Il existe une grande variabilité dans la réponse aux chimiothérapies anticancéreuses. Ses sources sont diverses: génétiques, physiologiques, comorbidités, médicaments associés, etc. La marge thérapeutique de ces médicaments étant généralement étroite, une telle variabilité peut avoir de graves conséquences: toxicités graves ou absence d'effet thérapeutique. Plusieurs approches pour adapter individuellement les posologies ont été proposées: a priori (basées sur l'information génétique, la taille corporelle, les fonctions d'élimination, etc.) et a posteriori (sur les informations de mesures d'exposition au médicament et/ou effets). La modélisation à effets-mixtes de la pharmacocinétique et de la pharmacodynamie (PK-PD), combinée avec une estimation bayésienne des effets individuels, est la meilleure méthode pour individualiser des schémas posologiques a posteriori. Dans cette thèse, une nouvelle approche pour ajuster les doses sur la base des prédictions données par un modèle pour les observations catégorielles de toxicité a été développée et explorée par simulation. Les aspects plus techniques concernant l'estimation des paramètres individuels ont été analysés pour déterminer les facteurs de bonne performance de la méthode. Ces travaux étaient basés sur l'exemple du syndrome mains-pieds induit par la capécitabine dans le traitement du cancer colorectal. Une revue des modèles pharmacodynamiques de données discrètes (catégorielles, de comptage, de survie) a été effectuée. Enfin, des analyses PK-PD de l'hydroxyurée dans le traitement de la drépanocytose ont été réalisées pour comparer des différentes posologies et déterminer les modalités optimales de suivi du traitement / There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment

Cette recherche porte sur une catégorie spécifique de travailleurs, les Travailleurs Indépendants Economiquement Dépendants (TIED), qui associent une indépendance juridique à une dépendance économique vis-à-vis d’un seul client. En cumulant des caractéristiques typiques des deux catégories classiques que sont les salariés et les travailleurs indépendants, les TIED s’inscrivent dans une zone grise du marché du travail. A partir d’une étude qualitative menée auprès de TIED français et brésiliens du secteur des Technologies de l’Information, nous nous interrogeons sur la signification sociale de cette forme d’emploi hybride et sur la façon dont elle émerge sur des marchés du travail aussi différents que ceux de la France et du Brésil. L’analyse des conditions de travail des enquêtés permet d’abord de situer les TIED sur un continuum entre salariat déguisé et véritable travail indépendant et de distinguer deux profils-types : les prestataires intégrés à la structure commanditaire et les indépendants en transition. Pour étudier les trajectoires professionnelles de ces travailleurs, nous mobilisons ensuite l’approche par les capabilités d’Amartya Sen (2000) : nous montrons que les parcours des TIED – privés des protections du droit du travail par leur indépendance juridique – reposent sur des processus d'accumulation et de conversion de différents types de ressources en libertés réelles (ou capabilités). De plus, si l’approche de Sen permet d’expliquer les différences de capabilités observées au sein de notre échantillon, nous proposons d’enrichir son cadre d’analyse afin de l’adapter à l’étude de trajectoires socioprofessionnelles. Les analyses réalisées nous conduisent enfin à distinguer deux groupes d’enquêtés, les "TIED réticents" et les "TIED épanouis" : les TIED réticents, plus nombreux au Brésil, expriment un attachement fort au salariat, alors que les TIED épanouis voient dans la position de TIED une façon d’échapper à des emplois décevants et trouvent souvent avantage à une situation qui leur offre plus d’autonomie que le salariat et plus de confort que la véritable indépendance. En nous appuyant sur les travaux de Fraser (2010) et Boltanski et Chiapello (2011), nous montrons comment le positionnement des TIED épanouis contribue indirectement à la remise en cause du rôle de l’Etat social.Les TIED apparaissent en définitive comme une figure emblématique d’un processus ambivalent d’individualisation qui contribue à l’émergence d’un sujet en quête d’autonomie, délié de ses appartenances traditionnelles, tout en favorisant une confrontation directe de l’individu avec le marché qui accroît les inégalités. Dès lors, si les désirs d’émancipation et d’autonomie des TIED épanouis nous semblent devoir être pris au sérieux, une réflexion s’impose sur les mesures susceptibles d’étendre les capabilités des