This research used human factors methods to investigate the relationship between no fault found (NFF) incident frequency and device usability. NFF reporting occurs when a medical device sent for repair is found to be operating normally. NFF incidents are one of the most recurrent failure modes, and therefore have considerable impact on cost, dependability and safety. An analysis of medical equipment maintenance data was conducted and six devices with a high NFF reporting frequency were identified. Semi-structured interviews and heuristics evaluations revealed that usability issues likely caused many of the NFF incidents. Other factors suspected to contribute to increased NFF reporting include accessory issues, intermittent faults and environmental issues. Finally, in order to validate the results, usability testing was conducted on three of the devices. 23 usability-related design flaws were identified. Therefore devices containing latent usability-related design flaws can be identified through analysis of medical equipment maintenance data.

Acute demyelination in children may be a monophasic illness or the sentinel attack of multiple sclerosis (MS) – a chronic inflammatory neurodegenerative demyelinating disease. MS risk is largely determined during childhood and vitamin D may protect against MS. The primary objective of this thesis was to evaluate vitamin D status in children presenting with acute demyelinating syndromes (ADS) as a potential contributor to MS outcome. The LIAISON “25 OH Vitamin D TOTAL” assay was validated to assess the biomarker of vitamin D status – serum 25-hydroxyvitamin D (25(OH)D) concentrations. Consecutive patients (<16 y) were enrolled at presentation with ADS and prospectively evaluated at 23 Canadian centres. MS was defined by a second clinical demyelinating event or by MRI evidence of new lesions over time. Cox proportional hazards regression models assessed risk of MS outcome as a function of serum 25(OH)D tertiles, accounting for factors associated with either MS risk or vitamin D status – age, sex, season, and HLA-DRB1*15 status. Of 211 children with 25(OH)D measured in sera obtained a median of 9 days from onset (interquartile range, 5 – 17 d; maximum 36 days), 20% (n = 41) were diagnosed with MS after 3.7 mos. (3.1 – 7.3 mos.). Risk of MS was lower in children with 25(OH)D levels in the highest tertile (≥ 74 nmol/L) at ADS versus those in the lowest tertile (<50 nmol/L) (HR 0.41; 95% CI 0.18 to 0.97, adjusted model). Children with higher circulating 25(OH)D concentrations at ADS have a lower risk of MS. Further evidence for a role of vitamin D insufficiency during childhood and adolescence contributing to MS risk comes from three MS patients with suboptimally managed pseudo-vitamin D deficiency rickets. Finally, a sun exposure questionnaire was validated in the latter part of this thesis for use in future research into determinants of vitamin D status and their association with risk of MS.

This qualitative research study examined the patient education experience from the point of view of health care professionals, namely doctors of chiropractic in the Greater Toronto Area practicing for up to ten years. Health care professionals’ views and beliefs of this important aspect of health care have not been well studied. Patient education is defined as, “the process by which patients learn or acquire knowledge about his/her health status or condition and may involve learning in the cognitive, affective, and/or psychomotor domains.” The study explored eight participants’ views on the nature of patient education in their early and current practices by examining their feelings, beliefs, and use of patient education, its role in their practices, as well as the perceptions of their roles as patient educators. Two semi-structured interviews were conducted with each of the participants. The transcribed interviews underwent detailed qualitative analysis to determine response trends and consensus. The key findings revealed that the participants felt that, while they were well prepared in their undergraduate curricula to diagnose and treat patients, they were not as well prepared to be effective patient educators when they entered practice. Early in their careers, they did not understand or appreciate patient education’s importance and value as a component of their practice. Over time, their beliefs and understanding of patient education changed and participants reported that with experience, they began to value patient education to a greater extent. Changing values reflected changing behaviours. For example, participants increased their time and efforts related to patient education with increased clinical experience. A variety of teaching aids were used with wall charts/posters, three dimensional anatomical models, printed materials and images from textbooks being among the most common. Most of the teaching described by the participants would be characterized as transmission with a one-way flow of information from the doctor to the patient. To a great extent, patient education involved speaking with individual patients. Participants reported encountering, throughout their careers, intrinsic and extrinsic barriers that interfered with the effectiveness of their patient education. The findings suggest that curricular planners for health care professional programs, and specifically for chiropractors, might consider developing content aimed at improving students’ patient education knowledge and skills.

