The research in this thesis has been undertaken to develop statistical tools for monitoring adverse events in hospitals that adjust for varying patient risk. The studies involved a detailed literature review of risk adjustment scores for patient mortality following cardiac surgery, comparison of institutional performance, the performance of risk adjusted CUSUM schemes for varying risk profiles of the populations being monitored, the effects of uncertainty in the estimates of expected probabilities of mortality on performance of risk adjusted CUSUM schemes, and the instability of the estimated average run lengths of risk adjusted CUSUM schemes found using the Markov chain approach. The literature review of cardiac surgical risk found that the number of risk factors in a risk model and its discriminating ability were independent, the risk factors could be classified into their "dimensions of risk", and a risk score could not be generalized to populations remote from its developmental database if accurate predictions of patients' probabilities of mortality were required. The conclusions were that an institution could use an "off the shelf" risk score, provided it was recalibrated, or it could construct a customized risk score with risk factors that provide at least one measure for each dimension of risk. The use of report cards to publish adverse outcomes as a tool for quality improvement has been criticized in the medical literature. An analysis of the report cards for cardiac surgery in New York State showed that the institutions' outcome rates appeared overdispersed compared to the model used to construct confidence intervals, and the uncertainty associated with the estimation of institutions' out come rates could be mitigated with trend analysis. A second analysis of the mortality of patients admitted to coronary care units demonstrated the use of notched box plots, fixed and random effect models, and risk adjusted CUSUM schemes as tools to identify outlying hospitals. An important finding from the literature review was that the primary reason for publication of outcomes is to ensure that health care institutions are accountable for the services they provide. A detailed review of the risk adjusted CUSUM scheme was undertaken and the use of average run lengths (ARLs) to assess the scheme, as the risk profile of the population being monitored changes, was justified. The ARLs for in-control and out-of-control processes were found to increase markedly as the average outcome rate of the patient population decreased towards zero. A modification of the risk adjusted CUSUM scheme, where the step size for in-control to out-of-control outcome probabilities were constrained to no less than 0.05, was proposed. The ARLs of this "minimum effect" CUSUM scheme were found to be stable. The previous assessment of the risk adjusted CUSUM scheme assumed that the predicted probability of a patient's mortality is known. A study of its performance, where the estimates of the expected probability of patient mortality were uncertain, showed that uncertainty at the patient level did not affect the performance of the CUSUM schemes, provided that the risk score was well calibrated. Uncertainty in the calibration of the risk model appeared to cause considerable variation in the ARL performance measures. The ARLs of the risk adjusted CUSUM schemes were approximated using simulation because the approximation method using the Markov chain property of CUSUMs, as proposed by Steiner et al. (2000), gave unstable results. The cause of the instability was the method of computing the Markov chain transition probabilities, where probability is concentrated at the midpoint of its Markov state. If probability was assumed to be uniformly distributed over each Markov state, the ARLs were stabilized, provided that the scores for the patients' risk of adverse outcomes were discrete and finite.

Abstract Schizophrenia and other psychotic disorders are severe and disabling mental disorders that break out during early adulthood, often when a person is in his/her early 20s. Furthermore, functional decline in many cognitive areas, including the ability to communicate in social interactions and impaired facial expression recognition, is typical to patients with schizophrenia. Understanding the risk factors of psychosis is essential as these disorders may be more amenable to treatment in their early stages. However, recognition of those at the highest risk of psychosis is challenging as no definitive biomarkers are available. Functional MRI is a promising tool that can potentially identify neural signals relating to the individual’s risk of psychosis onset. Psychotic disorders are etiologically heterogeneous disorders — both environmental and genetic factors have been linked to the onset of psychotic disorders. The most influential risk factor for a psychotic disorder is familial risk with genetic loading. The present study examines whether familial risk of psychosis (FR), the polygenic risk score for schizophrenia (PRS) and early adversity associate with brain response to faces. We used fMRI to measure blood oxygen level dependent (BOLD) response to faces. Our study showed that FR associated with deviant prefrontal cortex BOLD responses. In addition, we detected that interregional BOLD signal and grey matter volume varied as a function of PRS; the lowest functional and structural covariance was detected in individuals with high PRS. We also detected that early adversities associated with brain response to faces and that this association varied as a function of glucocorticoid receptor gene expression. Our findings indicate that the above risk factors of psychosis associate with brain response to faces. / Tiivistelmä Skitsofrenia ja muut psykoosisairaudet ovat vakavia mielenterveyden häiriöitä, jotka puhkeavat usein nuorella aikuisiällä. Eräs tyypillinen piirre psykoosisairauksille on vaikeus tunnistaa muiden ihmisten kasvonilmeitä. Psykoosisairauksien riskitekijöiden ymmärtäminen on tärkeää, sillä hoito tehoaa parhaiten sairastumisen alkuvaiheessa. Suurimmassa psykoosivaarassa olevien henkilöiden tunnistaminen on kuitenkin haastavaa, sillä luotettavia tautiin liittyviä biomarkkereita ei ole saatavilla. Toiminnallinen magneettikuvaus (fMRI) on lupaava työkalu, jolla saattaa olla tulevaisuudessa käyttöarvoa psykoosivaaraan liittyvien aivomuutosten tunnistamisessa. Etiologialtaan psyykoosisairaudet ovat heterogeenisiä: sekä ympäristö että perinnölliset tekijät vaikuttavat yksilön sairastumisriskiin. Voimakkain riskitekijä on suvullinen psykoosialttius. Tässä osajulkaisuväitöskirjassa tutkitaan suvullisen psykoosialttiuden, skitsofrenian polygeenisen riskipisteen (PRS) sekä varhaisten vastoinkäymisten yhteyttä aivojen kasvonilmeitä tulkitsevaan järjestelmään. Tutkimuksessa on hyödynnetty fMRI-kuvausta kasvonilmestimuluksen aikana. Tutkimuksessamme suvullinen psykoosialttius oli yhteydessä etuotsalohkon fMRI-signaalimuutoksiin. Tämän lisäksi havaitsimme, että kasvonilmejärjestelmän fMRI-signaalin ja harmaan aineen kovarianssi oli yhteydessä PRS:ään: matalin aivoalueiden välinen korrelaatio havaittiin henkilöillä, joiden PRS oli korkea. Havaitsimme myös, että varhaiset vastoinkäymiset ovat yhteydessä kasvonilmeiden aikaansaamiin aivovasteisiin. Tämä assosiaatio oli myös yhteydessä glukokortikoidireseptorin geenin ilmentymiseen. Väitöskirjan löydökset viittaavat siihen, että edellä mainitut psykoosin riskitekijät ovat yhteydessä kasvonilmeitä tulkitsevaan järjestelmään.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O diabetes mellitus(DM) e as disfunções tireoidianas(DT) são as duas desordens endocrinológicas mais comuns na prática clínica. A DT não reconhecida pode interferir no controle metabólico e adicionar mais risco a um cenário predisponente à doença cardiovascular. O objetivo deste estudo foi avaliar a prevalência da DT em pacientes com diabetes mellitus tipo 1 e tipo 2 (DM1 e DM2) e avaliar o risco cardiovascular em pacientes com DM2 com e sem DT utilizando parâmetros clínicos e laboratoriais. Trata-se de um estudo observacional de corte transversal. Foram avaliados 304 pacientes com DM2 e 82 pacientes com DM1. Os pacientes foram submetidos a um inquérito clínico-demográfico e avaliação laboratorial para determinação do perfil lipídico, glicídico e da função tireoidiana. Os pacientes com DM2 tiveram seus escores de risco cardiovascular em 10 anos determinados pelas equações de Framingham e do UKPDS risk engine. A frequência de disfunção tireoidiana entre os 386 pacientes foi de 14,7%, sendo de 13% nos que não possuíam disfunção prévia. A disfunção mais frequente encontrada foi de hipotireoidismo subclínico, com 13% no DM1 e de 12% no DM2. A prevalência de anticorpos anti-tireoperoxidase (TPO) positivos foi de 10,8%, sendo de14,6% em pacientes com DM1.Foram diagnosticados 44 (11,2%) novos casos de disfunção tireoidiana em pacientes que negavam ou desconheciam terem DT prévia.Destes novos casos, 12,8% em DM1 e 13,1% em DM2.Dos 49 pacientes com DT prévia, 50% dos DM1e 76% dos DM2 estavam compensados. Não foi observada diferença entre as médias do escore de risco de Framingham entre os pacientes DM2 com eutireoidismo e com hipotireoidismo subclínico. Observou-se uma associação entre o hipotireoidismo subclínico e risco cardiovascular nos pacientes com DM2 demonstrado pela diferença estatisticamente significativa entre as médias do escore UKPDS para doença coronariana não-fatal e fatal, acidente vascular cerebral fatal entre os dois grupos (p=0,007; 0,005;0,027 respectivamente). As demais funções tireodianas (hipotireoidismo clínico, hipertireoidismo clínico e subclínico) encontradas não foram analisadas devido ao pequeno número de pacientes em cada grupo.Concluímos que o rastreio da doença tireoidiana entre os pacientes com diabetes mellitus deve ser realizado rotineiramente considerando-se a prevalência de novos casos de DT diagnosticados e o fato de que os pacientes com DM2 e com hipotireoidismo subclínico avaliados possuírem um risco cardiovascular maior. Todavia, concluímos que estudos prospectivos e com maior número de pacientes são necessários para o esclarecimento do impacto da doença tireoidiana no risco cardiovascular do paciente com DM. / Diabetes mellitus and thyroid dysfunction (TD) are the two most common endocrine disorders in clinical practice. The unrecognized TD may adversely affect the metabolic control and add more risk to an already predisposing scenario for cardiovascular diseases. The objective of this study was to evaluate the prevalence of TD in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM) and to evaluate the cardiovascular risk of patients with T2DM with and without thyroid dysfunction using clinical and laboratory parameters. This is an observational cross-sectional study. We evaluated 304 patients with T2DM and 82 patients with T1DM. The patients underwent a clinical-demographic survey and laboratory evaluation to determine the lipid and glycemic profile and thyroid function. Patients with T2DM had their 10 years cardiovascular risk scores determined by Framingham equations and the UKPDS risk engine. The frequency of TD among the 386 patients was 14.7% and 13% who denied previous TD. The most frequently TD was subclinical hypothyroidism, in 13% of patients with T1DM and in 12% of patients with T2DM.The prevalence of anti-TPO antibodies was 10.8%, being more frequently among patients with T1DM (14.6%). Forty-four (11.2%) new cases of TD were diagnosed during the study in patients who denied or were unaware of this clinical condition. Of the 49 patients with prior TD,50% of the T1DM and 76% of T2DM were compensated. No differencies were observed between the mean scores of the Framingham risk among patients with T2DM who had normal thyroid function compared to those with subclinical hypothyroidism. An association between subclinical hypothyroidism and cardiovascular risk in T2DM patients was found by statistically significant difference between the mean UKPDS scores for non-fatal and fatal CHD and fatal stroke between the two groups (p = 0,007;0,005;0027; respectively). The other TD (clinical hypothyroidism, clinical and subclinical hyperthyroidism) found were not analyzed due to the small number of patients in each group.We conclude that screening for thyroid disease among patients with diabetes mellitus should be routinely performed considering the prevalence of new cases diagnosed and the fact that patients with DM2 and subclinical hypothyroidism evaluated had a higher cardiovascular risk. However, prospective studies and with more patients are warranted to determine the impact of thyroid dysfunction in the cardiovascular risk of patients with diabetes.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Ischemic heart diseases stands out among the diseases that affect the cardiovascular system due to its high prevalence and its impact on mortality in the general population. Ischemic heart disease is the leading worldwide cause of mortality. Fenomenum that also happens in the Americas and Brazil. The term acute coronary syndrome (ACS) is used to describe a heterogeneous spectrum of clinical conditions associated with acute myocardial ischemia, including unstable angina and acute myocardial infarction (AMI). The plurality in its clinical presentation represents a diagnostic challenge for clinicians. Moreover, appropriate risk stratification is mandadatory in all patients with ACS. Some clinical tools such as physical examination, electrocardiographic observations and risk scores are extremely usefull to identify patients at high risk of unfavorable clinical outcomes. Scores of risk stratification, among those the Global Registry of Acute Coronary Events (GRACE), are widely used in the prognostic evaluation of patients with ACS.Some plasma biomarkers have also been used to improove risk stratification. The GRACE score is a fundamental part of the assessment of patients with ACS and may even prevent or minimize adverse consequences in these individuals. Nevertheless, the search for new potential prognostic parameters that could add information to these establised scores has been the subject of intense research. In this context, stands out the use of routine hematological tests , since the complete blood count is readily available for clinical use and has a good cost-benefit relationship. Recent studies have investigated the potential role of some of red cell indices, especially anemia and red cell distribution width (RDW), in the prognostic evaluation of patients with several cardiovascular conditions. The presence of anemia and elevated RDW in patients with ACS have been independently associated with increased risk of adverse events such as heart failure, recurrent ischemic events, and death. We have hipotezazed that the addition of the hemalological indices to the GRACE score would improve its ability to stratify patients.The main objective of this study was to investigate whether inclusion of anemia or RDW, assessed at admission, in the GRACE score model to predic in-hospital mortality, could improve the discrimination and calibration of these model, as well as risk stratification in patients with ACS. For this, a cohort study, including 109 patients with AMI was carried out. Cox regression models including the variables of the GRACE score and RDW or anemia were constructed. Measures of calibration and discrimination, and reclassification of patients were also calculated for the new models. The new models, either with the inclusion of anemia, or the addition of RDW showed adequate calibration and discrimination. Furthermore, the addition of these parameters to the original model allowed adequate reclassification of patients in different categories of risk. The red cell indices, anemia and RDW showed potential prognostic for use in risk assessment of patients with ACS, allowing the improvement of risk stratification performed through the GRACE score. / A cardiopatia isquêmica destaca-se entre as doenças que acometem o sistema cardiovascular, devido à sua alta prevalência e a seu impacto sobre a mortalidade na população em geral. As doenças isquêmicas do coração são a principal causa de mortalidade mundial, nas Américas e no Brasil. O termo SCA é usado para descrever um espectro heterogêneo de condições clínicas associadas com isquemia aguda do miocárdio, incluindo angina instável e infarto agudo do miocárdio (IAM). A diversidade na apresentação clínica de pacientes com esta patologia representa um desafio para os clínicos em termos de diagnóstico e de estratificação de risco apropriada. Algumas ferramentas clínicas como exame físico, observações eletrocardiográficas e escores de risco, são de extrema relevância na identificação de pacientes com alto risco de desfechos clínicos desfavoráveis. Além disso, alguns biomarcadores plasmáticos também vêm sendo utilizados com este propósito e a busca por novos parâmetros com potencial prognóstico tem sido alvo de intensas pesquisas. Neste contexto, destaca-se a utilização dos testes hematológicos de rotina na estratificação de risco, uma vez que o hemograma é um exame amplamente disponível para uso clínico e possui uma boa relação custo benefício. Estudos recentes tem investigado o potencial papel de alguns dos índices hematimétricos, especialmente anemia e amplitude de distribuição dos eritrócitos (RDW), na avaliação prognóstica de pacientes apresentando diversas condições cardiovasculares. A presença de anemia, bem como valores elevados de RDW em pacientes com SCA tem sido independentemente associados com maior risco de eventos adversos como mortalidade, desenvolvimento de insuficiência cardíaca e ocorrência de eventos isquêmicos recorrentes. Os escores de estratificação de risco, principalmente o Global Registry of Acute Coronary Events (GRACE), são amplamente utilizados na avaliação prognóstica de pacientes com SCA. No entanto, os modelos disponíveis atualmente não incluem os índices hematimétricos na determinação do risco do paciente. Considerando que a estratificação de risco é parte fundamental da avaliação de pacientes com SCA, podendo evitar ou mesmo minimizar consequências adversas nestes indivíduos, o principal objetivo deste estudo foi investigar se a inclusão de anemia ou RDW, avaliados na admissão hospitalar, ao escore GRACE para a predição de mortalidade durante o período de internação hospitalar, podem melhorar a calibração e discriminação do modelo, bem como a estratificação de risco em pacientes com SCA. Para isso, um estudo de coorte, incluindo 109 pacientes com IAM, foi realizado. Modelos de regressão de Cox incluindo as variáveis do escore GRACE e o RDW ou a anemia foram construídos. Medidas de calibração e discriminação também foram calculadas, bem como o percentual de reclassificação dos pacientes para os novos modelos propostos. Os novos modelos, tanto com a inclusão de anemia, quanto com a adição de RDW, apresentaram adequada calibração e discriminação. Além disso, a adição destes parâmetros ao modelo original permitiu uma adequada reclassificação dos pacientes em diferentes categorias de risco. Os índices hematimétricos, anemia e RDW, demonstraram potencial prognóstico para utilização na avaliação de risco de pacientes com SCA, permitindo o aprimoramento da estratificação de risco realizada através do escore GRACE.

Le diabète de type 2 (DT2) est une maladie chronique grave et sa prévalence ne cesse d’augmenter partout dans le monde. La complication la plus sévère et la plus courante du diabète est la néphropathie diabétique dont le premier symptôme est l’albuminurie. Notre premier objectif est d’évaluer si un dépistage précoce de l’albuminurie permet une meilleure prise en charge de cette complication dans la pratique générale des médecins. Notre deuxième objectif est de valider l’efficacité de notre score de risque polygénique (SRP) sur la prédiction du risque d’albuminurie sur une cohorte canadienne composée de patients DT2, hypertendus provenant de groupe de médecine familiale (GMF) et de family health team (FHT) au Québec et en Ontario (CLINPRADIA I). Le SRP a permis de déterminer les 30% de patients à risque élevé de développer l’albuminurie. En effet, la prévalence d’albuminurie des 30% des sujets classés à haut risque génétique par le SRP était 2,6 fois plus élevée que le reste des patients de CLINPRADIA I. Dans la même cohorte, nous avons démontré que l’introduction d’un point of care testing (POCT) a amélioré la pratique et l’adhésion des médecins aux lignes directrices du traitement de l’albuminurie. Les valeurs d’albuminurie et le nombre de patients albuminuriques ont diminué significativement en réponse à l’introduction du POCT. Nous pouvons conclure de nos résultats que l’utilisation de notre SRP permettrait d’identifier les patients à risque élevés d’albuminurie alors que le POCT permettrait un dépistage précoce et un meilleur suivi de l’albuminurie chez ces patients. / Type 2 diabetes (T2D) is a serious chronic disease and its prevalence keeps increasing all over the world. The most severe and common diabetes complication is nephropathy of which the first symptom is albuminuria. Our first objective is to evaluate if early screening of albuminuria allows for a better patient care of this condition in general practitioner practice. Our second objective is to validate the efficacy of our polygenetic risk score (PRS) on the risk prediction of albuminuria on Canadian cohort composed of hypertensive TD2 patients from groupe de médecine familiale (GMF) and family health team (FHT) in Quebec and in Ontario (CLINPRADIA I). The PRS identified the 30% of T2D patients at high risk of developing albuminuria. Indeed, the albuminuria prevalence of the 30% of subjects at high genetic risk based on the PRS was 2.6 times higher than the remaining patients of CLINPRADIA I. In the same cohort, we established that the introduction of the point of care testing (POCT) improves the practice and the adherence of physicians to the guidelines for the treatment of albuminuria. The values of albuminuria and the number of patients with albuminuria decreased significantly after the introduction of the POCT. We can conclude from our results that the use of our PRS enables the early identification of the patients at high risk of albuminuria while the POCT enables the early detection of patients with albuminuria who benefited from an early intervention.

