<p>We evaluated the comparability of influenza-related events self-reported by research participants and their outpatient medical records using data collected from the Hutterite Influenza Prevention Trial. We also explored the implications of using data on influenza symptoms from both data sources, independently and in combination, as predictors of laboratory-confirmed influenza. Self-report of influenza symptoms, physician-diagnosed otitis media and antibiotics prescribed at outpatient consultations was collected from trial participants. Similar data were also collected by fax requests for medical record information to the medical facilities. We found lower rates of self-reported prevalence for fever, sore throat, earache and otitis media and higher rates of antibiotic prescriptions compared to the medical records. Total agreements between self-report and medical report of symptoms varied between 61% and 88%. Negative agreement was considerably higher than positive agreement for each symptom, except cough. Self report of otitis media was a very specific measure (93%), but had lower sensitivity (47%). Positive predictive value was moderate at 64% but negative predictive value was good at 86%. Self-reported antibiotic prescription was a highly sensitive measure (98%), but had low specificity (50%). Positive predictive value was high at 91% but negative predictive value was modest at 65%. Fever (on its own) and combined with cough and/or sore throat were highly correlated with laboratory-confirmed influenza for all data sources. The ILI surveillance definition of fever and sore throat, based on combined symptoms by both medical records and self report, was the best predictor laboratory confirmed influenza.</p> / Doctor of Philosophy (PhD)

<p>Bmi1 is a member of the Polycomb Group proteins and has been demonstrated as being vital in stem cell regulation. Bmi1 is overexpressed in many cancers, including glioblastoma, and has been shown to regulate cancer cell self-renewal and proliferation both <em>in vitro</em> and <em>in vivo</em>. This study aimed to determine if Bmi1 modulates brain tumour initiating cell properties using a spontaneous primary glioblastoma cell line and a commercial glioblastoma cell line. To determine the role of Bmi1 in glioblastoma cells, stem cell assays and <em>in vivo</em> analysis of tumour formation was performed on both control cells and Bmi1 knockdown cells. In both cell lines, Bmi1 was found to play a positive regulatory role in stem cell properties. When Bmi1 was knocked down in brain tumour initiating cells, properties such as self-renewal, proliferation and tumour formation were impaired compared to control cells. This study supports recent literature which shows that Bmi1 regulates stem cell properties in glioblastoma cells and supports the potential use of Bmi1 as a therapeutic target in glioblastoma brain tumours.<strong><br /> </strong></p> / Master of Science (MSc)

<p>Background: Previous studies have found that diabetes is associated with increased risk of fracture; however, the risk of non-traumatic fracture (of any bone) specific to individuals with diabetes across the Canadian population has not been studied.</p> <p>Methods: Ten years of data from the Canadian Multicenter Osteoporosis study was explored. Logistic regression models were used to study factors associated with a history of previous non-traumatic fracture at study baseline. Cox proportional hazards models were used to explore time-to-incident-fracture during the 10 years of study.</p> <p>Results: All women and men ≥ 50 years were included in the analyses (n=7753). This included 508 individuals with NIDDM and 98 with IDDM. Mean age was 67 (±9) years and 72% were female. Individuals with diabetes were found to be more likely to have a history of fragility fracture then non-diabetic CaMos participants (odds ratio [OR] =1.21, 95% confidence interval [CI] 1.00,1.46; p=0.04), but were less likely to be treated with bisphosphonate therapy during the 10 year study (OR: 0.58; 95% CI 0.46,0.75; p<0.001). History of a stroke/TIA or hypertension were found to be associated with previous non-traumatic fracture amongst the diabetic population (OR: 1.51; 95% CI 1.20,1.91; p<0.001; and, OR: 1.16; 95% CI 1.04,1.29; p=0.01 respectively).</p> <p>Conclusions: A treatment care gap exists amongst diabetics in Canada. Individuals with diabetes are at increased risk of non-traumatic fracture, but are less likely to be treated with bisphosphonate therapy. Clinicians can use specific fracture risk factors to identify which diabetics are at highest risk and target interventions accordingly.</p> / Master of Science (MSc)

