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Steric blocking of sulfur: a key to the reversible second oxidation of phenothiazine in neutral aqueous medium?
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Ivosidenib in refractory or relapsed IDH1-mutated Acute Myeloid Leukemia patients in real life settings: The ivoobs observational study from the french AML intergroup ALFA/filo
No full textInternational audienceBackground IDH1 R132 mutations are found in about 5-10% of AML at diagnosis. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of the mIDH1 enzyme, approved for IDH1mut newly diagnosed AML aged ≥75 years or who are ineligible for intensive induction chemotherapy. In relapse/refractory settings (R/R), IVO monotherapy yielded promising complete remission or complete remission with partial hematologic recovery (CR/CRi) rate of 30.4% associated with a median overall survival (OS) of 8.8 months (Di Nardo, NEJM, 2018). However, there are very few data regarding IVO use outside clinical trials. In this study, we aimed to evaluate the efficacy and safety of IVO in R/R AML patients in real life settings. Method IVOOBS (NCT06377579) is a retrospective, non-interventional, multicentric study including patients from 32 French centers with newly diagnosed or R/R IDH1mut AML treated with IVO through a compassionate use program. Here, we focused on R/R patients treated with IVO, either as monotherapy or in combination with other therapies between January 2017 and February 2024. The primary objective was OS. Secondary objectives were response rate (ELN2022 criteria), and toxicity. Overall response (ORR) was defined as patients reaching CR, CRi, or CRh at any time. Results Overall, 127 patients were included. Secondary AML were observed in 15.8% (post-MDS/MPN=16, t-AML=4). Median number of previous lines prior IVO onset were 1 [IQR:1-3]; 82 patients (67%) received intensive chemotherapy as first line,36 (29% ) were pre-exposed to VEN prior IVO initiation, while 20 (15.8%) patients received IVO as post hematopoietic stem cell transplantation (HSCT) salvage treatment. 93 patients received IVO monotherapy, 26 in combination with azacitidine (AZA) and 8 with venetoclax (VEN) +/- AZA (defined as AZA/IVO (+/-VEN) group) Most frequent co-mutations were NPM1 (32%), RUNX1 (23%), ASXL1 (21%) and BCOR (18%). Clinicians reported differentiation syndrome (DS) of any grade in of 12 patients (9.5%) (8 with IVO and 4 with IVO+AZA (+/-VEN)). QTc prolongation and febrile neutropenia was observed in 8 (7%) and 15 (12%) patients respectively. Regarding grade 3-4 hematological adverse events (AE), neutropenia, thrombocytopenia and anemia occurred in 4%, 14% and 18% respectively. There were 2 grade 5 AE related to IVO (1 pneumocystis carinii pneumonia and 1 DS) both in IVO monotherapy treated patients. ORR (CR/CRi/CRh) rates was 45.9% (35.8%/9.2%/0.9%), with 46.6% showing no response and 4.6% MLFS (6 patients died prior evaluation). Median time to best response was 2.8 months. Median time on IVO treatment was 6.2 months. ORRs were 39%, 48.6% (p=0.55) with a median time to achieve ORR of 3 months, and 2.8 months in IVO and IVO/AZA (+/-VEN) treated patients, respectively. 65% (68/102) and 75% (55/73) of patients were transfusion independent at 3 and 6 months after IVO initiation, respectively. Prior VEN exposition did not significantly influence ORR probability: (36.1% (13/36) in VEN pre-exposed vs 44.4% (40/90) in VEN naïve (p=0.39). Co-mutations at AML diagnosis did not influence ORR probability including MAPK/RTK mutations. In multivariate analysis for ORR, only higher platelets at IVO onset (HR=1.05, p=0.01) and HU use (HR=0.13, p=.002) were independently associated with ORR. In the 22 patients who received HU to manage initial leukocytosis, ORR rate was 13.6% compared to 53.5% for those without HU requirement (p<0.001). In responding patients, 22.8% (13/57) were bridged to HSCT after a median time of 4.2 months. Only 2 patients relapsed post-transplant. After a median follow-up of 13.9 months, median OS (mOS) of the entire cohort was 14 months. mOS with IVO monotherapy and AZA/IVO (+/-VEN) was 13.2 and 20.2 months, respectively (p=0.16). VEN exposure pre-IVO did not significantly influence OS compared to VEN-naïve patients (HR=0.90, p=0.69). In multivariate analysis, only higher platelets (HR=0.96, p=0.015) and HU use (HR=2.95, p<.001) were independently associated with OS. Conclusion In this real-life study, IVO compares favourably with previously reported prospective studies in R/R settings, with a manageable safety profile. HU use for proliferative disease at IVO onset is associated with a lower response rate and inferior outcome
