No description available.

Dans le but d’améliorer l’accès au traitement pour les patients souffrant des maladies rares, les gouvernements de certains pays ont mis en place une législation ‘orpheline’ dont le but est d’aider à promouvoir la recherche dans ce secteur. En conséquence, le nombre de médicaments orphelins approuvés a significativement augmenté et continue de croître. Cependant, beaucoup de questions restent encore sans réponses. Les coûts par patients élevés, le manque de connaissance sur les maladies, et d’autres spécificités des médicaments orphelins font obstacle à l’utilisation de méthodes d’évaluations standards. L’objectif de cette étude est d’identifier les critères qui permettraient de déterminer la valeur des médicaments orphelins et les préférences de la société vis-à-vis de ces critères.Dans la première phase de l’étude, un état de l’art du marché des médicaments orphelins a été mené. Les défis associés tant à la recherche & développement qu’à l’évaluation des médicaments pour les maladies rares ont été décrits et classifiés. Une revue de toutes les autorisations de mise sur le marché pour les médicaments orphelins en Europe, ainsi que du marché des médicaments orphelins en France, en Italie, en Angleterre et au Pays de Galles a été réalisée. La disponibilité des médicaments orphelins, leur prix et leur remboursement, ainsi que les détails de l’évaluation par les autorités de santé ont été analysés.Dans la seconde phase de l’étude, une revue de littérature a été effectuée afin d’identifier les déterminants potentiels de la valeur des médicaments orphelins. L’impact de certains de ces attributs - dont le choix a été fait en fonction de la disponibilité des données - sur les prix des médicaments orphelins en France, en Italie, en Angleterre et au Pays de Galles a été exploré à l’aide d’une analyse de régression.Enfin, une enquête en ligne a été menée auprès d’un échantillon représentatif de la population française, afin d’étudier ses préférences relatives à certains attributs, sélectionnés au préalable. La liste de déterminants a été développée en se fondant sur un groupe de discussion et des interviews avec des experts. La méthode de l’enquête a suivi la structure d’un questionnaire à choix discrets et a permis d’estimer les poids relatifs des déterminants étudiés.L’étude a permis d’identifier les caractéristiques des médicaments orphelins qui sont le plus appréciées par la société. Ces résultats pourraient être pris en considération dans la méthode d’évaluation des médicaments orphelins, afin de la rendre plus transparente et robuste. / In order to improve the access to treatment for patients suffering from rare diseases, the governments of several countries put in place specific ‘orphan’ legislation aiming at promoting research in the field. In response to these measures, the number of approved orphan drugs has dramatically increased and continues to grow. Nevertheless, a number of issues remain unresolved. Thus, high per-patient costs, poor knowledge of the diseases and other specificities of medicines for rare diseases make it impossible to apply standard methods of health technology assessment to orphan drugs. The objective of the present research was to identify the criteria that determine the value of orphan drugs and study public preferences regarding these criteria.In the first phase of the research, a detailed review was conducted of the current situation on orphan drug market. Challenges related to the development and appraisal of orphan drugs were described and catalogued. A review was carried out of all approvals of orphan drugs in Europe, as well as of orphan drug markets in France, Italy and England and Wales. Orphan drug availability, price and reimbursement status, as well as the details of assessment were analysed.In the second phase, a literature review was conducted to identify potential determinants of orphan drug value. The impact of some of these determinants (choice was based on the availability of data) on orphan drug prices in France, Italy and England and Wales was then explored in a regression analysis.Finally, preferences of French general population in relation to the most relevant determinants of orphan drug value were analysed using an online survey. The list of determinants was developed based on a focus group and expert interviews. The survey was designed as a discrete choice experiment and allowed estimating relative weights of the included determinants.The study allowed identification of orphan drug characteristics that are most valued by the society. Its results may be taken into consideration in drug appraisal process in order to enable a fair assessment and pricing of orphan drugs.

No description available.

