Magister Public Health - MPH / Background: The recognition of HIV/AIDS as a chronic life-long condition globally in recent years has demanded a different perception and an alignment to its association with other chronic diseases. Both HIV and other chronic non-communicable diseases are significant causes of morbidity and mortality. Their combined DALY contributions for Botswana would be significant if research and strategies in controlling these conditions are not put in place. Natural aging and specific HIV-related accelerated aging of patients who are on antiretroviral treatment means that age-related diseases will adversely affect this population. Princess Marina Hospital Infectious Diseases Care Clinic has been in operation since 2002. The clinic has initiated over 16 000 patients on anti-retroviral treatment (ART) since 2002. The current study estimated the prevalence of non-AIDS defining conditions (NADCs) in the attendees of the clinic in 2013. The majority of patients that attended the clinic had been on treatment for over three years with some patients more than ten years. These ART experienced patients were more likely to be susceptible to chronic non-communicable diseases, including non-AIDS defining conditions. The nomenclature used in classification of NADCs in the current study was appropriate for resource-limited settings; because the study setting offered HIV treatment under resources constraints. Aim: The current study characterised non-AIDS defining conditions, and determined their associations with virologic treatment failure in a cohort of patients that were enrolled at Princess Marina Hospital antiretroviral clinic in Gaborone, Botswana. Methods: A retrospective cross sectional study of records of patients who attended the Princess Marina Infectious Diseases Care Clinic in 2013. Stratified random sampling of a total of 228 patients’ records was achieved from a total population of 5,781 records. Data was transcribed into a Microsoft Excel Spreadsheet and then exported to Epi-Info statistical software for analysis. Results: Eighty (35%) cases of NADCs were reported/diagnosed in the study sample; with 27% (n=62) of the patients having at least one condition, 6.7% (n=17) two conditions, and 0.4% (n=1) three conditions. The top prevalent conditions were hypertension (n= 40), hyperlipidaemia (n=7) and lipodystrophy (n=7). The prevalence of NADCs on the various categories of patients compared with the total sample population was as follows: active patients (prevalence ratio= 0.70), transferred out patients (prevalence ratio = 1.24), patients who died (prevalence ratio=2.04) and patients who were lost to follow-up (prevalence ratio =2.86). The prevalence of NADCs was significantly associated with increasing age (p<0.001); having social problems (p=0.028); having been on treatment for over three years (p=0.007); an outcome of death (p = 0.03) and being lost to follow-up (p=0.007). The study showed that being controlled on second line or salvage regimen (p=0.014) and the presence of adherence problems in the past was associated with virologic failure (p=0.008). There was no association of presence of NADCs to virologic failure. Conclusions: There was significant morbidity of non-AIDS defining conditions in the Princess Marina Infectious Diseases Care Clinic shown by a prevalence of NADCs in the clinic of 35% in 2013.The significant associations of the presence of NADCs and virologic failure with outcomes of death and loss to follow-up illustrate the adverse effects that NADCs are having, and calls for strategies to address multi-morbidities in HIV patients on antiretroviral treatment.

Class of 2005 Abstract / Objectives: To evaluate the benefits of asthma and diabetes screening services at community pharmacies and determine patient satisfaction and willingness to pay. Methods: ASTHMA: A retrospective analysis of 342 patients were given one of two asthma screening surveys, based on whether or not they had asthma, which assessed asthma-related symptoms, associated conditions, family and social history, and the use of asthma medications. Peak flow measurements were also obtained and compared to predicted peak flow values. Based on these results, pharmacists referred patients to their physician or the emergency department if necessary. DIABETES: A retrospective analysis of 402 patients participated in diabetes screenings at Bashas’ United Drugs. Patients were given a questionnaire to complete, which included questions about diabetes diagnosis, related symptoms, and medication use. Level of control was measured by a fasting or casual finger-stick blood glucose test. Based on these results, pharmacists referred patients to their physician or the emergency department if necessary. PATIENT SATISFACTION: This is a retrospective analysis of patient satisfaction surveys collected from patients who volunteered to participate in asthma and diabetes screenings a t Bashas’ United Drugs stores. A total of 189 satisfaction surveys were collected, 73 from asthma screenings and 96 from diabetes screenings were used to evaluate patient awareness of pharmacist-run screening services, perception of pharmacist knowledge and ability to monitor health conditions, and willingness to pay for the screening services. Mean scores are based on Likert scaled data (1 = strongly disagree to 5 = strongly agree). Implications: The findings in this study suggest that community pharmacists play an essential role in the management of patients with asthma and diabetes. This study found community pharmacists are well trusted for their advice regarding medications, and would be receptive to other health related advice from their pharmacist. Respondents strongly agreed they would recommend this screening service to other patients and would be willing to pay for these services.

