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Methicillin-resistant Staphylococcus (MRS) infections are a significant public health concern. Anterior nares serve as a major reservoir and source of spread of MRS ssp. People living with HIV (PLWHIV) tend to be at higher risk of colonisation with MRS organisms due to frequent healthcare exposure. We assessed the prevalence of MRS nasal carriage and associated factors among PLWHIV at the HIV clinic of Kiruddu National Referral Hospital, Kampala, Uganda, from May to July 2024. Nasal swabs from 256 PLWHIV were cultured, and microbiological isolation was performed at MBN Clinical Laboratories. Prevalence was calculated as proportions, and logistic regression identified associations with clinical and socio-demographic factors (p < 0.05). Of 256 participants, 163 (63.7%) carried Staphylococcus, with 82 (32%) identified as MRS carriers (8.9% MRSA, 23% MRCoNS). Frequent hospital visits ([&ge;]3) (adjusted incidence risk ratio [A-IRR] = 1.18 x 107, p < 0.001), second-line antiretroviral therapy (ART) (A-IRR = 3.82, p = 0.041), and unsuppressed viral load (>1000 copies/mL) (adjusted odds ratio [AOR] = 11.3, 95% CI: 2.11-60.58, p = 0.005) were significantly associated with MRS carriage. Mask-wearing was protective against MRCoNS (A-IRR = 1.66, 95% CI: 1.06-2.58, p = 0.026). MRS isolates exhibited high resistance to erythromycin (81.7%) and trimethoprim-sulfamethoxazole (79.3%), but susceptibility to linezolid (93.9%). MRS nasal carriage is prevalent among PLWHIV. Individuals with frequent health care contact and those on second-line ART regimens are more susceptible to MRS colonization, while individuals who wear face masks and those with an undetectable HIV viral load are less susceptible. Antimicrobial Resistance (AMR) surveillance within HIV programs, enhanced infection control, ART adherence, and targeted screening for high-risk groups are critical to mitigate colonization.

Artificial intelligence (AI) tools have been rapidly adopted by medical researchers, yet whether early career researchers in low and middle income countries possess the awareness and habits needed to use these tools safely remains poorly documented. This study characterized AI adoption patterns, hallucination awareness, and verification and disclosure practices among early career medical researchers in Pakistan. A cross sectional anonymous online survey was conducted among medical students, house officers, residents, physicians, and faculty involved in research or academic work across Pakistan (May 2026). Descriptive statistics and chi square tests were applied to 373 eligible responses. AI use was near universal (99.7%), with 60.3% using AI tools daily. The most commonly reported tool in this sample was Claude (40.5%), followed by ChatGPT (29.2%) and Perplexity (26.0%), though this ranking likely reflects sampling characteristics. Despite high adoption, 59.2% typically did not verify AI outputs before use, and 40.2% had never heard that AI can generate fabricated scientific references. In behavioral vignettes, 36.5% assumed convincing AI generated references were authentic, and 54.2% would continue using remaining AI content after discovering one fabricated reference. Formal research training was strongly associated with consistent disclosure (51.7% vs. 17.1%; chi square=48.43, p less than 0.001). Role, daily use frequency, and research training were not significantly associated with verification behavior. Early career medical researchers in Pakistan demonstrate high AI adoption alongside incomplete hallucination awareness and infrequent verification, a pattern that may carry implications for research integrity. Formal training was the only factor significantly associated with consistent disclosure. Integration of AI literacy into medical curricula and institutional governance frameworks merits consideration.

