals and the environment is scarce. Because isolation of these organisms from both human and environmental samples is challenging, studies using molecular detection may help reduce this substantial knowledge gap and lead to targeted interventions to reduce the burden of disease. Methods and analysis: This longitudinal cohort study will enroll 100 index infants as well as their families in Haydom, Tanzania. Families will be followed for one year, with collection of stool samples monthly and during incident diarrhea from all household members. Additionally, we will sample from the index child's environment, including domestic animal stools, drinking water, milk, porridge, flies, and soil. All samples will undergo nucleic acid extraction and quantitative PCR for Campylobacter and Shigella. Serial serologic tests will also be performed to identify seroconversion to these pathogens. Associations between pathogen detection from the environment and household members and detection in index children will be estimated, and the temporal patterning of infection cases will be analyzed using transmission models. Ethics and dissemination: This trial has been approved by the Tanzanian National Institute for Medical Research and the University of Virginia Institutional Review Board.

Introduction: Household contacts (HHCs) of pulmonary TB patients remain at high risk for TB infection and disease progression, yet many remain asymptomatic and are missed by symptom-screening pathways. While India expanded its TB preventative guidelines to include all HHCs in 2021, chest X-ray (CXR) screening continues to be used selectively, representing a missed opportunity in early case detection. Methods: The analysis uses programmatic data from Project JEET 2.0 (Joint Effort for Elimination of Tuberculosis), implemented by the William J. Clinton Foundation in India, between October 2021 and March 2024. Eligible HHCs (>=5 years) were offered CXR screening as part of TB preventive therapy (TPT) evaluation. Descriptive and multivariable analyses examined predictors of CXR uptake and TB yield. A two-stage logistic regression model estimated potential TB yield under universal CXR coverage. Model performance was evaluated using the area under the curve (AUC), and bootstrap simulations generated counterfactual estimates of missed TB cases. Results: Among 1,034,621 HHCs, 1.02% individuals were found positive for TB, which includes 7,786 HHCs who were on TB treatment already, while an additional 2,812 were identified during pre-TPT evaluation. Among eligible HHCs (n = 1,026,835), 70% were screened with CXR, of which 2.4% had suggestive TB findings. Of these, 79% went for further TB assessment. Symptomatic HHCs were more likely to be CXR screened (84% vs 69%) and assessed for TB, yet two-thirds of all detected TB cases were asymptomatic. It is estimated that universal CXR coverage and TB testing for suggestive cases can increase TB detection by at least 87%. Conclusion: The study provides a scalable approach to expand CXR coverage through public-private partnerships, enabling early TB detection among HHCs, especially among asymptomatic contacts. Future implementations will benefit from integrating AI-enabled reading, along with systematic follow up for those with suggestive findings.

Tuberculosis (TB) is increasingly recognised as a spectrum of infection and disease, yet the prevalence of viable, asymptomatic Mycobacterium tuberculosis (M.tb) infection remains uncertain. Subclinical Tuberculosis (scTB), defined as microbiologically confirmed M.tb infection in the absence of recognised symptoms, is under detected by symptom, sputum and imaging-based approaches. We conducted postmortem examinations of 94 adults who died from non-infectious causes, none of whom were clinically suspected of TB or reported TB related symptoms prior to death. Lung and extrapulmonary tissues were cultured for M.tb. Viable M.tb was confirmed in six individuals, corresponding to a prevalence of 6.4% (95% CI: 2.4 to 13.4%). These findings provide direct tissue-based evidence that viable, asymptomatic M.tb infection can persist beyond the reach of conventional clinical detection. Our data suggest that a biologically active reservoir of infection may exist undetected within high-burden settings, with implications for surveillance strategies aimed at TB elimination.

Background: Pooled testing increases testing efficiency and reduces testing costs. This approach has been recently recommended by the World Health Organization for use with low-complexity nucleic acid amplification TB diagnostics to increase access to testing when resources are constrained. Pooled testing can also be used with novel near point of care tests, and evidence is needed on diagnostic performance of pooled testing in these more portable, lower cost tests. Methods: We evaluated pooled testing on the Pluslife MiniDock MTB assay with stored sputum collected from adults with presumptive TB. We assessed sensitivity and specificity against the reference standard of liquid culture and diagnostic agreement against Xpert MTB/RIF Ultra and individual MiniDock MTB; we also estimated pooled testing efficiency. Results: Swabs from sputum specimens were tested in 287 pools of 3 and on 861 individual tests. Against culture, sensitivity of testing was 88% (87/99, 95%CI, 80-93%) as compared to 89% (88/99, 95%CI, 81-94%) for individual MiniDock MTB testing, with pooled testing specificity of 99% (97-99%) as compared to 95% (94-97%) for individual testing. Pooled testing saved 32% of tests in this population that included 12% (100) people with culture-positive TB. Conclusions: Pooled testing with sputum swabs from three people had similar diagnostic accuracy against TB culture as individual sputum swab testing in this evaluation. These results provide evidence that pooled testing with near point of care tests could help to further reduce testing costs and help to expand access to molecular testing at the lowest levels of the health system.

