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The African Regional Efforts of The Pasteur Network to Guide Control Measures Against the Coronavirus Disease 2019 (COVID-19) Pandemic Among Healthcare Workers in Africa
No full textInternational audienceHealthcare workers (HCWs) play a critical role in preventing the spread of infectious diseases. The studies in the different African countries (Cameroon, CAR, Niger, Madagascar) showed a high infection rate early during the pandemic. Despite high rates of infection, HCWs have had mild or asymptomatic COVID-19 infections in Africa. For future, implementation of cohort studies can help in identifying risks of infection and track their medium-term effects on HCW health. HCW cohort studies should be recommended in all the countries and on all times
Élaboration par consensus d’experts d’une liste des thématiques d’information du patient à aborder lors de la dispensation d’une thérapie ciblée pour un patient atteint d’un rhumatisme inflammatoire en pharmacie d’officine
No full textInternational audienceIn the vast majority of cases, targeted therapies are positioned as the second line of treatment in the management of chronic inflammatory rheumatism. These treatments, even those still subject to initial hospital prescription, are mainly available in community pharmacies and dispensed by their chemists. The aim of this work is to determine, by consensus of multi-professional experts, the topics to be discussed with patients during dispensing. The Delphi method was chosen for this consensus. The experts consulted were community pharmacists, hospital pharmacists and rheumatologists, nurses, patients with inflammatory rheumatic diseases and academics of targeted therapy at the Department of Pharmacy linked to our establishment. Consultation period: 16/04/21 to 28/06/21. Thirty-four experts agreed to participate in this study, and 29 responded to the three solicitation rounds. Nineteen topics from a literature search were proposed to the experts, and seven new topics were proposed by the experts. A consensus was reached on nine topics (dosage, objective of treatment, therapeutic adherence, storage, method of administration, conditions for prescribing and dispensing, waste management, increased risk of infection and other possible side effects) that should be addressed during initial dispensing, and an advice sheet was drawn up. This work is a first in the field and will help to guide community pharmaceutical teams in advising patients. A study of the implementation of this advice will confirm the usefulness of this work with a view to abolishing the initial hospital prescription for certain biopharmaceuticals.Les thérapies ciblées sont positionnées, dans la très grande majorité des cas, dès la deuxième ligne de traitement dans la prise en charge des rhumatismes inflammatoires chroniques. Ces traitements, même pour ceux encore soumis à prescription initiale hospitalière, sont essentiellement disponibles en ville. C’est donc l’équipe pharmaceutique de l’officine qui en assure la dispensation. L’objectif de ce travail est de déterminer par consensus d’experts pluriprofessionnels, les thématiques à aborder avec les patients lors de leur dispensation. C’est la méthode Delphi qui a été choisie pour l’élaboration de ce consensus. Les experts sollicités sont pharmaciens d’officine, pharmaciens hospitaliers, rhumatologues hospitaliers, infirmières en éducation thérapeutique, patients atteints d’un rhumatisme inflammatoire chronique et enseignants-chercheurs intervenant sur la thérapie ciblée dans les études pharmaceutiques. Période de consultation : 16/04/21 au 28/06/21. Trente-quatre experts ont accepté de participer à ce travail, 29 ont répondu aux trois tours de sollicitation. Dix-neuf thématiques issues d’une recherche bibliographique ont été proposées aux experts, 7 nouvelles thématiques ont été proposées par les experts. Neuf thématiques (posologie, objectif du traitement, adhésion thérapeutique, conservation, mode d’administration, condition de prescription et délivrance, gestion des déchets, augmentation du risque infectieux et autres effets indésirables possibles) ont fait consensus pour être abordées en primo-dispensation et ont permis l’élaboration d’une fiche conseil. Ce travail est original car il permet de guider les équipes pharmaceutiques officinales dans le conseil au patient. Une étude de mise en place de ces conseils permettra de confirmer l’utilité de ce travail