La consommation de cannabis durant l'adolescence est associée à des risques accrus de problèmes de santé mentale, y compris la toxicomanie et la psychose. Tout en considérant qu'une partie de l'étiologie de ces troubles est héréditaire, nous avons étudié le risque génétique de psychose et de troubles liés à l'usage de substances et leurs relations avec le cannabis et le système endocannabinoïde. Dans notre premier travail, nous avons étudié la relation entre les marqueurs génétiques endocannabinoïdes et les troubles d’usage d'alcool (TUA) pour deux cohortes d'adolescents. À l’aide d’approches de gènes candidats, nous avons démontré une relation significative entre ces gènes endocannabinoïdes et les TUA, mais ces résultats n'ont pas été répliqués chez une deuxième cohorte indépendante. Lors d’une seconde étude, nous avons examiné si la relation entre le score de risque polygénique pour la schizophrénie (PRS-Sz) et les expériences prépsychotiques (PLE) est médiée et/ou modérée par la consommation de cannabis, pour deux cohortes indépendantes. Des modèles de régression de médiation et de modération ont été utilisés pour examiner dans quelle mesure la relation prospective entre PRS-Sz et PLE est expliquée par la consommation de cannabis. Les résultats des analyses de médiation et de modération n'étaient pas significatifs, bien que le PRS-Sz et la consommation de cannabis aient tous deux prédit indépendamment les PLE. Ces résultats suggèrent que la consommation de cannabis reste un facteur de risque de psychose, au-delà de la vulnérabilité génétique connue pour la schizophrénie et qu’il n'y a pas de preuve que les individus génétiquement vulnérables étaient plus sensibles aux conséquences psychotiques de la consommation de cannabis. Le travail décrit démontre que les risques posés par la consommation de cannabis chez les adolescents pourraient ne pas être associés à une prédisposition génétique aux maladies psychiatriques, nonobstant l’implication du système endocannabinoïde dans la pathogenèse de ces mêmes maladies. / Cannabis consumption during adolescence, increases the likelihood of adverse mental health outcomes, including substance abuse and psychosis. Considering that part of the etiology of these disorders are heritable, we aimed to elucidate the genetic risk for psychosis and substance use disorders and their relationships to cannabis and the endocannabinoid system. In our first work, we investigated the relationship between endocannabinoid genetic markers and alcohol use disorder in two adolescent cohorts. Through candidate gene approaches we demonstrated a significant relationship between these endocannabinoid genes and AUD, but the results were not replicated in the second cohort. In a second work, we examined if the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic like experiences (PLE) is mediated and/or moderated by cannabis use, in two cohorts. Mediation and moderation regression models were used to examine the extent to which the prospective relationship between PRS-Sz and PLE is accounted for by cannabis use. The results of both the mediation and moderation analyses were not significant, although PRS-Sz and cannabis use both independently predicted PLE. These results suggest that cannabis use remains a risk factor for psychotic-like experiences, over and above known genetic vulnerability for schizophrenia and there was no evidence that genetically vulnerable individuals were more susceptible to the psychosis-related outcomes of adolescent onset cannabis use. The work described demonstrates that the risks posed by adolescent cannabis consumption may be unrelated to one’s genetic predisposition to psychiatric disease, notwithstanding the involvement of the endocannabinoid system in the pathogenesis of these same diseases.

Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common severe surgical complication after pancreatic surgery. Current risk stratification systems mostly rely on intraoperatively assessed factors like manually determined gland texture or blood loss. We developed a preoperatively available image-based risk score predicting CR-POPF as a complication of pancreatic head resection. Frequency of CR-POPF and occurrence of salvage completion pancreatectomy during the hospital stay were associated with an intraoperative surgical (sFRS) and image-based preoperative CT-based (rFRS) fistula risk score, both considering pancreatic gland texture, pancreatic duct diameter and pathology, in 195 patients undergoing pancreatic head resection. Based on its association with fistula-related outcome, radiologically estimated pancreatic remnant volume was included in a preoperative (preFRS) score for POPF risk stratification. Intraoperatively assessed pancreatic duct diameter (p < 0.001), gland texture (p < 0.001) and high-risk pathology (p < 0.001) as well as radiographically determined pancreatic duct diameter (p < 0.001), gland texture (p < 0.001), high-risk pathology (p = 0.001), and estimated pancreatic remnant volume (p < 0.001) correlated with the risk of CR-POPF development. PreFRS predicted the risk of CR-POPF development (AUC = 0.83) and correlated with the risk of rescue completion pancreatectomy. In summary, preFRS facilitates preoperative POPF risk stratification in patients undergoing pancreatic head resection, enabling individualized therapeutic approaches and optimized perioperative management.

