Soluble amyloid-beta isoforms predict downstream Alzheimer’s disease pathology

Background: Changes in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer’s disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. Methods: We used CSF measurements of three soluble Aβ peptides (Aβ1–38, Aβ1–40 and Aβ1–42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. Results: Our findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. Conclusions: Our results demonstrate that, by applying a refined ML analysis, a combination of Aβ isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Full scale simulation and debriefing of non technical anesthesia-resuscitation skills : contribution to the drafting of a training framework for trainers

La formation par simulation dans le champ de la santé a pris son essor il y a une dizaine d’années en France, notamment en anesthésie-réanimation. Dans cette thèse, nous portons intérêt aux pratiques pédagogiques qui étayent ce dispositif et plus particulièrement au débriefing qui constitue l’axe central pour la conceptualisation de l’action, au regard de la didactique professionnelle (Pastré, 1999). Dans sa forme pleine échelle, la simulation vise à travailler des compétences techniques associées à des compétences dites non techniques (communication, leadership, émotions, …). Pour approcher les pratiques des formateurs dans le débriefing portant sur la construction des compétences non techniques, nous avons d’abord réalisé une enquête exploratoire auprès de formés puis nous avons mis en place un programme de recherche en trois phases : phase 1 - observations filmées à visée heuristique, phase 2 - observations filmées et entretiens d’auto confrontation en France et au Canada, phase 3 - focus groups avec des formateurs. Nous montrons, par l’analyse des données recueillies, que le passage de l’expertise professionnelle en anesthésie-réanimation à la posture de formateur dans le cadre d’un débriefing présente certaines difficultés. Nos résultats permettent alors d’appuyer des propositions pour accompagner un changement dans les pratiques des formateurs grâce à l’élaboration de la structure conceptuelle du débriefing, à la construction d’un référentiel de formation de formateurs et à un type d’artéfact cognitif pouvant soutenir le débriefing.Interest for simulation-based training in healthcare arose around ten years ago in France, especially in the field of anesthesia and resuscitation. Studies about the teaching practices underlying this type of training focus on several points but more particularly on debriefing, which constitutes the central axis for conceptualizing action, according to professional didactics (Pastré, 1999). In its full-scale form, simulation aims at improving technical skills in association to so-called non-technical skills (communication, leadership, emotion management, etc.). To study the practices of trainers in the debriefing of non-technical skills, we first conducted an exploratory survey with trainees, then we created a research program in three steps: step 1 – filmed observations with a heuristic objective, step 2 – filmed observations and self-confrontation interviews in France and Canada, step 3 – focus groups with trainers. Through the analysis of this data, we show that the transition from professional expertise to trainer status in the framework of debriefing is challenging. Our results allow us to back propositions supporting a change in the practices of trainers based on the design of the conceptual structure of debriefing, the creation of a curriculum for a training-of-trainers course, and a type of cognitive artifact to support the organization of debriefing

The endoscopic evaluation of the oral phase of swallowing ( Oral-FEES,O-FEES): a pilot study of the clinical use of a new procedure.

Oral FEES (O-FEES) is an endoscopic procedure conceived to directly visualise the oral phase of swallowing. In the perspective of clinical use, the feasibility, safety and acceptability of O-FEES has been evaluated. Subsequently, the procedure was compared with the radiological gold standard. The acceptability of O-FEES was compared to that of FEES using a 10 point questionnaire submitted to a sample of 52 outpatients complaining of swallowing disorders. Repeated measure analysis of variance (rm-ANOVA) models were used to test the mean difference of acceptability in the same subjects after FEES and O-FEES. Subsequently, another sample of 8 male outpatients underwent a simultaneous O-FEES and videofluoroscopic study (VFSS). The inter-rater reliability using 10 radiological landmarks, compared to O-FEES, was blindly determined between two raters. Inter-rater agreement between the two judges for O-FEES and VFSS scores was assessed with the single score intra-class correlation coefficient (ICC). Differences between FEES and O-FEES answers for each question and among all the items considered overall were statistically significant (rm-ANOVA; F-statistic p < 0.001). The inter-rater agreement concerning endoscopic and radiological evaluations between the two raters showed strong values of intra-class correlation coefficient (ICC) (95% confidence interval): 0.875 (0.373-0.979) and 0.921 (0.542-0.986), respectively. The Bland-Altman test showed a bias of -0.24 (95% limits of agreement; -1.77 to +1.19), which suggests that both methods produced almost identical results. In clinical practice and compared with FEES, O-FEES is a well tolerated and safe procedure. Compared with the radiological gold standard, O-FEES offers reliable information about oral preparation and oral propulsion of the bolu

Accompagner la professionnalisation des formateurs en simulation médicale

International audienceprofessionnalisation des formateurs en simulation médicale », Éducation et didactique [En ligne], 1 | 2017, mis en ligne le 20 juin 2019, consulté le 26 juin 2017. URL : http:// educationdidactique.revues.org/2659