Extension of the SAEM algorithm for nonlinear mixed models with two levels of random effects

This article focuses on parameter estimation of multi-levels nonlinear mixed effects models (MNLMEMs). These models are used to analyze data presenting multiple hierarchical levels of grouping (cluster data, clinical trials with several observation periods,...). The variability of the individual parameters of the regression function is thus decomposed as a between-sub ject variability and higher levels of variability (for example within-sub ject variability). We propose maximum likelihood estimates of parameters of those MNLMEMs with two levels of random effects, using an extension of the SAEM-MCMC algorithm. The extended SAEM algorithm is split into an explicit direct EM algorithm and a stochastic EM part. Compared to the original algorithm, additional sufficient statistics have to be approximated by relying on the conditional distribution of the second level of random effects. This estimation method is evaluated on pharmacokinetic cross-over simulated trials, mimicking theophyllin concentration data. Results obtained on those datasets with either the SAEM algorithm or the FOCE algorithm (implemented in the nlme function of R software) are compared: biases and RMSEs of almost all the SAEM estimates are smaller than the FOCE ones. Finally, we apply the extended SAEM algorithm to analyze the pharmacokinetic interaction of tenofovir on atazanavir, a novel protease inhibitor, from the ANRS 107-Puzzle 2 study. A significant decrease of the area under the curve of atazanavir is found in patients receiving both treatments

Introduction to skin aging

YesCutaneous science has seen considerable development in the last 25 years, in part due to the -Omics revolution, and the appreciation that this organ is hardwired into the body’s key neuroimmuno- endocrine axes. Moreover, there is greater appreciation of how stratification of skin disorders will permit more targeted and more effective treatments. Against this has been how the remarkable extension in the average human life-span, though in the West at least, this parallels worrying increases in lifestyle-associated conditions like diabetes, skin cancer etc. These demographic trends bring greater urgency to finding clinical solutions for numerous age-related deficits in skin function caused by extrinsic and intrinsic factors. Mechanisms for aging skin include the actions of reactive oxygen species (ROS), mtDNA mutations, and telomere shortening, as well as hormonal changes. We have also significantly improved our understanding of how to harness the skin’s considerable regenerative capacity e.g., via its remarkable investment of stem cell subpopulations. In this way we hope to develop new strategies to selectively target the skin’s capacity to undergo optimal wound repair and regeneration. Here, the unsung hero of the skin regenerative power may be the humble hair follicle, replete with its compliment of epithelial, mesenchymal, neural and other stem cells. This review introduces the topic of human skin aging, with a focus on how maintenance of function in this complex multi-cell type organ is key for retaining quality of life into old age

A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10−8 to 3 × 10−119), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair

Reprensatations and warranties provisions in international arbitration

L’arbitrage est devenu la règle dans les opérations du commerce international. Si les cessions de droits sociaux n’échappent pas à ce phénomène, il subsistait encore en droit français quelques complications qui ont été écartées au fil des réformes et de l’évolution de la jurisprudence sur les deux dernières décennies. Par ailleurs, la pratique a poursuivi son évolution, que ce soit du point de vue de l’arbitrage international ou de l’harmonisation qui s’opère entre les pratiques propres aux opérations de cessions de droits sociaux. Or, les garanties de passif concentrent une majeure partie des litiges post-acquisition, et révèlent de nombreuses particularités techniques. L’évolution favorable à la rencontre entre arbitrage international et garantie de passif en fait donc un sujet d’étude pertinent, aussi bien au regard de son utilité pratique, que des enseignements à tirer sur l’évolution des solutions de droit français. Cette thèse vise ainsi à étudier les particularités de cette rencontre, notamment compte tenu des spécificités techniques, parfois propres au droit français, qui s’attachent aux garanties de passif, et du contexte unique de l’arbitrage international. Les conclusions tirées s’attachent à la pratique du droit français d’abord, en dégageant la pertinence du choix de l’arbitrage pour les contrats de garantie de passif tout en prévoyant les conséquences et éventuels écueils d’une telle rencontre. Elles permettent également d’apporter des éléments aux sujets propres à l’arbitrage international.International arbitration became the natural choice when it comes to select a dispute resolution method in international comercial operations. Even if M&A operations followed this trend, some legal complications remained in French law, that have been gradually solved over the past twenty years. Yet, most of the post-closing disputes regard the execution of the so called ‘representations and warranties’ dispositions. These provision show some crucial specificities that parties must take into account when they negotiate an arbitration clause. Given the fast evolution of international arbitration and the practice of the M&A sector, these specificities can change rapidly in comparative law. The current trend in favor of arbitration for representations and warranties disputes make it a judicious research subject, being it from a practical point of view, as well as the insights given for the evolution of the solutions in French law. Thus, this work explores the opportunity of arbitration for international M&A operations, as well as the specific challenges brought by post-closing disputes for the international arbitration practice, with or without the application of French law. The results regard mainly French law practice, studying the opportunity of arbitration for representations and warranties, as well as the technical consequences and pitfalls. They also bring new elements to issues that regard international arbitration

Joseph de Longueil, sa vie, son oeuvre /

Cover and spine title: Joseph de Longueil, graveur du roi, 1730-1792, sa vie, son oeuvre.One of 200 copies.Includes index.Mode of access: Internet

Soins palliatifs chez les patients présentant un trouble psychiatrique sévère et persistant

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF