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PubMed2026

Causal Relationship Between Ischemic Stroke and Vascular Dementia: A Mendelian Randomization Study.

Ischemic stroke (IS) is a major cause of disability and mortality worldwide, and vascular dementia (VaD) is a common dementia subtype associated with cerebrovascular injury. Observational studies have suggested a relationship between IS and VaD, but these studies are vulnerable to confounding and reverse causality. This protocol describes a reproducible two-sample Mendelian randomization (MR) workflow for evaluating the potential causal association between IS and VaD using publicly available genome-wide association study (GWAS) summary statistics. Genetic instruments associated with IS were extracted from a public GWAS dataset, and outcome associations for VaD were obtained from a public VaD GWAS dataset. The corresponding dataset IDs are provided in the Protocol section. After outcome matching and allele harmonization, 51 single-nucleotide polymorphisms (SNPs) were retained for the final MR analysis. The workflow includes instrumental variable selection, linkage disequilibrium clumping, allele harmonization, instrument strength assessment, inverse variance weighted (IVW) analysis, weighted median analysis, MR-Egger analysis, heterogeneity testing, horizontal pleiotropy assessment, and leave-one-out sensitivity analysis. In the representative analysis, the IVW method showed a positive association between genetically predicted IS and VaD risk, and the weighted median method yielded a directionally concordant result. The MR-Egger estimate was directionally consistent but did not reach statistical significance. Therefore, these findings should be interpreted as suggestive evidence of a possible causal effect, rather than definitive proof of causality. This protocol may help researchers apply a transparent and reproducible MR workflow to investigate cerebrovascular disease-related outcomes using public GWAS data.

Humans↗

PubMed2026

Long-term outcomes of top-down therapy versus a conventional step-up strategy in adults newly diagnosed with Crohn's disease: 5-year follow-up of the PROFILE trial.

BACKGROUND: The PROFILE trial previously reported better 48-week outcomes for patients with Crohn's disease who received top-down anti-TNF treatment from diagnosis, compared with a conventional step-up strategy. Through subsequent follow-up of PROFILE participants, we aimed to assess whether the benefit of top-down treatment from diagnosis results in modification of the long-term disease course. METHODS: PROFILE was a multicentre, open-label, randomised controlled trial completed in 40 hospitals in the UK, which included patients aged 16-80 years with newly diagnosed Crohn's disease. Eligible patients were randomly assigned via a secure online platform to a top-down (infliximab plus immunomodulator) or a step-up protocolised treatment strategy for 48 weeks, after which participants reverted to local standards of care. Objective outcome data were extracted for up to 5 years after the week 48 visit, including need for Crohn's-related abdominal surgery as the primary outcome. Data were analysed based on the original PROFILE randomisation and intention-to-treat population. Participants without long-term follow-up data were censored at the week 48 visit. Time-to-event analyses were performed using the Kaplan-Meier method and Cox proportional hazards model. The trial was registered with the ISRCTN registry, number 11808228 and is complete. FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 483 patients were assessed for inclusion. 389 patients were enrolled and randomly assigned (three patients were excluded due to ineligibility), 193 to top-down treatment and 193 to step-up treatment. Of the 386 participants in the PROFILE primary trial, 358 (93%) had post-week 48 records available for review (182 [51%] top-down and 176 [49%] step-up). Median follow-up was approximately 5 years from randomisation (1809 days [IQR 1300-2101]), by which point 172 (89%) of 193 patients in the step-up group and 191 (99%) of 193 patients in the top-down group had received biological or immunomodulator therapy. Relating to the primary outcome, during follow-up there were 28 Crohn's disease-related abdominal surgeries in 26 patients treated with a step-up approach versus six surgeries in six patients treated with a top-down approach. Time to surgery was shorter in the step-up group than the top-down group (adjusted hazard ratio [aHR] 5·23 [95% CI 1·99-13·76]; p=0·0008). For the secondary outcomes, incidence of Crohn's disease-related hospital admissions was higher in patients originally managed with step-up treatment versus top-down treatment (41 [21%] of 193 patients vs 22 [11%] of 193 patients); and time to first hospital admission was shorter with step-up treatment than with top-down treatment (aHR 2·01 [95% CI 1·18-3·41], p=0·017). Progression to B2 or B3 complications was also more frequent in those originally managed with step-up treatment compared with top-down treatment (32 [17%] of 192 patients vs 13 [7%] of 193 patients); with time to disease progression being shorter in the step-up group than in the top-down group (aHR 2·46 [95% CI 1·25-4·86]; p=0·010). There was no difference in safety outcomes between groups for either serious infections (12 [6%] of 193 step-up patients and 14 [7%] of 193 top-down patients) or malignancies (five patients [3%] and three patients [2%] respectively). INTERPRETATION: Early top-down anti-TNF treatment from diagnosis was associated with improved long-term outcomes at 5 years compared with step-up treatment and is suggestive of a disease-modifying effect in Crohn's disease. FUNDING: Wellcome and Celltrion.

