Nonlinear Mixed-Effect Models for Prostate-Specific Antigen Kinetics and Link with Survival in the Context of Metastatic Prostate Cancer: a Comparison by Simulation of Two-Stage and Joint Approaches

In metastatic castration-resistant prostate cancer (mCRPC) clinical trials, the assessment of treatment efficacy essentially relies on the time-to-death and the kinetics of prostate-specific antigen (PSA). Joint modelling has been increasingly used to characterize the relationship between a time-to-event and a biomarker kinetics but numerical difficulties often limit this approach to linear models. Here we evaluated by simulation the capability of a new feature of the Stochastic Approximation Expectation-Maximization algorithm in Monolix to estimate the parameters of a joint model where PSA kinetics was defined by a mechanistic nonlinear mixed-effect model. The design of the study and the parameter values were inspired from one arm of a clinical trial. Increasingly high levels of association between PSA and survival were considered and results were compared with those found using two simplified alternatives to joint model, a two-stage and a joint sequential model. We found that joint model allowed for a precise estimation of all longitudinal and survival parameters. In particular the effect of PSA kinetics on survival could be precisely estimated, regardless of the strength of the association. In contrast, both simplified approaches led to bias on longitudinal parameters and two-stage model systematically underestimated the effect of PSA kinetics on survival. In summary we showed that joint model can be used to characterize the relationship between a nonlinear kinetics and survival. This opens the way for the use of more complex and physiological models to improve treatment evaluation and prediction in oncology.Comment: The AAPS Journal, 2015, pp.1550-741

Home education in Quebec : family first

In Canada, until now, no studies have focused on the practice of home education in the francophone province of Quebec. While the home-educating population in that province is tangible, it has remained largely unknown. Quebec’s distinctive character on three fronts political, historical and cultural make the application of results from the rare Canadian studies or data from the US home-educating population seem inappropriate. This research, conducted by questionnaire in 2003, documented the sociodemographic characteristics of Quebec’s home-educating families and their motivations for home education. Beginning with a portrait of Quebec’s particular context, this article presents the motivations underlying the choice of home education expressed by 203 Quebec families. The reasons why these families have chosen to homeschool are many and diverse; parents’ rationales for their choices are wide-ranging and multidimensional. One particularity of the results is that no religious, philosophical or anti-state viewpoint seems to dominate the combined discourse. Seven motivational factors for home education were identified. Collectively, the respondents express the following as their main motivations for home educating their children: a desire to pursue a family educational project; an objection to the organisational structure of the school system; a desire to offer curriculum enrichment; and finally, a preoccupation with their children’s socioaffective development

The metrological approach: a major key factor for the accreditation and continuous improvement of the wood preservation laboratory of Cirad

Depuis 2006, le laboratoire de préservation des bois du Cirad est accrédité par le COFRAC (Comité français d'accréditation - accréditation n°1-1686) pour ses essais sur la durabilité des bois et produits dérivés du bois et sur l'efficacité protectrice des produits de préservation et des produits anti-termites. La mise en place de la fonction métrologie au laboratoire de préservation du bois est un facteur clé de l'amélioration continue des pratiques. De tous les essais de caractérisation des bois, les essais de résistance aux agents biologiques de détérioration sont les plus délicats. Ils visent en effet à évaluer et à quantifier l'impact d'organismes vivants, comme les champignons et les termites, sur une matière lignocellulosique. On apprécie facilement l'importance de la variabilité de cet impact lié lui-même à la diversité de ces organismes. La validité et la fiabilité des résultats dépendront ainsi directement de la qualité du processus métrologique mis en oeuvre, comprenant le choix des appareils de mesure, leur gestion et leur mise en conformité avec les normes internationales. Mots clés: Métrologie, accréditation, traçabilité, incertitude, essais biologiques. (Résumé d'auteur

A carbon and nitrogen isotopic analysis of Pleistocene food webs in North America: implications for paleoecology and extinction

Carbon and nitrogen isotopic reconstructions of North American Pleistocene trophic relationships were used to examine the extinction within terrestrial mammals ~10,000 years ago and distinguish between two potential causal mechanisms - human over-hunting and climate change. Additionally, individual animals were examined for unique isotopic signatures associated with feeding specializations, digestive strategies, and juveniles. Bones representing a comprehensive set of Pleistocene mammalian genera were obtained from three fossil localities: McKittrick Brea, California; Saltville, Virginia; and several sites in Florida. Collagen, a durable bone protein whose carbon and nitrogen isotopic composition reflects dietary input, was extracted from specimens and analyzed for delta-13C, delta-15N, % collagen, %C, %N, and C:N. Radiocarbon dating and amino acid analyses were performed on select sample sets. Results indicated that several specimens contained well preserved collagen, the isotopic values of which indicated both trophic position and vegetation preference. Those samples that contained residual diagenetic proteinaceous material exhibited increased hydrolysis of collagen with time and leaching of disassociated amino acids. Trophic relationships were reconstructed from well preserved specimens for Aucilla River, Florida and the herbivores of Saltville, Virginia, with a less complete reconstruction established for McKittrick Brea, California. The following notable trends emerged: 1) absence of nitrogen isotopic distinction between ruminants and non-ruminants, 2) enriched juvenile nitrogen isotopic signature, 3) distinction of giant ground sloths as omnivores, 4) C4 grass grazers and open C4 grasslands restricted to southern North American latitudes, 5) generalized and opportunistic feeding habits of herbivores, 6) potential prey specializations of carnivores. A noticeable lack of competition and feeding specialists among herbivores suggested a stable base to these late Pleistocene ecosystems, which argues against climatically induced stress on plants. While carnivore specimens were fewer, the apex trophic levels appeared to exhibit a similar lack of competition, which would be expected in a human-driven extinction where carnivores were stressed due to rapidly over-hunted herbivores. The ultimate cause of the late Pleistocene mammalian extinction in North America can not be exclusively attributed to either of these two mechanisms at this point in time; rather, a combination of factors should be considered

