BMJ

Background. Recent meta-analyses of randomized controlled trials (RCTs) claimed efficacy of higher-dose fluvoxamine (2 x 100 mg/day, as opposed to 2 x 50 mg/day) in prevention of disease deterioration in adults with mild - moderate COVID-19 disease. Objectives. Investigate whether such claims are supported by the data. Methods. Systematic review and meta-analysis of RCTs evaluating higher-dose fluvoxamine in this indication. Results. Seven studies declared as RCTs were identified, one of which was severely biased (open-label, non-standardized and unreported standard of care as a control), and eventually ended as non-randomized (huge attrition). Composite endpoints of deterioration in the 6 included placebo-controlled trials contained elements susceptible to error and bias. Three trials were small (<100 patients/arm), three were larger (270 - 750 patients/arm). Deaths and need for mechanical ventilation were sporadic and observed in only one trial. Hospitalizations were also sporadic in 5/6 trials. Frequentist methods generally appropriate for random-effects analysis of low number of trials with rare outcomes (generalized linear mixed models, beta-binomial or binomial-normal) greatly underestimated heterogeneity, but still did not document benefits regarding the composite endpoints or hospitalizations. Bayesian hierarchical models revealed huge heterogeneity and indicated no benefit regarding: (i) composites of deterioration, large trials OR = 0.78 (95% CrI 0.55 - 1.21); multiplicity corrected OR = 0.87 (0.64 - 1.21); (ii) hospitalizations, small trials OR = 0.88 (0.45 - 1.72); large trials OR = 0.94 (0.52 - 1.75); all trials OR = 0.81 (0.47 - 1.43). Heterogeneity was unlikely due to clinical particulars (vaccination status, treatment duration, time horizon), and more likely due to unidentified bias. Conclusions. RCTs do not support efficacy of higher-dose fluvoxamine in prevention of disease deterioration in adults with mild - moderate COVID-19 disease.

Objectives To quantify the frequency of baseline control-group use in published long COVID prevalence studies and assess their key methodological features. Design Cross-sectional meta-epidemiological evaluation of published post-acute COVID-19 prevalence studies, supplemented by a corresponding-author survey. Setting Published studies identified through a systematic review by Hou et al. (2025) and supplementary data obtained through direct email contact with corresponding authors. Participants A total of 440 published long COVID prevalence studies. Main Outcome measures Presence and type of comparator group, reliance on solely self-reported outcomes, acknowledgment of lack of a control group among uncontrolled studies, and availability of additional comparator data through author survey. Results Among 440 studies, 372 (84.5%) reported no control group on their publication. Healthy or uninfected comparators were reported in 55 studies (12.5%) and other comparator types in 14 (3.2%); 1 study included both categories. Solely self-reported outcomes were used in 279 studies (63.4%). Among 372 uncontrolled studies, 244 (65.6%) did not explicitly acknowledge the absence of a baseline comparator as a limitation anywhere in text. Corresponding authors of 140 studies (31.8%) responded to the survey; among them, 126 (90.0%) reported no additional comparative data, while 14 (10.0%) mentioned some available comparative datasets (19 additional datasets). Almost all of that information (10/14, 17/19) had been already published in other articles not captured by the Hou et al. systematic review. Conclusions Most published long COVID prevalence studies lacked comparator groups and relied exclusively on self-reported outcomes without acknowledging this limitation. Direct author contact identified little additional comparator information. Much of the long COVID prevalence literature may therefore be poorly suited to estimating burden attributable specifically to SARS-CoV-2, underscoring the need for appropriately matched comparators and more objective outcome assessment. Registration The protocol was prospectively registered on the Open Science Framework (https://osf.io/f4hra).

BackgroundOnline professional learning offers a scalable alternative to traditional face-to-face learning, but there are doubts regarding how well it works and when it works best. This review assessed the effectiveness of online professional learning interventions on healthcare professionals knowledge and skill acquisition. MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials that compared online professional learning against static controls or face-to-face controls. We searched MEDLINE Complete, Scopus, Embase, CENTRAL, and PsycINFO from inception to January 31, 2025. Eligible studies included practising healthcare professionals in any clinical setting that measured knowledge or skill acquisition related to patient care. Data was extracted in duplicate, with disagreements resolved through discussion or by a third reviewer. We used multilevel meta-analyses to estimate the overall effect size and conducted moderation analyses for pre-specified factors. The study protocol was pre-registered on the Open Science Framework (OSF; https://osf.io/46zav). FindingsOf 55,376 records; 171 studies (391 effects, 25,412 participants) met the inclusion criteria. Online learning significantly improved knowledge and skill acquisition compared to static controls (g = 0.93, 95% CI [0.78,1.07], p < 0.001; I{superscript 2} = 89.8%), with larger effects in lower-middle income countries (g = 1.30, 95% CI [0.88, 1.72]) than in high income (g = 0.75, 95% CI [0.63, 0.86]). Online learning also significantly improves outcomes compared to face-to-face instruction (g = 0.45, 95% CI [0.31,0.59], p < 0.001; I{superscript 2} = 85.92%), with larger effects for knowledge outcomes (g = 0.46, 95% CI [0.33, 0.59]) than skills outcomes (g = 0.20, 95% CI [0.04, 0.36]). Effects did not differ significantly by profession, clinician experience, clinical setting, intervention characteristics or the learning design features (all p > 0.05). No studies had low overall risk of bias, and some evidence of publication bias was found. InterpretationFrom this body of evidence, we identified that online learning appears to improve healthcare professionals knowledge and skill acquisition, exceeding traditional teaching methods. Healthcare organisations can be confident implementing or expanding online professional learning to improve knowledge and skill acquisition. FundingNo funding

ObjectiveDetermine acceptability and feasibility of loop electrosurgical excision procedure (LEEP) combined with adjuvant intravaginal 5-fluorouracil (5FU) for treatment of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) in women living with HIV (WLWH). DesignDouble-blind, randomized, placebo-controlled Phase 2b feasibility trial. SettingPublic-sector hospital in Johannesburg, South Africa. Population180 WLWH aged 18+ years with CIN2/3 confirmed by LEEP and on antiretroviral therapy for [&ge;]60 days. MethodsParticipants underwent LEEP and were randomly assigned (1:1) to receive 8 doses of adjuvant 5FU or placebo cream every other week and followed for 24 weeks. Main Outcome MeasuresThe primary outcomes were acceptability and feasibility (adherence, retention, safety, tolerability). ResultsBetween March 2023 and January 2025, we randomized 180 WLWH. Median age was 41 years (interquartile range [IQR]: 35-45), median CD4+ count was 636 cells/mm3 (IQR: 376-873), and 98.9% were virologically suppressed. Acceptability (>94%) and adherence (>91%) were high and comparable between arms. Retention exceeded 92% in both arms, although Week 24 attendance was lower in the 5FU arm (92.2% vs. 98.9%, probability difference [PD] -6.7%, 95% confidence interval [CI] -14.4%, -0.5%). Safety events were mild, more common with 5FU, and primarily reported as Grade 1 or 2 cervical inflammation (49.2% vs. 26.7%, risk difference [RD] 22.5%, 95% CI 8.6%, 36.4%). One Grade 3 adverse event (an allergic reaction to 5FU) resulted in treatment discontinuation. ConclusionsLEEP plus adjuvant intravaginal 5FU is acceptable and feasible among WLWH in South Africa, supporting progression to a Phase 3 trial. Clinical Trial RegistrationNCT05413811. FundingUnited States National Institutes of Health (R01CA250850).

IntroductionObstetric litigation is the largest single category of NHS clinical negligence by cost. The last systematic analysis of NHS obstetric litigation data was published in 2012 [1]. Despite major national safety programmes, annual costs have continued to escalate. This study aims to update the analysis and consider ethical and resource implications. MethodsFOI claims data were obtained from NHS Resolution for 2015/16-2024/25, supplemented by cerebral palsy and brain damage (CP/BD) data for the most recent six years. Activity-weighted HRG unit costs for 2024/25 and 2023/24 were used to compare planned vaginal birth (PVB) and planned caesarean section (PCS) pathway costs, incorporating indemnity attribution by cause-code proportion. The consent architecture was reviewed against Montgomery v Lanarkshire Health Board [2015] UKSC 11. ResultsOver the period, 11,881 claims were notified (approximately one per 500 England NHS births); 7,216 were settled, with total damages of {pound}5,974 million, rising approximately 85% in real terms. Four intrapartum monitoring failure codes and seven labour-exclusive delivery complication codes together accounted for {pound}2,776 million paid (55.9% of all obstetric damages). CP/BD claims represented 16.6% of volume but 77.7% of obstetric damages over 2019/20-2024/25, at an average of {pound}3.58 million per claim. Activity-weighted HRG analysis at 2024/25 tariff showed PCS at {pound}6,202 versus PVB at {pound}6,339 per birth. ConclusionsObstetric litigation costs continue to escalate, driven overwhelmingly by labour-attributable harm. NHS England data show, for the first time, PCS tariff costs below PVB. Including indemnity under the primary eleven-code attribution, total system cost excess of PVB reaches approximately {pound}1,032-{pound}3,082 per birth (2024/25 cash to actuarial basis). Consent architecture for planned mode of delivery raises a potential inconsistency with Montgomery. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSObstetric litigation is the largest single category of NHS clinical negligence by cost, driven overwhelmingly by intrapartum harm, yet no systematic analysis of cause-code data has been published since 2012. What this study addsTen years of NHS Resolution FOI data show that eleven labour-exclusive cause codes account for 55.9% of obstetric damages; NHS England tariff data show, for the first time, that planned caesarean section ({pound}6,202) is less costly than the planned vaginal birth pathway ({pound}6,339), and when indemnity is included the total system cost excess of planned vaginal birth reaches {pound}1,032-{pound}3,082 per birth. How this study might affect research, practice or policyA formal comparative-risk consent process at booking, equivalent to that currently required for planned caesarean section under RCOG Consent Advice No. 14, should be considered standard for all women; NICE should update its economic analysis of mode of delivery to incorporate litigation costs; and NHS tariff methodology should be reviewed to ensure indemnity is allocated in proportion to the pathway-level mechanisms that generate it.

