Cancer is responsible for upward of 13% of human deaths. Contemporary chemotherapy of disseminated cancer is often thwarted by dose limiting systemic toxicity and by multi-drug resistance (MDR). Riminophenazines are a novel class of potential anticancer agents that possess a potent multi-mechanistic antineoplastic action. Apart from their broad action against intrinsic, non-classical resistance, Riminophenazines inhibit the action of Pgp and hypothetically all ABC transporters demonstrating their great utility against classical MDR. Considering that combination chemotherapy is the norm, the vision directing R&D efforts was that Riminophenazines could be used with benefit within many standard chemotherapeutic regimes. The strategic intent of this project was to attain improved therapeutic benefit for patients through gains in both pharmaco dynamic and pharmacokinetic specificity for cancer cells over what is currently available. Tactically, this was driven through the use of synergistic Fixed-Ratio Drug Combinations (FRDC) encapsulated within tumour-targeting Nanoparticulate Drug Delivery Systems (NDDS). Long-term aims of this R&D project were to: 1) Screen FRDC of clofazimine (B663) and the lead derivative (B4125) with etoposide, paclitaxel and vinblastine for synergistic drug interactions in vitro. 2) Design, assemble and characterize a novel nanoparticulate, synergistic, anticancer co-formulation. 3) Evaluate the in vivo safety and efficacy of the developed product/s in accordance with international regulatory guidelines. Using the median effect and combination index equations, impressive in vitro synergistic drug interactions (CI<1) were shown for various FRDC of the three standard chemotherapeutics tested (etoposide, paclitaxel and vinblastine) in combination with either B663 or B4125 against MDR neoplastic cell cultures. Considering in vitro results and with the view to advance quickly to clinical studies, the already approved clofazimine (B663) was elected as the combination partner for paclitaxel (PTX). Considering the potency and wide action of PTX, a novel coformulation (designed to circumvent drug resistance) has the potential to greatly impact upon virtually all cancer types, particularly if selectively delivered through innovative delivery systems and loco-regional administration. A passively tumour targeting, micellular NDDS system called Riminocelles™ that encapsulates a synergistic FRDC of B663 and PTX has been designed, assembled using thin film hydration methods and characterized in terms of drug loading, particle size, zeta potential, CMC and drug retention under sink conditions. An acute toxicity and a GLP repeat dose toxicity study confirmed Riminocelles to be well tolerated and safe at clinically relevant dosages whilst Taxol® (QDx7) produced statistically significant (P<0.05) weight loss within 14 days. The same study demonstrated statistically significant (P<0.05) tumour growth delays superior to that of Taxol at an equivalent PTX dosage of 10 mg/kg. Importantly, all components (amphiphiles and drugs) used in assembly of Riminocelles are already individually approved for medicinal use - this promotes accelerated development towards advanced clinical trials and successful registration. Although these results are very promising (outperforming Taxol), this system was however found in a pharmacokinetic study to suffer from in vivo thermodynamic instability due to the high concentration (abundance) of albumin present in plasma. For this reason, in vivo longevity within circulation, permitting passive tumour accumulation was not fully realized. A second NDDS called the RiminoPLUS™ imaging system was additionally developed. This lipopolymeric nanoemulsion system has successfully entrapped Lipiodol® Ultra fluid (an oil based contrast agent) within the hydrophobic core of a monodisperse particle population with a size of roughly 100 nm and a stability of one week. This formulation is therefore thought capable of CT imaging of tumour tissue and drug targeting after either intravenous or loco-regional injection. In vivo proof of the imaging concept is warranted. The results of this study serve to highlight the great potential of in vitro optimized synergistic FRDC against drug resistant cancers. Lipopolymeric micelles are an effective way to formulate multiple hydrophobic drugs for intravenous administration and present a means by which cancer can be readily targeted; provided that the delivery system possess the prerequisite in vivo stability and surface attributes. Further experiments exploring synergistic drug and biological combinations as well as “intelligent” NDDS actively guided through specific molecular recognition are called for. / Thesis (PhD)--University of Pretoria, 2012. / Pharmacology / unrestricted