Des décisions médicales en fin de vie sont souvent prises pour des patients inaptes. Nous avons souhaité connaître les argumentations éthiques entourant ces décisions difficiles. Notre objectif était de pouvoir comprendre et apprécier ces lignes d’argumentation. Pour atteindre cet objectif, nous avons répertorié et analysé les lignes argumentatives présentes dans des articles scientifiques, incluant les sections de correspondance et commentaires des journaux savants. Afin d’éviter que les résultats de notre analyse soient trop influencés par les caractéristiques d’un problème médical spécifique, nous avons décidé d’analyser des situations cliniques distinctes. Les sujets spécifiques étudiés sont la non-initiation du traitement antibiotique chez des patients déments souffrant de pneumonie, et l’euthanasie de nouveau-nés lourdement hypothéqués selon le protocole de Groningen. Notre analyse des lignes d’argumentation répertoriées à partir des débats entourant ces sujets spécifiques a révélé des caractéristiques communes. D’abord, les arguments avancés avaient une forte tendance à viser la normativité. Ensuite, les lignes d’argumentation répertoriées étaient principalement axées sur les patients inaptes et excluaient largement les intérêts d’autrui. Nous n’avons trouvé aucune des lignes d’argumentation à visée normative répertoriés concluante. De plus, nous avons trouvé que l’exclusion catégorique d’arguments visant l’intérêt d’autrui des considérations entrainait l’impossibilité d’ évaluer leur validité et de les exclure définitivement de l’argumentaire. Leur présence non-explicite et cachée dans les raisonnements motivant les décisions ne pouvait alors pas être exclue non plus. Pour mieux mettre en relief ces conclusions, nous avons rédigé un commentaire inspiré par les argumentaires avancés dans le contexte de l’arrêt de traitement de Terri Schiavo, patiente en état végétatif persistant. Nous pensons que l’utilisation d’un argumentaire qui viserait davantage à rendre les actions intelligibles, et sans visée normative immédiate, pourrait contribuer à une meilleure compréhension réciproque des participants au débat. Une telle argumentation nous semble aussi mieux adaptée à la complexité et l’unicité de chaque cas. Nous pensons qu’elle pourrait mieux décrire les motivations de tous les acteurs participant à la décision, et ainsi contribuer à une plus grande transparence. Cette transparence pourrait renforcer la confiance dans l’authenticité du débat, et ainsi contribuer à une meilleure légitimation de pratiques cliniques. / Medical decision making is often occurring at the end of life of inapt patients. We wished to learn about and appreciate the ethical arguments concerning these difficult decisions. Our objective was to understand and evaluate these lines of argument. To reach this objective, we have listed and analyzed lines of argument as they were presented in scientific articles, including the sections correspondence and commentary of scholarly journals. In order to avoid that our results are too much influenced by the specifics of one given clinical problem, we decided to analyze distinct clinical settings. The specific subjects studied are the non-initiation of antibiotic treatment for demented patients suffering from pneumonia, and active euthanasia of severely affected newborns following the Groningen protocol. Our analysis of the indexed lines of arguments from debates dealing with these specific subjects has revealed common characteristics. First, the issued argumentations had a strong normative tendency. Second, the indexed argumentation was principally oriented towards the patient himself, while largely excluding the interests of others. We found that none of the indexed normative lines of argument was compelling. Moreover, we found that the systematic exclusion of arguments based on the interests of others entailed the impossibility to evaluate them, and potentially to exclude them definitively from the considerations. It was thus also impossible to evaluate their potentially concealed persistence as a driving force motivating the decisions made. In order to illuminate these conclusions, we have written a commentary inspired by the lines of arguments evoked in the context of the treatment withdrawal of Terri Schiavo, a patient in persistently vegetative state. We believe that the use of lines of argument that render decisions intelligible, without however aiming at immediate normativity, could contribute to a better mutual understanding between the participants of such debates. Such argumentation also seems, in our opinion, more adapted to take the complexity and uniqueness of each single clinical case into account. We believe that such argumentation could better describe the respective motivations of the participants in the decision, and thus increase its transparency. Increased transparency would reinforce the confidence in the authenticity of the debate, and thus better legitimate clinical practice.

