Background:In patients with unprovoked venous thromboembolism (VTE), indefinite anticoagulation is recommended to prevent recurrence but may expose some patients to unnecessary long-term bleeding risk. Current clinical scores and biomarkers have limited discriminative performance, do not capture the time-dependent nature of VTE, and do not incorporate patients' perspectives or support shared decision-making. Objectives:To develop and validate time-dependent, multicomponent risk prediction scores and socio-anthropological scales (TDMI) integrated in a shared decision-making process to optimize long-term anticoagulation management after unprovoked VTE. Methods:MORPHEUS is an international, multidisciplinary research programme conducted in eight European countries. The TDMI will combine clinical, biological, imaging, and pharmacological biomarkers with socio-anthropological scales reflecting patients' lived experiences, preferences, and perceptions of risk. Candidate components will be identified through systematic literature review, Delphi consensus, qualitative interviews with patients and physicians, and pooled analyses of large prospective European VTE cohorts including clinical outcomes, biobanks, and imaging data. Dynamic, multi-level, time-dependent prediction models for recurrent VTE and anticoagulant-related bleeding will be derived using advanced statistical and machine-learning approaches. The clinical effectiveness and acceptability of TDMI integrated in a shared decision-making process will be evaluated in a stepped-wedge cluster randomized trial enrolling 2,400 patients with a first unprovoked VTE. Results:The TDMI is expected to improve individualized risk stratification, reduce unnecessary extended anticoagulation, lower bleeding complications, and improve patient satisfaction, treatment adherence, and quality of life. Conclusion:The MORPHEUS project will support personalized anticoagulation decisions and improve long-term outcomes in patients after unprovoked VTE.

ABSTRACT BACKGROUND In patients with venous thromboembolism (VTE), renal impairment increases the risks for both recurrence and bleeding. Because these patients are underrepresented in clinical trials, we assessed whether standard direct factor Xa inhibitor (DXI) lead-in followed by early dose reduction was noninferior to standard anticoagulation in patients with acute VTE and moderate-to-severe renal impairment. METHODS The VERDICT trial was a randomized, prospective, multicenter, open-label, blinded-endpoint, noninferiority trial. Consecutive patients with acute proximal deep-vein thrombosis or pulmonary embolism and chronic renal impairment (creatinine clearance 15–50 mL/min) were randomized 1:1 to an early DXI dose reduction strategy or standard therapy (heparin plus a vitamin K antagonist). Patients allocated to the DXI strategy underwent a second 1:1 randomization to apixaban or rivaroxaban, each administered at an initial standard lead-in dose followed by early dose reduction. The primary outcome was net clinical benefit at 3 months, defined as the composite of major bleeding and symptomatic recurrent VTE. RESULTS Due to slow recruitment, the trial was prematurely terminated after enrolling 200 of the planned 800 patients (DXI: n=104; standard: n=96). The median age was 85.9 years, 31% were male, and 29.0% had severe renal impairment. The primary outcome occurred in 8 patients (7.7%) in the DXI group and 9 patients (9.3%) in the standard therapy group (adjusted subhazard ratio [sHR], 0.87; 95% CI, 0.26 to 2.87; P = 0.19 for noninferiority; noninferiority margin 1.30). Major bleeding occurred in 6.7% and 6.2% of patients and recurrent VTE occurred in 1.0% and 3.1% of patients, respectively. CONCLUSION In patients with VTE and moderate-to-severe renal impairment, noninferiority of an early DXI dose-reduction strategy versus standard therapy could not be demonstrated for net clinical benefit. Although no major differences in efficacy or safety outcomes were observed between groups, the reduced sample size precludes definitive conclusions. Clinical Trial Registration URL: https://clinicaltrials.gov . Unique identifier: NCT02664155 Clinical Perspective What Is New? The VERDICT trial is the first randomized controlled trial specifically designed to assess an initial frontloaded standard dose of oral direct factor Xa inhibitor followed by early dose reduction strategy versus standard anticoagulation therapy for acute venous thromboembolism in patients with moderate-to-severe renal impairment. Reflecting real-world clinical practice, the study successfully enrolled an exceptionally elderly and frail population with a median age of 85.9 years. A meta-analysis incorporating VERDICT and renal impairment subgroups from previous VTE trials showed a 35% relative reduction in net clinical benefit and a 53% relative reduction in major bleeding with DXI versus standard therapy with heparins/VKA. What Are the Clinical Implications? Although premature trial termination limited statistical power to formally demonstrate noninferiority, the findings did not differ from those observed in renal impairment subgroups of previous randomized VTE trials. The available evidence provides a rationale for evaluating an early dose-reduction strategy in frail patients with VTE.