MAIT Cells Promote Cholesterol Excretion Pathways Mitigating Atherosclerosis
No full textInternational audienceBACKGROUND: Previous clinical studies have indicated reduced circulating mucosal-associated invariant T (MAIT) cells in individuals with coronary artery disease. However, the precise role and underlying mechanisms of MAIT cells in this context remain unclear. Immune homeostasis plays a pivotal role in the development of atherosclerosis. This study explores the impact of MAIT cells on atherosclerosis.METHODS: Vα19 +/-Ldlr -/-mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1 -/-(major histocompatibility complex-related molecule 1) Ldlr -/-mice and their respective controls were used. Starting at 6 weeks of age, mice were subjected to a 1% cholesterol diet for 16 weeks. Additionally, the study analyzed circulating MAIT cell frequency and cholesterol levels in 68 patients with hypercholesterolemia.RESULTS: In Vα19 +/-Ldlr -/-mice, increased MAIT cells demonstrated a protective effect against atherosclerosis by reducing VLDL-C (very-low-density lipoprotein cholesterol) levels through heightened cholesterol excretion. This effect was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented levels of Liver X receptor transcription and activation, likely through intestinal IL-22 (interleukin-22) signaling. Conversely, cholesterol reduction mediated by intestinal cholesterol excretion was blocked by inhibition of MAIT cells. Moreover, MAIT celldeficient MR1 -/-Ldlr -/-mice exhibited elevated total cholesterol levels and increased atherosclerotic lesions. In patients with hypercholesterolemia, circulating MAIT cell frequency displayed negative correlations with VLDL-C levels and positive correlations with HDL-C (high-density lipoprotein cholesterol) levels.CONCLUSIONS: Our findings demonstrate a new mechanism for plasma VLDL-C clearance by MAIT cell-mediated cholesterol excretion. The results provide further evidence that immunity is involved in cholesterol homeostasis. Targeting intestinal immunity to regulate cholesterol homeostasis holds promise as a new cholesterol-lowering modality to prevent atherosclerotic cardiovascular disease
Circulating tumor DNA strongly predicts efficacy of chemotherapy plus immune checkpoint inhibitors in patients with advanced gastro-esophageal adenocarcinoma
No full textInternational audienceBackground Efficacy of 2nd line treatment in advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma remains limited with no identified strong predictor of treatment efficacy. We evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in the randomized PRODIGE 59-FFCD 1707-DURIGAST trial. Methods ctDNA was evaluated before treatment (baseline) and at 4 weeks (before the third cycle of treatment, C3) using droplet-digital PCR assays based on the detection of CpG methylation.Results Progression-free survival (PFS) and overall survival (OS) were shorter in patients with a high (>1.1 ng/mL) versus low (<1.1 ng/mL) ctDNA concentration at baseline (2.3 vs. 5.8 months; HR = 2.19; 95% CI, 1.09-4.41; p = 0.03 and 4.5 vs. 12.9 months; HR = 2.73; 95% CI, 1.29-5.75; p < 0.01), respectively, after adjustment for identified prognostic variables. Patients with a ctDNA decrease ≤75% between baseline and C3 versus a ctDNA decrease >75% had a worse objective response rate (p = 0.007), shorter PFS (2.2 vs. 7.4 months, HR = 1.90; 95% CI, 1.03-3.51; p = 0.04) and OS (6.6 vs 16.0 months; HR = 2.18; 95% CI, 1.09-4.37; p = 0.03). Conclusions An early decrease in ctDNA concentration is a strong predictor of the therapeutic efficacy of ICI plus chemotherapy in advanced gastric/GEJ adenocarcinoma. Clinical Trial Information NCT03959293 (DURIGAST).The prognosis of advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma remains poor, with overall survival (OS) ranging from 10% to 15% at 5 years 1 . In Human Epidermal Growth Factor Receptor-2 (HER2) negative unresectable advanced/metastatic tumors, the most frequently used first-line palliative chemotherapy is a doublet of fluoropyrimidine (5fluorouracil (5FU) or capecitabine) plus a platinum salt (cisplatin or oxaliplatin) 2,3 . Recently, the addition of docetaxel (TFOX regimen), immune checkpoint inhibitors (ICI, in PD-L1 positive tumors) and anti-claudin 18.</div
ADRENALINE, a Learning Game to Improve Prescribing Skills in Undergraduate Medical Students: Descriptive Study.
