Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Comportement de l'arc électrique et fusion de l'électrode consommable dans un four de refusion VAR

La présente étude vise à améliorer notre connaissance de l'arc électrique établi dans le procédé de refusion à l'arc sous vide VAR, ainsi qu'à caractériser la fusion de la cathode dans ce procédé. La première étape consistait à observer, à l'aide d'un module expérimental, le comportement de l'arc électrique pendant la refusion d'alliages de zirconium, pour différentes conditions opératoires. Les observations par vidéo rapide ont mis en évidence l'influence de la forme de la base de la cathode et l'effet de l'application d'un champ magnétique externe sur le déplacement des clusters de spots cathodiques. Par ailleurs, les mesures par thermographie infrarouge montrent qualitativement que la hauteur de l'électrode affectée thermiquement par l'arc est très faible et dépend de la vitesse de fusion. La deuxième partie de ce travail a pour objectif le développement d'un modèle numérique pour représenter le déplacement des clusters à la base de la cathode. L'association de cette démarche et de la simulation du comportement du jet de plasma émis par un cluster isolé, mise au point précédemment au LSG2M, permet de calculer le profil de puissance électrique fournie au lingot VAR en fonction des conditions opératoires (intensité du courant, géométrie de l'électrode, champ magnétique externe). Dans une troisième étape, un modèle du comportement thermique de l'électrode consommable en cours de fusion a été développé dans une géométrie 2D axisymétrique. A partir des paramètres opératoires, il permet de prédire notamment la vitesse de fusion et l'évolution de la forme de la base de la cathode. Ce modèle a été validé globalement grâce à la simulation de trois refusions consécutives d'un alliage de zirconium, selon une gamme industrielle de production.The present study is aimed to improve our knowledge of the electric arc in the Vacuum Arc Remelting VAR process, as weil as characterize the cathode melting stage. The first step consisted in investigating, thanks to an experimental modulus, the behaviour of the electric arc during the remelting of zirconium alloys, for various operating conditions. High speed video camera observations have put in evidence the influence of the cathode tip shape and the effect of applying an external magnetic field on the movement of the clusters of cathode spots. Besides, infrared thermography measurements show qualitatively that the electrode height thermally affected by the arc is very sm ail and depends on the melt rate. The goal of the second part of this work is the development of a numerical model to simulate the motion of clusters of spots at the tip of the cathode. Coupling this approach with the simulation of the behaviour of a plasma jet emitted by a single cluster, previously established in LSG2M, enables calculating the power distribution at the VAR ingot top as a function of process parameters (current, electrode geometry and external magnetic field). ln a third step, a thermal model of the consumable electrode during melting has been written, assuming a 2D axisymmetrical geometry. Using the operating parameters as model inputs, it predicts in particular the melting rate value and evolution of the cathode tip shape. The model was validated through simulating the three successive remeltings of a zirconium alloy, following an industrial processing route.NANCY/VANDOEUVRE-INPL (545472102) / SudocSudocFranceF

Modélisation de la trempe gazeuse haute pression (application aux aciers de cémentation et de trempe)

L utilisation de fluides non vaporisables tels que les gaz pour tremper différentes pièces d acier rend possible, avec les outils numériques actuels, la simulation de l ensemble des phénomènes physiques mis en jeu dans ce traitement thermique et ainsi de prédire les comportements thermique, métallurgique et mécanique des pièces. Plusieurs auteurs s intéressent à la construction de ce type de modèles dont les enjeux sont de promouvoir l utilisation de la trempe gazeuse haute pression, en cherchant à remplacer les trempes à l huile plus polluantes et/ou à maîtriser les déformations pendant ou après la trempe. Lors de notre travail, un modèle décrivant ces phénomènes physiques, de l écoulement gazeux aux déformations, et leurs couplages a été construit par étapes en couplant les deux codes de calcul commerciaux Fluent et Sysweld. Les résultats de simulations ont ensuite été confrontés à des mesures de vitesses d écoulements de gaz (par PIV), de températures et de déformations in situ (détection de contours). Malgré quelques écarts dont les origines ont été analysées, la comparaison a révélé une très bonne concordance des résultats de calculs et expérimentaux, validant ainsi la démarche de calcul. Le modèle pourrait maintenant être testé pour des refroidissements plus rapides que ceux considérés mais son utilisation pour des applications industrielles (pièces de géométrie plus complexe, refroidissement de charges entières, ) peut d ores et déjà être envisagée avec confianceThe use of non vaporizable fluids such as gas to quench steel bodies makes the simulation of all the coupled physical phenomena involved in this heat treatment possible thanks to current numerical simulation tools. It gives access to the prediction of thermal, metallurgical and mechanical behaviour of steel pieces during quenching operation. Several authors have tried and build such kind of models in order to promote gas quenching use either by trying to replace less environmental friendly oil treatments or by trying to control distortions during or after quenching. In our work a model describing the physical coupled phenomena, from gas flow to distortion has been built step by step by coupling both commercial numerical codes Fluent and Sysweld. Simulation results have then been compared to gas flow velocities measurements (by PIV), temperature measurements and in situ distortions measurements (contour s detection method). This confrontation revealed a very good agreement between calculated and experimental data despite some slight differences, which have been analysed in detail. This validated the calculation method used in the model. One of the perspectives of this work could be the validation of the model for higher quenching rate. However, some industrial applications (tridimensional more complex bodies quenching simulation, quenching of full loads, ) can be run from now on with confidenceNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Numerical Modeling of Inclusion Behavior in Liquid Metal Processing