Journal Article↗

PubMed2026

Efficacy and Safety of Autologous Versus Prosthetic Grafts in the Repair of Popliteal Artery Aneurysms: A Systematic Review and Meta-Analysis.

BACKGROUND: Popliteal artery aneurysms (PAAs) present a severe risk of progression to acute limb ischemia. Open surgery (OS) is the gold standard treatment; however, prosthetic grafts are acceptable in highly selected cases, especially when the great saphenous vein is not available. METHODS: We performed a systematic review and meta-analysis of studies comparing autologous versus prosthetic grafts for patency and limb preservation outcomes in patients with PAAs. MEDLINE, Embase, and Cochrane Central were systematically searched from inception through October 2024. Outcomes were pooled using a frequentist random-effects model as odds ratios, mean differences, and hazard ratios (HRs) with 95% confidence intervals (CIs) on RStudio (Version 4.5.0). Risk-of-bias assessments were performed using ROBINS-I and MINORS. RESULTS: Twenty-two observational studies were pooled comprising 9,145 PAAs in 8,370 patients, of whom 6,434 (74.51%) were treated with autologous grafts and 2,200 (25.49%) with prosthetic grafts. Follow-up ranged from 12 to 86 months. Repair with autologous conduits significantly improved long-term primary patency (HR 3.93; P < 0.001), secondary patency (HR 6.02; P < 0.001), and long-term limb salvage (HR 2.69; P = 0.044) compared with prosthetic conduits. There were no significant differences in in-hospital amputation (P = 0.36), myocardial infarction (P = 0.61), mortality (P = 0.50), 2-year primary patency (P = 0.25), 5-year secondary patency (P = 0.06), or length of hospital stay (P = 0.95). Risk of bias was classified as moderate-to-high, reflecting confounding factors inherent to observational studies and moderate methodological quality by MINORS. Despite these limitations, treatment effects consistently favored autologous grafts in both short- and long-term analyses; however, caution is warranted given the limited number of available studies. CONCLUSION: The use of autologous conduits significantly favors both short-term and long-term efficacy and safety in the OS repair of PAAs. Given the limitations of the existing evidence, further comparative studies are needed.

Humans↗

PubMed2026

Non-small cell lung cancer and tumor-educated platelets: screening of biomarkers and construction of a prognostic model.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, emphasizing the urgent need for effective early detection strategies. Traditional Chinese medicine (TCM) provides a unique perspective on tumor pathogenesis, focusing on concepts such as "long-term stasis leading to accumulation". Tumor-educated platelets (TEPs) offer potential as biomarkers due to their ability to reflect cancer heterogeneity and facilitate less invasive diagnostic approaches. This study aims to identify TEP-related prognostic biomarkers for non-small cell lung cancer (NSCLC) and to construct and validate a multigene prognostic model by integrating platelet transcriptomic data with tumor tissue datasets. METHODS: We performed comprehensive analysis of gene expression datasets obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories to characterize transcriptomic differences among lung cancer specimens, normal tissue samples, and TEPs. Using R software, we identified Differentially expressed genes (DEGs) and subsequently applied a multi-stage analytical pipeline to TEP-associated DEGs, incorporating univariate Cox proportional hazards regression, least absolute shrinkage and selection operator (LASSO) regression, multivariate Cox regression, and stepwise regression modeling to pinpoint genes with prognostic significance. These prognostically relevant genes served as the foundation for developing a risk stratification model. We computed individual risk scores across both training and validation cohorts, enabling patient stratification into high- and low-risk categories. Model robustness was assessed through internal cross-validation and external validation procedures, while predictive performance was quantified using risk calibration metrics and receiver operating characteristic (ROC) curve analysis. RESULTS: Through systematic bioinformatics screening, we identified a four-gene prognostic signature comprising NELL2, C4orf48, PRAM1, and KLHL35, which served as the foundation for developing our risk stratification algorithm. Rigorous internal cross-validation and external cohort validation substantiated the moderate predictive performance of this signature. Comprehensive clinicopathological correlation analysis revealed that elevated risk indices, advanced pathological staging (stage III-IV), increased primary tumor dimensions, regional lymph node metastasis, and distant organ dissemination each demonstrated statistically significant associations with diminished overall survival (OS) outcomes in lung cancer patients. The clinical nomogram exhibited acceptable calibration, with calibration plots showing reasonable concordance between predicted and observed survival probabilities across all time points. Discriminative capacity assessment via time-dependent ROC analysis yielded area under the curve (AUC) values consistently surpassing 0.6, confirming moderate prognostic discrimination. Furthermore, decision curve analysis (DCA) demonstrated that our integrated multi-gene model conferred potential net clinical benefit compared to individual prognostic variables across the full spectrum of clinically relevant threshold probabilities (0-1 range), thereby establishing its potential utility for risk-informed clinical decision-making. CONCLUSIONS: This study identified NELL2, C4orf48, PRAM1, and KLHL35 as candidate TEP-related prognostic biomarkers for non-small cell lung cancer (NSCLC). The developed prognostic model shows preliminary potential for patient stratification, but its clinical application, particularly as a platelet-based liquid biopsy tool, requires further validation in independent TEP-based cohorts.