individus tout en luttant contre l’exacerbation des inégalités et en préservant un système de mutualisation des risques fondé sur la solidarité. / This research deals with a specific category of workers, the Economically Dependent Self-employed Workers (EDSW), who associate legal independence with an economic dependence upon a single client. Combining typical characteristics of two traditional labor categories, wage-labor and self-employment, EDSW fall within a grey zone of the labor market. Starting from a qualitative survey conducted among French and Brazilian EDSW from the Information Technology sector, we question the social significance of this hybrid employment form and the way it emerges in labor markets as dissimilar as those of France and Brazil. At first, the analysis of EDSW working conditions enables to place them on a continuum between disguised wage-labor and real self-employment and to identify two typical profiles: service providers integrated to the client structure and transitioning self-employed workers. To study their occupational path, we then mobilize Amartya Sen’s capability approach (2000): we show that the careers of EDSW – deprived of labor law protection by their self-employment status – rely on accumulation and conversion processes of various resources types into real freedom (or capabilities). Moreover, if Sen's approach helps explaining the observed differences in capabilities within our sample, we propose to enrich its analytical framework in order to adapt it to socio professional path study. Finally, the conducted analyzes lead us to split our sample into two groups: the ‘reluctant EDSW’ and the ‘fulfilled EDSW’. The reluctant EDSW, more numerous in Brazil, express a strong attachment to wage-labor, whereas the fulfilled EDSW see in EDSW position a way to exit disappointing jobs and often find benefits in a situation which offers them more autonomy than wage-labor and greater comfort than actual self-employment. Mobilizing the theoretical contributions of Fraser (2010) and Boltanski and Chiapello (2011), we demonstrate how the positioning of the fulfilled EDSW contributes to indirectly challenge the welfare state’s role.EDSW ultimately appear as an icon of an ambivalent process of individualization which contributes to the emergence of a subject who is seeking for autonomy, relieved from its traditional affiliations, while simultaneously promoting a direct confrontation of the individuals with the market that increases inequalities. Therefore, if the fulfilled EDSW’s wishes for emancipation and autonomy should be seriously considered, a reflection is needed on measures that may increase individual capabilities while struggling against increasing inequalities and maintaining a system of risks management based on solidarity. / Essa tese está dedicada a uma categoria específica de trabalhadores, os Trabalhadores Autônomos Economicamente Dependentes (TAEDs), que cumulam uma autonomia jurídica com uma situação de dependência econômica em relação a um único cliente. Ao associar características típicas das duas categorias clássicas que são os assalariados e os trabalhadores autônomos, os TAEDs inscrevem-se numa zona cinzenta do mercado de trabalho. A partir de uma pesquisa qualitativa realizada com TAEDs franceses e brasileiros do setor de Tecnologia da Informação, perguntamo-nos acerca do significado social dessa forma híbrida de trabalho e da sua emergência nos mercados de trabalho tão distintos da França e do Brasil. A análise das condições de trabalho dos entrevistados possibilita primeiro situar os TAEDs num continuum entre emprego assalariado e verdadeiro trabalho autônomo e diferenciar dois perfis: os prestadores integrados na estrutura cliente e os autônomos em transição. Para estudar as trajetórias profissionais desses trabalhadores, mobilizamos, em seguida, a abordagem pelas capacidades de Amartya Sen (2000): mostramos que os percursos dos TAEDs – que são privados das proteções trabalhistas pela sua autonomia jurídica – dependem de processos de acumulação e conversão de distintos tipos de recursos em liberdades reais (ou capacidades). Além disso, se a abordagem de Sen permite explicar as diferenças de capacidades observadas na nossa amostra, propomos enriquecer o seu marco de análise para adaptá-lo ao estudo de trajetórias socioprofissionais. As análises realizadas nos levam finalmente a distinguir dois grupos de entrevistados, os “TAEDs reticentes” e os “TAEDs satisfeitos”: os TAEDs reticentes, mais numerosos no Brasil, expressam um forte apego ao emprego assalariado enquanto os TAEDs satisfeitos