Messianicité structurelle et temps messianique

Dans le cadre de la réflexion sur l’héritage philosophique des messianismes, Jacques Derrida pense la « messianicité » comme structure universelle et quasi a priori de l’expérience, tandis que Gérard Bensussan, en croisant l’œuvre derridienne, appelle « temps messianique » l’événement interruptif qui met en cause le devenir historique. Tous deux accordent un rôle majeur à la tradition juive, au-delà de toute appartenance religieuse et au-delà d’une simple sécularisation, encore qu’avec bien des différences. La lecture de cette question chez les deux philosophes entend reconstruire le dialogue entre leurs positions respectives. Elle montre en fin de compte que la réflexion de Derrida s’achève sur une indécision apparente au sujet du rapport entre messianicité et messianismes, tandis que Bensussan signale cette aporie et indique la nécessité de situer le temps messianique au-delà dans la tradition du messianisme juif.Within the reflection on the philosophical heritage of messianisms, Jacques Derrida thinks “messianicity” as a universal and quasi a priori structure of the experience, while Gérard Bensussan, crossing Derrida’s work, calls “messianic time” the event as interruption of history. Both grant a major role to the Jewish tradition, beyond every religious confession and beyond a simple secularization, but some differences remain between their positions. The reading of this question along the work of the two philosophers aims to analyze these differences. It shows that Derrida’s reflection ends on an apparent indecision about the relation between messianicity and messianisms, while Bensussan points out this aporia and shows the necessity to put the messianic time at the same time beyond and inside the Jewish messianism’s tradition

The evaluation of the Youth Employment Initiative in Portugal using Counterfactual Impact Evaluation methods

The Youth Employment Initiative (YEI) in Portugal is the framework for a set of specific actions to take place in regions experiencing youth unemployment rates above 25%, and which aim to help young individuals who are not in education, employment, or training. This report evaluates the YEI implementation in Portugal, using counterfactual impact evaluation (CIE) methods to estimate its causal impact on young individuals’ labour market outcomes. The analysis was carried out using Portuguese administrative data from the Public Employment Service, and Social Security registers. Findings showed that when young individuals participated in internships or hiring support schemes funded by the European Social Fund (ESF), there was a positive and long-lasting effect on the individuals’ labour market outcomes. This effect varied in magnitude according to the type of intervention, and across specific population groups.JRC.I.1-Monitoring, Indicators & Impact Evaluatio

Evaluating the impact of changing inhaler color on perception of symptoms and disease burden in patients with asthma: the FEEL study

Objectives: Patient perception of treatment effectiveness is key to optimizing adherence. This is potentially impacted by color, yet no such studies have been conducted in asthma. This study assessed the influence of pink vs. white pressurized metered-dose inhaler (pMDI) actuators on asthma symptoms perception. Methods: In this double-blind, randomized, multicenter, crossover study, adults with moderate-to-severe asthma received extrafine formulation beclomethasone dipropionate/formoterol furoate (BDP/FF) pMDI for a 2-week run-in. During two, 2-week treatment periods they received BDP/FF pMDI, white in one, pink in the other, using an 'authorized deception' approach (patients were told the inhalers contained the same active ingredients, but device characteristics differed). Endpoints included patient-reported asthma symptoms and psychopharmacological aspects (prior to use: did patients expect an improvement; after use: did they think there had been an improvement; both on 100-point visual analog scales [VAS]). Results: Of 74 patients analyzed, 72 completed the study. There were no statistically significant differences between inhalers for asthma symptoms, with minimal changes from baseline. Patients were numerically more likely to expect symptoms improvement with the white than pink inhaler (mean VAS 64.5 vs. 60.8). Perceived improvements were lower than expected with both, numerically favoring the pink inhaler (mean VAS 41.1 vs. 44.6); 46.6% believed a change had been made, 51.9% of whom believed this impacted symptoms. Conclusions: Changing inhaler color had no impact on asthma symptoms, but did have a numerical impact on patients' expectations of subsequent treatment effect. This emphasizes the importance of communication between patients and healthcare practitioners when changing inhalers

Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis:Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)

Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequelae leading to intellectual disability, ataxia, impaired hearing and speech, recurrent infections, skeletal abnormalities, muscular pain, and weakness. This study aimed to investigate disability, pain, and overall health using the Childhood Health Assessment Questionnaire (CHAQ) and the EuroQol 5 Dimension-5 Level Questionnaire (EQ-5D-5L) in patients with alpha-mannosidosis participating in rhLAMAN-10, a phase III open-label, clinical trial of velmanase alfa, a recombinant human lysosomal alpha-mannosidase. Long-term prognoses for most patients with untreated alpha-mannosidosis are poor due to progressive neuromuscular, skeletal, and intellectual deterioration, leading to increased dependence in mobility and activities of daily living and increased caregiver and health-care burden. Long-term CHAQ and EQ-5D-5L data highlight improvement trends in health-related quality of life and a reduction in disability and pain in patients receiving up to 48 months of velmanase alfa treatment.</p

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase) : novel global treatment response model and outcomes in patients with alpha-mannosidosis

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n=15) compared with 30% of patients receiving placebo (n=10). Longer-term data from all patients in the clinical program (n=33) showed 88% of patients were global responders, including all (100%) pediatric patients (n=19) and the majority (71%) of adult patients (n=14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.Phase I/II studies rhLAMAN-02, -03, and -04 and phase III study rhLAMAN-05 were conducted under and co-funded by the EU FP7 project ALPHA-MAN [FP7-HEALTH-2010-261331]. Long-term continuation studies rhLAMAN-07 and -09 were initially sponsored by Zymenex A/S and are currently sponsored by Chiesi Farmaceutici S.p.A. Zymenex sponsored rhLAMAN-10. Chiesi Farmaceutici S.p.A. funded third-party writing assistance for the current manuscript, provided by PAREXEL.https://www.elsevier.com/locate/ymgmeam2019Paediatrics and Child Healt

The Competence Centre on Microeconomic Evaluation (CC-ME) Yearbook 2020

This brochure reports highlights of activities in 2020 of the European Commission's Competence Centre on Microeconomic Evaluation (CC-ME). CC-ME was founded on May 19, 2016 to support the evaluation function in the European Commission. CC-ME is part of Unit JRC.I.1 'Monitoring, Indicators & Impact Evaluation'. CC-ME builds on the experience of the Centre for Research on Impact Evaluation (CRIE), which started as a joint project of the Joint Research Centre (JRC) and the European Commission Directorate-General Employment, Social affairs and Inclusion (DG EMPL) in 2013; CRIE is now an integral part of CC-ME.JRC.S.3 - Science for Modelling, Monitoring and Evaluatio

The Competence Centre on Microeconomic Evaluation (CC-ME) — Yearbook 2021

This brochure reports highlights of activities in 2021 of the European Commission's Competence Centre on Microeconomic Evaluation (CC-ME). CC-ME was founded on May 19, 2016 to support the evaluation function in the European Commission. CC-ME is part of Unit JRC.I.1 'Monitoring, Indicators & Impact Evaluation'. CC-ME builds on the experience of the Centre for Research on Impact Evaluation (CRIE), which started as a joint project of the Joint Research Centre (JRC) and the European Commission Directorate-General Employment, Social affairs and Inclusion (DG EMPL) in 2013; CRIE is now an integral part of CC-ME.JRC.I.1 - Monitoring, Indicators & Impact Evaluatio

The Competence Centre on Microeconomic Evaluation – 2022 Yearbook

This brochure reports highlights of activities in 2022 of the European Commission's Competence Centre on Microeconomic Evaluation (CC-ME). CC-ME was founded on May 19, 2016 to support the evaluation function in the European Commission. CC-ME is part of Unit JRC.I.1 'Monitoring, Indicators & Impact Evaluation' (as of 1 January 2023, the Unit became part of S.3 'Science for Modelling, Monitoring and Evaluation'). CC-ME builds on the experience of the Centre for Research on Impact Evaluation (CRIE), which started as a joint project of the Joint Research Centre (JRC) and the European Commission Directorate-General Employment, Social affairs and Inclusion (DG EMPL) in 2013; CRIE is now an integral part of CC-ME.JRC.S.3 - Science for Modelling, Monitoring and Evaluatio

NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL