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To describe the results of a structured literature review of real-world outcomes with ixekizumab in patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). Literature databases, conference proceedings and additional sources were searched for relevant publications. Real-world studies of ≥25 ixekizumab-treated patients with PsO and/or PsA were included. Data on clinical effectiveness, treatment persistence/patterns, economic outcomes, patient-reported outcomes (PROs) and safety were extracted. Fifty-one publications were included. Most studies focused on patients with PsO, and the number of publications with a focus on PROs was low. Studies of treatment patterns found that in general, ixekizumab had similar or better persistence versus other biologics, and rates or risk of switching similar to or less than comparator drugs. Adherence to ixekizumab was high, and patients were less likely to discontinue ixekizumab than other biologics. Ixekizumab was effective in the real world, with a safety profile consistent with that reported in clinical trials. Real-world use of ixekizumab in PsO and PsA is effective and safe, with generally high treatment persistence and adherence. Further work is required to determine the impact of ixekizumab on PROs in PsO, and to gather more data on real-world use of ixekizumab in PsA.

International audience; Purpose: Complete congenital stationary night blindness (cCSNB) is an incurable inherited retinal disorder characterized by an ON-bipolar cell (ON-BC) defect. GRM6 mutations are the third most prevalent cause of cCSNB. The Grm6−/− mouse model mimics the human phenotype, showing no b-wave in the electroretinogram (ERG) and a loss of mGluR6 and other proteins of the same cascade at the outer plexiform layer (OPL). Our aim was to restore protein localization and function in Grm6−/− adult mice targeting specifically ON-BCs or the whole retina.Methods: Adeno-associated virus-encoding Grm6 under two different promoters (GRM6-Grm6 and CAG-Grm6) were injected intravitreally in P15 Grm6−/− mice. ERG recordings at 2 and 4 months were performed in Grm6+/+, untreated and treated Grm6−/− mice. Similarly, immunolocalization studies were performed on retinal slices before or after treatment using antibodies against mGluR6, TRPM1, GPR179, RGS7, RGS11, Gβ5, and dystrophin.Results: Following treatment, mGluR6 was localized to the dendritic tips of ON-BCs when expressed with either promoter. The relocalization efficiency in mGluR6-transduced retinas at the OPL was 2.5% versus 11% when the GRM6-Grm6 and CAG-Grm6 were used, respectively. Albeit no functional rescue was seen in ERGs, relocalization of TRPM1, GPR179, and Gβ5 was also noted using both constructs. The restoration of the localization of RGS7, RGS11, and dystrophin was more obvious in retinas treated with GRM6-Grm6 than in retinas treated with CAG-Grm6.Conclusions: Our findings show the potential of treating cCSNB with GRM6 mutations; however, it appears that the transduction rate must be improved to restore visual function.

Tout comme la France, le Québec a connu d’importants débats sur la laïcité au cours des dernières années. Dans ce contexte, une certaine lecture de l’histoire des femmes et le principe d’égalité entre les sexes ont été utilisés comme arguments pour justifier la mise en place de politiques ciblant particulièrement certains signes religieux, dont le hijab. Or, est-il exact d’affirmer que, historiquement, c’est essentiellement « la religion » qui aurait causé l’oppression des femmes ? Est-ce juste de présumer que, conséquemment, la laïcité garantirait une amélioration de leur condition ? En m’appuyant sur l’histoire des femmes à plusieurs moments de « modernisation » et de « laïcisation » au Québec, je propose de remettre en question ce postulat central aux discours en faveur d’une laïcité républicaine. In Quebec, like France, secularity has been the object of significant debate over recent years. In this context, a certain reading of women’s history and the principle of gender equality have been used as arguments to justify the implementation of policies targeting certain religious symbols, such as the Hijab. But is it correct to state that, historically, “religion” is what is primarily responsible for women’s oppression? Is it fair to assume, consequently, that secularization would guarantee an improvement in women’s situation? Drawing on the history of women at several points in the processes of “modernization” and “secularization” in Quebec, I question this central premise of discourses in favour of state secularity.