Blood flow visualization and quantification in the carotid vascular tree by phase contrast MRI
No full textInternational audiencePurpose:The objective is to build a phase-contrast (PC) MRI protocol, consistent with clinical practice, to provide a 3D blood flow visualization and quantification of hemodynamic parameters in the complete carotid vascular tree. Methods:The protocol composed of 2D and 4D PC-MRI sequences was applied on 6 volunteers and then on one patient diagnosed with facial cancer to prove the feasibility of clinical translation. The vessel geometry was reconstructed from the 4D sequences and the hemodynamic parameters quantified in the common, internal and external carotids and in the facial artery. Wall shear stresses (WSS) were quantified from the 2D PC-MRI sequences to benefit from their higher resolution.Results: Time evolution of the three-dimensional blood flow velocity and vorticity fields was successfully obtained in all the branches of the carotid vascular tree despite the large range of sizes.Consistent maps of blood flow distribution were provided by normalizing the local blood flows by that in the common carotid artery. They indicated that 72.4% (± 3.9 %) of blood flows into in the internal carotid. WSS is higher in the internal (0.95 Pa at peak systole) than in the external carotid (0.53 Pa) and facial artery (0.15 Pa). Conclusion:A PC-MRI protocol, applicable on patients, was designed to quantify hemodynamic parameters in vessels ranging from a few millimeters to the centimeter in diameter. It provided a complete characterization of the hemodynamic condition evolution along the carotid vascular tree, and reference values to be compared to in case of pathology.</div
Représentations et pratiques de la prescription d’activité physique chez les médecins ayant suivi une formation organisée par l’URPS des Hauts-de-France, sur la prescription d’activité physique et la lutte contre la sédentarité
No full textLa prescription d’activité physique (AP) constitue une thérapeutique non médicamenteuse efficace dans la prévention et la prise en charge des maladies chroniques. Cependant, son intégration dans la pratique médicale demeure limitée, en raison notamment du manque de formation et de la perception de freins multiples par les médecins. Cette étude qualitative, menée auprès de 9 médecins des Hauts-de-France ayant suivi une formation régionale de l’URPS sur la prescription d’AP, visait à explorer leurs représentations, leurs pratiques et leur ressenti vis-à-vis de cette formation. Les résultats montrent que l’AP est surtout abordée en prévention secondaire ou tertiaire, mais rarement en prévention primaire. La prescription écrite reste peu utilisée, jugée complexe et chronophage, au profit de conseils oraux simples. Les freins identifiés concernent à la fois les patients (manque de motivation, contraintes familiales, douleurs), les médecins (manque de temps, formation insuffisante, sentiment d’illégitimité), les structures (éloignement, délais) et le coût financier. La formation a été perçue comme utile mais trop théorique, avec un besoin exprimé d’outils plus pratiques et d’une meilleure visibilité des réseaux locaux. L’AP personnelle des médecins apparaît comme un levier facilitant son intégration dans les consultations. Cette étude souligne la nécessité de renforcer les formations pratiques, d’améliorer la lisibilité des dispositifs existants et d’accompagner les médecins dans la prescription d’AP afin de favoriser sa diffusion dans le parcours de soins
Impact en vie réelle de la supplémentation martiale intraveineuse sur la fatigue et la qualité de vie chez les patients atteints de MICI avec carence martiale sans anémie : étude prospective FATIFER
No full textIntroduction: While the management of iron deficiency anemia is well established, the treatment of isolated iron deficiency remains debated in patients with inflammatory bowel disease (IBD). However, this condition may affect fatigue and quality of life. The aim of this study was to assess the real-life impact of intravenous iron supplementation on fatigue and quality of life in patients with IBD presenting iron deficiency without anemia. Methods: All consecutive adult patients (>18 years) with IBD and isolated iron deficiency were included in a single-center prospective observational study. Fatigue, quality of life, and disability were assessed using a panel of four questionnaires (FACIT-F, EQ-5D-5L, IBD Disk, and SF-36), completed at baseline, and at 1 and 2 months following intravenous iron supplementation. Results: A total of 90 patients (71 % women, median age 32 years, IQR [23–43]) were included. 