Class of 2004 Abstract / Objective: To develop and populate a decision-analytic model comparing the cost and efficacy of imatinib versus allogenic bone marrow transplantation (BMT) with a matched unrelated donor in the treatment of newly-diagnosed, Philadelphia positive (Ph (+)), chronic phase, chronic myelogenous leukemia (CML). Design: Markov cohort analysis and Monte Carlo microsimulation. Measurements and Main Results: Direct medical costs were measured from the perspective of a third-party payer. Efficacy data and probabilities were obtained from survivability findings emanating primarily from randomized controlled trials (RCTs). A two-year time horizon was employed with three month treatment cycles. BMT was established as the baseline comparator and the base case was defined as a 35 year old, Ph(+) male patient with newly-diagnosed CML. Results from the Monte Carlo trial found that the incremental cost-efficacy ratio was −$5,000 for imatinib (95th % Confidence Interval: −$70,000, $84,000). Analysis of the cost-efficacy plane indicated that imatinib dominated BMT in 84.69 percent of cases, while BMT was dominant in 0.76 percent of cases. Sensitivity analyses of costs and discount rates found results to be robust. Conclusion: Imatinib was observed in a majority of cases to be both less costly and more efficacious relative to BMT in the treatment of CML, suggesting that this pharmaceutical agent is a dominant therapeutic strategy. When available, the incorporation of long-term clinical data are required to assess cost-efficacy beyond the two-year time horizon of this study.

Transcription factors (TFs) are key regulators of gene expression whose failure has been implicated in many diseases, including cancer. They bind at various sites at different specificity depending on the prevailing cellular conditions, disease, development stage or environmental conditions of the cell. TF binding specificity is how well a TF distinguishes functional sites from potential non-functional sites to form a useful regulatory network. Owing to its role in diseases, various techniques have been used to determine TF binding specificity in vitro and in vivo, including chromatin immuno-precipitation followed by massively parallel sequencing (ChIP-seq). ChIP-seq is an in vivo technique that considers how the chromatin landscape affects TF binding. Motif enrichment analysis (MEA) tools are used to identify motifs that are over-represented in ChIP-seq peak regions. One such tool, CentriMo, finds over-represented motifs at the center since peak calling software are biased to declaring binding regions centered at the TF binding site. In this study, we investigate the use of CentriMo and other MEA tools to determine the difference in motif enrichment attributed presence of Chronic Myeloid leukemia (CML)), treatment with Interferon (IFN) and Dexamethasone (DEX) compared to control based on Fisher’s exact test; using uniform peaks ChIP-seq data generated by the ENCODE consortium. CentriMo proved to be capable. We observed differential motif enrichment of TFs with tumor promoter activity: YY1, CEBPA, Egr1, Cmyc family, Gata1 and JunD in K562 while Stat1, Irf1, and Runx1 in Gm12878. Enrichment of CTCF in Gm12878 with YY1 as the immuno-precipitated (ChIP-ed) factor and the presence of significant spacing (SpaMo analysis) of CTCF and YY1 in Gm12878 but not in K562 could show that CTCF, as a repressor, helps in maintaining the required YY1 level in a normal cell line. IFN might reduce Cmyc and the Jun family of TFs binding via the repressive action of CTCF and E2f2. We also show that the concentration of DEX treatment affects motif enrichment with 50nm being an optimum concentration for Gr binding by maintaining open chromatin via AP1 TF. This study has demonstrated the usefulness of CentriMo for TF binding specificity analysis.

Chronic wounds represent an under-acknowledged socioeconomic epidemic, affecting 1.8 million new patients per year and costing the US health care system upwards of $25 billion annually. This substantial cost is rapidly growing due to a disproportionate occurrence in the ever-aging population. Key features associated with age-related impairment of wound healing include limited energy and nutrient exchange, unremitting inflammations, increased reactive oxygen species (ROS), and diminished blood flow. Most chronic wound therapies target specific molecular mechanisms; however, there are often multiple mitigating factors that prevent normal wound closure. This is likely one reason most wound therapies are minimally effective. In the standard American diet, carbohydrates are broken down for fuel (glucose). While fasting, starvation, and calorie or carbohydrate restriction, beta-oxidation of stored fats in the liver produces ketone bodies (primarily acetoacetate (AcAc) and β-hydroxybutyrate (βHB) to serve as energy metabolites for extra-hepatic tissues. In addition to enhancing metabolic physiology, ketone bodies have recently been discovered to have signaling properties that are independent of their function as energy metabolites. Here we present the evidence for a novel method of inducing therapeutic ketosis via exogenous ketone supplementation to promote enhanced ischemic wound healing in young and aged Fischer 344 rats. Preliminary mechanistic studies demonstrated that exogenous ketone supplementation enhanced wound healing via increasing proliferation and migration, decreasing lactate production, and decreasing ROS production as well as affecting inflammatory cytokines and growth factors. We conclude that exogenous ketone supplementation will be an effective, cost efficient, low toxicity therapy to promote enhancement of wound healing in an aged population.

Participation in decision-making and inclusion in the important matters of one’s life are upheld as measures of equality and indicators of the moral status of individuals in liberal democratic societies. To some extent, the status of children in western societies is a contested question, and hence, the nature of children’s contributions to decisions is a matter of debate. Evidence suggests that in spite of an apparent societal commitment to children’s participation in the important matters of their lives, children tend to be excluded from decisions in which they might reasonably be involved. This project investigated the participation of one group of children—chronically ill school-age children— in decisions related to their health care. Adopting interpretive description as methodology, data were collected and analyzed through interviews and participant observation with 31 chronically ill children (ages 7 to 12 years) and their parents, as well as through interviews with health care providers. In this study, children’s participation in health care decisions emerged as a complex activity, deeply embedded in relationship and history. Participation varied within two key domains: children’s opportunities and abilities to formulate and make known their intentions and desires in decisional contexts (the resonance of children’s voices); and the standing achieved by children’s views within decisional processes (the relevance of children’s voices). The interplay of adult authority and children’s agency at the nexus of the resonance and relevance of children’s voices created certain participatory spaces, depicted as moral and social realms variously characterized by children’s silence, children’s tangible expression, adult imposed authority, or adult assumed responsibility. The findings of this study demonstrate a need to re-think our concept of children’s participation, and point to the importance of developing a more relational and contextual understanding of how chronically ill children may contribute to important matters in their lives. The findings also support a view that nurses and other health care providers hold certain responsibilities to critically question the relationships and structures that comprise children’s health care encounters, toward a goal of creating conditions where possibilities for children’s participation are optimized. / Applied Science, Faculty of / Nursing, School of / Graduate

Little is known about the molecular biology of late onset Alzheimer’s disease (LOAD), the most common dementia in the elderly. Genetic loci associated with LOAD have been identified through genome-wide association studies (GWAS). However, the functional variants responsible for the observed GWAS association at each of the loci remain unknown. The aim of this project was to identify and assess potential functional rare variants at three associated loci, CD2AP, EPHA1 and CD33. Target enriched, pooled sequencing of 96 post-mortem confirmed LOAD patient samples was used to identify 1273 variants within the three GWAS loci. Variants were prioritised using a combination of in silico functional annotation and putative disease association. Disease association was assessed through comparison to an independent, imputed LOAD GWAS dataset (2067 cases, 7376 controls). 18 coding and untranslated region variants and 9 noncoding variants were prioritised for further investigation. Potential splicing variants in CD2AP (6:47544253A > G) and EPHA1 (rs6967117) were assessed using minigene assays, although neither were found to influence splicing products in vivo. Five untranslated variants from the three genes and a frameshift variant in CD33 (rs201074739) were assessed for potential cis-regulatory consequences using allelic expression imbalance in brain tissues and B-lymphoblast cell lines. Only the frameshift variant displayed significant allelic expression imbalance and was found to be targeted for nonsense-mediated decay. None of the prioritised variants investigated were both functional and significantly associated with LOAD. However, pooled next generation sequencing using target enrichment successfully identified potential functional rare variants in CD2AP, EPHA1 and CD33. Rare variants do have a role to play in late onset Alzheimer’s disease. With the development of additional functional databases and improvements imputing rare variants from GWAS datasets, the combined prioritisation strategy used in this thesis will be useful for similar studies investigating causal GWAS variants.

