There is an increase in the prevalence of obesity among people with schizophrenia thought to be due in part to the weight enhancing side-effects of medications commonly used to treat the symptoms of schizophrenia. Despite the deleterious health effects associated with obesity and its impact on quality of life and medication compliance, little is known about body composition and energy expenditure in this clinical group. The primary purpose of this thesis was to enhance understanding of body composition and energy expenditure, particularly resting energy expenditure in men with schizophrenia who take atypical antipsychotic medications. Unique to this investigation is the evaluation of clinical tools used to predict body composition and energy expenditure against reference methodologies in men with schizophrenia. Further, given the known links between obesity and physical activity, an additional but less comprehensive component of the thesis was a consideration of total and activity energy expenditure in addition to the interaction between psychiatric symptoms, side-effects of antipsychotic medications and physical activity also occurred as part of this thesis. Collectively, the goals of this thesis were addressed through a series of studies – the first two studies were related to the measurement and characteristics of body composition in men with schizophrenia, while the third and fourth studies were related to the measurement and characteristics of resting energy expenditure in men with schizophrenia. The fifth and sixth studies the utilised doubly labelled water technique to quantify activity and total energy expenditure in a small group of men with schizophrenia and explored the use of accelerometry in this cohort. The final study briefly considered the impact of psychiatric symptoms and self-reported medication side-effects on objectively measured physical activity. In the first study, thirty-one male adults previously diagnosed with schizophrenia and sixteen healthy male controls were recruited. Estimates of body composition derived from an anthropometry-based equation and from bioelectric impedance analysis (BIA) using deuterium dilution as the reference methodology to determine total body water were compared. The study also determined the validity of equations commonly used to predict body composition from BIA in the men with schizophrenia. A further aim was to determine the superiority of either BIA or body mass index (BMI) as an indicator of obesity in this cohort. The inclusion of the control group, closely matched for age, body size and body composition demonstrated that there was no difference in the ability of body composition prediction methods to distinguish between fat and fat-free mass (FFM) in controls and men with schizophrenia when both groups had similar body composition. However this study indicated that an anthropometry-based equation previously used in people with schizophrenia was a poor predictor of body composition in this cohort, as evidenced by wide limits of agreement (25%) and systematic variation of the bias. In comparison, the best predictor of percentage body fat (%BF) in this group was gained when impedance values were used to predict percentage body fat via the equation published by Lukaski et al (1986). Although percentage body fat was underpredicted using the Lukaski et al. (1986) equation, the mean magnitude was relatively small (1.3%), with the limits of agreement approximately 13%. Linear regression analysis revealed that %BF predicted using the Lukaski et al. (1986) equation explained 25% more of the variance in percentage body fat than BMI. Further, this study also indicated that BIA was more sensitive than BMI in distinguishing between overweight and obesity in this cohort of men with schizophrenia. Because of the almost exclusive use of BMI as an indicator of obesity in people with schizophrenia, the level of excess body fat may be in excess of that previously indicated. The second study extended the examination of body composition in men with schizophrenia. In this study, the thirty-one participants with schizophrenia (age, 34.2 ± 5.7 years; BMI, 30.2 ± 5.7 kg/m2) were individually matched with sedentary controls by age, weight and BMI. Deuterium dilution was used to distinguish between FFM and fat mass. The previous study had indicated that while BIA was a suitable group measure for obesity, on an individual level the technique lacked the precision required for investigating body composition in men with schizophrenia. Waist circumference was used as an indicator of body fat distribution. The findings of this study indicated that in comparison with healthy sedentary controls of similar body size and age, men with schizophrenia had higher levels of body fat which was more centrally distributed. Percentage body fat was on average 4% higher and waist circumference, on average 5 cm greater in men with schizophrenia than the sedentary controls of the same age and BMI. Further, this study indicates that the use of BMI to predict body fat in men with schizophrenia will result in greater bias than when it is used to predict body fat in other sedentary men. Commonly used regression equations to predict energy requirements at rest are based on the relationships between weight and resting energy expenditure (REE) and in such equations, weight acts as a surrogate measure of FFM. The objectives of study three were to measure REE in a small group of men with schizophrenia who were taking the antipsychotic medication clozapine and to determine whether REE can be predicted with sufficient accuracy to substitute for the measurement of REE in the clinical and/or research settings. Body composition was determined using deuterium dilution and REE was measured using a Deltatrac Metabolic Cart via a ventilated hood. The male participants, (aged 28.0 ± 6.7 yrs, BMI 29.8 ± 6.8 kg/m2) were weight stable at the time of the study and had been taking clozapine for 20.5 ± 12.8 months, with doses of 450 ± 140 mg/day. Of the six prediction equations evaluated, the equation of Mifflin et al. (1990) with no systematic bias, the lowest bias and the lowest limits of agreement proved to be the most suitable equation to predict REE in this cohort. The overestimation of REE can be corrected for by deducting 160 kcal/day from the predicted REE value when using the Mifflin et al. (1990) equations. However, the magnitude of the error associated with the prediction of REE for an individual is 370 kcal/day. The findings of this study indicate that REE cannot be predicted with sufficient individual accuracy in men with schizophrenia, therefore it was necessary to measure rather than predict REE in subsequent studies. In the fourth study, indirect calorimetry (Deltatrac Metabolic Cart via ventilated hood) and deuterium dilution were used to accurately determine REE, respiratory quotient (RQ) and FFM in 31 men with schizophrenia and healthy sedentary controls individually matched for age and BMI. Data from this study indicated that gross REE was lower in men with schizophrenia than in healthy sedentary controls of a similar age and body size. However, there was no difference between the groups in REE when REE was adjusted for FFM using the mathematically correct method (analysis of covariance with FFM as the covariate). There was however a statistically and clinically significant difference in resting, fasted RQ between men with schizophrenia and controls, suggesting that RQ rather than REE may be an important correlate worthy of further investigation in men with schizophrenia who take antipsychotic medications. Studies five and six involved the application of the doubly labelled water (DLW) technique to accurately determine total energy expenditure (TEE) and activity energy expenditure (AEE) in a small group of men with schizophrenia who had been taking the atypical antipsychotic medication clozapine. The participants were those who took part in study three. The purpose of these studies was to assess the validity of a commercially available tri-axial accelerometer (RT3) for predicting free-living AEE and to investigate TEE and AEE in men with schizophrenia. There was poor agreement between AEE measured using DLW and AEE predicted using the RT3. However, using the RT3 to measure inactivity explained over two-thirds of the variance in AEE. This study found that the relationship between current AEE per kilogram of body weight and change from baseline weight in men taking clozapine was strong although not significant. The sedentary nature of the group of participants in this study was reflected in physical activity levels, (PAL, 1.39 ± 0.27), AEE (435 ±352 kcal/day) and TEE (2511 ± 606 kcal/day) that fell well short of values recommended by WHO (2000) for optimal health and to prevent weight gain. Given the increasing recognition of the importance of sedentary behaviour to weight gain in the general community, further examination of the unique contributing factors such as medication side effects and symptoms of mental illness to activity levels in this clinical group is warranted. The final study used accelerometry (RT3) to objectively measure activity in a group of 31 men with schizophrenia who had been taking atypical antipsychotic medications for more than four months. The purpose of this study was to explore the relationships between psychiatric symptomatology, side-effects of medication and physical activity. Accelerometry output was analysed to provide a measure of inactivity and moderate intensity activity (MIA). The well-validated and reliable standardised clinical interview, the Positive and Negative Syndrome Scale (PANSS) was used as a measure of psychiatric symptoms. Perceived side-effects of medication were assessed using the Liverpool University Neuroleptic Rating Side-Effects Scale (LUNSER). Surprisingly, there was no relationship reported between any measures of negative symptoms and physical inactivity. However, self-reported measures of medication side-effects relating to fatigue, sleepiness during the day and extrapyramidal symptoms explained 40% of the variance in inactivity. This study found significant relationships between some negative symptoms and moderate intensity activity. Despite the expectation that as symptoms of mental illness reduce, inactivity may diminish and moderate intensity activity will increase, it may not be surprising that in practice this is an overly simplistic view. It may be that measures of social functioning and possibly therefore cognition may be better predictors of physical activity than psychiatric symptomatology per se.

