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.

BackgroundThe LP.8.1-containing COVID-19 mRNA vaccines were recommended for the 2025 seasonal vaccination campaigns in Europe and the United States. Safety data on these vaccines are limited. MethodsWe conducted a nationwide register-based cohort study in Denmark including all adults aged 65 years and older or at high risk of severe COVID-19 who had received previous COVID-19 vaccine doses. The study period was July 1, 2025, to December 3, 2025. We estimated incidence rate ratios using Poisson regression comparing rates of 30 adverse events within 28 days following LP.8.1-containing vaccination with reference period rates, adjusted for age, sex, region of residence, high risk of severe COVID-19, calendar time, and comorbidities. Self-controlled case series analysis was conducted as a complementary approach. ResultsAmong 1,565,697 individuals (mean age 69.5 years; 53.8% female), 958,633 received an LP.8.1-containing vaccine. Receipt of an LP.8.1-containing vaccine was not associated with a statistically significant increased rate of any of the 30 adverse events within 28 days after vaccination. The incidence rate ratio was 0.95 (95% CI, 0.86-1.06) for ischemic cardiac event, 0.83 (95% CI, 0.76-0.92) for cerebrovascular event, and 0.32 (95% CI, 0.04-2.50) for myocarditis. Results from the self-controlled case series analysis were similar. ConclusionsIn a nationwide cohort of more than 1.5 million adults, no increased risk of 30 adverse events was observed following vaccination with LP.8.1-containing COVID-19 mRNA vaccines.

BackgroundGLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited. ObjectivesTo compare the cardiovascular effectiveness of individual GLP-1RAs and SGLT2Is. MethodsWe conducted a multi-national, retrospective, new-user active-comparator cohort study using 10 US and non-US administrative claims and electronic health record databases. The study included 1,245,211 adults with T2DM receiving metformin who initiated second-line therapy with one of six GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or one of four SGLT2Is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin). Empagliflozin (393,499; 31.6%), semaglutide (235,585; 18.9%), dapagliflozin (208,666; 16.8%), and dulaglutide (207,348; 16.8%) were most commonly used. A secondary subgroup analysis included 316,242 patients with established cardiovascular diseases (CVD). Primary outcomes were 3-point major adverse cardiovascular events (MACE: acute myocardial infarction, stroke, sudden cardiac death) and 4-point MACE (adding hospitalization/ER visit with heart failure). Secondary outcomes included the individual components. Hazard ratios (HRs) were estimated for pairwise agent comparisons while on-treatment (per-protocol) and over total follow-up using Cox proportional hazards models, with propensity score adjustments, negative control calibration, and pre-specified study diagnostics to guard against potential confounding. Random-effects meta-analysis produced summary HR estimates across data sources that passed diagnostics. ResultsAcross the study cohort, individual GLP-1RAs and SGLT2Is demonstrated broadly similar cardiovascular effectiveness, both within and across drug classes. For example, semaglutide and empagliflozin showed comparable risks for 3-point MACE (meta-analytic HR 1.05; 95% CI 0.79-1.39) and 4-point MACE (meta-analytic HR 0.95; 95% CI 0.81-1.12), with consistent findings in the CVD subgroup. Study diagnostics confirmed adequate equipoise, covariate balance and statistical power to detect similarity in HRs between 0.8 and 1.2 for commonly used agents. ConclusionsIn this large-scale real-world study, individual GLP-1RAs and SGLT2Is exhibited largely comparable cardiovascular benefits, including in patients with established CVD. These findings align with network meta-analytic estimates from major cardiovascular outcome trials and broadly support current treatment guidelines. Clinical choices should be guided by relevant factors such as safety, adherence, tolerability, cost, and patient preference, where further work is needed.

The terms personalized, individualized and precision medicine are increasingly used to describe health interventions, yet their operational meaning in clinical research remains unclear. Despite extensive conceptual discussion, there is limited empirical evidence on how these labels are applied in randomized controlled trials (RCTs) and whether such trials meet standards of transparency and methodological rigor. We systematically examined 262 RCTs published between 2020 and 2022 that used the terms "personalized", "individualized", or "precision" in the title to describe an intervention. The term "personalized" was used most frequently (49.2%), followed by "individualized" (45.8%) and "precision" (5.0%). In most trials, personalization involved behavioral, digital, or pharmacological interventions, with few studies employing -omics approaches. Personalization was most often based on individual lifestyle factors, psychological characteristics, or disease classification. We also found that in most trials, personalization consisted of tailoring a single intervention to individuals (82.8%), often through individualized dosage (73.2%). Most included RCTs were judged to be at high risk of bias and showed limited transparency with respect to data and code sharing. Our study suggests that, in contemporary RCTs, the labels "personalized", "individualized", and "precision" are applied interchangeably to a wide range of heterogeneous interventions that are predominantly non-genomic. Greater conceptual clarity and stronger methodological standards are needed to ensure that claims of personalization in clinical research are empirically meaningful and reliable.