veem na posição de TAED uma forma de se livrarem de empregos decepcionantes e, na maioria dos casos, creem vantajosa uma situação que oferece uma autonomia maior que o emprego assalariado e um conforto maior que o trabalho verdadeiramente autônomo. A partir das obras de Fraser (2010) e Boltanski e Chiapello (2011), mostramos que o posicionamento dos TAEDs satisfeitos questiona indiretamente o papel do Estado social. Os TAEDs aparecem então como uma figura emblemática de um processo ambivalente de individualização que contribui para a emergência de um sujeito que busca autonomia e está livre de seus pertencimentos tradicionais, ao mesmo tempo em que favorece um confronto direto do indivíduo com o mercado que aumenta as desigualdades. Se achamos que os desejos de emancipação e autonomia dos TAEDs satisfeitos têm que ser levados a serio, é necessário refletir sobre as medidas que poderiam expandir as capacidades dos indivíduos, lutando contra o aumento das desigualdades e preservando um sistema solidário de gestão dos riscos.

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The study sought to determine, first, what the rules of the Hananwa family law were and, second, whether those rules were compatible with the Constitution. First, it documented the rules of the official family law. The problem that the study countenanced is that customary law is "corrupted, inauthentic and lacking authority".1 Second, it established and documented the rules of the Hananwa family law. The problem that the study countenanced in respect of Hananwa law was that it was difficult to ascertain the content of the rules of the "living" Hananwa law in order to determine their compatibility with the provisions of the Bill of Rights. Moreover, the traditional Hananwa community is inegalitarian and patriarchal. Section 9 of the Constitution provides that everyone is equal before the law and enjoys equal and full protection and benefit of the law. The study found that the Hananwas still observe their system of customary law. However, there are visible changes. For instance, nowadays the spousal consent is a validity requirement for all customary marriages. A parent or legal guardian must consent to a customary marriage of a minor. The individual spouses, not their families, are parties to their own customary marriages. African women enjoy equal status. This development is consistent with section 9 of the Constitution read with section 6 of the Recognition of Customary Marriages Act 120 of 1998. According to the Constitutional Court, in MM v MN and Another 2013 4 SA 415 (CC), the first wife must consent to her husband's customary marriage to another woman in addition to her customary marriage to him. However, some rules of the Hananwa law do not comply with the provisions of the Bill of Rights. For instance, according to the Hananwa law, extramarital children do not enjoy equal inheritance rights and maintenance rights yet. This discrimination is inconsistent with the constitutional right to equality and the provisions of the Reform of Customary Laws of Succession and Regulations of Related Matters Act 11 of 2009.The Constitution puts common law and customary law on a par. However, the courts have often replaced customary law dispute resolution rules with the common law rules. For instance, the Constitutional Court in Bhe and Others v Magistrate, Khayelitsha and Others; Shibi v Sithole and South African Human Rights Commission and Another v President of the Republic of South Africa and Another 2005 1 SA 580 (CC) and the High Court in Maluleke v Minister of Home Affairs 2008 JDR 0426 (W) substituted the rules of common law for those of customary law in order to resolve customary law disputes. The legislature could not be outdone. A meticulous study of the Recognition of Customary Marriages Act 120 of 1998 and the Reform of Customary Laws of Succession and Regulations of Related Matters Act 11 of 2009 reveals that their provisions almost appropriately reflect the common law marriage and intestate succession rules respectively. The Recognition of Customary Marriages Act has, furthermore, adopted the provisions of the Divorce Act of 1979. Section 28 of the Constitution read with the Children's Act 38 of 2005 has generally substituted the fundamental human rights for the unequal rights provided by the customary law of parent and child. The Maintenance Act 99 of 1998 has substituted the communal form of maintenance under customary law. / Public, Constitutional, & International Law / LLD (International and Constitutional Law)

