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Le mécanisme de surveillance unique (MSU) comme modèle, élément d’une dynamique de l’intégration ?
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Modeling Whole-Body Dynamic PET Microdosing Data to Predict the Whole-Body Pharmacokinetics of Glyburide in Humans
No full textInternational audienceIntroduction Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacokinetic studies based on blood sampling. Here, we build a pharmacokinetic (PK) model from WB4D PET data obtained using a microdose of radiolabeled glyburide ([ 11 C]glyburide) in humans, aiming to describe the biodistribution of this drug and compare estimated pharmacokinetic parameters with the parameters obtained in standard PK studies. Methods The present work analyzes data acquired over 40 min after injection of [ 11 C]glyburide in 16 healthy subjects using non-linear mixed-effect models (NLMEM). In 10 subjects, a second PET acquisition was performed after rifampicin administration, which may cause a drug-drug interaction and inhibit the liver uptake transport of glyburide. Arterial blood, liver, kidneys, pancreas, and spleen kinetics were modeled using NLMEM. The model-building strategy involved selecting the structural model using baseline [ 11 C]glyburide PET data and then selecting the covariate model (rifampicin, age, and gender) and refining the structure of the interindividual variability model using both administration periods. Model selection was based on the corrected Bayesian information criterion and implemented in Monolix software. ResultsThe final model included seven compartments, with two compartments each for the Liver and kidneys to account for within-tissue exchanges. Rifampicin decreased the Liver distribution by 261%. Discussion The estimated central volume of distribution (V = 3.6 L) and elimination rate (k = 0.8 h -1 ) were consistent with the known pharmacokinetics of glyburide, which is a promising first step in leveraging microdose data to study the WB4D biodistribution. Registration EudraCT identifier no. 2017-001703-69 Key PointsMicrodosing PET studies represent an opportunity to safely and dynamically follow the kinetics of radiolabeled drugs in the entire human body. Clinical pharmacokinetic parameters can therefore be obtained at an earlier stage, during phase 0 rather than phase I in the traditional process.We used glyburide as a model drug to build a PK model from dynamic PET imaging using compartmental approaches and relate it to the results of standard pharmacological approaches.Our model describes the biodistribution of this drug in five major organs and the influence of an inhibition of a key liver transporter
Algorithmes métaheuristiques pour quelques problèmes de routage
No full textThis thesis focuses on four routing problems: the traveling salesman problem with job times (TSPJ), the cumulative capacitated vehicle routing problem with single (CCVRP) and multiple depots (MDCCVRP), the latency location routing problem (LLRP), and the capacitated team orienteering problem (CTOP). These problems fre quently arise in real-world applications and are known to be NP-hard, making them computationally challenging to solve. To address this complexity, metaheuristic approaches are naturally con sidered for handling large-scale instances. This thesis is dedicated to developing advanced meta heuristic algorithms to push the state-of-the-art in solving these problems. Specifically, we design a breakout local search algorithm for the TSPJ, a two-individual evolutionary algorithm for the CCVRP and MDCCVRP, a reinforcement learning guided hybrid evolutionary algorithm for the LLRP, and a learning-driven memetic algorithm for the CTOP. Comprehensive experimental re sults demonstrate that the proposed algorithms perform competitively with state-of-the-art meth ods within reasonable computational time. Furthermore, we conduct an in-depth analysis of the key algorithmic components to provide insights into their impact on performance.Cette thèse porte sur quatre problèmes d’optimisation de tournées : le problème du voyageur de commerce avec des temps de tâches (TSPJ), le problème de routage de véhicules capacitaires cumulatifs avec un dépôt unique (CCVRP) et plusieurs dépôts (MDCC-VRP), le problème de localisation et routage avec latence (LLRP) et le problème d’orienteering d’équipe capacitaire (CTOP). Ces problèmes apparaissent fréquemment dans des applications réelles et sont connus pour être NP-difficiles, rendant leur résolution particulièrement complexe. Pour faire face à cette complexité, des approches métaheuristiques sont naturellement envisagées pour traiter des instances de grande taille. Cette thèse vise à développer des algorithmes métaheuristiques avancés afin de faire progresser l’état de l’art dans la résolution de ces problèmes. Plus précisément, nous proposons une recherche locale avec évasion (breakout local search) pour le TSPJ, un algorithme évolutionnaire à deux individus pour le CCVRP et le MDCCVRP, un algorithme évolutionnaire hybride guidé par l’apprentissage par renforcement pour le LLRP, et un algorithme mémétique guidé par l’apprentissage pour le CTOP. Les résultats expérimentaux montrent que les algorithmes proposés obtiennent des performances compétitives par rapport aux méthodes de référence, dans des temps de calcul raisonnables. De plus, une analyse approfondie des principaux composants algorithmiques est réalisée afin de mieux comprendre leur influence sur les performances des algorithmes proposés
Ageing of organic materials at the surface of Mars: A Raman study aboard Perseverance