Pulmonary vascular obstruction index (PVOI), assessed using the Qanadli index on computed tomography pulmonary angiography (CTPA) at pulmonary embolism (PE) diagnostic, has been associated with recurrence after unprovoked PE, but its complexity limits routine use. We aimed to evaluate simplified semiquantitative (Sq) measures of initial PVOI for predicting recurrent PE after anticoagulation discontinuation.This post hoc analysis, based on the double-blind, randomized PADIS-PE trial where patients with a first unprovoked PE initially treated during 6 months were allocated to receive either an additional 18-month warfarin or placebo, was restricted on the 180 patients who had PE diagnosed by CTPA. Initial PVOI was assessed using four methods: Qanadli score, modified Qanadli score, anatomical-based SqPVOI1, and lobe-based SqPVOI2. Accuracy and associations with recurrent PE were evaluated using area under the curve (AUC) analysis and Cox regression models.Among the 180 included patients (mean age 66.2 ± 16.5 years; 45.2% female), recurrent PE occurred in 42 patients (36-month median follow-up). Accuracy was comparable across the four PVOI scores, with AUCs ranging from 0.70 to 0.74. All scores showed comparable ability to predict recurrent PE. When using the anatomical-based SqPVOI1, recurrence risk increased progressively with more proximal thrombus location: compared with segmental artery involvement (36-month cumulative incidence, 10.5%; n = 76), risk was 2- to 3-fold with lobar artery involvement (HR 2.90, 95%CI, 1.20-7.05, p = 0.005; 36-month cumulative incidence, 25.6%; n = 63) and 4- to 5-fold increased risk (HR 4.59, 95%CI, 1.85-11.42, p = 0.001; 36-month cumulative incidence, 46.8%; n = 41) with main pulmonary artery involvement.Simplified anatomical assessment of PVOI showed prognostic information comparable to quantitative indices. Further prospective validation is needed.

BACKGROUND:The effect of low-molecular-weight heparin, administered from the time of diagnosis of fetal growth restriction (FGR), on fetal growth and birthweight remains uncertain. OBJECTIVES:To evaluate whether daily enoxaparin, administered from diagnosis of placenta-derived FGR up to 36 weeks of gestation or delivery, reduces the incidence of newborns with a birthweight below the 10th percentile for gestational age. METHODS:This open-label, randomized, multicenter trial (NCT02672566) included pregnant women with a single fetus (≥22 to <34 weeks) presenting placenta-derived FGR. Participants not requiring anticoagulation were randomly assigned via a web-based system to receive either 4000 IU of enoxaparin once daily with standard care or standard care alone. The primary outcome was the incidence of newborns with a birthweight below the 10th percentile. Secondary outcomes included gestational age at delivery, estimated weekly fetal growth, time to delivery, and perinatal morbidity and mortality. RESULTS:The study was prematurely discontinued due to insufficient recruitment. From July 2016 to November 2019, 81 participants were enrolled. The incidence of newborns with a birthweight below the 10th percentile did not differ significantly between the enoxaparin group with standard of care (27 of 40, 67.5%) and the standard of care alone group (30 of 41, 73.2%); relative risk, 0.92; 95% CI, 0.69-1.23; P = .63. No significant differences were observed between the groups regarding secondary outcomes or maternal complications. CONCLUSION:This study found no evidence that daily prophylactic enoxaparin during the antepartum period improves fetal growth or prolongs pregnancy in the context of constituted placenta-derived FGR.

