Farnesoid X receptor agonist for the treatment of chronic hepatitis B: a safety study

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-alpha 2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%-67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (-0.1 log(10) IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-alpha 2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Gene Expression Patterns in Peripheral Blood Correlate with the Extent of Coronary Artery Disease

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall

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Droit privé fondamenta

Organiser un parcours diversifié axé sur la citoyenneté : le jeu du collège

Professorat des lycées et collègesDispositif récent appliqué en classe de 5ème depuis 1997, le parcours diversifié est une nouvelle modalité d'enseignement favorisant l'acquisition de compétences transversales par une pédagogie du détour fondée sur les centres d'intérêt des élèves et par un travail interdisciplinaire. Nous proposons ce mémoire professionnel comme une base de réflexion à une meilleure application des parcours. Compte-rendu de notre expérience, il décrit l'organisation et la mise en place d'un parcours diversifié axé sur la citoyenneté à travers l'élaboration d'un jeu de société. L'interdisciplinarité y est présente par le biais de l'éducation civique, du français, des arts plastiques et de la technologie. Destiné à tous ceux qui souhaitent réfléchir aux questions relatives à la mise en place d'un parcours, ce mémoire restitue le cheminement effectué des textes officiels à leur mise en application

Testing the predictive capacity of a muscle fatigue model on electrically stimulated adductor pollicis

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Development of a force-endurance model able to describe the muscle fatigability in the severe domain and validation of the RACLET test

International audienceINTRODUCTION:Muscle fatigability corresponds to the decrease in the ability of muscles to generate force. The Critical Power (Pc) concept [1] predicts the point at which fatigue develops, in such a way that the required constant intensity will no longer be sustainable (W’ reserve is emptied). During all-out tests the power plateau reached at the end of the test and the work done above this value have been numerically and conceptually related to Pc and W’, respectively. These two mathematical models, characterizing similar phenomena but based on very different exercises (steady state versus all-out) have not been directly linked. Thus, the aims of this study were to i) develop an integrative model of exercise fatigability and ii) propose a submaximal test based on this model to determine critical intensity.METHODS:From Mortons 3-parameters model [2] one can make the assumption that fatigability is proportional to the impulse accumulation above the critical force (Fc) so Fmax(t)=(-1/Tau)integral(F(t)-Fc)dt+Fi. Since the model can be applied to any exercises, a specific Ramp Above CriticaL Exhaustion Test (RACLET) was proposed. The test was designed so that the target intensity starts above the critical intensity and decrease below it, before exhaustion of W’, so before exhaustion of the participant. It was tested for a cycling task with a 300s ramp test decreasing from 40% to 5% of initial force (Fi), where maximal capacities (Fmax) were assessed every 30s from 6-pedal-strokes sprints. Twenty participants realized 5 experimental sessions: 2 RACLET and 3 time to exhaustion (TTE). A custom friction regulated instrumented cyclo-ergometer was developed to measure crank torque and velocity. Each Fmax was used to adjust the model’s parameters. The model’s reliability and validity were tested by determination of individual parameters Fc & Tau by adjusting the model to Fmax and time data from RACLET and TTE tests.RESULTS:The model’s goodness of the fit on RACLET test experimental data was excellent (median adjusted R²=0.95; RMSE=3.4%Fi). Mean±SD Fc &Tau were 29.6±7.2%Fi and 22.7±13.9s, respectively. Fc parameter in RACLET demonstrated good relative (ICC=0.9) and absolute reliability (SEM=4.5%). The comparison of Fc between RACLET and reference TTE method was acceptable (R²=0.8, SEM=5.8%).CONCLUSION:The proposed model fit very well with the experimental data obtained during the RACLET. The latter showed very good test-retest reliability. Moreover, the fitted parameters were very similar to those obtained with the gold standard method TTE. The present results show that it is possible to determine individual model parameters (Fi, Fc, and Tau) from experimental data obtained from the proposed RACLET. As this test does not lead to the participants exhaustion, it could be interesting for athletes monitoring tranings, or patients with pathologies that make it difficult to use traditional methods (TTE and all-out tests).REFERENCES:[1] - Monod & Scherrer, Ergonomics 1965[2] - Morton et al, EJAP 199

A simple method for assessing running critical velocity without exhaustion: the Ramp Above Critical Level Endurance Test

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