BackgroundLong COVID affects millions worldwide, yet the long-term trajectory of healthcare costs remains poorly characterized. Prior studies with limited follow-up have documented elevated but stable excess costs, leaving uncertainty about whether the economic burden attenuates or persists over time. MethodsWe conducted a retrospective cohort study using electronic health record data from 12 hospitals and 20 community health centers (January 2018 through December 2024). Adults with documented SARS-CoV-2 infection were classified as having Long COVID using a validated precision phenotyping algorithm or as controls without Long COVID. We used two-part generalized estimating equation models to estimate adjusted quarterly healthcare costs over 20 quarters, decomposed costs into visit frequency and cost-per-visit components, and conducted subgroup and sensitivity analyses accounting for differential mortality. ResultsAmong 143,544 adults (27,986 with Long COVID; 115,558 controls), the adjusted excess quarterly cost for Long COVID widened progressively rather than attenuating, increasing from $79 (95% CI, $48-$118) at baseline to $236 (95% CI, $176-$287) at quarter 19 - a threefold increase in the cost differential. Long COVID was associated with 20% higher odds of any healthcare utilization (OR, 1.20; 95% CI, 1.18-1.23) and 30% higher costs when care was accessed (cost ratio, 1.30; 95% CI, 1.25-1.35). Visit frequency diverged over time, reaching 44% higher utilization by quarter 19, while cost-per-visit premiums remained stable. Excess costs concentrated in the upper distribution tail (99th percentile difference: $8,482). The widening trajectory was consistent across subgroups defined by hospitalization status, sex, and comorbidity burden. Cumulative 5-year excess costs were $7,124 per Long COVID patient after mortality adjustment. ConclusionsContrary to assumptions of post-acute recovery, Long COVID is associated with progressively widening healthcare costs over five years, driven primarily by increasing utilization rather than care intensity, suggesting an evolving chronic disease burden with substantial and growing economic implications.

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).

BackgroundEffective interventions are needed to support co-creation of diabetes care plans that fit patients lives. We evaluated the QBSafe agenda-setting kit (14 conversation cards) for its impact on care fit and glycemic control when added to usual primary care. MethodsThis single-center, clinician-level cluster-randomized, open-label trial was conducted at a federally qualified health center in New Haven, Connecticut (ClinicalTrials.gov NCT05553912). Clinicians and their patients with type 2 diabetes and HbA1c >8% were randomized 1:1 to usual care with or without QBSafe cards. In the intervention arm, patients selected up to 3 cards highlighting concerns about life with diabetes prior to their visit. Primary outcomes were change at 6 months in care fit (Illness Intrusiveness Ratings Scale, IIRS) and HbA1c, analyzed by intention to treat. Secondary outcomes were treatment burden (Treatment Burden Questionnaire, TBQ) and diabetes distress (Diabetes Distress Scale, DDS), and satisfaction with visits. ResultsBetween February 2023 and July 2024, 143 participants (mean age 56 years; 61% female; 73% Hispanic; mean HbA1c 10%) were enrolled: 74 received usual care with QBSafe, 69 usual care alone. At 6 months, there were no significant between-arm differences in changes in IIRS (-3.9 [95% CI -10.4, 2.6]), HbA1c (-0.2% [95% CI -0.9, 0.5]), TBQ (1.0 [95% CI -16.6, 18.6]), or DDS (-0.1 [95% CI -0.4, 0.2]). Clinicians reported greater satisfaction when using QBSafe. Patient satisfaction was high and did not differ across arms. ConclusionsQBSafe cards improved clinician satisfaction but did not improve care fit or glycemic control. Future tools should focus on helping clinicians respond effectively to patient-identified challenges.