ImportanceWomen have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. ObjectiveTo assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). DesignRetrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. SettingMultinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. ExposuresGLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and MeasuresCardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. ResultsDrug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13-1.70]) while non-differential risk among men (HR 0.91 [0.74-1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98-1.19]) while lower risk among men (HR 0.87 [0.78-0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and RelevanceThis large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.

Background and Aims SARS-CoV-2 infection is associated with an increased risk of cardiovascular, cerebrovascular and venous thromboembolism events. We aimed to assess the impact of COVID-19 vaccination prior to SARS-CoV-2 infection on the risk of these events post-infection. Methods Embase and MEDLINE were searched from January 2021 to 11 September 2025, supplemented by citation searching. Observational studies were included if they reported risks of cardiovascular, cerebrovascular, or venous thromboembolic events after SARS-CoV-2 infection between different vaccination groups (e.g. unvaccinated, vaccinated, or booster vaccinated), or reported risk of events after SARS-CoV-2 infection compared with no infection, stratified by vaccination status. Random-effects meta-analyses were conducted to estimate pooled hazard ratios (HRs) comparing vaccinated and unvaccinated individuals across prespecified outcomes. Results Twenty-three studies were included in the systematic review; most reported an association between vaccination and a reduced risk of post-infection vascular events. Ten studies were included across meta-analyses comparing vaccinated and unvaccinated individuals. Pre-infection vaccination was associated with significantly reduced risks of composite cardiovascular/cerebrovascular events (HR 0.60, 95% confidence intervals [CI] 0.51-0.69), stroke (HR 0.75, 95% CI 0.64-0.88), acute coronary syndrome (HR 0.70, 95% CI 0.52-0.95), arrhythmias (HR 0.82, 95% CI 0.69-0.98), and venous thromboembolism (HR 0.51, 95% CI 0.36-0.73). No statistically significant reduction was observed for heart failure (HR 0.72 [95% CI 0.47-1.10]). Conclusions Pre-infection COVID-19 vaccination is associated with lower risks of cardiovascular, cerebrovascular and venous thromboembolism events following SARS-CoV-2 infection in the pre- and post-Omicron eras, supporting its role within broader prevention strategies

BackgroundThe multicentre WOMAN trial showed that tranexamic acid reduces postpartum haemorrhage (PPH) deaths. Several studies have recommended adjusting for clustering at the country and centre level to improve power and reduce bias in the standard errors. We reanalysed data from the WOMAN trial, adjusting for these centre effects. MethodsThe WOMAN trial recruited 20,060 women with clinically diagnosed PPH from 193 centres in 21 countries. The intervention was intravenous tranexamic acid versus matching placebo and the outcome was death from bleeding within 42 days of randomisation. We reanalysed data for the 14,928 women treated within 3 hours of birth for whom tranexamic acid provided the most benefit. We used random effects logistic regression to calculate the effect of tranexamic acid taking into account variation in risk of death and treatment effectiveness by country and centre. We calculated intraclass correlations (ICCs) to quantify between country and between centre within country variation. Results216 (1.4%) women died from bleeding. Using a univariable analysis without adjusting for centre effects, we found tranexamic acid reduced the odds of death from bleeding by 31% (OR=0.69 95% CI: 0.52-0.90, p=0.007). Adjusting for baseline covariates (age, systolic blood pressure (SBP) and SBP2) but not country or centre yielded a 36% odds reduction (OR=0.64 95% CI: 0.48-0.85 p=0.002). Adjustment for baseline covariates, country and centre yielded a 37% odds reduction (OR=0.63 95% CI: 0.48-0.85 p=0.002). We found substantial between country and centre variation in outcomes but not treatment effectiveness. The ICC for outcome was 14% for country and 19% for centre within country. ConclusionsAdjusting for country and centre effects made negligible differences to the magnitude of the treatment effect estimate or its associated p-value. Consistent with other studies of large clinical trials for medicines with binary outcomes, we found considerable between country and centre variation in outcomes but not in relative treatment effectiveness. Despite substantial ICCs for the outcome, adjusting for country and centre effects had minimal impact on our results. Trial registrationclinicalTrials.gov:NCT00872469 (March 2009)

