Les Accidents Sur les Sites d’Orpaillage Traditionnel : Un Danger Pour la Vision au Niger

Nous avons colligé sur 18 mois 36 yeux ayant été victimes de traumatisme chez les orpailleurs clandestins du Niger. Les atteintes étaient bilatérales dans tous les cas mais volontiers asymétriques et touchent une ou plusieurs structures de l’œil et ses annexes, la présence des corps étrangers multiple était vus dans tous les yeux, nous avons retrouvé 9 cas d’éclatement du globe ayant nécessité une éviscération d’emblée. Il y avaient des lésions d’autres systèmes qui étaient dans 55% maxillo-faciales et dans 27% des fractures de membres. Le pronostic visuel était mauvais dans 94,43% des cas. Le manque d’infrastructures d’exploitation adéquates, la mauvaise manipulation des explosifs artisanaux sont à l’origine des accidents responsables de ces traumatismes. L’absence de structures de premiers soins, le manque de moyens de déplacement compliquent d’avantage les cas graves. Une formation substantielle en matière de santé et de sécurité est à envisager de même que des apprentissages pour aider les travailleurs à comprendre les dangers et les moyens de réduire les risques auxquels ils sont exposés.   Over 18 months, we collected 36 eyes that were victims of trauma among niger illegal gold panners. The lesions were bilateral in all cases but willingly asymmetrical and affect one or more structures of the eye and its adnnexias. The presence of multiple foreign bodies was seen in all eyes, we found 9 cases of bursting of the globe requiring immediate evisceration. Other systems were also affected in 55% maxillofacial and in 27% limb fractures. The visual prognosis was poor in 94.43% of the cases. The lack of adequate operating infrastructure and the improper handling of homemade explosives are at the origin of the accidents responsible for these traumas. The absence of first aid structures and the lack of means of transportation further complicate serious cases. Substantial health and safety training should be considered, as well as apprenticeship to help workers understand the dangers and how to reduce the risks to which they are exposed

Amphiphilic block copolymers enhance the cellular uptake of DNA molecules through a facilitated plasma membrane transport

Amphiphilic block copolymers have been developed recently for their efficient, in vivo transfection activities in various tissues. Surprisingly, we observed that amphiphilic block copolymers such as Lutrol® do not allow the transfection of cultured cells in vitro, suggesting that the cell environment is strongly involved in their mechanism of action. In an in vitro model mimicking the in vivo situation we showed that pre-treatment of cells with Lutrol®, prior to their incubation with DNA molecules in the presence of cationic lipid, resulted in higher levels of reporter gene expression. We also showed that this improvement in transfection efficiency associated with the presence of Lutrol® was observed irrespective of the plasmid promoter. Considering the various steps that could be improved by Lutrol®, we concluded that the nucleic acids molecule internalization step is the most important barrier affected by Lutrol®. Microscopic examination of transfected cells pre-treated with Lutrol® confirmed that more plasmid DNA copies were internalized. Absence of cationic lipid did not impair Lutrol®-mediated DNA internalization, but critically impaired endosomal escape. Our results strongly suggest that in vivo, Lutrol® improves transfection by a physicochemical mechanism, leading to cellular uptake enhancement through a direct delivery into the cytoplasm, and not via endosomal pathways

Structural variations in hyperbranched polymers prepared via thermal polycondensation of lysine and histidine and their effects on DNA delivery

The successful clinical translation of non-viral gene delivery systems has yet to be achieved due to the biological and technical obstacles to preparing a safe, potent and cost-effective vector. Hyper-branched polymers have emerged as promising candidates to address gene delivery barriers owing to their relatively simple synthesis and ease of modification compared to other polymers, which makes them more feasible for scale up and manufacturing. Here, we compare hyperbranched poly(amino acids) synthesised by co-polymerising histidine and lysine, with hyperbranched polylysine prepared using the well-known ‘ultra-facile’ thermal polycondensation route, to investigate the effects of histidine units on the structure and gene delivery applications of the resultant materials. The conditions of polymerisation were optimised to afford water-soluble hyperbranched polylysine-co-histidine of three different molar ratios with molecular masses varying from 13-30 kDa. Spectroscopic, rheological and thermal analysis indicated that the incorporation of histidine modulated the structure of hyperbranched polylysine to produce a more dendritic polymer with less flexible branches. Experiments to probe gene delivery to A549 cells indicated that all the new hyper-branched polymers were well-tolerated but, surprisingly, the co-polymers containing histidine were not more effective in transfecting a luciferase gene than hyper-branched poly(lysine)s synthesised as established literature comparators. We attribute the variations in gene delivery efficacy to the changes induced in polymer architecture by the branching points at histidine residues, and obtain structure-function information relating histidine content with polymer stiffness, pKa and ability to form stable polyplexes with DNA. The results are of significance to nanomedicine design as they indicate that addition of histidine as a co-monomer in the synthetic route to hyper-branched polymers changes not only the buffering capacity of the polymer but has significant effects on the overall structure, architecture and gene delivery efficacy