Whether the cumulative evidence for remote patient monitoring (RPM) in heart failure (HF) has reached a definitive threshold -- and whether benefits extend to geographically underserved populations -- remains uncertain. We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) of 65 RCTs (59 poolable; [~]23,000 participants) across four databases through February 2026, encompassing structured telephone support (15 trials), non-invasive telemonitoring (33), and invasive hemodynamic monitoring (11). Random-effects meta-analysis used REML with Hartung-Knapp-Sidik-Jonkman adjustment. RPM significantly reduced all-cause mortality (RR 0.890, 95% CI 0.819-0.966; P=0.007; I2=2.3%; k=41; NNT 84/year; prediction interval 0.820-0.965). TSA confirmed that accrued evidence exceeded the required information size, establishing firm evidence that additional RPM-versus-control trials are unlikely to overturn the mortality benefit. HF hospitalization was reduced (RR 0.782, 95% CI 0.711-0.859; P<0.001; k=39; NNT 17/year), though the prediction interval crossed 1.0 (0.589-1.038), indicating that in some settings the effect may be attenuated. No interaction by RPM type was observed (Pinteraction=0.15-0.24). GRADE certainty was moderate for mortality and low for HF hospitalization. A pre-specified geographic access analysis revealed that only 2 of 59 trials reported rural/urban subgroups -- a critical evidence gap that precludes conclusions about whether RPM differentially benefits underserved populations. HighlightsO_LITrial sequential analysis confirms firm evidence for RPM mortality benefit C_LIO_LIAll-cause mortality reduced 11% (NNT 84/yr, prediction interval excludes null) C_LIO_LIHF hospitalization reduced 22% (NNT 17/yr), though prediction interval crosses 1.0 C_LIO_LINo differential benefit by RPM type (STS vs TM vs invasive; Pinteraction=0.24-0.34) C_LIO_LIOnly 2 of 59 trials reported rural/urban subgroups -- a critical geographic evidence gap C_LI

BackgroundThere is uncertainty among physicians regarding the optimal clinical application of the novel high-sensitivity cardiac troponin I (hs-cTnI)-VITROS assay within the widely implemented upper reference limit (URL)-based ESC 0/3h-algorithm. MethodsThis prospective, international, multicenter study aimed to validate and compare different modifications of the URL-based ESC 0/3h-algorithm among adult patients presenting with suspected acute myocardial infarction (AMI) to the emergency department. Final diagnoses of AMI were centrally adjudicated by two independent cardiologists, blinded to hs-cTnI-VITROS concentrations. Discrimination was compared to the best validated hs-cTnT/I-assays. Clinical follow-up for cardiovascular death and AMI was conducted until five years. ResultsAmong 1225 eligible patients (median age 63 years (IQR 52-75), 31.9% women), 18.9% were adjudicated as NSTEMI. Diagnostic discrimination of hs-cTnI-VITROS at 0h was very high (AUC 0.949, 95% CI 0.941-0.958), and comparable to hs-cTnI-Architect and hs-cTnT-Elecsys. Using the ESC 0/3h algorithm, 30.9% of patients were classified as rule-out (sensitivity 99.1%, NPV 99.5%) and 19.0% as rule-in (specificity 96.0%, PPV 82.8%). Substituting the HEART score for the GRACE score increased rule-out efficacy to 43.9%, while maintaining very high safety (sensitivity 99.6%; NPV 99.8%). Findings were consistent across predefined subgroups, in sensitivity analyses restricted to type 1 NSTEMI, using the 2h study blood sample (n=2249), and for the composite of cardiovascular death or AMI during five-year follow-up. ConclusionsThe ESC 0/3h-algorithm demonstrated excellent performance for rule-out of NSTEMI with greater efficacy when combined with the HEART-instead of the GRACE score. Registrationhttps://clinicaltrials.gov/study/NCT00470587 Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn a prospective, international multicenter cohort, the URL-based ESC 0/3h algorithm using the FDA-cleared hs-cTnI-VITROS assay achieved very high rule-out safety (sensitivity 99.1%, NPV 99.5%) but limited efficacy (30.9% rule-out) when combined with GRACE score <140 and symptom resolution. C_LIO_LIReplacing GRACE with a HEART score (<5) increased rule-out efficacy to 43.9% while maintaining excellent safety (sensitivity 99.6%, NPV 99.8%), with consistent findings across subgroups, sensitivity analyses, and long-term outcomes. C_LI What Are the Clinical Implications?O_LIClinicians and health systems using hs-cTnI-VITROS can apply the ESC 0/3h algorithm with assay-conform decision values; adding clinical risk stratification is necessary to meet contemporary rule-out safety targets. C_LI

BACKGROUND Point-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. METHODS We 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. RESULTS Six 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). CONCLUSIONS Implementation 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.

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.