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This quantitative, descriptive study investigated risk factors for MDR-TB in Addis Ababa, Ethiopia. A total of 439 medical records belonging to MDR-TB and non MDR-TB patients managed in public health centres from January 2008 to December 2011 were analysed. Data were transcribed from each TB patient‟s medical records using a specifically designed checklist. The findings revealed that male gender, previous history of TB treatment, poor treatment adherence, an outcome of failure after TB re-treatment, previous category of failure, pulmonary involvement of TB infection and HIV infection were associated with MDR-TB. The findings illustrate that efforts should be made to prioritise the development and implementation of effective MDR TB screening and treatment protocols for these high risk groups to improve treatment outcome and minimize the emergence of XDR TB. / Health Studies / M. Public Health

Si l’approche par compétences au Canada et aux États-Unis est particulièrement valorisée pour orienter la pratique des professionnels de la santé (PDS) – et en bioéthique clinique –, les travaux permettant de mieux comprendre les fondements psychologiques, ontologiques et philosophiques de ces compétences sont peu présents dans la littérature en bioéthique. Les principaux outils actuellement disponibles se divisent généralement en quatre principales catégories : 1) les documents officiels (codes de déontologie, règlements institutionnels, etc.); 2) les principales théories éthiques (éthique de la discussion, éthique de la vertu, principisme, etc.); 3) les ouvrages de référence scientifiques; 4) les outils de prise de décision éthique. Ces documents sont des incontournables pour les bioéthiciens et les PDS, mais leur disparité, voire leur contenu parfois contradictoire, jumelée à une compréhension limitée de l’éthique, est souvent source de confusion dans les processus décisionnels et peut être la cause de comportements ne répondant pas aux standards éthiques des pratiques professionnelles. Notre recherche constitue une réflexion qui s’inscrit en amont de ces outils dont le caractère pragmatique a le désavantage de simplifier la réflexion théorique au profit de données plus concrètes. Nos travaux visent à développer les bases d’un modèle flexible et inclusif – le modèle de la déontologie réflexive (MDR) – permettant de : 1) poser les principaux repères philosophiques, sociaux et déontologiques des problématiques éthiques rencontrées en pratique; 2) saisir les principales tensions éthiques inhérentes à cette complexité; 3) mieux comprendre, dans une perspective psychologique et développementale, les exigences personnelles et professionnelles qu’impose le statut de professionnel de la santé dans le contexte actuel des soins de santé. Entreprise théorique, ce projet consiste principalement à mettre en relation dynamique un ensemble de dimensions (légale, éthique, clinique, sociale, psychologique) à l’oeuvre dans la rencontre du bioéthicien et du PDS avec la complexité des situations éthiques, en s’inspirant du concept de sensibilité éthique de la « petite éthique » de Paul Ricoeur (1990), du modèle des quatre composantes de Rest (1994) et de la théorie du soi et des modes identitaires d’Augusto Blasi (1993). Ce processus implique trois étapes successives : 1) une mise en ii perspective de la posture épistémologique particulière du bioéthicien et du PDS à la lumière de la « petite éthique » de Ricoeur; 2) une revue de la littérature interdisciplinaire sur le concept de sensibilité éthique afin d’en proposer une définition et de le mettre en perspective avec d’autres compétences éthiques; 3) le développement d’un cadre de référence en matière d’identité éthique professionnelle (professional ethics identity tendencies, PEIT), inspiré de la théorie du soi et des modes identitaires de Blasi. Ces PEIT proposent un repère normatif aux exigences liées à la construction de l'identité en contexte de pratique des PDS et suggèrent des pistes de réflexion quant à la formation et à la recherche en éthique professionnelle. Cette recherche souhaite établir des fondements théoriques pour le développement ultérieur du modèle de la déontologie réflexive (MDR). / If the competency approach seems to be particularly valorised in Canada and in the United States for orienting the practice of health care professionals (HCP) – and in clinical bioethics – material that could provide with a better understanding of the psychological, ontological and philosophical foundations of these competencies seems rather limited in the bioethical literature. The tools that are generally available can be divided into four main categories: 1) official documents (e.g., code of ethics, institutional policies); 2) the main ethical theories (e.g., virtue ethics, theories of justice, principlism); 3) scientific references (e.g., journals, books); 4) decision-making tools. These documents are important for bioethicists and HCPs, but their disparities