Background Erythema nodosum leprosum (ENL) is a severe inflammatory complication of lepromatous leprosy characterised by recurrent inflammatory episodes often requiring prolonged immunosuppression. The severity of ENL can be quantified using the validated and reliable ENLIST ENL Severity Scale (EESS). The longitudinal course of ENL and how it is captured using standardised severity measures has not been well described. We prospectively evaluated the changes in ENL severity over time using the EESS in a randomised clinical trial. Methods We conducted a post-hoc analysis of participants enrolled in the Methotrexate and Prednisolone Study in ENL, an international multicentre randomised controlled trial conducted in Ethiopia, India, Indonesia, and Nepal. Adults with severe ENL (EESS score [&ge;]9) were followed for 60 weeks with repeated EESS assessments. Longitudinal trajectories were analysed using mixed-effects regression models. Item-level analyses characterised the clinical phenotype captured by the scale. Associations between EESS score, prednisolone exposure, and dermatology-specific health-related quality of life measured using the Dermatology Life Quality Index (DLQI) were examined. Findings A total of 135 participants contributed 1,958 EESS assessments. Mean EESS declined rapidly during the first four weeks of treatment (-2.10 points/week; 95% CI -2.36 to -1.84; p<0.001), increased modestly during reduction in corticosteroid dose (weeks 4-20), and gradually declined thereafter. Severe ENL (EESS score [&ge;]9) occurred in 20.6% of visits and was characterised primarily by pain and cutaneous inflammatory manifestations. Participants who required additional prednisolone had persistently higher EESS scores and showed limited improvement compared with those who did not receive additional prednisolone. Longitudinal EESS scores were strongly correlated with the DLQI score (Spearmans {rho}=0.75; p<0.001). Conclusion The EESS captures clinically meaningful changes in ENL severity, aligns with treatment decisions, and reflects patient-reported severity over time. These findings support the use of the EESS as a robust tool for monitoring ENL severity in both clinical research and routine care.

Close to 50% of all bird species are reservoirs of potentially pathogenic fungi, including those listed as priority by the World Health Organization. In Malawi, data on diversity, pathogenic potential, and ecological avian sources of medically important yeast are scarce. A cross-sectional study using a descriptive approach was conducted in Blantyre, Southern Malawi, to characterise medically important yeasts recovered from environments contaminated with excreta/guano from synanthropic pigeons. A total of 20 samples were collected from 4 peri-urban areas, which yielded 71 yeast isolates. To assess the pathogenic potential of the environmental isolates, we compared their phenotypic virulence traits with those of 21 clinical yeast isolates collected from referral hospital laboratories. Pichia kudriavzevii (39%) and Candida orthopsilosis (30%) were the commonly isolated species in the pigeon-guano-contaminated environments. Candida parapsilosis sensu stricto (29%) and Candida albicans (24%) constituted most of the clinical yeast isolates. Half of the species isolated in the pigeon-guano-contaminated environments were also identified among the clinical isolates. A majority of the environmental isolates showed virulence traits similar to or stronger than clinical isolates. The findings underscore the critical need for integrated surveillance under the One Health framework, especially in bird-inhabited spaces close to human settlements.

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [&le;] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Background Oropouche virus (OROV) is an emerging vector-borne virus with rapidly expanding geographic range, increasing case counts, and growing evidence of severe outcomes including neuroinvasive disease and vertical transmission. Because OROV infection presents with nonspecific febrile illness that overlaps clinically with other viruses including dengue, zika, and chikungunya, accurate molecular diagnostics are essential for patient care and surveillance. Yet existing assays rely on single genomic targets and are vulnerable to detection failure as the virus evolves and reassorts. Methodology/Principal Findings To support diagnostic capacity, we developed and clinically validated a multiplexed qPCR assay targeting three regions of the OROV S segment, incorporating redundancy to preserve sensitivity across viral diversity while enabling robust clinical interpretation. The multiplex also includes an assay targeting RNaseP as an internal sample control to ensure adequate sample processing. We evaluated assay performance using both historical and contemporary OROV strains and validated the assay on contrived serum, plasma, and cerebrospinal fluid samples, assessing linearity, limit of detection (LOD), accuracy, specificity, precision, and sample stability. The assay met or exceeded all predefined acceptance criteria for clinical testing and achieved an LOD as low as 6 copies per reaction for contemporary outbreak strains. We further implemented a logic-based interpretation matrix that reduced false-positive risk while maintaining sensitivity near the analytical LOD. Conclusions/Significance Our assay sensitively and specifically detects OROV RNA in serum, plasma, and cerebrospinal fluid while incorporating safeguards against viral evolution and reassortment. The assay has been approved for use by CLIA at Nexus Medical Labs in 49 U.S. states, expanding access to timely OROV diagnostics in the United States and providing a durable framework for molecular detection of reassorting, rapidly evolving viruses as OROV continues to spread into new regions.

