Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Aims  To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results  In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). Conclusions  Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable

Vocational Values Scale: Development and testing of the Student form (VVS−S)

International audienceZiel dieses Manuskripts war die Entwicklung eines Instruments zur Erfassung von beruflichen Werten von Studierenden (VVS-S). Die Skala wurde in französischer Sprache entwickelt, wobei drei verschiedene Stichproben togoischer Teilnehmenden für die Itementwicklung ( N = 140), exploratorische ( N = 308) und konfirmatorische Analysen ( N = 300) verwendet wurden. Sie besteht aus 17 Items, die in die fünf Subskalen Macht, Familie, Helfen, Gehalt und Kreativität unterteilt sind. Die Korrelations-, Higher-Order- und Bifaktormodelle zeigten, dass diese Werte unabhängig voneinander betrachtet werden können. Außerdem korrelierten vier der Werte positiv, aber schwach mit der Lebenszufriedenheit. Die Nützlichkeit des VVS-S für Forschung und Praxis in der Beratung, insbesondere in Afrika südlich der Sahara, wird diskutiert.This manuscript aimed to develop an instrument assessing vocational values among students (VVS–S). The scale was developed in French using three different samples of Togolese participants for item development ( N = 140), exploratory ( N = 308) and confirmatory analyses ( N = 300). It consists of 17 items divided into the five subscales of Power, Family, Helping, Salary, and Creativity. The correlational, higher-order, and bifactor models showed that these values could be considered independently. Moreover, four of the values correlated positively but weakly with life satisfaction. The VVS–S’s usefulness for research and practice in counseling, particularly in sub-Saharan Africa, is discussed.Este manuscrito tuvo como objetivo desarrollar un instrumento de evaluación de los valores vocacionales entre los estudiantes (VVS–S). La escala se desarrolló en francés utilizando tres muestras diferentes de participantes togoleses para el desarrollo de ítems (N = 140), exploratorio (N = 308) y análisis confirmatorios (N = 300). Consta de 17 ítems divididos en las cinco subescalas de Poder, Familia, Ayuda, Salario y Creatividad. Los modelos correlacionales, de orden superior y bifactores mostraron que estos valores podían considerarse de forma independiente. Además, cuatro de los valores se correlacionaron positivamente pero débilmente con la satisfacción con la vida. Se discute la utilidad del VVS–S para la investigación y la práctica en asesoramiento, particularmente en el África subsahariana.Ce manuscrit visait à développer un instrument d'évaluation des valeurs professionnelles chez les étudiant•e•s (VVS-S). L'échelle a été développée en français à partir de trois échantillons différents de participant•e•s togolais•es pour l'élaboration des items (N = 140), les analyses exploratoires (N = 308) et confirmatoires (N = 300). Elle est composée de 17 items répartis en cinq sous-échelles: Pouvoir, Famille, Aide, Salaire et Créativité. Les modèles corrélationnels, d'ordre supérieur et bifactoriels ont montré que ces valeurs pouvaient être considérées indépendamment. De plus, quatre des valeurs sont corrélées positivement mais faiblement avec la satisfaction de vie. L'utilité du VVS-S pour la recherche et la pratique du conseil, en particulier en Afrique sub-saharienne, est discutée

Employability : Review and research prospects

Professional transition, employment, and reemployment are major concerns for nations facing adverse economic situations. The employability construct represents a scientific challenge in order to better understand the relationship between the job seekersâeuro? issues and the expectations of the world of work. This paper presents a review of the concept of employability. Three main perspectives (educational and governmental, organizational, and individual) that are not exclusive can be identified. This review highlights the importance of adopting a systemic integrative approach and a wider interpretation of employability. A research agenda to develop the theory and applications of the concept of employability is proposed

Elastoplastic behavior of jointed rock masses as homogenized media and finite element analysis

International audienceA comprehensive 3D formulation for the strength properties and elastoplastic constitutive equations of jointed rock masses are derived in this paper. The approach is based on the implementation of the homogenization method of randomly heterogeneous media within the frame works of limit analysis and elastoplasticity. A rigorous closed-form expression of the macroscopic strength criterion is first given as a function of the failure conditions of the rock matrix and of the joints. As an example of implementation of such a homogenized criterion, the stability analysis of an underground gallery in a jointed rockmasses is presented and the scale effects, which prevail if the number of joints is relatively low, are investigated through comparisons with the results derived from direct calculations. Assuming elastoplastic constitutive laws for the rock matrix and the joints, a micromechanical reasoning is used for the formulation of the overall behavior. The macroscopic elastic stiffness as well as the plastic criterion and the plastic flow rule are derived from the knowledge of the mechanical properties of the individual constituents. This anisotropic model is then implemented in a F.E computer code. Due to the multi-potential character of the macroscopic plastic flow rule, the numerical analysis is particularly focused on the iterative algorithm of plastic integration. Examples of numerical simulations dealing with jointed rock structures are finally given

