This dissertation examines brain lateralization and interhemispheric asymmetry patterns found in youths with Attention-Deficit / Hyperactivity Disorder (ADHD). Prior research groups have found mixed findings with respect to left and right hemisphere alterations from ADHD subjects using structural magnetic resonance imaging. In these investigations, we propose the use of Asymmetry Index (AI), a subject-specific metric that quantifies the extent of brain asymmetry and allows each subject to serve as their own control, thus reducing variability when pooling across different sites. We compare AI metric with laterality across volumetric, surface area, thickness, morphology, and white matter measures in order to characterize the ADHD brain over the course of neurodevelopment, psychotropic therapy, and behavioral presentations. Linear mixed effects models were characterized to account for individual differences and maturation. We reproduce the findings across several regional and international data consortiums that contain both cross-sectional and longitudinal ADHD neuroimaging data. Structural asymmetry group differences were more significant than lateralized comparisons across a number of volumetric and white matter measures, confirming asymmetry is robust at detecting differences between healthy controls and ADHD brains. However, the effects of medication and behavioral phenotypes failed to reproduce significant alterations across symmetry measures. We discuss these implications in light of recent evidence of possible neuroprotective features of ADHD. Future work may investigate the extent to which these brain asymmetry differences are causal or compensatory. Although structural AI is unlikely to provide a useful biomarker for ADHD, a deeper understanding of these asymmetry patterns could lead to better profiling of the clinical diagnostics and to personalized treatments.

Medical simulations provide hands-on training at various levels of medical expertise. Yet these simulators fail to accurately mimic the look, feel and behavior of human tissue. Applying measured mechanical properties from human cadaver tissues promises to improve the fidelity of simulated tissue behaviors when subjected to medical procedures. Samples of human parietal pleura were tested under uniaxial tension to failure and measured characteristics were replicated in synthetic pleura. Context specific parameters were then collected and compared between human pleura and the new synthetics. These comparisons tested the hypothesis; H1 Gaps exist between synthetic and human pleura performance, H2: Human tissue fracture mechanics define desired performance of synthetic tissues, H3: Synthetic and human tissues with similar stress/strain parameters will behave similarly when blunt punctured. The results promote the future development of high fidelity tissue simulants for medical training. The studied tissue is parietal pleura which contributes the critical haptic "pop" indicating access to the proper anatomic space during the tube thoracostomy procedure. Once accessed through blunt puncture, tube is then inserted to drain air and fluid from around the lungs. Stress/strain based hyper-elastic and fracture properties calibrated from fresh human cadaver pleura were used to define performance requirements. Synthetic pleura were then prototyped and their mechanical properties were characterized. Commercial pleura simulants were puncture tested and compared to compliant custom and off-the-shelf formulations. A non-compliant but commonly used pleura substitute was also tested. Blunt puncture force and displacement were compared for each of the materials to test the stated hypotheses.

<p>Parkinson’s disease (PD) is characterized by progressive cell death of the dopaminergic neurons of nigrostriatal pathway. Several causes have been implicated for PD via neurochemical research including mitochondrial dysfunction, oxidative stress, and protein misfolding, to list a few. The novel Catecholamine Regulated Protein 40 (CRP40) has certain dopaminergic and neuroprotective features that implicate its importance for PD research. Recent studies using post-mortem brain tissue of patients with PD found MOT-2/CRP40 depletion in the frontal cortex and substantia nigra. MOT-2/CRP40 reduction is also observed in striatal brain tissue samples from a hemi-lesioned preclinical animal model of PD. Most recently, work done at the University of Laval in collaboration McMaster University suggests that levels of CRP40 mRNA are in deficit in blood platelet samples from a primate model of PD.</p> <p>The studies presented in this thesis suggest that the CRP40 protein has a dual function with regards to PD. The full-length CRP40 binds dopamine and, upon injection at the striatum of 6-hydroxydopamine hemi-lesioned rats, alleviates behavioural symptoms for up to 7 days. On the other hand, a 7kDA fragment of CRP40 does not bind dopamine, but does confer the same alleviatory effect upon intra-striatal injection in 6-hydroxydopamine hemi-lesioned rats. Not only has a protein now been identified with novel potential as a therapeutic agent for PD, but also the approximate region of the CRP40 protein responsible for behavioural effects.</p> <p>The later studies of this thesis show that CRP40 is found dysregulated in platelets of PD patients and lymphocytes of SCZ patients. This evidence has revealed CRP40 as a novel PD biomarker, for which on going studies are now in place to explore the potential of CRP40 as a diagnostic for PD.</p> / Doctor of Philosophy (PhD)