A Síndrome da Imunodeficiência Adquirida (AIDS) é um problema de saúde pública. O Tenofovir Disoproxil Fumarato (TDF) foi o primeiro inibidor do nucleotídeo da transcriptase reversa e é a droga mais recomendada para o tratamento da AIDS. Entretanto, o uso prolongado de TDF está associado com a nefrotoxicidade. A deficiência de vitamina D tem alta prevalência em indivíduos infectados com o Vírus da Imunodeficiência Humana (HIV). A vitamina D participa da regulação de atividades fisiológicas de diversos órgãos, incluindo o rim, oferecendo proteção contra as lesões ocasionadas por diferentes causas. Portanto, pacientes com níveis baixos de vitamina D infectados com o HIV podem apresentar complicações renais e cardiovasculares durante a terapia antirretroviral. Sendo assim, a carência desta vitamina pode acelerar a progressão da doença renal. Tendo em vista o aumento da incidência de hipovitaminose D na população mundial, esse trabalho tem o objetivo de verificar os mecanismos que levam ao desenvolvimento da lesão renal em ratos depletados de vitamina D submetidos ao tratamento com TDF. Ratos Wistar foram divididos em quatro grupos: controle, animais que receberam dieta padrão por 60 dias; dVD, animais que receberam dieta depletada em vitamina D por 60 dias; TDF, animais que receberam dieta padrão por 60 dias com a adição de TDF (50 mg/kg de dieta) nos últimos 30 dias; e dVD+TDF, animais que receberam dieta depletada em vitamina D por 60 dias com a adição de TDF nos últimos 30 dias. Ao final dos 60 dias, os animais foram submetidos à eutanásia, amostras de sangue, urina e o tecido renal foram coletados para a análise dos mecanismos de lesão renal. O tratamento com TDF levou a insuficiência renal observada pela queda da filtração glomerular e lesão tubular proximal com aparecimento de fosfatúria ocasionada pela diminuição do cotransportador sódio/fosfato subtipo IIa. Essas alterações foram acompanhadas de hipertensão e modificações no perfil lipídico. A deficiência em vitamina D associada à administração de TDF agravou os efeitos renovasculares e a nefrotoxicidade induzida pelo TDF, pelo menos em parte, devido ao aumento nos marcadores de estresse oxidativo e a participação do sistema renina-angiotensina-aldosterona. Portanto, é essencial monitorar os níveis de vitamina D em pacientes infectados com o HIV tratados com TDF / Acquired Immunodeficiency Syndrome (AIDS) has become one of the world\'s most serious health problem. Tenofovir Disoproxil Fumarate (TDF) was the first available nucleotidic reverse transcription inhibitor and is a widely prescribed antiretroviral medication for treatment of Human Immunodeficiency Virus (HIV). However, the long-term use of TDF has been associated with a number of toxicities, including those affecting the kidney. Vitamin D deficiency is prevalent among HIVinfected individuals. Vitamin D not only regulates numerous physiological activities of multiple organ systems, but also protects the kidney from injury from different causes. Thus, HIV-infected subjects with low levels of vitamin D could experience increased complications during antiretroviral therapy, such as cardiovascular disease and renal impairment. In view of the high worldwide incidence of hypovitaminosis D, the aim of this study was to investigate the effects of vitamin D deficiency on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; dVD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and dVD+TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. At the end of the protocol, animals were euthanized and blood, urine and tissue samples were collected in order to evaluate the mechanisms responsible for renal injury. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of reninangiotensin- aldosterone system (RAAS). TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and vitamin D deficiency aggravated renovascular effects and TDFinduced nephrotoxicity at least in part by the increase of oxidative stress and the involvement of RAAS. Hence, it is important to monitor vitamin D levels in HIV-infected patients treated with TDF