International audience; Objectives: To evaluate the clinical and economic burden of head and neck squamous cell carcinoma (HNSCC) in France.Methods: All 53,255 incident adult patients discharged with a first diagnosis of HNSCC in 2010–2012 were identified from the 2008–2013 French National Hospital Discharge (PMSI) database. We conducted a retrospective longitudinal analysis of prognosis and direct costs attributable to HNSCC.Results: Direct medical costs attributable to HNSCC care amounted to 665 million euros in 2012 in France. The majority (62%) of incident patients were 64 years old or less at HNSCC diagnosis and incurred 1.3-fold higher mean direct costs as compared to elderly patients (41,909 vs 32,221 euros over 3 years, respectively; p

International audience; Optogenetic technologies paved the way to dissect complex neural circuits and monitor neural activity using light in animals. In retinal disease, optogenetics has been used as a therapeutic modality to reanimate the retina after the loss of photoreceptor outer segments. However, it is not clear today which ones of the great diversity of microbial opsins are best suited for therapeutic applications in human retinas as cell lines, primary cell cultures and animal models do not predict expression patterns of microbial opsins in human retinal cells. Therefore, we sought to generate retinal organoids derived from human induced pluripotent stem cells (hiPSCs) as a screening tool to explore the membrane trafficking efficacy of some recently described microbial opsins. We tested both depolarizing and hyperpolarizing microbial opsins including CatCh, ChrimsonR, ReaChR, eNpHR 3.0, and Jaws. The membrane localization of eNpHR 3.0, ReaChR, and Jaws was the highest, likely due to their additional endoplasmic reticulum (ER) release and membrane trafficking signals. In the case of opsins that were not engineered to improve trafficking efficiency in mammalian cells such as CatCh and ChrimsonR, membrane localization was less efficient. Protein accumulation in organelles such as ER and Golgi was observed at high doses with CatCh and ER retention lead to an unfolded protein response. Also, cytoplasmic localization was observed at high doses of ChrimsonR. Our results collectively suggest that retinal organoids derived from hiPSCs can be used to predict the subcellular fate of optogenetic proteins in a human retinal context. Such organoids are also versatile tools to validate other gene therapy products and drug molecules.

International audience; Protein O-mannosylation is crucial for the biology of Mycobacterium tuberculosis but the key mannosylated protein(s) involved and its(their) underlying function(s) remain unknown. Here, we demonstrated that the M. tuberculosis mutant (Δpmt) deficient for protein O-mannosylation exhibits enhanced release of lipoarabinomannan (LAM) in a complex with LprG, a lipoprotein required for LAM translocation to the cell surface. We determined that LprG is O-mannosylated at a unique threonine position by mass spectrometry analyses of the purified protein. However, although replacement of this amino acid by an alanine residue completely abolished LprG O-mannosylation, the increased release of the LAM/LprG complex was preserved. We found that the increased secretion of this complex is due to enhanced LAM production in the Δpmt M. tuberculosis and M. smegmatis mutants relative to their wildtype counterparts. This abnormal release of LAM/LprG has functional consequences on the induction of inflammatory responses and provides a possible explanation for the reduced virulence of the M. tuberculosis Δpmt mutant.