The association between pain and depression is well documented across various populations, but not in puerperal women. This study examined the association of childbirth pain with postpartum depression (PPD) in a nationally representative sample of Canadian women. Data from the Canadian Maternity Experiences Survey (n=6421) was used. Multivariate logistic regressions and partial proportional odds models were fitted and included socio-demographic, obstetric, health, psychological, and psychosocial factors. Chronic pain sufferers at mean 7.3 months postpartum had adjusted odds of PPD of 2.4 (95% CI: 1.6, 3.6) compared to women without pain. Adjusted odds of PPD increased with the number of areas of chronic pain, reaching 4.2 (95% C.I.: 0.7, 25.0) for 3 or more areas. Immigration, obesity, cesarean section and social support increased the strength of the association while smoking and the use of pain relief were protective effect modifiers. Persistent postpartum pain is a major risk factor for PPD.

Background: Health care needs to evolve to meet the needs of people living with HIV as they age and become a more diverse population. For HIV and other conditions, physician specialty and experience are often positively associated with disease-specific outcomes but negatively associated with primary care outcomes. The objectives of this thesis were to: 1) assess comorbidity prevalence among people living with HIV in Ontario; 2) describe the type and extent of care by physician specialty; 3) use a theoretical shared primary/specialist care typology to characterize this care; 4) measure the quality of care delivered related to this typology; and 5) assess the independent effect of family physician HIV experience. Methods: Population-based data were used to describe a cohort of 14,282 individuals living with HIV in Ontario. Health care visits to this cohort were categorized by physician specialty, physician HIV experience, and HIV-related versus HIV-unrelated care. A theoretically-based typology of care was developed by linking patients to usual family physicians and to HIV specialists with 5 possible patterns of care. Prevention and chronic disease management adherence, antiretroviral (ART) prescribing, and health care utilization were compared across typology models using multivariable hierarchical logistic regression analyses. The independent effect of family physician experience was also examined. Results: People with HIV had significant comorbidity. Family physicians provided the majority of care. Five patterns of care were described: exclusively primary care (45.4%); specialist-dominated co-management (30.7%); family physician-dominated co-management (10.1%); low engagement (8.6%); and exclusively specialist care (5.3%). After adjustment, HIV patients in exclusively specialist care had lower odds of colorectal cancer screening but higher odds of receiving ART. Odds of having an emergency department visit did not differ among models. Among HIV patients seeing only family physicians, those linked to family physicians with high HIV experience were significantly more likely to receive ART than those with lower HIV experience. Discussion: People with HIV in Ontario have substantial comorbidity. A typology of shared care between family physicians and HIV specialists had a strong influence on the quality of care delivered. These findings have important policy and practice implications and support emerging evidence that multi-specialty expertise is required to address the care needs of this population.

Background: Chronic traumatic encephalopathy (CTE) is an enigma that has become synonymous with combat sports over the past few decades. Mixed martial arts (MMA) is a combat sport that is growing in popularity world-wide. The objective of this study is to determine the factors associated with head trauma among MMA athletes. Methods: Logistic regression analyses using SPSS 20 was employed to model putative covariates against the dichotomous outcomes of unconsciousness (for the full dataset) and diagnosed concussion (for the enriched subset of fighters who were rendered unconscious). Results: Increasing age, black or African-American ethnicity, shorter rest periods between fights, increasing numbers of significant clinch strikes landed, significant distance body strikes landed and power strikes landed to the body at distance are all factors associated with being diagnosed with a concussion among the fighters rendered unconscious. Conclusion: If bolstered by confirming laboratory and clinical evidence, policies should be developed for implementation by MMA governing bodies to help reduce incidences of head trauma and concussion, built around fighters’ demographic and behavioural characteristics. In particular, enforcing a mandatory rest period between fights and placing an upper limit on fighters’ age are ideas worth exploring.