Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis

Background An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11–18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13–0.25), maintenance OCS use (OR 0.75, 95% CI 0.61–0.92) and dose (mean −3.93 mg·day−1, 95% CI −5.24–2.62 mg·day−1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors

International audienceBackground and aim: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. Approach and results: Retrospective multicentre analysis of liver disease (transaminases>30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n=1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease (PSVD) in 48%, and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and hepatocellular carcinoma occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group (80/396, (20%)), OR 12.9 (CI95% 7.8-21.3, p <0.001). Conclusions: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild they may be associated with severe disease. PSVD and cirrhosis were the most frequent lesions suggesting that the mechanism of action is multifactorial

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceIMPORTANCE Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis

L'âge d'or de l'Opéra-Comique / Verdi, Mozart, Gounod... [et al.], comp.

Titre uniforme : [Falstaff]. Extrait en françaisTitre uniforme : [Mignon]. ExtraitTitre uniforme : [Il barbiere di Siviglia]. Extrait en françaisTitre uniforme : [Don Giovanni. KV 527]. ExtraitTitre uniforme : [La Basoche]. ExtraitTitre uniforme : [Werther]. ExtraitTitre uniforme : [Richard cœur de lion]. ExtraitTitre uniforme : [Mireille. CG 8]. ExtraitTitre uniforme : [La dame blanche]. ExtraitTitre uniforme : [Les pêcheurs de perles. GB 4]. ExtraitTitre uniforme : [Carmen. GB 9]. ExtraitTitre uniforme : [La traviata]. Extrait en russeTitre uniforme : [La Basoche]. ExtraitTitre uniforme : [Werther]. ExtraitTitre uniforme : [Sapho]. ExtraitTitre uniforme : [Manon]. Extr.Titre uniforme : [Cavalleria rusticana]. ExtraitTitre uniforme : [La vida breve]. Extr. adapt.Titre uniforme : [La dame blanche]. ExtraitTitre uniforme : [Carmen. GB 9]. ExtraitTitre uniforme : [Il dottor Antonio]. ExtraitTitre uniforme : [Le châlet]. Extr.Titre uniforme : [Samson et Dalila. R 288]. ExtraitTitre uniforme : [Tosca]. Extrait en françaisTitre uniforme : [Tosca]. ExtraitTitre uniforme : [Madama Butterfly]. ExtraitTitre uniforme : [Fortunio]. Extr.Titre uniforme : [Manon]. Extr.Titre uniforme : [Fedora]. ExtraitTitre uniforme : [Don Pasquale]. ExtraitTitre uniforme : [Lakmé]. ExtraitTitre uniforme : [Louise]. ExtraitCollection : Bel cantoComprend : Falstaff. Quand j'étais page / Verdi, comp. ; Victor Maurel, BAR - Don Giovanni. Sérénade / Mozart, comp. ; Victor Maurel, BAR - Mireille. Valse / Gounod, comp. ; Lise Landouzy, S - La dame blanche. Ah ! quel plaisir d'être soldat / Boieldieu, comp. ; Edmond Clément, T - Les mousquetaires de la Reine. Air de Roland, Pas de beauté pareille / Halévy, comp. ; Hippolyte Belhomme, B - Werther. Air des larmes / Massenet, comp. ; Geneviève Vix, S - Mignon. Elle ne croyait pas / Thomas, comp. ; Léon David, T - Faust. Air des bijouxGounod, comp. ; Georgette Bréjan-Silver, S - Le barbier de Séville. Place au factotum de la ville / Rossini, comp. ; Valentin Soulacroix, BAR - Carmen. Air des cartesBizet, comp. ; Clotilde Bressler-Gianoli, MS - Le cor / Flégier, comp. ; Félix Vieuille, B - Les pêcheurs de perles. O Dieu Brahma / Bizet, comp. ; Jeanne Merey, S - La basoche. Quand tu connaîtras Colette / Messager, comp. ; Fernand Francell, T - Le soir / Charles Gounod, comp. ; Louis Azéma, B - Richard-Coeur-de-Lion. Si l'univers entier m'oublie / Grétry, comp. ; César Vezzani, T - Philémon et Baucis. Air de Jupiter, Que les songes heureux / Gounod, comp. ; Paul Payan, B - Mignon. Ah ! que ton âme enfin... / A. Thomas, comp. ; René Lapelletrie, T - La dame blanche. Viens, gentille dame / Boïeldieu, comp. ; David Devriès, T - La traviata. Grand air : en russe / Verdi, comp. ; Maria Kousnezoff, S - La basoche. Elle m'aime / Messager, comp. ; Etienne Billot, BAR - Le bon roi Dagobert. 2ème acte, air du roiMarcel-Samuel Rousseau, comp. ; Charles Friant, T - Manon. "Adieu, notre petite table / Massenet, comp. ; Emma Luart, S - Résurrection. Katiouchka, ce jour exquis / Franco Alfano, comp. ; René Maison, T - Werther. J'aurais sur ma poitrine / Massenet, comp. ; Gaston Micheletti, T - Carmen. Près des remparts de Séville / Bizet, comp. ; Rose Pocidalo, MS - Le chalet. Vallons de l'Helvétie / Adolphe Adam, comp. ; Pierre Dupré, B - Suzanne. Comme un petit oiseau / Paladilhe, comp. ; Victor Pujol, T - Sapho. Air de Divonne, Petit, voici ta lampe / Jules Massenet, comp. ; Germaine Cernay, MS - Le chemineau. Ici, c'était ici.. / Xavier Leroux, comp. ; Julien afont, BAR - Cavalleria rusticana. O Lola, blanche fleur : Sicilienne / Mascagni, comp. ; Enrico Di Mazzei, T - Danse espagnole n° 5 / Manuel de Falla, comp. ; La Argentina, castagnettes - Jota / Manuel de Falla, comp. ; Ninon Vallin, S - La Tosca. Prière / Puccini, comp. ; Germaine Lubin, S - Manon. "Le rêve de Des Grieux / Massenet, comp. ; Miguel Villabella, T - Lakmé. "Pourquoi dans les grands bois / Léo Delibes, comp. ; Leïla Ben Sedira, S - Fortunio. Couplets du chandelier : duo / Messager, comp. ; Roger Bourdin, BAR ; Ninon Vallin, S - Lakmé. Dans la forêt, près de vous / Delibes, comp. ; Solange Delmas, S - La Tosca. Le ciel luisait d'étoiles / Puccini, comp. ; Paul-Henri Vergne, T - Samson et Dalila. Printemps qui commence... / Saint-Saëns, comp. ; Conchita Supervia, MS - Louise. Berceuse / Gustave Charpentier, comp. ; André Pernet, B - L'attaque du moulin. Les adieux à la forêt / Alfred Bruneau, comp. ; René Verdière, T - Madame Butterfly. Un bel di vedremo : en italien) / Puccini, comp. ; Rosetta Pampanini, S - Don Paquale. Air de Norinaen italien / G. Donizetti, comp. ; Rosina Storchio, S - Fedora. Air de Loris, Amor ti vieta : en italien / Giordano, comp. ; Amedeo Bassi, T - La Tosca. Duo du Ier actePuccini, comp. ; Jan Kiepura, T ; Lotte Lehmann, SBnF-Partenariats, Collection sonore - BelieveContient une table des matière