Contexte L’occlusion d’une artère du cœur cause un syndrome coronarien aigu (SCA) soit avec une élévation du segment ST (IAMEST) ou sans élévation du segment ST (1). Le traitement des patients avec un IAMEST requiert soit une intervention coronarienne d’urgence (ICP primaire) ou une thérapie fibrinolytique (FL). La thérapie FL peut être administrée soit dans un contexte pré-hospitalier (PHL) ou à l’hôpital. Une prise en charge précoce des patients avec SCA peut être améliorée par un simple indice de risque. Objectifs Les objectifs de cette thèse étaient de : 1) comparer l’ICP primaire et la thérapie FL (2); décrire plusieurs systèmes internationaux de PHL; (3) développer et valider un indice de risque simplifié pour une stratification précoce des patients avec SCA. Méthodes Nous complétons des méta-analyses, de type hiérarchique Bayésiennes portant sur l’effet de la randomisation, d’études randomisées et observationnelles; complétons également un sondage sur des systèmes internationaux de PHL; développons et validons un nouvel indice de risque pour ACS (le C-ACS). Résultats Dans les études observationnelles, l’ICP primaire, comparée à la thérapie FL, est associée à une plus grande réduction de la mortalité à court-terme; mais ce sans bénéfices concluants à long terme. La FL pré-hospitalière peut être administrée par des professionnels de la santé possédant diverses expertises. Le C-ACS a des bonnes propriétés discriminatoires et pourrait être utilisé dans la stratification des patients avec SCA. Conclusion Nous avons comblé plusieurs lacunes importantes au niveau de la connaissance actuelle. Cette thèse de doctorat contribuera à améliorer l’accès à des soins de qualité élevée pour les patients ayant un SCA. / Background Acute occlusion of an artery of the heart results in acute coronary syndromes (ACS), either with ST-segment elevation (STEMI) or without ST-segment elevation (1). STEMI requires urgent treatment to restore coronary artery flow either by primary percutaneous coronary intervention (PCI) or fibrinolytic therapy (FL) (2). Although several randomized controlled trials (RCTs) demonstrate the superiority of primary PCI in reducing mortality compared to FL (2), the benefit of primary PCI over FL remains uncertain in unselected “real-life” patients (3,4). FL can be administered either in the pre-hospital setting (i.e., pre-hospital FL (PHL)) or at the hospital. PHL is rarely available outside Europe (5,6). Insights into the organization of PHL systems of care may promote more widespread use of PHL. Risk stratification of ACS patients should be prompt to ensure timely PCI for high-risk patients and to avoid unnecessary intervention in low-risk patients (7). Despite the availability of numerous ACS risk scores, there is still no simple risk score that can be easily applied in the initial management of ACS patients (8). Objectives The objectives of this doctoral dissertation were to address these current knowledge gaps in the optimal management of ACS. The objectives were to: 1) evaluate the efficacy, effectiveness, and safety of primary PCI and FL, (2) describe the infrastructure, processes and outcomes of several international PHL systems; and (3) develop and validate a novel clinical risk score for early risk stratification of ACS patients. Methods To address these objectives, I completed Bayesian hierarchical random-effects meta-analyses of published RCTs and observational studies which compare primary PCI and FL in patients with STEMI. I undertook a survey of the infrastructure, processes and outcomes of PHL in several European and North American pre-hospital emergency systems. Finally, I developed and validated an ACS risk score called the Canadian ACS (C-ACS). Results Primary PCI was superior to FL in reducing short-term mortality in RCTs and observational studies. However, the long-term survival benefit of primary PCI was noted only in RCTs, and not in the observational studies. PHL can be effectively delivered by health care professionals with variable levels of expertise. The new risk score, C-ACS, has good discriminant properties for short- and long-term mortality in patients with ACS. Conclusions The first manuscript of this dissertation has been recognized as one of the most valuable recent publications in STEMI management and has contributed to reorganization of STEMI care in Ontario. The other two manuscripts in this dissertation provide practical information and tools for health professionals caring for patients with ACS. In summary, this doctoral dissertation has and will continue to contribute to improve access to high quality care for patients with ACS.

