Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

Les traitements antirétroviraux de l’infection par le VIH sont responsables d’effets secondaires parfois sévères qui touchent en priorité le tissu adipeux, modifiant sa localisation (lipodystrophie avec lipoatrophie périphérique et hypertrophie centrale) et les paramètres du métabolisme glucido-lipidique (dyslipidémie, diabète). Les deux principales classes thérapeutiques, inhibiteurs de protéase et analogues nucléosidiques, sont délétères sur ces paramètres par des mécanismes différents mais qui convergent sur le tissu adipeux. Certaines des molécules de ces deux classes modifient profondément sa différenciation, son métabolisme, sa fonction mitochondriale et l’équilibre des hormones (leptine, adiponectine) et cytokines (TNFα, IL-6) qu’il sécrète. Ce syndrome de lipodystrophie induit un risque cardiovasculaire et de stéatohépatite grevant le pronostic vital. Le traitement reste difficile chez les patients atteints et privilégie le remplacement des molécules les plus délétères par des molécules antirétrovirales plus récentes et moins agressives sur le tissu adipeux.HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFα, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue

Adherence to self-administered tuberculosis treatment in a high HIV-prevalence setting: a cross-sectional survey in Homa Bay, Kenya.

Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Médecins sans Frontières introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Assessment of perception and adaptation to hearing or visual handicap in adults : validation of specific questionnaires and clinical studies

L’évaluation du handicap permet d’identifier les besoins spécifiques puis de cibler des préconisations thérapeutiques adaptées (médicales, techniques, rééducatives et psycho sociales). Le travail spécifique de cette thèse visait le développement de questionnaires d’évaluation de la perception et de l’adaptation au handicap auditif et visuel chez l’adulte, la validation de ces questionnaires et leur application clinique : le QUEPAHAA (Questionnaire d’Evaluation de la Perception et de l’Adaptation du Handicap Auditif chez l’Adulte) et le QUEPAHVA (Questionnaire d’Evaluation de la Perception et de l’Adaptation du Handicap Visuel chez l’Adulte). Les résultats statistiques ont attesté de leurs bonnes qualités psychométriques. Notre étude s’est prolongée par leur mise en application clinique. Les résultats ont montré les effets significatifs d’un parcours de soins pluridisciplinaire sur la perception et l’adaptation au handicap sensoriel. Puis, nous avons réalisé l’étude de deux cas individuels. Les entretiens cliniques et les questionnaires ont montré une amélioration de l’adaptation au handicap et de l’humeur à la suite de l’accompagnement pluridisciplinaire. Nouveaux outils interdisciplinaires, le QUEPAHAA et le QUEPAHVA recouvrent un intérêt diagnostic, thérapeutique et institutionnel. Outre qu’ils permettent une meilleure compréhension des personnes, ces questionnaires peuvent être intégrés dans des pratiques professionnelles, des protocoles de soins ou de recherche clinique.Handicap assessment makes it possible to identify specific needs and then to target adapted therapeutic recommendations (medical, technical, rehabilitation and psycho social). The specific work of this thesis aimed at the development of questionnaires to assess perception and adaptation to hearing and visual handicap in adults, the validation of these questionnaires and their clinical application: the QUEPAHAA (Questionnaire for the Assessment of Perception and Adaptation of Hearing Handicap in Adults) and the QUEPAHVA (Questionnaire for the Assessment of Perception and Adaptation of Visual Handicap in Adults). The statistical results have attested to their good psychometric qualities. Our study continued with their clinical application. The results showed the significant effects of a multidisciplinary care program on the perception and adaptation to sensory handicap.Then, we carried out the study of two individual cases. Clinical interviews and questionnaires showed improvement in handicap adaptation and mood following multidisciplinary care program. New interdisciplinary questionnaires, QUEPAHAA and QUEPAHVA cover a diagnostic, therapeutic and institutional interest. In addition to allowing a better understanding of people, these questionnaires can be integrated into professional practices, care protocols or clinical research

Evaluation de la perception et de l’adaptation au handicap auditif ou visuel chez l’adulte : validation de questionnaires spécifiques et études cliniques