Francisella tularensis is an intracellular Gram negative bacterium and the causative agent of tularemia. It is one of the most infectious agents known to date. Infection by the respiratory route leads to the deadly pulmonary form of tularemia. For these reasons, F. tularensis has been considered for years as a potential biological weapon. Pulmonary tularemia is characterized by an acute infection and a defect in immune responses. Particularly, the innate immune system plays a central role in F. tularensis infection and pathology. Macrophages, key cells of the innate immune system, are the main target for F. tularensis. This bacterium has evolved many strategies to escape host defenses that allow it to replicate within the cells and then disseminate into the whole organism. At this systemic stage, bacteria, along with alarm signals from infected cells, are recognized by innate immune receptors, triggering an inappropriate inflammatory response. The latter is characterized by a cytokine storm leading to a massive recruitment of immune cells, particularly neutrophils, in infected tissue. Tissue damages caused by this inflammation are a major cause of mortality associated with F. tularensis infections. Today, the treatment of tularemia is based on antibiotherapy. However, no specific symptoms can be assigned to pulmonary tularemia making its diagnosis difficult. This delays the administration of an appropriate antibiotiotherapy whose efficacy is therefore decreased. Thus, new therapeutic strategies are needed to replace or complement antibiotics. In this context, we investigated whether reducing the excessive inflammation induced by F. tularensis could be beneficial for the host and be considered as an adjunctive host- directed therapy. The aim of my work was to evaluate the anti-inflammatory properties and the therapeutic potential of mannodendrimer 3T (M3T), a synthetic coumpond designed in the team, in a mouse model of pulmonary infection by F. tularensis. M3T was previously designed to mimic the anti-inflammatory traits of a specific glycolipid from Mycobacterium tuberculosis. It was previously shown to inhibit the production of pro-inflammatory cytokines and neutrophils recruitment in a mouse model of LPS-induced pulmonary inflammation. Here, we used F. novicida as a surrogate for F. tularensis since it induces an identical inflammatory pathology. In vitro, M3T was found to inhibit the production of pro-inflammatory cytokines in human macrophages and dendritic cells infected by F. novicida. M3T modulates inflammatory response triggered by F. novicida via TLR2 most likely by the activation of a DC-SIGN-dependant pathway. In vivo, M3T was administered 6 h post-infection and then, daily for 3 days, by intraveinous injection and combined with a suboptimal antibiotic. This combination increases the survival rate of mice infected with F. novicida as compared to mice treated with antibiotic alone. M3T treatment has no impact on bacterial burden but seems to reduce tissue damages as observed by histological analyses of lungs, liver and spleen of infected mice. Altogether, our data demonstrate that M3T administration provides a therapeutic benefit in a mouse model of pulmonary infection by F. novicida. On a more general perspective our results suggest that targeting inflammation can be considered as an adjunctive treatment in acute pulmonary infections.; Francisella tularensis est une bactérie intracellulaire à Gram négatif et l'un des agents les plus infectieux connu à l'heure actuelle, en particulier par voie respiratoire. L'inhalation d'une dizaine de bactéries suffit à provoquer une maladie mortelle : la tularémie pulmonaire. Sa facilité de dissémination par aérosols, ainsi que le caractère létal de cette pathologie, ont contribué à considérer F. tularensis comme une arme biologique potentielle. La tularémie pulmonaire est une infection aigue qui s'accompagne d'une réponse immunitaire inadaptée. F. tularensis infecte en premier lieu les cellules phagocytaires, notamment les macrophages. Alors que ces derniers sont des acteurs majeurs de la défense contre les agents infectieux, de nombreux mécanismes d'échappement permettent à F. tularensis d'éviter ou de résister aux réponses de l'hôte et ainsi de se multiplier et de disséminer dans l'organisme. Ainsi, après un retard initial dans la mise en place de la réponse immunitaire, la présence d'un grand nombre de bactéries et de signaux de danger libérés par les cellules infectées, conduisent au déclenchement d'une réponse inflammatoire excessive. Celle-ci se caractérise par une tempête cytokinique provoquant un recrutement massif de cellules immunitaires, en particulier de neutrophiles, dans les tissus infectés. Les dommages tissulaires associés à cette réponse inflammatoire sont en grande partie responsable de la mortalité associée aux infections pulmonaires par F. tularensis. La tularémie est actuellement traitée par antibiothérapie. Malheureusement, l'absence de symptômes spécifiques de cette maladie rend le diagnostic difficile et, par conséquent, retarde la prescription du traitement adapté. Or, l'efficacité des antibiotiques est considérablement réduite par cette administration tardive. De nouvelles stratégies thérapeutiques sont donc nécessaires pour remplacer ou compléter l'antibiothérapie. Dans ce contexte, nous avons cherché à déterminer si la modulation de la réponse inflammatoire excessive induite par F. tularensis pouvait être bénéfique pour l'hôte infecté et ainsi être utilisée comme thérapie accessoire. L'objectif de mon travail de thèse était d'évaluer les propriétés anti-inflammatoires et le potentiel bénéfice thérapeutique du mannodendrimère 3T (M3T), un composé synthétisé par l'équipe de J. Nigou, dans un modèle murin d'infection pulmonaire par F. tularensis. Le M3T, conçu pour mimer les propriétés anti-inflammatoires d'un glycolipide de la paroi de Mycobacterium tuberculosis, a précédemment montré un effet inhibiteur sur la production de cytokines pro-inflammatoires et le recrutement de neutrophiles dans un modèle murin d'inflammation pulmonaire aigue induite par le LPS. La souche F. novicida, provoquant chez la souris une pathologie similaire à une infection pulmonaire par F. tularensis, a été utilisée comme souche de substitution dans ces travaux. In vitro, nous avons montré que le M3T inhibe la production de cytokines pro-inflammatoires induite par F. novicida dans des macrophages et cellules dendritiques humaines. D'un point de vue mécanistique, l'ensemble des données suggère que le M3T inhibe la réponse inflammatoire induite par F. novicida via le récepteur TLR2, en activant une voie de signalisation dépendante du récepteur DC-SIGN. In vivo, le M3T a été administré par injection intraveineuse 6 h post-infection, puis quotidiennement pendant 3 jours, en combinaison avec un traitement antibiotique sous-optimal.

