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.

Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Autism and associated gene mutations can be studied with genetic mouse models. Magnetic Resonance Imaging (MRI) of these animal models quantifies the impact of genetics on brain morphology. Using MRI, three genetic mouse models of autism were imaged: Neuroligin 3 R451C knock-in, Methyl-CpG binding protein-2 308-truncation and Integrin β-3 knock-out. Morphological differences were identified using a newly developed MRI mouse cerebellum atlas. The results show all three genes to alter cerebellar anatomy. Each studied gene affected a unique set of cerebellar structures. I hypothesize that the results and known behavioural phenotypes of the models are linked, with anatomy contributing to specific behaviours. In the future work section, a surface-based analysis method is presented to investigate the variance in cerebellum foliation across disease models and inbred strains. This work shows that autism risk-genes alter distinct regions of the cerebellum.

Glucagon-like peptide-2 (GLP-2) augments intestinal adaptation in animal models of short bowel syndrome (SBS) and in adult patients with SBS. However, GLP-2 has not been used as a therapy for pediatric SBS. In this thesis, it is hypothesized that exogenous GLP-2 therapy will improve outcomes of intestinal adaptation in proximal intestinal resection (JI) and distal intestinal resection (JC) neonatal piglet models of SBS. Improvements in morphological parameters (increased small intestinal length) and histological parameters (increased jejunal villus length or jejunal crypt depth) of intestinal adaptation in JI and JC neonatal piglets treated with GLP-2 were observed. However, improved clinical outcomes (fewer days of diarrhea, fewer days on parenteral nutrition, more days on enteral nutrition alone) were only observed in GLP-2 treated JC animals. Since the JC anatomical subtype (no remnant ileum) represents the majority of clinical cases of neonatal SBS, these results support a potential role for GLP-2 therapy in pediatric SBS.

Aim: To describe the predictive validity of reaching low disease activity (LDA) at 1 year on future disability and joint damage in patients with early rheumatoid arthritis (ERA). Methods: First a systematic literature review of prognostic studies assessing the association between disease activity and functional or radiographic outcomes in ERA was performed. Then data from the Study Of New-Onset RA (SONORA) were used to evaluate the impact of year-one LDA on 3-year disability and 2-year radiographic progression using multivariate regression analyses. Results: Our review demonstrated evidence for relationship between baseline disease activity and future disability and join damage. However evidence for the impact of early treatment response on long-term outcomes in ERA is sparse. Analysis of 984 patients showed year one LDA predicts lower HAQ (p<.0001) and less damage (p=0.04) in future. Conclusion: Reaching LDA early is associated with better long-term functional and radiographic outcomes in patients with early RA.

Autism and associated gene mutations can be studied with genetic mouse models. Magnetic Resonance Imaging (MRI) of these animal models quantifies the impact of genetics on brain morphology. Using MRI, three genetic mouse models of autism were imaged: Neuroligin 3 R451C knock-in, Methyl-CpG binding protein-2 308-truncation and Integrin β-3 knock-out. Morphological differences were identified using a newly developed MRI mouse cerebellum atlas. The results show all three genes to alter cerebellar anatomy. Each studied gene affected a unique set of cerebellar structures. I hypothesize that the results and known behavioural phenotypes of the models are linked, with anatomy contributing to specific behaviours. In the future work section, a surface-based analysis method is presented to investigate the variance in cerebellum foliation across disease models and inbred strains. This work shows that autism risk-genes alter distinct regions of the cerebellum.

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.

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.

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.