This dissertation uses population-based administrative healthcare data to evaluate the outcomes, processes-of-care and practice variation associated with preoperative medical consultation in Ontario, Canada. First, a multicentre cross-sectional study was conducted to develop a novel algorithm for identifying preoperative medical consultations using administrative data. The optimal claims-based algorithm was a physician service claim for a consultation by a cardiologist, general internist, endocrinologist, geriatrician, or nephrologist within 120 days before the index surgery. This algorithm had a sensitivity of 90% (95% confidence interval [CI], 86 to 93) and specificity of 92% (95% CI, 88 to 95). Second, we conducted a population-based cohort study to evaluate the association of preoperative medical consultation with outcomes and processes-of-care. After adjustment for measured confounders using propensity-score methods, consultation was associated with increased preoperative testing, preoperative pharmacological interventions, 30-day mortality [relative risk (RR) 1.16; 95% CI, 1.07 to 1.25], 1-year mortality (RR 1.08; 95% CI, 1.04 to 1.12), and mean hospital stay (difference 0.67 days; 95% CI, 0.59 to 0.76). These findings were stable across subgroups, as well as sensitivity analyses that tested for unmeasured confounding. Third, temporal trends and practice variation in consultation were evaluated within the population-based cohort. The proportion of patients undergoing consultation remained relatively stable over the study period, at approximately 39%. Although patient-level and surgery-level factors did predict consultation use, they explained only 6.8% of variation in consultation rates. By comparison, inter-hospital differences in rates were substantial (range, 1.9% to 86.8%), were not explained by surgical volume or teaching status, and persisted after adjustment for patient-level and surgery-level factors. Overall, this dissertation highlights the need for research to identify interventions for safely decreasing perioperative risk, define mechanisms by which consultation influences outcomes, examine factors that influence practice variation in medical consultation, and identify patients who benefit most from preoperative medical consultation.

Mechanisms to augment the cellular function and mass of beta-cells may be effective means of treating type 2 diabetes. Important in the physiological control of beta-cell function and nutrient disposal are factors released from gut enteroendocrine cells during nutrient digestion. In enteroendocrine L-cells, post-translational processing of proglucagon gives rise to a number of proglucagon-derived peptides. One such peptide, glucagon-like peptide-1 (GLP-1), acts via its own receptor (GLP-1R) to stimulate beta-cell insulin secretion, proliferation and survival. Another, oxyntomodulin (OXM), weakly activates the GLP-1R and inhibits food intake in a GLP-1R-dependent manner in rodents, which led us to hypothesize that OXM modulates GLP-1R-dependent glucoregulation. While OXM did not mimic the inhibitory effect of GLP-1 on gastric emptying in mice, OXM stimulated insulin secretion, beta-cell survival and improved glucose tolerance in a GLP-1R-dependent manner. In a similar manner to GLP-1, glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine K-cells, physiologically stimulates insulin secretion via a distinct GIP receptor (GIPR) in beta-cells. Beyond the beta-cell, GIP and GLP-1 appear to exert divergent actions for the control of glucose homeostasis. Moreover, I illustrate that physiological and pharmacological GLP-1R signalling may be comparatively more important for the preservation of beta-cell mass and glucose homeostasis in murine streptozotocin-induced diabetes. Lastly, studies in rodents and humans have showed that metformin increases circulating levels of GLP-1, leading us to hypothesize that GIP and GLP-1 may be involved in the glucoregulatory effects of metformin. Interestingly, transcripts for the Glp1r and Gipr were significantly increased within islets of metformin-treated mice, and metformin treatment enhanced the sensitivity of cultured beta-cells to GIP and GLP-1. In summary, these studies illustrate mechanisms by which enteroendocrine peptides compare and contrast with respect to beta-cell survival and function and the control of glucose homeostasis.

