Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect and infants with TOF incur significant right ventricular(RV) dysfunction due to perioperative injury. Insulin has been shown to reduce perioperative myocardial injury and significantly improve postoperative cardiac function. However, studies are limited to the adult population and the effects in a pediatric heart with a CHD are unknown. To the best of our knowledge, this is the first randomized, double blind, placebo-controlled clinical study designed to investigate insulin’s potential cardioprotective effects postoperatively and mechanisms of action during pediatric cardiac surgery. Thirty infants with TOF were equally randomly allocated to receive either standard cardioplegia (SC) or 10UI insulin-enhanced (IC). Expression profiles of surgery were generated from biopsies extracted from the right ventricular outflow tract (end ischemia and five minutes of reperfusion) and hybridized to Affymetrix HG-U133A GeneChips. Gene expression profiles were generated using two softwares, ArrayAssist V2.6 (paired t-test) and affylmGUI (ANOVA). Survival rate was 100%. Compared to patients in the SC group, patients in the IC group demonstrated a trend toward a 1.8 fold decrease (p = .06) in reperfusion duration (61.93 ± 61.12 vs. 35.20 ± 23.16 hrs., respectively), a significant 2-fold decrease in the length of ICU stay (p = .04) (4.2 ± 3.9 vs. 2.3 ± 1.1 days, respectively) and a trend toward a 2.5 fold decrease in intubation duration (p= .06) (2.5± 12.2 vs. 55.0 ± 67 hrs., respectively). Patients in the IC group also demonstrated significantly lower inotropic scores, calculated at 12-hour intervals across a 48-hour ICU period, (ANOVA p = .01) and significantly greater urine volume, by 71%, (p = .02). IC evoked a cardioprotective gene expression profile aimed at mitigating perioperative myocardial injury, specifically; apoptosis, inflammation, cardiac hypertrophy, arrythmias and fibrosis. The improved postoperative outcome and cardioprotective gene expression signature with IC suggests that, administration of insulin during cardiac surgery in infants with TOF may prevent cardiac dysfunction as a result of mitigating perioperative myocardial injury. Overall, this exploratory study demonstrated insulin-enhanced cardioplegia to be a potential cardioprotective agent during pediatric heart surgery.

Our objective was to examine the impact of palliative care (PC) on aggressive care near death for patients with advanced pancreatic cancer. Measures of aggressive care included (i) chemotherapy within 14 days of death; (ii) more than one emergency department (ED) visit; (iii) more than one hospitalization; and (iv) at least one intensive care unit (ICU) admission, all within 30 days of death. A retrospective population-based cohort study was conducted with patients diagnosed with advanced pancreatic cancer in Ontario. Multivariable logistic analyses were performed. Our final cohort consisted of 5,381 patients (median survival of 75 days). 52% received a PC consultation. PC consultation was associated with decreased use of chemotherapy near death (OR=0.34); and lower risk of ICU admission (OR=0.12), multiple ED visits (OR=0.19), and multiple hospitalizations near death (OR=0.24). A per unit increase in the monthly rate of PC visits was associated with lower odds of aggressive care.

Objective: To evaluate the SickKids Team Obesity Management Program (STOMP), an obesity management program for severely obese adolescents. Methods: Non-randomized study of 6 and 12 month outcomes in STOMP patients vs. a comparison group of obese adolescents. Results: At 6 months, STOMP patients stabilized their BMI (0.08±0.3 kg/m2;p=0.79) and reported improved psychological and health behaviour measures, whereas comparison participants increased their BMI (0.7±0.2 kg/m2;p=0.004) and had worsening of cardiometabolic outcomes. Between-group differences included improved cardiometabolic, psychological and health behaviour measures in STOMP patients. At 12 months, STOMP patients stabilized their BMI (0.8±0.5 kg/m2;p=0.07), had improvements in anthropometric and cardiometabolic outcomes and reported an increase in health behaviours, whereas comparison participants increased their BMI (1.2±0.4 kg/m2;p=0.001) and had worsening of cardiometabolic outcomes. Between-group differences included improved anthropometric, cardiometabolic and health behaviour outcomes in STOMP patients. Conclusions: Participation in STOMP improved anthropometric, cardiometabolic, psychological and health behaviour outcomes among severely obese adolescents.