Evaluating the integration of chronic disease prevention and management services into primary health care

Background The increasing number of patients with chronic diseases represents a challenge for health care systems. The Chronic Care Model suggests a multi-component remodelling of chronic disease services to improve patient outcomes. To meet the complex and ongoing needs of patients, chronic disease prevention and management (CDPM) has been advocated as a key feature of primary care producing better outcomes, greater effectiveness and improved access to services compared to other sectors. The objective of this study is to evaluate the adaptation and implementation of an intervention involving the integration of chronic disease prevention and management (CDPM) services into primary health care. Methods/Design The implementation of the intervention will be evaluated using descriptive qualitative methods to collect data from various stakeholders (decision-makers, primary care professionals, CDPM professionals and patients) before, during and after the implementation. The evaluation of the effects will be based on a combination of experimental designs: a randomized trial using a delayed intervention arm (n = 326), a before-and-after design with repeated measures (n = 163), and a quasi-experimental design using a comparative cohort (n = 326). This evaluation will utilize self-report questionnaires measuring self-efficacy, empowerment, comorbidity, health behaviour, functional health status, quality of life, psychological well-being, patient characteristics and co-interventions. The study will take place in eight primary care practices of the Saguenay region of Quebec (Canada). To be included, patients will have to be referred by their primary care provider and present at least one of the following conditions (or their risk factors): diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, asthma. Patients presenting serious cognitive problems will be excluded. Discussion In the short-term, improved patient self-efficacy and empowerment are expected. In the mid-term, we expect to observe an improvement in health behaviour, functional health status, quality of life and psychological well-being. At the organizational level, the project should lead to coordinated service delivery, improved patient follow-up mechanisms and enhanced interprofessional collaboration. Integration of CDPM services at the point of care in primary care practices is a promising innovation in care delivery that needs to be thoroughly evaluated

L'école à la maison au Québec : l'expression d'un choix familial marginal

L'éducation à domicile est une option éducative marginale, quoique légale et présente à travers le monde. Au Québec, jusqu'ici, aucune étude approfondie n'avait décrit cette pratique et la population des familles concernées était inconnue. Cet article porte sur les raisons du choix de l'«école à la maison», exprimées par 203 familles québécoises au moyen d’un questionnaire. Cette enquête, réalisée en 2003, visait à documenter les conceptions de l'éducation, les raisons du choix, l'expérience éducative et les caractéristiques sociodémographiques des familles. Les raisons évoquées sont multiples et hétérogènes. Les rationnels décisionnels des parents sont variés et multidimensionnels. Une des particularités de ces résultats est qu'aucune voix religieuse, anti-étatique ou philosophique ne semble dominer le discours des parents-éducateurs québécois. Pour l'ensemble des participants, les principaux facteurs à la base de ce choix sont un désir de poursuivre un projet éducatif familial, une objection aux modes d'organisation du système scolaire, une volonté d'offrir de l'enrichissement et un souci du développement socioaffectif des enfants.Home schooling is a borderline, though legal, option that is exercised throughout the world. Until now, there has been no in-depth study of this practice in Quebec and there has been no head count of the families concerned. This article deals with the reasons for choosing home schooling, as given by 203 Quebec families who responded to a questionnaire on the subject. The survey, carried out in 2003, was designed to document the families` representation of education, the reasons for their choice, their educational experience and their socio-demographic profiles. The reasons they gave were both numerous and diversified. The rationale of the parents’ decisions is both varied and multidimensional. One of the particularities of the results is that the discourse of these Quebec parental educators seems quite devoid of any religious, anti-State or philosophical overtones. For the participants as a whole, the basic factors that largely determined their choice were their desire to implement a family educational project, their objection to the modes of organization of the school system, a desire to offer an enriched learning experience and a concern with the socio-affective development of their children

How VASP enhances actin-based motility

The function of vasodilator-stimulated phosphoprotein (VASP) in motility is analyzed using a biomimetic motility assay in which ActA-coated microspheres propel themselves in a medium containing actin, the Arp2/3 complex, and three regulatory proteins in the absence or presence of VASP. Propulsion is linked to cycles of filament barbed end attachment-branching-detachment-growth in which the ActA-activated Arp2/3 complex incorporates at the junctions of branched filaments. VASP increases the velocity of beads. VASP increases branch spacing of filaments in the actin tail, as it does in lamellipodia in living cells. The effect of VASP on branch spacing of Arp2/3-induced branched actin arrays is opposed to the effect of capping proteins. However, VASP does not compete with capping proteins for binding barbed ends of actin filaments. VASP enhances branched actin polymerization only when ActA is immobilized on beads or on Listeria. VASP increases the rate of dissociation of the branch junction from immobilized ActA, which is the rate-limiting step in the catalytic cycle of site-directed filament branching