Analyse critique de la posture professionnelle attendue du programme Éthique et culture religieuse du MELS en regard de la politique interculturelle du Québec

RÉSUMÉ: Depuis septembre 2008, le ministère de l'Éducation, du Loisir et du Sport (MELS) a officiellement implanté à tous les niveaux du primaire et secondaire, à l'exception du secondaire 3, le nouveau programme Éthique et culture religieuse (ECR) en remplacement à l'enseignement moral laïque ou à l'une des deux options confessionnelles du Domaine du développement personnel du Programme deformation de l'école québécoise (PFEQ). Cette recherche spéculative pose une problématique se situant sur la posture professionnelle attendue du programme ECR en regard de certaines conduites citoyennes néanmoins prescrites par la politique interculturelle du Québec du ministère de l'Immigration er des Communautés culturelles (MICC). Conséquemment, cette recherche qualitative poursuit l'objectif central d'analyser la cohérence de la posture professionnelle attendue du programme ECR du MELS, niveau primaire et secondaire, en regard de la politique interculturelle du Québec. Pour ce faire, cette analyse critique procède en deux temps. Une phase documentaire rassemble et expose les données soumises aux enjeux de la problématique dont la polysémie du concept d'impartialité en regard de celui de neutralité. Une deuxième phase, critique cette fois, analyse ces données pour répondre à l'objectif central par le biais d'un canevas d'analyse critique partiellement adapté à celui de Jean-Marie Van der Maren. En référence au programme ECR du MELS, cette recherche qualitative présente le discours et les orientations professionnelles retenues pour dispenser cette formation. En référence au discours du MICC devenant une mesure étalon dans le cadre de cette stratégie d'analyse, cette recherche présente les principes et valeurs communes de la société québécois et telle qu'attendus par tout citoyen. En résultats à cette méthodologie d'analyses comparant la posture professionnelle attendue du MELS face aux attendus du MICC, mais également à d'autres avenues théoriques, un large tableau de faiblesses, voire d'incohérences, se détache de cette posture professionnelle promue du programme ECR du MELS: faiblesses en regard du politique, en regard du droit, en regard d'un processus de délibération éthique, en regard d'une éducation à la citoyenneté et au sein même du programme ECR. En fin de parcours méthodologique, un bilan d'analyse légitimant une révision de la posture professionnelle véhiculée dans le sens de travailler de concert avec la politique interculturelle du Québec. La politique interculturelle du Québec n'est pas neutre. Celle-ci a identifié des principes et valeurs communes aux fondements de la société québécoise et encadre tous les citoyens québécois, natifs ou immigrants, à s'y conformer. --ABSTRACT: Since September 2008, the ministère de l'Éducation, du Loisir et du Sport (MELS) has officially implemented at all levels of elementary and secondary schools, with the exception of secondary 3, the new Ethics and Religious Culture (ERC) program in replacement of the Moral Education course or one of the two confessional options proposed by the Personal Development subject area of the Québec Education Program. This speculative research raises a problematic issue regarding the professional posture expected of ERC pro gram relative of sorne citizens conducts nonetheless prescribed by intercuItural Quebec politic of the ministère de l'Immigration et des Communautés culturelles (MICC). Therefore, this qualitative research pursues the central objective to analyze the coherence of the professional posture expected of ERC program, elementary and secondary level, compared to intercultural Quebec politic. To do this, this critical analysis proceeds in two stages. A documentation phase collects and presents the data submitted to the problematic issues including the polysemy of the concept of impartiality compared to neutrality. A second phase, this critical time, analyzes these data to answer the central objective through a critical analysis framework partially adapted to that of Jean-Marie Van der Maren. ln reference of ERC program of MELS, this qualitative research presents the discourse and professional orientations to dispense this formation. In reference to MICC discourse becoming a étalon measure under this analysis strategy, this research presents the principles and common values of Quebec society and such as expected by every citizen . As results of this methodology analyzes comparing the professional posture expected of MELS with the expected conducts of MICC, but also with the other theoretical avenues, a wide array of weaknesses or incoherencies stands out this professional posture promoted of MELS ERC program : weaknesses in relation to the policy, in relation to the law, compared to a process of ethical deliberation, compared to a citizenship education and even within the ERC program. At the end of methodological course, a balance sheet analysis justifying a review of the professional posture conveyed in the direction of working with intercultural Quebec politic. Intercultural Quebec policy is not neutral. It identified the principles and common values to the foundations of Québec society and leads all Quebec citizens, native or immigrant, to comply

Mechanisms Models and Biomarkers in Amyotrophic Lateral Sclerosis

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery

Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1–4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1]. Here, we present updated results from the ACE-LY-004 study after a median 26-month follow-up. Eligibility criteria and study design were published previously (Supplementary methods) [1]. Analysis of minimal residual disease (MRD) was conducted after complete response (CR) or partial response (PR) was achieved using the quantitative ClonoSEQ next-generation sequencing (5 × 10−6 ) assay (Adpative Biotechnologies, Seattle, WA, USA) in consenting patients with available paired archival tumor and whole blood samples. Data are updated as of February 12, 2018

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Role of the phagocytosis of sphingolipid overloaded red blood cells in Gaucher disease pathophysiology

La Maladie de Gaucher est une maladie génétique rare caractérisée par une déficience enzymatique de la ß-glucocérébrosidase (GCase), conduisant à une accumulation de sphingolipides (SL) dans les macrophages appelés alors Cellules de Gaucher. Il a été reporté que les macrophages issus de patients Gaucher présentent certains marqueurs de surface et sécrètent des cytokines spécifiques. Ces macrophages sont communément tenus comme premiers responsables des symptômes de la maladie, en infiltrant les tissus (foie, rate) ce qui provoquerait des atteintes hématologiques, une splénomégalie, des atteintes osseuses ainsi que la survenue d'évènements ischémiques dans la rate et les os. Toutefois, depuis quelques années, certaines équipes s'intéressent à d'autres types cellulaires pouvant être impactés par cette déficience en GCase. Ces autres types cellulaires pourraient être impliqués dans la physiopathologie de la maladie et devenir des cibles thérapeutiques intéressantes. Certains symptômes de la maladie de Gaucher comme l'anémie modérée, la splénomégalie et les vaso-occlusions, indiquent que la lignée érythrocytaire pourrait être également impliquée dans la physiopathologie de la maladie. Notre laboratoire a mis en évidence des anomalies morphologiques, rhéologiques et d'adhérence des globules rouges (GRs), ainsi qu'une accumulation de différents SL dans ces cellules. Ces anomalies pourraient souligner le rôle essentiel des GRs dans la physiopathologie de la maladie. En effet, en plus d'une contribution dans la survenue d'évènements vaso-occlusifs, ces GRs anormaux pourraient être retenus dans la rate ou la moelle osseuse et être phagocytés par les macrophages. La rétention de ces GRs pourrait en partie expliquer l'anémie chez les patients. En outre, une demi-vie alterée des GRs aurait été rapportée, et de nombreux évènements d'érythrophagocytose par les cellules de Gaucher dans la moelle osseuse de patients ont été répertoriés. Tous ces éléments nous ont conduits à étudier durant mon travail de thèse, l'érythrophagocytose des GRs dans le contexte pathologique de maladie de Gaucher. Dans un premier temps, nous avons développé des tests d'érythrophagocytose in vitro à partir de macrophages dérivés de la lignée monocytaire THP-1. Nous avons mis en évidence une phagocytose importante des GRs issus de patients Gaucher, corrélée à leurs propriétés morphologiques anormales, leur déformabilité réduite et leur surcharge en SL. Nous avons également mis en évidence un effet du traitement par remplacement enzymatique sur l'érythrophagocytose. Des tests à partir de macrophages primaires dérivés de monocytes ont confirmé ces résultats dans un contexte plus physiologiques. Enfin, nous avons démontré un effet de l'érythrophagocytose de GRs Gaucher sur le phénotype des macrophages (augmentation de l'expression de certains marqueurs connus pour être élevés dans les macrophages Gaucher). Dans un second temps, nous avons étudié l'effet de la surcharge en SL sur les propriétés des GRs Gaucher. Nous avons observé que cette surcharge corrèle avec les propriétés anormales des GRs dont leur phagocytose. Afin de déterminer l'origine de la surcharge en SL dans les GRs Gaucher nous avons aussi réalisé des expériences in vitro de surcharge en lipides et d'érythropoïèse qui nous ont permis de mettre en évidence 1/ une incorporation passive des SL entre le compartiment plasmatique et les GRs 2/ une accumulation en SL au cours de l'érythropoïèse. L'ensemble de nos résultats démontrent le rôle essentiel des GRs dans la physiopathologie de la maladie de Gaucher, en mettant en évidence une érythrophagocytose anormale par les macrophages. Celle-ci pourrait contribuer aux modifications phénotypiques des macrophages conduisant à la formation des cellules de Gaucher. Enfin, nous avons mis en évidence le lien direct entre la surcharge en SL dans les GRs et leurs propriétés altérées.Gaucher disease is a lysosomal storage disorder caused by glucocerebrosidase (GCase) deficiency, leading to an accumulation of sphingolipids (SL) in macrophages, named Gaucher Cells. It has been reported that macrophages from Gaucher patients have certain surface markers and secrete specific cytokines. These macrophages are commonly considered as the culprits of the pathophysiology of Gaucher disease, infiltrating tissues (liver, spleen, bone marrow) and resulting in hematologic manifestations (anemia, thrombocytopenia), splenomegaly, and ischemic events in the spleen and bones. However, certain studies highlight the role of other types of cell affected by a GCase deficiency which seems to be involved in the pathophysiology of the disease and could therefore become interesting therapeutic targets. Some symptoms of the disease as anemia, splenomegaly and vaso-occlusive events suggest that the erythroid lineage could also be involved in the disease. Our team has already demonstrated that red blood cells (RBCs) from Gaucher patients exhibited abnormal morphologies, altered rheological, aggregation and adhesion properties, and exhibited also SL overload that reduces RBCs' deformability. These morphological and functional abnormalities highlight the role of RBCs in the pathophysiology of the disease. Indeed, in addition to a contribution in the occurrence of vaso-occlusive events, these abnormal RBCs could be retained in the spleen or the bone marrow and be phagocytosed by macrophages. The retention of these RBCs could partly explain anemia in patients. In addition, an altered half-life of RBCs as well as numerous events of erythrophagocytosis by Gaucher cells in the bone marrow of patients have been reported. All these elements led us to study during my thesis work, erythrophagocytosis of RBCs in the pathological context of Gaucher disease. In the first part, we conducted In vitro experiments of erythrophagocytosis using the monocytic THP-1 cell line differentiated in macrophages. Our results showed significant increases of the erythrophagocytosis process of Gaucher RBCs compared to healthy RBCs. We established strong correlations between the erythrophagocytosis rate and their abnormal morphologies, reduced deformability and their SL overload. We also highlighted an effect of the enzyme replacement therapy on the erythrophagocytosis rate. In addition, some in vitro experiments using primary macrophages derived from healthy monocytes have confirmed our results in a more physiological context. Finally, we have demonstrated an effect of the erythrophagocytosis of Gaucher RBCs on the macrophages' phenotype, with the induction of Gaucher Cell markers (increased expression of certain surface markers and secretion of cytokines known to be elevated in Gaucher macrophages). Second, we studied the effect of SL overload on the properties of Gaucher RBCs. We observed that the SL overload correlates with the abnormal RBCs properties including their phagocytosis. In order to determine the origin of SL overload in Gaucher RBCs we also carried out in vitro experiments of lipid overload and erythropoiesis which allowed us to highlight 1/ passive incorporation of SL between the plasma compartment and RBCs 2/ an accumulation in SL during the erythropoiesis. All of our results demonstrate the essential role of RBCs in the pathophysiology of Gaucher disease, by highlighting an abnormal erythrophagocytosis by macrophages. This increased erythrophagocytosis could contribute to phenotypic changes in macrophages leading to the formation of Gaucher cells. Finally, we have highlighted the direct link between the SL overload in RBCs and their altered properties. We emphasize in particular that SL overload in mature RBCs can be established as early as erythropoiesis