Tumor-educated platelets (TEPs)↗

PubMed2026

Effects of blood flow restriction training combined with resistance training on lower-limb strength and sport-specific performance in athletes: a systematic review and meta-analysis.

BACKGROUND: In contemporary sports science, athletes and coaches continuously explore strategies to reduce training load and injury risk while increasing muscular strength and sport-specific performance. This meta-analysis evaluated the effects of blood flow restriction training (BFRT) combined with resistance training (RT) on lower-limb muscle strength and sport-specific performance in athletes. METHODS: Relevant randomized controlled trials (RCTs) were systematically searched across major databases (e.g. PubMed, Web of Science, Cochrane, CNKI, Wanfang Data, and Embase) from inception until November 2024. Two independent reviewers carefully assessed the studies. Data analysis was carried out using RevMan 5.4 software, which included heterogeneity testing, meta-analysis, subgroup analysis, and assessment of publication bias. RESULTS: Ten RCTs (181 athletes; 91 in the BFRT and RT group, 90 in the control group) were included. Outcomes determined BFRT combined with RT yielded notable enhancements in lower-limb muscle strength (SMD = 1.09, 95% CI [0.52, 1.66], p < 0.05) and muscle hypertrophy (MD = 1.09, 95% CI [0.10, 2.09], p < 0.05) compared to control training. However, no significant improvement in sport-specific performance was found (SMD = 0.11, 95% CI [-0.18, 0.40], p = 0.46). Substantial heterogeneity was observed for strength outcomes (I2 = 75%), whereas low heterogeneity was observed for sport-specific performance and hypertrophy outcomes (I2 = 0%). No evidence of significant publication bias was detected. CONCLUSION: BFRT combined with RT appears to provide effective augmentation of lower-limb muscle strength and hypertrophy in athletes compared to RT or conventional training alone. It may be prudent to integrate this approach systematically into training cycles to optimize physiological muscle stimulation and training outcomes, despite not directly improving sport-specific performance.

Humans↗

PubMed2025

AI-HOPE: an AI-driven conversational agent for enhanced clinical and genomic data integration in precision medicine research.

MOTIVATION: The growing complexity of clinical cancer research has fueled a surge in demand for automated bioinformatics tools capable of integrating clinical and genomic data to accelerate discovery efforts. RESULTS: We present the Artificial Intelligence Agent for High-Optimization and Precision Medicine (AI-HOPE), an AI-driven system that enables domain experts to conduct integrative data analyses through natural language interactions. Powered by Large Language Models, AI-HOPE interprets user instructions, converts them into executable code, and autonomously analyzes locally stored data. It supports flexible association studies, subset comparisons, clinical prevalence assessments and survival analyses. In addition, AI-HOPE enables global variable scans to identify features significantly associated with a user-defined outcome, making a powerful and intuitive tool for advancing precision medicine research. Importantly, its closed-system design prevents clinical data leakage. To demonstrate its utility, AI-HOPE was applied to The Cancer Genome Atlas data to address two clinical questions. First, it identified significant enrichment of TP53 mutations in late-stage colorectal cancer compared to early-stage cases. Second, it uncovered a strong association between KRAS mutations and poorer progression-free survival in FOLFOX-treated patients. These findings align with established literature and demonstrate AI-HOPE's ability to generate meaningful insights independently, without prior assumptions. By removing programming barriers and simplifying complex analyses, AI-HOPE bridges the gap between data complexity and research needs. With its scalable and adaptable framework, AI-HOPE has the potential to support diverse biomedical research fields, driving innovation and efficiency in translational studies. AVAILABILITY AND IMPLEMENTATION: The AI-HOPE software and demonstration data is available at https://github.com/Velazquez-Villarreal-Lab/AI-HOPE.

Precision Medicine↗

PubMed2026

Community pharmacists' perspectives on resupplying and prescribing contraceptives: a descriptive qualitative study in Australia.