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is a clinical diagnosis characterized by sudden onset of obsessive compulsive disorder and is considered a type of Autoimmune Encephalitis. Pediatric Autoimmune Neuropsychiatric Disorder associated with Streptococcal Infection (PANDAS) is a subset of PANS characterized by a similar presentation but specifically results from infection by Group A β-hemolytic streptococcus. Early and accurate diagnosis is essential, as PANS can become a chronic condition. PANS and PANDAS are frequently misdiagnosed. There are a variety of differential diagnoses. The intent of this thesis is to evaluate differences in symptoms between PANDAS patients and those with a differential diagnosis and to synthesize existing knowledge to evaluate research areas that need improvement and reduce the rate of misdiagnosis. A review of clinical studies on the PubMed database was done using the key terms: "pediatric autoimmune encephalitis," "pediatric acute-onset neuropsychiatric syndrome," "pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection," and "clinical study." A literature review was done to examine research articles and case reports to compare symptom presentation between PANDAS Patients and Differential Diagnosis Patients. The results of this thesis show that clinical studies only make up 2.73% of the articles and references on PubMed, revealing a need for increased clinical research. 16 symptoms were compared between PANDAS patients and Differential Diagnosis Patients. A One-Way ANOVA test was done, and 12 symptoms were found to be significantly higher in the PANDAS Patients compared to the Differential Diagnosis Patients. Symptom overlap between PANDAS Patients and Differential Diagnosis Patients and the results of the One-Way ANOVA test were compiled into a PANS Diagnostic Form for clinician use.

The human body is a well tuned mechanism where systems work in synergy to provide a healthy quality of life. The human circulatory system transports oxygenated blood from the heart to the rest of the body delivering the proper nutrients for cells to function. When the heart malfunctions, serious complications can arise leading to sudden cardiac arrest. Congestive heart failure (CHF) is one heart disease that affects the synchrony of the heart’s ventricles. Cardiac resynchronization therapy (CRT) has been widely accepted as a treatment for CHF. Similar to traditional dual chamber pacing techniques, CRT adds a pacing lead to stimulate the left ventricle. Left ventricular leads are implanted via the coronary sinus which provides the easiest surgical access to the left ventricle. Another option for LV pacing is by using an epicardial lead. This option has proven to be safe and effective but requires major surgery. An epicardial lead is usually implanted by performing a thoracotomy. Many studies have been done to show the benefits of bi-ventricular pacing, therefore developing new methods to gain LV access safely and reliable are highly desirable. The epicardial satellite pacemaker, or EPI pacemaker, is a component of a larger CRT system. This implantable cardiac system is composed of a master pacing unit with leads and a remote satellite pacing unit. The master unit is a traditional CRT device electrically coupled to the right side of the heart. It controls the right atrium and ventricle via transvenous leads anchored to the endocardium of the heart. The master device generates the pacing pulses to stimulate the right atrium and right ventricle and a communications module to transmit pacing commands to the epicardial satellite device. The epicardial satellite pacemaker is a leadless device mounted directly on the epicardium of the left ventricle. The epicardial pacemaker can be implanted using a thoracoscopic procedure during implant of the master unit. In special events, it can be implanted using prophylactic techniques during heart bypass surgery of other surgical procedures where access to the heart is available. Much work needs to be done to prove the technology. But current RF communication capabilities in today’s devices offer the groundbreaking path to develop a satellite LV pacing design.