IntroductionCurrent UK guidelines recommend measurement of symphyseal fundal height and measurement of maternal blood pressure and urinalysis, with the aim of detecting women at increased risk of fetal growth restriction (FGR) and preeclampsia. Between 2008 and 2013 we conducted a prospective cohort study recruiting 4,512 nulliparous women at the Rosie Hospital, Cambridge, where we performed serial ultrasonic imaging and serial blood sampling and generated a novel screening test for preeclampsia and FGR. The method involved measuring the ratio of two placental biomarkers (soluble fms-like tyrosine kinase receptor-1 [sFLT1] and placenta growth factor [PlGF]) at [~]36 weeks of gestational age (wkGA) and combining the result with maternal characteristics and ultrasonic imaging. Women who screened positive had a [~]50% risk of a composite outcome, consisting of preeclampsia {+/-} delivery of a baby with a birth weight <3rd percentile for sex and gestational age {+/-} perinatal morbidity or death. It is plausible that screening and intervention using this method might improve pregnancy outcome. Methods and analysisNulliparous women with an apparently normal singleton pregnancy will be recruited at their dating ultrasound scan. Blood will be obtained at this visit, at their anomaly scan (20wkGA), and at two research appointments (28wkGA and 36wkGA) when research ultrasound scans will be performed. Blood for DNA will be obtained from the father of the baby where possible and the placenta will be sampled following birth. At 36wkGA, women will be consented for participation in the randomised controlled trial (RCT) element of the study and their risk of term preeclampsia and FGR will be assessed using the novel approach. Women who screen high-risk will then be randomly allocated to either having the result revealed or masked. Women randomised to having the result revealed will be offered early delivery and/or enhanced monitoring. Where the result is masked, there will be no communication between the research team and the participant, and she will continue to receive routine care at the Rosie Hospital. The primary outcome is a composite of preeclampsia, FGR and perinatal morbidity and mortality. The study will also generate data and biological samples to support future research in novel screening methods and disease mechanisms. Ethics and disseminationThe study received ethical approval from the East of England Research Ethics Committee. All women provide written informed consent to participate in the cohort. Women provide a second written informed consent to participate in the RCT. The study results will be disseminated by presentation at international conferences and publication in peer reviewed journals. Trial registration07/10/2019 ISRCTN12181427 (https://doi.org/10.1186/ISRCTN12181427) Strengths and limitations of the study [Table 1]

Background: The observational literature on comparative effectiveness is expanding rapidly but remains difficult to synthesize. Discordant findings often stem from structural differences in cohort definitions, inclusion criteria, and follow up windows, leaving stakeholders without a cohesive evidence base. Furthermore, studies typically focus on a narrow subset of outcomes, neglecting the broader needs of diverse healthcare stakeholders 1,2,3,4. Methods We developed a high throughput evidence generation workflow using linked EHR and administrative claims data. The cornerstone is a prespecified measurement architecture applied uniformly across clinical scenarios: six post index windows (acute to two year follow.up); 28 Elixhauser comorbidities; 14 healthcare resource utilization (HCRU) categories; 29 laboratory measures with 52 binary thresholds; and 42 adverse event categories. We generated unadjusted treatment comparisons across ~1,038 outcomes per scenario, including effect-measure modification (EMM) assessments across 130 baseline features. Results Across 40 clinical domains, the workflow produced approximately 32,982,552 outcome evaluations. An evaluation included a treatment comparison outcome population effect estimate with uncertainty bounds and supporting diagnostics. Approximately 5,000 narrative summaries underwent structured clinical and statistical quality control before dissemination. Conclusions Standardized, high throughput workflows can shift evidence generation away from fragmented studies toward comprehensive evidence packages. This shared evidence base supports precision medicine by making treatment effect heterogeneity visible across clinically meaningful subpopulations, reducing the need for redundant, stakeholder-specific studies.

