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The risks related to fluconazole use during the first trimester of pregnancy (T1) remain controversial. The aims of this systematic review and meta-analysis were to assess the association between oral fluconazole during T1 and major congenital malformations (MCM) overall and by subtype, minor malformations and miscarriages.We searched MEDLINE, EMBASE, Cochrane, ICTRP and ClinicalTrials.gov from inception to 02/12/24. Randomized controlled trials and observational studies were included. ROBINS-I was used for risk of bias assessment. Both fixed- and random-effects models meta-analyses were performed. GRADE was used to assess the certainty of the evidence.Among 1403 references, nine observational studies were included (3,764,897 pregnancies, including 116,425 exposed to fluconazole). The association between any fluconazole use during T1 and overall MCM was significant when combining crude estimates (ORc 1.18, 95%CI (1.08-1.29), I 2 23%, seven studies), but not when combining adjusted estimates (ORa 1.02, 95%CI (0.98-1.07), I 2 0%, six studies). Results were consistent for cumulative dose of fluconazole. In sensitivity analyses considering only studies with a valid definition of MCM, the association between fluconazole > 150 mg and overall MCM remained significant when combining adjusted estimates. For the subtypes of MCM (cardiac, genito-urinary, musculoskeletal) we found no significant association. A significant association was found between fluconazole use and miscarriages (ORa 1.60, 95% CI (1.06-2.42).Fluconazole use during T1 does not significantly increase the risk of MCM overall or by subtype when considering adjusted estimates. However, potential risks, particularly at cumulative doses greater than 150 mg which show a potential association with MCM, deserve much attention.PROSPERO Registration The protocol was registered on the 23rd September 2021 (registration number: CRD42021274003)., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. Springer Nature B.V.)

Background: During a pandemic like COVID-19, hospital resources are constrained and accurate severity triage of the patients is required., Objective: The objective of this study is to estimate the predictive performances of candidate biomarkers for short-term worsening (STW) of COVID-19., Design: Prospective, multicenter (20 hospitals in Paris) cohort study of consecutive COVID-19 patients with systematic biobanking at admission, during the first waves of COVID-19 in France in 2020 (COVIDeF cohort)., Setting and Participants: Consecutive COVID-19 patients were screened for inclusion. They were excluded in presence of severity criteria defined by either an ICU admission, mechanical ventilation (including noninvasive ventilation), acute respiratory distress, or in-hospital death before sampling. Routine blood tests measured during usual care and centralized systematic measurement of creatine kinase, C-reactive protein (CRP), procalcitonin, soluble urokinase plasminogen activator receptor (suPAR), high-sensitive troponin T (TnT-hs), N terminal pro-B natriuretic peptide (NT-proBNP), calprotectin, platelet factor 4, mid-regional pro-adrenomedullin (MR-proADM), and proendothelin were performed., Outcome Measures and Analyses: The primary outcome was STW, defined by a severity criteria within 7 days. A backward stepwise logistic regression model and a 'best subset' approach were used to identify independent association, and the area under the receiving operator characteristics (AUROC) was computed., Results: Five hundred and eleven patients were analyzed, of whom 60 (11.7%) experienced STW. Median time to occurrence of a severity criteria was 3 days. At admission, lower values of eosinophils, lymphocytes, platelets, alanine aminotransferase, and higher values of neutrophils, creatinine, urea, CRP, TnT-hs, suPAR, NT-proBNP, calprotectin, procalcitonin, MR-proADM, and proendothelin were predictive of worsening. Stepwise logistic regression identified three biomarkers significantly associated with worsening: CRP [adjusted odds ratio (aOR): 1.10, 95% confidence interval (95% CI): 1.06-1.15 for a 10-unit increase, AUROC: 0.73 (0.66-0.79)], procalcitonin [aOR: 0.42, 95% CI: 0.22-0.81, AUROC: 0.69 (0.64-0.88)], and MR-proADM [aOR: 2.85, 95% CI: 1.74-4.69, AUROC: 0.75 (0.69-0.81)]. These biomarkers outperformed clinical variables except diabetes and cancer comorbidities., Conclusion: In this multicenter prospective study that assessed a large panel of biomarkers for COVID-19 patients, CRP, procalcitonin, and MR-proADM were independently associated with the risk of STW., Trial Registration: ClinicalTrials.gov NCT04352348., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Factors associated with the appropriateness of antibiotic prescribing in primary care have been poorly explored. In particular, the impact of computerised decision-support systems (CDSS) remains unknown., Objectives: We aim at investigating the uptake of CDSS and its association with physician characteristics and professional activity., Methods: Since May 2022, users of a CDSS for antibiotic prescribing in primary care in France have been invited, when registering, to complete three case vignettes assessing clinical situations frequently encountered in general practice and identified as at risk of antibiotic misuse. Appropriateness of antibiotic prescribing was defined as the rate of answers in line with the current guidelines, computed by individuals and by specific questions. Physician's characteristics associated with individual appropriate antibiotic prescribing (< 50%, 50-75% and > 75% appropriateness) were identified by multivariate ordinal logistic regression., Results: In June 2023, 60,067 physicians had registered on the CDSS. Among the 13,851 physicians who answered all case vignettes, the median individual appropriateness level of antibiotic prescribing was 77.8% [Interquartile range, 66.7%-88.9%], and was < 50% for 1,353 physicians (10%). In the multivariate analysis, physicians' characteristics associated with appropriateness were prior use of the CDSS (OR = 1.71, 95% CI 1.56-1.87), being a general practitioner vs. other specialist (OR = 1.34, 95% CI 1.20-1.49), working in primary care (OR = 1.14, 95% CI 1.02-1.27), mentoring students (OR = 1.12, 95% CI 1.04-1.21) age (OR = 0.69 per 10 years increase, 95% CI 0.67-0.71)., Conclusion: Individual appropriateness for antibiotic prescribing was high among CDSS users, with a higher rate in young general practitioners, previously using the system. CDSS could improve antibiotic prescribing in primary care.

