Thesis (M. Nursing Science) --University of Limpopo, 2018 / Introduction: Diabetes mellitus has become a worldwide problem that is continuing to rise resulting in morbidity and mortality in developing countries.Finland developed the FINDRISC tool. Canada uses the Finnish Diabetes Risk Score (FINDRISC) tool and the Canadian Diabetes Risk Questionnaire (CANRISC), Germany has developed the German Diabetes Risk Score (GDRS). These risk scores are all self-assessment tools meant for assessing the risk of diabetes. They cover variables such as age, waist circumference, height, history of hypertension, physical activity, consumption of alcohol, coffee, whole grains and red meat (Buijsse, Simmons, Griffin & Schulze, 2010). Aim: To determine the feasibility of Home-Based Carers (HBCs) on the use of the FINDRISC tool to assess diabetes mellitus (DM) patients at Ga-Dikgale Village, South Africa. Methodology: A quantitative, descriptive cross–sectional design has been used to describe knowledge and practices of HBCs in using FINDRISC tool to assess the Diabetes Mellitus patient at the Dikgale village. Fifty two (52) HBCs have been assessed and homogeneous purposive convenience sampling has been used. A modified (tool) has been used by the HBCs to assess the risk status of people to determine diabetes risk status while the researcher scored the HBCs on the utilisation of modified FINDRISC tool after they have demonstrated all sections of the risk assessment tool. Data analysis has been done using (Statistical Package for Social Sciences) IBM ABSTRACT vii SPSS version 24 software and Microsoft excel sheet. Results: This study has found that HBCs can play in important role in the assessment of patients at risk of developing diabetes in the communities by using the assessment tool. The knowledge and skills of the HBCs that have been acquired throughout the years can be augmented by strengthening the primary health care re-engineering programme and in-service training that can be tailored for proper functioning of the HBCs within the health care team. Conclusion and recommendation: The burden of DM can be alleviated through the use of FINDRISC tool by determining diabetes risk status and employ necessary precautions to assist people who are at risk. This study recommend that the FINDRISC tool be modified in order to be relevant to the African perspective by validating of the tool through taking blood samples from people who are at risk . Keywords: diabetes mellitus, home-based carers, Finnish diabetes risk score tool, feasibility, assessment of patients at risk.

L’hypercholestérolémie familiale à transmission autosomique dominante (ADH), caractérisée par une élévation des taux plasmatiques en cholestérol total et LDL-C, est due à des altérations de 4 gènes : LDLR, APOB, PCSK9 et APOE. L’objectif principal de cette thèse est d’identifier de nouveaux gènes impliqués dans l’ADH. L’identification de nouveaux gènes sera suivie de l’étude des mécanismes physiopathologiques liés à leurs mutations. Un deuxième objectif est de calculer le score génétique (GRS) chez tous les individus appartenant à 5 familles où une mutation FH a déjà été identifiée afin de déterminer si une forme polygénique expliquerait les cas de phénocopies observés. Parallèlement, nous avons mené une étude dans la population libanaise caractérisée par une fréquence élevée de dyslipidémie et qui représente un outil d’étude remarquable au plan génétique du fait de l’existence d’une forte homogénéité du fond génétique.Ce projet de recherche a permis de révéler un gène candidat pouvant être impliqué dans l’ADH : LRP6. De plus il a permis de remettre en question le rôle du récepteur LRP6 jusqu’à présent considéré comme un protagoniste important dans l’internalisation des LDL. Des études supplémentaires sont encore nécessaires afin de confirmer ou non l’implication de ce gène dans l’ADH et de déterminer son rôle exact dans le métabolisme du cholestérol. Concernant le score polygénique, nous avons montré que le GRS ne peut pas être considéré comme un outil de diagnostic pour différencier les sujets avec une hypercholestérolémie monogénique de ceux avec une hypercholestérolémie polygénique et ne peut pas être utilisé pour expliquer les cas de phénocopies / Atherosclerosis and its cardiovascular complications are the leading causes of morbidity and mortality in industrialized countries. Hypercholesterolemia is one of the major cardiovascular risk factors and it affects one in 20 subjects in the general population. Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma total cholesterol and LDL-C levels, is due to alterations in 4 genes: LDLR, APOB, PCSK9 and APOE. The fundamental work of Brown and Goldstein revealed the important role of the mutations in the LDLR gene in ADH and contributed to the development of a major class of cholesterol-lowering drugs: statins. Similarly, the discovery by Abifadel et al. in 2003 of the first hypercholesterolemic mutations of PCSK9 was the starting point of an adventure which resulted, 12 years later, in the development of a new class of cholesterol-lowering drugs: anti-PCSK9 antibodies. The main objective of this thesis is to discover new genes, major genetic factors and modifiers involved in ADH. The identification of new genes will be followed by the study of the pathophysiological mechanisms linked to their mutations. A second objective of this work is to calculate the genetic risk score (GRS) in all individuals belonging to 5 families where a mutation responsible of the hypercholesterolemic phenotype has been already identified in order to determine whether a polygenic form would explain the phenocopies observed in these families. In parallel to these two projects, we conducted a study in the Lebanese population which is characterized by a high incidence of dyslipidemia. In this population, it is interesting to conduct genetic studies because of the existence of a limited number of sub-populations that constitute "genetic isolates" with a high homogeneity of their genetic background, making it easier to study many hereditary diseases such as familial hypercholesterolemia. The results obtained in this project revealed a candidate gene that could be involved in ADH: LRP6. Moreover, it allowed us to question about the exact role of the LRP6 receptor until now considered as an important protagonist in the internalization of LDL particles. Further studies are still needed to confirm whether or not this gene is involved in ADH and to determine its exact role in cholesterol metabolism. Concerning the genetic score, we have shown that the GRS does not seem to be a reliable diagnostic tool to identify polygenic hypercholesterolemia at the individual level. The 6-SNP score did not give us a clear answer and thus we cannot use the GRS to identify phenocopies within ADH families

<p>During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world.</p><p>The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality.</p><p>The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM).</p><p>The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. </p><p>It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. </p><p>The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. </p><p>A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.</p><p>In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.</p>

résumé Du fait de son impact sur la morbidité et la mortalité infantile, ainsi que de ses implications sur la santé à l’âge adulte, le petit poids de naissance constitue un problème majeur de santé publique. Le Burkina Faso, pays sahélien enclavé au cœur de l’Afrique occidentale est classé dans le groupe des pays pauvres très endettés et présente une forte prévalence de petit poids de naissance, imputable dans la majorité des cas au retard de croissance intra-utérine. Le contexte de ce travail, réalisé en milieu rural, se caractérise par une situation socioéconomique précaire se traduisant par un faible niveau des indicateurs de l’état de santé et une faible accessibilité aux services sociaux de base. Objectifs, hypothèses Ce travail repose sur les hypothèses que les facteurs socioéconomiques influencent la survenue du petit poids de naissance et que le petit poids de naissance a un impact négatif sur la croissance et la survie au cours de la première année de vie. Ce travail s’est fixé pour objectifs de : •connaître l’importance du petit poids de naissance à terme ; •analyser les déterminants du petit poids de naissance ; •proposer un score pour l’identification des femmes enceintes à risque de mise au monde d’un enfant de petit poids ; •identifier les facteurs influençant la croissance des enfants nés de petit poids ; •étudier l'impact du déficit pondéral à la naissance sur la morbidité et la mortalité infantile ; •formuler des recommandations pour la prévention et la prise en charge du petit poids de naissance en milieu défavorisé dans le but d’orienter les stratégies de réduction de la mortalité infantile. Méthodologie Trois types d’études ont été réalisés: •une étude de cohorte rétrospective portant sur 435 enfants dans le but d’explorer les facteurs de risque, la croissance, le statut nutritionnel et la mortalité des enfants nés de petit poids de naissance à terme. •Une étude transversale portant sur 1013 naissances vivantes à terme qui a permis de déterminer la fréquence du petit poids de naissance et d’analyser les facteurs associés qui lui étaient associés. •Une étude de cohorte prospective au cours de laquelle les 1013 enfants enrôlés dans l’étude transversale ont été suivis afin d’analyser leur croissance et leur survie au cours des 12 premiers mois de vie. Principaux résultats •Le petit poids de naissance représente 15,8% des naissances à terme. •Le sexe féminin est prédominant chez les enfants de petit poids. •Les facteurs sociodémographiques associés au petit poids de naissance sont essentiellement