Introdução: Tenofovir disoproxil fumarate (TDF) é um inibidor da transcriptase reversa análogo nucleotídeo que tem sido usado por gestantes para o tratamento da infecção pelo vírus da imunodeficiência humana (HIV), bem como para a prevenção da transmissão vertical do vírus. Até o momento, não há estudos experimentais ou em humanos sobre a incidência de alterações renais nos fetos expostos a esquemas contendo TDF. Objetivo: Verificar a ocorrência de alterações renais e sistêmicas fetais causadas pelo uso do TDF durante a gestação. Metodologia: Ratos Wistar fêmeas receberam dieta padrão com ou sem adição de TDF (100mg/Kg de dieta) desde uma semana antes do cruzamento até o parto. A prole proveniente do grupo TDF foi colocada com uma mãe adotiva não tratada durante o período de amamentação e foi comparada com a prole de ratas que receberam dieta padrão durante a gestação (grupo controle). Controle e TDF foram acompanhados até três (n=9 para cada grupo) e seis (n=12 e n=10, respectivamente) meses de idade. Foram avaliados: peso corporal (PC) e pressão arterial sistólica (PAS) mensais, contagem de glomérulos, função renal (através do clearance de inulina), parâmetros bioquímicos (proteinúria, colesterol total, sódio e potássio séricos e urinários), e expressão proteica do tecido renal para componentes do sistema renina angiotensina aldosterona (SRAA) e para transportadores de sódio. Resultados: A prole TDF apresentou menor PC ao nascimento em comparação com o controle. Após o 3º mês, o grupo TDF demonstrou um crescimento compensatório, atingindo o sexto mês com maior PC. O peso renal foi menor no grupo TDF, porém, não houve diferença do número de néfrons entre os grupos. O grupo TDF apresentou alterações estruturais glomerulares. Observou-se também um aumento progressivo da PAS após o segundo mês de idade no grupo TDF. Não houve diferença estatística na função renal entre os grupos. Os níveis plasmáticos de aldosterona foram mais elevados no grupo TDF, em associação com um aumento da expressão renal do SRAA. Ratos do grupo TDF apresentaram menor excreção renal de sódio e maior expressão renal de transportadores de sódio. Conclusões: Esta é a primeira descrição, a partir de um modelo experimental, que a utilização do TDF durante a gestação resulta em hiperativação do SRAA, aumento da expressão dos transportadores renais de sódio e hipertensão arterial da prole / Introduction: Tenofovir disoproxil fumarato (TDF) is a nucleotide reverse transcriptase inhibitor that has been used in pregnants for treatment of maternal HIV infection and for prevention of vertical transmission. Currently, there are no published studies providing data regarding the occurrence of renal abnormalities in fetuses exposed to TDF-containing regimens. Objective: To evaluate the occurrence of systemic and renal abnormalities in offspring of Wistar rats exposed to TDF during pregnancy. Methods: Female Wistar rats received a standard diet, with or without addition of TDF (100 mg/Kg diet), one week before mating and during pregnancy. Offspring from the TDF group were placed with an untreated foster mother during breastfeeding and compared with offspring from rats maintained on a standard diet during mating and pregnancy (control). Control and TDF were followed up at three and six months of age. Analyzed data: monthly body weight and systolic blood pressure (SBP), glomerular counting, renal function, biochemical parameters, and renal tissue immunoblotting for renin angiotensin aldosterone system (RAAS) and renal sodium transporters. Results: TDF offspring showed lower birth weight compared with the control group. After the third month, growth among the TDF group experienced a rapid catch-up. SBP increased progressively after the second month of age in the TDF group. The nephron number did not differ between groups. The TDF group showed glomerular structural changes. There was no significant difference in renal function between the groups studied. Plasma aldosterone was higher in the TDF group, associated with a significant increase in renal expression of RAAS. The TDF rats showed upregulation of renal sodium transporters and consequently lower urinary sodium excretion. Conclusions: This is the first demonstration using an experimental model that maternal exposure to TDF during gestation results in over activation of RAAS, upregulation of renal sodium transporters and hypertension of the offspring