Objectives: To investigate factors associated with dermatomyositis (DM) complete clinical response and overall survival with a focus on the use of immunosuppressive therapies in patients with cancer-associated DM., Methods: We performed a multicentre, retrospective cohort study. Multivariable survival analyses used a Cox model with time-dependent covariates and adjustments with inverse probability censoring weighting., Results: We included 73 patients with cancer-associated DM. Median follow-up was 3.92 years. Overall, 40 (54.8%) patients achieved cancer remission, with DM complete clinical response in 28/40 (70.0%). DM complete clinical response was associated with cancer remission (hazard ratio [HR] 2.46, 95%CI [1.13-5.32]) and younger age (HR 0.68, 95%CI [0.49-0.95]). Risk of mortality was associated with sustained cancer activity (HR 12.93, 95% CI [2.42-69.25]), male sex (HR 2.82, 95% CI [1.19-6.70]), and older age (HR 1.86, 95% CI [1.26-2.79]) but not sustained DM activity (HR 0.40, 95%CI [0.13-1.26]). Oral corticosteroids use was a protective factor only on univariate analysis (HR 0.18, 95% CI [0.08-0.42])., Conclusion: This study provides strong evidence of a significant association between the evolutions of DM and cancer, both in terms of overall survival and DM complete clinical response. Immunosuppressive treatments for DM were not significantly associated with mortality., Trial Registration: ClinicalTrials.gov, NCT04637672., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Target trial emulation is an approach that is increasingly used to improve transparency in observational studies and help mitigate biases. For studies declaring that they emulated a target trial, we aimed to evaluate the specification of the target trial, examine its consistency with the observational emulation and assess the risk of bias in the observational analysis., Design: Methodological systematic review reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement., Data Sources: The database MEDLINE (Medical Literature Analysis and Retrieval System Online) was interrogated for all studies published from 1 January 2021 to 3 July 2022. We performed an additional manual search of 20 general medical and specialised journals that spanned the same period., Eligibility Criteria: All studies that declared emulating a hypothetical or real randomised trial were eligible., Data Extraction and Synthesis: Two independent reviewers performed the whole systematic review process (screening and selection of studies, data extraction and risk of bias assessment). The main outcomes were the definition of the key protocol components of the target trial and its emulation, consistency between the target trial and its emulation and risk of bias according to the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions) tool., Results: Among the selected sample of 100 studies, 24 (24%) did not specify the target trial. Only 40 studies (40%) provided detailed information on all components of the target trial protocol. Eligibility criteria, intervention strategies and outcomes were consistent between the target trial and its emulation in 35 studies (46% of those specifying the target trial). Overall, 28 studies (28%) exhibited serious risk of bias and 41 (41%) had misalignments in the timing of eligibility assessment, treatment assignment and the start of follow-up (time-zero). As compared with studies that did not specify the target trial, those that did specify the trial less frequently seemed to have both time-zero issues (39% vs 52%) and serious risk of bias (26% vs 33%)., Conclusions: One-quarter of studies declaring that they emulated a target trial did not specify the trial. Target trials and their emulations were particularly inconsistent for studies emulating a real randomised trial. Risk of methodological issues seemed lower in observational analyses that specified versus did not specify the target trial., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare that they have no competing interest related to the study. GLM declares consulting fees from Synapse Medicine, unrelated to the study., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim of the Study: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase., Methods: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018., Results: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%)., Conclusion: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Preoperative identification of patients with hemostasis abnormalities leading to an increased bleeding risk is based on routine hemostasis tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count. Because of their low predictive performance, guidelines recommend replacing them with structured bleeding risk questionnaires, but none is validated in this population., Objectives: To assess the diagnostic accuracy of 3 strategies, performed at the preanesthesia visit before scheduled interventions, and to identify patients with hemostasis abnormalities leading to an increased bleeding risk METHODS: A multicenter study was performed in 7 French academic hospitals, involving patients scheduled for surgical intervention, without antiplatelet/anticoagulant treatment. The 3 strategies consisted of 1-a structured screening questionnaire; 2-PT, APTT, and platelet count ordered in selected patients; and 3-systematic PT, APTT, and platelet count. The reference standard comprised von Willebrand factor activity/antigen, factor (F)VIII, FIX, FXI, platelet function analyzer, and, when required, FII, FV, FX, and FVII and hemostasis consultation., Results: Eighteen (1.2%) of 1484 patients had a hemostasis abnormality leading to an increased bleeding risk according to reference standard. In the overall cohort, sensitivity of the questionnaire-based strategy was 50% (95% CI, 26%-74%; specificity, 87% [95% CI, 85%-88%]); sensitivity was 0% (95% CI, 0%-41%) in men vs 82% (95% CI, 48%-98%) in women. For selective routine tests, sensitivity was 33% (95% CI, 13%-59%) and specificity 97% (95% CI, 96%-98%). Corresponding values for systematic routine tests were 44% (95% CI, 22%-69%) and 93% (95% CI, 91%-94%)., Conclusion: Sensitivity was low for all 3 strategies investigated. The structured screening questionnaire had clinically acceptable diagnostic accuracy only in women., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Status epilepticus (SE) imposes a significant burden in terms of in-hospital mortality and costs, but the relationship between SE causes, patient comorbidities, mortality, and cost remains insufficiently understood. We determined the in-hospital mortality and cost-driving factors of SE using a large and comprehensive database., Methods: We conducted a retrospective cohort study involving patients experiencing their first hospitalization with an ICD-10 code diagnosis of SE, spanning from January 1, 2015, to December 31, 2019, using the French health insurance database which covers 99% of population. Patient characteristics, SE causes, Intensive Care Unit (ICU) admissions, mechanical ventilation, discharge status, and health insurance costs were extracted for each hospitalization., Results: We identified 52,487 patients hospitalized for a first SE. In-hospital mortality occurred in 11,464 patients (21.8%), with associated factors including age (Odds Ratio [OR], 10.3, 95% Confidence Interval [CI] 7.87-13.8 for ages over 80 compared to 10-19), acute causes (OR, 15.3, 95% CI 13.9-16.8 for hypoxic cause), tumors (OR, 1.75, 95% CI 1.63-1.8), comorbidities (OR, 3.00, 95% CI 2.79-3.24 for 3 or more comorbidities compared to 0), and prolonged mechanical ventilation (OR, 2.61, 95% CI 2.42-2.82). The median reimbursed cost for each SE hospitalization was 6517€ (3364-13,354), with cost factors mirroring those of in-hospital mortality., Conclusion: Causes and co-morbidities are major determinants of mortality and hospital costs in status epilepticus, and factors associated with higher mortality are also often associated with higher costs. Further studies are needed to identify their long-term effects., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

In preparation for a new version of the CRAT (Centre de référence sur les agents tératogènes) website, an evaluation of user satisfaction was carried out. An invitation to complete an online questionnaire covering the various dimensions of the website (appearance, content, interactivity, ease of use, technical performance) was sent in April 2022 to healthcare professionals who referred to CRAT for clinical expertise over the previous two years. After sending out 3224 individual e-mail invitations, 758 evaluators completed the questionnaire in full (response rate: 23.5%). The evaluation revealed a high-level of overall satisfaction among site users (98.0% very satisfied or satisfied). Satisfaction with the site's appearance was also high, although comments were made about the site's lack of a modern web design. Health professionals recognized in their responses the reliable, relevant and up-to-date nature of the content of this free, public online resource, independent of the pharmaceutical industry. On the basis of these highly favorable assessments, with content that has been widely acclaimed and areas for improvement that have caught the attention of site users (evolution of its appearance, of the search tool, implementation of a mobile site), a new version of www.lecrat.fr was launched in the fall of 2023., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified., Competing Interests: Declaration of interests E.T.C., K.M.S.B., and A.B. are employees of Helix., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD)., Background: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres., Methods: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis)., Results: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users., Conclusions: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background and Aims: A recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection., Methods: We conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal., Results: We identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL., Conclusion: This study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C SCHEIFER, A DECHARTRES and B LEBRUN-VIGNES declare that they have no conflicts of interest. P LEBRAY has served as a speaker or a consultant from ASTELLAS and GILEAD and has received research funding from GILEAD. F Tubach is head of the clinical research unit of Pitié-Salpêtrière and Charles Foix hospitals and the pharmacoepidemiology center of Assistance Publique Hôpitaux de Paris, that have received research funding, grants and fees for consultant activities from a large number of pharmaceutical companies, that have contributed indiscriminately to the salaries of its employees. She is not employed by these structures and didn't receive any personal remuneration from these companies., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

