Dissertationen zum Thema „Clinical determinant“

A não adesão à terapêutica é determinante do aumento de taxas de morbilidade e de mortalidade dos doentes e de perturbações e gastos financeiros das organizações de saúde. O presente estudo teve como objectivo identificar determinantes de não adesão à terapêutica antiagregante plaquetária em doentes que foram submetidos a angioplastia transluminal percutânea coronária. Participaram neste estudo duas amostras de doentes com características demográficas semelhantes mas que deferiam no seu comportamento de adesão. Como metodologia para a identificação das crenças dos doentes em relação à doença ao tratamento foi utilizada um entrevista semi-estruturada baseada nas dimensões do Modelo de Crenças de Saúde. Os resultados evidenciam diferenças entre os dois grupos em especial no que diz respeito a: conhecimento da situação clínica e do tratamento; benefícios/custo do tratamento; consequências; percepção de auto-eficácia e vulnerabilidade. Baseado nos resultados apontam-se pistas de intervenção para a melhoria da qualidade dos cuidados de saúde prestados a estes doentes, numa perspectiva de governança clínica. – ABSTRACT: Non-adherence to treatment prescription is determinant of morbidity and mortality and is associated to organizational problems and financial costs. This study aimed to identify determinants of non-adherence to patients with Percutaneous Transluminal Coronary Angioplasty. The sample was constituted by two groups of patients with similar demographic characteristics and with different adherence behaviour. As methodology we used a semi-structured interview based on the Health Belief Model. Results show differences between the two groups in dimensions as: knowledge about the clinical situation and the treatment; benefits/costs of the treatment; consequences of adherence behaviour; self-efficacy and vulnerability: Based on the results we present some contributions to the quality of care of these patients and doing so hope to contribute to better organization in health services.

Hepatitis C virus (HCV) infection is characterized by a broad spectrum of clinical outcomes. An estimated 14%-46% of individuals exposed to HCV are able to clear the virus, while the other portion develops chronic (persistent) infections. Among the individuals with chronic HCV who are treated with interferon-based therapies, only a portion are able to experience sustained virological suppression. Similarly, a number of chronically infected individuals have autoimmune extrahepatic manifestations such as the presence of autoantibodies. The pathological mechanisms behind these phenomena are not known, but it is believed that host genetic factors may play a role. This thesis examines the hypothesis that host genetic factors may contribute to the diverse spectrum of HCV clinical outcomes. In addition, it examines the pathogenesis of antinuclear antibodies (ANA) in chronic HCV, and the effect of ANA positivity on the natural history of HCV. Correlations were observed between female gender and geographic location and ANA positivity. No relationships were observed for an effect of ANA positivity on response rates to interferon therapy. We observed a trend of ANA positivity with faster progression of HCV-related fibrosis, although this failed to achieve statistical significance. ANA-positive individuals tended to have more plasma cells in their liver than ANA-negative individuals. This study also observed a number of correlations between genotypes of the interferon induced genes encoding the myxovirus resistance 1 protein (MxA), 2'-5'oligo-adenylate synthase 1 (OAS-1), and protein kinase (PKR), as well as genes encoding cytotoxic T-lymphocyte antigen-4 (CTLA4), and inducible nitric oxide synthase (iNOS) (encoded by the NOS2A gene) with several outcomes including self-limiting versus chronic HCV infection, along with the response to interferon therapy. This study identified several factors to be correlated with ANA positivity in HCV. These factors may serve as future points for investigation by basic scientists understanding the mechanisms of HCV-mediated autoimmunity. Importantly, this study suggests that low titre ANA positivity should not be a contraindication to therapy. This study also highlighted the importance of several genetic pathways in HCV infection. These may serve as targets for future pharmacologic interventions or genetic tests designed to screen for those who will not benefit from interferon therapies.

Diabetic retinopathy is a microvascular complication of type 1 and type 2 diabetes, affecting the retinal vasculature of the eye. In the Scottish diabetic retinopathy grading scheme (version 1.1), the severity of diabetic retinopathy is classified as no retinopathy, mild background, observable background, severe non-proliferative and proliferative retinopathy. In the GoDARTS (Genetics of Diabetes Audit and Research Tayside) cohort, we have longitudinal data of retinopathy in diabetic patients since 1990. 3,734 and 3,673 GoDARTS patients were genotyped in the Affymetrix Genome-wide Human SNP Array 6.0 and Illumina HumanOmniExpress BeadChip, respectively. As the pathophysiology of diabetic retinopathy remains elusive, the aim of this thesis is to use the GoDARTS phenotype and genotype data to study clinical and genetic determinants for diabetic retinopathy.

Up to one third of patients with schizophrenia show only limited response to dopamine blocking antipsychotic medication. This could be due to distinct neurobiological abnormalities in this subgroup of patients. While there is robust evidence to suggest that the neurobiology of schizophrenia involves increased presynaptic striatal dopaminergic elevation, little is known as to whether this abnormality is present in treatment resistance, and consequently the relationship between this dopamine abnormality and the lack of response to treatment remains unknown. Furthermore, it remains unclear whether treatment resistance manifests at the outset of illness, and perhaps has a neurodevelopmental origin, or whether it evolves over time, possibly as a result of a neurodegenerative process. The first study in this thesis investigated striatal presynaptic dopamine synthesis in twelve treatment resistant schizophrenic patients, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers, using [18F]-DOPA Positron Emission Tomography (PET). Thus, it was possible to test the hypothesis that the response to treatment is determined by differences in presynaptic dopamine function. The results demonstrated that there were no significant differences in striatal dopamine synthesis capacity between treatment resistant patients and healthy volunteers, whilst dopamine synthesis capacity was significantly increased in responders relative to treatment resistant patients. The difference was most marked in the associative and the limbic striatal subdivisions. A second, large follow-up study of first episode psychosis (FEP) patients, examined the course of treatment resistance over the 10 year follow up. It was found that over 80% of treatment resistant patients were persistently resistant from the initiation of antipsychotic treatment. My PET study, due to its cross sectional design, could not determine whether the normal dopamine levels predate the antipsychotic exposure in treatment resistant patients. However, by demonstrating that a great majority of treatment resistant patients are resistant to dopamine blocking antipsychotics at first ever initiation of treatment, my second study raises the possibility that these patients may have had normal dopamine levels even at the outset of their psychotic illness. In the same FEP cohort it was possible to investigate neurodevelopmental predictors of treatment resistance. The finding that the negative symptom dimension and younger age of onset were significant predictors of treatment resistance is compatible with the view that TRS may be of neurodevelopmental origin. Overall, my observations in this thesis indicate that TRS may be a distinct and enduring subtype of schizophrenic illness of a possible neurodevelopmental origin whose pathophysiology is not marked by alterations in dopamine synthesis capacity. Findings emerging from this thesis provide a platform for future studies, which may lead to the discovery of much needed new treatments for this disabling and intractable condition.

La maladie des petites artères cérébrales (MPAC) constitue une étiologie importante d’accident vasculaire cérébral (AVC), de déclin cognitif et de démence. Les marqueurs en imagerie par résonance magnétique (IRM) de MPAC comprennent les hypersignaux de la substance blanche (HSB), les infarctus lacunaires (IL), les microsaignements (MS) et les espaces dilatés périvasculaires (EdPV). Une revue systématique et méta-analyse incluant plus de 16,000 participants a permis de mieux caractériser l’association des HSB, IL et MS avec le risque d’AVC et de démence, ainsi que leurs sous-types, et la mortalité. En raison de données limitées sur les EdPV dans cette revue systématique, nous avons étudié l’association entre les EdPV et le risque incident d’AVC au sein de la cohorte 3C-Dijon en population générale et avons mis en évidence une association significative des EdPV, en particulier au niveau des noyaux gris centraux et de l’hippocampe, avec le risque incident d’AVC, surtout hémorragique. Nous avons ensuite estimé l’héritabilité des EdPV à partir de génotypes pangénomiques, mettant en évidence une héritabilité plus élevée que pour les autres marqueurs IRM de MPAC, notamment pour les EdPV au niveau de la substance blanche. Dans un second temps, nous avons réalisé une méta-analyse d’études d’associations génétiques pangénomiques (GWAS) des EdPV qui nous a permis d’identifier 2 loci significativement associés au seuil pangénomique avec une sévérité plus importante des EdPV au niveau de la substance blanche. Ces associations orientent vers des gènes impliqués dans le développement cérébral, le fonctionnement des vaisseaux cérébraux et la tumorigenèse. Nous avons mis en évidence une corrélation génétique significative entre les EdPV au niveau des noyaux gris centraux et les AVC (tout type) et les AVC ischémiques. Enfin, nous avons étendu ces recherches à la cohorte Nagahama en population générale japonaise afin de (i) comparer la reproductibilité des 3 principales échelles visuelles de quantification des EdPV dans cette cohorte, et (ii) de réaliser un GWAS des HSB en population japonaise, qui a permis de confirmer dans cette population le locus du chr17q25.1 et d’identifier de nouveaux loci associés avec le volume d’HSB dans différentes régions du cerveau. En conclusion, nous avons apporté de nouveaux éléments sur la signification clinique des marqueurs IRM de MPAC, en particulier les EdPV, et sur les déterminants génétiques des marqueurs IRM de MPAC, avec une première estimation de l’héritabilité et une première méta-analyse de GWAS des EdPV, et un premier GWAS des HSB en population japonaise
Cerebral small vessel disease (cSVD) is a major cause of stroke, cognitive impairment and dementia. Magnetic resonance imaging (MRI) markers of cSVD comprise white matter hyperintensities (WMH), MRI-defined lacunes of presumed vascular origin (Lac), cerebral microbleeds (CMB) and dilated perivascular spaces (dPVS). A systematic review and meta-analysis on > 16,000 participants enabled to characterize the association of WMH, BI and CMB with risk of stroke and dementia, as well as their subtypes, and with mortality. Because of limited data on dPVS, we examined the longitudinal relationship of dPVS burden with incident stroke risk in the population-based 3C-Dijon study, and found a significant association between dPVS burden, especially in basal ganglia and hippocampus, and incident risk of any stroke and intracerebral hemorrhage. We then explored the heritability of dPVS burden using genome-wide genotypes and found highest heritability for dPVS burden compared with other MRI-markers of cSVD, especially in the white matter. Second we conducted a genome-wide association study (GWAS) meta-analysis of dPVS burden and identified two genome-wide significant loci associated with extensive dPVS burden in the white matter, implicated in brain development, brain vascular function and oncogenesis. We found significant genetic correlation of dPVS burden in basal ganglia with all stroke and ischemic stroke. Finally, we conducted an extension of this work in the Japanese Nagahama population-based study to: (i) compare the reproducibility of three dPVS visual rating scales (ii) conduct the first GWAS of WMH volume in a Japanese cohort, confirming the chr17q25.1 locus and identifying new loci associated with regional WMH volume. In conclusion, we provide novel information on the clinical significance of MRI-markers of cSVD, especially dPVS, and new insight into the genetic contribution to MRI-markers of cSVD, by conducting the first heritability assessment and GWAS meta-analysis of dPVS burden, and the first GWAS of WMH volume in a Japanese population