Genome sequencing has resulted in the identification of >55,000 cytochrome P450 enzymes, many of which have an unknown function and regulation. In mammals, CYP3 genes appear in only one subfamily (CYP3A), which metabolize >50% of pharmaceuticals and some steroids in humans. Unlike mammals, fish contain genes in the CYP3A, CYP3B, CYP3C and CYP3D subfamilies. While it is commonly assumed that fish and mammalian CYP3A are functional similar, the function and regulation of fish CYP3 remains largely unknown. In this thesis, the receptors and compounds that regulate CYP3C genes in zebrafish were assessed. The induction of CYP3C genes in response to the aryl hydrocarbon (AHR) and estrogen receptor (ER) ligands, β-naphthoflavone and 17β-estradiol, was measured using quantitative PCR in intestine, liver and gonads. Zebrafish CYP3C genes were inducible by β-naphthoflavone and 17β-estradiol, implicating the aryl hydrocarbon and estrogen receptor in CYP3C gene regulation and suggesting that regulation of CYP3 genes in fish differs from that in mammals. To define the function of zebrafish CYP3A65 and CYP3C1, fluorogenic compounds which are specific markers of CYP1 and CYP3A activity in humans, were screened for metabolism by CYP3A65 and CYP3C1. Both CYP3A65 and CYP3C1 had the capacity to metabolize several of these compounds and the substrate profile overlapped with zebrafish CYP1A, suggesting that these compounds are not specific in fish. A high throughput approach was employed to screen ~4000 small biologically and pharmacologically active compounds for metabolism by CYP3A65 and CYP3C1, using NADPH consumption to assess catalytic activity. The substrate profiles of CYP3A65 and CYP3C1 largely overlapped and were different than mammalian CYP3A4. CYP3A65 and CYP3C1 appeared to have a bias for quinone-based compounds but further studies are required to confirm quinones as substrates and to assess a strong structure-activity relationship. Overall, this study provides insight on the regulation, function and evolution on CYP3 genes in fish. / Dissertation / Doctor of Philosophy (PhD) / Cytochrome P450 (CYP) enzymes break down compounds such as hormones and pharmaceuticals. While mammals have genes in the CYP3A subfamily, fish have unique subfamilies not found in mammals. The function and regulation of the CYP3 family in fish is unknown, but commonly assumed to be like human CYP3. The purpose of this thesis was to identify what receptors and compounds regulate CYP3C enzymes in zebrafish. We found that regulation of CYP3C enzymes in zebrafish is different than humans. Zebrafish CYP3C genes are regulated by the aryl hydrocarbon receptor and estrogen receptor, while human CYP3A is regulated by the pregnane-x-receptor. I used a high throughput approach to screen thousands of compounds to identify the function of CYP3A65 and CYP3C1 from zebrafish. CYP3A65 and CYP3C1 metabolize several plant-based and pharmaceutical compounds. CYP3A65 and CYP3C1 are more functionally similar to each other than to CYP3A in humans.