Etat d'avancement du procédé d'enrichissement de l'uranium par échange chimique

Voici cinq ans, le Commissariat à l'Energie Atomique français révélait, au cours de la Conférence de Salzbourg organisée par l'AlEA, l'existence d'un nouveau procédé d'enrichissement isotopique de l'uranium par échange chimique. Ce procédé possédait un coefficient d'enrichissement élevé, sa consommation d'énergie était faible et sa mise en œuvre ne faisait appel qu'aux techniques conventionnelles de l'industrie chimique. D'autres précisions furent apportées par la suite : il s'agit d'un échange réalisé au moyen de deux phases liquides, l'une aqueuse, l'autre organique, amenées à interagir dans des colonnes puisées de grande taille. Ces colonnes sont disposées en série de manière à constituer des cascades d'enrichissement interconnectées selon un schéma original qui permet de concevoir des assemblages industriels modulaires et ajustables en fonction des besoins du marché. Les progrès réalisés depuis l'annonce de Salzbourg sont remarquables. Pour ne citer qu'un chiffre, la puissance de séparation délivrée annuellement par mètre cube de phases a été triplée. Ainsi, la valeur absolue du coût de l'Unité de Travail de Séparation a été notablement diminuée et l'intérêt économique du procédé est désormais amplement confirmé, tout particulièrement dans le cas des usines de petite capacité. Les auteurs présentent les caractéristiques de ce procédé qui, tout en restant impropre à la prolifération, est l'un des plus séduisants parmi ceux qui ont été développés à ce jour

Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter.

International audienceMultidrug resistance of cancer (MDR) is the major cause of failure of chemotherapy. The typical MDR phenotype is due to the overexpression of membrane proteins among which the main representative is P-glycoprotein (Pgp) encoded by the MDR1 gene. Many attempts to modulate MDR by chemosensitizers have been unsuccessful in human therapy due to their intrinsic toxic effects. In an effort to modulate the MDR phenotype efficiently we designed an antisense and a transcriptional decoy strategy targeting the TATA-less human MDR1 gene promoter. The choice of the start point of transcription in a multiple start site window is related to an upstream MED-1 cis-element, the sequence and configuration of which are specific to human MDR1 gene expressed in Pgp-overproducing cancer cells. A 12mer antisense oligodeoxynucleotide (ODN) and a 12mer double-stranded ODN, both containing the MED-1 sequence, were designed and efficiently vectorized into the nucleus with the chimerical MPG peptide. A synthetic cellular model (NIH-EGFP) and highly resistant human CEM/VLB0.45 leukemia cells, significantly responded to transfection with the ODN/MPG complex. The level of EGFP fluorescence in NIH-EGFP cells decreased, and thus its production, and viability of CEM/VLB0.45 cells decreased by 63% in the presence of vinblastine, revealing that their resistance to the anticancer drug was reversed. These results open new insights into transcriptional decoy and anti-gene therapies of MDR cancers that overproduce Pgp. Gene Therapy (2000) 7, 1224-1233.Multidrug resistance of cancer (MDR) is the major cause of failure of chemotherapy. The typical MDR phenotype is due to the overexpression of membrane proteins among which the main representative is P-glycoprotein (Pgp) encoded by the MDR1 gene. Many attempts to modulate MDR by chemosensitizers have been unsuccessful in human therapy due to their intrinsic toxic effects. In an effort to modulate the MDR phenotype efficiently we designed an antisense and a transcriptional decoy strategy targeting the TATA-less human MDR1 gene promoter. The choice of the start point of transcription in a multiple start site window is related to an upstream MED-1 cis-element, the sequence and configuration of which are specific to human MDR1 gene expressed in Pgp-overproducing cancer cells. A 12mer antisense oligodeoxynucleotide (ODN) and a 12mer double-stranded ODN, both containing the MED-1 sequence, were designed and efficiently vectorized into the nucleus with the chimerical MPG peptide. A synthetic cellular model (NIH-EGFP) and highly resistant human CEM/VLB0.45 leukemia cells, significantly responded to transfection with the ODN/MPG complex. The level of EGFP fluorescence in NIH-EGFP cells decreased, and thus its production, and viability of CEM/VLB0.45 cells decreased by 63% in the presence of vinblastine, revealing that their resistance to the anticancer drug was reversed. These results open new insights into transcriptional decoy and anti-gene therapies of MDR cancers that overproduce Pgp. Gene Therapy (2000) 7, 1224-1233