des caractéristiques sociodémographiques maternelles : le jeune âge de la mère (moins de 20 ans), le faible niveau d’instruction, le mauvais état nutritionnel et la faible accessibilité géographique aux structures de santé. •Les facteurs obstétricaux associés au petit poids sont : la primiparité, la survenue de vomissements gravidiques, l’exécution de travaux champêtres et une charge de travail plus importante en cours de grossesse. •Le score proposé pour l’identification des femmes à risque a un pouvoir de discrimination acceptable et présente une bonne stabilité et une faible marge d’erreur de prédiction. •Indépendamment de la catégorie de poids à la naissance, tous les enfants demeurent en dessous des médianes des courbes de référence internationales pour l’ensemble des indices nutritionnels entre 0 et 12 mois. •Malgré des gains plus importants mais de façon non significative, les enfants de PPN montrent une incapacité à combler leur retard en taille et en poids. •Le PPN est associé à un risque significativement plus élevé de retard de croissance et d’insuffisance pondérale au cours de la première année de vie. •Le petit poids de naissance et la non-complétude de la consultation prénatale étaient associés à un risque deux fois plus important de décès. •L’état nutritionnel à l’âge de 3 mois ainsi qu’à l’âge de 6 mois joue un rôle plus important dans la survie chez les enfants de PPN que chez les enfants nés de poids normal. Conclusions Les solutions au problème du petit poids de naissance impliquent un paquet d’interventions intégrant des stratégies avant, pendant et après la grossesse et des programmes de prise en charge ciblant les enfants de petit poids après leur naissance. Il s’agit prioritairement de : •l’information et de la sensibilisation des populations pour un meilleur suivi de la grossesse et une complétude de la consultation prénatale ; •l’adoption de pratiques et d’habitudes en faveur d’une alimentation équilibrée des femmes enceintes ; •un plaidoyer pour un allègement de la charge de travail des femmes enceintes ; •l’utilisation de méthodes opérationnelles pour l’identification des femmes à risque ; •l’amélioration de la qualité des prestations de surveillance de la grossesse ; •la redéfinition du contenu et des protocoles des programmes de suivi et de promotion de la croissance des jeunes enfants avec une attention particulière pour les enfants nés de petit poids ; •la lutte contre certaines pratiques sociales comme les mariages précoces et les grossesses chez les adolescentes et les femmes de moins de 20 ans ; •la promotion de la scolarisation des jeunes filles et l’alphabétisation des mères ; •l’amélioration de l’état nutritionnel de la population ; •la réalisation d’études pour évaluer l’impact de certains déterminants et interventions sur l’incidence du petit poids et le devenir des enfants nés avec un handicap pondéral : rôle de l’infection palustre, interventions nutritionnelles ciblant les enfants de petit poids, apports nutritionnels pendant la grossesse. Summary Due to its impact on infant morbidity and mortality, and its effects on adult’s health, low birth weight (LBW) is a major issue in the public health sector. Burkina Faso, a Sahelian country land-locked in the heart of West Africa is listed among the heavily indebted poor countries, with a high prevalence of Low Birth Weight, caused in most cases by intra uterine growth retardation. The context of the current study, conducted in urban area, is characterised by a poor socio-economic situation resulting in weak health indicators and difficult access to the basic social services. Objectives, assumptions The study is based o the assumptions that socio-economic factors have an influence on the occurrence of Low Birth Weight and that Low Birth Weight has a negative impact on growth and survival during the first year of the infant. The study has the following objectives: •To assess the importance of low birth weight a term; •To analyse the determinant factors of low birth weight; •To suggest a classification for the identification of pregnant women at risk of giving birth to low birth weight infants ; •To identify factors which have an impact on the growth of low birth weight children ; •To look at the impact of body weight deficiency at birth on infant morbidity and mortality ; •To give recommendations on the prevention and treatment of low birth weight children from underprivileged background with the aim to orientate strategies for infant mortality reduction. Methodology Three types of studies were conducted: •A retrospective cohort study of 435 children aiming at exploring risk factors, growth, nutritional status, and mortality of low birth weight infants in the long run. •A cross-sectional study of 1013 live full-term births, which led to determining the frequency of low birth weight and at analysing associated factors which are linked to low birth weight. •A prospective cohort study during which the 1013 