Medulloblastoma is a devastating disease of the cerebellum, and the most common solid pediatric malignancy of the central nervous system. Recently, transcriptome-wide profiling has dissected medulloblastoma from one single disease into four disparate molecular subgroups – namely WNT, SHH, Group3 and Group4. Distinct genomic, cytogenetic, mutational and clinical spectra associated with these subgroups highlight the pressing need for targeted therapies, of which encouraging preliminary results have been generated. While the promise of personalized medicine is within our reach, improved understanding of the molecular mechanisms driving pathogenesis is critical to this process. The intent of my PhD thesis research was to characterize the molecular mechanisms contributing to medulloblastoma pathogenesis, and the clinical impact of these aberrations. Through a combinatorial use of genetic and epigenetic profiling, next-generation sequencing and bioinformatics analyses we have identified subsets of tumors with transcriptional signatures that influence their clinical properties. Furthermore, our results have shed light on the establishment of the normal cerebellar cytoarchitecture, identifying a physiological glutamate gradient with critical implications to both cerebellar development and disease. This thesis stresses the importance of interrogating medulloblastoma in a subgroup-specific manner. Our findings demonstrate the utility of pursuing an integrated (copy number, mutational, transcriptional and epigenetic) molecular approach, to further our understanding of the pathobiology of medulloblastoma. Finally, we propose rationale therapeutic targets that may improve the treatment of aggressive variants of this disease.

Medulloblastoma is a devastating disease of the cerebellum, and the most common solid pediatric malignancy of the central nervous system. Recently, transcriptome-wide profiling has dissected medulloblastoma from one single disease into four disparate molecular subgroups – namely WNT, SHH, Group3 and Group4. Distinct genomic, cytogenetic, mutational and clinical spectra associated with these subgroups highlight the pressing need for targeted therapies, of which encouraging preliminary results have been generated. While the promise of personalized medicine is within our reach, improved understanding of the molecular mechanisms driving pathogenesis is critical to this process. The intent of my PhD thesis research was to characterize the molecular mechanisms contributing to medulloblastoma pathogenesis, and the clinical impact of these aberrations. Through a combinatorial use of genetic and epigenetic profiling, next-generation sequencing and bioinformatics analyses we have identified subsets of tumors with transcriptional signatures that influence their clinical properties. Furthermore, our results have shed light on the establishment of the normal cerebellar cytoarchitecture, identifying a physiological glutamate gradient with critical implications to both cerebellar development and disease. This thesis stresses the importance of interrogating medulloblastoma in a subgroup-specific manner. Our findings demonstrate the utility of pursuing an integrated (copy number, mutational, transcriptional and epigenetic) molecular approach, to further our understanding of the pathobiology of medulloblastoma. Finally, we propose rationale therapeutic targets that may improve the treatment of aggressive variants of this disease.

The surgical culture values certainty and confidence, and this was proposed to be a source of internal conflict for surgeons, particularly during times of stress and uncertainty. Surgeons previously described the need to manage their image during these times, putting on an external appearance that is inconsistent internally. As part of a larger program of research on surgical judgment and decision making, this study used a constructivist grounded theory approach to explore 15 general surgery trainees’ perceptions and experiences of impression management during moments of decision making. Residents described their perceived expectations in training, and the impression management strategies they used to appear as though they were meeting them in circumstances when they were not. Participants described those who did not meet these expectations as branded the ‘struggling resident’. Concerns about one’s impression had implications for residents’ evaluations, learning opportunities, decision making, and wellness.

The surgical culture values certainty and confidence, and this was proposed to be a source of internal conflict for surgeons, particularly during times of stress and uncertainty. Surgeons previously described the need to manage their image during these times, putting on an external appearance that is inconsistent internally. As part of a larger program of research on surgical judgment and decision making, this study used a constructivist grounded theory approach to explore 15 general surgery trainees’ perceptions and experiences of impression management during moments of decision making. Residents described their perceived expectations in training, and the impression management strategies they used to appear as though they were meeting them in circumstances when they were not. Participants described those who did not meet these expectations as branded the ‘struggling resident’. Concerns about one’s impression had implications for residents’ evaluations, learning opportunities, decision making, and wellness.