Stepped-wedge cluster randomised trials (SW-CRTs) increasingly evaluate complex interventions, yet methodological guidance for analysing composite endpoints using generalized pairwise comparisons (GPC)remains limited. This work investigates the performance of several GPC-based estimators in the presence of clustering, temporal trends, and varying correlation structures typical of SW-CRTs. We conducted an extensive simulation study covering a range of intraclass correlations (ICC), cluster autocorrelation coefficients (CAC), time effects, and treatment effect sizes. Eight analytical approaches were compared, including unadjusted estimators, cluster-stratified win odds, mixed-effects models applied to cluster-period win odds, and probabilistic index models (PIMs). Type I error control was strongly compromised for methods ignoring time or clustering, whereas only two approaches consistently maintained nominal error rates: a hierarchical mixed-effects model with sequence and cluster-level random slopes (b4) and a cluster-restricted PIM (c2). These two methods were further evaluated in terms of statistical power, where c2 generally showed higher efficiency, particularly under strong clustering, low CAC, or the presence of temporal trends, while both converged to similar performance for large treatment effects. Overall, our findings identify b4 and c2 as the most reliable GPC-based strategies for SW-CRT analysis and provide practical guidance for their application, including for ongoing trials such as ETHER.

Background: Apixaban and rivaroxaban are approved for the initial and extended treatment of venous thromboembolism (VTE). Both drugs have shown similar efficacy to prevent recurrent VTE, but cohort studies and a recent randomized controlled trial (RCT) suggest that, over the first 3 months of treatment, rivaroxaban use is associated with a significantly higher risk of clinically relevant bleeding (CRB) than apixaban. Whether the same phenomenon is observed during extended treatment, either at full or reduced dose, is unknown. Methods: The RENOVE open-label multicenter RCT compared full-dose vs reduced-dose direct oral anticoagulants in patients with VTE who had completed at least 6 months of full-dose treatment and had an indication for extended anticoagulation (Lancet 2025, doi: 10.1016/S0140-6736(24)02842-3). Apixaban or rivaroxaban were permitted in the trial, and randomization was stratified according to the drug used. In this post hoc analysis, we aimed to compare the risk of bleeding between patients who received full-dose apixaban (5 mg bid) vs full-dose rivaroxaban (20 mg daily), and in patients who received reduced-dose apixaban (2.5 mg bid) vs reduced-dose rivaroxaban (10 mg daily). The primary endpoint for this analysis was CRB, and the primary outcome measure was the 5-year cumulative incidence of CRB. The incidence of recurrent VTE, major bleeding, the composite of CRB and recurrent VTE, arterial events and death from any cause were secondary outcome measures. Except for the effect of dose reduction, hazard ratios (HR) were adjusted on center, age, sex, BMI, and use of antiplatelet drugs. Results: Of 2,768 patients in the intention-to-treat population, 1,385 patients assigned to full-dose received apixaban (n=630) or rivaroxaban (n=755), and 1383 patients assigned to reduced-dose received apixaban (n=625) or rivaroxaban (n=758). Baseline characteristics were broadly well-balanced between patients given apixaban or rivaroxaban, but median age (66.5 vs 62.6 years), the proportion of women (38.7 vs 32.1%) and proportion of patients with BMI ≥30 kg/m² (32.6 vs 28.8%) were slightly higher in patients given apixaban than in those given rivaroxaban. The maximum follow-up was 5 years, with a median of 37 months. In the full-dose subgroups, the 5-year cumulative incidence of CRB was 16.5% in patients given apixaban vs 14.4% in patients given rivaroxaban (adjusted HR [aHR] 1.02, 95% confidence interval [CI] 0.72-1.43). In the reduced-dose subgroups, the 5-year cumulative incidence of CRB was 11.0% in patients given apixaban vs 9.0% in patients given rivaroxaban (aHR 1.31, 95% CI 0.85-2.01). The 5-year cumulative incidence of major bleeding events was not significantly different between patients on apixaban or rivaroxaban, both in the full-dose subgroups (4.6% vs 3.5%, respectively, aHR 1.35, 95%CI 0.69-2.67) and reduced-dose subgroups (3.0% vs 1.6%, respectively, aHR 0.85, 95%CI 0.28-2.59). The 5-year cumulative incidence of recurrent VTE in the full-dose subgroups was 2.0% with apixaban vs 1.7 % with rivaroxaban (aHR 1.22, 95% CI 0.37-3.99), and 1.4% vs 2.7% in the apixaban and rivaroxaban reduced-dose subgroups, respectively (aHR 0.85, 95%CI 0.32-2.28). There was no significant difference between the two drugs at full or reduced dose in the incidence of the composite of CRB and recurrent VTE, arterial thromboembolic events, and death from any cause. Finally, the effect of dose reduction was consistent across the two drugs regarding the risk of CRB (aHR 0.68 [95%CI 0.47-0.98] for apixaban vs 0.57 [0.40-0.81] for rivaroxaban), the risk of VTE recurrence (aHR 1.33 [0.42-4.19] for apixaban vs 1.34 [0.55-3.27] for rivaroxaban), and the composite of CRB and VTE recurrence (aHR 0.74 [0.52-1.05] for apixaban vs 0.64 [0.46-0.89] for rivaroxaban). Conclusion: In this post hoc analysis of the strata of a large RCT of patients with VTE who had completed at least 6 months of full-dose anticoagulation and had an indication for extended treatment, apixaban and rivaroxaban showed similar safety profiles at 5 years, both in the full- and reduced-dose subgroups comparisons, while dose reduction showed similar benefit on CRB risk with both drugs. In contrast with the first months of full-dose anticoagulation, rivaroxaban proved as safe as apixaban during extended treatment, whether at full or reduced dose. Ideally, these results would need to be confirmed in a specific randomized trial.