Regenerative medicine (RM) has the potential to develop new treatments for chronic disease and injury that are desperately needed in developing countries. Several emerging economies are actively participating in RM, producing new knowledge and initiating clinical trials. This thesis presents case studies of RM in China and Brazil and a comparative analysis of RM across Brazil, China and India. I aim to better understand the state of RM, how it has developed and what is needed for RM innovation to succeed within these countries. Case studies were conducted using face-to-face in-depth semi-structured interviews with RM experts from different areas including research institutes, hospitals, firms, educational institutes, government, policy agencies, and bioethics groups. Interviews were analysed using thematic analysis and triangulated with the analysis of research articles, government reports, laws and other primary and grey literature. China is now the 5th most prolific publisher on stem cells in the world. Chinese RM benefits from permissive regulations and the expertise of Chinese returnees that have trained abroad, but the field’s reputation is challenged by a weak regulatory system and the clinical availability of untested stem cell therapies. Brazil has created a small but strong RM program, but needs to address challenges to the field including inconsistent funding, slow importation of materials, and weak linkages between stake-holders. Comparative analysis of the three countries identifies several common elements that support RM, including linkages between stake-holders, government support, infrastructure, human resources, and good governance. RM capacity is clustered in large urban centres, which could exacerbate socio-economic and health disparities unless measures are taken to ensure equitable distribution of benefits. RM does not adhere to classical views of southern innovation, suggesting that new models are needed to describe innovation in emerging technologies, where countries are keeping up instead of catching up.

Regenerative medicine (RM) has the potential to develop new treatments for chronic disease and injury that are desperately needed in developing countries. Several emerging economies are actively participating in RM, producing new knowledge and initiating clinical trials. This thesis presents case studies of RM in China and Brazil and a comparative analysis of RM across Brazil, China and India. I aim to better understand the state of RM, how it has developed and what is needed for RM innovation to succeed within these countries. Case studies were conducted using face-to-face in-depth semi-structured interviews with RM experts from different areas including research institutes, hospitals, firms, educational institutes, government, policy agencies, and bioethics groups. Interviews were analysed using thematic analysis and triangulated with the analysis of research articles, government reports, laws and other primary and grey literature. China is now the 5th most prolific publisher on stem cells in the world. Chinese RM benefits from permissive regulations and the expertise of Chinese returnees that have trained abroad, but the field’s reputation is challenged by a weak regulatory system and the clinical availability of untested stem cell therapies. Brazil has created a small but strong RM program, but needs to address challenges to the field including inconsistent funding, slow importation of materials, and weak linkages between stake-holders. Comparative analysis of the three countries identifies several common elements that support RM, including linkages between stake-holders, government support, infrastructure, human resources, and good governance. RM capacity is clustered in large urban centres, which could exacerbate socio-economic and health disparities unless measures are taken to ensure equitable distribution of benefits. RM does not adhere to classical views of southern innovation, suggesting that new models are needed to describe innovation in emerging technologies, where countries are keeping up instead of catching up.

Medicine has been called a science, as well as an art or a craft, among other terms that express aspects of its practical nature. Medicine is not the abstract pursuit of knowledge. Medical researchers and clinical practitioners aim primarily to help people. As a first approximation then, given its practical focus on the person, the most important question in medicine is: what works? To answer that question, however, we need to understand how we know what works. What are the standards, methods and limits of medical knowledge? That is the central focus and subject of this inquiry: how we know what works in medicine. To explore medical knowledge and its limits, this thesis examines the common notion that laughter is the best medicine. Focusing on laughter provides a robust case study of how we know what works in medicine; it also, in part, reveals the thin, perhaps even non-existent, distinction in medicine between empirically-grounded knowledge and intuition. As there is no single academic discipline devoted to laughter in medicine, the first chapter situates and charts the course of this unusual project and explains why inquiry into laughter in medicine matters. In the following chapters, we encounter claims from distinguished sources that laughter and humor are the best medicine. These claims are examined from a variety of perspectives including not only the orthodox view of evidence-based medicine, but also from narrative, evolutionary and complexity views of medicine. The rarely explored serious negative side of laughter is also examined. No view provides a firm foundation for belief in laughter medicine. A general conclusion from this inquiry is that none of the approaches effectively tame the complexity of medical phenomena; indeed each starkly reveals a greater complexity than found at first glance. A narrower conclusion is that providing a basis for claims about laughter in medicine poses its own specific challenges. A third conclusion is that, as things stand, none of the existing approaches seems up to the task of determining whether something such as laughter is the best medicine.