Background Planned caesarean birth (CB) is an increasingly utilised intervention, observed in almost 1 in 6 first-time mothers giving birth in the UK in 2023-24. Outcomes of planned (or actual) CB have been compared with planned (or actual) vaginal birth (VB) in a UK national guideline, but the scope of the comparison does not fully reflect the range of outcomes of interest to stakeholders. This review provides a comprehensive synthesis of outcomes of planned or actual CB with planned or actual VB to shape information resources which support informed birth planning. Methods The UK NICE Caesarean Birth Guideline NG192 evidence review of outcomes associated with planned CB (or actual CB where no planned CB data was available) was updated and expanded to incorporate additional outcomes prioritised by stakeholders. Results A total of 33 new study reports were combined with 32 reports previously included in NG192. All new reports were observational cohort studies or systematic reviews at low risk of bias. Only 3 studies reported outcomes of planned CB compared with planned VB (regardless of actual mode of birth), whereas all remaining studies reported actual VB outcomes. Planned CB was followed by more maternal infection (wound infection, mastitis, endometritis and urinary tract), venous thrombosis and lower neonatal unit admission rates than a planned VB. In the long-term, CB was linked to one or more sexual problems (insufficient lubrication and dyspareunia) being more common, future pregnancy being less common, and infertility being more frequent than after VB. For offspring, infant urinary tract infection after any CB, gastrointestinal tract infections and autism after planned CB were more common compared with VB. New findings highlight conflicting reports on childhood asthma and type 1 diabetes risk after planned CB, suggesting that prior positive associations may be explained by confounding. Existing evidence in NG192 suggests that cardiac arrest, maternal death and hysterectomy are more common after planned CB, but arise from studies at high risk of bias. NG192 also reports that placenta accreta and uterine rupture in a future pregnancy are more common after any CB. No new evidence was identified on these outcomes. Conclusion This review provides stakeholder-relevant information to populate decision-support materials on outcomes of planned (and actual) CB compared with planned (and actual) VB. The existing evidence base lacks data on long-term outcomes of planned (rather than actual) VB.

BackgroundThe 2025-2026 COVID-19 vaccine season introduced updated formulations targeting the LP.8.1 lineage. This study assessed the absolute vaccine effectiveness (aVE) of mRNA-1283 and BNT162b2 on COVID-19 outcomes in adults aged [&ge;]65 years. MethodsThis retrospective study used linked electronic health record and administrative claims data through Jan 31, 2026. Adults [&ge;]65 years who received the mRNA-1283 or BNT162b2 2025-2026 COVID-19 vaccine were matched to unvaccinated individuals. Inverse probability of treatment weighting was applied to each vaccines matched cohorts to balance covariates. Each vaccine was evaluated independently against its own unvaccinated comparator group. aVE against COVID-19 related hospitalization and medically-attended COVID-19 was estimated using Cox proportional hazards models; aVE = 100 x (1 - hazard ratio [HR]). ResultsWe identified 233,072 mRNA-1283 recipients and 422,610 BNT162b2 recipients [&ge;]65 years. The aVE (95% confidence interval) of mRNA-1283 against COVID-19 related hospitalization and medically-attended COVID-19 was 59.3% (39.0%, 72.9%) and 42.0% (35.0%, 48.3%) among adults [&ge;]65 years and 66.9% (45.9 %, 79.8%) and 50.2% (42.1%, 57.2%) in [&ge;]75 years, respectively. The aVE of BNT162b2 against COVID-19 related hospitalization and medically-attended COVID-19 was 48.3% (32.4%, 60.5%) and 41.2% (36.2%, 45.8%) in [&ge;]65 years and 45.9% (26.0%, 60.4%) and 44.0% (37.8%, 49.6%) in [&ge;]75 years, respectively. ConclusionsThis is the first real-world evidence showing that mRNA-1283 prevents COVID-19-related hospitalizations and medically attended events in vulnerable older adults at highest risk of severe disease. These findings support mRNA-1283 as an important public health tool for reducing the ongoing burden of COVID-19.

Objective To map the presence, public availability, and content of clinical trial data sharing policies (DSP), data management and sharing plans (DMSP), and data use agreements (DUA) among the most prolific public and private clinical trial sponsors operating in the European Union, and to identify key areas of convergence, divergence, and constraint in the context of General Data Protection Regulation (GDPR). Eligibility criteria We included organisation-level documents describing approaches to clinical trial data sharing or data management from the top 20 public and top 20 private sponsors ranked by the number of trials registered in the EU Clinical Trials Information System (CTIS). Eligible materials comprised publicly available or sponsor-shared policies, guidelines, statements, templates, and agreements relevant to clinical trial data sharing or management. Sources of evidence Evidence was identified through systematic searches of sponsors' public websites, structured Google searches, and major data management plan platforms (DMPTool, DMPonline, DMP Assistant), complemented by direct contact with sponsors to verify findings and request missing documentation. All sources were archived and catalogued. Charting methods Two reviewers independently extracted data using a structured form, capturing the existence, accessibility, and content of data sharing policies, data management and sharing plans, and data use agreements. Quantitative data were summarised descriptively, and a non-interpretive descriptive content analysis was conducted to characterise recurring policy elements and areas of heterogeneity. Results Among 40 sponsors, private sponsors were substantially more likely than public sponsors to make trial-specific data sharing policies and data use agreements publicly accessible, often via established data sharing platforms. Public sponsors more frequently referenced data management and sharing plans, but these were heterogeneous in scope and often embedded within broader institutional governance documents rather than tailored to clinical trials. Across sectors, GDPR compliance, data protection, and legal safeguards were emphasised, while operational aspects such as dataset readiness, review criteria, and downstream responsibilities varied widely. Overall response rate to sponsor verification was 37.5%. Conclusion Clinical trial data sharing governance in the EU shows a marked sectoral imbalance among the top sponsors. Private sponsors tend to provide more detailed and operationally explicit documentation, whereas public sponsors often articulate high-level commitments without trial-specific guidance. Greater clarity and standardisation, particularly among public sponsors, could improve transparency and facilitate responsible data reuse, while remaining compatible with GDPR requirements.