Introduction Obstructive lung diseases (OLDs) are responsible for high rates of illness and death worldwide. Inflammation, chronic airflow limitation, and bronchial remodeling occur in OLD and eventually result in the unique respiratory sounds. Despite its subjective and having low reproducibility, still traditional auscultation using a manual stethoscope is the main method used to identify the lung sounds. Nevertheless, the combination of recent advancements in digital stethoscopes and AI (Artificial Intelligence) has permitted the objective measurement of lung sounds. Nevertheless, there is a lack of standardized, region-specific databases for AI training and validation. Even though lung sound classification is an emerging aspect in research and telerehabilitation the lobar wise acoustic pattern is still novel due to lack of prevailing database to train AI models. Identifying this gap this study aims to develop an acoustic repository and analyze the data using segmental lung sounds from patients with OLDs and healthy controls through an electronic stethoscope. Methods and analysis This is a cross sectional observational study involving 120 participants (60 OLD patients and 60 healthy controls). Lobar wise acoustic signals will be captured using an electronic stethoscope in healthy and diseases population. The data will be analyzed using Audacity software for annotations and then it will be used for feature extraction and statistical analysis. The acoustic features extracted through Audacity, will include frequency, intensity, pitch, and root mean square (RMS) energy. Repeated measures ANOVA will be applied to compare mean sound intensities across lung segments while Pearson correlation will be used to assess associations with body composition parameters. The data will then be standardized for AI-based diagnostic applications. Ethics and dissemination The study is being reviewed from the Ethics Review Committee, Faculty of Medicine, University of Peradeniya (2025/EC/87) will be sought. Informed consent will be obtained in writing. The dissemination of results will take place through peer-reviewed publications and the creation of a public database containing lung sounds from the region.

Background African immigrants in the United States bear a disproportionate HIV burden, with incidence approximately sixfold higher than the general population, yet remain largely absent from targeted prevention research. HIV vulnerability among this population is mediated through relationship and family systems that are restructured by migration, reorganizing household composition, gender norms, trust, and communication patterns through which prevention engagement occurs. Despite this, migration has rarely been examined as a force that transforms the relational contexts shaping engagement with HIV testing, HIV self-testing (HIVST), and pre-exposure prophylaxis (PrEP). Methods The MiST-Pathways Study will use a sequential mixed-methods, community-based pilot design among first-generation African immigrant adults (ages 18-50) residing in New York and Massachusetts. The study will proceed in three phases: Aim 1 will use semi-structured interviews (n = 15) and a structured survey (n = 75) to identify relationship typologies and migration-related relational mechanisms influencing HIV prevention engagement; Aim 2 will employ Palava Hut Conversations (PHC) (an African-centered deliberative method) with up to 30 participants to co-develop and prioritize relationship-tailored intervention components; and Aim 3 will conduct a proof-of-concept assessment of the prioritized component using a single-group pre-post design (n = 24), incorporating surveys and cognitive interviews to assess feasibility, acceptability, and preliminary evidence of mechanism activation. All activities will be conducted virtually via Zoom and WhatsApp, with eligibility screening administered through REDCap. The study has been approved by the University at Buffalo Institutional Review Board (STUDY00010347) and registered at ClinicalTrials.gov (NCT07565584). Discussion This protocol outlines the planned evaluation of a sequentially designed, community-engaged pilot study to examine how migration reshapes relational contexts that influence HIV prevention decision-making among African immigrants. Findings will inform the development of culturally grounded, relationship-tailored prevention strategies and the design of a future, larger-scale intervention study.

