Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Design chromatique : La carte et la collection, outils du coloriste

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Recherche Action pour la création artistique et design

International audienceEn quoi les directives données par l'extérieur sociétal aujourd'hui peuvent permettre de réécrire une recherche en création artistique et design ? Comment un praticien chercheur mais encore un étudiant en design peuvent-ils s'inscrire dans le champ de la profession et ceux de la recherche pour définir une posture engagée dans le cadre de l'action ? Par quelle constitution, quels outils et dans quelle définition ? Cet ouvrage s'attache ainsi à questionner la recherche action comme méthode permettant de chercher, de trouver, d'inventer, de concevoir, voire de produire son espace de liberté au cur même du système dans lequel nous sommes tous impliqués désormais. La recherche action concerne plus particulièrement les modalités de l'expérience qui découle de l'environnement actuel à travers l'idée de projet. En ce sens, elle n'est pas un dérivé de la création-recherche mais une veine entre projet-recherche-innovation et professionnalisation de la recherche. Dans cette réflexion théorique sur la pratique du design aujourd'hui, et plus généralement sur le statut de l'artiste, l'auteur propose de prendre en compte le réel extérieur comme une contrainte notamment économique au sens donné à la création et comme une sémantique et une pragmatique à déchiffrer afin d'approcher des postures spécifiques au chercheur, au praticien, au designer, au chercheur praticien, au praticien chercheur. S'appuyant sur l'étude de cas tournés plus particulièrement sur la création artistique et le design graphique et chromatique, le design d'objet, d'espace ou encore sensoriel, l'ouvrage permet de confronter la création à la société de consommation

A framework to characterise the reproducibility of meta‐analysis results with its application to direct oral anticoagulants in the acute treatment of venous thromboembolism

International audienceAbstract The number of meta‐analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy‐to‐use, and specialised statistical software. Even when meta‐analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta‐analysis provides an example of the variation of effect ‘naturally’ observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta‐analysis results, a bivariate linear mixed‐effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta‐analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism

Replication of Systematic Reviews: Is It to the Benefit or Detriment of Methodological Quality?

International audienceOBJECTIVE: To perform an overview of the overlap of systematic reviews (SR) assessing direct oral anticoagulants (DOACs) and characterise these reviews in terms of bias and methodological quality (PROSPERO: CRD42022316273). STUDY DESIGN AND SETTING: A PubMed-indexed search was performed from inception to 31 January 2022 to identify SR evaluating DOACs in patients treated for an acute venous thromboembolism. The risk of bias of these SR was assessed according to the Risk Of Bias In Systematic reviews (ROBIS) tool. Redundancy was defined as overlap in terms of the type of population considered, the interventions compared and the studies included. RESULTS: A total of 144 SR were evaluated, of which 26 (18.1%) were classified as original, 87 (60.4%) as conceptual replications and 31 (21.5%) as excessive replications. The risk of bias was high in 19 (73.1%) of the original SR, 65 (74.7%) of the conceptual replications and 21 (67.7%) of the excessive replications. Compared to the original SR, the overall methodological quality was not improved in either conceptual or excessive replications. CONCLUSION: A large number of SR were classified as replications, a fifth constituted excessive replications. The replications showed no improvement in overall methodological quality compared to the original SR

Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells

International audienceIn the interphase cell nucleus, chromosomes adopt a conserved and non-random arrangement in subnuclear domains called chromosome territories (CTs). Whereas chromosome translocation can affect CT organization in tumor cell nuclei, little is known about how aneuploidies can impact CT organization. Here, we performed 3D-FISH on control and trisomic 21 nuclei to track the patterning of chromosome territories, focusing on the radial distribution of trisomic HSA21 as well as 11 disomic chromosomes. We have established an experimental design based on cultured chorionic villus cells which keep their original mesenchymal features including a characteristic ellipsoid nuclear morphology and a radial CT distribution that correlates with chromosome size. Our study suggests that in trisomy 21 nuclei, the extra HSA21 induces a shift of HSA1 and HSA3 CTs out toward a more peripheral position in nuclear space and a higher compaction of HSA1 and HSA17 CTs. We posit that the presence of a supernumerary chromosome 21 alters chromosome compaction and results in displacement of other chromosome territories from their usual nuclear position

Early detection of the existence or absence of the treatment effect: A cumulative meta-analysis

International audienceObjectives: An unexpected promising effect of low molecular weight heparins (LMWHs) on survival in patients with cancer was observed in early trials in post hoc subgroup analyses but not found in more recent trials. To highlight a possible regression over time toward the lack of the antitumoral effect of LMWHs, we performed a cumulative meta-analysis of survival data from randomized controlled trials (RCTs).Study design and setting: Medical databases were searched to identify RCTs comparing, in patients with cancer, LMWHs with placebo or no treatment in patients free of venous thromboembolism (VTE), or to vitamin K antagonists in patients who experienced an acute VTE in overall survival. The cumulative hazard ratio (HR) was estimated after each study inclusion in chronological order.Results: Twenty-three studies (12,970 patients) were included. The cumulative meta-analysis of the earlier trials showed a significant improvement in overall survival with LMWHs. This apparent benefit then gradually regressed over time toward an absence of the effect of LMWHs on survival (HR: 0.98 [95% confidence interval, 0.93; 1.03]).Conclusion: Despite supportive experimental data and early clinical findings, the promising antitumoral effect of LMWHs in patients with cancer gradually vanished over time toward a lack of impact on overall survival. This result suggests 'p-hacking' and selective reporting of the positive results from post hoc subgroup analyses in the early studies

Decline of Humoral and Cellular Immune Responses Against SARS-CoV-2 6 Months After Full BNT162b2 Vaccination in Hospital Healthcare Workers

International audienceClinical trials and real-world evidence on COVID-19 vaccines have shown their effectiveness against severe disease and death but the durability of protection remains unknown. We analysed the humoral and T-cell immune responses in 110 healthcare workers (HCWs) vaccinated according to the manufacturer’s recommended schedule of dose 2 three weeks after dose 1 from a prospective on-going cohort in early 2021, 3 and 6 months after full vaccination with the BNT162b2 mRNA vaccine. Anti-RBD IgG titres were lower in HCWs over 60 years old 3 months after the second dose (p=0.03) and declined in all the subjects between 3 and 6 months with a median percentage change of -58.5%, irrespective of age and baseline comorbidities. Specific T-cell response measured by IGRA declined over time by at least 42% (median) in 91 HCWs and increased by 33% (median) in 17 others. Six HCWs had a negative T-cell response at 6 months. Ongoing follow-up should provide correlates of long-term protection according to the different immune response profiles observed. COVIDIM study was registered under the number NCT04896788 on clinicaltrials.gov

Comparative T and B immune responses of four different anti-COVID-19 vaccine strategies 6 months after vaccination

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