Translational Medical Research Commons^™

Sex And Gender Differences In Arthritis Health Information, Tania Al-Jilawi

Electronic Thesis and Dissertation Repository

Arthritis is a common disorder that may result in pain and inflammation, making it challenging to move or continue being active. Arthritis comes in a variety of forms. The two studies of this thesis aimed to identify the influence of intersectionality, especially sex and gender, in arthritis. The first study, a structured review, evaluated the inclusion of sex/gender and intersectional identities in patient resources of three arthritis societies: the Canadian Arthritis Society, the American Arthritis Foundation, and the National Rheumatoid Arthritis Society. The appraisal tool, the Sex/Gender and Intersectional Considerations in Patient/Consumer Health Information Appraisal Tool was used to evaluate …

Shedding Light On Hearing In Coma: Investigating The Applicability Of Functional Near-Infrared Spectroscopy For Assessing Auditory Function And Aiding Prognosis In Patients With Acute Disorders Of Consciousness, Reza Moulavi Ardakani

Electronic Thesis and Dissertation Repository

There is a critical need for a bedside neuroimaging tool to aid in the prediction of functional recovery outcomes for patients with acute disorders of consciousness (DoC) in the early days following severe brain injury. Current neurobehavioral examinations and prognosis tools have limitations in predicting good outcomes, leading to potential mistreatment or premature withdrawal of life support. Functional near-infrared spectroscopy (fNIRS) is a viable candidate for such purposes due to its portability and cost-effectiveness. Auditory processing, viewed as a multi-level and multifaceted brain function, could provide a sensitive and specific marker of residual cognitive function in unresponsive patients. This study …

The Effect Of Kidney Preservation At 10°C With Hemopure And Hydrogen Sulfide Donor, Sodium Thiosulfate, In A Syngeneic Model Of Rat Renal Transplantation, Maria Abou Taka

Electronic Thesis and Dissertation Repository

Kidney transplantation is preferred for patients with end-stage renal disease. The current gold standard for preserving kidneys is static cold storage (SCS) at 4°C in University of Wisconsin (UW) solution. However, SCS contributes to ischemia-reperfusion injury (IRI), which involves cell death and inflammation. Our group showed that SCS of kidneys with hydrogen sulfide donors, like sodium thiosulfate (STS), that reduce tissue injury enhanced kidney survival. Though, there is still a risk of cold renal IRI at 4°C. Recent evidence suggests that preserving organs at 10°C enhanced graft function and survival. Therefore, this thesis will evaluate the effect of 10°C kidney …

Impact Of Clinical And Pharmacogenetic Variables On The Risk Of Fluoropyrimidine-Related Adverse Events Within Ontario, Theodore J. Wigle

Electronic Thesis and Dissertation Repository

Severe life-threatening adverse events are a major limitation of fluoropyrimidine chemotherapy, these events are disastrous for patients and costly to the healthcare system. Identifying patients at high risk for developing adverse events would allow for preventive dose reduction, improving patient outcomes and reducing healthcare cost. This thesis uses data pulled from provincial databases to quantify the adverse event burden of fluoropyrimidines in Ontario. We found that 31% of Ontario patients treated with fluoropyrimidine systemic chemotherapy developed a severe adverse event that requires acute medical care. Patients that required acute medical therapy were significantly costlier to the public system averaging an …

Genetic Approaches For The Study Of Complex Human Diseases, Julieta Lazarte

Electronic Thesis and Dissertation Repository

The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

Functional Role Of Dream And Dyrk1a In High-Grade Serous Ovarian Cancer Cell Dormancy, Pirunthan Perampalam

Electronic Thesis and Dissertation Repository

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM …

Cancer Detection In Radical Prostatectomy Histology Using Convolutional Neural Networks, Laurie Huang

Electronic Thesis and Dissertation Repository

Radical prostatectomy (RP) is a common treatment for prostate cancer. We used RP whole-mount tissue samples from 68 patients stained with haematoxylin and eosin to create cancer maps using four pretrained networks: AlexNet, NASNet, VGG16 and Xception, to classify regions of interest (ROIs) as cancer or non-cancer. Models were trained on either raw images or as tissue component maps (TCMs) containing nuclei, lumina and stroma/other components generated from a trained U-Net.

All models performed similarly; however, VGG16 trained on raw images performed with the highest area under the receiver operating characteristic curve (AUC) of 0.994 (95% confidence interval 0.992-0.996). Ensemble …

Applying Knowledge Translation In Rehabilitation: An Exploration Of What It Means To Change Clinical Practice, Stacey D. Guy

Electronic Thesis and Dissertation Repository

Health care providers are often required to implement evidence-based recommendations into the care they deliver. Resources that support health care providers’ efforts are a useful knowledge translation strategy. This thesis describes the development and usability evaluation of an evidence-informed clinical practice implementation toolkit to support implementation efforts. Two studies were undertaken to provide insight into what was needed to support health care providers, and to inform the development of the toolkit. A retrospective evaluation analyzed the performance of a team implementing a pressure ulcer risk assessment for patients with spinal cord injury. The rates of adherence to the risk assessment …

The Symbiome Project: An Exploratory Investigation Of The Biological, Psychological, And Social Mechanisms That Contribute To The Transition From Acute To Chronic Musculoskeletal Pain, Joshua Y. Lee

Electronic Thesis and Dissertation Repository

This dissertation presents the initial findings of the SYMBIOME project; which attempts to combine the objective and subjective aspects of musculoskeletal pain to develop a prognostic clinical phenotype. Chapter 2 presents a moderator analysis of functional outcomes (pain interference and pain severity). Psychosocial moderators can affect the relationship between biomarkers and pain. For pain severity, TNF-α, TGF-β1, and CRP were moderated by employment status, pre-existing psychopathology, and sex. For pain interference, IL-1β, cortisol, TGF-β1, CRP, and IL-6 were moderated by pre-existing pain, peri-traumatic fear, region of injury, and peri-traumatic stress. Chapter 3 presents a latent growth curve analysis in determining …

Understanding The Nursing Practices And Perspectives Of Premedication And Transfusion Reaction Reporting: A Qualitative Description Study, Wenxin Miao

Electronic Thesis and Dissertation Repository

This qualitative description study is a sub-study of a knowledge translation (KT) project to implement evidence-based blood transfusion practices at an urban tertiary hospital. The goals of the KT project are to reduce the use of pre-transfusion medications (premedication) and to improve transfusion reaction (TR) reporting practices at this institution. This study explored the nursing practices and perspectives of premedication and TR reporting by conducting interviews with 25 nurses. The findings showed a lack of standardized premedication and TR reporting practices at this institution. A practice change is needed to achieve the goals of the KT project. The study also …

Investigating The Mechanisms Of Breast Cancer Metastasis Using Multimodality Molecular Imaging, Katie Parkins

Electronic Thesis and Dissertation Repository

Introduction: Breast cancer recurrence continues to be a significant challenge in the clinic. Despite successful removal and/or treatment of the original tumour, many patients experience relapse in the breast or at distant sites. Furthermore, the diagnosis of metastatic disease often occurs too late for effective treatment. Methods: In this thesis, we combine iron-based cellular MRI and longitudinal BLI to noninvasively track the fate of cancer cells into overt tumours in the mouse brain. We then apply this imaging model to study the effect of a primary breast tumour on the growth of secondary metastases in an immune competent …

Anaplastic Thyroid Cancer: Identification Of Candidate Therapeutics And Mechanisms Of Disease Progression, Nicole Pinto

Electronic Thesis and Dissertation Repository

Malignancies derived from follicular cells of the thyroid can be divided into well-differentiated thyroid cancer (WDTC), poorly differentiated thyroid cancer and anaplastic (undifferentiated) thyroid cancer (ATC). While the majority of thyroid cancers are well-differentiated in nature and have an excellent prognosis, ATC is rare, nonresponsive to conventional therapies, and is nearly universally fatal. In this study, I employed high-throughput screening of kinase inhibitors to identify candidate drugs to control ATC and expanded these studies to include a focus on studying the underlying progression from WDTC to ATC. Two compounds, lestaurtinib (JAK2 inhibitor) and flavopiridol (pan-CDK inhibitor) were selected from the …

The Development And Evaluation Of Resources To Improve The Quality Of Care For Patients With Knee Osteoarthritis, Laura K. Churchill

Electronic Thesis and Dissertation Repository

Purpose: The non-operative management of patients with knee osteoarthritis (OA) is often considered suboptimal. Sub-optimal management includes inadequate use of non-surgical treatments, misuse of diagnostic imaging, and non-operative referrals to surgeons in consideration of total knee replacement (TKR). These inefficiencies result from an interplay of factors involving primary care physicians, patients, and the systems in which they function. The overall purpose of this thesis is to develop a means to optimize the management of patients with knee OA, and the timing and quality of referrals to TKR.

Methods: This thesis includes three studies. In study 1, we identified and cross-validated …

The Role Of Tbx3 In Early Breast Cancer Progression, Milica Krstic

Electronic Thesis and Dissertation Repository

TBX3 is a transcriptional regulator involved in embryonic development and in tumorigenesis of several cancer types. There are two isoforms of TBX3 (TBX3iso1 and TBX3iso2) with different DNA binding domains. The large-scale functional roles of TBX3iso1 and TBX3iso2 were characterized in a breast cancer context. Both TBX3 isoforms induced invasiveness and an epithelial-to-mesenchymal (EMT) phenotype. Coupling data from genome-wide ChIP-array and RNA-Seq studies provided a novel list of genes regulated by each isoform. Both TBX3 isoforms regulate expression of several EMT-related genes, including SLUG and TWIST1. Importantly, TBX3 is a direct regulator of SLUG, and SLUG expression is required for …

Drug Response And Metabolism In Crohn's Disease, Aze Wilson

Electronic Thesis and Dissertation Repository

Inflammatory bowel disease (IBD) is an illness of chronic intestinal inflammation comprised of Crohn's disease (CD) and ulcerative colitis (UC). Specialists rely heavily on drugs that target a dysregulated immune system. There is a staggering degree of variation in drug response in CD. Our understanding of drug metabolism and response in IBD is limited. Gaining new insights into IBD-specific modifications of drug metabolism may allow for improved drug efficacy and reduced toxicity. Cytochrome P450 (CYP) 3A4 is the most relevant determinant of drug metabolism and exposure for medications prescribed today. CYP3A4 is highly expressed in the liver, but is also …

From Evidence To Practice: A Systematic Approach To Implementing Electrical Stimulation Therapy For Treating Pressure Injuries In Community Dwelling Individuals With Spinal Cord Injury, Deena Lala

Electronic Thesis and Dissertation Repository

Pressure injuries are a common secondary health complication among individuals with a spinal cord injury (SCI) and can have a profound effect on quality of life. Unfortunately, pressure injury care in community dwelling individuals with SCI is often fragmented and inconsistent across Canada. Current best practice guidelines strongly recommend the use of electrical stimulation therapy (EST) to manage pressure injury in this population; however, there is little uptake of EST, and is not considered as a first-line treatment by many clinicians. Therefore, the objective of this dissertation is two-folds 1) to determine the impact of pressure injuries on individuals with …

Clinical And Pharmacogenetic Determinants Of Plasma Factor Xa Inhibitor Systemic Exposure, Markus Gulilat

Electronic Thesis and Dissertation Repository

Inhibition of blood coagulation via oral anticoagulant therapy is the mainstay for preventing a cardioembolic stroke in patients with atrial fibrillation (AF). Factor Xa inhibitors (FXaIs), rivaroxaban and apixaban, represent a new class of oral anticoagulants that are now widely prescribed in AF patients as an alternative to traditional warfarin therapy. An important advantage of these drugs is that routine monitoring of anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, FXaI antithrombotic effect can be inferred based on the observed drug plasma concentration, with prolonged periods of elevated FXaI systemic exposure associated with increased risk for …

Prostate Cancer Microparticles In Men Undergoing Radical Prostatectomy, Malcolm James Dewar

Electronic Thesis and Dissertation Repository

Objectives: To determine changes in prostate microparticle (PMP) concentrations in men with prostate cancer (PCa) after digital rectal examination (DRE), after radical prostatectomy (RP), and at follow-up.