No full textInternational audienceBackground: Junior doctors often demonstrate insufficient prescribing skills, highlighting the need to enhance undergraduate medical training in this area. Serious games (SGs) have proven effective in teaching knowledge and skills across various medical specialties including surgery and emergency care. To our knowledge, no SG specifically dedicated to prescribing has been developed to date. Our objective was to develop a new educational program, based on a learning game designed to enhance medical students' competencies in safe and effective prescribing.Objective: This study aimed to describe ADRENALINE, a learning game designed to promote safe and effective prescribing, and to report feedback from sixth-year undergraduate medical students at our medical school after the first year of its implementation in the therapeutics curriculum.Methods: This study implemented an interactive educational program based on Kolb experiential learning theory to enhance safe and effective prescribing skills among sixth-year medical students. The program followed 3 phases: a preliminary in-person lecture introducing the SG ADRENALINE, autonomous gameplay, and a final debriefing lecture. ADRENALINE, accessible via university platform Moodle (Andrews Lyons) on multiple devices, was developed using MOSAIC software (Katia Quelennec), a software program created to develop evolutive SG based on real-life professional situations, and includes 20 realistic clinical scenarios of varying difficulty, requiring students to make therapeutic decisions and receive immediate feedback. Players advance through levels based on performance, with ongoing support from professors via feedback and a dedicated forum. The program was integrated into the therapeutic curriculum of Lille University, and participation was voluntary. All 598 sixth-year students were invited to access the game via email and to participate in pre- and postintervention surveys assessing usage patterns, satisfaction, and learning outcomes.Results: Between November 2023 and March 2024, 272 sixth-year students accessed the ADRENALINE program. Of these, 201/272 (73.9%) students completed at least one scenario and obtained scores ranging from 16.5 to 100 out of 100. Pretest survey responses (n=99 answers) indicated that 92/99 (93%) students identified as gamers and believed that SGs could be relevant for their medical education. Posttest survey responses (n=50 answers) reflected a high level of satisfaction among participants. Most students reported that ADRENALINE helps them apply academic knowledge in real-world context, feel more confident with prescribing and managing adverse drug reactions, improve their prescribing skills, and better prepare for the national Objective Structured Clinical Examination.Conclusions: We developed a learning game focused on medical prescribing, designed to be easily shared with other French-speaking medical schools. Although only 201/598 (33.6%) students engaged with this initial version, 85% (42/50) of the feedback received was positive, indicating strong student interest and supporting the educational value of a game-based approach to enhance prescribing skills among undergraduate medical students
MED13L pathogenic missense variants impair protein stability and interaction, underlying diverse clinical outcomes
No full textInternational audienceHeterozygous pathogenic variants in the Mediator complex subunit 13-like gene located in the locus 12q21.21 (MED13L) are associated with intellectual disability, developmental delay, and distinctive facial features. While nonsense and frameshift variants typically cause haploinsufficiency, resulting in a well-characterized clinical presentation, missense variants have been associated with a broader range of phenotypes, including epilepsy and severe motor delay. In this study, we investigated five pathogenic missense variants in MED13L-c.2597C>T p.Pro866Leu, c.2605C>T p.Pro869Ser, c.3392G>A p.Cys1131Tyr, c.5695G>A p.Gly1899Arg, and c.6485C>T p.Thr2162Met-associated with different clinical severities. We identified significant reductions in protein stability across these variants, with some exhibiting aberrant cytoplasmic localization, suggesting disruptions in structural integrity and function. In particular, exon 15 variants (p.Pro866Leu and p.Pro869Ser) correlated with severe phenotypes, including epilepsy and severe motor impairment, whereas p.Gly1899Arg and p.Thr2162Met were associated with milder manifestations. 3D protein modeling suggested that these missense variants may disrupt MED13L's interaction with the CDK8 kinase module, leading to functional deficits. Our findings highlight different pathogenic mechanisms, ranging from protein instability to altered molecular interactions, that contribute to the clinical variability observed in MED13L-related disorders
Backbone and Methyl resonance assignment of an active PETase
No full textInternational audienceLCCICCG, a bioengineered variant of a cutinase called LCC (Leaf-branch Compost Cutinase), is a high-performance, industrial-grade enzyme capable of efficiently degrading polyethylene terephthalate (PET). This engineered enzyme exhibits significantly enhanced thermal stability and PET hydrolysis activity compared to its predecessor and competing PETases. Here, we report the comprehensive resonance assignment of the polypeptide backbone and the side chain methyl groups of the active LCCICCG. Taking advantage of its exceptional thermostability all the experiments were conducted at 60 °C on a single, uniformly 15N-13C-labeled sample of this 27 kDa serine-hydrolase enzyme. LCCICCG represents a leap forward in enzymatic PET recycling, combining speed, efficiency, and scalability. The residue-specific information through both backbone and methyl side chain assignment represents a critical step toward detailed structural and dynamic NMR analyses