OBJECTIVES: Australia has commenced implementing contraceptive resupply and prescribing by community pharmacists to improve equity in method access. This study aimed to investigate pharmacist's acceptability of hormonal contraceptive resupply and prescribing. METHODS: Participants were recruited via convenience sampling and had provided contraceptive counseling consistent with the ALLIANCE intervention (i.e. structured, patient-centered, effectiveness-based care) to women seeking the emergency contraceptive pill or presenting prescriptions for medical abortion medicines. This qualitative descriptive study was embedded within the ALLIANCE trial, whose process evaluation included semi-structured interviews with pharmacist participants. The interview guide, containing questions on pharmacists' views of the resupply and prescribing service, was reviewed by the ALLIANCE Trial Chief Investigators and piloted in June 2024 with the SPHERE Pharmacy Advisory Circle. Thirteen questions were developed using the Theoretical Framework of Acceptability (TFA). Two researchers conducted line-by-line coding using an iteratively refined codebook, with codes mapped to TFA constructs to examine operationalization in pharmacists' delivery of hormonal contraception. KEY FINDINGS: Although pharmacists (n = 24) perceived that the service could be cost- and time-saving to patients, they raised concerns of unintentionally removing general practitioner (GP)-led monitoring of patients and overstepping GPs' roles. While pharmacists felt confident in their expertise and generally supported the service, they expressed hesitation about initiating contraceptive prescriptions, for which they felt further training and access to comprehensive medical records were required. Additional barriers included increased workload pressures, lack of reimbursement, and inadequate staffing. CONCLUSIONS: Overall, providing a resupply service appears to be acceptable to community pharmacists because it relies on the GP's initial assessment but prescribing less so. However, evaluation is needed post-implementation to explore sustainability, feasibility, and long-term impact on patient outcomes.

contraception↗

PubMed2026

Fibroblast Growth Factor 23 as a Prognostic Biomarker in Post-Myocardial Infarction Outcomes: Influence of Renal Function and Its Modulation by Klotho.

BACKGROUND: Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. METHODS: We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. RESULTS: We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. CONCLUSIONS: FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.

Fibroblast Growth Factor-23↗

PubMed2026

BIOCARD framework: integrating fecal bile acids, lipids, and metabolites to assess response to a cardiovascular health intervention.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, particularly in under-resourced populations. Although nutritional interventions are important for CVD prevention, their outcomes are commonly evaluated using conventional clinical and behavioral indicators, which may not fully capture early molecular responses. In this study, we developed the BIOCARD framework, an exploratory fecal multi-omics platform integrating bile acids, lipids, and metabolites to evaluate intervention outcomes related to cardiovascular health. Fecal samples were collected from caregiver-child participants enrolled in a 10-week randomized controlled trial comparing a multicomponent garden-based intervention (SHA) with an education-only control group (MSP). Fecal polar metabolites, lipids, and bile acids were analyzed by UHPLC-HRMS-based approaches and integrated with conventional health indicators. Traditional clinical indicators in the present study showed limited sensitivity for detecting intervention-related differences. In contrast, fecal multi-omics analyzes revealed intervention-associated differences in metabolites, lipids, and bile acids, with children showing more apparent molecular variation than parents. Network analysis further revealed associations between selected molecular features and cardiovascular-related indicators, including blood pressure, body fat, skin carotenoids, and Healthy Eating Index scores. Together, these findings suggest that the BIOCARD framework may serve as an exploratory molecular approach to complement traditional outcome measures and improve the evaluation of nutritional interventions for cardiovascular health.

Humans↗

PubMed2026

Impact of Commercial Artificial Intelligence on Radiologist Reading Time for Pulmonary Nodule Evaluation at Chest CT.

Background Chest CT is a primary method for identifying pulmonary nodules, yet interpreting scans remains time-intensive and demanding. Currently, artificial intelligence (AI) is expected to reduce reading times, but the effect of AI on reporting times in this setting is unknown. Purpose To evaluate the impact of a commercial AI software on radiologists' reading time for pulmonary nodule assessment on chest CT scans within a real-world clinical setting. Materials and Methods This retrospective study included patients who underwent chest CT examinations at a tertiary medical center between September 2021 and May 2024. The study period was divided into pre- and post-AI phases. The primary outcome was radiology reporting time. The association between AI implementation and reporting time was evaluated using a multivariable parametric Weibull shared frailty survival model adjusted for reader function, examination type, patient location, and requesting specialty, with clustering at the radiologist level. Interaction analyses assessed heterogeneity across prespecified subgroups. An exploratory extrapolation estimated projected workforce and financial impact. Results This study included 19 433 patients (mean age, 62 years ± 14.2 [SD]; 21 814 men; 39 323 chest CT examinations, 19 190 pre-AI, and 20 133 post-AI). AI implementation was associated with faster report completion (adjusted hazard ratio, 1.17; 95% CI: 1.14, 1.21; P < .001). The adjusted median reporting time decreased from 21.3 minutes pre-AI to 18.2 minutes post-AI (14.6% reduction; P < .001). Heterogeneity was observed across reader function (P < .001), examination type (P = .048), and requesting specialty (P = .03). The largest relative reductions were observed for CT thorax electrocardiogram-gated examinations (-41.1%; P < .001) and thoracic radiologists (-25.0%; P < .001), whereas emergency department examinations showed increased median reporting time (7.1%; P < .001). At institutional scan volumes (approximately 20 000-22 000 chest CT examinations annually), exploratory modeling suggested an approximate reduction of 0.5 full-time equivalent radiologist workload. Conclusion Implementation of commercial AI-assisted pulmonary nodule assessment on chest CT scans reduced radiologist reporting time in a real-world clinical setting. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Iwasawa in this issue.