<p><strong>BACKGROUND</strong></p> <p>Amiodarone is believed to inhibit the hepatic metabolism of warfarin, potentiating its hypoprothrombinemic effect and increasing the risk of hemorrhage. The consequences of this drug interaction on important clinical outcomes are unknown.</p> <p><strong>METHODOLOGY</strong></p> <p>Using linked health administrative databases, we conducted a population-based retrospective cohort study among Ontario residents aged 66 years or older who had been treated with warfarin therapy for at least 6 months. Within this group, we identified subjects who initiated amiodarone while on warfarin. Each of these subjects was matched to a subject not treated with amiodarone on age, sex, year of cohort entry, and a high dimensional propensity score. The primary outcome was a hospitalization due to a hemorrhagic event within 30 days of follow-up. In a secondary analysis, we examined in-hospital mortality following hospitalization for major hemorrhage.</p> <p><strong>RESULTS</strong></p> <p>We identified 60,497 eligible patients between July 1, 1994 and March 31, 2009. Of these, 11,665 (19.3%) received a new prescription for amiodarone while receiving ongoing warfarin therapy and 7,124 (61.1%) of these were matched to a subject who was not exposed to amiodarone while receiving warfarin therapy. The median age at cohort entry of the matched cohort was 76 years, 51.6% in the cohort were male, 14.5% lived in a rural location, 2.8% had a bleed in the past year, and 21.6% had a diagnosis of congestive heart failure in the past year. Fifty-six amiodarone recipients experienced a hemorrhagic event (0.8%) as compared to 23 individuals (0.3%) in the non-exposed group at 30 day follow-up (adjusted hazard ratio (HR) = 2.45; 95% CI, 1.49 to 4.02). Seven patients in the amiodarone group died after hospitalization for a hemorrhage versus four in the non-exposed group (adjusted HR = 1.74; 95% CI, 0.25 to 12.24).</p> <p><strong>CONCLUSION</strong></p> <p>Initiation of amiodarone in patients on chronic warfarin therapy was associated with a two-fold increase in the risk of hospitalization due to a hemorrhagic event. Physicians should closely monitor the response to warfarin following initiation of amiodarone.</p> / Master of Science (MSc)

<p>Older adults with chronic health conditions experience limitations participating in everyday activities. Neighbourhood characteristics and social support can offset individual impairments and help to facilitate participation; however, gaps in this literature exist. This thesis presents the results of three studies that explore the influence of neighbourhood and social factors on participation in everyday activities among older adults with chronic health conditions. The first paper describes a scoping review of academic literature regarding neighbourhood influences on participation. The findings of the review indicated that neighbourhood economic status, amenities, problems, mobility barriers, cohesion, and safety may influence participation but the pathways through which this occurs are not clear.</p> <p>The second paper uses findings from a cross-sectional survey (n=248) that examined the relationship between perceptions of neighbourhood characteristics and satisfaction with participation among older adults with chronic health conditions. Path analysis showed that fewer neighbourhood problems directly predict higher participation while higher neighbourhood cohesion and safety indirectly predict higher participation.</p> <p>The third paper uses data from the same cross-sectional survey to examine the types of social support that most strongly predict satisfaction with participation. Regression analyses showed that participants who perceived greater tangible support and positive social interaction support had more satisfaction with participation than participants with lower levels of these types of support.</p> <p>The findings in this thesis extend previous research by showing that neighbourhood characteristics influence participation even after accounting for social and individual factors. This research identified a potential pathway from neighbourhood characteristics to participation that includes neighbourhood cohesion and social support and established a link between positive social interaction support and participation. The findings in this thesis help to better understand neighbourhood and social influences on participation. These influences may be addressed through clinical or policy interventions to facilitate participation in older adults with chronic health conditions.</p> / Doctor of Philosophy (PhD)

