This thesis uses the methods of sychometrics and clinimetrics to develop and evaluate a Pediatric Ulcerative Colitis Activity Index (PUCAI). The initial phases of item generation and reduction were performed previously. This thesis comprises five main studies. Study one: the weighting and formatting of an initial draft PUCAI using a cohort of 157 children with ulcerative colitis, enrolled prospectively in five pediatric IBD centers. Study two: the validation of the final draft on a separate prospective cohort of 48 children undergoing complete colonoscopy. The PUCAI was highly correlated with physician global assessment (PGA) (r=0.91), Mayo score (r=0.95) and colonoscopic appearance (r=0.77). The PUCAI was able to differentiate the different categories of disease activity, and cutoff points were defined. Study three: Assessment of the responsiveness of the PUCAI. The index demonstrated excellent responsiveness on 75 children seen twice during the study period (effect size=1.9, standardized response mean=2.2, responsiveness statistics=2.6, correlation with PGA of change=0.84, and area under the ROC curve=0.97 95%CI 0.93- 0.99). Study four was aimed at evaluating the predictive validity of the PUCAI, on a retrospective cohort of 99 children with severe ulcerative colitis admitted for intravenous corticosteroid therapy. The PUCAI, calculated on the third and fifth day of therapy was highly predictive of therapy failure at discharge and one year post discharge (area under the ROC curve 0.84 (95%CI 0.76-0.92). Study five: a methodological study evaluating the preferred way to determine the minimal clinically important difference (MCID) of health-related outcome measures. This study was conducted using the PUCAI and three other well established instruments. It was concluded that the MCID should be determined primarily by the anchor-based approach using the ROC curve method on the entire cohort, supplemented by calculating the minimal detectable difference beyond statistical error using the standard error of measurement. Small, moderate and large MCID values could be presented based on the degree of expected relevant change. Together, these studies have contributed to the rigorous development and thorough evaluation of a novel, non-invasive tool for assessing disease activity in pediatric ulcerative colitis clinical studies and practice.

The past two decades have witnessed an accelerated effort to understand the nature of schizophrenia and related psychotic disorders, but no causative gene(s) has been discovered yet. Family, twin, and adoption studies indicate that genetic factors are clearly implicated in the etiology of these disorders (Cardno and Gottesman, 2000; Cardno et al., 2002; McGuffin et al., 2003; Weinberger, 2005). Several aspects of 22q11 Deletion Syndrome (22qDS) - the most common chromosomal microdeletion found in humans - create a unique opportunity for susceptibility gene identification. For instance, the reported risk of psychotic disorders in 22qDS is 25-fold higher than in the general population (Murphy et al., 1999) and genome-wide linkage studies in families with schizophrenia without 22qDS indicate that the 22q11.2 region is a strong susceptibility locus for psychosis (Badner and Gershon, 2002; Lewis et al., 2003). This thesis aims to identify genetic factors associated with the development of psychosis in 22qDS by i) investigating the relationship between the length of the 22q11.2 deletions and the presence of a psychotic disorder in patients with 22qDS; ii) studying diagnostic molecular methods that improve detection of 22q11.2 deletions and duplications; and iii) exploring the relationship between 22qDS-psychotic phenotype and gene expression patterns. The central hypothesis was that psychosis in 22qDS would not be associated with haploinsufficiency (having one copy of the gene), but rather, it would be associated with distinct 22q11.2 gene expression profiles. Chapter 2 showed that 22q11.2 deletion size did not appear to be associated with the development of psychosis in adults with 22qDS. In Chapter 3, a molecular method that detects and size 22q11.2 deletions and duplications of various sizes was shown to be superior to the traditional molecular diagnostic technique used for molecular diagnostic of 22qDS. Finally, in Chapter 4, decreased gene expression of three genes located in the 22q11.2 region (SNAP29, COMT and BID) was significantly associated with psychosis in adults with 22qDS. Focusing on genes located in the 22q11.2 region has helped revealing genetic alterations associated with the frequent development of psychosis in 22qDS. Future studies focusing on investigating the heterogeneity of the psychotic presentation in 22qDS and further elucidating potential genetic mechanisms likely to explain the gene expression changes in the 22q11.2 region demonstrated here will help advance the scientific understanding of the etiology of psychosis.

This research examines the activation of the Rapid Response Team (RRT) through the Early Warning Score (EWS) model as a system of predicting adverse event outcomes. Modeling the input parameters of this system concluded that although conventional parameters associated with EWSs were predictive,the most predictive clinical and laboratory parameters are those of hematological and nephritic function, related to the model of multi-organ system decompensation. Upon examining different EWSs, the Modified Early Warning Score exhibited superior operating characteristics, however, it was not statistically different than other common EWSs from literature. Accounting for temporal features of the dataset shows that the International Normalized Ratio is the most predictive parameter, however, the hazard model exhibits poor discriminative ability. Therefore, clinically, parameters outside the EWS models are predictive of the outcomes in question, and their incorporation into future policy would serve to better inform the prevention of adverse events.