Abstract Coronary artery bypass grafting (CABG) is the treatment of choice for patients with three-vessel disease or left main stenosis. However, it is associated with considerable risk of perioperative complications such as myocardial infarction, stroke, infections, and mortality to which excessive bleeding is a contributing factor. This thesis aims to determine the factors involved in and clinical implications of bleeding after CABG. The 1st study evaluated the effects of preoperative ASA discontinuation on the patient’s outcome after CABG. The results showed that late or no discontinuation of low-dose ASA before CABG may decrease the risk of postoperative stroke without increasing the risk of postoperative bleeding. In the 2nd study the use of warfarin was found to be a safe during CABG with no excess bleeding nor other major complications. The 3rd study estimated the impact of surgeons´ performances on blood loss and need for re-exploration after CABG. With 2001 study patients, this study clearly demonstrated that an individual surgeon is a powerful determinant of postoperative bleeding and need for re-exploration after CABG. Using systematic review and meta-analysis, we estimated the risk of complications related to re-exploration for bleeding after CABG. In literature search in 2011, 8 articles with 557 923 patients fulfilled the inclusion criteria. Re-exploration for bleeding after cardiac surgery carries a significantly increased risk of postoperative mortality and morbidity, and thus has a major impact on the patient’s immediate postoperative outcome. We also studied the impact of blood transfusion on the development of post-operative stroke after CABG. Of the study population of 2 226 CABG patients, stroke occurred postoperatively in 53 patients (2.4%). The statistical analysis showed that transfusion of blood products after CABG has a strong, dose-dependent association with the risk of stroke. The use of Octaplas® and platelet transfusions seem to have an even larger impact on the development of stroke than red blood cell transfusions. The 6th study investigated the impact of transfusion of blood products on intermediate outcome after CABG in 2001 patients. The findings indicated that transfusion of any blood product is associated with a significant risk of all-cause and cardiac mortality after CABG
Tiivistelmä Sepelvaltimotauti on yleisin kuolinsyy ja sepelvaltimoiden ohitusleikkaus hyvine pitkäaikaistuloksineen on todettu parhaaksi hoidoksi potilailla, joilla on monen suonen tai vasemman päärungon tauti. Ohitusleikkaukseen liittyy kuitenkin verenvuodon sekä näihin kytkeytyvien komplikaatioiden riski. Tämän väitöskirjan tavoitteena oli määrittää verenvuodon riskitekijöitä sekä verituotteiden siirtojen vaikutusta ohitusleikkauspotilaiden ennusteeseen. Verenhyytymistä estävien lääkkeiden tiedetään lisäävän verenvuotoja. Ensimmäinen tutkimus osoitti, että ASA:n jatkaminen keskeytyksettä ohitusleikkauksissa vähentää aivoinfarktien riskiä lisäämättä silti verenvuodon riskiä. Toisessa tutkimuksessa pitkäaikainen warfariinihoito osoittautui turvalliseksi ohitusleikkauksen aikana eikä sen käyttö lisännyt verenvuotoja eikä muita komplikaatioita. Kolmas tutkimus osoitti kirurgin taidon merkityksen verenvuotojen ja uusintaleikkausten määrään 2001 potilaalla. Verenvuotojen vuoksi tehtävien uusintaleikkausten negatiivinen vaikutus postoperatiiviseen mortaliteettiin sekä morbiditeettiin on todettu yksiselitteisesti useissa tutkimuksissa. Vuonna 2011 tehdyllä systemaattisella kirjallisuuskatsauksella ja meta-analyysillä selvitimme yhteensä 557 923 ohitusleikkauspotilaan aineistosta, että verenvuodon jälkeisiin uusintaleikkauksiin liittyy huomattava kuoleman ja komplikaatioiden riski. Verenvuotoja hoidetaan yleisesti verensiirroilla, vaikkakin useat tutkimukset ovat osoittaneet verituotteiden annon lisäävän mortaliteettia sekä komplikaatioriskiä. Viides tutkimus selvitteli sepelvaltimoleikkauksissa potilaalle annettujen verituotteiden ja leikkauksen yhteydessä sairastettujen aivoinfarktien välistä yhteyttä. Osoittautui, että verituotteiden käyttöön liittyy annosriippuvaisesti lisääntynyt riski saada aivoinfarkti leikkauksen yhteydessä. Varsinkin verihiutale- ja jääplasmasiirtoihin on todettu liittyvän vielä suurempi aivoinfarktin riski kuin punasolusiirtoihin. Kuudes tutkimus selvitteli sepelvaltimoleikkauksien yhteydessä annettujen verituotteiden vaikutusta 2001 potilaan keskipitkään ennusteeseen. Tutkimus osoitti, että minkä tahansa verituotteen antoon sepelvaltimoleikkauksissa liittyy lisääntynyt kuoleman ja sydänkuoleman riski

Thesis (M.S.) -- University of Maryland, College Park, 2005.
Thesis research directed by: Dept. of Family Studies. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

The primary objectives of this study were: to determine the predictors of psychological distress and social maladjustment (i.e., social interaction, work, and home management functioning), to determine the relationship between specific coping strategies and psychological distress and social maladjustment, and to determine the effects of program participation on patients' level of personal mastery, cardiac functional capacity, frequency of stressors, and coping strategies. The sample comprised 223 males between the ages of 27 and 66 who had heterogeneous CHD diagnoses. The data were collected by means of standardized questionnaires using a mailing procedure which achieved a response rate of approximately 90% across time points. The results of multiple hierarchical regression analyses revealed that number of hassles and disengagement coping contributed significant increments to the variance explained in psychological distress. Higher levels of engagement and symptom management coping, however, were not found to be significant predictors of lower psychological distress in this study. For social maladjustment, in general, neither stress nor coping emerged as consistent predictors of social maladjustment across time points. Coping consistently emerged as a stronger predictor of both psychological distress and social maladjustment when current coping strategies were used as predictors (Model B), as opposed to when coping strategies from the previous time point were entered (Model A). Regarding the relationships among specific coping strategies and psychological distress and social maladjustment, the disengagement coping strategies had stronger positive correlations with psychological distress and one of the three social maladjustment outcomes than did engagement coping, which had fewer and weaker positive correlations with these outcomes. Program participation did not predict personal mastery or use of coping strategies, but did predict fewer hassles. The number of physiotherapy sessions received predicted level of cardiac functional capacity. Furthermore, greater cardiac functional capacity was predicted by higher personal mastery, fewer hassles, lower psychological distress, and less impairment in domestic activity. This study demonstrates the importance of psychosocial variables as predictors of cardiac functional capacity, and provides empirical evidence that these variables moderate the relationship between physical status and recovery level. The findings concerning the identification of predictors of adjustment provide information for developing rehabilitation interventions for CHD patients. Patients' adjustment may be facilitated by reduction of hassles, limiting use of disengagement coping strategies, and strengthening personal mastery. The methodological strengths and weaknesses of this study are discussed, as are its implications for coping theory and research. (Abstract shortened by UMI.)

This thesis aims to investigate the role of innate immunity and the bacterial endotoxin lipopolysaccharide (LPS) in inflammation in adipose tissue. It attempts to do this by: 1) Describing the presence of Toll-like Receptors (TLR) in adipose tissue and adipocytes and their response to stimulation by LPS. It was demonstrated that both Toll-like receptor 2 and 4 were present in adipose tissue and that the receptors were present in greater amount in subjects with diabetes at a protein level and in subjects with obesity at both a RNA and protein level. It was also shown that these receptors responded to stimulation by LPS and that TLR-2 could be seen to be upregulated. 2) It was further shown that LPS induced production of inflammatory cytokines in cultured whole adipose tissue and adipocytes and caused downregulation of adiponectin in whole adiposes tissue. Blockade of NFκB in adipocytes was shown to regulate the levels of inflammatory cytokines produced and to differentially effect this levels dependent on whether whole adipose tissue or isolated adipocytes were cultured. 3) It was shown that LPS levels are significantly higher in the serum of T2DM subjects than controls and that these levels appeared to correlate with insulin. It was also seen that the LPS could be seen to correlate with inflammatory cytokines. It was also demonstrated that treatment with rosiglitazone significantly reduced both insulin and LPS levels in tandem. 4) It was also shown that LPS is significantly higher in NAFLD subjects, correlated with inflammatory cytokines and can be reduced by the use of Orlistat, an intestinal lipase inhibitor.

Benefits are measurable improvements that result from project outcomes. There is an emphasis in clinical trials literature that clinical trial benefits must always outweigh the risks yet there is limited clarity on processes to manage and ensure delivery of those benefits. With uncertainty around the delivery of clinical trial benefits, it is worth adopting a balanced management approach. This study looked to establish whether there were any comprehensive benefits management processes in HIV clinical trials and compared these practices to those described in the literature. Methods: To assess the current benefits management practices used to manage HIV clinical trials, a cross-sectional study used a critical review of clinical trials guidelines and publications as well as an online survey that was distributed to stakeholders in clinical trials management. Results: The critical review of the guidelines and literature revealed a high emphasis on risk benefit assessment, but very limited mention of the processes used for the assessment and management of those risks and benefits. The diverse group of clinical trials managers that responded to the online survey were involved at the strategic level of their respective clinical trials and 74% of them had never heard of Benefits Realization Management (BRM) and BRM processes. The respondents however, acknowledged that their lack of awareness did not necessarily mean lack of existence of BRM or BRM processes in HIV clinical trials. There were aspects of benefits management practices in clinical trials that were found to be similar to those in literature and other industries such as benefits planning, benefits identification, benefits review, setting time scale to benefits realization and allocating benefits champions. Even though there was confidence from the respondents in how clinical trial benefits were managed and in clinical trials delivering their promise, the respondents still believed there was room for improvement in the current BRM processes. Conclusion: BRM processes are not readily visible or documented in HIV clinical trials. There is a management bias towards safety and ethics in clinical trials which seems to have resulted in limited focus on benefits management. Compared to other industries, there appears to be more room and opportunity to implement published BRM processes. The findings from this study will serve as a starting point for future studies on how BRM can be incorporated into current management practices in order to achieve the most out of clinical trials.