BackgroundThe self-management of type 2 diabetes (T2D) typically requires enacting various lifestyle changes, which can challenge people living with T2D. Clinical encounters between people with T2D and their clinicians, however, are often focused on metabolic management, leaving less time available for other self-management topics. The QBSAFE cards help patients articulate aspects of their experience with diabetes and prioritize issues for discussion. MethodsThis report details secondary outcomes of a randomized controlled trial; primary outcomes are reported elsewhere. All data was collected at Fair Haven Community Health Care, a federally qualified primary care clinic. 11 clinicians were randomly assigned to provide either usual care or usual care with QBSAFE cards to 155 of their patients with type 2 diabetes and hemoglobin A1c >8%. All patient encounters were video recorded for analysis. Patients and clinicians were not blinded to arm allocation but were kept unaware of the specific aims of the trial. Encounter video reviewers were blinded to arm allocation, but not to specific aims of the trial. The outcomes of interest for this report were the extent to which the QBSAFE cards were used as intended, their effect on the topics of discussion, and whether they enabled clinicians to notice and respond to each patients situation; comparisons between arms were conducted by a linear mixed model with fixed effect of arm and cluster effect of clinician, analyzed in both intent-to-treat and per-protocol populations. Findings12 patients were excluded post-randomization (A1c <8%). Of 143 eligible patients, 137 encounters (65 in the usual care arm, 72 in QBSAFE) yielded evaluable videos. QBSAFE was used as intended in 61 (85%) QBSAFE arm encounters. Conversations about burden of treatment related to non-pharmacological interventions (17 vs 33, p= 0{middle dot}04) and taking medications (11 vs 33, p= 0{middle dot}0008) and about the patients challenging environment (2 vs 10, p= 0{middle dot}04) were more prevalent in the QBSAFE group. There was no difference in the rate of conversations about metabolic management or of new care plans as a result of conversations between groups. InterpretationWhile there was a difference in the types of conversations observed between the two study arms, this difference was small and only apparent in a few domains. Future work could aim to modify the QBSAFE cards to more effectively stimulate patient-centered discussions and to further prepare clinicians to respond to a variety of issues raised during the clinical visit. FundingThis work was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK129616).

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.

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.

ObjectiveTo evaluate whether hyaluronan-enriched transfer medium improves live birth rates in biopsied euploid blastocyst transfers and to examine the role of zona pellucida disruption in mediating this effect. DesignRetrospective cohort study. ParticipantsA total of 1,221 single frozen euploid blastocyst transfers performed between January 2011 and December 2024. InterventionEmbryo transfer using hyaluronan-enriched transfer medium compared with standard zwitterionic-buffered transfer medium. All embryos underwent trophectoderm biopsy resulting in zona pellucida disruption. Main Outcome MeasuresLive birth rate. Secondary outcomes included biochemical pregnancy and clinical pregnancy rates. ResultsHyaluronan-enriched transfer medium was associated with significantly higher live birth rates compared with standard medium (59.1% vs. 43.2%; absolute difference 15.9%, 95% confidence interval 10.3%-21.5%; relative risk 1.37, 95% confidence interval 1.22-1.54; P < 0.001). Clinical pregnancy and biochemical pregnancy rates were also significantly higher in the hyaluronan group (P < 0.001 for both comparisons). Sensitivity analysis restricted to first transfers per patient (n = 715) confirmed persistence of the live birth benefit (61.2% vs. 47.1%; absolute difference 14.1%, 95% confidence interval 6.9%-21.3%; relative risk 1.30, 95% confidence interval 1.13-1.49; P < 0.001). Maternal age was comparable between groups. ConclusionUse of hyaluronan-enriched transfer medium is associated with a clinically meaningful increase in live birth rates in biopsied euploid blastocyst transfers. Zona pellucida disruption created during trophectoderm biopsy may facilitate enhanced embryo-endometrial interaction, improving implantation efficiency.

Importance Women 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. Objective To 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). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational 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. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular 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. Results Drug 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 Relevance This 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.