This diploma thesis exmines the negative aspects of using information and communication technologies. The main attention is fosused on virtual reality, especially 3D projection in order to decide wheather the using of it has negative impact on phycal and psychological state of the user or not, which exactly are these impacts and what probably cause them. This first part is dedicated to expain concept and history of ICT, explonation of the multidimensional princip and content of each dimension. The following is determination of which ICT areas are currently struggling in their use with negative effects. Detected list of these areas is reduced to six specific technologies which common user has opportunities to experience. These particular technologies were examined as a form of questionnaire, which resulted in a determination of the most used one, ie virtual reality. Shortly afterwards was conducted an experiment imparting undesirable effects caused by using virtual reality. The other five selected technologies are discussed for the most important negatives with which has to face today. The main finding of this study is the identification the side effects of virtual reality based on different types of technologies which are anaglyf 3D projection, passive 3D projection, active 3D projection and comparing if adverse effects depends on the type. It also includes determining the rate of uptake in virtual reality.

Chemical substance abuse and dependence constitute an increasing international and national phenomenon. Individuals, groups and communities are at risk of the mental, biological, legal and environmental implications associated with substance dependence. Human sexual behaviour is no new phenomenon to be studied. Human beings experience sexual behaviour and gratification as important. Sexual behaviour is not vital for the survival of the individual but vital for survival of the species. Sexual behaviour in combination with chemical substance abuse might pose further dangers to a person or group. Sexual behaviour where persons engage in sexual actions when using or abusing chemical substances could construct certain positive functions for persons. Qualitative researchers are interested in discovering the meaning persons attach to experiences. In understanding the dynamics of the phenomenon, possible contributions to the human sciences could be made. Chemical substance abuse and dependency affect the individual, his/her family systems and the community. Depressants and stimulants change the chemical functioning of the human brain and the mental health of the user. Despite the harm caused to the dependent person, abuse of the chemical substance is continued. The substance has various functions that the biological and psychological person becomes dependent on. Sexual behaviour is inherent in human nature, but not chemical substance abuse. It is expected by the researcher that there might be certain function(s) served by chemical substances in the sexual behaviour of persons. A literature study on the topic on the function of chemical substances in the sexual behaviour of persons yielded unsatisfactory results. Little research was found with regard to the function of chemical substances in relation to people’s sexual behaviour. In response to this need the researcher embarked on a qualitative research journey to explore the function of the chemical substances within the context of an individual’s sexual behaviour and practices. Chemical substances have different functions and affect the sexual behaviour, functioning and experiences of the users of such substances. Six objectives were set with the aim of developing an in-depth understanding of the function of chemical substances in sexual behaviour. The research question of this investigation leads to a clear inquiry into the phenomenon that was examined and analysed and yielded useful new information. This qualitative research project is characterised by its inductive features, openness to change and interest in human behaviour. The study is characterised by an interpretive nature as an interpretative investigation. An effort was made towards understanding the phenomenon through observation and exploration. Persons were invited to participate in the research and reported themselves to the researcher, the process of self-selection sampling was utilised. In drawing a sample from the population of patients at a treatment centre an interactive approach to the process was followed by conducting semi-structured and in-depth interviews as a method of data collection. Data analysis and processing was executed according to the eight steps for qualitative data analysis as proposed by Tesch (in Creswell, 2009). Data verification for the assessment of the trustworthiness of the research findings was achieved by utilizing Guba’s model as espoused in Krefting (1991). Informed consent, confidentiality