BackgroundRare diseases (RD; enfermedades poco frecuentes, EPoF, in Chilean policy terminology) collectively affect 3.5-5.9% of the population and are associated with long diagnostic trajectories. Chile lacks a reproducible national operational definition for identifying RD in administrative hospital data. MethodsWe conducted a retrospective observational analysis of Chilean GRD-IR events (IR-29301 version) for 2019-2024 released through FONASA Datos Abiertos, covering hospital discharges and major ambulatory surgery reported by 72 public establishments for FONASA-covered persons. The canonical analytical cohort contained 5,779,482 DRG events in 4,027,921 linked patients. We constructed a Chilean Orphanet-ICD-10 homologation and audited it through an agentic human-in-the-loop pipeline, yielding a conservative RD operational catalogue (434 final ICD-10 codes in the KEEP + MAP_TO_SPECIFIC_ORPHA scenario). RD-coded DRG events were labeled as observed inpatient odysseys when at least one prior DRG event existed for the same patient. We quantified prior events, DRG-observed inpatient trajectory time, nonspecific prior diagnoses, DRG weight, and bridge-code associations. Bridge-code enrichment was estimated using patient-level Fisher exact tests with Benjamini-Hochberg false-discovery correction; event-level estimates were retained as sensitivity analyses. ResultsThe audited conservative catalogue identified 55,284 primary-diagnosis RD-coded DRG events in 45,784 patients and 374,866 RD-coded events in any diagnostic field. We characterized 63,685 observed inpatient odyssey cases in 25,648 unique patients across 371 audited RD ICD-10 codes. Median DRG-observed inpatient trajectory time to RD-coded diagnosis was 241 days, and mean prior events per odyssey was 8.1. Bridge-code analysis identified 616 associations with support [&ge;] 10 patients and 390 with q < 0.05; 350 significant associations were no-same-code administrative trajectory signals. These signals varied in interpretation, including clinically plausible precursors, diagnostic refinement, and care-process bridges. The Odyssey Index reordered conditions relative to raw prior-event counts, separating high-volume entities from stronger trajectory signatures. ConclusionsTo our knowledge, we provide the first nationwide audited and reproducible characterization of inpatient RD diagnostic odysseys in Latin America using administrative hospital data. The framework supports trajectory surveillance, registry design, quality-control analyses, and prioritization of candidate signals for prospective clinical validation under Chiles Law 21,743. Bridge-code associations should be interpreted as statistically enriched administrative signals, not as validated causal or clinical pathways. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/26352213v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@42593borg.highwire.dtl.DTLVardef@1f0690aorg.highwire.dtl.DTLVardef@803365org.highwire.dtl.DTLVardef@ae41af_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. Updated canonical FONASA DRG/GRD-IR 2019-2024 cohort, audited RD catalogue, odyssey cohort, and bridge-code signal summary. C_FIG

Background: COVID vaccination with periodically updated compositions remains important as SARS-CoV-2 continues to circulate, cause disease, and evolve. Available COVID-19 vaccines in the 2024-2025 season differed by platform, including mRNA-1273, an mRNA-based vaccine, and NVX-CoV2705, a recombinant protein-based vaccine and antigen composition (KP.2-targeted and JN.1-targeted, respectively). There is limited head-to-head real-world evidence comparing the effectiveness of these different approaches to prevention of severe outcomes with COVID-19. We compared mRNA-1273 with protein-based NVX-CoV2705 in insured US adults vaccinated during the 2024-2025 season. Methods: We conducted a retrospective matched cohort study in a large US claims database. Adults aged 18 years or older who received mRNA-1273 or NVX-CoV2705 between Aug 31, 2024 and Feb 28, 2025 were eligible. Recipients were exactly matched 2:1 on key demographic and clinical factors and then weighted with stabilized inverse probability of treatment weights. Outcomes were medically-attended COVID-19 and hospitalization with COVID-19 from day 7 after vaccination through up to 180 days of follow-up. We calculated comparative vaccine effectiveness (cVE) as 100 x (1-- hazard ratio). Results: Of 858,138 eligible mRNA-1273 recipients and 34,667 eligible NVX-CoV2705 recipients, 69,140 and 34,570, respectively, entered the matched cohort. Median (Q1, Q3) follow-up was 180 (163, 180) days for mRNA-1273 and 180 (162,180) for NVX-CoV2705. Medically attended COVID-19 occurred in 706 (1.02%) mRNA-1273 recipients and 512 (1.48%) NVX-CoV2705 recipients; adjusted cVE (95% CI) was 31.7% (23.4%, 39.1%). Hospitalization with COVID-19 occurred in 61 (0.09%) and 49 (0.14%) recipients, respectively; adjusted cVE (95% CI) was 40.7% (13.5%, 59.4%). In the 47,754 mRNA-1273 recipients matched to 23,877 NVX-CoV2705 recipients aged [&ge;]65, adjusted cVE (95% CI) was 25.7% (15.4%, 34.8%) against medically-attended COVID-19 and 41.7% (14.3%, 60.4%) against hospitalization with COVID-19. Conclusions: In this insured US adult population, mRNA-1273 demonstrated greater effectiveness against medically attended COVID-19 and hospitalization with COVID-19 than the protein-based NVX-CoV2705. These findings highlight the potential public-health importance of considering vaccine platform and variant selection when planning for upcoming seasons.