Humans↗

PubMed2025

Oral Lachnoanaerobaculum Levels and Survival in Patients With Head and Neck Cancer.

IMPORTANCE: The oral microbiome plays a critical role in cancer treatment responses, yet its influence on outcomes in patients with head and neck squamous cell carcinoma (HNSCC) undergoing (chemo)radiotherapy remains poorly understood. Identifying specific microbiome signatures associated with treatment effectiveness could provide novel prognostic biomarkers and therapeutic targets. OBJECTIVE: To investigate the association between salivary Lachnoanaerobaculum spp abundance and treatment outcomes in patients with HNSCC undergoing (chemo)radiotherapy and to explore potential mechanisms. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed saliva samples from patients with HNSCC who were enrolled in 2 independent prospective biomarker studies (SALIVA and ZissTrans) and underwent definitive (chemo)radiotherapy. Oral microbiome composition was assessed using 16S rRNA gene sequencing. Tumor-infiltrating lymphocytes (TILs) were evaluated via immunohistochemistry in patients with available data. Findings were further assessed using data from The Cancer Microbiome Atlas and The Cancer Genome Atlas. Sample collection occurred from 2008 to 2011 (SALIVA) and from 2017 to 2022 (ZissTrans), and the data for this study were analyzed from July to December 2024. EXPOSURE: Definitive (chemo)radiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was locoregional recurrence-free survival (LRFS) and a secondary outcome was overall survival (OS). Additional secondary analyses evaluated the association between Lachnoanaerobaculum spp levels and TIL levels, and the incidence of severe radiation-induced oral mucositis. RESULTS: The analysis included 92 patients with HNSCC (mean [SD] age, 61.1 [7.9] years; 15 female [16.3%] 77 male [83.7%] individuals) and found that higher Lachnoanaerobaculum spp abundance was associated with substantially improved LRFS (median, 69 vs 11 months; hazard ratio [HR], 0.50; 95% CI, 0.29-0.86) and OS (median, 75 vs 27 months; HR, 0.54; 95% CI, 0.30-0.98). This finding was confirmed by multivariable Cox regression (LRFS: HR, 0.50; 95% CI, 0.25-1.00; OS: HR, 0.37; 95% CI, 0.16-0.85). TILs were evaluated in 76 patients (82.2%) and showed that increased Lachnoanaerobaculum spp levels were associated with higher CD4-positive and CD8-positive TIL counts. Lachnoanaerobaculum spp abundance showed no meaningful association with severe radiation-induced oral mucositis. Data from The Cancer Microbiome Atlas (n = 157) indicated that higher intratumoral Lachnoanaerobaculum spp levels were associated with improved OS (HR, 0.62; 95% CI, 0.39-0.98). Transcriptomic analyses in The Cancer Genome Atlas cohort further supported an immune-stimulated tumor microenvironment in Lachnoanaerobaculum-high tumors. CONCLUSIONS AND RELEVANCE: This prognostic study found that higher salivary Lachnoanaerobaculum spp abundance was associated with improved tumor control and survival in patients with HNSCC undergoing (chemo)radiotherapy. These findings support further investigation into microbiome-targeted interventions to improve HNSCC treatment effectiveness.

Humans↗

PubMed2026

Five decades of pneumococcal meningitis in Spain: a single-centre, clinical and genomic, retrospective, observational study.