Cette étude a pour but de tester si l’ajout de variables biomécaniques, telles que celles associées à la morphologie, la posture et l’équilibre, permet d’améliorer l’efficacité à dissocier 29 sujets ayant une scoliose progressive de 45 sujets ayant une scoliose non progressive. Dans une étude rétrospective, un groupe d’apprentissage (Cobb: 27,1±10,6°) a été utilisé avec cinq modèles faisant intervenir des variables cliniques, morphologiques, posturales et d’équilibre et la progression de la scoliose. Un groupe test (Cobb: 14,2±8,3°) a ensuite servit à évaluer les modèles dans une étude prospective. Afin d’établir l’efficacité de l’ajout de variables biomécaniques, le modèle de Lonstein et Carlson (1984) a été utilisé à titre d’étalon de mesures. Le groupe d’apprentissage a été utilisé pour développer quatre modèles de classification. Le modèle sans réduction fut composé de 35 variables tirées de la littérature. Dans le modèle avec réduction, une ANCOVA a servit de méthode de réduction pour passer de 35 à 8 variables et l’analyse par composantes principales a été utilisée pour passer de 35 à 7 variables. Le modèle expert fut composé de huit variables sélectionnées d’après l’expérience clinque. L’analyse discriminante, la régression logistique et l’analyse par composantes principales ont été appliquées afin de classer les sujets comme progressifs ou non progressifs. La régression logistique utilisée avec le modèle sans réduction a présenté l’efficience la plus élevée (0,94), tandis que l’analyse discriminante utilisée avec le modèle expert a montré l’efficience la plus faible (0,87). Ces résultats montrent un lien direct entre un ensemble de paramètres cliniques et biomécaniques et la progression de la scoliose idiopathique. Le groupe test a été utilisé pour appliquer les modèles développés à partir du groupe d’apprentissage. L’efficience la plus élevée (0,89) fut obtenue en utilisant l’analyse discriminante et la régression logistique avec le modèle sans réduction, alors que la plus faible (0,78) fut obtenue en utilisant le modèle de Lonstein et Carlson (1984). Ces valeurs permettent d’avancer que l’ajout de variables biomécaniques aux données cliniques améliore l’efficacité de la dissociation entre des sujets scoliotiques progressifs et non progressifs. Afin de vérifier la précision des modèles, les aires sous les courbes ROC ont été calculées. L’aire sous la courbe ROC la plus importante (0,93) fut obtenue avec l’analyse discriminante utilisée avec le modèle sans réduction, tandis que la plus faible (0,63) fut obtenue avec le modèle de Lonstein et Carlson (1984). Le modèle de Lonstein et Carlson (1984) n’a pu séparer les cas positifs des cas négatifs avec autant de précision que les modèles biomécaniques. L’ajout de variables biomécaniques aux données cliniques a permit d’améliorer l’efficacité de la dissociation entre des sujets scoliotiques progressifs et non progressifs. Ces résultats permettent d’avancer qu’il existe d’autres facteurs que les paramètres cliniques pour identifier les patients à risque de progresser. Une approche basée sur plusieurs types de paramètres tient compte de la nature multifactorielle de la scoliose idiopathique et s’avère probablement mieux adaptée pour en prédire la progression. / The purpose of this study is to examine whether the addition of biomechanical variables, such as variables associated with morphology, posture and balance, produce an increase in dissociation efficiency of 29 subjects with progressive scoliosis from 45 subjects with non progressive scoliosis. In a retrospective study, a learning group (Cobb: 27,1±10,6°) was used with five models comprising clinical, morphological, postural and balance variables and scoliosis progression. A testing group (Cobb: 14,2±8,3°) was then used to evaluate the models in a prospective study. In order to establish the efficiency of the addition of biomechanical variables, Lonstein and Carlson’s (1984) model was used as a reference. The learning group was used to develop four classification models. The model without reduction was composed of 35 variables taken from the literature. In the model with reduction, an ANCOVA served as a reduction method to go from 35 to 8 variables and principal component analysis was used to go from 35 to 7 variables. The expert model was composed of eight variables selected according