and even contradictions, coupled with poor knowledge in professional ethics, may be a significant source of confusion in the decision making process and even lead to behaviour that does not meet the ethical standards of HCP. This thesis is an upstream reflection regarding these tools, whose pragmatic character has the disadvantage of simplifying theoretical reflection at the benefit of more concrete evidence useful for practical decision making. This project aims at developing the foundations for a flexible and inclusive model – a model of deontological reflexivity (MDR) – that will: 1) present the main philosophical, psychological, sociological and deontological landmarks characterising ethical issues encountered in practice; 2) understand, from a psychological and developmental perspective, the personal and professional requirements inherent to the status of the health care professional in the current context of health care. A theoretical enterprise, this project primarily consists in relating, in a dynamic manner, a variety of dimensions (legal, ethical, clinical, psychological) at work in complex ethical situations encountered by HCPs and bioethicists, inspired by the concept of ethical sensitivity, the “petite éthique” of Paul Ricoeur (1990), the self theory along with Blasi's Identity modes (Blasi, 1993). The analysis process will consist in three successive phases: 1) a putting into perspective of the bioethicist's and HCPs’ epistemological posture in light of the “petite éthique” of Paul Ricoeur (1990); 2) an interdisciplinary literature review of “ethical sensitivity” in order to propose a definition of the concept and place it into perspective with other ethical competencies; 3) the development of a framework regarding professional ethics iv and identity (professional ethics identity tendencies, PEIT), inspired both by the self theory and Blasi's Identity modes. These PEITs provide a normative benchmark related to the construction of identity in the health care context and suggest some innovative avenues for professional ethics research and education. This research wish to elaborate the theoretical foundations that will be utilised further in the future to develop the model of deontological reflexivity (MDR).

L'objectif de cette thèse est de fournir une meilleure compréhension des différents phénomènes physiques liés aux microplasmas/microdécharges. Pour cela, des matrices de microréacteurs sur silicium ont été étudiées. De nombreuses configurations ont été construites de manière à analyser l’influence de chaque paramètre physique sur le fonctionnement de ces dispositifs. Le présent travail porte sur l'élaboration et la caractérisation de dispositifs micro-décharge à base de silicium. Dans ce travail de thèse, les régimes de courant continu (DC) et de courant alternatif (AC) sont étudiés en utilisant des configurations de décharges différentes. Pour la fabrication de ces réacteurs, nous sommes partis de wafers de Silicium que nous avons structurés et traités en salle blanche. La technologie de fabrication utilisée est compatible avec les méthodes de fabrication de dispositifs CMOS. Les microréacteurs sont constitués d’électrodes de nickel et de silicium séparés par une couche diélectrique de SiO2 de 6 μm d’épaisseur. L’épaisseur du diélectrique est ici beaucoup plus faible que celle des microréacteurs étudiés jusqu’à présent. Les dispositifs sont constitués de cavités de 25 à 150 microns de diamètre. Les essais de microdécharge ont été effectués dans des gaz inertes à une pression comprise entre 100 et 1000 Torrs. Nous avons d’abord étudié les phénomènes d’allumage et d’extinction à partir de microdispositifs monocavité en alumine. Puis, nous avons étudié le fonctionnement en DC/AC de microréacteurs en silicium comportant un nombre de cavité compris entre 1 et1024. Les caractéristiques des microdécharges ont été étudiées grâce à des mesures électriques, des mesures de spectroscopie d'émission optique (OES), de spectroscopie d’absorption à diode laser (DLAS) et de spectroscopie d'émission optique résolue en temps (PROES). Ces différents diagnostics nous ont permis de mettre en évidence les phénomènes d’allumage, d’extinction, d’instabilité et les mécanismes de défaillance de nos microdispositifs. Ce travail de thèse a permis de tester les performances et les limites technologiques des matrices de microdécharges sur silicium. Une attention particulière a été portée sur leur durée de vie. / The objective of this thesis is to provide a better understanding of various physical phenomena related to microplasmas/microdischarges. For this purpose, arrays of microreactors on silicon were studied. Different array configurations were fabricated to analyse the influence of each parameter on the physical operation of these devices. The present work focuses on the development and characterisation of micro-discharge devices based on silicon. In