No description available.

Contexte L’occlusion d’une artère du cœur cause un syndrome coronarien aigu (SCA) soit avec une élévation du segment ST (IAMEST) ou sans élévation du segment ST (1). Le traitement des patients avec un IAMEST requiert soit une intervention coronarienne d’urgence (ICP primaire) ou une thérapie fibrinolytique (FL). La thérapie FL peut être administrée soit dans un contexte pré-hospitalier (PHL) ou à l’hôpital. Une prise en charge précoce des patients avec SCA peut être améliorée par un simple indice de risque. Objectifs Les objectifs de cette thèse étaient de : 1) comparer l’ICP primaire et la thérapie FL (2); décrire plusieurs systèmes internationaux de PHL; (3) développer et valider un indice de risque simplifié pour une stratification précoce des patients avec SCA. Méthodes Nous complétons des méta-analyses, de type hiérarchique Bayésiennes portant sur l’effet de la randomisation, d’études randomisées et observationnelles; complétons également un sondage sur des systèmes internationaux de PHL; développons et validons un nouvel indice de risque pour ACS (le C-ACS). Résultats Dans les études observationnelles, l’ICP primaire, comparée à la thérapie FL, est associée à une plus grande réduction de la mortalité à court-terme; mais ce sans bénéfices concluants à long terme. La FL pré-hospitalière peut être administrée par des professionnels de la santé possédant diverses expertises. Le C-ACS a des bonnes propriétés discriminatoires et pourrait être utilisé dans la stratification des patients avec SCA. Conclusion Nous avons comblé plusieurs lacunes importantes au niveau de la connaissance actuelle. Cette thèse de doctorat contribuera à améliorer l’accès à des soins de qualité élevée pour les patients ayant un SCA. / Background Acute occlusion of an artery of the heart results in acute coronary syndromes (ACS), either with ST-segment elevation (STEMI) or without ST-segment elevation (1). STEMI requires urgent treatment to restore coronary artery flow either by primary percutaneous coronary intervention (PCI) or fibrinolytic therapy (FL) (2). Although several randomized controlled trials (RCTs) demonstrate the superiority of primary PCI in reducing mortality compared to FL (2), the benefit of primary PCI over FL remains uncertain in unselected “real-life” patients (3,4). FL can be administered either in the pre-hospital setting (i.e., pre-hospital FL (PHL)) or at the hospital. PHL is rarely available outside Europe (5,6). Insights into the organization of PHL systems of care may promote more widespread use of PHL. Risk stratification of ACS patients should be prompt to ensure timely PCI for high-risk patients and to avoid unnecessary intervention in low-risk patients (7). Despite the availability of numerous ACS risk scores, there is still no simple risk score that can be easily applied in the initial management of ACS patients (8). Objectives The objectives of this doctoral dissertation were to address these current knowledge gaps in the optimal management of ACS. The objectives were to: 1) evaluate the efficacy, effectiveness, and safety of primary PCI and FL, (2) describe the infrastructure, processes and outcomes of several international PHL systems; and (3) develop and validate a novel clinical risk score for early risk stratification of ACS patients. Methods To address these objectives, I completed Bayesian hierarchical random-effects meta-analyses of published RCTs and observational studies which compare primary PCI and FL in patients with STEMI. I undertook a survey of the infrastructure, processes and outcomes of PHL in several European and North American pre-hospital emergency systems. Finally, I developed and validated an ACS risk score called the Canadian ACS (C-ACS). Results Primary PCI was superior to FL in reducing short-term mortality in RCTs and observational studies. However, the long-term survival benefit of primary PCI was noted only in RCTs, and not in the observational studies. PHL can be effectively delivered by health care professionals with variable levels of expertise. The new risk score, C-ACS, has good discriminant properties for short- and long-term mortality in patients with ACS. Conclusions The first manuscript of this dissertation has been recognized as one of the most valuable recent publications in STEMI management and has contributed to reorganization of STEMI care in Ontario. The other two manuscripts in this dissertation provide practical information and tools for health professionals caring for patients with ACS. In summary, this doctoral dissertation has and will continue to contribute to improve access to high quality care for patients with ACS.