Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 10 8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SL

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update

Objective In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aimed to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. Methods A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014-September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a two-step modified Delphi procedure to reach >80% consensus on the inclusion, wording and grading of each new and revised recommendation. Results Eleven new and 16 revised recommendations were created, and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary appendix for practical use was revised to reflect the updated recommendations. Conclusion The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts

Dynamiques de polarisation et génération de forces à la synapse immunologique du lymphocyte B

B lymphocytes are able to produce high affinity antibodies against antigens, making them central players of the adaptive immune response. In vivo, their activation typically takes place in secondary lymphoid organs, where they can encounter antigens at the surface of neighbouring cells. The engagement of a B cell receptor (BCR) with its cognate antigen triggers signalling in the B lymphocyte and the formation of an immune synapse between the B cell and the opposing cell. The immune synapse is a communication platform where the B cell gathers information from the opposing surface by accumulating antigen at the centre of the cell-cell contact and reorganizing its organelles to ultimately enable antigen extraction and specific antibody production. Antigen extraction can be achieved through two different pathways: by mechanical pulling on the antigen, or by polarized secretion of proteases at the immune synapse. Both pathways are intimately linked with the cell cytoskeleton, with mechanical extraction relying on actomyosin contractility, based on previous data from the lab, and polarized secretion relying on the polarized reorganisation of the microtubule and actin network. This work focuses on the role of the cytoskeleton in both these pathways, studying (1) the force-generating structures at the B cell immune synapse and their regulation and (2) the role of microtubules and F-actin in regulating dynamics of immune synapse formation and B cell polarization. In a first part, we used a soft substrate grafted with antigen to allow the B cell to extract the antigen mechanically, and to measure the forces applied by the cell in this context using traction force microscopy. This allowed us to uncover an actomyosin-dependent spatiotemporal force patterning at the immune synapse, with tangential forces at the periphery of the immune synapse, and normal, local forces associated with antigen extraction sites and invadosome-like protrusions at the centre of the synapse. These protrusions are also regulated in number, stability, and mobility by signalling and actomyosin contractility. In a second part, we focused on the establishment of polarity in B cells, which is a technical challenge, as this process is occurring in 5-10min. To overcome this difficulty, we designed a custom microfluidic system to reconstitute immune synapses between a B cell and an antigen-coated droplet, and control the time and angle of the contact. With this system, we can image immune synapse formation and B cell polarization from the first instants, which gave us unprecedented insights into this process. A sequence emerged, happening in ~5min: F-actin is transiently nucleated at the immune synapse, then cleared as the centrosome polarizes. The centrosome then detaches from the nucleus, allowing the latter to be transported away from the synapse. The polarization of the centrosome also allows the recruitment of lysosomes, indispensable for protease secretion. Using chemical treatments targeting the cytoskeleton, we were able to establish a map of dependencies of organelle movement during B cell polarization: early events (immune synapse formation - antigen accumulation, cell signaling) highly depend on F-actin, while the establishment and maintenance of cell polarity - including the polarity of actin polymerization- relies on microtubules. By creating a new set of experimental and analytical tools to investigate the dynamics of B cell polarization, we provide an unprecedented systematic characterization of organelles polarization dynamics and organelle-cytoskeleton interactions during B cell polarization, that can bring insights into polarization mechanisms in general. Our results decipher the role of the cell cytoskeleton in different contexts of B lymphocyte activation, immune synapse formation and antigen extraction, and highlight the versatility of B lymphocytes that adapt their behavior to the conditions of antigen presentation.Les lymphocytes B peuvent produire des anticorps de haute affinité contre les antigènes, ce qui en fait des acteurs centraux de la réponse immunitaire adaptative. In vivo, leur activation a lieu dans les organes lymphoïdes secondaires où ils rencontrent des antigènes à la surface des cellules voisines. Le contact entre un antigène et un récepteur de cellule B qui lui est spécifique déclenche la signalisation du lymphocyte B et la formation d'une synapse immunologique avec la cellule voisine. La synapse immunologique est une plate-forme de communication où le lymphocyte B recueille des informations sur la surface de l'autre cellule en accumulant l'antigène au centre du contact et en réorganisant ses organelles, pour permettre in fine l'extraction d'antigène et la production d'anticorps spécifiques. L'extraction de l'antigène peut être réalisée par deux voies différentes: l'application de forces mécaniques sur l'antigène ou la sécrétion polarisée de protéases au niveau de la synapse immunologique. Les deux voies sont liées au cytosquelette, l'extraction mécanique reposant sur la contractilité de l'actomyosine d'après des observations antérieures du laboratoire, et la sécrétion polarisée reposant sur la réorganisation polarisée des réseaux de microtubule et d'actine. Ce travail se concentre sur le rôle du cytosquelette dans ces deux voies, en étudiant (1) les structures qui génèrent des forces à la synapse immunologique et leur régulation et (2) le rôle du cytosquelette dans la régulation de la dynamique de formation de la synapse immunologique et la polarisation des lymphocytes B. Dans la première partie, nous avons utilisé un substrat déformable couvert d'antigène pour permettre l'extraction mécanique, ainsi que la mesure des forces appliquées par la cellule par microscopie de force de traction. Cela a révélé une organisation spatio-temporelle des forces à la synapse immunologique reposant sur l'activité de l'actomyosine : la périphérie de la synapse présente des forces tangentielles centripètes, alors que le centre de la synapse présente des forces locales normales associées aux sites d'extraction d'antigène et à des protrusions de type invadosome. Le nombre, la mobilité et la stabilité de ces protrusions sont également régulés par la signalisation et la contractilité de l'actomyosine. Dans un second temps, nous nous sommes concentrés sur l'établissement de la polarité du lymphocyte B, ce qui représente un défi technique car ce processus ne dure que 5-10min. Nous avons conçu un système microfluidique pour reconstituer des synapses immunologiques entre un lymphocyte B et une goutte recouverte d'antigène, et contrôler le temps et l'orientation du contact. Avec ce système, nous pouvons imager la formation de synapses et la polarisation des lymphocytes B dès les premiers instants, ce qui nous a permis d'étudier de nombreuses dynamiques de polarisation. Nous proposons une séquence en deux étapes : pendant les premières minutes, l'actine est nucléée à la synapse, ce qui permet l'accumulation de l'antigène et la signalisation. Ensuite, le centrosome se repositionne à la synapse et permets la polarisation des lysosomes puis du noyau. Cette séparation temporelle se retrouve dans les dépendances au cytosquelette : les événements précoces nécessitent l'actine, tandis que l'établissement et le maintien de la polarité cellulaire - dont la polarité de l'actine - repose sur les microtubules. Grace à un nouvel ensemble d'outils expérimentaux et analytiques, nous fournissons une caractérisation systématique de la dynamique de polarisation des organelles et des interactions organelles-cytosquelette pendant la polarisation des cellules B. Nos résultats décrivent le rôle du cytosquelette dans différents contextes d'activation des lymphocytes B, de formation de synapse immunologique et d'extraction d'antigène, et mettent en évidence la polyvalence des lymphocytes B qui adaptent leur comportement aux conditions de présentation de l'antigène