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.

Background: Reduced bone mineral density (BMD) is an established complication of anorexia nervosa (AN). There is inconclusive evidence as to whether this reduction in bone mass is permanent or can be reversed with recovery from AN. The objectives of this study were to: i. determine the extent of reversal of skeletal deficits with recovery from AN, and the duration of recovery required for complete reversal, if this occurred; and, ii. evaluate the effect of key illness characteristics on BMD. Methods: Women (aged 17-40 years) who had previously received inpatient treatment for AN at one of two hospital-based programs were selected for this cross-sectional study; 514 healthy premenopausal women recruited from the community served as a control group. A detailed lifetime illness history was obtained by a Life History Calendar interview. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the spine, hip and total body. Low BMD was defined as a weight and age-matched standard deviation (Z-score) of ≤ -1.5 at one or more skeletal sites. Participants were considered recovered if they had maintained a body mass index ≥ 18.5 kg/m2 and resumed regular menstruation for ≥ 1 year. Results: Of 190 AN participants, 77 were considered recovered and 113 were ill. The prevalence of low BMD was 11.7% in the recovered group, 47.3% in the ill group and 6.8% in the control group. The odds of low BMD in the recovered participants was significantly lower than in the ill participants (odds ratio [OR] = 0.17, 95% CI 0.07, 0.36, p<0.0001) and was not significantly different from the controls (OR = 1.81, 95% CI 0.79, 3.78, p=0.15). Duration of illness was associated with low BMD (OR = 1.16, 95% CI 1.08, 1.25, p<0.0001) and was negatively associated with the odds of AN recovery. Normal mean BMD values at each skeletal site were observed in women recovered ≥ 3 years. Conclusion: The results emphasize the importance of early and sustained AN recovery for the prevention and treatment of low bone mass in this population and may offer motivation for AN patients to make positive behavioural changes leading to successful, long-term recovery.

Background: Reduced bone mineral density (BMD) is an established complication of anorexia nervosa (AN). There is inconclusive evidence as to whether this reduction in bone mass is permanent or can be reversed with recovery from AN. The objectives of this study were to: i. determine the extent of reversal of skeletal deficits with recovery from AN, and the duration of recovery required for complete reversal, if this occurred; and, ii. evaluate the effect of key illness characteristics on BMD. Methods: Women (aged 17-40 years) who had previously received inpatient treatment for AN at one of two hospital-based programs were selected for this cross-sectional study; 514 healthy premenopausal women recruited from the community served as a control group. A detailed lifetime illness history was obtained by a Life History Calendar interview. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the spine, hip and total body. Low BMD was defined as a weight and age-matched standard deviation (Z-score) of ≤ -1.5 at one or more skeletal sites. Participants were considered recovered if they had maintained a body mass index ≥ 18.5 kg/m2 and resumed regular menstruation for ≥ 1 year. Results: Of 190 AN participants, 77 were considered recovered and 113 were ill. The prevalence of low BMD was 11.7% in the recovered group, 47.3% in the ill group and 6.8% in the control group. The odds of low BMD in the recovered participants was significantly lower than in the ill participants (odds ratio [OR] = 0.17, 95% CI 0.07, 0.36, p<0.0001) and was not significantly different from the controls (OR = 1.81, 95% CI 0.79, 3.78, p=0.15). Duration of illness was associated with low BMD (OR = 1.16, 95% CI 1.08, 1.25, p<0.0001) and was negatively associated with the odds of AN recovery. Normal mean BMD values at each skeletal site were observed in women recovered ≥ 3 years. Conclusion: The results emphasize the importance of early and sustained AN recovery for the prevention and treatment of low bone mass in this population and may offer motivation for AN patients to make positive behavioural changes leading to successful, long-term recovery.

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.