Metformin has been associated with a reduction in breast cancer incidence, however its effect on mortality following cancer has not been adequately examined. The purpose of this study was to evaluate the impact of metformin therapy on mortality in women with breast cancer. Using Ontario health databases, this retrospective cohort examined the impact of metformin on mortality among women aged 66 years or older with diabetes and breast cancer. After a mean follow-up of 4.5 years, there was no association between cumulative metformin use and either all-cause or breast cancer-specific mortality (HR 0.97, 95% CI 0.92-1.07; HR 0.91, 95% CI 0.81-1.03 respectively per additional year of cumulative metformin use). Though metformin was not associated with a reduction in mortality in our study of older women with breast cancer, there is still a need to examine whether metformin has an effect on mortality in other breast cancer populations.

This thesis presents an examination of how the body is situated within the field of physical fitness: it examines how individuals learn what a ‘fit’ body looks and ‘performs’ like, and explores the benefits of having the appearance of a fit body in our society. The research findings, observations, and conclusions contained within this text are drawn from two inter-related sources: a commonly used fitness industry textbook called Foundations of Professional Personal Training (Anderson, Bates, Cova, & Macdonald, 2008) and my own experiences as a professional within that industry, captured in an auto-ethnographic journal. There are three main, highly interconnected, hegemonic discourses that frame the Foundations of Professional Personal Training text: biomedical expert knowledge, neoliberal biopedagogy, and, most importantly, the discourse of risk management mediated by healthiest risk discourse.

This thesis presents an examination of how the body is situated within the field of physical fitness: it examines how individuals learn what a ‘fit’ body looks and ‘performs’ like, and explores the benefits of having the appearance of a fit body in our society. The research findings, observations, and conclusions contained within this text are drawn from two inter-related sources: a commonly used fitness industry textbook called Foundations of Professional Personal Training (Anderson, Bates, Cova, & Macdonald, 2008) and my own experiences as a professional within that industry, captured in an auto-ethnographic journal. There are three main, highly interconnected, hegemonic discourses that frame the Foundations of Professional Personal Training text: biomedical expert knowledge, neoliberal biopedagogy, and, most importantly, the discourse of risk management mediated by healthiest risk discourse.

Background: There are a number of treatment options for colon cancer. These regimens have different toxicity profiles and the age of the patient may affect outcomes of care and cost-effectiveness. An economic evaluation was conducted to explore treatment options for stage III colon cancer. Methods: A Markov model was developed to compare the cost-effectiveness of capecitabine with oxaliplatin combined with fluorouracil/leucovorin (FOLFOX) for the adjuvant treatment of stage III colon cancer. Results: At age 70, FOLFOX was the preferred option, costing $25,314 per quality-adjusted life-year gained. However, the difference in effect between the regimens ranged by 6 months and the model was sensitive to a number of variables. At age 80, capecitabine became the preferred option. Conclusion: FOLFOX is the most cost-effective treatment option in Ontario, but above age 80, capecitabine becomes the favoured option. Uncertainty remains in determining the most cost-effective treatment option for stage III colon cancer.

“Off-label” use occurs when a medication is prescribed for non-approved purposes. This case study explored physician experiences with prescribing gabapentin off-label. Semi-structured interviews with 10 specialists in the Greater Toronto Area provided data that were analyzed using qualitative content analysis. Specialists described prescribing gabapentin off-label as common practice and few expressed concerns about its safety. Knowledge from various interconnected sources influenced off-label prescribing decisions. These included: social knowledge, scientific knowledge, knowledge of the drug, knowledge of the patient, and experiential knowledge. Findings were similar to previous studies examining physician prescribing behaviour. Furthermore, lack of provincial-government reimbursement for off-label uses of gabapentin (knowledge of drug coverage) was a significant barrier to prescribing. Off-label prescribing differs from other types of prescribing since there is often a lack of scientific evidence for off-label uses. The complexities of the off-label prescribing process and the degree of importance between the various influences require further exploration.

Down syndrome (DS), caused by an extra chromosome 21, affects 1 in 750 live births, and is characterized by cognitive impairment as well as several congenital defects. Currently, little is known about the molecular pathogenesis of DS and no direct genotype-phenotype relationship has yet been confirmed. The current screening test for DS subjects many women to undergo invasive procedures such as amniocentesis due to suboptimal sensitivity and specificity. Therefore, this study aimed to discover novel biomarkers to improve screening tests, and to discovery dysregulated molecular pathways in DS-affected fetus to better understand pathogenesis. To achieve this objective, proteomic analyses of amniotic fluid (AF) and amniotic fluid cells (amniocytes) were performed using mass spectrometry (MS), which allows discovery of a large number of proteins in complex biological samples. Since AF contains the most information of the developing fetus, we first generated the most comprehensive list of proteins present in AF by using high resolution MS. We then performed quantitative analyses of proteins from AF as well as amniocytes to reveal novel biomarkers and clues to altered molecular mechanisms of DS. Comparison between the proteome of AF from unaffected and DS-affected pregnancies allowed selection of 60 candidate biomarkers based on spectral counting. Two candidates, APP and TNC-C, were verified by immunoassays to show two-fold increase in AF from DS-pregnancies. Additionally, CPA4, MUC13, CEL, DPP4 and MMP2 were verified to be differentially expressed in trisomy 21-AF via selected reaction monitoring assays using triple-quadruple mass spectrometer. Amniocytes from DS-affected and unaffected fetuses were also quantitatively analyzed by using Stable Isotope Labelling of Amino acids in Cell culture technique. Over 4900 proteins were identified from amniocyte lysate and supernatant by LTQ-Orbitrap mass spectrometer, and 85% of these proteins were quantified based on MS/MS spectra ratios of peptides containing isotope-labelled amino acids. Proteins that consistently showed aberrant expression from affected amniocytes have been selected for further verification and molecular network analyses since they may play a role in DS pathogenesis.