66 patients had Crohn’s disease and 23 had ulcerative colitis. 61 % of Crohn’s disease and 39 % of ulcerative colitis patients were in clinical remission (Harvey-Bradshaw Index < 5, partial Mayo score < 1). Fatigue was reported in 72 % of patients. Intravenous iron was well tolerated, with only two episodes of skin rash, none of which were severe. A significant improvement in the FACIT-F fatigue score was observed at one month (+3.9 points; 95% CI: 2.6 to 6.7; p < 0.01) and at two months (+3.7 points; 95% CI: 2.4 to 6.1; p < 0.01) after supplementation.In the subgroup of patients classified as fatigued at baseline, a reduction in fatigue risk of 16.6% at one month (OR = 0.2; 95% CI: 0.1 to 0.6; p < 0.01) and 17.5% at two months (OR = 0.2; 95% CI:0.1 to 0.5; p < 0.01) was observed. Regarding quality of life, a statistically significant improvement in the SF-36 score was noted (+5.1 points; 95% CI: 2.0 to 8.2; p = 0.001) at one month. Improvements were also found in the EQ-5D-5L (parts 1 and 2) at both one and two months. No baseline demographic, clinical, or biological factors were associated with the benefit of iron infusion on fatigue. Conclusion: Intravenous iron supplementation improved fatigue and quality of life in patients with IBD and iron deficiency without anemia. Randomized controlled trials are now required to confirm these findings.Introduction : alors que la prise en charge de l’anémie par carence martiale est consensuelle, celle de la carence martiale isolée fait débat chez les patients atteints de maladies inflammatoire chronique de l’intestin (MICI). Celle-ci peut pourtant influencer la fatigue et la qualité de vie. L’objectif de cette étude était d’évaluer l’impact en vie réelle de la supplémentation martiale intraveineuse sur la fatigue et la qualité de vie chez les patients atteints de MICI présentant une carence martiale sans anémie. Méthodes : tous les patients majeurs (> 18 ans) consécutifs présentant une MICI compliquée d’une carence martiale isolée étaient inclus dans une étude prospective observationnelle monocentrique. La fatigue, la qualité de vie et le handicap étaient évaluées par le biais d’un panel de 4 questionnaires (FACIT-F, EQ-5D-5L, IBD Disk et SF-36) qui ont été remplis le jour de l’inclusion, puis à 1 mois et à 2 mois après une supplémentation martiale intraveineuse. Résultats : au total, 90 patients (71% de femmes, âge médian 32 ans, IQR [23-43]) ont été inclus. 66 patients présentaient une maladie de Crohn et 23 une RCH. 61 % des maladies de Crohn et 39 % des RCH étaient en rémission clinique (Score Harvey-Bradshaw < 5, Score Mayo Clinic partiel < 1). Une fatigue était observée chez 72 % des patients. La tolérance du fer IV était excellente, avec seulement deux épisodes d’éruption cutanée sans critère de gravité. Une amélioration significative du score de fatigue FACIT-F était observé à un mois (+3,9 points ; IC 95 % : 2,6 à 6,7 ; p < 0,01) et à deux mois (+3,7 points ; IC 95 % : 2,4 à 6,1 ; p < 0,01) après la supplémentation. Sur le sous-groupe de patients considérés comme fatigués à l’inclusion, une réduction du risque de fatigue à 1 mois de 16,6 % (OR = 0,2 ; IC 95 % : 0,1 à 0,6 ; p < 0,01) et de 17,5 % à 2 mois (OR = 0,2 ; IC 95 % : 0,1 à 0,5 ; p < 0,01) était observée. Concernant la qualité de vie, on observait une amélioration statistiquement significative du score SF-36 (+5,1 points (IC 95 % : 2,0 à 8,2 ; p = 0,001) à 1 mois. Une amélioration était également retrouvée sur le score EQ-5D-5L (partie 1 et 2) à 1 et 2 mois. Aucun facteur à l’inclusion, qu’il soit démographique, clinique ou biologique n’était associé au bénéfice de la perfusion de fer sur la fatigue. Conclusion : la supplémentation martiale IV améliorait la fatigue et la qualité de vie chez les patients atteints de MICI avec carence martiale sans anémie. Des essais randomisés contrôlés, sont désormais nécessaires pour confirmer ces résultats
Phenothiazine Dimer as Efficient and Recyclable p‐Type Organic Positive Electrode Material for Anion‐Ion and Dual‐Ion Batteries