Introduction Chronic hip prosthetic joint infection (PJI) treatment needs non-conservative surgery. The recommended treatment follows a two-stage protocol. Between the two surgeries, full-weight bearing is prohibited, and joint stiffness and pain are rather usual complications. The single-stage procedure is thought to be less susceptible to late functional complications with a shorter, single hospital stay. However, infection control could be less efficient; the protocol highly relies on antibiotics and has a list of contra-indications. Most of these contra-indications are directly related to the biofilm formation. As no randomised control trial has ever compared single-stage versus two-stage surgery on infection treatment, the level of evidence for recommending one procedure over the other is low. An antibiotic-loaded hydrogel coating (Defensive Antiadhesive Coating (DAC), Novagenit SRL) has been proven to mechanically prevent biofilm formation while allowing a prolonged intra-articular antibiotic release. The addition of this biofilm inhibitor to a single-stage surgery might stand as a promising strategy for PJI. Moreover, using this device to prevent biofilm formation could expand one-stage surgery to patients who are in theory contra-indicated to one-stage surgery.Methods and analysis SINBIOSE-H is a Prospective Randomized Open, Blinded End-point clinical trial that will include patients with a chronic hip PJI as defined by the Musculoskeletal Infection Society (MSIS), with at least one theoretical contra-indication for single-stage surgery. Patients needing a cemented implant will not be included. 440 patients will be randomised in two groups: the experimental group is composed of single-stage procedure associated with the use of biofilm inhibitor (DAC) loaded with topical antibiotics, and the control group is composed of two-stage procedure without biofilm inhibitor. The primary objective will be to demonstrate that single-stage surgery with antibiotic-loaded hydrogel-coated implants is non-inferior to two-stage surgery for chronic hip PJI treatment. The secondary objectives will be to demonstrate that single-stage surgery with antibiotic-loaded hydrogel-coated implants is superior to two-stage surgery on the prevention of functional complications, patient satisfaction scores, death rate, postoperative complications or early revision surgery for any cause other than infection. Based on a failure rate of two-stage surgery of 20% and a reduction of the infection rate using the DAC biofilm inhibitor from 3 to 0.7%, with a non-inferiority margin of 1.35 and power set at 90%, we estimated to enrol 420 patients.Ethics and dissemination The protocol is in accordance with ethical principles established by the Helsinki World Medical Assembly and its amendments and will be conducted in accordance with the recommendations of International Conference on Harmonisation Good Clinical Practice. A core information and informed consent form will be provided. The written approval of the Ethics Committee (EC)/Institutional Review Board (IRB) together with the approved subject information/informed consent forms must be filed in the study files. Written informed consent must be obtained before any study-specific procedure takes place. The data will be saved on the internal network in a secured directory, dedicated to the study. At the end of the research, all documents (case report files, investigator files, etc) will be archived and stored for 15 years in each centre. Data on SAEs will be included in the study documentation file. All data and documents will be made available if requested by relevant authorities. The EC and IRB were submitted and approved in France (CPP Ile De France X, 93 602 AULNAY-SOUS-BOIS). Ethics approval covers all centres.Trial registration number The study is registered on clinicaltrials.org under NCT04251377 (EUDRACT NUMBER, 2019-A01491-56; trial sponsor, St Etienne University Hospital Center; date of the last version, 24 February 2006).