and management of information were some of the ethical considerations adhered to in the planning and execution of this research project. The nature of this study is marked by the person-centred approach in combination with the qualitative methodology and philosophy. The researcher found the two to be appropriate when a sensitive and private topic was to be explored. Participants were able to evaluate the meanings that were attached to their experiences within a psychologically sound environment. Themes became evident through the data analysis process. These themes were contrasted against a body of existing theory. The wholeness of human beings came to the fore and literature from a bio-neurological and humanistic perspective was found to be applicable. The social sciences and, in particular, social workers are concerned with the wellbeing of persons, their relevant systems and context. These dimensions of human beings were addressed by this study and aimed to contribute to further development in the science of psychotherapy and the understanding of the person within the phenomenon being studied. Therapists should be willing and demonstrate a sensitive ability to understand the client’s experiences from the person’s own point of view (Rogers, 1950: 444). In a relationship that is constructed for the purpose the aim should be mainly to understand the whole person (Rogers, 1952: 343). Therapists should develop an ability to see completely through the client’s eyes and adopt the person’s frame of reference. This is the basis for implementing “client-centred” therapy (Rogers 1950: 444). A key role of social work practice is facilitating the empowerment of persons, and their personal and interpersonal strengths according to their own self-determination (Zastrow, 2012:39); the researcher recommends a holistic full understanding of the person in his/her wholeness (Rogers, 1987: 486). / Department of Social Work / M.A. (Social Work)

Bakgrund: I slutet av 2019 upptäcktes flertalet fall av pneumoni av okänd etiologi i Wuhan, Kina. Efter isolering och sekvensering framkom det att det rörde sig om ett coronavirus, benämnt SARS-CoV-2. Sociala restriktioner och munskydd har inte lyckats stoppa denna pandemi, och hoppet ligger nu på de olika vaccinkandidater som började utvecklas under 2020. Syfte: Syftet var att jämföra olika vaccins effektivitet och förekomst av olika biverkningar. Metod: En systemisk litteraturstudie utfördes, där en sökning i Pubmed utfördes och fyra artiklar valdes ut till arbetet för att jämföra vaccineffektivitet och biverkningar för de tre vaccin som var godkända av läkemedelsverket i februari. Resultat: Pfizer/BioNTechs mRNA-vaccin hade en effektivitet på 94,8%, Modernas mRNA-vaccin en effektivitet på 94,1% och Oxford-AstraZenecas vektorvaccin uppvisade en effektivitet på 70,4%. De vanligaste biverkningarna vid vaccinering var smärta vid injektionsplatsen, huvudvärk samt utmattning. Slutsats: En tillfredsställande jämförelse kunde inte genomföras då de olika fas III studierna utfördes på olika åldersgrupper och i olika delar av världen där SARS-CoV-2 mutationerna skiljde sig åt, vilket kan ha påverkat resultaten. / Background: At the end of 2019, several cases of pneumonia of unknown ethology were discovered in Wuhan, China. After isolating and sequencing the pathogen it became apparent that it was a Coronavirus, named SARS-CoV-2. Social restrictions and mask wearing mandates have not managed to stop this pandemic, and the hope lies with the different vaccine candidates that started to be developed during 2020. Aim: The aim was to compare different vaccines efficacy and prevalence of side effects. Method: A systemic literature study was implemented, the search was done in Pubmed and four papers were selected to compare vaccine efficacy and side effects for the three vaccines that were approved by Läkemedelsverket in February. Results: Pfizer/BioNTech’s mRNA-vaccine showed an efficacy of 94,8%, Moderna’s an efficacy of 94,1% and Oxford-AstraZeneca’s vector vaccine showed an efficacy of 70,4%. The most common side effects following vaccination was pain at the site of injection, headache and fatigue. Conclusion: A satisfying comparison could not be achieved since the different phase III studies were performed on different age groups and in different parts of the world where SARS-CoV-2 mutations differ, which could impact the results.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.