to clinical experience. Discriminant analysis, logistic regression and principal component analysis were applied in order to classify the subjects as progressive or non progressive. Logistic regression used with the model without reduction presented the highest efficiency (0,94), whereas discriminant analysis used with the expert model showed the lowest efficiency (0,87). These results show a direct relation between a group of clinical and biomechanical parameters and idiopathic scoliosis progression. The testing group was used to apply the models developed from the learning group. The highest efficiency (0,89) was obtained with the use of discriminant analysis and logistic regression and the model without reduction, as the lowest (0,78) was obtained with the use of Lonstein and Carlson’s (1984) model. These values suggest that the addition of biomechanical variables to clinical data increases dissociation efficiency between progressive and non progressive scoliotic subjects. In order to verify the precision of the models, the area under the ROC curve was calculated. The largest area under the ROC curve (0,93) was obtained with the discriminant analysis used with the model without reduction, whereas the lowest (0,63) was obtained with Lonstein and Carlson’s (1984) model. Lonstein and Carlson’s (1984) model could not separate the positive cases from the negative cases with the same amount of precision compared with the biomechanical models. The addition of biomechanical variables to clinical data allowed increasing dissociation efficiency between progressive and non progressive scoliotic subjects. These results suggest that factors other than clinical parameters can identify patients at risk of progression. An approach based on many types of parameters takes into account the multi-factorial nature of idiopathic scoliosis and appears to be better adapted to predict it’s progression.

L’encéphalopathie hépatique (EH) se développe chez les patients atteints d’une maladie du foie et se caractérise par de nombreuses anomalies neuropsychiatriques. L’insuffisance hépatique aiguë (IHA) se caractérise par une perte progressive de l’état de conscience, par une augmentation rapide de l’œdème cérébral et une augmentation de la pression intracrânienne entraînant une herniation cérébrale et la mort. Plusieurs facteurs sont responsables du développement de l’EH mais depuis une centaine d’années, l’hyperammonémie qui peut atteindre des concentrations de l’ordre de plusieurs millimolaires chez les patients atteints d’IHA aux stades de coma est considérée comme un facteur crucial dans la pathogenèse de l’EH. La présente thèse comprend 4 articles suggérant l’implication de nouveaux mécanismes pathogéniques dans le développement de l’EH et de l’œdème cérébral associés à l’IHA et tente d’expliquer l’effet thérapeutique de l’hypothermie et de la minocycline dans la prévention de l’EH et de l’œdème cérébral: 1. L’IHA induite par dévascularisation hépatique chez le rat se caractérise par une augmentation de la production de cytokines pro-inflammatoires cérébrales (IL-6, IL-1, TNF-). Cette observation constitue la première évidence directe que des mécanismes neuro-inflammatoires jouent une rôle dans la pathogenèse de l’EH et de l’œdème cérébral associés à l’IHA (Chapitre 2.1, articles 1 et 2). 2. L’activation de la microglie telle que mesurée par l’expression de marqueurs spécifiques (OX42, OX-6) coïncide avec le développement de l’encéphalopathie (stade coma) et de l’œdème cérébral et s’accompagne d’une production accrue de cytokines pro-inflammatoires cérébrales (Chapitre 2.1, article 1 et 2). 3. Un stress oxydatif/nitrosatif causé par une augmentation de l’expression de l’oxyde nitrique synthétase et une augmentation de la synthèse d’oxyde nitrique cérébral participe à la pathogénèse des complications neurologiques de l’IHA (Chapitre 2.3, articles 3 et 4). 4. Des traitements anti-inflammatoires tels que l’hypothermie et la minocycline peuvent constituer de nouvelles approches thérapeutiques chez les patients atteints d’IHA (Chapitre 2.1, article 1; Chapitre 2.2, article 2). 