Projeto de Graduação apresentado à Universidade Fernando Pessoa para obtenção do grau de Licenciada em Enfermagem
A adoção de estilos de vida (EV) saudáveis deve ser vista como uma oportunidade e um desafio da pessoa, família e comunidade, possibilitando uma atitude preventiva de saúde. A entrada no ensino clínico (EC) é um momento de mudança marcante na biografia do estudante. Consiste numa formação aglutinadora, mobilizando aprendizagens, permitindo a aquisição de competências ao futuro enfermeiro. Na transição para o EC o estudante deverá mobilizar recursos, desenvolvendo respostas adaptativas ao novo processo. Quando tal não acontece, reflete-se negativamente ao nível da saúde e do seu bem-estar. Este estudo teve como objetivos conhecer os EV dos estudantes de enfermagem em EC e promover a adoção de comportamentos promotores de saúde. É um estudo descritivo, transversal e quantitativo. Com uma população representada por todos os estudantes da licenciatura de enfermagem de uma Universidade do Norte do País. Amostra de conveniência, constituída por 39 estudantes de enfermagem em EC. O instrumento de colheita de dados foi o questionário “Estilos de Vida Fantástico”. Os dados foram tratados recorrendo a estatística descritiva e apresentados sobre a forma de gráficos e tabelas. Dos 39 estudantes 82% são género feminino e 18% do masculino. Situam-se numa média de idades de 23 anos. Destes 95% são solteiros e 5% são casados. Quanto aos fatores determinantes dos EV dos estudantes em EC, no item “família e amigos”, 95% referem ter com quem falar de assuntos importantes e 89,7% recebe carinho e afetos. Relativamente à “atividade física/associativismo” 51,3% dos inquiridos refere “quase nunca” participar em atividades associativas, 40,3% menciona andar cerca de 30 minutos diários, enquanto que 48,7% refere fazer atividade física 3 ou mais vezes por semana. Foram encontrados indicadores de comportamentos saudáveis nas dimensões “álcool e drogas”, “tabaco”, “comportamento sexual e saúde” e “outros comportamentos”. Quanto à “nutrição” e “sono e stress” deparamo-nos com comportamentos pouco consentâneos. Relativamente ao “trabalho/tipo de personalidade”, 71,8% diz sentir-se feliz, 54% refere sentir-se acelerado e/ou atarefado, 46% mencionam sentir-se tensos e/ou oprimidos e 30% triste ou deprimido. Os resultados confirmam comportamentos não tão saudáveis nas principais determinantes da saúde, havendo necessidade de intervenções especificas para a promoção de EV saudáveis. Durante esta transição, os hábitos saudáveis, são deixados de lado. A adoção de EV requer a proposição de estratégias que favoreçam a adesão e a participação dos estudantes na realização de ações de promoção de saúde.
The adoption of healthy lifestyles (EV) should be seen as an opportunity and a challenge for the person, family and community, enabling a preventive health attitude. The entry into clinical teaching (EC) is a moment of remarkable change in the student's biography. It consists of an agglutinative formation, mobilizing learning, allowing the acquisition of skills to the future nurse. In the transition to the EC the student must mobilize resources, developing adaptive responses to the new process. When this does not happen, it reflects negatively on the level of your health and well-being. This study aimed to know the EV of nursing students in CHD and to promote the adoption of health promoting behaviors. It is a descriptive, cross-sectional and quantitative study. With a population represented by all the students of the degree of nursing of a University of the North of the Country. Sample of convenience, made up of 39 nursing students in EC. The data collection instrument was the "Fantastic Lifestyles" questionnaire. The data were treated using descriptive statistics and presented in the form of graphs and tables. Of the 39 students 82% are female and 18% are male. They are located at an average age of 23 years. Of these 95% are single and 5% are married. Regarding the determinants of students' EVs in CS, in the item "family and friends", 95% refer to whom they talk about important matters and 89.7% receive affection and affection. Concerning "physical activity / association" 51.3% of respondents said "almost never" participate in associative activities, 40.3% said to walk about 30 minutes a day, while 48.7% referred to physical activity 3 or more times per week. Indicators of healthy behaviors were found in the dimensions "alcohol and drugs", "tobacco", "sexual behavior and health" and "other behaviors". As for "nutrition" and "sleep and stress" we are faced with inconsistent behaviors. Regarding "work / personality type", 71.8% said they felt happy, 54% reported feeling rushed and / or busy, 46% mentioned feeling tense and / or oppressed and 30% sad or depressed. The results confirm not so healthy behaviors in the main determinants of health, and there is a need for specific interventions to promote healthy VS. During this transition, healthy habits are left out. The adoption of EV requires the proposition of strategies that favor students' participation and participation in health promotion actions.
N/A

Urban Bioethics
M.A.
In the current healthcare landscape, parents generally make decisions regarding whether or not their children are allowed to take part in clinical research, with the general assumption being that parents know what is best for children. Investigations have been conducted regarding what is likely to lead parents to consent or not consent to their child’s participation in a trial, but research plans seldom incorporate the consideration that not all parents come into the consent process with equal social, academic, and economic footing. Since the burden of the ultimate decision lies primarily on the parents, it is supremely important that they are capable of making a well-informed and thoughtful choice. Bioethical understanding of the influence of parental decisions in clinical research must consider demographic variables and how they may affect parents’ decisions to allow or disallow their child to participate in a clinical trial. Those differences could affect the consent process and have ramifications for the research findings, as research results are affected in numerous ways by which children do, and do not, participate in studies. This paper looks specifically at parents in the process of informed consent for pediatric research, taking into account several social determinants of health and how they affect who participates in research and how that affects research as a whole.
Temple University--Theses

L'herpèsvirus humain 8 (HHV-8) est impliqué dans toutes les formes de maladie de Kaposi (MK) mais également dans certaines formes de maladie de Castleman multicentrique (MCM) et dans le lymphome primitif des séreuses (LPS). Ce travail avait pour objectif d’étudier les déterminants cliniques et virologiques impliqués dans l’infection HHV-8 et les maladies qui lui sont liées. Ainsi dans l’étude 1, la charge virale HHV-8 associée à la MK était inférieure à celles retrouvées dans les hémopathies, probablement dû à la physiopathologie de chaque maladie, mais d’autres facteurs pourraient également intervenir. En effet dans l’étude 2, le sous-type HHV-8 influençait la charge virale et la sévérité du tableau clinique dans la MK. De plus, nous avons identifié un nouveau variant systématiquement associé à des formes cliniques graves, renforçant le postulat de déterminants virologiques intervenant dans la physiopathologie des différentes maladies. Malgré l’ère des antirétroviraux, l’immunité jouerait également toujours un rôle important puisque dans l’étude 1, le taux de CD4 était faible et inversement corrélé à la charge virale HHV-8 dans la MK et la MCM alors que dans l’étude 3, les MK épidémiques avec une réponse immunologique et virologique soutenue pour l’infection VIH, étaient associées à un ratio CD4/CD8 inférieur à 1. Enfin dans l’étude 4, l‘analyse in vitro de l’effet du poppers sur le HHV-8 a montré qu’il stimulait la réplication virale. Ce résultat suggère que son utilisation in vivo pourrait être un facteur environnemental favorisant la transmission HHV-8 mais également le développement de MK chez des patients avec une immunité apparente normale ou restaurée
The human herpesvirus 8 is an oncogenic virus involved in the development of all forms of Kaposi’s sarcoma (KS), but also in certain forms of multicentric Castleman disease (MCD) and in primary effusion lymphoma (PEL). The aim of this work was to study the clinical and virological determinants in HHV-8 infection and associated with its three main diseases. Thus, in the study 1, the HHV-8 DNA viral load associated with KS was lower compared with that found in hemopathies, probably due to the pathophysiology of each disease, but other factors could also be involved. Indeed, in the study 2, the HHV-8 subtype influenced the viral load and the severity of the clinical presentation of KS. In addition, we have identified a new variant associated with severe clinical forms, reinforcing the postulate of virological determinants involved in the pathophysiology of the different diseases. Despite the era of antiretrovirals, immunity would still play an important role because in the study 1, the CD4 count was low and inversely correlated with the HHV-8 viral load in KS and MCD whereas in study 3, epidemic KSs with a sustained immunological and virological response for HIV infection were associated with a CD4 / CD8 ratio of less than 1. Finally, in the study 4, in vitro analysis of the effect of poppers on BC-3 cells chronically infected by HHV-8 has been shown to stimulate viral replication. This result suggests that poppers used in vivo could be an environmental factor favoring the transmission of HHV-8 but also the development of MK in patients with apparent normal or restored immunity

Introduction – Objectives. The cardiovascular system is in direct and constant interaction with its environment. Exposure to various environmental parameters, such as low temperature, air pollution and tobacco smoke, has been strongly associated with serious or even fatal cardiovascular outcomes. Arterial stiffening and greater wave reflection are age-related vascular modifications that lead to an increased risk of cardiovascular events. The aim of this work was to explore the relationship between selected environmental factors and arterial elastic properties in an effort to elucidate the underlying mechanisms that link these factors to increased cardiovascular mortality.

Study 1: Effects of cold exposure on central and peripheral vascular tone. Our first study explored the effects of cold exposure on aortic stiffness and peripheral microvascular tone. We observed that cold exposure, in addition to its chronotropic effects, provoked an increase in aortic stiffness, as assessed by aortic pulse wave velocity, as well as significant vasoconstriction of peripheral arterioles in the microcirculation. Moreover, we explored the magnitude of this effect in a different population (Black subjects of African origin), which is traditionally characterized by exaggerated reactions to adrenergic stimuli. We noted that the vascular reactions, in terms of both aortic stiffness and microvascular vasoconstriction, were more profound in Black Africans than in age-matched Caucasian-Whites. These results argue for a direct effect of cold exposure on arterial stiffness and peripheral vascular tone, probably through activation of the orthosympathetic system.

Study 2: Exposure to ambient particulate matter and arterial stiffness. We explored the effects of acute exposure to outdoor particulate matter on aortic stiffness and aortic wave reflection. We studied the relationship between central hemodynamic parameters and ambient concentration of particulate matter in a population of patients who attended the Hypertension Clinics of Athens University. After statistical correction for a number of potential confounders, we did not observe an association between ambient concentrations of particulate matter and aortic stiffness. However, in men, particulate matter concentration was related to the amplitude of the reflected wave reaching the aorta from the periphery. These results suggest a direct acute interaction between particulate matter concentration and vascular tone, leading to an enhanced arterial wave reflection.

Study 3: The role of nicotine on the vascular effects of environmental tobacco smoke. Environmental tobacco smoke is considered as the most important source of particulate matter in the indoor environment. We recently demonstrated that exposure to tobacco smoke augmented wave reflection, an effect that was not seen after equivalent exposure to the smoke of non-tobacco, herbal cigarettes. We also noticed that the increased wave reflection was proportional to the plasma concentrations of nicotine. However, a direct causal effect between nicotine, arterial wave reflection and aortic stiffness has never been clearly demonstrated. We observed that increasing nicotine plasma concentration to levels comparable to those seen after extensive exposure to environmental tobacco smoke, provoked an increase in both aortic stiffness and arterial wave reflection after correction for heart rate and blood pressure changes. These results confirm the significant participation of nicotine in the vascular effects of passive smoking.

Conclusions. Globally, our results reveal the deleterious effects of cold, particulate matter exposure, and nicotinic stimulation on arterial stiffness, peripheral microcirculation and aortic wave reflection. The hemodynamic modifications associated with these effects may at least partially explain the causal relation between cold exposure, ambient air pollution and cardiovascular mortality.

Introduction-Objectifs. Le système cardiovasculaire est en relation directe et constante avec l’environnement. L’exposition au froid, la pollution atmosphérique et le tabagisme passif sont associés à des événements cardiovasculaires aigus graves et même fatals. La rigidification des artères et l’intensification de la réflexion de l’onde de pouls au niveau de l’aorte accompagnent le vieillissement et prédisent un risque cardiovasculaire accru. Nous avons testés l’hypothèse que les effets cardiovasculaires délétères des facteurs environnementaux comportent une altération des propriétés élastiques artérielles. Ceci pourrait être un des mécanismes physiopathologiques qui lie la mortalité cardiovasculaire aux variables environnementales.

Étude 1 :Exposition au froid ;effets centraux et périphériques. Notre première étude portait sur l’effet de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artérioles périphériques. Nous avons démontré que l’exposition au froid, hormis ses effets chronotropes, provoquait une augmentation de la rigidité artérielle – mesuré par la vitesse de l’onde de pouls au niveau de l’aorte - ainsi qu’une vasoconstriction importante au niveau des artérioles de la microcirculation. Nous avons ensuite déterminé l’amplitude de cet effet dans une autre population (sujets Africains-Noirs) qui se caractérise par des réactions plus prononcées aux différentes stimulations adrénergiques. Nous avons observé que les réactions vasculaires, tant au niveau de la rigidité aortique qu’au niveau de la microcirculation, étaient plus marquées chez les Africains-Noirs que chez les Caucasiens. Ces résultats révèlent un effet délétère de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artères périphériques, probablement via une activation du système orthosympathique.

Étude 2 :Exposition aux microparticules atmosphériques et rigidité artérielle. Nous avons ensuite investigué les effets de la pollution atmosphérique sur la rigidité artérielle et la réflexion de l’onde de pouls vers l’aorte. Nous avons étudié la relation entre les paramètres hémodynamiques centraux et la concentration atmosphérique de microparticules dans une population de patients qui ont consulté la Clinique Universitaire d’Hypertension Artérielle d’Athènes. Après correction statistique pour les facteurs confondants, nous n’avons pas observé de corrélation entre la rigidité artérielle et le taux de microparticules atmosphériques dans l’ensemble de la population investiguée. Par contre, si on restreint l’analyse aux résultats obtenus chez les sujets masculins, on s’aperçoit que la concentration atmosphérique de microparticules était associée de façon significative avec l’amplitude de l’onde réfléchie par la périphérie vers l’aorte et la pression pulsée aortique. Ces résultants suggèrent un effet direct des microparticules au niveau de la microcirculation. L’augmentation de l’amplitude de l’onde réfléchie consécutive à une vasoconstriction périphérique, modifie vraisemblablement les pressions au niveau de l’aorte chez le sujet masculin lors de pics de pollution.

Etude 3 :Le rôle de la nicotine dans les effets vasculaires du tabagisme passif. Le tabagisme passif est considéré comme la source la plus importante d’émission de microparticules au niveau domestique. Cependant, la composition chimique des particules semble jouer un rôle essentiel sur les ondes de réflexion. Nous avons démontré récemment que l’exposition passive à la fumée des cigarettes du tabac augmente l’intensité de la réflexion de l’onde de pouls. Ceci n’a pas été observé avec l’exposition à la fumée des cigarettes non tabagiques, en dépit d’une concentration ambiante tout à fait comparable de microparticules. Par ailleurs, nous avons observé que l’augmentation de l’incidence de l’onde de pouls au niveau de l’aorte était fortement associée à la concentration plasmatique de la nicotine. Un lien causal entre la nicotine, réflexion de l’onde de pouls et rigidité artérielle n’avait jamais clairement été établi. Nous avons testé cette hypothèse en administrant la nicotine pure chez des sujets sains. Nous avons observé que l’augmentation des taux plasmatiques de la nicotine à des valeurs comparables à celles qui surviennent après une exposition intensive au tabagisme passif, intensifiait la réflexion de l’onde de pouls et augmentait la rigidité artérielle. La correction statistique pour l’augmentation de la fréquence cardiaque et l’augmentation de la pression artérielle en réponse à la nicotine ne modifiait pas ces conclusions. Nos résultats démontrent ainsi les effets cardiovasculaires importants de faibles concentrations de nicotine, similaires à ceux qui sont atteints en cas d’exposition à un tabagisme passif.

Conclusions. Nos résultats révèlent les effets néfastes de l’exposition au froid et aux microparticules atmosphériques sur la rigidité artérielle, la microcirculation périphérique et la réflexion de l’onde de pouls. Nous avons pu également démontrer le rôle de la stimulation nicotinique dans les effets vasculaires aigus du tabagisme passif, comme en témoigne l’augmentation de la réflexion de l’onde de pouls au niveau aortique. Ces modifications hémodynamiques favorisent l’ischémie myocardique, et constituent un des mécanismes par lesquels l’exposition au froid et à la pollution atmosphérique favorisent la pathologie cardiovasculaire.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Background: As Alzheimer's disease (AD) becomes an increasingly urgent public health problem, much effort has been made by medical researchers and public health professionals to further our understanding of AD etiology and causal factors that contribute toward its onset, progression, and severity. AD research has recently focused on identifying and examining preclinical traits associated with the onset and progression of AD with the goals of early detection discovery, mechanism elucidation, and ultimately treatment and prevention. By understanding the genetic components that make one susceptible to pre-clinical traits that are correlated with future development of AD, we can increase our understanding of what and how genes are involved in the molecular pathways as well as identify risk factors that contribute to the onset of a presently elusive, costly, and devastating disease. Specific Aims: This study sought to complete the following; identify MRI and cognitive endophenotypes that are co-heritable with the future onset of Alzheimer's disease; determine cross-trait co-heritability of endophenotypes heritable with AD; select a co-heritable endophenotype combination that has predictive value for AD development; assess which potential genes may be responsible for the co-heritability of this endophenotype combination and prepare for further candidate gene analysis. Methods: Data from the Framingham Heart Study was analyzed to determine heritability of MRI and cognitive endophenotypes with AD development, and co-heritability of the traits with each other. A bivariate, Genome-Wide Association Study (GWAS) was then conducted on the selected MRI-cognitive endophenotype combination to determine which single nucleotide polymorphisms (SNPs) are most associated with co-heritability of the selected trait combination. The results of the GWAS directed further study, including gene-based association studies and assessment of protein interaction pathways, that resulted in selection of potential candidate genes. Results: Twenty-four MRI and cognitive traits were found to be heritable with future AD onset. The most co-heritable MRI and cognitive trait combination among the AD-heritable traits was temporal horn brain volume (THBV) and trail-making test B (TrB) scores. This combination was selected to drive our hypothesis of a significant association between pre-clinical endophenotypes and future AD. The GWAS results indicate that several SNP markers are associated with the co-heritability of THBV and TrB scores. Subsequent regional analyses implicate several genes likely to be causally involved in expression of this endophenotype expression, including SPON1, which directly interacts with APP. Based on a combination of evidence, the genes selected for candidate gene analysis are SPON1, DICER1, GPR177, ADCY9, VAMP3, and FOXF2. Conclusion: Our study validated several previous findings of MRI and cognitive heritability with AD. We then used estimates of co-heritability to successfully run a bivariate analysis of two pre-clinical traits to identify genes explaining their impact on future AD development. The genes selected for candidate gene analysis appear to be involved in amyloid precursor protein processing, which is the primary pathway that leads to plaque deposition and AD pathology. Further study of these genes, especially SPON1, will allow for determination of replicable findings, assessment of whether the candidate genes are causative, and determination of whether these genes are also related to progression and severity of AD symptoms. Importantly, this method of gene discovery, through bivariate analyses of pre-clinical traits, allows for insights into disease susceptibility, molecular pathways, early detection, and more focused treatments.

Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppressive therapy following transplantation; however, immunosuppressive drug regimens consist of multiple medications with narrow therapeutic indices and substantial inter-patient variability. Despite intensive therapeutic monitoring, considerable time can elapse before the desired therapeutic concentration is achieved, which increases the risk of graft rejection or drug-related toxicities. In addition, maintaining therapeutic concentrations of CNIs does not prevent the development of toxicities, such as nephrotoxicity. Pharmacogenomics can greatly benefit solid organ transplant recipients through individualized drug therapy; tacrolimus is a widely used CNI and a substrate of cytochrome P450 3A (CYP3A) metabolizing enzymes and the efflux transporter p-glycoprotein (PGP) encoded by the ATP-binding cassette subfamily B member 1(ABCB1) gene. This dissertation describes work conducted in order to examine the effect of genetic variability in the above mentioned genes on the pharmacokinetics of tacrolimus and their contribution to a predisposition to adverse events or drug interactions in the transplant population. Our retrospective study investigating the effect of genetic polymorphisms on the risk of CNI-induced renal dysfunction identified a time-sensitive effect for the CYP3A5 expressor genotype, which predicts increased renal tubular CYP3A5 expression, in modifying the risk for renal dysfunction in liver transplant patients. This dissertation also examines the hypothesis that local tissue levels of tacrolimus and/or its major metabolite may be an improved indicator of nephrotoxicity, and through development of a robust and sensitive liquid chromatography/ mass spectrometry (LC/MS) analytical method to co-determine tacrolimus and its major metabolite, 13-O-demethyl tacrolimus (13-ODMT), in rat kidney tissues, we identified a possible relationship between tacrolimus dose and the extent of metabolite accumulation in the kidneys of rats receiving tacrolimus intra-peritoneally, paving the way for examining this relationship in kidney transplant recipients with calcineurin inhibitor-induced nephrotoxicity (CNIT). Overall, my research aims to identify biomarkers that might assist in early prediction of optimal tacrolimus starting and maintenance doses. Importantly, these studies provide the foundation for prospectively identifying patients at higher risk for adverse effects or drug interactions, with the ultimate goal of improving treatment outcome and quality of life for the transplant recipient receiving tacrolimus.

The main focus of this PhD thesis is the research of the mechanisms of resistance to beta-lactam antibiotics in health-care associated multi-resistant gram-negative bacteria (mainly Enterobacteriaceae). In particular, a novel class D beta-lactamase with carbapenemase activity, named OXA-372 was characterized from a multi-resistant Citrobacter freundii isolated from hospital-wastewater. Other interesting isolates included in this work are the first NMCA-producing Enterobacter ludwigii, the first IMI-2-producing E. ludwigii and a VIM-1-producing Aeromonas caviae. Moreover a cfr-positive linezolid resistant isolate of MRSA was characterized. Multiple techniques of molecular biology were applied during this thesis including PFGE, MLST, Real Time PCR and Whole-Genome Sequencing. Part of this work included also the italian epidemiology of carbapenemase and ESBL in a large collection of Escherichia coli and Klebsiella pneumoniae isolated from 14 different centers in 2013.

While the role of obesity in health outcomes has been well described, the role of low body mass index (BMI), body weight relative to height, has largely been ignored. Those with low BMI are commonly excluded completely or combined with the normal BMI category in BMI studies. However, there have been some studies indicating poorer health outcomes among those with lower BMI, particularly that of increased risk of mortality. The purpose of this study is to explore the role of low BMI throughout the lifespan. Data from the Health and Retirement Study was used to evaluate 1) the association between childhood health and socioeconomic status (SES) exposures and low BMI in midlife adulthood, 2) the association between low BMI and health related outcomes in midlife adulthood (ages 50 to 65), and 3) the association between low BMI in midlife and health related outcomes, including mortality, over a longer follow-up (maximum of 20 years). To increase sample size, two low BMI definitions were used: the traditional Few significant results were found. Low BMI status was consistently associated with older age and female gender as well as current smoking status. Childhood exposure of respiratory disease and greater SES disadvantages was more common among those with low BMI in adulthood. In midlife adulthood, low BMI status was associated with increased difficulties with activities of daily living with either definition of low BMI. Increased risk of fracture was associated with a low BMI definition of <18.5. Increased risk of lung disease and decreased risk of high blood pressure was associated with a low BMI definition of ≤20. An analysis of those 30 years old or older found low BMI to be associated with increased risk of mortality and decreased risk of diabetes regardless of low BMI definition. When low BMI was defined as <18.5, those with low BMI were also more likely to experience difficulty with one or more activities of daily living. When low BMI was defined as ≤20, low BMI status was associated with greater risk of lung disease and decreased risk of high blood pressure. Further research is needed to fully characterize the role of low BMI on health outcomes as well as the role of SES on low BMI. Additionally, there is a need for greater understanding of the potential biological mechanisms of low BMI for health outcomes. Currently, there are few studies evaluating health outcomes and SES of low BMI. Limiting studies to the extreme upper end of the BMI spectrum limits the overall understanding of the role of BMI in health and may overlook unique characteristics and challenges those with low BMI may face.

Abstract: Social Determinants of Health in Belize Free Clinic Introduction: To determine the most appropriate ways to serve patients in rural Belize through medical mission work, it is important to assess social determinants of health (SDOH). It has long been agreed that a variety of factors affect health, including environment, community and social context, access to healthcare, stress, income, mental health, education, and transportation. Many people in Roaring Creek, Belize, a village with a population of approximately 2,000, use Body and Soul Ministries, a nonprofit that invites medical teams from all over to deliver medical care, as their primary source of healthcare. During one of these trips, a medical team from East Tennessee State University (ETSU) provided medical care and employed the TeamCare survey, already used in several clinics in east Tennessee to assess the SDOH needs of the patient population in Roaring Creek. The purpose of this study was to use a survey that assesses several SDOH to determine better ways to address health needs in the community of Roaring Creek as well as connect patients with resources to meet those needs. Methods: A team of ETSU medical students, a resident, and five physicians served in a free clinic in Roaring Creek, Belize in October 2017. The team saw approximately 500 patients. Some patients were randomly selected to take the TeamCare survey to assess for six SDOH, including literacy, financial needs, drug use, abuse, transportation, and mental health. Based on the results of the survey, patients were connected with their local community health worker to assist in locating resources for patients. Using SPSS, results from the survey were arranged for frequencies and measures of central tendency. Results: Overall, a total of 106 patients responded to the TeamCare survey. Based on the survey results, 83.2% of patients responded “yes” to at least one question regarding needs related to SDOH. In fact, 7.9% of patients answered “yes” to five questions. Of note, 53.5% of patients responded positively for financial need, 46.5% positive for mental health needs, 37.6% positive for environmental alcohol or drug abuse, and 32.7% positive for transportation needs. More women stated positively for physical or verbal abuse compared to men (-1.48, p=0.001). Discussion and Conclusion: Roaring Creek, Belize is a rural community that illustrates how SDOH can impact health outcomes. There has been a recent effort for clinicians to address SDOH, especially in rural areas, but perhaps not enough globally. One way this can be done is by surveying for SDOH at clinic visits and then linking patients with relevant community resources. However, resources are not always readily available in Roaring Creek, Belize. Many patients are positive for SDOH, but with an overall lack of resources, it is important to do more research to determine how global health efforts can best serve these populations. Perhaps the best way for SDOH needs to be addressed is for Body and Soul to collaborate with community health workers and mission teams to establish ongoing programs and longstanding resources for the community.

The aim of the present research was to determine a range of principles for the development of virtual natural environments (VNEs), using low-cost commercial-off-the-shelf simulation technologies, for bedside and clinical healthcare applications. A series of studies have been conducted to systematically investigate different aspects of the VNEs on a wide variety of participants, ranging from undergraduate and postgraduate students, hospital patients and clinicians, to West Country villagers. The results of these studies suggest that naturalistic environmental spatial sounds can have a positive impact on user ratings of presence and stress levels. High visual fidelity and real-world-based VNEs can increase participants’ reported ratings of presence, quality and realism. The choice of input devices also has a significant impact on usability with these types of virtual environment (VE). Overall, the findings provide a strong set of principles supporting the future development of VNEs. Highly transferrable tools and techniques have also been developed in order to investigate the exploitation of new digital technology approaches in the generation of believable and engaging real-time, interactive virtual natural environments that can be modified and updated relatively easily, thereby delivering a system that can be regularly modified and updated to meet the needs of individual patients.

Projeto de Graduação apresentado à Universidade Fernando Pessoa para obtenção do grau de Licenciada em Enfermagem
O estilo de vida na juventude desempenha um papel significativo na prevenção de doenças e na promoção da saúde durante todo o ciclo de vida de um indivíduo. A transição para o ensino superior, trás consigo certos desafios, que podem obrigar a alterações nas rotinas, nas relações interpessoais e na forma como o individuo se auto perceciona e como perceciona o mundo. Estas transições obrigam o estudante a se apoiar em certos recursos, tais como o suporte social, de modo a desenvolver respostas adaptativas. Quando isto não acontece, pode refletir-se negativamente ao nível da sua saúde. Os EV são um conjunto de hábitos e atitudes que se vão adquirindo ao longo da vida, sendo estes de grande importância para a promoção da saúde na adolescência, refletindo-se assim na idade adulta. Como objetivo de investigação propusemos conhecer os Estilos de Vida dos Estudantes do 4º ano da Licenciatura em Enfermagem, em Ensino Clínico, de uma Escola Superior de Saúde. Trata-se de um estudo descritivo, quantitativo e transversal, com uma amostra não probabilística por conveniência, constituída por 30 estudantes do 4º ano da Licenciatura em Enfermagem. Para realizar a colheita de dados, foi utilizado o Questionário “Estilo de Vida Fantástico”, adaptado e validado para a população portuguesa por Amado, Brito e Silva (2014). Após a recolha de dados, procedeu-se ao tratamento estatístico dos dados recorrendo ao SPSS versão 23.0 para Windows. Os resultados demonstram que os estudantes com melhor estilo de vida são os mais novos, pertencentes ao sexo feminino e solteiros. Na maioria do questionário “Estilo de Vida Fantástico” obtivemos resultados iguais ou superiores a 85.00 pontos para mais de metade dos estudantes (66,7%), podendo classificar o estilo de vida do estudante desta instituição como “Muito Bom” ou “Excelente”. Podemos concluir que ao nível dos domínios Família e Amigos, Introspeção, e Outros Comportamentos, os estudantes apresentam melhor pontuação, sendo que os domínios da Atividade Física/Associatividade, Nutrição, Tabaco e Álcool e Outras Drogas refletiram resultados um tanto alarmantes onde é necessária intervenção para promoção de estilos de vida saudáveis.
Youth lifestyle plays a role in preventing disease and promoting health throughout an individual's life. The transition to higher education brings with it certain challenges, which can force changes in routines, interpersonal relationships and in the way individuals perceive themselves and how they perceive the world. These transitions force the student to rely on certain resources, such as social support, in order to develop adaptive responses. When this does not happen, it can reflect negatively on the students health. Healthy lifestyles are a set of habits and attitudes that are acquired throughout life, which are very important for the promotion of health in adolescence, thus being reflected in adulthood. As an objective of this investigation, it is proposed to study the Lifestyles of year 4 Students of a Bachelor in Nursing, during Clinical Teaching, at a Higher School of Health. This is a descriptive, quantitative and cross-sectional study, with a non-probabilistic convenience sample, found by 30 students in the year 4 of a Bachelor of Nursing. To carry out data collection, the “Fantastic Lifestyle” Questionnaire was used, adapted and validated for the Portuguese population by Amado, Brito and Silva (2014). After collecting the data, the statistical treatment carried out using SPSS version 23.0 for Windows. The results show that the students with the best lifestyle are the youngest, female and single. In most of the “Fantastic Lifestyle” questionnaire, we obtained results equal to or greater than 85.00 points for more than half of the students (66.7%), being able to classify the student's lifestyle of this institution as “Very Good” or “Excellent”. In conclusion, the research has identified that in the category of Family and Friends, Introspection, and Other Behaviors, students have better scores, and the category of Physical Activity/Associativity, Nutrition, Tobacco and Alcohol and Other Drugs reflected somewhat alarming results where intervention is needed for promoting healthier lifestyles.
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Firstly, the importance of corticosteroid resistance/dependence as a co-factor in disease progression was studied in a detailed 5-year inception cohort (1998-2003). Secondly, a risk score to stratify the likelihood of response to standard medical therapy (high dose corticosteroids) identifying 3 distinct risk groups – low, intermediate and high risk; based on 167 consecutive patients (largest series studied) with acute severe UC was developed. A novel robust model was formulated with a sensitivity/specificity of 85% and 75% respectively to predict failure of medical therapy. These initial studies have provided the assimilation of highly accurate phenotypic and follow-up data, permitting very detailed statistical analyses to be performed in subsequent genetic studies. In this study, allelic variations of the MDR1 gene were found to be implicated in disease susceptibility in UC, in particular extensive and severe disease subphenotype (p=0.003, OR 2.64 and T-allele, p=0.009, OR 1.70). Bi-directional haplotypic contribution to susceptibility in UC (with protective and susceptible haplotypes) was observed. The novel ‘gene-wide’ haplotype tagging approach confirmed a more significant association with UC (p=4.22x10-7) but not CD (p=0.22). The strongest association was with the sub-phenotype extensive UC (p=1.7 X 10-7), and critically dependent on one tSNP rs3789243 (p= 3.2 x 10-7 – 3.6 x 10-12). Significant and replicable association of haplotypic variations of the ABCC3/MRP3 gene (also involved in epithelial barrier defence) with IBD (p=0.00004, 1200 IBD and 700 controls) have now been demonstrated. The characterisation of these genes has implicated this novel class of transport proteins as important regulators of mucosal defence and is critical in determining susceptibility to inflammatory bowel disease.

The purpose of this grounded theory study is to define the process that nurse anesthesia program administrators use to determine if a student nurse anesthetist’s unsatisfactory clinical performance warrants intervention by the program. There is little room for error in anesthesia practice as mishaps typically result in significant injury and death. Students who exhibit unsatisfactory clinical performance may pose an immediate risk to patient safety as well as a future risk if allowed to progress in the program. The lack of guidance in the form of clearly articulated expectations and processes contribute to the emotional strain nurse anesthesia faculty and administrators experience when observing unsatisfactory clinical performance. From the data collected in the interviews with ten nurse anesthesia program administrators, a five-phase decision-making model entitled the Nurse Anesthesia Program Administrator Decision Making Model was developed. The five phases of the model include: receiving the feedback, validating the concern, assessing accountability and planning for remediation, removing the student from clinical training and moving to dismissal, and notifying the student of the decision. The guiding principle of this model is the importance of following institutional and program policies throughout the process. This study is intended to provide guidance to nurse anesthesia program administrators who are faced with a student demonstrating unsatisfactory clinical performance regarding what behaviors may require an intervention by the program.

This applied theoretical paper explores the underlying capacity for caregivers to raise emotionally intelligent, well-adjusted children who grow up able to respond effectively to the demands of a complex world. A guiding supposition of the research is that diminished access to institutional privilege, especially when unrecognized and unprocessed by caregivers, is likely a risk factor connected to a variety of deleterious outcomes associated with the social determinants of health as defined by the U.S. Department of Health and Human Services. This connection resulted from asking the question, “How does the underlying capacity for caregivers to understand and manage diverse and complex dimensions of their personal identity, especially in terms of how they relate to institutional power and privilege, serve as a protective factor in meeting the developmental needs of their children for a safe, stable, and nourishing emotional environment?” To answer this question, two well-respected theoretical orientations were identified that each spoke to half of the question, but when brought together, could much more elegantly address many more aspects of the question in an integrated and holistic fashion. Specifically, John Bowlby’s Attachment Theory provided important context as to what developmental needs children have for a safe, stable, and nourishing emotional environment. On the other hand, Jean Baker Miller’s Relational-Cultural Theory was adept at offering a nuanced perspective on understanding diverse and complex dimensions of personal identity, especially as those dimensions interfaced with institutional privilege. Bringing these two perspectives together and synthesizing them into a new approach, an approach named Attachment-Informed Relational-Cultural Therapy, was the culmination of the research. One important outcome of the research was how it framed secure attachment as an unearned privilege (i.e. attachment privilege) that is affected by and simultaneously affects multiple variables in the caregiver and child dyad. These variables can themselves then become either protective factors supporting further secure attachment or risk factors threatening to damage or destroy it. Through the process of linking childhood attachment themes to the theme of access to institutional privilege it is hoped a greater capacity may be achieved for supporting caregivers in understanding and managing diverse and complex dimensions of their personal identity.

The purpose of this dissertation is to review research on predictors of success when students return to high school, and to investigate the power of several risk and protective factors as predictors of success of students returning to school. Research findings regarding factors associated with initial departure from high school, returning to school, and repeated departure from high school are reviewed. Theories regarding departure from school are presented. A developmental psychopathology approach to predicting repeated departure from high school programs is presented which integrates cognitive, behavioural, social, and developmental theories. Findings are presented from a study on students returning to school who responded to questionnaires about demographics, vocational identity, stress level, coping style, and perceived social support. A total of 453 students participated who were returning to four types of academic environments: alternative outreach high schools (n = 267), a school for mothers (n = 46), a fourth year high school (n = 42), and college high school upgrading and completion programs (n = 98). The participants included 288 females (79 mothers and 209 nonmothers) and 165 males. The primary analyses were focused on how vocational identity, stress, coping behaviours, and social support predicted the outcome variables of attrition, attendance, number of credits completed, and grades at the end of the students' first 4 to 6 month term back in high school programs. Age, SES, and achievement were not found to be consistently predictive of outcomes. Males were more likely to leave school again, although no specific psychological variables were found to predict their departure. Females were found to be more likely to leave school again if they had a lower level of vocational identity, and if they had experienced a greater number of stressful life events in the year prior to returning to school. Gender, vocational identity, and life stress were not found to interact as moderators on outcomes. The results of this empirical study are believed to enrich theoretical understanding of success in returning to high school and will enable teachers and other professionals to more effectively evaluate and counsel students returning to school.

Introduction: Sub-arachnoid haemorrhage (SAH) occurs when cerebral artery ruptures and blood leaks out into the sub-arachnoid space. This is often a catastrophic event for the individual and morbidity and mortality rates are significantly influenced by early intervention. This makes the role of the clinical biochemistry laboratory in early diagnosis vitally important, as delays in diagnosis can have a major clinical impact. The cerebrospinal fluid (CSF) of healthy individuals is optically clear. It has, however, been recognised for over a century that it can become coloured (xanthochromia) following a cerebrovascular incident such as a SAH. This has made the main role of the clinical biochemistry laboratory in SAH diagnosis that of detecting xanthochromia in the CSF. The majority of laboratories which offer a xanthochromia screening service use the national guidelines that are based upon ultra-violet scanning spectrophotometry (350 nm to 600 nm). This analytical technique is not without its problems: it is subjective, has a possibility of inter-operator variability and due to the specialised nature of the test can take many hours or even days for a result to be issued. This project aimed to improve the current laboratory service by investigating: turnaround times, users opinions of the current service and potential alternative analytical methods. Methods: An audit of the current analytical provision was used to assess its effectiveness and in order to elucidate the service users’ perception. This was effected by a questionnaire that was distributed to service users across three different NHS Trusts in England and Wales. In an attempt to improve the laboratory service, alternatives to scanning spectrophotometry were investigated. These were selected through consideration of the nature of SAH i.e. blood is released into the subarachnoid space and the brain is damaged. Laboratory analysis therefore needed to focus on detecting the presence of blood and/or its breakdown products, any change in CSF constituents that arise as a direct consequence of blood being introduced in to the subarachnoid space or a specific analyte which would only be present if brain damage occurred. Investigation of current research into subarachnoid haemorrhage identified the following analytes as potential alternatives: CSF diazo bilirubin, CSF Ferritin, CSF protein S100 and serum protein S100. Results: The audit revealed the average turnaround time for reporting xanthochromia results to be 26 hours, with almost 20% of samples being reported as equivocal. The service user’s questionnaire revealed a general lack of awareness of current United Kingdom National External Quality Assurance Scheme (UKNEQAS) guidelines for the ‘Analysis of cerebrospinal fluid for bilirubin in suspected Subarachnoid haemorrhage’ and a lack of understanding regarding the timing of lumbar punctures. Additionally, one third of users felt that the turnaround time for results was inadequate. CSF protein S100 was found to be unsuitable due to the difficulty in achieving a suitable balance between sensitivity and specificity; at a cut-off of 0.40 μg/l sensitivity is 80% and specificity is 4%, at a cut-off of 1.60 μg/l sensitivity is 40% and specificity is 94%. Serum protein S100 was found to be unsuitable due to the difficulty in achieving a suitable balance between sensitivity and specificity at appropriate cut-offs (66 % and 73%, respectively, at a cut-off of 0.09 μg/l). When the CSF diazo bilirubin and CSF ferritin were compared to current laboratory practises using pre-defined criteria then CSF diazo bilirubin was found to be the analyte of choice to base new guidelines upon. CSF diazo bilirubin was then used as an initial ‘rule-out’ step in a new set of guidelines for the determination of SAH utilising CSF analysis. Conclusion: The new guidelines employ CSF diazo bilirubin analysis as a ‘rule-out’ step with all samples that are above the cut-off (300 nmol/l) being processed through the UKNEQAS guidelines. In order for the guidelines to be introduced and accepted, local training and education programmes for laboratory and clinical staff will need to be developed and implemented and they will need to be disseminated through publication of articles in journals relevant to both the clinical biochemistry community and requesting clinicians.