BACKGROUND: Pneumococcal meningitis remains a major threat, with high fatality rates and long-term sequelae, despite advances in vaccination and treatment. We aimed to examine the associations between pneumococcal serotypes, Global Pneumococcal Sequence Cluster (GPSC), antimicrobial resistance, source of infection, and clinical outcomes in adults with pneumococcal meningitis. METHODS: In this single-centre, clinical and genomic, retrospective, observational study, we analysed all laboratory-confirmed cases of adult pneumococcal meningitis recorded at Hospital Universitari de Bellvitge, Spain. Clinical data were obtained from a prospectively maintained clinical database and linked to microbiological and genomic data by unique patient identifiers. Clinical sources of infection were classified as cerebrospinal fluid leakage, acute otitis media, or haematogenous origin. Disease severity was defined as shock at presentation, sequelae as any persistent neurological deficit at discharge, and mortality as death within 30 days. Serotype data were available for 265 isolates, and whole-genome sequencing was done on 200 viable isolates. For outcome analyses, patients who did not receive dexamethasone were excluded. Serotype, GPSCs, antimicrobial susceptibility, phylogenetic, and genome-wide association study (GWAS) data were analysed to assess determinants of meningitis source, disease severity, sequelae, and 30-day mortality. FINDINGS: 387 adult patients (median age 58 years [IQR 45-68]; 54% male) with pneumococcal meningitis were recorded between Jan 1, 1974, and Dec 31, 2023. Acute otitis media was the most frequent source of pneumococcal meningitis (174 [45%] of 387 cases) and was mainly caused by serotype 3 (pneumococcal conjugate vaccine [PCV]13; GPSC12). The 30-day case-fatality rate in this group was 17 (10%) of 174 (95% CI 5·8-15·2). Haematogenous episodes accounted for 104 (27%) of 387 cases and had a significantly higher 30-day case-fatality rate (50 [48%] of 104; 95% CI 38·2-58·1; p<0·0001) with a higher frequency of serotype 4. Cerebrospinal fluid leakage accounted for 105 (27%) of 387 cases and had the lowest 30-day case-fatality rate (nine [9%] of 105; 95% CI 4·0-15·6) and broader serotype diversity. The introduction of PCV7 and PCV13 resulted in declines in vaccine-targeted serotypes and β-lactam resistance. Whole-genome sequencing identified 60 distinct GPSCs. Among prevalent lineages, GPSC16 (20 [10%] of 200; serotypes 19A and 23F) and GPSC6 (18 [9%] of 200; serotypes 9V, 11A, and 14) were associated with β-lactam resistance. GWAS did not identify genetic variants significantly associated with severity, sequelae, or mortality. INTERPRETATION: This longitudinal study provides a comprehensive view of adult pneumococcal meningitis over five decades, revealing changes in sources of infection, serotype distribution, pneumococcal lineages, and antimicrobial resistance patterns over time. Lineage-level findings suggested variability in clinical outcomes, underscoring the importance of continued genomic surveillance and supporting consideration of broader vaccine targets. GPSC12 predominance and its association with mortality and more severe outcomes highlight the need for preventive measures against serotype 3, although these findings require confirmation in larger multicentre cohorts. FUNDING: Instituto de Salud Carlos III, cofunded by European Social Fund, and the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, both at the Instituto de Salud Carlos III.

Journal Article↗

PubMed2026

Paediatric outcomes after maternal nipocalimab for haemolytic disease of the fetus and newborn: an open-label, single-arm study.

OBJECTIVES: To describe haemolytic disease outcomes, growth, neurodevelopment and health-related quality of life (HRQoL) through 24 months of life in infants exposed to nipocalimab in pregnancies at high risk of early-onset severe haemolytic disease of the fetus and newborn (EOS-HDFN). DESIGN: A multicentre, open-label, single-arm trial. SETTING: Centres with expertise in HDFN management. PATIENTS: Pregnant individuals with previous EOS-HDFN and maternal anti-D titres ≥32 or anti-K titres ≥4. INTERVENTIONS: Weekly nipocalimab (30 and/or 45 mg/kg) from 14 to 35 gestational weeks. MAIN OUTCOME MEASURES: Infants' cord-blood alloantibody titres at birth, HDFN management, growth through 6 months, neurodevelopment (caregiver-reported Ages and Stages Questionnaire, third edition (ASQ-3)) and HRQoL assessments through 24 months of life. RESULTS: Of 13 pregnancies, 12 resulted in live births; one fetal loss occurred due to intrauterine transfusion (IUT) complications. A single simple transfusion was administered in one of seven infants delivered after a maternal nipocalimab course without IUTs, where cord blood alloantibody titres were <8. Multiple transfusions (one to seven simple transfusions/infant; one exchange transfusion) were administered to five infants delivered after early nipocalimab discontinuation and IUTs, with cord-blood alloantibody titres ranging from 512 to 32 768. No unusual growth patterns were observed through 6 months. No neurodevelopmental delays were identified through 24 months of life, with mean ASQ-3 domain scores within normal ranges. HRQoL outcomes were positive across physical, emotional, social and cognitive functioning. CONCLUSIONS: Maternal nipocalimab in pregnancies at high risk of EOS-HDFN may reduce adverse neonatal outcomes correlating with low cord-blood alloantibody titres, without affecting growth through 6 months, neurodevelopment or HRQoL through 24 months of life. TRIAL REGISTRATION NUMBER: NCT03842189.