This thesis provides a first description and proof-of-concept of iterative cardiac output measurement (ICO) – a respiratory, carbon-dioxide (CO2) based method of measuring cardiac output (CO). The ICO method continuously tests and refines an estimate of the CO by attempting to maintain the end-tidal CO2 constant. To validate the new method, ICO and bolus thermodilution CO (TDCO) were simultaneously measured in a porcine model of liver transplant. Linear regression analysis revealed the equation ICO = 0.69•TDCO + 0.65 with a Pearson correlation coefficient of 0.89. Analysis by the method of Bland and Altman showed a bias of -0.2 L/min with 95% limits of agreement from -1.1 to 0.7 L/min. The trending ability of ICO was determined using the half-circle polar plot method where the mean radial bias, the standard deviation of the polar angle, and 95% confidence interval of the polar angle were -8º, ±17º, and ±33º, respectively.

Research into adverse events in home care is at a very early stage worldwide. Adverse event research in other health care sectors has demonstrated that patients can and do suffer harm, much of which is preventable, during the receipt of health care services. A stratified, random sample of patients who had received home care nursing service and were discharged in 2004/05 from three Ontario home care programs was studied to develop basic exploratory and descriptive evidence to advance the understanding of AEs in home care. The outcome is an estimate of the incidence of adverse events among patients, description of adverse event types and factors associated with adverse events, and the development of models predictive of home care patients with higher and lower potential for adverse events, and of the location of patients with adverse events. Positive critical indicators were identified in 66.5% of 430 cases. Sixty-one adverse events were identified in 55 (19.2%) of these 286 cases. When adjusted for sampling methodology, the adverse event rate was 13.2 per 100 patients (95%, CI 10.4% - 16.6%, SE 1.6%). Thirty-three percent of the adverse events were rated as having more than a 50% probability of preventability; 1.4% of all patients experienced an adverse event related death. Eight of the 45 factors significantly associated with adverse events formed a single factor model predictive of adverse events. Six two-factor interactions and the absence of one factor were also predictive of the occurrence of adverse events. Five of the 12 critical indicators significantly related to adverse events, as well as 7 critical indicator combinations formed models that reliably located about two-thirds of patients who had, and almost all patients who had not, experienced an adverse event. This study suggests that a significant number of home care patients experience adverse events, two-thirds of which are preventable. Use of adverse event sensitive factors as a screening tool for patients that may benefit from enhanced case management and clinical vigilance, and those unlikely to be placed at increased adverse event risk by maintaining current levels of vigilance, presents an opportunity to improve patient safety. Retrospective critical indicator models identifying home care patients who have experienced an adverse event can be used to estimate adverse event incidence rates and changes in rates over time.

Ovarian high-grade serous cancer (HGSC) is the most lethal gynecologic malignancy and well-characterized models may improve patient outcomes. Patient-derived xenografts (PDXs) recapitulate disease heterogeneity; however, to be useful in predicting response to novel chemotherapeutics, they must reflect the response of the donor tissue to standard chemotherapy. The objectives of this study were: first, to evaluate the response of PDXs’ to platinum therapy and compare this response to that of the donor; and second, to determine whether treatment with chemotherapy enriches for tumourigenic cells. Eighteen samples formed tumours in the mammary fat pads of NOD-Scid-IL2Rγnull mice and were treated with Carboplatin. There was a 100% concordance between sample status and PDXs response to chemotherapy. HGS histology was confirmed for all cases. A conclusion regarding post-chemotherapy tumourigenicity could not be made due to inadequate statistical power. PDXs represent useful tools for evaluation of novel therapies and identification of patients who are platinum-resistant/sensitive.

Introduction: Trauma centers (TC) are the only institutions with resources to manage patients with severe traumatic brain injury (TBI). We chose to examine potential barriers to access to TC care for TBI patients. Methods: Administrative datasets were used to evaluate access to TC among patients with severe TBI. We examined triage practices of EMS in TBI. Finally, we analyzed surveys to capture the beliefs, perceptions and knowledge of ED physicians with respect to TBI. Results: 57% of patients in Ontario had any access to a TC following TBI. Of patients who had potential access to a TC from the scene of injury as defined by pre-hospital triage guidelines, 60% of patients were undertriaged. Challenges that ED physicians faced with managing TBI, included lack of beds at TC and difficulty attaining transport resources. Conclusion: Access to TC care for patients with TBI is impeded by patient and system level factors.