COVID-19 is associated with heterogeneous outcome. Early identification of a severe progression of the disease is essential to properly manage the patients and improve their outcome. Biomarkers reflecting an increased inflammatory response, as well as individual features including advanced age, male gender, and pre-existing comorbidities, are risk factors of severe COVID-19. Yet, these features show limited accuracy for outcome prediction. The aim was to evaluate the prognostic value of whole blood transcriptome at an early stage of the disease. Blood transcriptome of patients with mild pneumonia was profiled. Patients with subsequent severe COVID-19 were compared to those with favourable outcome, and a molecular predictor based on gene expression was built. Unsupervised classification discriminated patients who would later develop a COVID-19-related severe pneumonia. The corresponding gene expression signature reflected the immune response to the viral infection dominated by a prominent type I interferon, with IFI27 among the most over-expressed genes. A 48-genes transcriptome signature predicting the risk of severe COVID-19 was built on a training cohort, then validated on an external independent cohort, showing an accuracy of 81% for predicting severe outcome. These results identify an early transcriptome signature of severe COVID-19 pneumonia, with a possible relevance to improve COVID-19 patient management., (© 2024. The Author(s).)

Objectives: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research., Study Design and Setting: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool., Results: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias., Conclusion: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS., Competing Interests: Declaration of competing interest G.L.M. reports a relationship with Synapse Medicine that includes employment. C.P. reports a relationship with Parexel International that includes employment. L.L. reports a relationship with Synapse Medicine that includes board membership and employment. There are no competing interests for any other author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Annually, the French Ministry of Health funds clinical research projects based on a national call for projects. Since 2013, the Ministry has prioritized funding of primary care. Projects selected for funding are made public without distinguishing the specific area of research. The objective of this study was to identify and describe the evolution of the primary care research projects funded by the Ministry of Health between 2013 and 2019., Method: We reviewed all of the 1796 medical research projects funded between 2013 and 2019 and categorized projects as primary care projects by using a list of specific keywords. This list was established through two approaches: (1) selected by an expert committee, the RECaP primary care working group, and (2) using an automated textual analysis of published articles in the field. The keywords were used to screen the titles of the medical research projects funded. The abstracts (at www., Clinicaltrials: gov ) or details (from project leaders) were then analyzed by two independent reviewers to determine true primary care projects., Results: Finally, 49 primary care projects were identified, representing 2.7% of all medical research projects funded, without any significant change over the period. These projects were predominantly interventional (69%), with a median number of patients expected per project of 902., Conclusion: Despite the prioritization of primary care research in 2013 by the French ministry of health, the number and proportion of projects funded remains low, with no significant change over the years., Trial Registration: Not applicable., (© 2024. The Author(s).)

Objective: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications., Methods: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy., Results: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39])., Significance: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy., (© 2024 International League Against Epilepsy.)

