Les enjeux sociaux du changement climatique

L’IGAS a souhaité dans le cadre de son programme de travail, mener une comparaison internationale de la manière dont les enjeux sociaux, relatifs aux populations vulnérables et aux travailleurs, sont intégrés par les pays dans leurs politiques climatiques, qu’elles soient d’adaptation aux effets du changement climatique ou d’atténuation des émissions de gaz à effet de serre. L’objectif était multiple, visant à regrouper les connaissances éparses sur ce sujet éminemment transversal, à situer la France par rapport aux autres pays comparables, à repérer des bonnes pratiques à introduire dans nos politiques climatiques et nos gouvernances. Sans avoir la prétention d’être exhaustif, ce rapport rassemble suffisamment d’informations pour établir les deux principaux constats suivants : (1) la France progresse comme les autres pays pour ce qui est de l’intégration des enjeux sociaux à ses politiques climatiques, et des marges de manœuvre sont identifiées par le monde de la recherche ; (2) il est urgent de s’organiser face au défi social majeur que représente l’adaptation, pour lequel aucun pays n’apparaît avoir développé un modèle de soutenabilité exemplaire. La mission propose dans ce cadre des orientations de travail et des actions concrètes, qui constituent une feuille de route pour la définition d’une politique social-écologique nationale

Influence of age on retinochoroidal healing processes after argon photocoagulation in C57bl/6j mice

PURPOSE: To analyze the influence of age on retinochoroidal wound healing processes and on glial growth factor and cytokine mRNA expression profiles observed after argon laser photocoagulation. METHODS: A cellular and morphometric study was performed that used 44 C57Bl/6J mice: 4-week-old mice (group I, n=8), 6-week-old mice (group II, n=8), 10-12-week-old mice (group III, n=14), and 1-year-old mice (group IV, n=14). All mice in these groups underwent a standard argon laser photocoagulation (50 microm, 400 mW, 0.05 s). Two separated lesions were created in each retina using a slit lamp delivery system. At 1, 3, 7, 14, 60 days, and 4 months after photocoagulation, mice from each of the four groups were sacrificed by carbon dioxide inhalation. Groups III and IV were also studied at 6, 7, and 8 months after photocoagulation. At each time point the enucleated eyes were either mounted in Tissue Tek (OCT), snap frozen and processed for immunohistochemistry or either flat mounted (left eyes of groups III and IV). To determine, by RT-PCR, the time course of glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and monocyte chemotactic protein-1 (MCP-1) gene expression, we delivered ten laser burns (50 microm, 400 mW, 0.05 s) to each retina in 10-12-week-old mice (group III', n=10) and 1-year-old mice (group IV', n=10). Animals from Groups III' and IV' had the same age than those from Groups III and IV, but they received ten laser impacts in each eye and served for the molecular analysis. Mice from Groups III and IV received only two laser impacts per eye and served for the cellular and morphologic study. Retinal and choroidal tissues from these treated mice were collected at 16 h, and 1, 2, 3, and 7 days after photocoagulation. Two mice of each group did not receive photocoagulation and were used as controls. RESULTS: In the cellular and morphologic study, the resultant retinal pigment epithelium interruption expanse was significantly different between the four groups. It was more concise and smaller in the oldest group IV (112.1 microm+/-11.4 versus 219.1 microm+/-12.2 in group III) p<0.0001 between groups III and IV. By contrast, while choroidal neovascularization (CNV) was mild and not readily identifiable in group I, at all time points studied, CNV was more prominent in the (1-year-old mice) Group IV than in the other groups. For instance, up to 14 days after photocoagulation, CNV reaction was statistically larger in group IV than in group III ((p=0.0049 between groups III and IV on slide sections and p<0.0001 between the same groups on flat mounts). Moreover, four months after photocoagulation, the CNV area (on slide sections) was 1,282 microm(2)+/-90 for group III and 2,999 microm(2)+/-115 for group IV (p<0.0001 between groups III and IV). Accordingly, GFAP, VEGF, and MCP-1 mRNA expression profiles, determined by RT-PCR at 16 h, 1, 2, 3, and 7 days postphotocoagulation, were modified with aging. In 1-year-old mice (group IV), GFAP mRNA expression was already significantly higher than in the younger (10-12 week) group III before photocoagulation. After laser burns, GFAP mRNA expression peaked at 16-24 h and on day 7, decreasing thereafter. VEGF mRNA expression was markedly increased after photocoagulation in old mice eyes, reaching 2.7 times its basal level at day 3, while it was only slightly increased in young mice (1.3 times its level in untreated young mice 3 days postphotocoagulation). At all time points after photocoagulation, MCP-1 mRNA expression was elevated in old mice, reaching high levels of expression at 16 h and day 3 respectively. CONCLUSIONS: Our results were based on the study of four different age groups and included not only data from morphological observations but also from a molecular analysis of the various alterations of cytokine signaling and expression. One-year-old mice demonstrated more extensive CNV formation and a slower pace of regression after laser photocoagulation than younger mice. These were accompanied by differences in growth factors and cytokine expression profiles indicate that aging is a factor that aggravates CNV. The above results may provide some insight into possible therapeutic strategies in the future

Effectiveness and Safety of Tralokinumab in Atopic Dermatitis: 1-year Results From a Real-world Multicentre Study