Multiple sclerosis is a chronic, inflammatory disorder of the central nervous system, thought to primarily affect persons of Caucasian ancestry. Despite growing recognition of multiple sclerosis and clinical variants such as neuromyelitis optica in persons of other ethnicities, relevant research in emerging populations is comparatively scant. Consequently, current understanding with respect to clinical outcomes and risk factors in this ethnic group is remarkably under-developed. The overarching objective of this dissertation was to address these knowledge gaps using a multi-disciplinary approach focusing on Asian-ethnic populations in Canada and China. The prevalence of multiple sclerosis in an Asian-ethnic population of Canada was found to be intermediate to that typically reported in Asia and in the general Canadian population. Longitudinal analysis also revealed an increase in incidence among females of Asian ancestry in Canada. In comparative analysis in a Canadian clinic population, long-term clinical outcomes of multiple sclerosis in patients of Asian ancestry were remarkably similar to those in non-Asian patients. Male sex and later age at onset were associated with less favourable clinical outcomes, irrespective of ethnicity or region. In immigrant and Canadian-born patients, duration of exposure to the Canadian environment prior to onset was associated with multiple sclerosis, whereas exposure to the regional environment of Asia was associated with neuromyelitis optica. Case-control analysis revealed a robust association of smoking with multiple sclerosis risk and clinical outcomes in Canadians of Asian ancestry. Genetic studies confirmed the overall low rate of familial recurrence in this ethnic group, but also identified novel variants associated with risk and clinical phenotypes. The findings underscore the importance of ethnicity-related genetic and environmental factors in modifying susceptibility to and clinical presentation of multiple sclerosis and related disorders in persons of Asian ancestry. Nevertheless, these results also suggest that the clinical trajectory in patients of Asian ancestry may be more comparable to classic clinical descriptions than previously believed. Taken together, the findings presented in this dissertation contribute new perspectives to the epidemiology and etiology of multiple sclerosis and related disorders, and advance knowledge in an emerging patient population in Canada and globally.
Medicine, Faculty of
Medical Genetics, Department of
Graduate

While most clients show improvement in therapy, anomalously, 5% to 10% actually worsen, and a significant minority of clients shows little or no response to therapy. Earlier studies developed clinical support tools (CSTs) designed to provide feedback to therapists about potential problem areas and to improve the likelihood of a positive outcome for clients identified as at-risk for a negative outcome in therapy (Harmon et. al. 2007; Slade, Lambert, Harmon, Smart, & Bailey, 2008; Whipple et al., 2003). While varying from study to study, the CSTs looked at five domains: therapeutic alliance, motivation to change, social support, life events, and perfectionism. More than 100 questions were used to assess these domains. The major goal of this study was to streamline the CST measures to increase efficiency. Toward that end, a new instrument consisting of 37 questions was developed by administering questionnaires to 169 patients at a rural Utah mental health center. In addition, the life events and social support questions were given to 76 students at Brigham Young University and 88 randomly selected residents of Utah County. Using item response analysis and mean scores for each dimension, subscale cut scores were developed for four dimensions: therapeutic alliance, motivation for therapy, social support, and life events. The perfectionism subscale was dropped from the questionnaire because perfectionism was deemed to be too stable to be useful for the intended use of the measure. Cut scores were also developed for each individual question. These subscale and individual item cut scores are intended to help clinicians identify potential problem areas to be explored during the course of therapy.

Cancer immunotherapy has achieved tremendous results, however the outcome of therapies targeting immune inhibitory pathways, specifically CTLA-4 and the axis between programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) has many genetic and environmental sources of variability. Many studies demonstrated the influence of gut microbiome on immune checkpoint inhibitors (ICIs) outcome. Besides ICIs, oncolytic vaccines (OVs) are a promising therapeutic alternative in cancer immunotherapy with possible relevant contribution to treatment of several types of tumors; OVs are, in fact, able to convert immunologically “cold” tumors into “hot” ones. OVs represent an optimum candidate to combine with ICIs, increasing their response blockade both in immunogenic and poorly immunogenic tumors. We hypothesized that manipulation of intestinal gut microbiota could also affect OVs therapeutic efficacy; at this aim, we determined whether efficacy of the oncolytic adenovirus Ad5D24-CpG (Ad-CpG) therapy could be affected by the gut microbiome in a syngeneic mouse model of melanoma. Sterilization of the gut microbiota with highdose vancomycin impaired efficacy of Ad-CpG therapy, reducing the tumor-infiltrating IFN-gamma CD8 T-cell. Cohousing mice pre-treated with vancomycin and a control group, with consequent microbiota restoration, prior to treatment with Ad-CpG, ablated the negative effect of antibiotic, confirming that Ad-CpG-reduced efficacy was mediated by the intestinal microbiota. Considering the ability of Bifidobacterium as a positive regulator of antitumor immunity in vivo, by promoting pro-inflammatory signals in innate immune cells, we evaluated tumor regression in syngeneic mouse model of melanoma treated with a combination of Ad-CpG and Bifidobacterium spp. cocktail. The group receiving the combined regimen showed the best tumor control and an enrichment of bacteria belong to Firmicutes phylum, evaluated by fecal microbiome profiling by 16S rRNA. Our data indicates that gut microbiota affects the immune responses elicited by oncolytic adenovirus Ad-CpG and Bifidobacterium supplementations maximize its activity.

Class of 2010 Abstract
OBJECTIVES: To determine the clinical significance of a population of scorpions, C. sculpturatus, found in New Mexico. This includes the toxicity of the venom as well as the interactions of venom and antivenom. METHODS: This project will include a descriptive retrospective study of clinical and laboratory data obtained through a patient chart and analytical laboratory procedures to positively identify the species of scorpion responsible for the envenomation. Scorpion Collection Scorpions from the location of the reported sting will be collected for venom analysis. Specific details and directions will be obtained from the grandparent of the victim regarding the campsite at Caballo Lake State Park. Human Subject – N/A Sample Size The sample size of specimens needed should be a minimum of 50 scorpions. This is due to factors which include; extremely small volumes of venom produced by each individual, the possibility of no venom production, damaged telson during collection (anatomical feature used in the delivery of venom), size variation in specimens and short window of opportunity to collect. Since these scorpions are more active during summer months, and travel time must also be accounted for, only a few months a year are acceptable. Instrumentation and Variables This is primarily laboratory assays rather than clinical. The clinical aspect, a case study involving the victim of a scorpion envenomation, was the reason behind needing to identify this Centruroides species. The analytical laboratory findings will be what will determine the exact species of Centruroides. A number of laboratory instrumentations and tests will be used or performed. These include; sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), SDS-PAGE with hyaluronic acid, turbidimetric absorbances of hyaluronidase, reverse phase high pressure liquid chromatography (RPHPLC), enzyme-linked immunosorbent assay (ELISA), lethal dose 50 (LD%) and effective dose 50 (ED50). Variables regarding these findings will include two main factors; the human factor and the instrumentation factor. First the human factor, samples collected must remain free of contaminants up to the point of analysis. The instruments RESULTS: 104 specimens were collected at Caballo Lake State Park. Four of these specimens were sent to a taxonomist and identified as C. sculpturatus. SDS-PAGE, turbidimetric HA, and RPHPLC showed no significant difference in venom between the New Mexico and Arizona Centruroides, but did show a significant difference between these two groups and the Mexico Centruroides. SDS-PAGE/HA and ELISA assays showed no significant differences between groups. LD50 and ED50 data were similar between New Mexico and Mexico Centruroides, both being more potent and more readily reversed by antivenom than the Arizona Centruroides. CONCLUSIONS: The assays which show possible differences between species, SDS-PAGE, SDS-PAGE-HA, turbidimetric HAase, RPHPLC, and ELISA were all identical between the New Mexico Centruroides species and the Arizona Centruroides sculpturatus. These findings were opposite when comparing New Mexico Centruroides species and the Mexico Centruroides limpidus limpidus. Three of the five assays showed a significant difference. Since the Mexico Centruroides limpidus limpidus is a known different species, this was expected. With this data the scorpion specimens collected in New Mexico have been identified as Centruroides sculpturatus. An interesting difference between the New Mexico and Arizona Centruroides sculpturatus was toxicity of the venom. The New Mexico groups had close to a two fold increase in toxicity. In fact, the toxicity of the New Mexico groups was equivalent to the Mexico Centruroides limpidus limpidus which is well documented as having an increased toxicity.

Total body fat and muscle mass depletion has been reported in some patients with COPD. This study used simple anthropometric measurements to compare the body composition of patients with moderate-severe COPD to that of healthy controls, and examines relationships between body composition, disease severity, habitual physical activity and resting and exercise energy expenditure. Results show no significant differences in overall Heath-Carter somatotype characteristics, percent body fat, fat free mass and girth measurements between COPD and control subjects although when stratified by gender, female COPD patients exhibited a greater body fat component. Measured VO2 (L/min) at rest or during steady-state exercise was not significantly different between COPD and control subjects despite a higher exercise ventilation in patients. Neither resting or exercise energy expenditure was related to body composition, however it was related to DLCO/VA (ml·min-1·mmHg -1·L-1). Findings from this study suggest that COPD patients capable of participating in dynamic exercise studies do not exhibit total body fat and muscle depletion. Findings in women suggest that the relative decrease in FFM may be related to a relatively higher proportion of body fat and not a decrease in absolute muscle mass.

Globally, neonatal mortality, and still births are major public health problems. Though preventable, nearly three million babies die every year in their first month of life and a similar number are stillborn, accounting for 7% of global burden of disease, which is higher than the burden of Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome (HIV/AIDS). Up to 50% of all deaths within the first month occur within the first 24 hours of life, and up to 75% occur in the first week. Zimbabwe’s Neonatal Mortality Rate (NMR) rose from 33/1000 deaths per 1000 live births in 1990 to 39/1000 in 2012. The country is far from reaching Millennium Development Goal 4 (MDG4) on child survival as the pattern on rising NMR is evident in districts like Mutare. Though interventions like result based financing (RBF), increase in midwifery training, provision of Basic Emergency Obstetric and Neonatal Care (BEMNOC) have been implemented in the district, the district has a high NMR of 55.2 deaths per 1000 live births. This study aims to explore the determinants of adverse pregnancy outcomes in Mutare facilities. The primary objective of the research is to determine if pregnancy outcomes differ by socio-economic, maternal, neonatal, delivery and health system factors. The study will employ a retrospective cross-section analytical approach. Records of pregnant women who delivered at 7 sampled facilities during the period January 2014 to June 2014 will be reviewed. The working definition for adverse pregnancy outcomes for this study will be women who had a fresh still birth or early neonatal deaths. The results from the study will be presented as a report in partial fulfilment of the requirements for the award of the degree on Master of Public Health by the University of Pretoria. A presentation of the results will be made to the Health Executive of Mutare districts as well as Manicaland Province. The results will also be published in a reputable journal and availed for public consumption.
Dissertation (MPH)--University of Pretoria, 2014.
tm2015
School of Health Systems and Public Health (SHSPH)
MPH
Unrestricted

Orientador: João Luiz Pinto e Silva
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-07-24T02:29:00Z (GMT). No. of bitstreams: 1 Nogueira_ClarissaWaldigeMendes_D.pdf: 194313 bytes, checksum: 7c2a9acc675f0b37c8689d7cb883021e (MD5) Previous issue date: 1998
Doutorado