Les dispositifs médicaux innovants à l'hôpital (quel niveau de preuve scientifique ?)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Les dispositifs médicaux innovants dans le traitement de l'anévrisme de l'aorte (un modèle pour la réforme du financement des dispositifs médicaux couteux dans les établissements de santé ?)

Les dispositifs médicaux sont soumis à une réglementation stricte visant en particulier à garantir qu'ils remplissent les exigences essentielles concernant leur sécurité et leurs performances, et à protéger les patients et les tiers de tous dangers. Jusqu'à aujourd'hui, le mode de financement des dispositifs médicaux était très différent dans les établissements de sopins publics et privés. La Loi de finanement de la Sécurité Sociale pour 2003 a mis en œuvre un système d'allocation des ressources de l'ensemble des établissements de soins fondé sur une tarification à l'activité, dans le but d'harmoniser la prise en charge de ces produits. Cette réforme modifie considérablement le mode de finanacement des dispositifs médicaux référencés sur le marché hospitalier, c'est-à-dire les plus innovants et coûteux. En effet, seuls ceux inscrits sur la liste des produits et des prestations remboursables pourront être pris en charge dans le but d'assurer la sécurité et la qualité des produits utilisés. Les endoprothèses aortiques, dispositifs médicaux très coûteux, sont soumis à ces exigences. Elles font l'objet, depuis plusieurs années, de recommandations de la part des autorités françaises de santé suite à la constatation d'un nombre significatif d'incidents de matériovigilance. Le nombre d'endoprothèses aortiques remboursables à la disposition des praticiens est alors limité. On peut donc s'interroger sur l'impact des cette nouvelle réforme. Ces exigences, très contraignantes pour le fabricant, ne seront-elle pas un frein au développement et à l'innovation thérapeutique ?CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Ouverture d'un service de stérilisation centrale dans un hôpital neuf (mise en œuvre des bonnes pratiques de stérilisation et informatisation)