Objective: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission., Methods: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression., Results: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4)., Conclusion: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Overtreatment with glucose-lowering treatment (GLT) is frequent and a source of high morbidity and mortality in older adults with type 2 diabetes mellitus (T2DM). This study aimed to identify and synthesize barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM., Design: Systematic review of qualitative and mixed-methods studies., Setting and Participants: Older adults with T2DM, any participants [patients, health care providers (HCPs), caregivers], any settings., Methods: Two researchers (and a referred third researcher at all stages) independently screened original articles reporting qualitative and mixed-methods studies exploring barriers and enablers for deprescribing GLT in older adults published during 2010-2023, identified from MEDLINE, Embase, CINAHL, and gray literature. Quality of the included studies was assessed with the Mixed-Methods Appraisal Tool. Verbatim statements on barriers and enablers were extracted, and determinants of behaviors were identified with the Theoretical Domains Framework (TDF) version 2, and related intervention functions (targets for future interventions) were proposed according to the Behavior Change Wheel (BCW)., Results: We identified only 4 studies from 2 countries (United States and the Netherlands), all recently published (2019-2023), that primarily reported barriers to GLT deprescribing from interviews or focus groups of patients or HCPs practicing outpatient medicine. Knowledge, fear, poor communication, inertia, and trust with HCPs were the main determinants of behaviors that influenced deprescribing, and education, training, persuasion and environmental restructuring were the main intervention functions for proposing future interventions. Studies did not cover financial aspects, physician characteristics, or caregiver and family viewpoints., Conclusions and Implications: The use of a behavioral theory and a validated implementation framework provided a comprehensive approach to identifying barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM. The behavioral determinants identified may be useful in tailoring interventions to improve the implementation of GLT deprescribing in older adults in ambulatory settings., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: In older adults with type 2 diabetes (T2D), overtreatment with hypoglycaemic drugs (HDs: sulfonylureas, glinides and/or insulins) is frequent and associated with increased 1-year mortality. Deintensification of HD is thus a key issue, for which evidence is though limited. The primary objective of this study will be to estimate the effect of deintensifying HD on clinical outcomes (hospital admission or death) within 3 months in older adults (≥75 years) with T2D., Methods: We will emulate with real-world data a target trial, within The Health Improvement Network cohort, a large-scale database of data collected from electronic medical records of 2000 general practitioners in France. From 1 January 2010 to 28 February 2019, we will include eligible patients ≥75 years who will have T2D, a stable dose of HDs, glycated haemoglobin A1c (HbA1c) value <75 mmol/mol (9.0%) and no deintensification in the past year. The target trial will be sequentially emulated (ie, eligibility assessed) every month in the database. Patients will be classified at baseline of each sequential trial in the intervention arm (deintensification of HDs: decrease of ≥50% in the total dose of HDs, including complete cessation) or control arm (no deintensification of HDs). The pooled dataset for all sequential emulated trials will be analysed. The primary outcome will be time to first occurrence of hospital admission or death, within 3 months. Secondary outcomes will be hospitalisation, death, appropriateness of glycaemic control and occurrence of HbA1c >75 mmol/mol within 1 year. Participants will be followed from baseline to 12 months after randomisation, administrative censoring, or death, whichever occurs first. A pooled logistic regression will be used to estimate the treatment effect on the incidence of the outcomes., Dissemination and Ethics: No ethical approval is needed for using retrospectively this fully anonymised database. The results will be disseminated during conferences and through publications in scientific journals., Competing Interests: Competing interests: Antoine Christiaens is employed by the Fund for Scientific Research, as a postdoctoral researcher. He received the “Edouard et Lucie Chaffoteaux” Award – 7th edition – from the Société Française de Gériatrie et Gérontologie (SFGG), and the Fondation de France. He received honoraria for a lecture during the Journées de Gériatrie de Nouvelle Aquitaine (Bordeaux, France), from NovoNordisk in April 2022 (This company did not give any guidance, nor did take part in the content of the lecture). He is member of the board of the Belgian Society of Gerontology and Geriatrics (unpaid activity). Florence Tubach is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière hospital, both these structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies, that have contributed indiscriminately to the salaries of its employees. Florence Tubach is not employed by these structures and did not receive any personal remuneration from these companies. Other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Older studies uncovered an increased risk of cancer in patients with rheumatoid arthritis between 10% and 30% compared to the general population, with a lack of data concerning infrequent cancers. In recent year, major therapeutic breakthroughs might have affected this risk of cancer by mitigating disease activity or on the contrary by impairing antitumoral immune response. The objectives of this study are to compare cancer risk in patients with treated rheumatoid arthritis to the general population, in all treated patients and according to treatment exposure., Methods: This is a nationwide population-based study within the French national claims database "Système National des Données de Santé" (SNDS) between January 1st 2010 and December 31st 2020, to estimate the age and sex-standardized incidence ratios of cancer (all sites and site specific) of treated rheumatoid arthritis patients, with the French population as reference (by use of the French Network of Population-Based Cancer Registries [FRANCIM])., Findings: During the study period, 257,074 treated patients with rheumatoid arthritis contributed to a total of 2,098,238 person-years for the main analysis. The all-cancer risk was increased in rheumatoid arthritis patients, with a SIR (Standardized Incidence Ratio) of 1.20 (95% CI [1.17-1.23]). This risk was increased particularly for lung (SIR 1.41, 95% CI [1.36-1.46], bladder (SIR 2.38 95% CI [2.25-2.51]), cervix (SIR 1.80, 95% CI [1.62-2.01]), prostate (SIR 1.08, 95% CI [1.04, 1.13]) cancers, melanoma (SIR 1.37, 95% CI [1.29-1.46]), diffuse large B cell lymphoma (SIR 1.79, 95% CI [1.63-1.96], multiple myeloma (SIR 1.42, 95% CI [1.27-1.60]) and Hodgkin's lymphoma (SIR 2.73, 95% CI [2.31-3.23]). Some cancers were less frequent than in the general population such as pancreatic (SIR 0.90, 95% CI [0.83-0.97]) as well as breast and endometrial cancers (SIR 0.91, 95% CI [0.88-0.94] and SIR 0.77, 95% CI [0.71-0.84] respectively). Although we observed a modest but significant relative increase of all-cancer risk over-time in rheumatoid arthritis patients, there was a trend towards a decrease in risk of non-Hodgkin's lymphoma. Patients treated with rituximab were the patients displaying the highest risk of cancer., Interpretation: Compared to the general population, treated rheumatoid arthritis patients were at greater risk of all-cancer and some site specific cancers, except for breast, pancreatic and endometrial cancers which were less frequent than in the general population., Funding: This work was supported by unrestricted grants from the InCA (national institute against cancer) and AP-HP (Assistance Publique des Hôpitaux de Paris)., Competing Interests: XM received fees from Astra-Zeneca, BMS, Galapagos, GSK, Novartis, Pfizer; RS received consulting fees from GSK, Bristol Myer Squib, Boerhinger, Amgen, Pfizer and Janssen; travel fees from Amgen and GSK; BF received research grants from AbbVie, Pfizer, Lilly, MSD, and consulting fees from AbbVie, Amgen, Biogen, BMS, Celltrion, Chugai, Fresenius Kabi, Galapagos, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, OWKIN, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Viatris and support for meetings/travel from Lilly; FT redistributed to her hospital consulting fees from MSD and Novartis., (© 2023 The Authors. Published by Elsevier Ltd.)