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

People living with HIV (PLWH) are known to maintain a degree of immune deficiency despite efficient antiretroviral therapy and may exhibit diminished responses to vaccines. In this study, we assessed the immune response to SARS-CoV-2 infection and vaccines in two geographically distinct PLWH populations. PLWH and HIV-negative (HIV-) participants were recruited from Qu&bec City (QC), Canada, and Bobo-Dioulasso (BD), Burkina Faso, for two visits at 24-week intervals during the predominance of the Omicron variant, from May 2022 to September 2023. Blood samples were collected at each visit for the detection of antibodies against spike (anti-S) and nucleocapsid (anti-N) proteins of SARS-CoV-2 in platelet-free plasma. A total of 360 participants were enrolled. We detected anti-S antibodies in 99% of participants, indicating that nearly all had prior exposure to the SARS-CoV-2 spike antigen, either through vaccination or prior infection. Anti-S titers showed no difference between PLWH and HIV& participants in each location, while significantly higher titers were observed in participants from QC compared to BD. In contrast, anti-N antibodies, indicative of prior infection, were detected in 39% and 86% of the participants in QC and BD, respectively, suggesting that the virus circulated largely in the latter population. No difference in anti-N levels was observed between PLWH and HIV& participants in BD. However, participants in QC had significantly lower titers compared to HIV participants. Overall, this study shows that PLWH develop robust antibody responses to SARS-CoV-2 vaccination, comparable to those observed in HIV& participants. Significant geographic differences were observed in anti-S titers, irrespective of HIV status, with participants from QC displaying higher titers. In contrast, participants from BD had higher anti-N antibody prevalence and titers, reflecting more SARS-CoV-2 infections in BD than in QC. Finally, analysis of anti-S antibody titers against several circulating variants revealed significantly lower levels in unvaccinated participants and in those vaccinated with monovalent vaccines in BD. No significant difference was observed between monovalent and bivalent vaccines administered in QC. All authors have seen and approved the manuscript.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

Background: Climate mitigation policies can lower air pollutant concentrations and deliver substantial health co-benefits. The French Ecological Transition Agency (ADEME) proposed four contrasting Transitions 2050 net-zero scenarios. We quantified mortality, morbidity, and health-economic co-benefits from projected PM2.5 and NO2 reductions across all four scenarios in continental France. Methods: Emission projections were input to the CHIMERE chemistry-transport model to estimate PM2.5 and NO2 concentrations for 2030 and 2050. Health impacts were assessed using disease-specific cessation-lag assumptions relative to 2019, covering premature mortality, morbidity, DALYs, and economic benefits across nine outcomes (hypertension, lung cancer, ischaemic heart disease, stroke, COPD, type-2 diabetes, acute lower respiratory infections, and asthma in children and adults). Findings: Population exposure is projected to decline by about 40% for PM2.5 and 70% for NO2 by 2050, with health gains remaining substantial and broadly equivalent across all four scenarios and modest differences between sufficiency-oriented and technology-driven pathways. Under delayed-impact assumptions, avoided premature deaths ranged from 21,300 to 22,100 for PM2.5 and 24,500 to 26,200 for NO2. Morbidity and disability-adjusted life year (DALY) reductions, as well as economic savings, spanned similarly; total avoided morbidity cases were 84,000-88,000, direct medical cost reductions were e1.0-1.1 billion/year, and intangible cost savings of e41-43 billion and e36-39 billion, respectively. Interpretation: Health co-benefits are substantial, consistent across contrasting scenarios, and increase markedly from 2030 to 2050. Explicitly incorporating these co-benefits into climate policy appraisals may strengthen the case for ambitious mitigation and improve decision-maker acceptability.

Abstract Aims To examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Meta's algorithms actually delivered the adverts to. Design Cross-sectional analysis of advert-level data from the Meta Ad Library. Setting Meta social media platforms (including Facebook and Instagram) in the UK. Cases A random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general). Measurements Outcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR). Findings Advertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0-8.2). Conclusions Nicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.