The study sought to determine, first, what the rules of the Hananwa family law were and, second, whether those rules were compatible with the Constitution. First, it documented the rules of the official family law. The problem that the study countenanced is that customary law is "corrupted, inauthentic and lacking authority".1 Second, it established and documented the rules of the Hananwa family law. The problem that the study countenanced in respect of Hananwa law was that it was difficult to ascertain the content of the rules of the "living" Hananwa law in order to determine their compatibility with the provisions of the Bill of Rights. Moreover, the traditional Hananwa community is inegalitarian and patriarchal. Section 9 of the Constitution provides that everyone is equal before the law and enjoys equal and full protection and benefit of the law. The study found that the Hananwas still observe their system of customary law. However, there are visible changes. For instance, nowadays the spousal consent is a validity requirement for all customary marriages. A parent or legal guardian must consent to a customary marriage of a minor. The individual spouses, not their families, are parties to their own customary marriages. African women enjoy equal status. This development is consistent with section 9 of the Constitution read with section 6 of the Recognition of Customary Marriages Act 120 of 1998. According to the Constitutional Court, in MM v MN and Another 2013 4 SA 415 (CC), the first wife must consent to her husband's customary marriage to another woman in addition to her customary marriage to him. However, some rules of the Hananwa law do not comply with the provisions of the Bill of Rights. For instance, according to the Hananwa law, extramarital children do not enjoy equal inheritance rights and maintenance rights yet. This discrimination is inconsistent with the constitutional right to equality and the provisions of the Reform of Customary Laws of Succession and Regulations of Related Matters Act 11 of 2009.The Constitution puts common law and customary law on a par. However, the courts have often replaced customary law dispute resolution rules with the common law rules. For instance, the Constitutional Court in Bhe and Others v Magistrate, Khayelitsha and Others; Shibi v Sithole and South African Human Rights Commission and Another v President of the Republic of South Africa and Another 2005 1 SA 580 (CC) and the High Court in Maluleke v Minister of Home Affairs 2008 JDR 0426 (W) substituted the rules of common law for those of customary law in order to resolve customary law disputes. The legislature could not be outdone. A meticulous study of the Recognition of Customary Marriages Act 120 of 1998 and the Reform of Customary Laws of Succession and Regulations of Related Matters Act 11 of 2009 reveals that their provisions almost appropriately reflect the common law marriage and intestate succession rules respectively. The Recognition of Customary Marriages Act has, furthermore, adopted the provisions of the Divorce Act of 1979. Section 28 of the Constitution read with the Children's Act 38 of 2005 has generally substituted the fundamental human rights for the unequal rights provided by the customary law of parent and child. The Maintenance Act 99 of 1998 has substituted the communal form of maintenance under customary law. / Public, Constitutional, and International Law / LLD (International and Constitutional Law)

Définie à l’origine comme l’aptitude à la sanction, la capacité pénale peut s’entendre plus largement comme résumant l’ensemble des aptitudes subjectives, c’est-à-dire propres au délinquant, indispensables à l’engagement et à la sanction de sa responsabilité pénale. Ces aptitudes sont de deux ordres. L’aptitude à l’infraction et l’aptitude à l’imputation de cette infraction conditionnent le jugement de responsabilité et contribuent à en assurer la dimension morale. L’aptitude à la sanction ou capacité pénitentiaire joue un rôle plus original puisqu’elle apparaît comme le fondement de la personnalisation de la peine, permettant d’adapter la sanction pénale à la personnalité et aux besoins de celui qui doit la subir. / Originally defined as the capacity to be punished, criminal capacity can be understood more widely as summarizing mental abilities that are required for criminal responsibility. Some are needed to commit the offense, others for criminal responsibility but both ensure the moral meaning of criminal law. Applied to the penalty, criminal capacity can be used to adapt the sentence to the personality and needs of those who must endure it.