Child Health↗

PubMed2026

Physical Activity and Cardiovascular Outcomes in Phenotype-Negative Cardiomyopathy Variant Carriers.

IMPORTANCE: Exercise may lead to disease progression and higher risk of sudden death in individuals with genetic cardiomyopathies, but the effects of exercise among individuals carrying a cardiomyopathy-associated variant without clinical manifestations (G+P-) are unclear. OBJECTIVE: To examine whether the effects of moderate to vigorous physical activity (MVPA) on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and malignant ventricular arrhythmias (VAs) vary by G+P- status. DESIGN, SETTING, AND PARTICIPANTS: UK Biobank participants with whole-genome sequencing providing 1 week of accelerometer-based physical activity data and without prevalent heart failure (HF), atrial fibrillation (AF), cardiomyopathy, VAs, or implantable cardioverter-defibrillators were included in this cohort study. The study was conducted at 22 assessment centers throughout the UK from February 2013 to December 2015 with a median follow-up of 8 years. Data were analyzed from March 2024 to June 2025. EXPOSURE: Accelerometer-measured MVPA (minutes/week). MAIN OUTCOMES AND MEASURES: Associations were analyzed between MVPA volume and future incidence of adverse CV outcomes (AF, HF, myocardial infarction [MI], and stroke), cardiac magnetic resonance (CMR)-based measures of cardiac remodeling, and surrogates for clinical cardiomyopathy onset (cardiomyopathy and VA). Associations were compared between G+P- carriers and noncarriers. RESULTS: Among 84 699 individuals (mean [SD] age, 62 [8] years; 48 353 [57%] women; 3979 G+P- carriers), greater MVPA was associated with a lower risk of adverse CV outcomes over a median (IQR) 8.0 (7.5-8.5) years, irrespective of genotype. In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in G+P- carriers (hazard ratio [HR] at optimal MVPA level vs zero [95% CI], AF: 0.68 [0.58-0.79]; HF: 0.58 [0.47-0.71]; MI: 0.49, [0.24-1.00]; stroke: 0.35 [0.12-0.99]). For G+P- carriers, MVPA in the range of 100 to 400 minutes per week was generally associated with lowest risk. Among individuals with CMR imaging, MVPA was associated with a similar pattern and extent of cardiac remodeling (eg, left ventricular dilation and left ventricular hypertrophy) in G+P- carriers vs noncarriers. Among G+P- carriers, higher MVPA was associated with lower risk of incident cardiomyopathy (HR at optimal MVPA vs 0, 0.03; 95% CI, 0.00-0.98) with no increase in risk of VA (eg, HR at 400 minutes of MVPA vs 0, 0.98; 95% CI, 0.83-1.14). Findings were generally consistent across variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy, although precision of estimates for arrhythmogenic right ventricular cardiomyopathy were limited. CONCLUSIONS AND RELEVANCE: In this cohort study, MVPA within the general range of guideline-based recommendations was associated with lower risk of adverse CV outcomes and similar degrees of cardiac remodeling for G+P- carriers compared to noncarriers. Findings support the appropriateness of guideline-based MVPA recommendations for G+P- carriers.

Humans↗

PubMed2026

Effect of renin-angiotensin system inhibitors on survival in glioma patients: A systematic review and meta-analysis.

PURPOSE: To evaluate the effect of renin-angiotensin system inhibitors (RASIs) on the survival outcomes of glioma patients, determine whether using RASIs correlates with survival benefit, and provide evidence-based guidance for the clinical treatment. METHODS: Studies assessing the effects of using RASIs versus non-use in glioma patients were retrieved from the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to April 17, 2024. The included studies reported hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and/or progression-free survival (PFS), as well as the effect on brain edema and steroid dosing in patients. RESULTS: Seven articles involving 2660 patients were included in this study. Pooled results indicated there was no significant difference in OS (HR = 0.89, 95% CI 0.75-1.06, P = 0.204) or PFS (HR = 0.98, 95% CI 0.82-1.18, P = 0.847) between RASIs-treated patients and non-RASIs-treated patients. Sensitivity analysis identified the ACEIs-focused trial reported by Happold et al. as a major contributor to inter-study heterogeneity. Subgroup analyses revealed that in recurrent glioblastoma, pooled OS was significantly longer in RASIs-treated patients than non-RASIs-treated patients (HR = 0.70, 95% CI 0.54-0.92, P = 0.01). Similarly, compared with bevacizumab monotherapy, bevacizumab combined with RASIs significantly extended OS in glioblastoma patients (HR = 0.73, 95% CI 0.63-0.86, P < 0.001). CONCLUSION: The results revealed that treatment with RASIs may show a trend toward prolonged overall survival (OS) in patients with glioma. For patients with glioblastoma, RASI therapy could prolong OS in those with recurrent disease. Furthermore, compared with bevacizumab monotherapy, the combination of RASIs and bevacizumab was associated with improved OS in glioblastoma patients.

Humans↗

PubMed2026

Empirical Meropenem Versus Piperacillin/Tazobactam for Critically Ill Adults With Sepsis: Feasibility of a Randomised Trial.

BACKGROUND: Meropenem and piperacillin/tazobactam are commonly used empirical antibiotics in critically ill adults with sepsis, but whether one is superior to the other is uncertain. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an ongoing investigator-initiated, randomised, open-label, adaptive clinical trial with an integrated feasibility phase comparing empirical treatment with meropenem versus piperacillin/tazobactam in critically ill adults with sepsis. The integrated feasibility phase enrolled 200 participants across 10 intensive care units (ICUs) in Denmark between 28 June and 12 December 2025. Five pre-specified feasibility criteria were evaluated; if all feasibility criteria were met, the trial would proceed unaltered, whereas failure to meet one or more criteria would require intervention and re-evaluation. RESULTS: We randomised 200 of 284 screened patients (70.4%). The median age was 70 years (interquartile range (IQR): 60-77), 65.5% were males. At randomisation, 80.0% received vasopressors or inotropes, and 43.5% were on invasive mechanical ventilation. Four of five pre-specified feasibility criteria were met: time to completion of the feasibility phase (5.5 months vs. threshold < 12.0 months), recruitment proportion (70.4% vs. threshold ≥ 50.0%), proportion of participants without consent to the continued collection of data (2.5% vs. threshold < 5.0%) and protocol adherence (81.0% vs. threshold ≥ 75.0%). The proportion of participants with timely primary outcome data availability (30-day mortality) within 45 days was 85.5% and below the pre-specified threshold of ≥ 95.0%. The proportions were low in the first 3 months (33.3%, 22.2% and 30.8%, respectively), increasing to 95.8% in the last month of the feasibility phase. All-cause mortality at 30 days was 30.5%, and specific serious adverse reactions occurred in 4.0% of participants. CONCLUSIONS: In this integrated feasibility evaluation of the EMPRESS trial comparing empirical meropenem versus piperacillin/tazobactam in critically ill adults with sepsis, four of five pre-specified feasibility criteria were met. The unmet criterion, timely primary outcome data availability, improved substantially during the feasibility phase. We consider the trial feasible and will proceed without modifications. EDITORIAL COMMENT: This feasibility study assessed recruitment, randomised allocation and data collection for the multicentre EMPRESS trial. For adaptive trials on trial platforms, careful interim checking of trial design functions is an important and necessary process. TRIAL REGISTRATION: Clinical Trials Information System EUCT number: 2023-509703-33-00; ClinicalTrials.gov identifier: NCT06184659; Universal Trial Number: U1111-1301-6379.

Humans↗

PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗

PubMed2026

The prevalence and clinical significance of clonal monocytosis.

The terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms to describe cases of clonal hematopoiesis (CH) and concurrent monocytosis that did not meet the diagnostic criteria of chronic myelomonocytic leukemia. To date, their practical relevance as clinicopathological entities at a population level has not been assessed. Here, we assess the prevalence, significance, and natural history of CMUS and CCMUS among 431 531 UK Biobank participants through analysis of clinical, genomic, and health outcome data. We find that CMUS with an absolute monocytosis and CCMUS are high-risk entities strongly associated with incident myeloid neoplasia (MN), cardiovascular disease, and renal disease. Noting the overall higher monocyte counts in men and the low rate of progression of DNMT3A-CMUS, we reveal that amending the definition of CMUS/CCMUS to incorporate sex-specific monocyte thresholds and the exclusion of isolated DNMT3A mutations from the definition significantly strengthens the association with incident MN. Finally, given their association with poor outcomes, we develop MoSAIC, a machine-learning classifier, to infer the presence of SRSF2 mutations (associated with high MN risk) among individuals with monocytosis, based on complete blood count indices alone. We corroborate our findings in an independent cohort of 625 328 Danish primary care patients. Our findings underscore the clinical relevance of CMUS and CCMUS as distinct high-risk states within the spectrum of CH and establish an evidence base to refine their diagnostic definition.

Humans↗