PARIS-BIUP (751062107) / SudocSudocFranceF

Benefits of 3D printing applications in jaw reconstruction: A systematic review and meta-analysis

International audienceBackground: Three-dimensional (3D) printing has changed surgical practice over the past few years, especially in maxillofacial surgery. However, little is known about its real clinical impact. The objectives of our study were to identify clinical outcomes that have been evaluated in the literature regarding 3D printing applications in jaw reconstruction, and to quantify the impact of this technology on operating times.Methods: A systematic review was conducted by searching PubMed and EMBASE to collect comparative studies on 3D printing applications in jaw reconstruction. A meta-analysis of operating times was then performed. A Cochran's Q test was used to determine heterogeneity, and the overall effect size was calculated using a random effects model.Results: Fourteen studies were included in our review. Eighteen clinical end-points were identified, of which the most frequently reported were operating time (n = 5; 35.7%) and the final aesthetic result (n = 4; 28.6%). Operating times were significantly lower in the 3D printing groups, with an overall estimated effect of 21.2% (95% CI 10-33%; p < 0.001).Conclusion: The use of 3D printing in jaw reconstruction was associated with a significant reduction in operating times. The end-points evaluated differed largely among the studies. More studies with higher levels of evidence are needed to confirm our results

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

International audienceImmune synapse formation is a key step for lymphocyte activation. In B lymphocytes, the immune synapse controls the production of high-affinity antibodies, thereby defining the efficiency of humoral immune responses. While the key roles played by both the actin and microtubule cytoskeletons in the formation and function of the immune synapse have become increasingly clear, how the different events involved in synapse formation are coordinated in space and time by actin–microtubule interactions is not understood. Using a microfluidic pairing device, we studied with unprecedented resolution the dynamics of the various events leading to immune synapse formation and maintenance in murine B cells. Our results identify two groups of events, local and global, dominated by actin and microtubules dynamics, respectively. They further highlight an unexpected role for microtubules and the GEF-H1-RhoA axis in restricting F-actin polymerization at the lymphocyte–antigen contact site, thereby allowing the formation and maintenance of a unique competent immune synapse

A Systematic Review of the Level of Evidence in Economic Evaluations of Medical Devices: The Example of Vertebroplasty and Kyphoplasty.

ContextEconomic evaluations are far less frequently reported for medical devices than for drugs. In addition, little is known about the quality of existing economic evaluations, particularly for innovative devices, such as those used in vertebroplasty and kyphoplasty.ObjectiveTo assess the level of evidence provided by the available economic evaluations for vertebroplasty and kyphoplasty.Data sourcesA systematic review of articles in English or French listed in the MEDLINE, PASCAL, COCHRANE and National Health Service Economic Evaluation databases, with limits on publication date (up to the date of the review, March 2014).Study selectionWe included only economic evaluations of vertebroplasty or kyphoplasty. Editorial and methodological articles were excluded.Data extractionData were extracted from articles by two authors working independently and using two analysis grids to measure the quality of economic evaluations.Data synthesisTwenty-one studies met our inclusion criteria. All were published between 2008 and 2014. Eighteen (86%) were full economic evaluations. Cost-effectiveness analysis (CEA) was the most frequent type of economic evaluation, and was present in 11 (52%) studies. Only three CEAs complied fully with the British Medical Journal checklist. The quality of the data sources used in the 21 studies was high, but the CEAs conforming to methodological guidelines did not use high-quality data sources for all components of the analysis.ConclusionsThis systematic review shows that the level of evidence in economic evaluations of vertebroplasty and kyphoplasty is low, despite the recent publication of a large number of studies. This finding highlights the challenges to be faced to improve the quality of economic evaluations of medical devices