No full textInternational audienceThis article presents the electrochemical properties of a series of phenothiazine and phenoxazine dimers, by involving an aromatic central core, efficiently synthesized in a single step through a Buckwald–Hartwig coupling reaction. A synergistic approach combining experimental and quantum chemical studies was used in view of providing a thorough characterization of their capabilities as electrodes in the context of electrochemical energy storage applications. A detailed study of the electrochemical activity was then conducted with the aim of optimizing performance, i.e., achieving a specific capacity of around 100 mAh.g −1 , close to the theoretical values at a potential of 3.6 V relative to Li metal. The dimerization strategy also emerged as an interesting methodology, since it gives rise to molecular materials having specific solubility properties. This finding opens up the possibility of recovering the active material from the electrode at the end of its life, thus paving the way for improved organic electrodes and batteries, especially with respect to their recyclable character
Le travail féministe : le militantisme au Planning familial à l’épreuve de sa professionnalisation Rennes, Presses universitaires de Rennes, coll. « Archives du féminisme », 2022, 256 pages
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Prognostic impact of the number and Temporality of heart failure Hospitalisations: Analysis of a National healthcare database
No full textInternational audienceAims: To assess the prognostic impact of both the frequency and timing of prior heart failure (HF) hospitalisations on outcomes in patients with reduced left ventricular ejection fraction (LVEF).Methods and results : This nationwide retrospective cohort study used the French national health insurance database to identify 730,052 adults with HF in 2017. A validated algorithm classified 226,747 as HF with reduced LVEF (<45 %), of whom 54,504 (24 %) had at least one HF-related hospitalisation >24 h within the preceding 24 months (worsening HF group). Patients were stratified by (1) time since the last HF hospitalisation (0–6, 6–24 months) and (2) number of hospitalisations (1, 2, ≥3). Mean age was 76 ± 15 years. Prior HF hospitalisation was the strongest predictor of mortality among all variables. After multivariable adjustment, prior hospitalisation was associated with increased risk of all-cause death (HR 1.61, 95 % CI 1.56–1.65), all-cause hospitalisation (HR 1.34, 95 % CI 1.32–1.37), and recurrent HF hospitalisation (HR 2.51, 95 % CI 2.43–2.59). Risks were greatest when the most recent hospitalisation occurred within 6 months and rose progressively with the number of prior events.Conclusion : In patients with reduced LVEF, both recent and recurrent HF hospitalisations are strong predictors of mortality and rehospitalisation. These two simple markers identify highly vulnerable patients and should trigger intensified follow-up, optimisation of guideline-directed therapies, and implementation of transitional care and remote monitoring programs
La traduction du Commentarium in Platonis Conuiuium de Marsile Ficinpar Simon Sylvius (1546) : la première translatio indirecte du Banquet grec en langue française
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Unlocking TRPM7 Interactions: A Database-Driven Quest
No full textInternational audienceTransient receptor potential cation channel subfamily M member 7 (TRPM7) is a dual function protein comprising a non-selective cation channel and an atypical kinase domain. TRPM7 has been involved in many diseases including malignancies. Indeed, TRPM7 is proposed as a promising target for therapeutical drug design. Numerous studies have shown that TRPM7 interacts with proteins involved in regulating intracellular signaling. Therefore, a better understanding of the TRPM7 interactome would provide insight into pathophysiological mechanisms at the cellular and molecular levels. It could also open up new therapeutic avenues for molecules targeting either the proteins of interest directly or protein-protein interactions.In the first part of this work, we present the interaction partners described in the literature for TRPM7 and their potential impacts on cell biology. In the second part of the manuscript, we use public databases and protein interaction modeling tools to characterize the TRPM7 interactome. In particular, the analysis of the TRPM7 interactome using experimental data (BioGRID) and modeling tools (ProteinPrompt) has allowed us to isolate 19 genes of interest mainly related to small GTPase pathways involved in digestive neoplasia such as colorectal and pancreatic cancers.In summary, we provide an extended overview of potential TRPM7 interactors which need to be validated in cellular models. This will provide crucial insights into the molecular mechanisms at the tumor cell membrane, helping us to propose new therapeutic targets for precision medicine