BackgroundMulti-system impacts of long COVID remain unknown. We compared multi-system deficits between people with long COVID and controls. MethodsA case-control study recruited from the Avon Longitudinal Study of Parents and Children and TwinsUK population cohorts. Cases (141) had long COVID (evidence of COVID-19 infection and persistent symptoms [&ge;]4 weeks post infection); controls (280) included people making a full recovery in <4 weeks, people self-reporting long COVID like symptoms but without wild-type SARS-CoV-2 virus antibodies, and people without symptoms or history of COVID-19 infection. Participants underwent multi-system MRI, (cardiac, brain, lung, kidney), measurement of blood pressure and autonomic function, tests of exercise performance, spirometry, renal function, strength and physical capability. System-specific deficits were summed to a total potential score of 27. FindingsParticipants attended clinic between 2021-23. Overall deficit score in cases was 0.22 (95% CI -0.44,0.88) units greater than controls, adjusted for age, sex, ethnicity, cohort membership and relatedness. This estimate was little changed (0.32 (-0.34, 0.98)) when additionally adjusted for educational status, index of multiple deprivation, physical activity, smoking and co-morbidity. Restricting cases to those reporting at least fatigue (46) increased the excess deficit score to 0.81 (-0.19,1.81) units in the minimally adjusted model. A difference was only observed in the vascular domain, largely attributable to elevated blood pressure, showing a 1.76 (1.04,2.97) multivariable adjusted odds ratio excess in cases, and 3.04 (1.36,6.80) when restricted to cases with fatigue. InterpretationPeople with community-based long COVID should be reassured that there is not marked residual deficit across multiple systems. However, blood pressure measurement and control should be included in clinical follow-up. FundingJointly funded by the National Institute for Health and Care Research and UK Research and Innovation (CONVALESCENCE, COV-LT-0009, MC_PC_20051).

Background: The 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. Methods: Background: The 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. Methods: This 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 matched cohorts of each vaccine 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]). Results: We 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. Conclusions: This 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.Results: We 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. Conclusions: This 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: Anthropometric data are critical in paediatric care, routinely assessed during clinical visits, and available in electronic health records (EHRs). We describe the feasibility of extracting anthropometric data from heterogeneous EHR systems of Swiss childrens hospitals, evaluate their availability and quality, and assess the cohorts representativeness of the general population. METHODS: In this multicentre study (SwissPedGrowth), we retrospectively collected EHRs from patients <20 years who visited hospitals in Basel, Bern, Geneva, Lausanne, Luzern, St. Gallen, or Zurich between 2017-2023. Sociodemographic, administrative, and clinical information from EHRs were provided in a standardized way by a paediatric national data stream (SwissPedHealth), including the Swiss Neighbourhood Index of Socioeconomic Position (Swiss-SEP). We counted anthropometric recordings per visit to describe availability and used a self-developed and an existing (growthcleanr) algorithm to investigate data quality. To assess representativeness, we compared sociodemographic characteristics between SwissPedGrowth and the general paediatric population in Switzerland, computed standardized differences (effect size: 0.2 small, 0.5 medium, 0.8 large), and weighted the study population to reduce differences. RESULTS: We included 477,531 patients and 2,171,633 hospital visits; 54% boys, 71% Swiss, mean Swiss-SEP 65 (SD: 11), and median age at visit 6.3 [IQR: 2.3, 11.8] years. Height recordings were available for 20% of the visits, weights for 43%, and head circumferences for 5%, with better availability for inpatient stays than outpatient or emergency visits. Combining the self-developed and existing algorithm, 4% of heights and 3% of weights were flagged as outliers and 29% of heights and 31% of weights as carried forward from previous visits or same day duplicates. Sociodemographic differences between SwissPedGrowth and the general population were small or small-to-medium and disappeared after weighting. CONCLUSION: SwissPedGrowth demonstrates feasibility of extracting high-quality anthropometric data for paediatric growth research, but challenges regarding completeness and harmonization of EHR data across Swiss hospitals remain.

ObjectivesTo inform users about the impact of two updated study filters for limiting database search results to randomized controlled trials on Ovid MEDLINE: a sensitivity-maximizing version (SM) and a sensitivity-and-precision-maximizing version (SaPM). To provide an updated understanding of how they compare to each other. MethodsUsing the final included records of 14 Cochrane reviews that had used the SM filter, we determined how many available records on Ovid MEDLINE would have been retrieved with each filter; investigated why records were missed; the unique yield; precision; and number-needed-to-read (NNR) for each filter. We also performed forwards and backwards citation searching on missed records (to determine if this could mitigate the risk of missing includes) and calculated the percentage change in the overall number-needed-to-screen (ONNS) when applying each filter to reproduction strategies. ResultsOn average, the SaPM filter reduced ONNS by 83% and retrieved 95.9% of includes compared with 98.2% retrieved by the SM filter. The SaPM filter offered a further 28.2% mean reduction in ONNS over the SM filter. The SM filter had a unique yield of 12 and a precision of 1.5%, versus a unique yield of three and precision of 4.4% for the SaPM filter. NNR was 68 for the SaPM filter versus 189 for the SM filter. ConclusionThe SaPM filter reduced the screening burden with minimal risk of missing eligible records (which could be mitigated by citation searching). Decisions about which filter to use should consider both the needs and resources of the review.