Background: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Objectives. Despite the body of literature on genetic risk factors for dementia, little is known on protective genetic factors associated with favourable cognitive ageing in the oldest population. In Europe, Italy has a leading position with a swelling population of centenarians, and the urban area of Genoa in the Liguria region has one of the highest prevalence of centenarians. The COOL study is a not-for-profit, multicentric study involving a cohort of centenarians (aged >99) living in the Genoa area. The ultimate aim is the identification of genomic biomarkers associated with cognition in the oldest old population. Results. Participants underwent a semi-structured interview on personal, disease and family history, and a neuropsychological assessment of the main cognitive domains. As of July 2025, we enrolled 88 centenarians (age range: 99-108, median 100.56) with and without cognitive impairment; 32 subjects were followed up. All participants were of Italian ancestry, 81% were female. The cognitive profile in assessed subjects showed a wide range of cognitive health measures (CDR 0-5; MMSE 3-30, median 24). Whole peripheral blood and DNA samples from 67 participants were stored. Conclusions. We demonstrated that the protocol is feasible, and acceptable by participants and their families. A comprehensive phenotype dataset was established, and DNA samples were stored. Centenarians exhibited a broad spectrum of cognitive profiles, from preserved cognition to severe dementia. These findings will eventually allow to interpret the profiles of genomic variants as associated with variability of cognitive performance in centenarians. The molecular underpinnings of healthy cognitive ageing could inform health policy strategies in the general population.

Importance: While gut dysbiosis is known to impair response to immune checkpoint inhibitors (ICIs), the relative clinical impact of antibiotic timing (pre- vs. post-ICI initiation) remains unclear. Objective: To evaluate whether antibiotic timing differentially influences overall survival (OS) in a large, multi-institutional pan-cancer cohort. Design, Setting, and Participants: This retrospective cohort study utilized deidentified electronic health record data from six academic medical centers within the University of California Health system. We included 21,108 adults with any malignancy who received PD-1, PD-L1, or CTLA-4 inhibitors between January 2014 and December 2024. Exposures: Antibiotic exposure windows were categorized as pre-only (-60 to -1 days), post-only (+1 to +60 days), both windows, or none. Main Outcomes and Measures: The primary outcome was overall survival (OS) calculated from the first ICI dose. Multivariable Cox proportional hazards models adjusted for demographics, tumor type, line of therapy, and baseline health indicators (albumin, NLR, and recent hospitalization). Results: Among 21,108 patients, 17.3% had pre-only exposure, 13.3% had post-only exposure, and 60.6% had no exposure. In the multivariable model, post-only exposure (HR, 1.27; 95% CI, 1.20-1.35) and combined pre- and post- exposure (HR, 1.31; 95% CI, 1.23-1.40) were significantly associated with higher mortality. Pre-only exposure was not significantly associated with OS (HR, 1.04; 95% CI, 0.99-1.10). Subgroup analyses by tumor type showed consistent trends across major malignancies, including head and neck (Post HR, 1.46) and renal cell carcinoma (Post HR, 1.26). Conclusions and Relevance: In contrast to some smaller studies, this large-scale analysis indicates that antibiotic exposure after ICI initiation carries a greater risk than exposure prior to treatment. These findings highlight the need for rigorous antibiotic stewardship strategies specifically during the early phases of immunotherapy treatment.

Rationale: Efficacious dose selection for anti-tuberculosis drugs has traditionally relied on achieving plasma exposures above the minimum inhibitory concentration, but this approach has not consistently aligned with clinical outcomes. Objectives: We sought to identify early pharmacokinetic-pharmacodynamic targets most predictive of clinical efficacious dose. Methods: We conducted a back-translational, pharmacokinetic-pharmacodynamic simulation-based analysis of 15 anti-tuberculosis drugs. Using pharmacokinetic data from multiple biological matrices and a range of pharmacodynamic metrics, we established candidate exposure-response targets for attainment. We systematically evaluated the predictive accuracy of each target pair against established clinical doses to formulate a decision-making framework linking key drug properties to the most predictive targets. Measurements and Main Results: Depending on the target used, projected clinical doses varied widely - both within and across compounds - highlighting the importance of target selection for dose projection and go/no-go decisions. In general, targeting cellular lesion-level drug exposures relative to in vivo preclinical potency provided an effective approach for early dose selection. However, for highly penetrating drugs, targeting site-of-action therapeutic exposures in the caseum was more predictive of clinical dose. Based on these findings, we developed a preliminary dose prediction tool that enables drug developers to estimate clinically relevant dose ranges of compounds using in vitro and early in vivo data. Conclusions: This work establishes and validates a simple, evidence-based framework to standardize early translational decision-making on dose selection of anti-tuberculosis candidates in development.