The focus of this thesis was to capture and measure carbon dioxide concentrations upon exhalation to determine if an apnea event is occurring. Research in the fields of respiratory physiology and apnea built the foundation for the design of the standoff infant apnea monitor. The monitor is designed to track infant respiration using carbon dioxide and sound signatures of breath without touching the infant. Each detection system, audio and carbon dioxide, were designed separately and brought together for a final proof-of-concept device. The software was developed using LabView and run on a Netbook. Testing was conducted on healthy adults to fine tune the carbon dioxide sensor and measure its response during simulated apnea events. Overnight testing showed that the combined system detected fewer false alarms than either system alone. Infant testing was conducted to determine if the proof-of-concept standoff monitor could detect infant breath at specified distance. The results showed that both detection systems can detect infant breath consistently at distances less than one foot from the infant and poorly at distances exceeding one foot. Finally, conclusions were drawn and interpreted to aid in the design of future generations of the standoff infant apnea monitor. Other research avenues where this technology may be useful were also discussed.

Context: Computerized clinical decision support systems (CCDSSs) give practitioners patient-specific care advice and are considered an important increment to electronic clinical documentation and order entry systems. Despite decades of research on CCDSS, results from rigorous clinical evaluations remain mixed and systems vary greatly in design and implementation. Objective: To identify factors differentiating CCDSSs that improve the process of care or patient outcomes from those that do not. Data Sources: We searched major bibliographic databases and scanned reference lists for eligible articles up to January 2010. Study selection: 162 eligible comparisons from randomized controlled trials of CCDSS to non-CCDSS care. We deemed successful those systems that improved either 50% of reported process of care outcomes or 50% of patient outcomes. We extracted system characteristics hypothesized to impact patient care and tested them for association with system effectiveness in logistic models. Results: Our primary analysis showed that CCDSSs presented in electronic health records or order entry systems were less likely to be effective than their counterparts (OR, 0.37; 95% CI, 0.17 to 0.80). Systems more likely to succeed than their counterparts provided advice for patients in addition to practitioners (OR, 2.77; 95% CI, 1.07 to 7.17), required from practitioners a reason to override advice (OR, 11.23; 95% CI, 1.98 to 63.72), or were evaluated by their developers (OR, 4.35; 95% CI, 1.66 to 11.44). These findings remained consistent across different statistical methods, sensitivity analyses, and adjustment for other potentially important factors. Conclusions: We identified several factors that may partially explain why some systems succeed and others fail. Primary studies should investigate the impact and optimal implementation of advice provided to patients and practitioners and advice that requires reasons to be overridden. Researchers should also address the reasons for failure of advice presented within charting and order entry systems. / Master of Science (MSc)

<p><strong>Background </strong>External cephalic version (ECV) is an effective intervention to reduce breech presentation and the corresponding Caesarean section (CS) rate. The Early ECV (EECV) trials were international multicentre randomized controlled trials that compared the timing of ECV (early or delayed) on obstetric and neonatal outcomes. In consideration of current recommendations that multicentre trials should account for centre effects in their analysis, a secondary analysis of the EECV trials was undertaken.</p> <p><strong>Purpose</strong> To analyse the EECV Trial data using statistical methods that account for centre effect and compare the results to standard analysis.<strong></strong></p> <p><strong>Methods </strong>Fisher’s exact test was used to provide overall results unadjusted for centre effects. The outcomes of interest were CS, preterm birth, and non-cephalic presentation at birth.</p> <p>Seven statistical models that accounted for centre effects were applied to the data: i) Mantel-Haenzsel test, ii) fixed effects regression, iii) fixed effects regression with a treatment-by-centre interaction term (weighted and iv) un-weighted by centre size), v) random intercept model, vi) random intercept and random slope model, and vii) generalized estimating equations.</p> <p><strong>Results </strong>Accounting for centre effects showed strengthened statistical associations with point estimates moving away from the null value.</p> <p><strong>Conclusion </strong>Effect estimates and confidence intervals changed for the three selected outcomes after accounting for centre effects, but the overall conclusions of the trial did not change. For this application, the Mantel-Haenzsel test and the random effects regressions performed the best. This study provides empirical evidence to support recommendations that multicentre trials account for centre in both design and analysis.</p> / Master of Health Sciences (MSc)

