Modèle de planification tactique de chaîne d'approvisionnement soumise à des régulations environnementales

La problématique environnementale étant mise en avant lors des dernières décennies, la gestion de la chaîne d’approvisionnement devient de plus en plus complexe. Les grandes chaînes logistiques étant des acteurs majeurs du réchauffement climatique et des dommages causés à notre environnement, les entreprises concernées se retrouvent au centre de la polémique et de plus en plus elles doivent rendre des comptes au gouvernement ainsi qu’à leurs consommateurs. On utilise communément le terme de chaîne logistique durable lorsque les traditionnelles considérations économiques sont élargies aux dimensions environnementales et sociales, représentant ainsi un équilibre permettant à une activité industrielle de perdurer dans le temps sans causer de dommage à son entourage. C’est dans cette logique que s’inscrit ce travail de recherche, visant en particulier deux règlementations environnementales d’actualité pour les entreprises Québécoises : les limitations relatives aux émissions de gaz à effet de serre et le principe de compensation aux services de collecte. Dans ce travail nous avons mis en place un modèle d’optimisation linéaire permettant d’analyser les décisions tactiques d’approvisionnement en composants éco-conçus versus standards chez différents fournisseurs. Aussi la formulation mathématique utilisée permet d’évaluer le plan optimal de production aux usines manufacturières au moyen de deux technologies distinctes : standard versus propre. Le raisonnement appliqué suit trois étapes principales : tout d’abord une résolution préliminaire permet d’établir le plan optimal d’approvisionnement et de production dans le cas où l’entreprise étudiée n’est pas encore assujettie aux lois environnementales. Par la suite les simulations réalisées permettent de tester ce plan optimal lorsqu’il est soumis tout d’abord à une seule puis aux deux législations mentionnées plus haut simultanément. Si dans un premier temps nous privilégions les données réelles en vigueur actuellement dans la province du Québec, la suite de notre étude admet l’hypothèse que ces récentes règlementations vont être renforcées dans les prochaines années. Ainsi nous analysons les éventuelles conséquences d’un durcissement des législations sur le plan tactique optimal d’approvisionnement et de production de notre chaîne logistique

Multicentric randomized evaluation of a tricuspid valve percutaneous repair system (clip for the tricuspid valve) in the treatment of severe secondary tricuspid regurgitation Tri.Fr Design paper

International audienceAIMS: Tricuspid regurgitation (TR) is associated with significant morbidity and mortality. Its independent prognostic role has been repeatedly demonstrated. However, this valvular heart condition is largely undertreated because of the increased risk of surgical repair. Recently, transcatheter techniques for the treatment of TR have emerged, but their implications for the clinical endpoints are still unknown. METHODS AND RESULTS: The Tri.fr trial will be a multicentre, controlled, randomized (1:1 ratio), superior, open-label, and parallel-group study conducted in 300 patients with severe secondary TR that is considered non-surgical by heart teams. Inclusion will be possible only after core laboratory review of transthoracic and transoesophageal echocardiography and after validation by the clinical eligibility committee. A description of the mechanisms of the TR will be conducted by the core laboratory. Atrial or ventricular impacts on the severity of the secondary TR will be taken into account for the randomization. The patients will be followed for 12-month, and the primary outcome will be the Packer composite clinical endpoint [combining New York Heart Association class, patient global assessment (PGA), and major cardiovascular events]. It will test the hypothesis that a tricuspid valve percutaneous repair strategy using a clip dedicated to the tricuspid valve is superior to best guideline-directed medical therapy in symptomatic patients with severe secondary TR. CONCLUSION: Tri.fr will be the first randomized, academic, multicentre study testing the value of percutaneous correction in patients with severe secondary TR

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

International audiencePurpose Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. Results We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. Conclusion In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome

Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

International audienceThe transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

International audienceBackground - An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods - We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results - We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions - In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical trial registration - URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185