5. Les effets bénéfiques de l’hypothermie et de la minocycline sur les complications neurologiques de l’IHA expérimentale s’expliquent, en partie, par une diminution du stress oxydatif/nitrosatif (Chapitre 2.3, article 3; Chapitre 2.4, article 4). / Hepatic encephalopathy (HE) contains a spectrum of neuropsychiatric abnormalities observed in patients with liver disease. A quick worsening of consciousness and increasingly growing cerebral edema, high intracranial pressure, which leads to cerebral herniation and death, are characteristics of acute liver failure (ALF). Multiple factors are found responsible for the development of HE, whereas, over 100 years, hyperammonia is considered the most crucial factor in defining the pathogenesis of HE in ALF, which can increase to millimolar concentrations in the brain at the coma stages of HE. The present thesis comprises 4 articles, which demonstrates new pathogenic mechanisms involved in the development of HE and cerebral edema in ALF, and elucidates part of the therapeutic mechanism of hypothermia and minocycline in the prevention of HE and cerebral edema during ALF. The major findings are listed below: (1) Experimental ALF leads to the increase in brain production of proinflammatory cytokines (IL-6, IL-1, TNF-α), and provides the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the encephalopathy and brain edema in ALF (chapter 2.1 - article 1; chapter 2.1 - article 2). (2) Activation of cerebral microglia, measured by OX-42, OX-6, predicts the presence of severe encephalopathy (coma) and brain edema in rats with ischemic ALF, which accompanies the increased production of brain proinflammatory cytokines (chapter 2.1 - article 1; chapter 2.2 - article 2). (3) Oxidative/nitrosative stress participates in the pathogenesis of brain edema and its complications in experimental ALF animals with ischemic liver failure. The increases in cerebral NOS isoform expression caused by ALF were sufficient to cause increased NO production in the brain (chapter 2.3 - article 3; chapter 2.4 - article 4). (4) Anti-inflammatory treatment, such as hypothermia or antibiotics, may be beneficial in patients with ALF (chapter 2.1 - article 1; chapter 2.2 - article 2). (5) The beneficial effect of both hypothermia and minocycline on the neurological complications of experimental ALF is mediated, at least in part, by reduction of brain-derived oxidative/nitrosative stress (chapter 2.3 - article 3; chapter 2.4 - article 4).

Medicine has been called a science, as well as an art or a craft, among other terms that express aspects of its practical nature. Medicine is not the abstract pursuit of knowledge. Medical researchers and clinical practitioners aim primarily to help people. As a first approximation then, given its practical focus on the person, the most important question in medicine is: what works? To answer that question, however, we need to understand how we know what works. What are the standards, methods and limits of medical knowledge? That is the central focus and subject of this inquiry: how we know what works in medicine. To explore medical knowledge and its limits, this thesis examines the common notion that laughter is the best medicine. Focusing on laughter provides a robust case study of how we know what works in medicine; it also, in part, reveals the thin, perhaps even non-existent, distinction in medicine between empirically-grounded knowledge and intuition. As there is no single academic discipline devoted to laughter in medicine, the first chapter situates and charts the course of this unusual project and explains why inquiry into laughter in medicine matters. In the following chapters, we encounter claims from distinguished sources that laughter and humor are the best medicine. These claims are examined from a variety of perspectives including not only the orthodox view of evidence-based medicine, but also from narrative, evolutionary and complexity views of medicine. The rarely explored serious negative side of laughter is also examined. No view provides a firm foundation for belief in laughter medicine. A general conclusion from this inquiry is that none of the approaches effectively tame the complexity of medical phenomena; indeed each starkly reveals a greater complexity than found at first glance. A narrower conclusion is that providing a basis for claims about laughter in medicine poses its own specific challenges. A third conclusion is that, as things stand, none of the existing approaches seems up to the task of determining whether something such as laughter is the best medicine.