Ankylosing spondylitis (AS) is associated with HLA-B*2704 and B*2705 but not with HLA-B*2706 and B*2709. Genome wide studies recently identified ERAP1 as an important genetic association in AS and could be the missing link in the pathogenesis of AS. I studied the implications of the two known actions of ERAP1 on AS pathogenesis. For assessing the peptide trimming function, surface HLA-B27 and MHC-I free heavy chain (FHC) expression on peripheral blood mononuclear cells of AS patients were studied. Subsequently, in an in vitro system of C1R cells expressing different AS-associated and AS-neutral HLA-B27 subtypes, I studied the effect of ERAP1 suppression on HLA-B27 and FHC expression. To assess the cytokine receptor shedding function, I studied serum cytokine receptor level variation with ERAP1 polymorphisms and its relationship to disease activity in AS patients. Finally, I studied the effect of variants of ERAP1 and other members of the antigen presentation machinery on radiographic severity in AS patients. AS patients with the major allele of the ERAP1 rs27044 polymorphism had higher FHC expression on monocytes. In C1R cells ERAP1 suppression led to an increase in intracellular FHC (IC-FHC) and B27-peptide complexes identified by a special MARB4 antibody, but only in C1R cells expressing the AS-associated subtypes HLA-B*2704 and B*2705. ERAP1 variants had no effect on serum cytokine receptor levels. Baseline radiographic severity was associated with ERAP1 polymorphism in univariate analysis only. LMP2 variants were associated with baseline radiographic severity in multivariate analysis. ERAP1 affects peptide presentation and FHC formation by HLA-B27 and could be the missing link in the pathogenesis of AS. ERAP1 through its differential HLA-B27 subtype interaction could explain why certain subtypes of HLA-B27 are associated with AS while others are not. Larger studies are required to look closely at the effect of ERAP1 on radiographic severity and progression in AS.

The function of skeletal adaptation to mechanical load is to adjust the amount and distribution of bone tissue (geometry); such that stresses experienced within the bone are kept within certain physiological limits and fractures are prevented. Genetic, environmental or hormonal factors may cause heterogeneity in this adaptive response, altering geometry and consequently fragility. The purpose of this thesis was to explore the skeletal response to load in vivo, by evaluating stress at the hip under three different conditions: FRACTURE (Study 1), DIABETES (Study 2) and ESTROGEN deficiency (STUDY 3). We studied women 25 years of age or older who participated in the Canadian Multicentre Osteoporosis Study and had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized according to fracture status (fracture or no fracture), diabetes status (diabetes or no diabetes) and estrogen use (current users or never users). We computed stress (megapascals=MPa) at the infero-medial margin of the femoral neck in a one-legged iii stance using a 2-D engineering beam analysis. We used linear regression to determine associations between femoral neck stress and each categorical variable. Study 1 (n=2168) demonstrated higher stresses in postmenopausal women with fractures compared to women without fractures (10.57 ± 2.19 vs. 10.30 ± 2.03 MPa; p=0.0031). Study 2 (n=3665) demonstrated higher stresses in women with Type 2 Diabetes Mellitus compared to non-diabetic women (10.98 ± 2.33 vs. 10.57 ± 2.20 MPa; p=0.0194). Study 3 (n=2447) demonstrated higher stresses in postmenopausal women not on estrogen than in premenopausal women (10.66 ± 2.14 vs. 10.09 ± 2.01 MPa; p<0.0001), but no differences in stresses between postmenopausal women on estrogen and premenopausal women (10.16 ± 2.00 vs. 10.09 ± 2.01 MPa; p=0.6102). Since stress is an indicator of underlying geometry, and geometry should be adapted to prevalent loads, higher stress indicates weaker geometry and suggests an impaired modeling response in these three conditions. Compromised modeling has important clinical implications in terms of treatment selection, as individuals with reduced load sensitivity may respond best to metabolic agents that would improve modeling responses to load stimuli.

This study is a prospective longitudinal outcome study investigating the presence of response shift in disease and generic functional outcome measures in 105 patients undergoing spinal surgery. The then-test method which compares pre-test scores to retrospective pre-test scores was used to quantitate response shift. There was a statistically significant response shift for the Oswestry Disability Index (ODI) (p=0.001) and the Short Form-36-PCS (p=0.078). At three months, seventy-two percent of patients exhibited a response shift with the ODI. Fifty-six and 21 percent of patients exhibited a response shift with the SF-36 physical and mental component scores respectively. When accounting for response shift and using the minimal clinically important difference, the success rate of the surgery at 3 months increased by 20 percent. The presence of response shift has implications for the measurement properties of standard spinal surgery outcome measures including the effect size of treatment and the number of responders to treatment.