Background: Vancomycin-resistant Enterococcus (VRE) species are common healthcare-associated pathogens that cause difficult-to-treat infections. Whole genome sequencing of patients has revealed a substantial burden of patient-to-patient VRE transmission in hospitals, with patients in intensive care units (ICUs) at particularly high risk of acquisition. However, few studies adequately characterize the pathways of VRE transmission between patients in acute care settings, a necessary step to identify current gaps in infection prevention practices. By harnessing genomic clustering analyses of whole genome sequences of VRE isolates from patients, environmental surfaces, and healthcare providers (HCP) in ICUs, we aim to reconstruct indirect pathways of pathogen movement to identify patterns of VRE spread and opportunities for transmission prevention. Methods and Findings: We collected daily samples (N = 6848) from ICUs in two hospitals over 13 weeks from four main sampling sources: patients, HCP hands, patient rooms, and shared surfaces. Samples were cultured on selective media and sent for whole genome sequencing (WGS). We used genomic thresholds to identify clusters of related VRE isolates and distinguish unrelated isolates. VRE was detected in samples from 20 out of 322 unique occupant-stays (6.22%). VRE isolates were detected from all sampling sources except for shared surfaces. A total of 44 unique VRE isolates were identified, 43 Enterococcus faecium (VREfm) and one Enterococcus faecalis (VREf). Two distinct patterns of VREfm spread were observed: 1) an outbreak setting with observed patient-to-patient transmission and low VRE diversity, and 2) high VRE diversity and pathogen movement between occupant-stays facilitated by persistent HCP and environmental contamination, but no observed transmission events. VRE detection probabilities were not significantly different between occupant-stays in outbreak and non-outbreak settings (OR = 0.63, 95% CI (0.23, 1.83), p = 0.32). However, inclusion of VRE isolated from non-patient samples increased the number of occupant-stays with VRE detection from 6 to 20, a 3.3-fold increase, as compared to patient samples alone. Inclusion of non-patient samples also increased the number of VRE multi-isolate genomic clusters detected by 7-fold. Our findings are limited because sampling was primarily conducted in ICUs. Due to the combination of short ICU stay durations and imperfect test sensitivity, VRE transmission events were probably underdetected. Conclusions: Our findings characterize the complex nature of VRE transmission pathways in ICU settings. Even without an ongoing outbreak, we found substantial evidence of VRE movement between occupant-stays, facilitated by a combination of HCP hands and environmental surfaces. This study highlights the importance of environmental sampling for understanding VRE transmission potential, which is likely to be underestimated using patient sampling alone. We recommend that future studies incorporate follow-up sampling after discharge to better understand the true burden of transmission.

Background Quantifying the effect of Shigella diarrhea with and without antibiotic treatment on linear growth faltering is critical to understanding the potential impact of Shigella vaccines. Methods Using individual-level data from five multisite studies, we estimated the effect of Shigella diarrhea on length/height-for-age z-score (HAZ) 60-90 days after the episode compared to diarrhea episodes with no etiology identified and non-diarrheal controls. Effects were estimated under treatment with and without antibiotics using augmented inverse probability weighted estimators with ensemble machine learning. Findings Among 26,752 diarrhea episodes, 5,503 (20.6%) were attributed to Shigella and of those, 2,567 (46.6%) were treated with guideline recommended antibiotics. Compared to other diarrhea episodes, Shigella diarrhea without treatment with guideline recommended antibiotics was associated with small reductions in HAZ (HAZ difference: -0.03, 95% CI: -0.05, -0.01), but not when treated with guideline recommended antibiotics (HAZ difference: -0.01, 95% CI: -0.02, 0.01). Compared to non-diarrheal controls, Shigella diarrhea was associated with decrements in HAZ in the following 60-90 days regardless of antibiotic treatment (HAZ difference overall: -0.08, 95% CI: -0.10, -0.07). A larger impact of Shigella diarrhea was observed among younger children. Interpretation Shigella diarrhea was associated with short-term decrements in height. Treatment with guideline recommended antibiotics prevented the impact of Shigella on linear growth compared to other diarrhea episodes but not compared to non-diarrheal controls. These results suggest that improved recognition and treatment or prevention of Shigella could improve child growth.