Current therapy for chronic kidney disease (CKD) is limited; however, recent studies have shown that a subpopulation of cells derived from the bone marrow, known as early outgrowth cells (EOCs), are able to attenuate kidney injury. Here we examined the efficacy of a modular tissue engineering system whereby the EOCs might be easily removed in the event of malignant change. While modular therapy mimicked the effects seen with standard EOC therapy, the modules degraded allowing the encapsulated EOCs to enter systemic circulation. Given the presumed egress of EOCs, we explored an alternative strategy for kidney protection. Here we investigated the long-term effectiveness of administering the conditioned medium (EOC-CM) that contains the factors the EOCs secrete, rather than the cells themselves. In these studies, repeated administration of EOC-CM attenuated the structural and functional manifestations of kidney injury suggesting that this approach may provide an effective and feasible, cell-free approach for CKD.

Current therapy for chronic kidney disease (CKD) is limited; however, recent studies have shown that a subpopulation of cells derived from the bone marrow, known as early outgrowth cells (EOCs), are able to attenuate kidney injury. Here we examined the efficacy of a modular tissue engineering system whereby the EOCs might be easily removed in the event of malignant change. While modular therapy mimicked the effects seen with standard EOC therapy, the modules degraded allowing the encapsulated EOCs to enter systemic circulation. Given the presumed egress of EOCs, we explored an alternative strategy for kidney protection. Here we investigated the long-term effectiveness of administering the conditioned medium (EOC-CM) that contains the factors the EOCs secrete, rather than the cells themselves. In these studies, repeated administration of EOC-CM attenuated the structural and functional manifestations of kidney injury suggesting that this approach may provide an effective and feasible, cell-free approach for CKD.

This research examines the activation of the Rapid Response Team (RRT) through the Early Warning Score (EWS) model as a system of predicting adverse event outcomes. Modeling the input parameters of this system concluded that although conventional parameters associated with EWSs were predictive,the most predictive clinical and laboratory parameters are those of hematological and nephritic function, related to the model of multi-organ system decompensation. Upon examining different EWSs, the Modified Early Warning Score exhibited superior operating characteristics, however, it was not statistically different than other common EWSs from literature. Accounting for temporal features of the dataset shows that the International Normalized Ratio is the most predictive parameter, however, the hazard model exhibits poor discriminative ability. Therefore, clinically, parameters outside the EWS models are predictive of the outcomes in question, and their incorporation into future policy would serve to better inform the prevention of adverse events.

Chronic denervation and chronic axotomy present independent barriers for axonal regeneration. Chronic denervation occurs when nerves are no longer connected to their neuronal cell bodies; chronic axotomy occurs when neurons are not connected to their targets for prolonged periods of time. The harmful effects of chronic denervation can be addressed by the side-to-side bridge surgical technique. Additionally, the negative effects of chronic axotomy can be reversed by GDNF delivery to the nerve. The experiments in this thesis were designed to evaluate nerve regeneration in a rat model of chronic injury after treatment with local GDNF delivery, side to-side bridge protection, or both. The GDNF delivery system consisted of poly(lactic-co-glycolic acid) microspheres embedded in fibrin for controlled delivery of GDNF. Overall, the side-to-side bridges technique was effective in protecting against the negative effects of chronic denervation regardless of treatment with or without GDNF. Local delivery of GDNF did not increase axonal regeneration or functional recovery.

A relationship between overweight and excessive daytime sleepiness (EDS) has been suggested in the adult population, and to a limited extent in the pediatric population. Daytime sleepiness can interfere with various components of daytime function. In light of the increase in the rates of pediatric overweight and obesity, the aim of this study was to investigate the relationship between weight and EDS in a pediatric population. Using a retrospective approach, data collected in a pediatric sleep clinic was analyzed. Objective measures of EDS were correlated with age, gender, body mass index percentile, and overnight sleep test recording variables. In males and in all children under the age of 13 years old, EDS was more common in those weighing above the normal range, EDS was present particularly during mid-morning hours. Additionally, weight above the normal range correlated with evidence of EDS after adjusting for measures of sleep pathologies.

A relationship between overweight and excessive daytime sleepiness (EDS) has been suggested in the adult population, and to a limited extent in the pediatric population. Daytime sleepiness can interfere with various components of daytime function. In light of the increase in the rates of pediatric overweight and obesity, the aim of this study was to investigate the relationship between weight and EDS in a pediatric population. Using a retrospective approach, data collected in a pediatric sleep clinic was analyzed. Objective measures of EDS were correlated with age, gender, body mass index percentile, and overnight sleep test recording variables. In males and in all children under the age of 13 years old, EDS was more common in those weighing above the normal range, EDS was present particularly during mid-morning hours. Additionally, weight above the normal range correlated with evidence of EDS after adjusting for measures of sleep pathologies.

Chronic denervation and chronic axotomy present independent barriers for axonal regeneration. Chronic denervation occurs when nerves are no longer connected to their neuronal cell bodies; chronic axotomy occurs when neurons are not connected to their targets for prolonged periods of time. The harmful effects of chronic denervation can be addressed by the side-to-side bridge surgical technique. Additionally, the negative effects of chronic axotomy can be reversed by GDNF delivery to the nerve. The experiments in this thesis were designed to evaluate nerve regeneration in a rat model of chronic injury after treatment with local GDNF delivery, side to-side bridge protection, or both. The GDNF delivery system consisted of poly(lactic-co-glycolic acid) microspheres embedded in fibrin for controlled delivery of GDNF. Overall, the side-to-side bridges technique was effective in protecting against the negative effects of chronic denervation regardless of treatment with or without GDNF. Local delivery of GDNF did not increase axonal regeneration or functional recovery.