International audienceThermomechanical performance of metallic alloys is directly related to the metal cleanliness that has always been a challenge for metallurgists. During liquid metal processing, particles can grow or decrease in size either by mass transfer with the liquid phase or by agglomeration/fragmentation mechanisms. As a function of numerical density of inclusions and of the hydrodynamics of the reactor, different numerical modeling approaches are proposed; in the case of an isolated particle, the Lagrangian technique coupled with a dissolution model is applied, whereas in the opposite case of large inclusion phase concentration, the population balance equation must be solved. Three examples of numerical modeling studies achieved at Institut Jean Lamour are discussed. They illustrate the application of the Lagrangian technique (for isolated exogenous inclusion in titanium bath) and the Eulerian technique without or with the aggregation process: for precipitation and growing of inclusions at the solidification front of a Maraging steel, and for endogenous inclusions in the molten steel bath of a gas-stirred ladle, respectively

Modélisation de la purification de l'aluminium liquide par procédé de flottation en cuve agitée

L élimination des inclusions indésirables par flottation en cuve agitée est un procédé largement utilisé dans l industrie de l aluminium. Ce procédé consiste en l injection de gaz au sein de la cuve par le biais d un rotor ; les bulles ainsi formées captent, lors de leur ascension dans le métal liquide, les inclusions et les drainent en surface où elles sont éliminées mécaniquement.Dans le but de prédire l évolution numérale de la population d inclusions dans la cuve de flottation au cours du temps, un modèle 2D a été développé. Afin de rendre compte du transport convectif des inclusions au sein de l écoulement diphasique métal liquide bulles, des phénomènes de décantation, d agglomération et de flottation, ce modèle couple la Mécanique des Fluides Numérique et la technique des Bilans de Population. Une attention particulière a été portée aux modèles d agglomération et de flottation pour qu ils soient applicables sur une grande plage de conditions de turbulence.Les simulations numériques réalisées, nous ont notamment permis de mettre en évidence l importance de veiller à une bonne répartition des bulles dans la cuve, en particulier dans les zones de forte turbulence. En parallèle de ce travail de modélisation, une analyse de la littérature et des travaux expérimentaux sur métal liquide ont été réalisés, afin de mieux comprendre le rôle du chlore dans le procédé de flottation. Un effet de seuil a ainsi pu être mis en évidence : une certaine quantité de chlore injectée dans le métal est nécessaire pour que la flottation devienne efficace. La compréhension du rôle du chlore reste cependant partielle, mais des pistes de recherche prometteuses ont put être identifiéesInclusions removal by flotation in mechanically agitated vessels is widely used in liquid aluminium treatments. This process consists of gas injection in a molten aluminium reactor using an impeller. Inclusions are attached to the bubbles while rising into the liquid bulk and released in the froth at the vessel surface.With the aim of both a better understanding of the physical processes acting during flotation and the optimization of the refining process, a 2D mathematical modelling of the flotation tank was set up. Transport phenomena, sedimentation, agglomeration and flotation of inclusions were considered here. The model couples Population Balance with convective transport of the inclusions, in the multiphase flow field. Simulations showed that a good dispersion of the bubbles into the tank, especially in the high turbulence zones, is essential for an efficient process. This situation was achieved with a strong agitation. Gas flow affected the process efficiency weakly.Theoretical and experimental studies on chlorine effects were done. It was noticed that a critical amount of chlorine into the melt is required for the flotation to be efficient. Complete understanding of chlorine role is not achieved yet, but promising ideas for future research have been exhibitedNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Le palais des comtes de Champagne à Provins (XIIe-XIIIe siècles)

Mesqui Jean, Bellot Marcel, Garrigou Grandchamp Pierre. Le palais des comtes de Champagne à Provins (XIIe-XIIIe siècles). In: Bulletin Monumental, tome 151, n°2, année 1993. pp. 321-355

Aggregation kernel of globular inclusions in local shear flow: application to aggregation in a gas-stirred ladle

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Usage de la refusion par bombardement électronique pour la purification et le recyclage des alliages Application of the electron beam remelting for the purification and the recycling of alloys

Parmi les techniques de purification ultime de métaux à hauts points de fusion, le procédé de refusion par bombardement électronique associe une puissance thermique garantissant la fusion du métal, et une refusion sous vide permettant l'élimination d'impuretés par distillation. Ce papier présente la technique et le potentiel d'élimination par distillation. <br> Among the ultimate purification techniques applied to the high melting point metallic materials, the electron beam remelting process, combining a high thermal power and vacuum, is particularly conducive to volatilization. This paper describes the technique and its efficiency to remove impurities by distillation

Local behavior of inclusions in reactors metallurgical: Aggregation and deposition on the walls

Populations of inclusions conditioned very early in the alloy production process metals, during the refining and liquid metal treatment stages, are likely to drastically impact mechanical performance, especially fatigue resistance. Control performance of these materials therefore requires control of the inclusion populations, requiring in particular a very good knowledge of the mechanisms which govern their evolution in number and size in refining reactors. Inclusive behaviors in supply chains steel and aluminum have already been the subject of numerical studies at the process scale (Bellot et al., 2014 ; Waz et al., 2016) in which the transport and agglomeration of inclusions are modelled. In order to improve the modelling of key phenomena such as the aggregation and capture of wall inclusions, local simulations, at the scale of an inclusion pair and a layer limit to the wall of a reactor, are carried out here using a lattice Boltzmann method (Sungkorn and Derksen, 2012)

Industrial applications of modelling tools to simulate the PAMCHR casting and VAR process for Ti64

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