<p>Commensal intestinal microbiota number in the realm of 10¹⁴organisms per gram of colonic contents. This considerable bacterial load is acquired during birth and in the early postnatal days and has a defining, extensive impact on host physiology. We now have persuasive evidence that the intestinal microbiota influence the development of the nervous system. The following body of work describes alterations in the nervous system of germ free mice – mice bred and maintained with no exposure to bacteria of any kind. Here we examine diverse measures of neural activity, ranging from stress reactivity and stress-associated behaviours, to changes in neurochemistry of brain regions mutually involved in feeding and stress, to electrophysiological measures of sensory cells in the enteric nervous system. We see that in the absence of colonizing microbiota that neural activity is considerably altered both peripherally and centrally. Specifically, germ free mice exhibit a reduction in basal anxiety-like behaviour accompanied by consistent changes in mRNA gene expression of plasticity-related genes in brain tissue, lifelong reduction in circulating plasma leptin, increases in mRNA gene expression of hypothalamic leptin receptors and neuropeptide Y, and decreased excitability in sensory neurons in the myenteric plexus of the enteric nervous system. Furthermore, while it appears that central systems responsible for stress may have an early critical window for bacterial-induced change, it would seem that the peripheral enteric nervous system retains plasticity into adulthood. This novel work provides insight into the microbial-gut-brain axis and suggests potential avenues for therapies aimed at treating the frequently comorbid gastrointestinal and psychiatric illnesses.</p> / Doctor of Philosophy (Medical Science)

<p>One of the hallmark features of cancer is altered metabolism, whereby rates of glucose and fatty acid turnover are constitutively elevated to support uncontrolled propagation. The key regulator of energy metabolism is the enzyme AMP-activated protein kinase (AMPK), which suppresses anabolic pathways that increase proliferation and enhanced catabolic pathways that liberate energy, all in an attempt to maintain energy homeostasis in the cell. In addition to regulating metabolism, AMPK has also been implicated as a tumour suppressor and we have suggested that it may be a modulator of radiation responses in cancer cells <em>in vitro</em>. Moreover, we investigated the molecular mechanisms that facilitate ionizing radiation (IR)-induced AMPK activation, as well as demonstrated that certain AMPK activating drugs can work as radiation sensitizers in a variety of cancer cell lines. Stemming from this framework, we also provided experimental evidence that suggests AMPK is centrally involved in pathways that regulate DNA damage and proliferation at the basal level, and in response to IR. One of the targets involved in these pathways that can also influence AMPK regulation is the stress-activated Sestrin 2 protein. We have provided evidence that Sestrin 2 mediates IR-induced activation and expression of AMPK. Taken together, this work has provided novel insight into the ability of IR to modulate the activity and expression of AMPK, which in turn is required to facilitate the appropriate stress-response in cancer cells. Given its emerging interest in the cancer field, AMPK may become an important biomarker for evaluating clinical outcomes in patients undergoing radiation therapy.</p> / Doctor of Philosophy (PhD)

<p>Type 4 pili (T4P) are fibrous appendages found on the surfaces of a wide range of bacteria. They are used for adherence to biotic and abiotic surfaces, twitching motility, and biofilm formation. Despite their ubiquitous distribution, identifying the core components required for T4P expression has been difficult due to conflicting data about the functions of orthologous components from the most common model organisms, <em>Neisseria</em> and <em>Pseudomonas</em>. By inactivating the retraction component of pilus function, genes essential for T4P assembly versus disassembly were discriminated in <em>P. aeruginosa</em>. In contradiction to data from the <em>Neisseria </em>system<em>,</em> we found that components of the inner membrane sub-complex consisting of PilN/O/P are not essential for surface pilus expression, while the highly conserved inner membrane protein, PilC is essential. The current model of T4P biogenesis suggests that PilC coordinates the activity of cytoplasmic extension (PilB) and retraction (PilT) ATPases via their interaction with its two large cytoplasmic domains. Hydrolysis of ATP by PilB or PilT is proposed to induce domain movements in PilC, resulting in the addition or removal of single pilin subunits from the base of the pilus. Using<em> </em><em>in vitro</em> co-affinity purification we showed that PilB is a potential interaction partner of the N-terminal cytoplasmic domain of PilC. Also, mutagenesis of the C-terminal cytoplasmic domain of PilC produced mutant proteins with a reduced capacity to support twitching motility, suggesting impairment of PilC-PilT interactions. The indispensability of PilC and its potential interactions with the ATPases PilB and PilT suggest that it is a core element required for function of the T4P system of <em>P. aeruginosa</em>.</p> / Master of Science (MSc)