Handicap assessment makes it possible to identify specific needs and then to target adapted therapeutic recommendations (medical, technical, rehabilitation and psycho social). The specific work of this thesis aimed at the development of questionnaires to assess perception and adaptation to hearing and visual handicap in adults, the validation of these questionnaires and their clinical application: the QUEPAHAA (Questionnaire for the Assessment of Perception and Adaptation of Hearing Handicap in Adults) and the QUEPAHVA (Questionnaire for the Assessment of Perception and Adaptation of Visual Handicap in Adults). The statistical results have attested to their good psychometric qualities. Our study continued with their clinical application. The results showed the significant effects of a multidisciplinary care program on the perception and adaptation to sensory handicap.Then, we carried out the study of two individual cases. Clinical interviews and questionnaires showed improvement in handicap adaptation and mood following multidisciplinary care program. New interdisciplinary questionnaires, QUEPAHAA and QUEPAHVA cover a diagnostic, therapeutic and institutional interest. In addition to allowing a better understanding of people, these questionnaires can be integrated into professional practices, care protocols or clinical research.L’évaluation du handicap permet d’identifier les besoins spécifiques puis de cibler des préconisations thérapeutiques adaptées (médicales, techniques, rééducatives et psycho sociales). Le travail spécifique de cette thèse visait le développement de questionnaires d’évaluation de la perception et de l’adaptation au handicap auditif et visuel chez l’adulte, la validation de ces questionnaires et leur application clinique : le QUEPAHAA (Questionnaire d’Evaluation de la Perception et de l’Adaptation du Handicap Auditif chez l’Adulte) et le QUEPAHVA (Questionnaire d’Evaluation de la Perception et de l’Adaptation du Handicap Visuel chez l’Adulte). Les résultats statistiques ont attesté de leurs bonnes qualités psychométriques. Notre étude s’est prolongée par leur mise en application clinique. Les résultats ont montré les effets significatifs d’un parcours de soins pluridisciplinaire sur la perception et l’adaptation au handicap sensoriel. Puis, nous avons réalisé l’étude de deux cas individuels. Les entretiens cliniques et les questionnaires ont montré une amélioration de l’adaptation au handicap et de l’humeur à la suite de l’accompagnement pluridisciplinaire. Nouveaux outils interdisciplinaires, le QUEPAHAA et le QUEPAHVA recouvrent un intérêt diagnostic, thérapeutique et institutionnel. Outre qu’ils permettent une meilleure compréhension des personnes, ces questionnaires peuvent être intégrés dans des pratiques professionnelles, des protocoles de soins ou de recherche clinique

Nouvelles adipokines

International audienceAdipose tissue is now widely recognized as “an organ” able to synthesize and secrete hundred factors collectively called adipokines. These secreted molecules exert pleiotropic actions, notably on the regulation of glucose and lipid metabolism, inflammation, reproduction, or angiogenesis. Over the past two decades, a considerable amount of work was performed on the two “star” adipokines, leptin and adiponectin, particularly because of their involvement in energy metabolism. The present review is focused on the three most recently discovered adipokines that are clearly emerging as important actors in metabolism: apelin, fibroblast growth factor-21, and neuroregulin-4. Moreover, given a number of clinical and experimental data, these three adipokines represent promising targets in the context of metabolic disorders associated with obesity.Le tissu adipeux est désormais largement reconnu en tant qu’« organe » capable de synthétiser et de sécréter de nombreux facteurs rassemblés sous le terme d’adipokines. Ce tissu sécrète vraisemblablement plusieurs centaines de molécules, qui exercent des actions pléiotropes, notamment sur la régulation du métabolisme glucido-lipidique, l’inflammation, la reproduction, ou l’angiogenèse. Au cours des deux dernières décennies, une somme considérable de travaux a été réalisée sur les adipokines « vedettes », la leptine et l’adiponectine, notamment en raison de leur implication dans le métabolisme énergétique. De parti pris, cette revue est focalisée sur trois adipokines de découverte plus récente, mais dont l’intérêt émerge clairement : l’apéline, le FGF21, et la neuroréguline-4. Au vu de plusieurs données cliniques et expérimentales, ces trois adipokines représentent des cibles prometteuses dans le contexte des désordres métaboliques associés à l’obésité

Dynamics of livestock-associated methicillin resistant Staphylococcus aureus in pig movement networks: Insight from mathematical modeling and French data

International audienceLivestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) colonizes livestock animals worldwide, especially pigs and calves. Although frequently carried asymptomatically, LA-MRSA can cause severe infections in humans. It is therefore important to better understand LA-MRSA spreading dynamics within pig farms and over pig movement networks, and to compare different strategies of control and surveillance. For this purpose, we propose a stochastic meta-population model of LA-MRSA spread along the French pig movement network (n = 10,542 farms), combining within- and between-farm dynamics, based on detailed data on breeding practices and pig movements between holdings. We calibrate the model using French epidemiological data. We then identify farm-level factors associated with the spreading potential of LA-MRSA in the network. We also show that, assuming control measures applied in a limited (n = 100) number of farms, targeting farms depending on their centrality in the network is the only way to significantly reduce LA-MRSA global prevalence. Finally, we investigate the scenario of emergence of a new LA-MRSA strain, and find that the farms with the highest indegree would be the best sentinels for a targeted surveillance of such a strain’s introduction

Chirurgie de l’arthrose des membres inférieurs chez le sujet âgé

International audienc