Background: Little is known about phototype and the response to systemic treatment in psoriasis., Objectives: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype., Methods: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1., Results: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups., Conclusions: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient., Competing Interests: Conflicts of interest F.T. is Head of the Clinical Research Unit at Pitié-Salpêtrière Hospital and the Centre de Pharmacoepidemiologie (Cephepi) (Pharmacoepidemiology Centre) of the Assistance Publique–Hôpitaux de Paris (Paris Hospitals); she has received research funding, grants and fees for consultancy activities from a large number of pharmaceutical companies that have contributed to employee salaries (but no personal remuneration for F.T.). M.V. has undertaken activities as a paid consultant, advisor or speaker for AbbVie, Arrow, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Galderma, Janssen, LEO Pharma, Lilly, medac, MSD, Novartis and Pfizer. M.B.-B. offers a consultancy service and is an investigator for AbbVie, Amgen, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis and Pfizer. N.B. has been an investigator for Novartis and Pfizer; she is a consultant for Janssen and has received speaker remuneration from Janssen. P.J. is a consultant for GSK, Lilly, Principia Biopharma, Roche and Sanofi Aventis. D.J. is a consultant for AbbVie, Biogen, Celgene, Fresenius Kabi, Janssen, Lilly, medac, Merck Sharp & Dohme, Novartis, Pfizer and UCB. E.M. is a consultant for AbbVie, Janssen, Novartis and Pfizer; she has also been an investigator for AbbVie, Amgen, AstraZeneca, LEO Pharma, Novartis and Pfizer; and has received speaker remuneration from AbbVie, Janssen, Novartis and Pfizer. C.P. has been an investigator and consultant for AbbVie, Amgen, Boehringer Ingelheim, Celgene, GSK, Janssen, LEO Pharma, Lilly, Novartis and Pfizer. M.-A.R. is a consultant for AbbVie, BMS, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer and Pierre Fabre. H.B. has undertaken activities as a paid consultant, advisor or speaker for AbbVie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sun Pharmaceuticals and UCB; he has also received grant funding from Pfizer. The other authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mortality is high in older patients hospitalized with COVID-19. Previous studies observed lower mortality during the Omicron wave, yet no data is available on older patients. The objective was to compare in-hospital mortality between the Omicron and previous waves in older patients hospitalized with COVID-19., Methods: This retrospective observational multicenter cohort study used the Greater Paris University Hospitals Group's data warehouse (38 hospitals). Patients aged ≥ 75 years with a confirmed COVID-19 diagnosis and hospitalized from March 2020 to January 2022 were included. The study period was divided into five waves. The fifth wave (January 1st to 31st 2022) was considered as the Omicron wave as it was the predominant variant (≥ 50%), and was compared with waves 1 (March-July 2020), 2 (August-December 2020), 3 (January-June 2021) and 4 (July-December 2021). Primary outcome was in-hospital mortality. Secondary outcome was occurrence of ICU admission or in-hospital death. Multivariate logistic regression was performed, with a sensitivity analysis according to variant type., Results: Of the 195,084 patients hospitalized with COVID-19, 19,909 patients aged ≥ 75 years were included (median age 85 [IQR 79-90] years, 53% women). Overall in-hospital mortality was 4,337 (22%), reaching 345 (17%) during wave 5. Waves 1 and 3 were significantly associated with increased in-hospital mortality in comparison with wave 5 (adjusted Odds Ratios aOR 1.42 [95%CI 1.21-1.66] and 1.56 [95%CI 1.33-1.83] respectively). Waves 1 to 3 were associated with an increased risk of occurrence of ICU admission or in-hospital death in comparison with wave 5: aOR 1.29 [95% CI 1.12 to 1.49] for wave 1, aOR 1.25 [95% CI 1.08 to 1.45] for wave 2 and aOR 1.56 [95% CI 1.36 to 1.79] for wave 3. Sensitivity analysis found that Omicron variant was associated with decreased mortality, in comparison with previous variants., Conclusions: Mortality was lower during the 5th Omicron wave in the older population, but remained high, implying that this variant could be considered as "milder" but not "mild". This persistently high mortality during the 5th Omicron wave highlights the importance of including older patients in clinical trials to confirm the benefit/risk balance of COVID-19 treatments in this fragile population., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: The aim was to evaluate the ability of baseline multi-biomarker disease activity (MBDA) score to discriminate between patients with rheumatoid arthritis (RA) in remission who are at high risk versus low risk of relapse after TNF-inhibitor (TNFi) tapering., Methods: The study is a post-hoc analysis of patients who completed the Spacing of TNFi injections in Rheumatoid ArthritiS Study (STRASS), a multicentre 18-month equivalence randomised controlled study, of TNFi tapering in RA patients in remission, and had baseline serum samples available for MBDA testing. The primary endpoint of this study was the ability of the baseline MBDA score to predict relapse at any time during the 18 months following initiation of TNFi tapering. Secondary endpoints were the ability of baseline MBDA score to predict TNFi discontinuation at Month 18, and structural damage progression on x-rays assessed by the change in total van der Heijde-modified Sharp score from baseline to month 18., Results: 64 and 73 patients were included in the spacing (S)-arm and maintenance (M)-arm, respectively. In the M-arm, the mean MBDA score at baseline was higher among patients who relapsed during the 18-month follow-up than those who did not relapse: 32.5 compared to 27.2 (p=0.053) whereas no difference in the MBDA score was observed in the S-arm between patients who relapsed or not 27 compared to 26.2 (p=0.57) 13 patients (21.3%) of the S-arm were able to discontinue TNFi, for which the predictive value of the MBDA score was low (AUC=0.560). Radiographic progression in both arms, although low (n=9) was not correlated with the MBDA score at baseline with a poor discriminative value in both arms (AUC=0.558)., Conclusions: In our study MBDA score in baseline was not predictive of relapse, discontinuation of TNFi in patients with long-standing RA patients tapering TNFi.

Objectives: To describe patient and public involvement (PPI) in randomized controlled trials (RCTs) addressing a chronic condition and to analyze whether PPI is associated with trial characteristics., Study Design and Setting: We used PubMed search to identify RCTs addressing a chronic condition and published in journals with a mandatory PPI statement., Results: Across 101 RCTs; 40 (40%) reported PPI at any stage of the research process. PPI contribution occurred mostly at the design stage of RCTs (n = 36), especially for assessing the burden of the intervention (n = 24), and at the conduct stage (n = 21), with the elaboration of communication materials (n = 14). Less than one-third (13/40) of RCTs included PPI in the development or choice of outcome measures. As compared with non-PPI RCTs, PPI RCTs more frequently were published in The BMJ, had a corresponding author from the United Kingdom, reported a public funding source, had a higher inclusion rate, used usual care as a control and evaluated a digital intervention. PPI RCTs were associated with less frequent use of placebo as a control group., Conclusion: Our results underline that PPI is not uncommon in RCTs of chronic conditions but infrequently occurred at a key stage. Yet, the engagement of patients as a real partner in RCTs of chronic conditions should be enhanced., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Context: Midurethral slings (MUSs) are the most used therapy for the treatment of stress urinary incontinence (SUI). While warning signals about potential complications have been raised worldwide, there is a lack of safety data especially in the long term., Objective: Our objective was to evaluate synthetic MUS safety outcomes at long term in adult women., Evidence Acquisition: We included all studies evaluating MUSs in adult women with SUI. All synthetic MUSs have been considered: tension-free vaginal tape (TVT), transobturator tape (TOT), and mini-slings. The primary outcome was the reoperation rate at 5 yr., Evidence Synthesis: Of 5586 references screened after duplicate removal, 44 studies (8218 patients) were included. Among these, nine were randomized controlled trials and 35 were cohort studies. The overall reoperation rates at 5 yr varied between 0% and 19% for TOT (11 studies), 0% and 13% for TVT (17 studies), and 0% and 19% for mini-slings (two studies). The overall reoperation rates at 10 yr varied between 5% and 15% for TOT (four studies) and between 2% and 17% for TVT (four studies). There were few safety data beyond 5 yr: 22.7% of the articles reported a follow-up at ≥10 yr and 2.3% at ≥15 yr., Conclusions: The incidence rates of reoperations and complications are heterogeneous, and data beyond 5 yr are rare., Patient Summary: There is an urgent need to improve safety monitoring of mesh as our review highlights that available safety data are heterogeneous and of insufficient quality to guide the decision., (© 2023 The Authors.)