children taken into consideration for the cross-sectional study were followed up so as to analyse their growth and survival all along the first 12 months of their life. Main results •Low birth weight represents 15.8% of full-term births. •Female babies are predominant among low birth weight babies. •Socio-demographic factors linked to low birth weight are mainly maternal socio-demographic characteristics: young mother (below 20 years old), low educational level, poor nutritional status and limited geographical access to health infrastructures. •Obstetrical factors linked to low birth weight are the following: primiparity, occurrence of vomiting during pregnancy, field work and a heavier workload during pregnancy. •The suggested classification for the identification of women at risk proves to have an acceptable power of discrimination and shows good stability and limited margin of error for prediction. •Regardless of weight categories at birth, all children remain below medians of international reference curves for all nutritional indicators between 0 and 12 months. •In spite of more important but not significant weight gains, LBW children prove not to be able to catch up on height and weight. •LBW is linked to a significantly higher risk in growth retardation and weight deficiency during the newborn’s first year of life. •LBW and non-complete antenatal visits are linked to a death risk multiplied by two. •The nutritional status at the age of 3 months and 6 months old plays a more important role in the survival in LBW children than in children born with normal weight. Conclusions Solutions to LBW imply a package of interventions which should integrate strategies before, during and after pregnancy, together with treatment programmes targeting LBW children after their birth. In priority, these are: •Information and awareness given to population for a better follow-up of pregnancies and complete cycles antenatal visits ; •New practices and habits to be taken on favouring a balanced diet of pregnant women ; •Advocacy actions aiming at reducing the workload of pregnant women ; •The use of operational methods to identify women at risk ; •Improving the quality of monitoring of pregnancy; •Redefined content and procedures of monitoring programs and promoting young children growth, with particular focus on LBW children ; •The fight against some social practices such as early marriages and pregnancies of teenagers and women below 20 years; •The promotion of school education for young girls and literacy for mothers ; •Improving the nutritional status of the population; •The realisation of studies to assess the impact of some determinant factors and interventions on the occurrence of low birth weight and on the future of children born with weight deficiency: role of malaria, nutritional interventions targeting LBW children, nutritional intakes during pregnancy

During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world. The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality. The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM). The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors. In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13398号 / 論医博第2222号 / 新制||医||1051(附属図書館) / (主査)教授 妹尾 浩, 教授 中山 健夫, 教授 西浦 博 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Health policy makers are struggling to manage health care and spending. To identify strategies for improving health quality and reducing health spending, policy makers need to first understand health risks and outcomes. Despite lacking some desirable clinical detail, existing health care databases, such as national health surveys and claims and enrollment data for insured populations, are often rich in information relating patient characteristics to heath risks and outcomes. They typically encompass more inclusive populations than can feasibly be achieved with new data collection and are valuable resources for informing health policy. This dissertation illustrates how the Medicare Current Beneficiary Survey (MCBS) and MassHealth data can be used to develop models that provide useful estimates of risks and health quality measures. It provides insights into: 1) the benefits of a proxy for the Framingham cardiovascular disease (CVD) risk score, that relies only on variables available in the MCBS, to target health interventions to policy-relevant subgroups, such as elderly Medicare beneficiaries, based on their risk of developing CVD, 2) the importance of setting appropriate risk-adjusted quality of care standards for accountable care organizations (ACOs) based on the characteristics of their enrolled members, and 3) the outsized effect of high- frequency hospital users on re-admission measures and possibly other quality measures. This work develops tools that can be used to identify and support care of vulnerable patients to both improve their health outcomes and reduce spending – an important step on the road to health equity.