Background: There are a number of treatment options for colon cancer. These regimens have different toxicity profiles and the age of the patient may affect outcomes of care and cost-effectiveness. An economic evaluation was conducted to explore treatment options for stage III colon cancer. Methods: A Markov model was developed to compare the cost-effectiveness of capecitabine with oxaliplatin combined with fluorouracil/leucovorin (FOLFOX) for the adjuvant treatment of stage III colon cancer. Results: At age 70, FOLFOX was the preferred option, costing $25,314 per quality-adjusted life-year gained. However, the difference in effect between the regimens ranged by 6 months and the model was sensitive to a number of variables. At age 80, capecitabine became the preferred option. Conclusion: FOLFOX is the most cost-effective treatment option in Ontario, but above age 80, capecitabine becomes the favoured option. Uncertainty remains in determining the most cost-effective treatment option for stage III colon cancer.

“Off-label” use occurs when a medication is prescribed for non-approved purposes. This case study explored physician experiences with prescribing gabapentin off-label. Semi-structured interviews with 10 specialists in the Greater Toronto Area provided data that were analyzed using qualitative content analysis. Specialists described prescribing gabapentin off-label as common practice and few expressed concerns about its safety. Knowledge from various interconnected sources influenced off-label prescribing decisions. These included: social knowledge, scientific knowledge, knowledge of the drug, knowledge of the patient, and experiential knowledge. Findings were similar to previous studies examining physician prescribing behaviour. Furthermore, lack of provincial-government reimbursement for off-label uses of gabapentin (knowledge of drug coverage) was a significant barrier to prescribing. Off-label prescribing differs from other types of prescribing since there is often a lack of scientific evidence for off-label uses. The complexities of the off-label prescribing process and the degree of importance between the various influences require further exploration.

Warfarin has well-proven benefit (stroke prevention) but an associated increase in harm (major bleeding) in patients with atrial fibrillation (AF). Current clinical prediction rules (CPRs) are limited in that stroke CPRs predict only the probabilities of “stroke” and “no stroke” and bleeding CPRs predict only “bleed” and “no bleed” despite the fact that outcomes actually include combinations of these four groups. The study objective was to evaluate methods to create a CPR that calculates individual patient probabilities of warfarin’s four combined benefit/harm outcome groups: i) no stroke/no bleed; ii) no stroke/bleed; iii) stroke/no bleed; iv) stroke/bleed. Methods: Patient-level data were analyzed from a randomized controlled trial database (n=9,155) and an observational anticoagulant clinic database (n=5,475) from start of trial or time of AF diagnosis respectively (baseline), until end of follow-up. Patients were stratified into the four groups based on their outcomes during follow-up. Due to high mortality in both datasets, death was included as an outcome. Decision tree modeling and polytomous logistic regression (PLR) were conducted to identify baseline patient factors predicting each outcome group. Results: Based on a literature review of recent high quality RCTs, benefit and harm are reported separately and not at a more individualized level than subgroup analysis. In this individualized combined benefit/harm analysis, both PLR and decision tree modeling identified predictors of no stroke/no bleed, no stroke/bleed, stroke/no bleed and death without a prior stroke or bleed. PLR results predicted probabilities of combined benefit/harm outcomes for every patient but required detailed computation. However, results could potentially be converted into automated form for ease of use. Decision trees provided a visual algorithm approach to risk assessment but did not i) predict the probability of warfarin’s combined benefit/harm outcomes based on all predictors simultaneously, ii) predict the probability of these outcomes for every patient or iii) provide statistical parameters of predictive value (odds ratios). Conclusions: The PLR technique could be used to predict patient probabilities of combined benefit/harm outcomes with warfarin. The study results require validation, preferably prospectively, in other cohorts. If validated, this approach should be tested to determine if it aids patient decision-making.

Objective: To conduct an open label clinical pilot trial using Ginkgo biloba in the treatment of vitiligo in Toronto to test the feasibility of recruitment, patient retention, variability of outcome measures, identify safety concerns, and magnitude of treatment effect ahead of a full randomized clinical trial. Methods: 12 participants 12 to 35 years old were recruited to a prospective nonrandomized open-label pilot trial and treated with 60 mg of standardized G. biloba BID for 12 weeks. The primary outcome was the validated Vitiligo European Task Force (VETF). Secondary outcomes included the Vitiligo Area Scoring Index (VASI), photographs, and adverse reactions. Results: Ingestion of Ginkgo biloba was associated with a trend towards improvement on VETF measures of vitiligo lesion area and staging, and significant improvement in VETF spread and total VASI vitiligo measures. Conclusions: By achieving full recruitment, showing benefit, and indicating no adverse reactions the pilot study shows that a future RCT is feasible.