Francisella tularensis is an intracellular Gram negative bacterium and the causative agent of tularemia. It is one of the most infectious agents known to date. Infection by the respiratory route leads to the deadly pulmonary form of tularemia. For these reasons, F. tularensis has been considered for years as a potential biological weapon. Pulmonary tularemia is characterized by an acute infection and a defect in immune responses. Particularly, the innate immune system plays a central role in F. tularensis infection and pathology. Macrophages, key cells of the innate immune system, are the main target for F. tularensis. This bacterium has evolved many strategies to escape host defenses that allow it to replicate within the cells and then disseminate into the whole organism. At this systemic stage, bacteria, along with alarm signals from infected cells, are recognized by innate immune receptors, triggering an inappropriate inflammatory response. The latter is characterized by a cytokine storm leading to a massive recruitment of immune cells, particularly neutrophils, in infected tissue. Tissue damages caused by this inflammation are a major cause of mortality associated with F. tularensis infections. Today, the treatment of tularemia is based on antibiotherapy. However, no specific symptoms can be assigned to pulmonary tularemia making its diagnosis difficult. This delays the administration of an appropriate antibiotiotherapy whose efficacy is therefore decreased. Thus, new therapeutic strategies are needed to replace or complement antibiotics. In this context, we investigated whether reducing the excessive inflammation induced by F. tularensis could be beneficial for the host and be considered as an adjunctive host- directed therapy. The aim of my work was to evaluate the anti-inflammatory properties and the therapeutic potential of mannodendrimer 3T (M3T), a synthetic coumpond designed in the team, in a mouse model of pulmonary infection by F. tularensis. M3T was previously designed to mimic the anti-inflammatory traits of a specific glycolipid from Mycobacterium tuberculosis. It was previously shown to inhibit the production of pro-inflammatory cytokines and neutrophils recruitment in a mouse model of LPS-induced pulmonary inflammation. Here, we used F. novicida as a surrogate for F. tularensis since it induces an identical inflammatory pathology. In vitro, M3T was found to inhibit the production of pro-inflammatory cytokines in human macrophages and dendritic cells infected by F. novicida. M3T modulates inflammatory response triggered by F. novicida via TLR2 most likely by the activation of a DC-SIGN-dependant pathway. In vivo, M3T was administered 6 h post-infection and then, daily for 3 days, by intraveinous injection and combined with a suboptimal antibiotic. This combination increases the survival rate of mice infected with F. novicida as compared to mice treated with antibiotic alone. M3T treatment has no impact on bacterial burden but seems to reduce tissue damages as observed by histological analyses of lungs, liver and spleen of infected mice. Altogether, our data demonstrate that M3T administration provides a therapeutic benefit in a mouse model of pulmonary infection by F. novicida. On a more general perspective our results suggest that targeting inflammation can be considered as an adjunctive treatment in acute pulmonary infections.; Francisella tularensis est une bactérie