Introduction: La procédure d'implantation de valve aortique transcathéter (TAVI) a été développée comme une alternative à la chirurgie cardiaque conventionnelle de remplacement de la valve aortique (RVA) chez des patients à plus haut risque («Society of Thoracic Surgery» (STS) ≥3%) présentant une sténose aortique sévère symptomatique. Cependant, la sélection de potentiels candidats peut demeurer un défi, en partie dû à la paucité de données sur des métriques de performance déterminées pour ce genre de procédure. Les objectifs de cette thèse étaient: 1) l'évaluation du taux de réadmissions hospitalières (une métrique importante de performance) post procédure de TAVI et l'identification des prédicteurs qui y sont associés; 2) l'évaluation de la performance de 4 marqueurs de fragilité communément utilisés comme prédicteurs de résultats cliniques précoces et tardifs chez des patients qui ont eu une procédure de TAVI et l'identification de seuils optimaux pour la stratification du risque; et 3) l'évaluation des résultats cliniques au cours des années de patients avec sténose aortique sévère symptomatique discutés par un «Heart Team» afin d'évaluer si les résultats cliniques TAVI versus RVA standard s'améliorent sur différentes périodes de temps et quelles en sont les raisons. Méthode: Une étude de cohorte rétrospective a été menée afin d'évaluer la valeur des comorbidités de base ainsi que des complications procédurales comme prédicteurs de réadmissions hospitalières précoces et tardives suivant une procédure de TAVI. L'extension de Fine et Gray des modèles de régression de Cox a été utilisée afin de considérer dans l'analyse les risques compétitifs. Quatre variables déterminantes de la fragilité (i.e., albumine sérique, le test de marche de 5 mètres, la force de préhension, et le questionnaire d'index Katz sur l'autonomie) ont été évaluées dans une seconde étude de cohorte. Les associations entre les indicateurs de fragilité et un composé d'évènements d'effets adverses majeurs ont été évaluées selon des modèles de régression logistique, avec des seuils optimaux identifiés pour chacun des indicateurs de la fragilité en utilisant la méthode statistique des courbes de ROC. Finalement, la mortalité à 30 jours et les complications post-procédurales ont été examinées chez des patients évalués en majorité par un «Heart Team» entre 2012 et 2019. Une analyse de scores de propension-appareillés a été effectuée. Résultats: Nous avons identifiés des comorbidités de base et des complications procédurales qui étaient directement associées avec des réadmissions précoces et tardives suivant une procédure de TAVI. L'anémie et un AVC post-opératoire ont été associés avec une augmentation de la mortalité. Parmi les patients à risque élevé qui vont subir un TAVI, l'albumine sérique, être autonome dans ses activités de la vie quotidienne, le test de marche de 5 mètres ont indépendamment prédit la survenue du composé d'évènements adverses à 30 jours. Un nouveau modèle de fragilité (4 indicateurs de fragilité, l'âge et le sexe) a été proposé et a démontré avoir une meilleure discrimination que le score de risque habituellement utilisé, celui de la «Society of Thoracic Surgeons (STS) ». Aussi, des seuils individuels d'augmentation du risque ont été trouvés pour chaque variable individuelle de fragilité. Finalement, une amélioration des résultats cliniques post TAVI et RVA standard a été observée au cours des années, démontrant une réduction de la mortalité à 30 jours (4,0% à 0,4%), des AVCs (2,5% à 0,9%), de l'insuffisance rénale (3.5% à 1.5%), de pneumonie (10.0% à 1.5%) et de la durée de séjour (de 7 jours à 2 jours). Nous avons identifié des complications différentes pour chacune de ces interventions et discuterons des explications possibles pour l'amélioration de ces résultats au cours des années. Conclusions: Cette thèse a identifié des métriques simples qui peuvent assister les «Heart Team» dans leur sélection de patients à plus haut risque qui présentent une sténose aortique sévère pour une procédure TAVI. Nous avons également redéfini des seuils de risque aux indicateurs de fragilité connus. Finalement, l'augmentation du nombre de procédures TAVI au cours des années, a résulté en une diminution de la mortalité et de morbidités autant chez les patients ayant eu une procédure TAVI que chirurgicale. / Objective: Transcatheter aortic valve intervention (TAVI) has emerged as an alternative to conventional surgical replacement of the aortic valve (SAVR) in high-risk patients (STS score ≥3%) with symptomatic aortic stenosis. Nevertheless, the selection of suitable