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

[BACKGROUND] Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.[METHODS] We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.[RESULTS] A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).[CONCLUSIONS] Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)Peer reviewe

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Synthese et structure de derives soufres, hydroxyles et phosphoryles d'isocannabinoiedes et de tetrahydrocannabinols

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Public health and environmental health risks associated with water in Cotonou, Benin : spatial modeling and analysis approaches

Notre travail doctoral contribue à l’analyse de la gestion des risques sanitaires liés à l’eau à Cotonou au Bénin par la mise en place d’un Système d’Information Géographique (SIG). Relevant à la fois de la géographie physique et humaine, le sujet de cette thèse est une approche intégrée des interfaces de la Nature et de la société. Plus que les différences et les approches dualistes, c’est l’interdépendance entre mode de vie et santé que nous avons mis en évidence. Pour ce faire, il parait opportun d’inscrire dans une dynamique les évolutions de l’environnement biophysique de notre zone d’étude (la ville de Cotonou), d’en connaître les rythmes de progression et de régression au cours du temps, et d’apprécier les phénomènes à plusieurs échelles spatio-temporelles.Sur le plan méthodologique, pour traiter les phénomènes spatiaux les méthodes d’inspiration hypergraphique et ensembliste apparaissent de nos jours comme des plus efficaces. Les SIG appuient cette approche dans la mesure où ils permettent la spatialisation de données de nature et de sources différentes. Deux axes de recherche complémentaires ont formé l’épine dorsale de cette contribution: la modélisation et l’analyse spatiales. La modélisation spatiale se matérialise sous forme d’un Modèle Conceptuel de Données d’inspiration hypergraphique et ensembliste adapté à notre sujet. La prise en compte de l’analyse spatiale dans le domaine de la santé est une démarche émergeante, assurant une surveillance globale de l’environnement pour la lutte contre les maladies et le suivi correctif de facteurs impliqués dans des cycles épidémiologiques. La distribution des maladies et les résultats sanitaires auxquels on aboutit sont grandement affectés par les lieux de vie. Pour atteindre nos objectifs, nous avons opté pour une entrée par l’espace en privilégiant la télédétection aérienne et spatiale. L’intégration des données issues des outils d’observation de la Terre dans le SIG mis en place a apporté des informations nouvelles et intéressantes. La télédétection a permis de délimiter les espaces pertinents pour nos recherches, de repérer les biotopes propices au développement des parasites, les milieux et leurs évolutions, les infrastructures, etc. Le SIG a en outre permis d’utiliser de façon complémentaire les données issues des outils d’observation de l’espace pour analyser les mutations en cours dans la ville littorale de Cotonou, afin de rendre compte du fonctionnement des systèmes d’utilisation de l’espace par les communautés qui peuplent la ville. Les faits sanitaires et les zones à risques ont été localisés et leur organisation spatiale, détectée grâce aux technologies du SIG. La recherche de zones à risques sanitaires a été effectuée à plusieurs échelles et le niveau de précision des résultats obtenus dépend étroitement de la qualité des données utilisées.Our Ph.D. dissertation contributes to the analysis of the management of health risks associated with water in Cotonou, Benin through the implementation of a Geographic Information System (GIS). Pertaining to both physical and human geography, the topic of this dissertation is an integrated approach of nature and society interfaces. Going beyond the differences and dualistic approaches this dissertation has highlighted the interdependence between lifestyle and health. To achieve that objective, we put in context the dynamics of the changes in the biophysical environment of our study area (the city of Cotonou), we study its progression and regression over time, and assess the phenomena through several spatial and temporal perspectives.On the methodological level, Data Model based on the theories of the hypergraphs (Hypergraph Based Data Structure) and the sets methods are the most efficient ones for assessing spatial phenomena. GIS are compatible with that approach as they make it possible to map geographically data of different types and sources. Our contribution consists of two complementary research axes that are modeling and spatial analyses.The spatial modelling materializes in through of a conceptual model of the hypergraphs and the sets data adapted to the problem. The inclusion of spatial analysis in health studies is an emerging approach that allows for a comprehensive monitoring of the environment in order to fight against diseases. It also makes it possible to provide corrective changes related to epidemiological cycles. The distribution of diseases and health outcomes obtained through this exercise is greatly affected by where people live.We use space remote sensing to achieve our objectives. The data obtained from GIS brought new and interesting insights. Remote sensing has delineated the areas relevant to our research, to identify habitats for the development of parasites, and their development environments, infrastructure, etc.GIS has also made it possible to use data from observation tools to analyze the space changes taking place in the coastal town of Cotonou, to reflect the operation of systems using the space by the city dwellers. The facts and health risk areas were located and their spatial organization, detected through GIS technologies. The search for health-risk areas was conducted at multiple scales and the accuracy of the results depends strongly on the quality of data used