Background: CD8+ tumor-infiltrating lymphocytes (TILs) are established prognostic markers in colorectal cancer, yet the clinical significance of CD103+CD8+ tissue-resident memory-like (TRM-like) T cells in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (NACRT) remains unknown. Methods: We quantified CD8+ and CD103+CD8+ T-cell densities in stromal and intratumoral compartments of post-NACRT resection specimens from 40 LARC patients using Cu-Cyto, a deep learning-based imaging cytometry platform. Associations with survival, pathological response, and adjuvant chemotherapy (AC) were examined. Treatment-induced T-cell dynamics were assessed in paired pretreatment biopsies and post-NACRT resections (n = 9). Results: High stromal CD103+CD8+ density independently predicted better 5-year RFS (67.4% vs. 12.1%, p < 0.001) and OS (80.0% vs. 26.6%, p = 0.016); intratumoral density showed no prognostic significance. Pathological response correlated with stromal CD8+ but not CD103+CD8+ density. Paired analysis revealed a selective non-expansion of the CD103+ subset: stromal CD8+ T cells increased significantly after NACRT while CD103+CD8+ density remained unchanged. AC may preferentially benefit patients with low stromal CD103+CD8+ density. Conclusions: Stromal CD103+CD8+ T-cell density is a robust independent prognostic biomarker in rectal cancer after NACRT that appears to reflect pre-existing rather than treatment-induced immunity. Given its stability across NACRT, pretreatment biopsy assessment may provide equivalent prognostic information, with potential implications for patient stratification before treatment initiation.

Background and Objective: Access to real-world electronic health records (EHRs) remains limited by privacy, governance and annotation constraints, hindering the development of clinical natural language processing models. Realistic synthetic progress notes may provide EHR-like corpora that preserve clinically rigorous information on diagnoses, treatments, symptoms, imaging, laboratory findings and therapeutic trajectories without relying directly on sensitive patient records. This study evaluates whether large language models (LLMs) can generate realistic Spanish prostate cancer progress notes from published case reports, preserving clinical content, temporality and hospital-style conventions.

Background: RNA sequencing (RNA-seq) is increasingly recognized as a complementary tool to DNA-based sequencing for improving the diagnostic yield in Mendelian disorders. However, how the diagnostic performance of RNA-seq varies across molecularly and phenotypically distinct patient subgroups remains poorly defined. This study aimed to evaluate and compare the diagnostic utility of RNA-seq across three stratified groups of patients with non-diagnostic exome sequencing. Methods: We performed RNA-seq on whole blood samples from 90 patients with suspected Mendelian disease in whom clinical exome or whole-exome sequencing had failed to establish a molecular diagnosis. Patients were prospectively stratified into three groups of 30: (i) patients with a candidate variant of uncertain significance (VUS) with predicted splicing impact (Group 1), (ii) patients with a specific clinical pre-diagnosis but no identified pathogenic variant (Group 2), and (iii) patients without a specific pre-diagnosis or candidate variant (Group 3). Aberrant splicing, gene expression outliers, and allele-specific expression were analyzed using multiple bioinformatic tools and compared against a GTEx-derived control cohort. Results: RNA-seq contributed to a molecular diagnosis in 29 of 88 evaluable patients (32.9%). Diagnostic yield differed substantially across groups: 82.8% (24/29) in Group 1, 6.9% (2/29) in Group 2, and 10% (3/30) in Group 3. In Group 1, RNA-seq enabled reclassification of candidate VUS through direct demonstration of aberrant splicing events. In Group 2, RNA-seq identified a somatic mosaic ACTB variant missed by exome sequencing and reclassified a previously deprioritized APPL1 VUS. In Group 3, a deep intronic pseudoexon-activating variant in IGBP1 was identified in two siblings with severe microcephaly, providing evidence for a candidate X-linked microcephaly gene, and a pathogenic RNU4-2 variant was detected in a patient with ReNU syndrome, a non-protein-coding gene not captured by standard exome sequencing. Conclusions: RNA-seq has the highest diagnostic utility when applied to evaluate candidate splice variants identified by prior DNA testing but also provides independent diagnostic value in patients without candidate variants. The systematic comparison across stratified patient groups supports the integration of RNA-seq into clinical genomic workflows and highlights the need for standardized analytic frameworks.