candidates remains challenging, in part due to a paucity of data regarding performance metrics. The objectives of this thesis were: 1) to assess the rate of hospital readmission (an important performance metric) following TAVI and identify associated predictors; 2) to evaluate the performance of four commonly used frailty markers as predictors of early and late outcomes among patients undergoing TAVI and identify optimal cutoff values for risk stratification; and 3) to assess the clinical results over time of patients with aortic stenosis with a procedural indication who were discussed by a «Heart Team» in order to evaluate if TAVI and conventional surgical outcomes improve over different time periods and what are the reasons. Methods: A retrospective cohort study was conducted to assess the value of baseline comorbidities and procedural complications in predicting early and late hospital readmissions following TAVI. The Fine and Gray extension of Cox regression models was used to account for competing risks. Four frailty variables (i.e., serum albumin, 5-meter walk test, grip strength, and Katz index of independence) were assessed in a second cohort study. Associations between frailty indicators and a composite endpoint of major adverse events were assessed in logistic regression models, with optimal cutoff values for each frailty indicator identified using receiver-operating characteristics curves. Finally, 30-day mortality and post-procedural complications were examined in patients triaged in majority by a «Heart Team» between 2012 and 2019. A propensity-matched analysis was performed. Results: We identified baseline comorbidities and procedural complications that were directly associated with early and late readmissions following TAVI. Anemia and post-operative stroke were associated with increased mortality. Among high-risk patients undergoing TAVI, serum albumin, activities of daily living, and 5 meters walk test independently predicted the 30-day composite endpoints. A new frailty model (four frailty indicators, age, and sex) was proposed and found to provide superior discrimination compared to The Society of Thoracic Surgeons risk model. Individual frailty variable cutoff values were identified. Finally, improvement in both TAVI and conventional surgical outcomes were observed over time, with a reduction in 30-day mortality (4,0% to 0,4%), stroke (2,5% to 0,9%), renal failure (3,5% to 1,5%), pneumonia (10,0% to 1,5%), and length of stay (7 to 2 days). The two interventions (TAVI and AVR) were associated with different complications and we will discuss about the possible explanations for the improvement in outcomes. Conclusion: This thesis identified simple metrics that could assist the «Heart Team» in selecting appropriate candidates with severe symptomatic aortic stenosis for TAVI, and refined cut-off values for common frailty indicators. Finally, an increased use of TAVI over the years with broadening indications resulted in a decrease in complications and mortality in patients who received a TAVI, but also patients who received a standard AVR.

<p>This dissertation evaluated the complex inter-relatedness between co-occurring childhood maltreatment exposures, physical intimate partner violence (perpetration and victimization), substance use frequency, and molecular genetics for substance use, utilizing appropriate developmental models and theoretical approaches. Three studies were proposed within this dissertation. Data for the three studies come from a national longitudinal panel study: The National Longitudinal Study of Adolescent to Adult Health (Add Health; Harris, 2013). Across studies, latent profile analysis was used to evaluate co-occurring childhood maltreatment exposures based on type and severity of exposures, which resulted in three homogenous sub-groups. The first sub-group was composed of individuals that had high levels of physical abuse exposure and moderate levels of childhood neglect and emotional abuse exposures (high physical abuse sub-group). The second sub-group (high sexual abuse sub-group) included individuals with high severity of sexual abuse exposure and moderate severity of all other childhood maltreatment types (i.e., physical abuse, emotional abuse, and neglect). This second sub-group was, therefore, the most vulnerable in terms of their childhood maltreatment exposure. A final normative sub-group was also found that included a majority of individuals with low severity of childhood maltreatment exposure across types. Additionally, across all three studies, a probabilistic multifaceted genetic risk