No full textInternational audienceThe Perseverance rover is exploring Jezero crater on Mars, one of its goals being to collect samples to be returned to Earth to search for organic remains of ancient Martian life. However, the organic content of these rocks has likely suffered from the radiation environment on the surface of Mars to an extent yet to be quantified. For the first time, a 1000 sols long ageing experiment was conducted at the surface of Mars, i.e. under actual Martian conditions, relying on the 100 % organic Ertalyte target carried by Perseverance. White at landing, the Ertalyte target has turned brown with time, while its Raman signal changed, with a modification of the background (its maximum has shifted from 1500 to 2000 cm -1 ) and a reduction of the contribution of the Raman signal of Ertalyte (by a factor of 5 over the first 500 sols). Given the intrinsic resistance of the Ertalyte to UV exposure, which is not anticipated for most Martian organic materials, these results suggest that exposure at the surface of Mars will make the detection of Martian organic molecules challenging
Knowledge of Immunosuppressants and Transplant Patient Management in Community Pharmacy
No full textInternational audienceBackground: Immunosuppressive therapies are essential for transplant recipients and are increasingly prescribed in autoimmune and oncologic conditions. In France, community pharmacists are legally involved in Therapeutic Patient Education (TPE) and medication counseling. However, their level of knowledge regarding immunosuppressive therapies remains poorly documented.Objectives: This study aimed to assess the knowledge of French pharmacy professionals-pharmacists, pharmacy technicians, and pharmacy students-regarding Immunosuppressive therapies, particularly in the context of transplant patient management. It also sought to identify gaps in counseling practices and educational needs.Methods: A cross-sectional survey was conducted from April 2022 to March 2023 using a 20-item online questionnaire. The survey was distributed nationally to community pharmacy professionals. Questions covered immunosuppressive therapy, patient education, lifestyle risks, and infectious precautions. Responses were weighted based on clinical importance, and group comparisons were performed using non-parametric statistical tests.Results: A total of 265 participants completed the survey (177 pharmacists, 50 students, 38 technicians). Pharmacists scored significantly higher than technicians (11.76 ± 6.2 vs. 8.00 ± 6.5; p = 0.004). Students showed intermediate scores with greater variability. Major knowledge gaps were observed regarding missed doses, food interactions, rejection signs, and self-medication risks. Only 22.6% identified self-medication as unsafe for transplant patients. Lifestyle and travel counseling practices were inconsistent across groups. TPE training was reported by 51.4% of pharmacists, 28% of students, and 5.3% of technicians.Conclusion: The study revealed heterogeneous knowledge and counseling practices among pharmacy professionals regarding immunosuppressive therapies. These findings highlight the need for targeted education, integration of immunosuppressive topics into pharmacy curricula, and enhanced collaboration between hospital and community pharmacists to support safe and effective long-term care for immunosuppressed patients
Who are the healthcare professionals involved in interprofessional team meetings in French multidisciplinary primary care centres? A quantitative analysis of eight centres
No full textEn ligne sur ResearchSquare : https://www.researchsquare.com/article/rs-7086890/v1International audienceAbstract Background: Interprofessional collaboration is crucial for providing high-quality care to patients with complex conditions in primary care. In France, multidisciplinary primary care centres (MPCC) receive funding if they organise at least 6 interprofessional team meetings (ITM) per year to discuss complex patient situations and collectively define care strategies. It remains unclear how ITM have been implemented in France. This study analyses healthcare professionals’ involvement in ITMs within MPCCs. Method: A multicenter retrospective quantitative study in 8 French MPCCs based on the analysis of ITM reports for the period from 2018 to 2019 was conducted. Results: 1733 patients’situations (n=1733 cases) discussed during ITMs were analysed. The 8 MPCCs were heterogeneous in terms of geographical location, creation date, and size (3 MPCCs with >20,000 patients followed by more than 60 professionals and 3 MPCCs with <20 professionals). On average, five healthcare professionals attended each ITM, with huge variations among MPCCs. The nurse-general practitioner (GP) pair was central. At least one GP was present at 89% (n=1469) and nurses at 38.15% (n=630) of ITMs. Participation of other professionals was less frequent and varied according to the MPCC. Physiotherapists were present at 7.8% of ITMs, and other healthcare professionals were present at <6% of ITMs, including pharmacists (3% of ITMs). In some cases, external healthcare professionals, particularly those related to mental health, were also involved in ITMs. Conclusions: Depending on the MPCC, the professionals involved in ITM vary widely, with the nurse-GP pair at the centre. The relative absence of certain professionals needs to be analysed in order to encourage interprofessional working. Trial registration: not applicable
Excitation‐Wavelength‐Dependent Emission of Congruently Melting Iodocuprate Hybrid Materials