this thesis, direct current (DC) and alternating current (AC) regimes are studied using different discharge configurations. For the fabrication of these reactors, Silicon wafers are structured and processed in a cleanroom. Fabrication technology used is compatible with the CMOS technology. The microreactors are fabricated with nickel and silicon electrodes, separated by a dielectric layer of SiO2 with a thickness of 6 μm. The thickness of the dielectric is much lower here than the microreactors studied so far. The devices consist of cavities with 25 to 150 μm in diameter. Experiments of the microdischarges are performed in inert gases at a pressure between 100 and 1000 Torr. We first studied the phenomena of ignition and extinction for the microdevices based on alumina. Then, we studied the microreactors based on silicon containing 1 to 1024 cavities under DC and AC regimes. Characteristics of microdischarges were studied by electrical measurements, measurements of optical emission spectroscopy (OES), laser diode absorption spectroscopy (DLAS) and phase resolved optical emission spectroscopy (PROES). These diagnostics allowed us to investigate the phenomena of ignition, extinction, instability and failure mechanisms of the microplasma devices. This thesis work allowed testing the performance and technological limitations of the silicon based microdischarge arrays. Particular attention was paid to their life time.

This quantitative, descriptive study investigated risk factors for MDR-TB in Addis Ababa, Ethiopia. A total of 439 medical records belonging to MDR-TB and non MDR-TB patients managed in public health centres from January 2008 to December 2011 were analysed. Data were transcribed from each TB patient‟s medical records using a specifically designed checklist. The findings revealed that male gender, previous history of TB treatment, poor treatment adherence, an outcome of failure after TB re-treatment, previous category of failure, pulmonary involvement of TB infection and HIV infection were associated with MDR-TB. The findings illustrate that efforts should be made to prioritise the development and implementation of effective MDR TB screening and treatment protocols for these high risk groups to improve treatment outcome and minimize the emergence of XDR TB. / Health Studies / M.A. (Public Health)

On the 26th of May 2021 the new regulation for medical devices, MDR 2017/745, will come into force. The underlying incentives to go from the medical device directive (MDD 93/42/EEC) to MDR are a series of adverse events involving medical devices. The main goal of MDR is to strengthen and improve the already existing legislation and thus will entail large changes for manufactures, one of them being manufacturers of Electronic Health Record (EHR) systems. For medical software, such as EHR systems, the new regulation will imply an upgrade in risk classification. This upgrade will bring additional requirements for EHR manufacturers. Furthermore, the released guidelines have been insufficient regarding the specific requirements for medical device software and thus EHR manufacturers are in need of tools and guidance to fulfill MDR. This thesis examines the new regulation for medical devices and thus identifies main requirements for EHR manufacturers. A qualitative approach was conducted comprising a literature study as well as a document study of the medical device regulation along with interviews with experts within the field of medtech regulatory affairs and quality assurance. The information gathered was analyzed to create a process description on how EHR manufacturers are to fulfill MDR. The process description is a general outline and presents the main steps on the route to be compliant with MDR in a recommended order of execution. The main steps are: divide the system into modules, qualify the modules, classify the modules, implement a quality management system, compile a technical documentation, compile the declaration of conformity, undergo a conformity assessment and finally, obtain the CE-mark. To each of the main steps additional documentation provides further information and clarification. The process description functions as a useful tool for EHR manufacturers towards regulatory fulfillment. Even though the process description is created for EHR manufacturers, it can be useful for other medical device software manufacturers. The process description provides an overview of the path to a CE mark and functions as a guidance. It can be used in educational purposes as well as to serve as a checklist for the experienced manufacturer to make sure everything is covered. However, it is not sufficient to rely solely on the process description in order to be in full compliance with MDR. Moreover, there is still a need for further clarifications from the European Commission regarding specific requirements on medical device software.