Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Clinical Evaluation of Medical Devices: Main Constraints and Specificities

Abstract -The purpose of the Giens round table no. 1 was to make proposals and recommendations regarding the clinical evaluation of medical devices. First, the European and French regulatory rules were examined and compared with the US FDA approach. Thereafter, the main specificities and constraints of the MD sector were underlined and their impact in clinical evaluation described and analyzed. Two areas, cumulating most of these constraints, were consecutively analyzed for concrete case study. Considering a patient-centered approach, the RT issued eight recommendations directed to manufacturers, physicians and policymakers in order to improve clinical evaluation in the medical device field

Clinical Evaluation of Medical Devices: Main Constraints and Specificities

The purpose of the Giens round table no. 1 was to make proposals and recommendations regarding the clinical evaluation of medical devices. First, the European and French regulatory rules were examined and compared with the US FDA approach. Thereafter, the main specificities and constraints of the MD sector were underlined and their impact in clinical evaluation described and analyzed. Two areas, cumulating most of these constraints, were consecutively analyzed for concrete case study. Considering a patient-centered approach, the RT issued eight recommendations directed to manufacturers, physicians and policymakers in order to improve clinical evaluation in the medical device field

Contraintes et spécificités de l’évaluation clinique des dispositifs médicaux

L’objet de cette table ronde était de faire des propositions et recommandations concernant l’évaluation clinique des dispositifs médicaux (DM). Dans un premier temps, un rappel du parcours réglementaire tant au niveau européen que français est indispensable pour aborder ce champ encore jeune et très évolutif. Puis les principales spécificités des DM sont soulignées avec leurs implications sur l’évaluation clinique. Deux domaines, les DM implantables et les DM de compensation du handicap, sont plus particulièrement analysés pour les illustrer. Huit propositions et recommandations ont été retenues par la table ronde. Elles s’adressent à tous les acteurs du DM : industriels, utilisateurs, institutionnels et ont pour but d’améliorer une évaluation clinique centrée sur le patient et à son service

Télémédecine : quel cadre, quels niveaux de preuves, quelles modalités de déploiement

Le concept de télémédecine a été officialisé en France avec la loi hôpital patients santé territoires (HPST) de 2009 et le décret d’application de 2010. De nombreuses expérimentations ont été mises en œuvre et les institutions de régulation (Ministère, Agence régionale de santé [ARS], Haute autorité de santé [HAS]…) ont émis diverses orientations et recommandations tant sur le volet organisationnel que sur les attentes d’évaluation. C’est dans ce contexte que la table ronde a souhaité émettre des recommandations sur différents axes de la télésurveillance médicale (la place de la télésurveillance médicale, le parcours réglementaire, les principes d’évaluation, les modalités de prises en charge et les conditions pour un déploiement pérenne et fluide). Si les nouvelles approches utilisant la télésurveillance médicale, font l’objet de nombreuses études conduisant au postulat qu’il existe un bénéfice à la fois sur un plan clinique et pour la qualité de vie du patient, la démonstration de l’impact sur l’organisation des soins et du bénéfice médico-économique restent à mieux préciser (critères, méthodes, moyens). De même, les cadres contractuels du déploiement de la télésurveillance existent mais sont complexes ; ils font appels à de nombreux interlocuteurs (Direction générale de l’offre de soins [DGOS], ARS, HAS, Agence des systèmes d’information partagés de santé [ASIP], Commission nationale informatique et libertés [CNIL], Conseil national de l’ordre des médecins [CNOM]…) qui bénéficieraient du partage d’une même approche et de fluidifier les partenariats. À ce stade, l’enjeu est aussi de définir les conditions permettant la validation d’un modèle économique stable pour engager des changements organisationnels. La problématique est ici de mener de front son évaluation et sa mise en œuvre. L’accès aux données patients, en particulier à celles des caisses d’Assurance maladie et leur exploitation, pourrait permettre une plus grande efficacité de la démarche. De plus, la non-fongibilité budgétaire des différentes enveloppes budgétaires des différents secteurs d’activités limite la consolidation des impacts économiques. Les modalités de financement devront donc être adaptées à cette nouvelle répartition des rôles, à la fois au cœur du système de santé et de l’écosystème industriel. Toutes ces évolutions contribueront à ce que les responsables de notre système de santé puissent porter cette nouvelle ambition en étroite relation avec tous les acteurs de cette économie

Telemedicine: What Framework, What Levels of Proof, Implementation Rules

The concept of telemedicine was formalised in France in the 2009 “Hospital, patients, health territories” (loi hôpital, patients, santé, territoire) law and the 2010 decree through which it was applied. Many experiments have been carried out and the regulatory institutions (Ministry, Regional Health Agency [Agence régionale de santé, ARS], French National Health Authority [Haute autorité de santé, HAS], etc.) have issued various guidance statements and recommendations on its organisation and on the expectations of its evaluation. With this background, the round table wanted to produce recommendations on different areas of medical telemonitoring (the role of telemonitoring, the regulatory system, the principles for assessment, methods of use and conditions for sustained and seamless deployment). Whilst many studies carried out on new medical telemonitoring approaches have led to the postulate that it offers benefit, both clinically and in terms of patient quality of life, more information is needed to demonstrate its impact on the organisation of healthcare and the associated medico-economic benefit (criteria, methods, resources). Similarly, contractual frameworks for deployment of telemonitoring do exist, although they are complicated and involve many different stakeholders (Director General fo the Care Offering [Direction générale de l’offre de soins, DGOS], ARS, HAS, Agency for Shared Health Information Systems [Agence des systèmes d’information partagés de santé, ASIP], French National Data Protection Commission [Commission nationale informatique et libertés, CNIL], French National Medical Council [Conseil national de l’Ordre des médecins, CNOM], etc.) that would benefit from a shared approach and seamless exchange between the partners involved. The current challenge is also to define the conditions required to validate a stable economic model in order to promote organisational change. One topical issue is placing the emphasis on its evaluation and operation. Access to patient data, particularly data from the health insurance funds and the use of these data, may enable the process to be more effective. In addition, the budgetary non-fungibility of the various financial envelopes for the different areas of work, restricts the consolidation of financial impact. Funding methods will need to be adapted to this new distribution of roles, both at the centre of the healthcare system and in the industrial ecosystem. All of these changes will help the leaders of our healthcare system to bring this new ambition closer to all of the people working in the health economy

Changing Kidney Allocation Policy in France: the Value of Simulation

This paper advocates the value of simulation to promote changes in kidney allocation. Due to the scarcity of organs and to the competition between transplantation centers to obtain the best organs for their patients, any change in organ allocation policy remains a sensitive issue in public health decision-making. Organ allocation is not easily available for prospective experimental study. Observational studies only support limited changes. A simulation tool in this context permits the comparison of observed results against simulated ones. In our experience in France, it has shown to be a helpful tool during the allocation design phase providing objective facts for the debates and increasing the potential for change