Introduction Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterised by inflammatory low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first treatment in axSpA. In case of inadequate response to NSAIDs, biological disease-modifying antirheumatic drugs (bDMARDs) should be introduced according to the recommendations of the European League Against Rheumatism (EULAR) and the American College of Rheumatology. Until 2015, only bDMARD was recommended for axSpA in case of failure to anti-tumour necrosis factor (TNF). The 2022 Assessment of SpondyloArthritis International Society (ASAS)-EULAR recommendation proposed to start an alternative bDMARD but without advocating a switch in mode of action as proposed in rheumatoid arthritis. Since 2015, the inhibition of interleukin (IL)-17 has demonstrated efficacy in axSpA. Then, we designed a randomised multicentre clinical trial to identify the more effective treatment after a first anti-TNF failure in axSpA, comparing an anti-IL-17 to a second anti-TNF.Methods and analysis The ROC-SpA (Rotation Or Change of biotherapy after first anti-TNF treatment failure in axSpA patients) study is a prospective, randomised, multicentre, superiority open-label phase IV trial comparing an anti-IL-17 strategy (secukinumab or ixekizumab) to a second TNF blocker in a 1:1 ratio. Patients with an active axSpA (Bath Ankylosing Spondylitis Disease Activity Index >4 or ankylosing spondylitis disease activity score (ASDAS) >3.5) with inadequate 3 months response to a first anti-TNF and with a stable dose of conventional synthetic DMARDs, oral corticosteroids and/or NSAIDs for at least 1 month are included in 31 hospital centres in France and Monaco. The primary outcome is the ASAS40 response at week 24. The secondary outcomes are ASAS40 at weeks 12 and 52, other clinical scores (ASAS20, partial remission rate, ASDAS major improvement rate) at weeks 12, 24 and 52 with the drugs and anti-drugs concentrations at baseline, weeks 12, 24 and 52. The primary analysis is performed at the end of the study according to the intent-to-treat principle.Ethics and dissemination Ethics approval was obtained from the committee for the protection of persons (Comité de protection des personnes Ouest IV #12/18_1, 6 February 2018) and registered in ClinicalTrials.gov and in EudraCT. Results of this study, whether positive or negative, will be presented at national and international congresses, to national axSpA patient associations and published in a peer-reviewed journal. It could also impact the international recommendation to manage patients with axSpA.Trial registration number NCT03445845 and EudraCT2017-004700-22.

Ce travail est une synthèse de la thèse du Dr Ghazi et est basée sur une revue systématique de la littérature et une étude clinique observationelle transversalle en cours de publication. Introduction Au cours des cinq dernières décennies, la concentration en spermatozoïdes a diminué de 50 % dans la population masculine [1]. Parallèlement, l’exposition à l’aluminium a augmenté de manière significative. Une revue systématique de la littérature réalisée sur 40 articles sélectionnés à partir de 111 publications sur le sujet, nous a permis d’évaluer la reprotoxicité masculine de l’aluminium. Dans l’ensemble, elle révèle une toxicité limitée mais réelle de l’aluminium sur le système reproducteur masculin. Cette toxicité se manifeste par une altération modérée de l’épithélium séminifère entraînant une réduction limitée mais significative du nombre de spermatozoïdes dans l’éjaculat. Le mécanisme de cette toxicité pourrait être la génération d’un stress oxydatif au niveau des testicules. Par ailleurs, l’aluminium semble s’accumuler au sein de la tête du spermatozoïde [2] à proximité de l’ADN spermatique [3]. Matériel et méthodes Nous avons évalué le lien entre la concentration d’aluminium et la fragmentation de l’ADN dans le sperme de 80 patients effectuant une insémination intra-utérine. Nous avons également évalué l’exposition à l’aluminium des patients à l’aide d’un questionnaire. Résultats Aucune corrélation significative entre la quantité d’aluminium dans le sperme et la fragmentation de l’ADN des spermatozoïdes n’a été trouvée. De même, aucune différence de concentration d’aluminium dans le sperme n’a été trouvée entre les patients exposés à l’aluminium et les autres dans l’une ou l’autre des modalités d’exposition explorées, à savoir : exposition professionnelle, alimentaire, cosmétique ou médicale. Conclusion L’aluminium présent dans le sperme ne semble pas induire un taux plus élevé de fragmentation de l’ADN des spermatozoïdes. Toutefois, au vu de la littérature, l’aluminium pourrait être l’un des nombreux toxiques environnementaux contribuant à la baisse de la fertilité masculine observée dans le monde.