Background: The nature of the COVID-19 pandemic led to concerns among patients and physicians about the potential impact of immunosuppressive treatments for chronic diseases such as psoriasis on the risk of severe COVID-19., Objectives: To describe treatment modifications and determine the incidence of COVID-19 infection among psoriasis patients during the first wave of the pandemic, and identify the factors associated with these events., Methods: Data from PSOBIOTEQ cohort relating to the first COVID-19 wave in France (March to June, 2020), as well as a patient-centred COVID-19 questionnaire, were used to evaluate the impact of lockdown on changes (discontinuations, delays or reductions) in systemic therapies, and to determine the incidence of COVID-19 cases among these patients. Logistic regression models were used to assess associated factors., Results: Among the 1751 respondents (89.3%), 282 patients (16.9%) changed their systemic treatment for psoriasis, with 46.0% of these changes being initiated by the patients themselves. Patients were more likely to experience psoriasis flare-ups during the first wave if they changed their treatment during this period (58.7% vs 14.4%; P < 0.0001). Changes to systemic therapies were less frequent among patients with cardiovascular diseases (P < 0.001), and those aged ≥ 65 years (P = 0.02). Overall, 45 patients (2.9%) reported having COVID-19, and eight (17.8%) required hospitalization. Risk factors for COVID-19 infection were close contact with a positive case (P < 0.001) and living in a region with a high incidence of COVID-19 (P < 0.001). Factors associated with a lower risk of COVID-19 were avoiding seeing a physician (P = 0.002), systematically wearing a mask during outings (P = 0.011) and being a current smoker (P = 0.046)., Conclusions: Discontinuation of systemic psoriasis treatments during the first COVID-19 wave (16.9%) - mainly decided by patients themselves (46.0%) - was associated with a higher incidence of disease flares (58.7% vs 14.4%). This observation and factors associated with a higher risk of COVID-19 highlight the need to maintain and adapt patient-physician communication during health crises according to patient profiles, with the aim of avoiding unnecessary treatment discontinuations and ensuring that patients are informed about the risk of infection and the importance of complying with hygiene rules., Competing Interests: Disclosure of interest HA, YD, ES, and OC have no conflicts of interest to disclose. EM is a consultant and has received speaker remunerations from Novartis, AbbVie, LEO Pharma, Lilly, Celgene, Amgen, and Janssen-Cilag. MAR is a consultant for Pfizer, LEO Pharma, Janssen, Galderma, AbbVie, Novartis, Pierre Fabre, Merck and BMS. MV has undertaken activities as a paid consultant, adviser or speaker for Janssen, AbbVie, MSD, Pfizer, LEO Pharma, Medac, Boehringer Ingelheim, Novartis and Arrow. MBB offers a consultancy service and is an investigator for AbbVie, Amgen, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis and Pfizer. AD has undertaken activities as a paid consultant for Sanofi-Aventis, outside of the submitted work. NB has been an investigator for Pfizer and Novartis. She is currently a consultant for Janssen and has received speaker remuneration from Janssen. PJ is a consultant for Roche, GSK, Lilly, Principia Biopharma, and Sanofi-Aventis. DJ is a consultant for AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius-Kabi, Janssen-Cilag, LEO Pharma, Lilly, MEDAC, Novartis, Pfizer, Sanofi and UCB. HB has undertaken activities as a paid consultant, adviser or speaker for AbbVie, Almirall, Anaptysbio, Amgen, Aristea Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, UCB and Xion Pharmaceuticals. He has also received grant funding from Bristol Myers Squibb, Janssen, LEO Pharma and Pfizer. CP has been an investigator and consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GSK, Janssen, LEO Pharma, Lilly, Novartis, Pierre Fabre, Pfizer and Sanofi. FT is head of the Pharmaco-Epidemiology Centre (Cephépi) of the Assistance Publique – Hôpitaux de Paris and of the Clinical Research Unit of Pitié Salpêtrière Hospital, both of which structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed indiscriminately to the salaries of its employees. Florence Tubach is not employed by these structures and has not received any personal remuneration from these companies., (Copyright © 2023. Published by Elsevier Masson SAS.)

Importance: In patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course., Objective: To assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS)., Design, Setting, and Participants: This multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death., Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab)., Main Outcomes and Measures: The main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age., Results: A total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS., Conclusions and Relevance: In this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

Objectives: To compare intent to share individual participant data (IPD) between COVID-19 and non-COVID-19 trials registered at ClinicalTrials.gov between 01/09/2020, and 01/03/2021. We also evaluated factors independently associated with intent to share IPD and whether intent to share IPD has improved as compared with the prepandemic period., Methods: We searched ClinicalTrials.gov for all interventional phase 3 studies registered between 01/09/2020, and 01/03/2021. Then, we identified COVID-19 trials and selected a random sample of non-COVID-19 trials with a ratio 2:1. We compared the intent to share IPD between these trials and with 292 trials registered between 01/12/2019, and 01/03/2020 (prepandemic period)., Results: We included 148 COVID-19 trials and 296 non-COVID-19 trials. Intent to share IPD did not significantly differ between COVID-19 and non-COVID-19 trials (22.3% vs. 27.0%, P = 0.3). Intent to share IPD was independently associated with industry-sponsorship (odds ratio [OR] = 2.92; 95% confidence interval [CI]: 1.65-5.27) and location in the United States (OR = 2.93; 95% CI: 1.64-5.41) or the European Union (OR = 2.06; 95% CI: 1.03-4.19). The intent to share IPD has not significantly improved compared with the prepandemic period (P = 0.16)., Conclusion: Data-sharing intent at registration does not seem better for COVID-19 trials., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases., Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded., Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10 -4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10 -4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10 -3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10 -8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10 -5 )., Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old., (© 2023. The Author(s).)

Background: Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient's prognosis., Patients and Methods: This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy., Results: One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not., Conclusions: In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration., Trial Registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient., (© 2023. The Author(s).)

Competing Interests: Conflicts of interest: M.B.-B. is a consultant for AbbVie, Celgene, Janssen-Cilag, Lilly, Novartis, Medac and UCB. N.B. is a consultant for Novartis, Celgene, MSD, Janssen, Lilly, Pfizer and AbbVie. P.J. is a consultant for AbbVie, Celgene, Janssen-Cilag, Lilly and Novartis. D.J. is a consultant for AbbVie, Amgen, Celgene, Fresenius-Kabi, Janssen-Cilag, LEO, Lilly, Pfizer, MEDAC, Novartis and UCB. E.M. is a consultant for AbbVie, LEO Pharma, Celgene, Pfizer, Janssen-Cilag and Novartis. C.P. is a consultant for AbbVie, Almirall, Amgen, Boerhinger, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Pfizer, Novartis, Pierre Fabre, Sanofi and UCB. M.-A.R. is a consultant for AbbVie, Amgen, Boehringer, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Nordic, Novartis, Pfizer and Medac. H.B. is a consultant for AbbVie, Almirall, Amgen, Biocad, Boerhinger, Celgene, Dermavant, Janssen, LEO Pharma, Eli Lilly, Mylan, Novartis, Pfizer, Pierre Fabre, Sun Pharmaceuticals and UCB. H.A. is a consultant for AbbVie, Novartis, Janssen-Cilag, Almirall, Leo and Lilly.

Systematic reviews and meta-analyses have been proposed as an approach to synthesize the literature and counteract the lack of power of small preclinical studies. We aimed to evaluate (1) the methodology of these reviews, (2) the methodological quality of the studies they included and (3) whether study methodological characteristics affect effect size. We searched MEDLINE to retrieve 212 systematic reviews with meta-analyses of preclinical studies published from January, 2018 to March, 2020. Less than 15% explored the grey literature. Selection, data extraction and risk of bias assessment were performed in duplicate in less than two thirds of reviews. Most of them assessed the methodological quality of included studies and reported the meta-analysis model. The risk of bias of included studies was mostly rated unclear. In meta-epidemiological analysis, none of the study methodological characteristics was associated with effect size. The methodological characteristics of systematic reviews with meta-analyses of recently published preclinical studies seem to have improved as compared with previous assessments, but the methodological quality of included studies remains poor, thus limiting the validity of their results. Our meta-epidemiological analysis did not show any evidence of a potential association between methodological characteristics of included studies and effect size., (© 2022. The Author(s).)