La recherche dans le domaine des maladies sans traitement existant obéit à plusieurs impératifs définis par le législateur européen dans le règlement (CE) n° 141/2000 du 16 décembre 1999 concernant les médicaments orphelins. Les patients atteints de maladies rares et négligées ont le droit à « la même qualité de traitement que les autres » ce qui suppose de prendre les mesures d'incitation nécessaires pour « promouvoir la recherche, le développement et la commercialisation de traitements adéquats ». C'est un « domaine prioritaire ». Après avoir désigné les médicaments concernés, l'Union européenne veut « éviter la dispersion de ressources limitées » notamment par la promotion d'une « coopération transnationale ». Dans une démarche téléologique, cette recherche décrit les effets de la législation européenne sans ignorer la réception de ce droit par les États membres. Des fondements théoriques à même d'assurer une meilleure performativité du droit et des propositions concrètes en vue de conformer le droit positif à l'intention du législateur et aux attentes des parties prenantes sont proposés. En se focalisant sur le seul levier de la propriété intellectuelle, ce droit spécial et incitatif ne semble pas en mesure d'apporter aux patients la plupart des traitements attendus. La régulation de la concurrence et la compétence nationale sur le prix des médicaments perpétuent un seuil de rentabilité éloignant de nombreuses recherches de la phase du développement. L'accès aux médicaments orphelins demeure très restreint. Un changement de paradigme dans la construction de ce droit apparaît nécessaire afin qu'un modèle économique favorable se mette en place. Il convient que le profit des pharmaciens de l'industrie ne dépende plus de la conquête de parts de marché, mais de l'intérêt de leurs inventions pour les besoins de santé non satisfaits. / Research in the field of diseases without an existing treatment is governed by several requirements defined by the European legislator in Regulation (CE) No 141/2000 of 16 December 1999 on orphan medicinal products. Patients with rare and neglected diseases have the right to "the same quality of treatment as other patients" which means taking the necessary incentives to stimulate research, development and bringing to the market of appropriate medications". It is a "priority area". After designating the drugs concerned, the European Union wants to "avoid the dispersion of limited resources", in particular by promoting "cross national co-operation". In a teleological approach, this research analyses the positive law endeavouring to implement the objectives of Orphan Drug Law. It describes the effects of European legislation without ignoring the receipt of this law by the Member States. Theoretical foundations that can ensure a better performativity of the law, as well as concrete proposals to conform the positive law to the intention of the legislator and to the stakeholders' wills are proposed. By focusing solely on the leverage of intellectual property rights, this special and incentive law does not seem to be able to provide patients with many of the expected treatments. Competition regulation and setting of the price which is a national competency perpetuate a high profitability threshold, often withholding research projects from reaching the development phase. Access to orphan drugs remains very limited. A paradigm shift in the construction of this law appears necessary in order for a favorable economic model to emerge. The profit of the industry's pharmacists should no longer depend on the conquest of market shares, but on the value of their inventions for unmet health needs.

Five years ago at the age of 14, Rutendo Chaibva was double-orphaned by AIDS. A "Family Post Bereavement Property and Responsibilities Disbursement Committee" assigned her uncle Eric Gara as "replacement parent". Rutendo and her " replacement mother" Gerlinda were co-participants in the Participatory Action Research Study. It started in a therapeutic relationship after the family experienced some difficulties in integrating Rutendo into the reconstituted family. Both the therapy and research conversations explored and identified several pastoral and other challenges that militated against the integration process. Rutendo and Gerlinda's road was littered with, among others, minefields of silence and tears, secrecy, multiple losses, unresolved bereavement, unfinished business, anger, fear, and groping for Christian fellowship. It was concluded that personal, family, pastoral and other challenges, and, HIV/AIDS related complexities had militated against the integration process. At the end, Rutendo and Gerlinda acknowledged that therapy and the research processes had impacted positively on the integration process that improved significantly. / Practical Theology / M. Div. (Pastoral therapy)

school learnersChild-headed household is a phenomenon that is growing in South Africa. As such, it is imperative to uncover the realities of children in this situation. This study explores and describes the schooling experiences of secondary school learners from child-headed households. This qualitative study included a sample of 20 grade 10 and 11 learners from four secondary schools. Data were collected through structured interviews and document analysis. The Interpretative Phenomenological Analysis (IPA) was used to analyze the data. The findings suggest that secondary school learners from child-headed households live in poverty and encounter experiences such as absenteeism, psychological trauma, gender-based discrimination, lack of adequate food and scholastic materials, drug abuse and teenage pregnancy. These experiences impact negatively on their schooling. The study recommends that learners from child-headed households should get more care and support from educators and other stakeholders. / Science and Technology Education / M.A. (Socio-Education)