BackgroundReceiving fewer COVID-19 vaccine doses than recommended ("undervaccination") may increase risks of death, severe COVID-19, and post-COVID condition. However, population-scale evidence from Italy remains limited. We aimed to characterise determinants of undervaccination in Lombardy and to quantify its association with mortality, severe COVID-19, and long COVID outcomes. MethodsWe conducted a population-based study including all residents of Lombardy aged [&ge;]30 years who were alive on June 1, 2022 (n=6,836,566), and followed them until Dec 31, 2024. Vaccine deficit was defined as the difference between age-specific recommended doses (three for <60 years; four for [&ge;]60 years) and doses received, and was modelled as a time-varying exposure. Outcomes were all-cause mortality, severe COVID-19 (hospitalisation or COVID-19-related death), and long COVID defined using symptom-based ICD codes recorded [&ge;]1 month after infection. Determinants of undervaccination were assessed using multivariable logistic regression. Age-stratified Cox models estimated adjusted hazard ratios (HRs). Counterfactual vaccination scenarios were simulated using fitted survival models. ResultsOn June 1, 2022, 1,668,014 individuals (24{middle dot}4%) were not up to date with recommended vaccination. Undervaccination was more frequent in younger adults, women, individuals born outside Europe, rural residents, and those with high comorbidity burden. During follow-up, 265,383 deaths, 52,121 severe COVID-19 events, and 23,780 long COVID events occurred. In adults aged [&ge;]60 years, increasing vaccine deficit was associated with progressively higher risks of mortality (HR up to 1{middle dot}63) and severe COVID-19 (HR up to 2{middle dot}16). Associations were weaker in younger adults. For long COVID, effect estimates were modest and sensitive to outcome definition. Simulated universal booster coverage in adults [&ge;]60 years was associated with substantial reductions in expected deaths and severe COVID-19 events. ConclusionAbout one in four adults in Lombardy was undervaccinated by mid-2022. An increasing vaccine deficit was associated with a higher risk of severe COVID-19 and mortality, particularly in older adults. Sustaining booster uptake in high-risk groups remains central to mitigating the COVID-19 burden.

BACKGROUNDPoint-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODSWe conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTSSix sites participated with 59,980 ED presentations (44,747 individuals, 61{+/-}19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONSImplementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing. (Australia New Zealand Clinical Trials Registry ACTRN12619001189112) Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIPoint-of-care troponin assays with good precision have become available and received regulatory approval as high-sensitivity assays. C_LIO_LIA pragmatic stepped-wedge cluster randomized trial implementing the validated Siemens VTLi high-sensitivity point-of-care assay into 6 emergency departments investigating [~]60,000 patients, was conducted to ascertain if the rapid turnaround time reduced lengths of stay. C_LIO_LIIntroduction of the VTLi high-sensitivity point-of-care assay into clinical pathways reduced emergency department lengths of stay by an average 13% (47 minutes) without compromising safety. C_LI What are the clinical implications?O_LIEarly decision-making using a point-of-care high-sensitivity troponin assay within a structured clinical pathway was safe. C_LIO_LIFaster turnaround means troponin results are consistently available when clinicians first seek them. This can facilitate earlier decisions and reduce patient length of stay. C_LI

Title and abstract screening limit the timeliness of systematic reviews used for clinical guidelines. We evaluated audited large language model (LLM) triage at Sweden's National Board of Health and Welfare. Ten LLMs from five model families were tested on 419 Cochrane reviews comprising 26,892 records, and the selected ensemble was externally validated on 133 reviews including 8,501 records matched to planned guideline topics. The same locked model pair was then used prospectively across 24 systematic reviews in two national guideline programmes. On the 419-review selection benchmark, the selected Gemini-3-flash plus GPT-5.1 ensemble achieved 98.0% (95% CI, 97.3-98.7) mean review-level sensitivity, while topic-matched validation yielded 96.7% sensitivity (95% CI, 93.7-98.9). Prospective deployment screened 74,679 records, placed 63,858 (85.5%) in the AI-excluded pool and reduced estimated first-pass screening effort from 415 to 34 person-days. Across 600 randomly sampled AI-excluded records from the migraine and dementia programmes, none was confirmed as a final false negative after post-unblinding adjudication; across the completed 680-record audit, all 38 final retained records had been AI flagged, whereas locked blinded human consensus missed seven. These findings support locked, audited LLM triage, with human oversight and programme-specific monitoring, for systematic reviews used in national guidelines.