Background: Biologics are the cornerstone of treatment of patients with moderate-to-severe plaque psoriasis and switches between biologics are frequently needed to maintain clinical improvement over time., Objectives: The main purpose of this study was to describe precisely switches between biologics and how their pattern changed over time with the recent availability of new biologic agents., Methods: We included patients receiving a first biologic agent in the Psobioteq multicenter cohort of adults with moderate-to-severe psoriasis receiving systemic treatment. We described switches between biologics with chronograms, Sankey and Sunburst diagrams, assessed cumulative incidence of first switch by competing risks survival analysis and reasons for switching. We assessed the factors associated with the type of switch (intra-class - i.e. within the same therapeutic class - vs. inter-class) in patients switching from a TNF-alpha inhibitor using multivariate logistic regression., Results: A total of 2153 patients was included. The cumulative incidence of switches from first biologic was 34% at 3 years. Adalimumab and ustekinumab were the most prescribed biologic agents as first and second lines of treatment. The main reason for switching was loss of efficacy (72%), followed by adverse events (11%). Patients receiving a TNF-alpha inhibitor before 2016 mostly switched to ustekinumab, whereas those switching in 2016 or after mostly switched to an IL-17 inhibitor. Patients switching from a first-line TNF-alpha inhibitor before 2016 were more likely to switch to another TNF-alpha inhibitor compared with patients switching since 2018. Patients switching from etanercept were more likely to receive another TNF-alpha inhibitor rather than another therapeutic class of bDMARD compared with patients switching from adalimumab., Conclusion: This study described the switching patterns of biologic treatments and showed how they changed over time, due to the availability of the new biologic agents primarily IL-17 inhibitors., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Osteoporosis carries a high medical, economic, and societal burden principally because of the risk of severe fractures. The objective of this cost-of-illness study was to describe health resource utilization and associated costs in all patients aged ≥50 years hospitalized for a severe osteoporotic fracture over a 6-year period (2009 to 2014) in France. Data were extracted from the French national healthcare database (SNDS) on all health care resource utilization between the index date (date of hospitalization for first fracture during the enrollment period) and study end (December 31, 2016) or until the patient died. Costing was restricted to direct costs and determined from the payer perspective. Variables related to costs were identified through multivariate logistic regression analysis. A total of 356,895 patients were included (median follow-up 39.1 months). In the year after the index fracture, 36,622 patients (10.5%) were rehospitalized for a fracture-related reason. Only 18,474 (5.3%) underwent bone densitometry and 58,220 (16.7%) received a specific treatment. The total annual per capita osteoporosis-related cost in the year after the index severe osteoporotic fracture was €18,040 (from €8598 for multiple ribs to €21,085 for hip fracture) of which €17,905 was incurred by fracture-related costs. The cost incurred by management of osteoporosis was €135. Over years 2 to 5, the mean annual per capita costs of fracture treatment (€806, mostly attributable to the treatment of refractures) continued to dominate those of osteoporosis management (€99). Total annual cost of care was €1260 million (year 2014). Variables associated with higher cost were older age, male sex, site of fracture, a history of prior osteoporotic fracture, and the number of refracture events. The 5-year cost of severe osteoporotic fractures to the French health care system is high and mostly attributable to the treatment of refractures. Improved fracture prevention measures in patients with osteoporosis is crucial to reduce the economic burden of the disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Mobile health applications (apps) are increasing in interest to enhance patient self-management. Few apps are actually used by patients and have been developed for patients with inflammatory arthritis (IA) treated with disease-modifying anti-rheumatic drugs which use entails risk of adverse effects such as infections., Objective: To develop Hiboot, a self-management mobile app for patients with IA, by using a user-centred step-by-step approach and assess its real-life use., Methods: The app development included first a qualitative study with semi-guided audiotaped interviews of 21 patients to identify the impact of IA on daily life and patient treatments practices and an online cross-sectional survey of 344 patients to assess their health apps use in general and potential user needs. A multidisciplinary team developed the first version of the app via five face-to-face meetings. After app launch, a second qualitative study of 21 patients and a users' test of 13 patients and 3 rheumatologists led to the app's current version. The number of app installations, current users and comments were collected from the Google Play store and the Apple store., Results: The qualitative study revealed needs for counselling, patient-health professional partnership, and skills to cope with risk situations; 86.8% participants would be ready to use an app primarily on their rheumatologist's recommendation. Six functionalities were implemented: a safety checklist before treatment administration, aids in daily life situations based on the French academic recommendations, treatment reminders, global well-being self-assessment, periodic counselling messages, and a diary. The Hiboot app was installed 20,500 times from September 2017 to October 2020, with 4300 regular current users. Scores were 4.4/5 stars at Android and iOS stores., Conclusion: Hiboot is a free self-management app for patients with IA developed by a step-by-step process including patients and health professionals. Further evaluation of the Hiboot benefit is needed., Competing Interests: CB, TP, AL, CV, GD, PB, SD, FT, DL, LG, FAL, MA, SP and JS declare no competing interests in relation is this study. SG, FM were paid by Unknowns Research department for their contribution to the study. GM, JLC, MQ, were employed by Unknowns Conseil en stratégie et innovation, Paris, France HJ and LB are owners of Unknowns Conseil en stratégie et innovation, Paris, France Disclosures of interest apart from the study Catherine Beauvais reports research grants from BMS, Fresenius Kabi, Lilly, Mylan and was an occasional speaker for BMS, Abbvie, MSD, Mylan, Pfizer, Roche, Sanofi, UCB. She participated to a medical board for Sandoz and Novartis. Thao Pham reports speaker and consulting fees from Abbvie, Amgen, Biogen, BMS, Celgene, Fresenius-Kabi, Janssen, Lilly, MSD, Nordic, Novartis, Pfizer, Sandoz, Sanofi and UCB. Florence TUBACH is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and the Clinical Research Unit of Pitié-Salpêtrière hospital; both of these structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed indiscriminately to the salaries of its employees. Florence Tubach is not employed by these structures and did not receive any personal remuneration from these companies. Jérémie Sellam reports fees from MSD, Pfizer, Abbvie, Fresenius Kabi, BMS,Roche Chugai, Sandoz, Lilly, Gilead, Novartis, Janssen, grant research fromSchwa Medico, MSD and Roche.