Phagocytosis of Erythrocytes from Gaucher Patients Induces Phenotypic Modifications in Macrophages, Driving Them toward Gaucher Cells

Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named &ldquo;Gaucher&rsquo;s Cells&rdquo;. These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to infiltrate tissues resulting in hematological manifestations, splenomegaly, and bone diseases. We have already demonstrated that Gaucher red blood cells exhibit altered properties suggesting their key role in GD clinical manifestations. We hypothesized that Gaucher&rsquo;s erythrocytes could be prone to premature destruction by macrophages contributing to the formation of altered macrophages and Gaucher-like cells. We conducted in vitro experiments of erythrophagocytosis using erythrocytes from Gaucher&rsquo;s patients or healthy donors. Our results showed an enhanced erythrophagocytosis of Gaucher red blood cells compared to healthy red blood cells, which is related to erythrocyte sphingolipids overload and reduced deformability. Importantly, we showed elevated expression of the antigen-presenting molecules CD1d and MHC-II and of the iron-regulator hepcidin in macrophages, as well as enhanced secretion of the pro-inflammatory cytokine IL-1&beta; after phagocytosis of GD erythrocytes. These results strongly suggested that erythrophagocytosis in GD contribute to phenotypic modifications in macrophages. This present study shows that erythrocytes-macrophages interactions may be crucial in GD pathophysiology and pathogenesis

Molecular basis of biotin-responsive multiple carboxylase deficiency

Multiple carboxylase deficiency (MCD) results from a decreased activity of holocarboxylase synthetase (HCS) which is responsible for the biotinylation of the four biotin-dependent carboxylases found in humans. The disease can be treated with pharmacologic doses of oral biotin (biotin-responsiveness). The cDNA for HCS contains a biotin-binding domain deduced by analogy with the sequence and crystal structure of the E. coli BirA biotin ligase. E. coli birA$sp-$ mutations causing biotin-auxotrophy all localize to this region. Of six point mutations I have identified in MCD patients, four localize to the biotin-binding region. In order to assess the HCS activity associated with patient mutations, I used an assay based on the expression of mutant HCS in E. coli. The method is based on the ability of mutant HCS to biotinylate the biotin carboxyl carrier protein (BCCP) of acetyl-CoA carboxylase in a temperature-sensitive birA$sp-$ E. coli strain using 3H-biotin as tracer. I have shown that all of the mutations cause a severe decrease in HCS activity. In addition, I have shown that five of the mutant HCS are biotin-responsive. These findings are a major contribution to the understanding of the mechanism of biotin-responsiveness

SIDSI : simulation de la démarche en soins infirmiers /

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