Indiana University-Purdue University Indianapolis (IUPUI) / Traditional treatment strategy development for diseases involves the identification of target proteins related to disease states, and the interference of these proteins with drug molecules. Computational drug discovery and virtual screening from thousands of chemical compounds have accelerated this process. The thesis presents a comprehensive framework of computational drug discovery using system biology approaches. The thesis mainly consists of two parts: disease biomarker identification and disease treatment discoveries. The first part of the thesis focuses on the research in biomarker identification for human diseases in the post-genomic era with an emphasis in system biology approaches such as using the protein interaction networks. There are two major types of biomarkers: Diagnostic Biomarker is expected to detect a given type of disease in an individual with both high sensitivity and specificity; Predictive Biomarker serves to predict drug response before treatment is started. Both are essential before we even start seeking any treatment for the patients. In this part, we first studied how the coverage of the disease genes, the protein interaction quality, and gene ranking strategies can affect the identification of disease genes. Second, we addressed the challenge of constructing a central database to collect the system level data such as protein interaction, pathway, etc. Finally, we built case studies for biomarker identification for using dabetes as a case study. The second part of the thesis mainly addresses how to find treatments after disease identification. It specifically focuses on computational drug repositioning due to its low lost, few translational issues and other benefits. First, we described how to implement literature mining approaches to build the disease-protein-drug connectivity map and demonstrated its superior performances compared to other existing applications. Second, we presented a valuable drug-protein directionality database which filled the research gap of lacking alternatives for the experimental CMAP in computational drug discovery field. We also extended the correlation based ranking algorithms by including the underlying topology among proteins. Finally, we demonstrated how to study drug repositioning beyond genomic level and from one dimension to two dimensions with clinical side effect as prediction features.

Mindfulness meditation programs, benefits, and outcomes were examined through research previously conducted and published by professionals within five differing disciplines: health and wellness, psychology, elementary education, exceptional education, and medicine. The goal was to find common themes within the differing disciplines in order to gather information about the effectiveness of a mindfulness meditation program to be used in an elementary classroom. In this thesis, the chapter of Health and Wellness is a review of literature that tells the benefits found within meditators, which are not found within non-meditators. The chapter of Psychology explains the social-emotional needs of students, the causes of stress and anxieties amongst students, and the benefits that meditation provides in order to counter the negative effects of stress, anxiety, poverty, etc. The chapter of Elementary Education reviews research literature on the existing mindfulness meditation programs within the United States. This chapter also describes the implementation of such a program in an elementary school, as well as the documented data of the outcomes of the programs. The chapter of Exceptional Education is a review of the research literature on the benefits mindfulness meditation has on students with exceptionalities, such as specific learning disabilities, attention deficit hyperactivity disorder, and autism spectrum disorder. The chapter of Medicine is a retelling of previously published scholarly articles that list the neurological benefits of meditation, and also references the negative side effects to the currently prescribed medications that are being used in the treatment of ADHD.

Contraceptives are available free of charge throughout South Africa. Nevertheless the number of requests for termination of pregnancy (TOP) services continues to increase. This research investigated challenges preventing women from using contraceptives effectively. Structured interviews were conducted with 47 women who requested TOP services. Gender and financial issues posed challenges for some women to access contraceptives as well as their reported inability to access contraceptives. Most (85,5%) of the respondents used contraceptives. They discontinued using contraceptives because they experienced side-effects, necessitating them to request TOPs. Knowledge about, access to, nor the actual use of contraceptive enabled these women to prevent unwanted pregnancies. More effective counselling about the side-effects of contraceptives and enhanced accessibility of contraceptives during weekends and lunch breaks could enable more women to prevent unwanted pregnancies and reduce the number of requests for TOPs in the Gert Sibande District (Mpumalanga). / Health Studies / M.A. (Health Studies)