BACKGROUND Venous thromboembolism is a common, potentially fatal disease. Beyond the first 3 months of anticoagulation treatment, extending anticoagulation up to 12 or 24 months reduces the risk of recurrence by at least 80% in patients at high risk of recurrence, but this benefit is lost after stopping anticoagulation. Consequently, guidelines recommend indefinite anticoagulation in such patients. However, continued anticoagulation exposes patients to a linear increase in bleeding risk, which is expected to ultimately exceed the risk of recurrent venous thromboembolism after stopping anticoagulation.To address this issue, lower-dose anticoagulation may reduce bleeding risk while maintaining similar efficacy in preventing recurrent venous thromboembolism. In the EINSTEIN-CHOICE and AMPLIFY-EXT studies, extended reduced-dose anticoagulation appeared as effective as and safer than full-dose. However, with the inclusion of a placebo or aspirin control group, both studies enrolled patients in whom physicians were uncertain about continuing anticoagulation. Consequently, robust evidence for recommending reduced- over full-dose anticoagulation in patients with a strong indication for extended treatment is lacking. METHODS The Reduced Dose Versus Full-Dose of Direct Oral Anticoagulant After Unprovoked Venous Thromboembolism (RENOVE) trial (ClinicalTrials.gov Identifier: NCT03285438) is an academic, multicenter, prospective, randomized, open, blinded end-point (PROBE) trial. In this study, we compared, using hierarchical sequential testing, extended anticoagulation with reduced-dose versus full-dose direct oral anticoagulants in patients with venous thromboembolism at high risk of recurrence initially treated for 6 to 24 months. Primary outcome was recurrent symptomatic venous thromboembolism (noninferiority hypothesis). Key secondary outcomes were clinically relevant bleeding and the composite of recurrent venous thromboembolism and clinically relevant bleeding (superiority hypotheses). Critical events were adjudicated by an independent committee blinded to treatment allocation. RESULTS During the 36-month median follow-up, recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 2.2%; 95% confidence interval [CI], 1.1 to 3.3 versus 1.8%; 95% CI, 0.8 to 2.7; hazard ratio, 1.32; 95% CI, 0.67 to 2.60; P=0.23 for noninferiority). Clinically relevant bleeding occurred in 96 and 154 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 9.9%; 95% CI, 7.7 to 12.1 versus 15.2%; 95% CI, 12.8 to 17.6). The composite outcome occurred in 113 and 166 patients in the reduced- and full dose groups, respectively (5-year cumulative incidence 11.8%; 95% CI, 9.4 to 14.3 versus 16.5%; 95% CI, 14.0 to 19.0). All-cause death occurred in 35 (4.3%) and 54 (6.1%) patients in the reduced- and full-dose groups, respectively. CONCLUSIONS In patients with venous thromboembolism who need extended anticoagulation, the noninferiority of a reduced-dose versus a full-dose of direct anticoagulants to prevent recurrent venous thromboembolism could not be proven. In the reduced-dose group, clinically relevant bleeding and the composite of recurrent venous thromboembolism or clinically relevant bleeding were lower than in the full-dose group and did not appear to be offset by an increased risk of death or arterial thromboembolic events.