Syftet med denna retrospektiva kvalitativa studie är att öka kunskapen om tre systrars upplevelse av sina relationers utveckling före och efter båda föräldrarnas död. Som forskningsdesign valdes en kvalitativ metod. Två syskongrupper om tre systrar i medelåldern 49-62 år intervjuades. Datamaterialet analyserades med empirisk tematisk analys. I resultatet framträdde en struktur med fyra olika tidsintervall med femton teman. Resultaten visar att trots de oerhört starka anknytningarna av dysfunktionell natur i ursprungsfamiljerna får systrarna syn på varandra när föräldrarna dör. Syskonrelationerna har kommit i skymundan av föräldrarnas närvaro och deras problem. Det har påverkat syskonrelationerna. Relationerna mellan systrarna och rollerna förändrades i processen före och efter föräldrarnas död och mognar till något annat. Detta går som en röd tråd genom hela materialet; att existera i tillvaron, syskonrelationer omprövas och detta leder till närhet, autonomi och differentiering, en acceptans att alla är olika i triaden som vägleder dem till att värna om varandra än mer i medelåldern. / The aim of this retrospective qualitative study is to increase knowledge about three sisters' experience of the development of their relationships before and after both parents death. A qualitative research method was chosen. Two sibling groups of three sisters in middle age 49-62 years were interviewed. The data were analyzed with empirical thematic analysis. The result showed a structure with four different time intervals with fifteen themes. Despite the extremely strong dysfunctional nature of the relations in their origin families the sisters caught sight of each other when the parents died. The sibling relationships have been overshadowed by the parents' presence and their problems. Relationships and roles changed in the process before and after parental death between the sisters and matured into something else. This runs as a thread throughout the material; to exist in life, sibling relationships are reviewed, and it leads to intimacy, autonomy and differentiation, an acceptance that everyone is different in the triad that guides them to protect each other even more in middle age.

The purpose of this thesis is to explore the importance of the orphan hero in film and his resonance with the American people. It explores the orphan and the American identities, the archetypes found in myths, and the hero in American culture. The three heroes (Batman, Anakin Skywalker, and Harry Potter) represent certain aspects of orphan heroes: the capacity for sacrifice and the need to resist focusing on oneself. The type of hero each becomes has its source in the response he takes to his orphanhood. These young men suffered great loss early in their lives, but found the strength to sacrifice themselves for others, the ultimate sign of a hero.