ImportanceCesarean delivery is the most common surgery in the US with more than 1 million performed each year; it is also the most significant risk factor for postpartum infection. The Cesarean Section Optimal Antibiotic Prophylaxis trial demonstrated that the addition of azithromycin at the time of cesarean birth performed in labor reduces postpartum infection. ObjectiveTo determine the real-world adoption and effect of this trial on clinical practice and postpartum infections among U.S. pregnant persons undergoing cesarean delivery in labor. DesignDifference-in-differences analysis from 2013-2024. SettingPopulation-based, patient-level analysis using Epic Cosmos, a large longitudinal national electronic health record database of patients seen in health systems using Epic. ParticipantsPregnant individuals who received outpatient prenatal care in the system, who labored and gave birth to a liveborn singleton infant at 24-43 weeks of gestation were included. Exclusion criteria included unknown mode of delivery and intraamniotic infection. ExposuresThe treatment group included those delivered by cesarean and the control group included those who delivered vaginally. The pre-period was defined as 2013-2016, excluding a washout period from trial publication until December 31, 2016, and the post-period was defined from 2017-2024. Main Outcomes and MeasuresThe primary outcomes were perioperative azithromycin administration and postpartum infection within 6 weeks of delivery. Results1,663,341 participants were included in the final analysis. In the pre- and post-periods, azithromycin was administered in 0.01% and 0.04% of vaginal births and in 2.2% and 39.6% of cesarean births, respectively. In the pre- and post-periods, postpartum infection occurred in 2.0% and 2.7% of vaginal births and 9.2% and 8.0% of cesarean births. In the adjusted difference-in-difference analysis, the trial resulted in an absolute increase in azithromycin use by 37.6 percentage points (pp) (95% CI: 33.1 to 42.2 pp); postpartum infection decreased by 2.0 pp (95% CI: -2.5 to -1.4 pp), a relative decrease of 20%. Conclusions and RelevanceOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among pregnant persons undergoing a cesarean delivery in labor. Key PointsO_ST_ABSQuestionC_ST_ABSDid evidence from the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial change real-world clinical practice and decrease postpartum infections among U.S. pregnant persons who underwent a cesarean delivery in labor? FindingsIn this difference-in-differences analysis of 1.6 million births, azithromycin use increased 37.6 percentage points and postpartum infections decreased by 2.0 percentage points following the C/SOAP trial. MeaningOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among individuals having a cesarean delivery in labor.

Background Home Test-to-Treat (HTTT) programs deliver timely antiviral treatment for acute respiratory infections, including COVID-19 and influenza, through at-home testing and telehealth. Because access is often measured by visit occurrence, variation in how and when care is delivered may be overlooked. We hypothesized that telehealth access follows distinct process-based patterns. Methods We analyzed de-identified encounters from the national HTTT program (September 2023-July 2024); 6,213 of 8,160 eligible individuals remained after exclusions for missing data. Phenotypes were derived by k-means clustering of standardized variables capturing encounter timing, modality preference, process duration, and sociodemographic and digital access attributes. Ten-day surveys assessed symptom duration and healthcare utilization. Results Three phenotypes emerged: Delayed/Disrupted Access (n = 1,537; 24.7%), Digitally Engaged but Socioeconomically Vulnerable (n = 1,460; 23.5%), and Mainstream Access and Efficient Utilization (n = 3,216; 51.8%). Mean process duration differed (15.93 [SD 3.84] vs 3.69 [3.31] vs 2.87 [2.41] hours; p < 0.001). Synchronous preference was lowest in the Digitally Engaged group (22.9%); antiviral prescribing was high (88.6%-91.9%). Among 10-day respondents (n = 1,023), symptom duration did not differ. Emergency department visits were most frequent in the Digitally Engaged group (2.3% vs 0.0% and 0.5%; p = 0.02) and urgent care in the Delayed/Disrupted group (5.8% vs 4.1% vs 2.0%; p = 0.02). Conclusions Telehealth use in a national HTTT program formed distinct phenotypes defined by timing, modality, and care-process efficiency. Evaluating equity requires attention to how and when care is delivered, not simply whether it occurred.