score (i.e., polygenic risk score) was created to evaluate substance use related genetic risk. The first study evaluated the role of co-occurring childhood maltreatment exposure on substance use development from adolescence to young adulthood while evaluating substance use related genetic moderation. Generalized estimating equations were used to test the proposed model in study 1. Findings suggest that the high physical abuse sub-group was more susceptible to genetic risk and had increases in substance use frequency only at high levels of genetic risk. In contrast, for the high sexual abuse sub-group, childhood maltreatment and environmental exposures were more ubiquitous for substance use development from adolescence to young adulthood. To elaborate, the high sexual abuse sub-group demonstrated increases in substance use from adolescence to young adulthood irrespective of genetic risk. In study 2, substance use frequency in young adulthood was tested as a mechanism between childhood maltreatment sub-groups and subsequent physical intimate partner violence perpetration in adulthood. Once again, genetic moderation for the direct association between childhood maltreatment sub-groups and substance use frequency in young adulthood was tested within the larger mediation model. In study 3, physical partner violence victimization in young adulthood was tested as a mediator of the association between childhood maltreatment sub-groups and substance use frequency in adulthood. In study 3, in addition to the above-mentioned genetic risk score, an additional substance use related dopamine polygenic risk score was also tested. Specifically, in study 3, genetic moderation by both genetic risk scores was tested on 1) the direct pathway from childhood maltreatment sub-groups to substance use frequency in adulthood, and 2) the direct pathway from physical intimate partner violence victimization in young adulthood to substance use frequency in adulthood. In both studies 2 and 3, product of co-efficient method was used to estimate mediation hypothesis, and moderated-mediation models were used to test for genetic moderation within the mediation model. Research aims for studies 2 and 3 were largely not supported. However, supplementary models indicate that substance use frequency may not be a causal mechanism but may be a contextual factor exacerbating the association between childhood maltreatment exposures and physical intimate partner violence perpetration. Implications for findings are discussed in detail. </p>

Hintergrund: Es ist bislang unklar, inwieweit etablierte Scores zur Abschätzung des kardiovaskulären Risikos (PROCAM-Score, Framingham-Score, ESC-Score Deutschland) untereinander sowie mit der subjektiven Arzteinschätzung übereinstimmen. Methodik: An einer bundesrepräsentativen Stichprobe von 8 957 Hausarztpatienten im Alter von 40–65 Jahren ohne bekannte vorangegangene kardiovaskuläre Ereignisse wurde mittels unterschiedlicher Methoden das Risiko bestimmt, innerhalb der nächsten 10 Jahre einen Herzinfarkt oder Herztod zu erleiden. Ergebnisse: Das mittlere koronare 10-Jahres-Morbiditätsrisiko wurde mit dem PROCAM-Score auf 4,9% und mit dem Framingham-Score auf 10,1% geschätzt, das mittlere kardiovaskuläre 10-Jahres-Mortalitätsrisiko mit dem ESC-Score auf 2,9%. Die behandelnden Ärzte klassifizierten nur 2,7% der Patienten als kardiovaskuläre Hochrisikofälle. Nach Framingham wurden die meisten Patienten in die Hochrisikokategorie eingeordnet (22,6%). Bezüglich der Risikokategorisierung ergab sich eine nur moderate Übereinstimmung zwischen den drei Scores (bei 34% aller Risikofälle). Bei 5,9% der Patienten kamen die drei Scores zu einer komplett unterschiedlichen Risikobewertung. Den nach den verschiedenen Risikoscores in die Hochrisikogruppe kategorisierten Patienten wurde von den behandelnden Ärzten nur in ca. 8% der Fälle ebenfalls ein hohes kardiovaskuläres Risiko zugeordnet, in ca. 48% ein mittleres Risiko und in 41–46% (je nach Score) ein geringes Risiko. Schlussfolgerung: Die Methoden ergeben nur eine relativ geringe Übereinstimmung in der Beurteilung von Risikopatienten. Besonders niedrig fällt die Übereinstimmung bei der Hochrisikogruppe mit der Einschätzung der klinischen Risikoprädiktion durch den behandelnden Hausarzt aus. Die erhebliche Abweichung zur Arztbeurteilung scheint anzudeuten, dass die etablierten Risikoscores in der Praxis derzeit einen nur eingeschränkten praktischen Stellenwert besitzen. Welche der Vorhersagen mit dem tatsächlichen Risiko am besten übereinstimmen, wird derzeit mit den prospektiven DETECT-Studiendaten geprüft.