: Tralokinumab is a monoclonal antibody selectively targeting IL-13, approved for moderate-to-severe atopic dermatitis (AD), for which real-world data are scarce. This prospective, observational, multicentric study aimed to assess the long-term effectiveness and safety of tralokinumab in patients with AD in a real-world setting. Primary outcomes included 50%, 75%, and 90% improvement in Eczema Area and Severity Index score (EASI50, EASI75, EASI90, respectively) and improvements in Dermatology Life Quality Index (DLQI) at 1 year. A total of 136 patients with AD were enrolled in the study; data at 1-year follow-up were available for 111 patients. After 1 year, 68.5% and 33.3% of patients achieved an EASI75 and EASI90, respectively. A significantly higher percentage of patients with than without foot involvement achieved EASI50 (p = 0.009) and EASI75 (p = 0.022). Similarly, hand involvement was significantly associated with higher EASI50 response (p = 0.005). Median DLQI score decreased from 9.00 (interquartile range (IQR): 6.00, 13.75) to 1.00 (IQR: 0.00, 4.00) after 1 year of treatment. Adverse events included blepharitis (n = 10), conjunctivitis (n = 6), and injection-site reactions (n = 2). Tralokinumab can be an effective and safe treatment for patients with moderate-to-severe AD. Involvement of certain body areas, such as hands and feet, might positively predict a clinical response to tralokinumab

Impact of Baricitinib on Patients’ Quality of Life after One Year of Treatment for Atopic Dermatitis in Real-World Practice: Results of the Observatory of Chronic Inflammatory Skin Diseases Registry

The efficacy and safety of baricitinib for treatment of atopic dermatitis have been demonstrated in clinical trials; however, very few real-life studies have been published to date. The Observatory of Chronic Inflammatory Skin Diseases (OMCCI) registry was initiated to prospectively determine the long-term impairment caused by chronic inflammatory dermatoses on patients’ lives. The study included 88 patients starting baricitinib for treatment of atopic dermatitis. Clinical evaluation and patient-reported outcomes were recorded at baseline and after 6 and 12 months. After 6 months and 1 year of follow-up, 65 and 47 patients, respectively, were still being treated with baricitinib. Treatment failure was the main reason for discontinuation. Only 1 patient stopped baricitinib because of a side-effect. After 1 year of follow-up, the mean Eczema Area and Severity Index score decreased significantly from 20.7 to 6.4; the percentage of patients with severe atopic dermatitis decreased from 42.9% to 6.5% and a significant improvement in most patient-reported outcomes was noted. There was no difference in terms of efficacy whether or not patients were previously treated with dupilumab. The results remained stable after 6 and 12 months of treatment, which suggests a sustained efficacy of the treatment in patients who initially responded well

Immune checkpoints are predominantly co-expressed by clonally expanded CD4⁺FoxP3⁺ intratumoral T-cells in primary human cancers

Background In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. Methods We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. Results Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8⁺ T-cells (~ 40%), CD4⁺ FoxP3⁻ T-cells (~ 40%) and CD4⁺FoxP3⁺ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4⁺FoxP3⁺ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3⁺ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8⁺ T-cells and of CD4⁺ FoxP3⁻ T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4⁺ FoxP3⁺ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. Conclusions Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type

Prostatectomie radicale robot-assistée par abord extrapéritonéal (10 ans d expérience)

Objectifs : Décrire les résultats de 1000 prostatectomies radicales robot-assistées (PRRA) par voie extrapéritonéale. Méthodes : De 2001 à 2011,1019 patients ont été opérés par PRRA pour un cancer de la prostate localisé. Le suivi moyen était de 24.6 mois. Les données démographiques, chirurgicales et post-opératoires étaient collectées dans une base de données prospective. Résultats : L âge moyen était de 62.7 ans, le PSA pré-opératoire moyen de 9,27 et le score de Gleason pré-opératoire moyen de 6,4 (Gleason 6 : 59,8% ; Gleason 7 : 33,1%). La durée opératoire et les pertes sanguines moyennes étaient respectivement de 129 minutes et 514 mL. La durée moyenne de séjour et de sondage urinaire était respectivement de 4 et 7,9 jours. Le taux de complication était de 15,6%. Le taux de préservation nerveuse unilatérale et bilatérale était respectivement de 9,2% et 70,3%. Il y avait 31,7% pT3a et 10,4% pT3b-pT4 (25,2% de bas risques et 59,4% de risques intermédiaires selon D Amico). Le taux de marges chirurgicales positives était de 19,8% dans les cancers pT2, 42.4% dans les pT3a et 62.8% dans les pT3b et pT4 pour un taux moyen de marge de 31,8%. La continence était de 75% à 12 mois et la puissance sexuelle de 52,2%. Le taux de progression à 5 ans est de 21,5% et 7% des patients ont eu d un traitement complémentaire. Conclusions : En 10 ans la PRRA s'est imposée comme une alternative aux traitements de référence avec des résultats oncologiques et fonctionnels comparables associés à certains avantages spécifiques. La sélection des patients et de la technique opératoire reste le principal enjeu afin de réduire le taux de marge en conservant des résultats fonctionnels satisfaisantsPARIS12-CRETEIL BU Médecine (940282101) / SudocSudocFranceF