Regular physical activity (PA) reduces morbidity and mortality in prostate cancer. Prescribing PA in cancer is a necessary awareness but is a real challenge in the case of prostate cancer. Motivational peer support seems to be an innovative strategy for lifestyle change. Therefore, we developed the Acti-Pair programme and demonstrated its feasibility. We want to evaluate its effectiveness in promoting PA in patients with prostate cancer. The Acti-Pair 2 study is an interventional, comparative, multicentre, randomised, stepped-wedge cluster study. The control group will consist of patients being followed for prostate cancer and receiving advice and recommendations for PA during consultations to make patients more active in their daily lives (=usual practice, PA to be performed independently at home). The intervention group will consist of patients being followed up for prostate cancer and benefiting from the Acti-Pair programme, which combines three interventions: (1) motivational support from a peer; (2) construction of a personalised and realistic project and (3) support from health and adapted PA professionals. This study will assess the effectiveness, implementation and efficiency of the Acti-Pair programme. It will allow the identification of key success factors for implementing the Acti-Pair programme to prepare for its transferability. Trial registration number: Clinical trial, NCT05739565, registered on 20 February 2023, https://clinicaltrials.gov/study/NCT05739565.

Background Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.Methods In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).Findings Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).Interpretation In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.Funding French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Metropole.Copyright & COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Background:In France, 62,000 hysterectomies are performed per year, 70% of which are benign. The choice of approach (laparotomy, laparoscopy or vaginal route) is particularly important in the case of large uterus (> 280g) which are associated with a higher risk of complications. The current data are not sufficient to favour one or other approach. A new medical device, the vNOTES (Natural Vaginal Orifice Transluminal Endoscopy System), offers the advantage of both laparoscopic and vaginal route for pelvic surgery.Objectives:To demonstrate the superiority in terms of intraoperative and postoperative complications of the use of a natural orifice transluminal endoscopic hysterectomy system (vNOTES) versus laparoscopic hysterectomy for benign pathologies on estimated large volume uteri (>280g).Materials and Methods:A randomised, double-blind, superiority trial will be performed at five hospital centres. Women with benign uterine pathology requiring hysterectomy and with a large uterus (> 280g) will be randomised to receive either laparoscopic or vNOTES hysterectomy.Main outcome measures:The primary outcome will be the occurrence of intraoperative and postoperative complications within 6 weeks of surgery. Secondary outcomes will be conversion during surgery, duration of surgery and hospitalisation, postoperative pain, postoperative complications, resumption of sexual life and satisfaction with the surgical team.Results:248 women will be randomised.Conclusion:This trial will provide a better understanding of the approach to large uteri optimise the care of these thousands of women undergoing hysterectomy.What’s new?:This trial will evaluate the vNotes for large uteri.

AIM:To test the association between perinatal inflammation exposure and Full-Scale IQ (FSIQ) score 7 years after neonatal arterial ischaemic stroke (NAIS).METHOD:We conducted a cross-sectional ancillary study nested in a multicentric longitudinal French cohort of infants born at term with NAIS between November 2003 and October 2006. Seventy-three children were included (45 males, 28 females). The a priori defined primary outcome measure was the FSIQ score assessed with the Wechsler Intelligence Scale for Children, Fourth Edition at 7 years of age.RESULTS:Seventeen (23%) of the included children were exposed to perinatal inflammation. Exposure to perinatal inflammation was independently associated with an increase of FSIQ score (coefficient 13.4, 95% confidence interval 1.3-25.4; p = 0.03). Children exposed to perinatal inflammation had a higher median cerebral volume, a lower median lesion volume, and less extensive lesion distributions compared to non-exposed children.INTERPRETATION:We propose the existence of two NAIS categories: arteritis-associated NAIS in children exposed to perinatal inflammation and embolism-associated NAIS in children non-exposed to perinatal inflammation. Identifying these two NAIS categories would open the possibility for specific curative strategies: anti-inflammatory strategy in arteritis-associated NAIS and recanalization strategy in embolism-associated NAIS.

BACKGROUND:Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. OBJECTIVE:To determine the frequency and predictors for CTEPH after a first unprovoked PE. PATIENTS/METHODS:In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. RESULTS:During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01]). CONCLUSION:After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.