intracellulaire à Gram négatif et l'un des agents les plus infectieux connu à l'heure actuelle, en particulier par voie respiratoire. L'inhalation d'une dizaine de bactéries suffit à provoquer une maladie mortelle : la tularémie pulmonaire. Sa facilité de dissémination par aérosols, ainsi que le caractère létal de cette pathologie, ont contribué à considérer F. tularensis comme une arme biologique potentielle. La tularémie pulmonaire est une infection aigue qui s'accompagne d'une réponse immunitaire inadaptée. F. tularensis infecte en premier lieu les cellules phagocytaires, notamment les macrophages. Alors que ces derniers sont des acteurs majeurs de la défense contre les agents infectieux, de nombreux mécanismes d'échappement permettent à F. tularensis d'éviter ou de résister aux réponses de l'hôte et ainsi de se multiplier et de disséminer dans l'organisme. Ainsi, après un retard initial dans la mise en place de la réponse immunitaire, la présence d'un grand nombre de bactéries et de signaux de danger libérés par les cellules infectées, conduisent au déclenchement d'une réponse inflammatoire excessive. Celle-ci se caractérise par une tempête cytokinique provoquant un recrutement massif de cellules immunitaires, en particulier de neutrophiles, dans les tissus infectés. Les dommages tissulaires associés à cette réponse inflammatoire sont en grande partie responsable de la mortalité associée aux infections pulmonaires par F. tularensis. La tularémie est actuellement traitée par antibiothérapie. Malheureusement, l'absence de symptômes spécifiques de cette maladie rend le diagnostic difficile et, par conséquent, retarde la prescription du traitement adapté. Or, l'efficacité des antibiotiques est considérablement réduite par cette administration tardive. De nouvelles stratégies thérapeutiques sont donc nécessaires pour remplacer ou compléter l'antibiothérapie. Dans ce contexte, nous avons cherché à déterminer si la modulation de la réponse inflammatoire excessive induite par F. tularensis pouvait être bénéfique pour l'hôte infecté et ainsi être utilisée comme thérapie accessoire. L'objectif de mon travail de thèse était d'évaluer les propriétés anti-inflammatoires et le potentiel bénéfice thérapeutique du mannodendrimère 3T (M3T), un composé synthétisé par l'équipe de J. Nigou, dans un modèle murin d'infection pulmonaire par F. tularensis. Le M3T, conçu pour mimer les propriétés anti-inflammatoires d'un glycolipide de la paroi de Mycobacterium tuberculosis, a précédemment montré un effet inhibiteur sur la production de cytokines pro-inflammatoires et le recrutement de neutrophiles dans un modèle murin d'inflammation pulmonaire aigue induite par le LPS. La souche F. novicida, provoquant chez la souris une pathologie similaire à une infection pulmonaire par F. tularensis, a été utilisée comme souche de substitution dans ces travaux. In vitro, nous avons montré que le M3T inhibe la production de cytokines pro-inflammatoires induite par F. novicida dans des macrophages et cellules dendritiques humaines. D'un point de vue mécanistique, l'ensemble des données suggère que le M3T inhibe la réponse inflammatoire induite par F. novicida via le récepteur TLR2, en activant une voie de signalisation dépendante du récepteur DC-SIGN. In vivo, le M3T a été administré par injection intraveineuse 6 h post-infection, puis quotidiennement pendant 3 jours, en combinaison avec un traitement antibiotique sous-optimal.