<p>The process of ‘‘structure-switching’’ enables biomolecular switches to function as effective biosensing tools. Biomolecular switches can be activated or inactivated by binding to a specific target that triggers a precise conformational change in the biomolecules involved. Examples of aptamer-based biomolecular switches can be found in nature. Furthermore, efforts have been made in the last decade to engineer structure-switching sensors using DNA aptamers whereby, the aptamer is coupled to a signal transduction method to generate a readout signal upon target binding to the aptamer domain. Conversely, RNA aptamers have been relatively underexplored for sensor development, largely due to its susceptibility to nuclease degradation and chemical instability. Despite these shortcomings, many RNA aptamers possess superior sensing capabilities, and the abundance of RNA aptamers provides new opportunities to further advance the field. In effect, this thesis uses a structure-switching design to demonstrate the power of RNA aptamers for fluorescence-based sensor development. Herein, we demonstrate generalizable structure-switching strategies to make use of the abundance of RNA aptamers, monitor the quality control of detection and correct detection error, as well as enhance RNA aptamer sensing capability by using regulated graphene adsorption. Furthermore, our findings have expanded for secondary applications involving collaborations with other research labs. In one application, we demonstrate that entrapment of structure-switching RNA aptamers in sol-gel material confers protection against nuclease degradation and chemical instability. In another application, we further validate the use of riboswitches, or natural structure-switching RNA aptamers, as potential targets for drug discovery. Overall, these results demonstrate the capability of RNA aptamers for sensor development. We conclude with a discussion of possible areas for further inquiry, as well as future applications for the advancement of structure-switching RNA aptamers.</p> / Doctor of Philosophy (PhD)

<p>Allergic asthma is a disease involving airway inflammation, commonly linked to allergen exposure. Computed tomography (CT) is used to quantitatively assess changes in density, hence inflammation, in the lung. CT imaging provides the ability to non-invasively and longitudinally study disease progression and evaluate treatment efficacy. The objective of this study was to determine the sensitivity of CT to detect the anti-inflammatory effects of budesonide (BUD) by measuring airway tissue density in a rat model of allergic airway disease.</p> <p>Female<strong> </strong>Brown Norway rats were exposed intratracheally to house dust mite (HDM) extract (250 µg in 100µL saline) or saline control every other day for a total of five administrations (inflammatory phase). ABUD dose and temporal response study was performed usingBUD 0, 10, 100, and 300 µg/kg administered concurrently with HDM for three and six treatments (treatment phase). CT scanning was performed at baseline, post inflammatory phase, and after three and six BUD treatments. From the CT, density was measured in a defined volume of interest surrounding the major airways. Bronchoalveolar lavage (BAL) and histological samples were collected at the same time points.</p> <p>After the inflammatory phase, a significant increase in peribronchial density was found in the HDM group compared to controls. This corresponded to a significant increase in inflammation by histology andBALtotal cell count (TCC), specifically eosinophils. Within the treatment phase after three treatments,BUD100 and 300 µg/kg led to a significant shift in lung density compared to HDM exposure alone, to a state similar to baseline. All BUD treated groups expressed a significant reduction in peribronchial density after six treatments. However, histology andBALTCC only showed a significant decrease in inflammation after six treatments for all three BUD doses.</p> <p>CT densitometry is a sensitive, non-invasive method of evaluating the anti-inflammatory effects of budesonide and can be used for future screening of therapies in allergic lung models. Airway segmentation of CT permits the localized assessment of peribronchial inflammation, while other outcome measurements, such as BAL cytology, provide whole lung assessment which may not accurately reflect important regional changes.</p> / Master of Science (MSc)