Background and Aims The optimal treatment for first episodes and first recurrences of Clostridioides difficile infections (CDI) is unknown and there is emerging evidence for pulse and taper (P-T) regimens. Therefore, we sought to estimate the relative efficacy of treatment options. Methods MEDLINE and CENTRAL were searched from database inception to May 21, 2025 and unpublished conference abstracts were searched from recent infectious disease conferences. RCTs on the treatment of first episodes or first recurrences of CDI comparing fixed-dose or P-T regimens of fidaxomicin or vancomycin were included. The primary and secondary outcomes were 40- and 56-day CDI recurrence, respectively. A random-effects network meta-analysis on the risk ratio (RR) scale was conducted using a standard regimen (10-14 days) of vancomycin as the comparator. Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results 8 RCTs were included comprising a total of 2181 patients. For 40-day recurrence, fidaxomicin P-T had the highest probability of ranking best (RR=0.10, 95%Confidence Interval [95%CI]=0.10-0.49, SUCRA=1.00), followed by vancomycin P-T (RR=0.49, 95%CI=0.32-0.76, SUCRA=0.61), fixed-dose fidaxomicin (RR=0.61, 95%CI=0.49-0.76, SUCRA=0.39), and, finally, fixed-dose of vancomycin (SUCRA=0.00). The treatments ranked in the same order for 56-day recurrence, though only 3 RCTs reported on this timepoint. Conclusion Vancomycin P-T, fidaxomicin P-T, and fixed-dose fidaxomicin were all superior to a fixed-dose vancomycin. Head-to-head comparative effectiveness RCTs are needed to quantify their relative effect sizes of and impact on long-term prevention of recurrent CDI.

Background: Nontuberculous mycobacteria (NTM) are environmental pathogens causing pulmonary and extrapulmonary infections. First Nations people in Australia experience higher burdens of communicable diseases, comorbidities, and systemic barriers to care, increasing NTM risk. This study examined the incidence and spatial distribution of NTM infections in First Nations people in Queensland. Methods: A retrospective longitudinal analysis was conducted using NTM notifications from the Queensland Health Notifiable Conditions Database, stratified by Indigenous status. Incidence was calculated using population denominators and Indigenous Region boundaries, with direct rate comparisons between 2011 and 2024. Results: Between 2001 and 2024, 717 NTM notifications were recorded from 606 First Nations people, with a significant male predominance among those aged 30-44 years ({chi}^2=21.63, P<0.0001). NTM incidence was higher in 2024 than in 2011, increasing from 4.6 to 26.3 per 100,000 (incidence rate ratio (IRR): 5.74, 95% confidence interval (CI): 2.97-11.08, P<0.0001). Although incidence in 2024 was lower than in the non-Indigenous population (35.81 per 100 000), the rate of increase was 4.4 times greater. Pulmonary infections predominated (569/717, 79.36%) and were more frequent in 2024 than in 2011 (IRR: 6.95, 95% CI: 3.00-19.75, P<0.0001). Extrapulmonary incidence increased by 140% from 2020 primarily due to an outbreak of Mycobacterium abscessus infections among incarcerated First Nations males. Marked geospatial heterogeneity was observed, with the greatest increases in incidence in the Brisbane, Rockhampton, Townsville-Mackay, and Cairns-Atherton Indigenous Regions (P<0.001). Conclusions: NTM incidence among First Nations people in Queensland has increased substantially, with a faster rate of rise than in the non-Indigenous population despite lower absolute incidence, consistent with under-ascertainment. These findings highlight gaps in detection and diagnostic access, alongside heterogeneous geographic and outbreak-associated transmission dynamics. Strengthening culturally appropriate surveillance and improving access to timely diagnosis are required to better define disease burden and inform targeted clinical and public health responses in First Nations and other underserved populations.

Respiratory syncytial virus (RSV) contributes to substantial morbidity and mortality in young children each year. In 2023, two new prevention products were licensed and recommended in the United States (US), including a prefusion F protein subunit vaccine (RSVpreF) administered during pregnancy and a long-acting monoclonal antibody (mAb) administered in infants. Although post-licensure real-world studies support the effectiveness of RSVpreF vaccine during pregnancy, existing studies have been conducted in settings where only RSVpreF vaccine is available. The real-world effectiveness of RSVpreF vaccine in settings where both RSVpreF vaccine and mAbs are available is not yet well understood. The goal of this study is to estimate the real-world effectiveness of the RSVpreF vaccine against severe infant RSV by applying causal mediation analysis with receipt of mAbs as a mediating variable. Using a national cohort of mother-infant dyads with the Optum Labs Data Warehouse (OLDW), we will model vaccine and mAb effects in a longitudinal cohort spanning the 2023-24, 2024-25, and 2025-26 RSV seasons. Results will be used to better understand the total effect of RSVpreF vaccination when it is used as one component within a hybrid infant RSV prevention program.

Importance: Respiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season. Objectives: To describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups. Design, Setting, and Participants: Surveillance registry of children 8- <24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV). Exposure: Preexisting health conditions potentially increasing risk of severe RSV disease. Main Outcomes and Measures: Patients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared. Results: Among 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001). Conclusions and Relevance: Approximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.