En raison des présentes transformations du marché du travail, le mouvement syndical est à la recherche d’un nouvel équilibre. Dans ce contexte plutôt changeant, réorganisations et flexibilité se négocient en échange d’une protection accrue pour ceux qui demeurent en emploi. Si d’une part, ceci mène à une prolifération de nouvelles formes d’emploi atypiques et de disparités de traitement, d’autre part la constitutionnalisation du droit du travail change le rapport quant à l’universalisme syndical. Nous nous sommes alors interrogée sur les impacts que cela peut avoir sur le devoir syndical de représentation. Prenant cela en considération, nous avons voulu au cours de notre recherche faire la lumière tant sur certains impacts de la négociation de clauses de disparité de traitement dans les milieux de travail syndiqués que sur les défis contemporains du droit du travail et de l’emploi. Cette thèse propre au champ d’études que sont les relations industrielles se distingue des autres recherches dans le même domaine en se concentrant sur l’effet empirique de la mise en œuvre d’une norme, par l’étude de deux cas suggestifs. Plus précisément, notre thèse avait comme principal objectif de répondre à la question suivante : Quels sont les effets sur l’acteur (action) syndical du recours à la norme d’égalité, à la suite la négociation de clauses « orphelin »? Pour y parvenir, nous avons dû reconstituer comment les acteurs syndicaux s’étaient approprié l’espace ouvert par la constitutionnalisation du droit du travail. Nous avons utilisé une méthode qualitative, impliquant une revue de la littérature sociohistorique, théorique et juridique, une analyse de la jurisprudence existant à ce sujet et l’étude de deux cas portant sur la négociation d’une clause « orphelin » le tout représentant soixante entrevues semi-dirigées dans plusieurs casernes et palais de justice. Les connaissances acquises permettent au plan empirique une meilleure compréhension des interactions possibles entre acteurs, institutions et stratégies lors de la mise en œuvre de la norme d’égalité ainsi que des déterminants de l’action (ou de l’inaction) syndicale. Sur le plan pratique, nous espérons que notre thèse puisse guider toute personne ou tout groupe de personnes désirant mettre en œuvre des mesures égalitaires, tant pour éviter certains écueils reliés à ces actions ou réactions suscitées par la mise en œuvre du droit à l’égalité, que pour mesurer l’efficacité des actions entreprises. De surcroît, sur le plan théorique, nous croyons que de mettre à l’épreuve un modèle théorique recoupant stratégies et institutions permettra d’aborder les problèmes à la fois au niveau de l’acteur et au niveau structurel. Les résultats obtenus aident à comprendre en quoi et comment peut se construire l’action syndicale dans certains (2) cas de mise en œuvre de la norme d’égalité. Le choix de différentes stratégies ne peut pas être dissocié des différents contextes économiques, sociaux et juridiques, ni des capacités stratégiques des différents acteurs en cause. Les principales contraintes identifiées ont pu être imputées tant aux structures de l’association syndicale qu’aux différents univers normatifs mobilisés. Les sources de tensions vécues dans les milieux à l’étude ont été rattachées notamment aux perceptions d’injustice et à la méconnaissance des différentes normes juridiques. En conséquence, il faut conclure que pour les associations syndicales (sans se restreindre à celles à l’étude), la question d’iniquité pourrait avoir de graves conséquences et non seulement sur le devoir de représentation. Nous avons spécialement souligné la fragilisation de leurs assises, dans leurs deux pôles d’actions : d’acteur économique (faille dans la capacité d’action traditionnelle) et d’acteur politique (climat hostile au syndicalisme). Nous souhaitons que l’acteur syndical puisse mobiliser, à la lumière des résultats de notre recherche, des arguments concourant à repenser l’action syndicale, que nous croyons être plus pertinente que jamais. Nous croyons également que les différents acteurs du monde du travail pourraient s’approprier certaines de nos recommandations afin de favoriser une citoyenneté au travail plus inclusive. / As a result of the present transformation of the labour markets, trade union movements are in constant search for a new equilibrium. If in this context of instability, reorganizations and flexibility are negotiated in exchange for increased protection for those who remain in employment. If on the one hand, this leads to a proliferation of new atypical forms of employment and disparities of treatment, on the other hand, the entrenchment of human rights law in the field of labour relation changes the relationship with the union majority rule. This has raised an important question about the impact this will have on the union's duty of fair representation. Taking this into consideration, we wanted in the course of our research to shed light both on the impacts of the negotiation of disparity of treatment (two-tier wage plan) clauses have on unionized workplaces and on the contemporary challenges of labour and employment law. While still being specific to our field of research (industrial relations), our work differs from other studies that have been carried out on this matter by focusing on the empirical effects of the implementation of the norm of equality through the analysis of two suggestive cases. More specifically, the main objective of our thesis was to answer the following question: What are the effects of the implementation of the norm of equality in unionized work environments in the province of Québec? In order to achieve this goal, we had to recreate how the trade union actors can fit within the entrenchment of human rights law. We used a qualitative approach, involving a review of historical, theoretical and legal literature, analysis of the existing jurisprudence on this matter and the study of two selected cases involving the negotiation of a "orphan" clause (representing sixty semi-structured interviews in total). It was in our intention to demonstrate that gained knowledge from previous applications provides a better understanding on the empirical level of possible interactions between actors, institutions and strategies during the implementation of a strategy, as well as important determinants concerning the union action (or inaction). On a practical level, we hope that our thesis can guide any individual (or group of individuals) wishing to implement equality measures, both to avoid some of the pitfalls related to these actions or reactions to the implementation of the right to equality, and to measure the effectiveness of undertaken actions. Additionally, on a more theoretical level, we believe that testing a conceptual model overlapping different strategies and institutions will address these problems both at actor and structural level. The results we obtained provide insights into how and to what extent trade union action can be built in the case of equality norm implementation. The selection of different strategies cannot be disembodied from its economic, sociological and legal contexts, nor from the strategic capacities of the different actors involved. The main constraints identified could be attributed both to the structures of the union association and to different normative spaces. The tensions experienced in the studied cases were linked to particular perceptions of injustice and lack of knowledge of different legal standards. Subsequently, we must come to the conclusion that the question of iniquity may have some serious repercussions for trade unions far beyond the duty of fair representation. We specially emphasize the weakening of their foundations, mainly in their two poles of action: as economic players (loophole in the traditional ability of action) and political actors (cultivating a climate that is hostile to unionism). Based on the results of our research, we want union actors to be able to mobilize concurrent arguments to rethink union action altogether, something we believe is more relevant than ever. We also believe that the different actors of today's working world could take ownership of the recommendations set forth in our work to foster a more inclusive citizenship at work.