Alzheimer's disease (AD) is the commonest neurodegenerative disorder that has become increasingly prevalent in most countries. The chronic progressive deteriorating course is characterized by great variations in individual pathways of decline. This abstract summarizes the findings of a prospective study to examine the factors that affect clinical decline in a group of Chinese subjects with Alzheimer's disease (AD).
At the follow up, 19 (18.3%) subjects had died. 74 (71.2%) subjects were alive and were reassessed. Of the subjects reassessed, 49 (66.2%) remained stable at the same CDR, and 25 subjects (33.8%) had deteriorated to a more advanced stage of dementia. A significant deterioration in global cognitive scores (MMSE and DRS) was found (paired t-tests, p<.001). The estimated annual deterioration in MMSE and DRS scores was 1.34 and 4.93. There was a non-significant trend for overall reduction of NP symptoms at the follow up, but a sizable proportion of subjects still exhibited a variety of NP symptoms.
Development of research plan and study objectives is discussed in the third chapter. Due to escalating problem of care for dementia sufferers, a prospective study to examine the clinical factors that affect decline in Chinese elderly people with AD is needed. Four main research objectives are developed. The first objective is to examine the clinical profiles of Chinese subjects with AD. The second objective is to evaluate the relationships between different clinical dimensions of the dementia syndrome. Thirdly, the differences in clinical characteristics between mild and moderate AD would be examined. Finally, significant factors that affect the rate of clinical decline would be determined.
The baseline global cognitive performances were similar among different outcome groups. The 'deteriorated' group had a higher educational level (One way ANOVA, F=4.85, p=.01, Bonferroni comparisons). There was an excess of number of cerebrovascular risk factors (CVRF) in subjects who had deteriorated (Kruskal Wallis test, z=6.6, p=.04). For subjects with CDR 1 at baseline, a significant excess of Apo E4 allele was found in those who had deteriorated at follow up (Pearson chi square 5.72, p=.017; OR = 6.3, CI 1.3 to 30.53). The difference in Apo E4 allele frequency was not significant in subjects with CDR 2 at the baseline. The 'Deceased' group had more advanced age, lower scores in the recognition tests of the Hong Kong List Learning Test (HKLLT) (Kruskal Wallis test, z=8.06, p=.008) and significantly higher scores of 'Parkinsonian signs' (Mann-Whitney U, z=2.99, p=.003). Concerning baseline NP syndromes, 70% of subjects in the 'Affective' groups remained stable at follow up; 31.8% of subjects in the 'Disturbing' groups died, another 31.8% deteriorated at follow up. Logistic regression analysis revealed that a lower score of recognition test of HKLLT, a higher score of 'Parkinsonian signs' and old age were significant predictors for mortality at the 22-month follow up. No significant predictor, apart from a higher premorbid educational level, for the deterioration to a more advanced level of dementia could be identified.
The fifth chapter reports the main research findings. The mean (SD) age at the baseline assessment was 78.18 (5.97) years. The mean (SD) of the Chinese version of the Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (DRS) scores were 16.21(3.69) and 94.88(13.17) respectively. Subjects with moderate AD (Clinical Dementia Rating, CDR=2), compared to subjects with mild AD (CDR=1), performed worse across all cognitive tests. NP symptoms, as evaluated by the Chinese version of the Neuropsychiatric Inventory (NPI), were prevalent and could be classified into 3 subgroups using Latent Class Analysis (LCA): the 'non-disturbing', 'affective' and 'disturbing' groups. The severity of soft neurological signs (SNS) and NP symptoms was more prominent as dementia became more severe. Strong associations between 'Motor coordination' and Sensory integration' signs with cognitive functions were found. The association between NP syndromes and cognitive functions were not as significant.
The following chapter describes the methodology. A group of 104 Chinese subjects with NINCDS-ADRDA criteria for AD were assessed twice in a naturalistic observational study with an average duration of 22 months. Comprehensive evaluation of cognitive, neuropsychiatric (NP), neurological characteristics, cerebrovascular risk and Apolipoprotein E gene polymorphism status was performed at the baseline. The progression of cognitive and clinical decline was compared at the follow up assessment. Baseline and follow up characteristics of cognitive, neuropsychiatric (NP) symptoms and soft neurological signs (SNS) were compared with a group of normal control (NC-FU, CDR=0) and questionable dementia (QD-FU, CDR=0.5). Significant factors influencing progression to a more advanced dementia and mortality were determined.
The introductory chapter outlines the major findings of recent studies on the clinical aspects of AD. Clinical AD is found in 3.6 % of Hong Kong Chinese elders over 70 years old. Literature review suggested that it is a genetically predisposed complex disorder with disease manifestations strongly modulated by health and lifestyle factors.
The last chapter lays out the conclusions of this study. Careful characterization of clinical profile should be emphasized in the management of elderly suffering from AD. This information will be useful for the assessment of prognosis and the formulation of care plan for AD sufferers.
The second chapter focuses on review of recent literature concerning factors that affect cognitive deterioration and clinical decline in AD. The potential determinants of disease progression included genetic predispositions, cognitive and neuropsychiatric profiles, neurological deficits and medical comorbidity.
The sixth Chapter comprises the discussion. The findings of this study provided information about the rate of cognitive and clinical decline in Chinese subjects with AD. The performance characteristics in cognitive tests, inter-subject variations, prevalence of Apo E4 allele and NP symptoms are potential factors that would influence the assessment of cognitive function with time. The universal occurrence of NP symptoms in AD supported a biological explanation for this clinical dimension. The findings also support the notion that cognitive and NP symptoms are relatively independent dimensions of the clinical dementia syndrome. The association between SNS and severity of cognitive impairment suggests that bedside neurological assessment is a feasible way to detect subtle neurological deficits in subjects with very early AD. The presence of 'Parkinsonian signs' predicted mortality, which indicated that the presence of co-morbid subcortical pathology play a significant role in determining the overall outcome. It appeared that trait factors such as the presence of the Apo E4 allele, a higher educational level and pre-existing cerebrovascular diseases, are associated with a faster rate of disease progression, although individual factors may operate differently at different phase of illness.
Lam Chiu Wa.
Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6299.
Thesis (M.D.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (p. 150-185).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.

L’anémie falciforme est une maladie monogénique causée par une mutation dans le locus de la β-globine. Malgré le fait que l’anémie falciforme soit une maladie monogénique, cette maladie présente une grande hétérogénéité clinique. On présume que des facteurs environnementaux et génétiques contribuent à cette hétérogénéité. Il a été observé qu’un haut taux d’hémoglobine fœtale (HbF) diminuait la sévérité et la mortalité des patients atteints de l’anémie falciforme. Le but de mon projet était d’identifier des variations génétiques modifiant la sévérité clinique de l’anémie falciforme. Dans un premier temps, nous avons effectué la cartographie-fine de trois régions précédemment associées avec le taux d’hémoglobine fœtale. Nous avons ensuite effectué des études d’association pan-génomiques avec deux complications cliniques de l’anémie falciforme ainsi qu’avec le taux d’hémoglobine fœtale. Hormis les régions déjà identifiées comme étant associées au taux d’hémoglobine fœtale, aucun locus n’a atteint le niveau significatif de la puce de génotypage. Pour identifier des groupes de gènes modérément associés au taux d’hémoglobine fœtale qui seraient impliqués dans de mêmes voies biologiques, nous avons effectué une étude des processus biologiques. Finalement, nous avons effectué l’analyse de 19 exomes de patients Jamaïcains ayant des complications cliniques mineures de l’anémie falciforme. Compte tenu de la taille des cohortes de réplication disponibles, nous n’avons pas les moyens de valider statistiquement les variations identifiées par notre étude. Cependant, nos résultats fournissent de bons gènes candidats pour des études fonctionnelles et pour les réplications futures. Nos résultats suggèrent aussi que le β-hydroxybutyrate en concentration endogène pourraient influencer le taux d’hémoglobine fœtale. De plus, nous montrons que la cartographie-fine des régions associées par des études pan-génomiques peut identifier des signaux d’association additionnels et augmenter la variation héritable expliquée par cette région.
Sickle cell disease is a monogenic disease caused by a mutation in the β-globin locus. Although it is a monogenic disease, it shows a high clinical heterogeneity. Environmental and genetic factors are thought to play a role in this heterogeneity. It has been observed that a high fetal hemoglobin (HbF) levels correlates with a diminution of the severity and mortality of patients with sickle cell disease. The goal of my project was to identify genetic modifiers of the clinical severity of sickle cell disease. First, I performed the fine-mapping of three regions previously associated with HbF levels. Second, I performed genome-wide association studies with two clinical complications of sickle cell disease as well as with HbF levels. Since no new loci reached array-wide significance for HbF levels, I performed a pathway analysis to identify additional HbF loci of smaller effect size that might implicate shared biological processes. Finally, I performed the analysis of 19 whole exomes from Jamaican sickle cell disease patients with very mild complications. In conclusion, given the sample size of the replication cohorts available, we do not currently have the means to statistically validate the association signals. However, these results provide good candidate genes for functional studies and for future replication. Our results also suggest that β-hydroxybutyrate in endogenous levels could influence HbF levels. Furthermore, we show that fine-mapping the loci associated in genome-wide association studies can identify additional signals and increase the explained heritable variation.

Sarcoidosis is a complex, multisystem inflammatory disease with highly varied presentations, organ involvement and natural history. Its aetiology has remained enigmatic and previous attempts at investigating the cellular and genetic mechanisms that give rise to this disease have yielded conflicting and inconsistent results, largely due to the heterogeneous composition of patient cohorts studied. This project set out to address the problem of phenotypic heterogeneity in sarcoidosis in order to facilitate a more productive investigation into cellular and molecular determinants associated with this disease. We hypothesised that extreme or homogeneous presentations of sarcoidosis would be associated with distinct cellular and molecular characteristics. Through the establishment of a quaternary referral sarcoidosis clinic, patients with diverse presentations of sarcoidosis underwent clinical phenotyping to identify subgroups with consistent clinical characteristics and disease outcomes. Our phenotypic model identified 3 subgroups (neurosarcoidosis, sarcoid uveitis and hepatosplenic sarcoidosis) that were significantly associated with organ limited disease or associated with a distinct presentation that correlated with organ involvement. Patients with a newly described presentation of isolated tattoo and ocular inflammation were also studied as a distinct subgroup. Genetic analysis which focussed on NOD2 variants, demonstrated a significant association between the carriage of P268S and the development of sarcoid uveitis and multisystem disease. Patients with the extreme clinical phenotype of neurosarcoidosis were found to possess a baseline peripheral cellular signature consisting of reduced effector T regulatory cells and increased T effector memory, Th1 and Th2 cells, that was distinct from other clinical phenotypes of sarcoidosis. Finally, we identified global downregulation of chemokine receptor CXCR5 on lymphocyte populations in patients with active tattoo uveitis which normalised upon remission. This finding of chemokine receptor dysregulation is likely to be significant in a disease process that is characterised by organ restricted inflammation. Our results have demonstrated the utility of clinical phenotyping in heterogeneous disease processes. Further investigation will be required to clarify the mechanistic implications of the genetic and cellular associations identified.