Objective: Osteoporosis is underdiagnosed and undertreated, although severe complications of osteoporotic fractures, including vertebral fractures, are well known. This study sought to assess the feasibility and results of an opportunistic screening of vertebral fractures and osteoporosis in a large database of lumbar or abdominal CT scans., Material and Methods: Data were analysed from CT scans obtained in 35 hospitals from patients aged 60 years or older and stored in a Picture Archiving and Communication System in Assistance-Publique-Hôpitaux de Paris, from 2007 to 2013. Dedicated software was used to analyse the presence or absence of at least 1 vertebral fracture (VF), and the radiodensity of the lumbar vertebrae was measured Hounsfield Units (HUs). A simulated T-score was calculated., Results: Data were analysed from 152 268 patients [mean age (S.D.) = 73.2 (9.07) years]. Success rates for VF assessment and HUs measurements were 82 and 87%, respectively. The prevalence of VFs was 24.5% and increased with age. Areas under the receiver operating characteristic curves for the detection of VFs were 0.61 and 0.62 for the mean HUs of the lumbar vertebrae and the L1 HUs, respectively. In patients without VFs, HUs decreased with age, similarly in males and females. The prevalence of osteoporosis (sT-score ≤ -2.5) was 23.8% and 36.5% in patients without and with VFs, respectively., Conclusion: It is feasible on a large scale to screen for VFs and osteoporosis during opportunistic screening in patients 60 years or older having lumbar or abdominal CT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To explore challenges in recruitment and intervention implementation in recent stepped-wedge cluster randomized trials (SW-CRTs)., Study Design and Setting: We searched PubMed to identify primary reports of SW-CRTs (2019-2020). Two reviewers independently screened studies and extracted data from each report. A recruitment challenge was defined as a planned number of clusters or participants not achieved or any reported changes made to the design to address recruitment difficulties. An implementation challenge was defined as early, late, or no implementation of the intervention in at least one cluster., Results: Of 55 SW-CRTs, 18 (33%) had a recruitment challenge, 23 (42%) had none, and for 14 (26%) it was impossible to judge. At least one implementation challenge was present in 24 (44%), eight (15%) had none, and for 23 (42%) it was impossible to judge. Of the 35 (64%) trials with recruitment or implementation challenges, 18 (72%) had one or more modifications of their design, most often a modification of the trial duration., Conclusion: Investigators must be aware of the risks of recruitment or implementation challenges when considering the use of an SW-CRT design. Mitigating strategies should be adopted when planning the trial. More transparent reporting of planned and actual design features is required., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Patients with ulcerative colitis [UC] are at increased risk of colorectal cancer. Anti-tumour necrosis factor agents [anti-TNF] aim to reduce chronic colonic inflammation and may lower the risk of colorectal cancer [CRC], but the impact of anti-TNF exposure has not yet been assessed in population-based cohort studies. The aim of this nationwide study was to assess the risk of CRC in patients with UC exposed to anti-TNF., Methods: Based on the French health insurance database, patients aged 18 years or older with a diagnosis of UC, previously exposed to or initiating immunosuppressive treatment, were followed from January 1, 2009, until December 31, 2018. The risk of CRC associated with anti-TNF exposure was assessed using marginal structural Cox proportional hazard models adjusting for baseline and time-varying comorbidities including primary sclerosing cholangitis, UC disease activity, colonoscopic surveillance, and other medications., Results: Among 32 403 patients with UC, 15 542 [48.0%] were exposed to anti-TNF. During a median follow-up of 6.1 years [198 249 person-years], 246 incident CRC occurred (incidence rate per 1000 person-years, 1.24; 95% confidence intrval [CI], 1.10-1.41). Whereas the risk of CRC associated with anti-TNF exposure was not decreased in the overall group of patients with UC (hazard ratio [HR], 0.85; 95% CI, 0.58-1.26), anti-TNF exposure was associated with a decreased risk of CRC in patients with long-standing colitis [disease duration ≥10 years] [HR, 0.41; 95% CI, 0.20-0.86]., Conclusions: In a nationwide cohort of patients with UC, anti-TNF exposure was associated with a decreased risk of CRC in patients with long-standing colitis., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Despite growing evidence that aortic valve repair improves long-term patient outcomes and quality of life, aortic valves are mostly replaced. We evaluate the effect of aortic valve repair versus replacement in patients with dystrophic aortic root aneurysm up to 4 years., Methods: The multicentric CAVIAAR (Conservation Aortique Valvulaire dans les Insuffisances Aortiques et les Anévrismes de la Racine aortique) prospective cohort study enrolled 261 patients: 130 underwent standardized aortic valve repair (REPAIR) consisting of remodelling root repair with expansible aortic ring annuloplasty, and 131 received mechanical composite valve and graft replacement (REPLACE). Primary outcome was a composite criterion of mortality, reoperation, thromboembolic or major bleeding events, endocarditis or operating site infections, pacemaker implantation and heart failure, analysed with propensity score-weighted Cox model analysis. Secondary outcomes included major adverse valve-related events and components of primary outcome., Results: The mean age was 56.1 years, and valve was bicuspid in 115 patients (44.7%). Up to 4 years, REPAIR did not significantly differ from REPLACE in terms of primary outcome [Hazard Ratio (HR) 0.66 (0.39; 1.12)] but showed significantly less valve-related deaths (HR 0.09 [0.02; 0.34]) and major bleeding events (HR 0.37 [0.16; 0.85]) without an increased risk of valve-related reoperation (HR 2.10 [0.64; 6.96]). When accounting for the occurrence of multiple events in a single patient, the REPAIR group had half the occurrence of major adverse valve-related events (HR 0.51 [0.31; 0.86])., Conclusions: Although the primary outcome did not significantly differ between the REPAIR and REPLACE groups, the trend is in favour of REPAIR by a significant reduction of valve-related deaths and major bleeding events. Long-term follow-up beyond 4 years is needed to confirm these findings., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To evaluate in clinical practice the persistence and safety of golimumab, together with the evolution of disease activity and patient reported outcomes, in adult patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis (axSpA). This article focuses on the outcomes of golimumab treatment in axSpA patients., Methods: Golimumab persistence 24 months after initial prescription (primary outcome) was assessed using Kaplan-Meier estimates. Secondary outcomes included evaluations of disease activity evolution (ASDAS and BASDAI), patient-reported outcomes (EQ-5D, SF-12 and HAQ), and golimumab's safety profile., Results: Of 478 axSpA patients, 60.9% were biologic-naïve. Mean age and proportion of females were higher in biologics-pretreated patients (46.8 vs. 40.2 years, p<0.001 and 62.0% vs. 49.8%, p=0.009, respectively). Golimumab persistence at 24 months was 52.6% [95% CI 47.9-57.1%] in the axSpA cohort. It was 59.2% [95% CI 53.1-64.8%] and 42.7% [95% CI 35.3-49.8%] respectively, for biologics-naïve and biologics-pretreated patients (p<0.01), and 65.9% [95% CI 58.9-72.0%] and 41.5% [95% CI 35.2-47.6%], respectively for males and females (p<0.01). Reasons for golimumab discontinuation were primary non-response (37.4%), secondary non-response (24.8%) and intolerance (21.5%). Disease activity and patient reported outcomes improved significantly for those who persisted at 24 months and were higher for biologics-naïve patients., Conclusions: Golimumab persistence at 2 years in axSpA patients was 52.6%. Previous treatment with another biologic and female gender were associated with earlier discontinuation. Golimumab was a well-tolerated therapy for axSpA, with no new safety signals observed.

Purpose: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia., Methods: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28., Results: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups., Conclusion: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)