Prevalence and clinical implications of major and minor ANCAs in Tunisian (North African) patients with systemic lupus erythematosus
No full textInternational audienceIntroduction: Anti-neutrophil cytoplasmic antibodies (ANCAs) have been reported in systemic lupus erythematosus (SLE). Their clinical significance remains unclear especially in the African populations. This study aimed to assess the prevalence, antigenic targets, and clinical correlations of ANCAs in SLE patients in a Tunisian (North African) cohort.Methods: We conducted a cross-sectional case-control study involving 30 patients with systemic lupus erythematosus (SLE) and 30 healthy controls. Blood samples were screened for antineutrophil cytoplasmic antibodies (ANCAs) using indirect immunofluorescence (IIF) (FA 1201-1005-13, Euroimmun®). Enzyme-linked immunosorbent assay (ELISA) (Euroimmun®) was performed on IIF-positive samples to assess six ANCA antigenic targets: proteinase 3, lactoferrin, myeloperoxidase, elastase, cathepsin G, and bactericidal/permeability-increasing protein (BPI). Clinical and immunological evaluations were conducted for all SLE patients at the time of the study. No ANCA- associated vasculitis-SLE overlap cases were identified.Results and discussion: ANCAs were detected in 16 of 30 SLE patients (53%) and in 1 of 30 healthy controls (3%). Among the ANCA-positive patients, nine showed reactivity to lactoferrin, while the antigenic target remained undetermined in 7 cases. The median SLEDAI-2K score at inclusion was 8 [1.75–12]. In univariate study, ANCA positivity was significantly associated with acute cutaneous manifestations (p=0.021), lupus nephritis (p=0.001), as well as use of glucocorticoids (p=0.014) and mycophenolate mofetil (p=0.009). Besides, it was associated with lower C3 (p=0.0036) and C4 (p=0.0032) titers and higher anti-dsDNA titers (p<0.0001). In multivariate analysis, ANCA positivity was correlated to anti-ds DNA (p=0.008). When comparing anti-LF positive and anti-LF negative patients, univariate analysis found an association with articular involvement (p=0.011), renal activity index (p=0.036) and ELISA titers (p=0.0004). ANCAs were frequent in our SLE cohort, with lactoferrin as the only identifiable antigenic target, unlike previous reports, which suggests a role to ethnicity and environment components. Their presence was associated with higher disease activity and more severe renal involvement
Early Aortic Valve Intervention in Asymptomatic Severe Aortic Stenosis: A Clinical Dilemma in Evolution
No full textInternational audienceThe management of asymptomatic severe aortic stenosis (AS) has traditionally relied on watchful waiting until the onset of symptoms or left ventricular dysfunction. However, the FDA's approval of transcatheter aortic valve replacement (TAVR) with the Sapien 3 platform in May 2025, based on the EARLY TAVR trial, has intensified the debate over early intervention. This Viewpoint synthesizes evidence from randomized trials (RECOVERY, AVATAR, EVOLVED, EARLY TAVR) and registries (HAVEC, VALVENOR) to evaluate the role of early aortic valve replacement (AVR). Early intervention is associated with reductions in combined endpoints of cardiovascular hospitalizations, stroke, and mortality in selected patients, with the EARLY TAVR demonstrating a 50% reduction in major cardiovascular events. Nonetheless, evidence remains inconsistent, particularly in low-risk populations, as the EVOLVED trial showed no mortality benefit in patients with myocardial fibrosis, warranting cautious interpretation. A conservative surveillance strategy remains appropriate in some cases, supported by the low annual risk of sudden death (i.e., 0.65% per year) and ongoing concerns over valve durability and procedural risks. Given the heterogeneity of patient and valve phenotypes, a personalized risk assessment, combining clinical evaluation, biomarkers (troponin, BNP), and imaging (echocardiography, CMR), is proposed to identify high-risk patients and optimize the timing of early intervention. Expert heart team guidance is essential, and routine early intervention cannot yet be recommended. Further research is needed to refine strategies and improve outcomes in this evolving clinical landscape
Maternal obesity increases breast milk bile acid levels.
No full textInternational audienceContextBreast milk (BM) provides the optimal combination of essential nutrients and bioactive molecules for infant growth and development. However, accumulating evidence from our group and others indicates that maternal factors, such as obesity, can alter BM composition, potentially affecting offspring health outcomes. Bile acids (BA), both primary and secondary, have been identified in human BM but the precise composition and their role in BM remain largely underexplored.ObjectiveIn this study, we analyzed BA profiles in BM and plasma in lactating mothers with obesity or not, across 2 independent clinical cohorts.MethodsBM and plasma samples were collected from breastfeeding women classified as normal weight (N) or with obesity (O). BA concentrations were quantified by reverse phase liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).ResultsBAs were present in BM, primarily as glyco- and tauro-conjugated of the primary BAs cholic (CA) and chenodeoxycholic acid (CDCA), although at lower levels than in plasma under normal-weight conditions. Maternal obesity led to a marked increase in total BM BA levels while plasma BA concentrations and composition remained unchanged. Additionally, BM BA levels were positively correlated with maternal pre-pregnancy body mass index, circulating leptin (a marker of adiposity), and insulin levels.ConclusionOur findings identify maternal obesity as a significant modifier of BM BA composition, with potential implications for neonatal digestion, maturation, and health. Further research is warranted to elucidate the impact of these alterations on infant health and development