International audience; no abstract

International audience; The macroscopic behavior of polycrystalline materials is largely influenced by the shape, the arrangement and the orientation of crystallites. Different methods have thus been developed to determine the effective behavior of such materials as a function of their microstructural features. In this work, which focuses on polycrystalline materials with an elastic-viscoplastic behavior, the self-consistent (SC) method [1], the finite element (FE) method and the spectral (FFT) method [2] are compared. These common methods are used to determine the effective behavior of different 316L polycrystalline aggregates subjected to various loading conditions (uniaxial tension, cyclic tension/compression).(...)

Colloque avec actes et comité de lecture. Internationale.; International audience; Les modélisations numériques des matériaux à l'échelle de la microstructure se sont fortement développées au cours des deux dernières décennies. Malheureusement, les méthodes de résolution classiques ne permettent pas de simuler les agrégats polycristallins au-delà de quelques dizaines de cycles à cause du temps de calcul prohibitif. Ce travail présente le développement d'une méthode numérique pour la résolution par la méthode des éléments finis d'agrégats polycristallins soumis à un chargement cyclique. La première idée est de maintenir la matrice de rigidité constante. La deuxième proposition est d'utiliser une méthode de réduction dimensionnelle en espace/temps. Les résultats montrent un gain de temps relativement important tout en gardant une très bonne précision.

This study aims at the developing of a numerical method for the resolution of the finite element for nonlinear viscoplastic problems. For this, two ideas are used. The first is to maintain a constant stiffness matrix [4] to do only one factorization. The second con-cerns the use of a model reduction method to decouple the dimensions of space and time. This method, which is based on radial approximation , hasshown its effectiveness in solving problems with a large number of degrees of freedom

International audience; In the present study, the effects of both the microstructure and voids on the high-cycle fatigue behaviour of the 316L austenitic stainless steel are investigated by using finite element simulations of polycrystalline aggregates. The numerical analysis relies on a metallurgical and mechanical characterization. In particular, fatigue tests are carried out to estimate the fatigue limits at 2.106 cycles under uniaxial and multiaxial loading conditions (combined tension and torsion and biaxial tension) using both smooth specimens and specimens containing an artificial hemispherical defect. The simulations are carried out with several configurations of crystalline orientations in order to take into account the variability of the microstructure in the predictions of the macroscopic fatigue limits. These predictions are obtained, thanks to a probabilistic fatigue criterion using the finite element results. The capability of this criterion to predict the influence of voids on the average and the scatter of macroscopic fatigue limits is evaluated.

International audience; In the present study, the effects of both the microstructure and defects on the high cycle fatigue behavior of the 316L austenitic stainless steel are investigated thanks to finite element simulations of polycrystalline aggregates. The numerical analysis relies on a metallurgical and mechanical characterization. To complete the experimental study, load-controlled fatigue tests are also carried out to determine the fatigue limits at 2.106 cycles under uniaxial and multiaxial loading conditions using both smooth specimens and specimens containing an artificial hemispherical surface defect. In the finite element models, where the grain morphologies are explicitly modeled, the anisotropic behavior of each crystal is described by the generalized Hooke's law and by a single crystal visco-plastic model. From the simulations carried out with different defect sizes and orientation sets, statistical informations regarding mesoscopic mechanical fields are analyzed. Then, using the FE results, the ability of a probabilistic fatigue criterion to predict the influence of defects and biaxiality on the average fatigue limits is evaluated thanks to a comparison with the experimental data.