No full textInternational audienceIn the context of the emergence of metal halide perovskites for optoelectronic materials, the lead‐free and earth‐abundant copper(I)‐based halide hybrids are of high interest. Here, we report on two iodocuprate hybrids (HO2C(CH2)n‐1NH3)CuI2 (n = 3, 4) exhibiting excitation‐wavelength‐dependent emission. The thermodynamically stable n = 4 compound (2D‐C4) is based on a rare 2D iodocuprate network, while a more common 1D network of edge‐sharing tetrahedra is found both in the n = 3 compound (1D‐C3) and in the metastable n = 4 (1D‐C4) hybrid. Depending on the excitation wavelength, 2D‐C4 and 1D‐C3 hybrids exhibit yellow emission, red emission, or white light emission—resulting from the emission of both components,—while 1D‐C4 does not emit in the red region. The description of the electronic structure based on density functional theory (DFT) indicates two different origins for the emissions of 2D‐C4 and 1D‐C3, in particular from iodide vacancies (red emission), which involve mid‐gap states. The emission of 2D‐C4 can also be modulated from red to yellow depending on applied pressure. 2D‐C4 also has an exceptionally low congruent melting temperature of 110 °C, allowing the solvent‐free preparation of thin films. Finally, phosphor‐converted‐LED based on 2D‐C4 have been prepared, showing that either pink or nearly white emission is produced
Obesity: A Modulator in Acne Management
No full textInternational audienceAcne vulgaris is an inflammatory and multifactorial skin disease involving the sebaceous gland and the skin microbiome. Different exposome factors, including hormonal and family factors, have been suggested to influence acne. Obesity is an increasingly observed condition worldwide, and is considered as a public health problem by the World Health Organization. Recently, a high body mass index has been identified as an acne severity risk factor in adolescents. A group of 5 dermatologists from different institutions and private practices from France involved in the research and clinical fields of acne -analysed recent literature on “obesity and acne” focusing on epidemiology, the pathogenesis of acne and obesity, as well as the management of acne in obese patients. The authors selected, prior to their discussion in November and December 2024 and again in March 2025, and discussed 52 articles concerning acne and obesity published since 2000 and available from the PubMed database. The authors agreed that, considering these common metabolic features, managing both acne and obesity in parallel and helping patients through a global approach including dermatological, endocrinal, psychological and nutrition, as well as lifestyle support is mandatory, and may allow for the improvement of both acne and obesity. Moreover, in order to allow dermatologists to manage acne in obese patients in the most efficient way, the authors developed and propose a decision tree. The authors consider that acne in obese patients is not a fatality, and taking care of acne should not be considered an isolated task in this specific patient population
Divergent Mechanisms of Internode Elongation in Response to Far-Red in Two Rose Genotypes
No full textInternational audienceThe quality of potted ornamental plants depends on their architecture, which should be compact and branched. Among the techniques for controlling this architecture, LED lighting, by manipulating light quality, offers an effective means of regulating elongation and branching. In rose, the addition of far-red (FR) light stimulated branching but induced excessive stem elongation, i.e., internode elongation. However, some varieties remained insensitive to this effect, demonstrating phenotypic stability. This study investigated the underlying mechanisms of internode elongation in response to FR in two rose cultivars, ‘The Fairy’ (TF) and Knock Out® Radrazz (KO), selected for their respective architectural plasticity and stability to FR. In TF, exposure to FR induced elongation of internodes, driven by cell division, with an increase in gibberellin A4 (GA4) level and a reduction in defense hormones (salicylic acid and jasmonic acid; JA). In contrast, in KO, exposure to FR did not induce internode elongation but caused cell elongation. This effect was accompanied by a reduction in cell number, modulated by hormonal changes (particularly GA4 and JA) and the inhibition of Block of cell proliferation 1, thereby limiting cell division. A deeper understanding of the mechanisms underlying architectural stability might lead to developing strategies to produce compact, branched plants, regardless of environmental conditions
Systematic identification of lincRNA-derived immunogenic peptides in melanoma
No full textInternational audienceThe search for reliable shared tumor-specific antigens (TSAs) to improve cancer immunotherapy is on-going. The so-called non-coding regions of the genome have recently been shown to give rise to immunogenic peptides, including the melanoma-specific antigen MELOE-1 which is translated from the long intergenic non-coding RNA (lincRNA) meloe in an IRES-dependent manner. Here, we present a strategy to systematically identify tumor-specific antigens produced by ORFs within lincRNAs with IRES-like upstream structures. We provide evidence suggesting that in the melanocytic lineage a significant proportion of the selected lincRNAs can produce immunogenic peptides. T cell repertoires against some of these peptides were found in peripheral blood mononuclear cells (PBMCs) from healthy donors and melanoma patients, and in tumor-infiltrating lymphocytes (TILs) from metastatic melanoma patients. Finally, CD8+ T cell lines from melanoma patients specific for three of the characterized HLA-A *0201 epitopes could recognize melanoma cell lines, which were enhanced by reticular stress. Thus, these peptides may represent a new class of shared TSAs in melanoma and are attractive candidates for evaluation as targets for immunotherapy in preclinical studies. In addition, our selection strategy has the potential to identify new lincRNA-derived antigens in other cancers