<p>Osteoarthritis (OA) is a progressive degenerative joint disease affecting over 4 million Canadians. The knee is most commonly affected joint, making knee OA a leading cause of chronic disability. Leg power is more closely related to physical performance than leg strength in healthy older adults, but power has yet to be studied in people with knee OA. Self-efficacy beliefs, or the confidence one has in their own abilities, is a variable closely related to physical performance in people with knee OA.</p> <p>The objective of this study was to identify the extent to which knee extensor strength, knee extensor power and self-efficacy explained variance in physical performance measures in adults with knee OA.</p> <p>Thirty-three participants diagnosed with clinical knee OA were included (5 men; mean age 61.1 ± 6.2 y). Dependent variables included a timed stair ascent, a timed stair descent, and the six minute walk test (SMWT). Independent variables included self-efficacy beliefs for pain, mean peak knee extensor power and mean knee extensor strength.</p> <p>Pearson correlations and linear regression models were completed using SPSS 15.</p> <p>Average values on the numeric pain rating scale (NPRS), self-efficacy beliefs for pain and mean peak knee extensor power explained 34.7 % and 42.7% of the variance observed on the timed stair ascent and the timed stair descent, respectively. The determinants of the SMWT were different, with 29.4 % of the variance being explained by average NPRS and body mass index.</p> <p>Similar to previous work conducted on healthy older adults, it appears that in adults with knee OA, knee extensor power is a closer determinant of physical performance when compared to knee extensor strength, on challenging everyday tasks, like ascending or descending a flight of stairs. For longer endurance type activities like the SMWT, the physical requirements may be different. Clinicians should consider these results when advising patients on the exercise interventions needed to maintain or improve physical performance.</p> / Master of Science (MSc)

<p>Worldwide, more than 2 million patients die within 30 days after noncardiac surgery anually. Postoperative ischemic myocardial injury is frequent, however, no consensus exists about its definition.</p> <p><strong>Objective: </strong>to develop a term Myocardial Injury after Noncardiac Surgery (MINS) caused by myocardial ischemia, requiring at least, troponin T (TnT) elevation, and with prognostic relevance at 30 days after surgery.</p> <p><strong>Methods: </strong>we performed a prospective study including 15,167 patients ³45 years-old undergoing noncardiac surgery, who had fourth-generation TnT measurements during the first 3 postoperative days. We undertook Cox regression analyses with 30-day mortality after surgery as the dependent variable, using different TnT thresholds, clinical features and several perioperative variables. Non-ischemic etiologies were excluded. Furthermore, we developed a scoring system to predict risk in MINS patients.</p> <p><strong>Results:</strong> MINS was defined as TnT ≥0.03 ng/mL with or without clinical features, and it was an independent predictor of 30-day mortality (adjusted HR 3.82, CI 95% 2.84-5.10). We determined that MINS incidence was 8%, its population attributable risk 33.7%, and 30-days mortality rate 9.6%. Patients did not experience ischemic symptoms in 84% of MINS cases. Additionally, we developed a scoring system in patients suffering MINS with 3 independent predictors of death (age ≥75 years, new ST elevation or left bundle branch block, and anterior location of ECG changes),</p> <p><strong>Conclusion: </strong>Among patients undergoing noncardiac surgery, we defined MINS based on a TnT threshold ≥0.03 ng/mL. Mostly, MINS patients were asymptomatic. Therefore, this strongly suggests the importance of a troponin monitoring during the first few days after surgery.</p> / Master of Health Sciences (MSc)