Materials and Methods: 22 men were recruited before RP. Four blood specimens were collected – baseline (specimen 1), post-DRE (specimen 2), immediately post-RP (specimen 3), and follow-up (specimen 4). Pre- and post-DRE urine was collected (Specimen A and B respectively). Flow cytometric analysis of biofluids was performed with fluorescent-labeled antibodies against prostate-specific membrane antigen (PSMA) and polysialic acid. Total MP (TMP) and dual positive (PMP) events per µl of plasma or urine were …

Intraoperative Photoacoustic Imaging Of Breast Cancer, Ivan Kosik

Electronic Thesis and Dissertation Repository

Breast cancer is one of the most common cancers to affect women, presenting a lifetime risk of 1 in 8. Treatment of stage 1 and 2 cancers usually involves breast conserving surgery (BCS). The goal of BCS is to remove the entire tumour with a surrounding envelope of healthy tissue, referred to as a negative margin. Unfortunately, up to 50% of surgeries fail to remove the whole tumour. To minimize the risk of cancer recurrence, a second surgery, must therefore be performed. Currently, there is no widely accepted intraoperative tool to significantly mitigate this problem. Employed systems are usually based …

A Clinico-Pathological Study Of The Structural And Functional Changes In The Retina And Optic Nerve Following Diabetic Retinopathy Treatments, Richard Filek

Electronic Thesis and Dissertation Repository

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on …

The Drosophila Melanogaster Model Of Human Uric Acid Nephrolithiasis As A Novel In Vivo Drug Screening Platform, Aymon N. Ali

Electronic Thesis and Dissertation Repository

Nephrolithiasis involves the supersaturation of a stone-forming solute in urine leading to the formation of a calculus. The development of novel therapeutic agents for this multifactorial urological disorder has been hindered by lack of a practical pre-clinical model. Currently established medical treatments can possess unfavorable side effect profiles and inconsistent efficacies in certain metabolic milieus. Here, Drosophila melanogaster ̶ an emerging model for calcium oxalate nephrolithiasis ̶ was investigated as a potential disease model and high throughput drug discovery platform for human uric acid nephrolithiasis. Through disruption of the Uro gene and purine-rich dietary manipulation, we successfully demonstrate the formation …

Daily Hydrogen Sulfide Treatment Enables Early Recovery Of Renal Function And Mitigates Renal Injury Following The Relief Of Prolonged Urinary Obstruction, Shouzhe Lin

Electronic Thesis and Dissertation Repository

Prolonged urinary obstruction can lead to renal dysfunction and irreversible injury. The recovery of renal function following decompression is heavily dependent on the degree of renal injury. This suggests that treatments aimed at mitigating renal injury could improve the recovery of renal function following decompression. Previous studies have shown that hydrogen sulfide (H₂S), an endogenous gasotransmitter, can reduce the histopathological markers of renal injury following unilateral ureteral obstruction (UUO). However, the effects of H₂S on renal function following decompression is unknown. Using the UUO and reimplantation (UUO-R) model, we demonstrate that H₂S accelerates the …

Design Of Radio-Frequency Arrays For Ultra-High Field Mri, Ian R O Connell

Electronic Thesis and Dissertation Repository

Magnetic Resonance Imaging (MRI) is an indispensable, non-invasive diagnostic tool for the assessment of disease and function. As an investigational device, MRI has found routine use in both basic science research and medicine for both human and non-human subjects.

Due to the potential increase in spatial resolution, signal-to-noise ratio (SNR), and the ability to exploit novel tissue contrasts, the main magnetic field strength of human MRI scanners has steadily increased since inception. Beginning in the early 1980’s, 0.15 T human MRI scanners have steadily risen in main magnetic field strength with ultra-high field (UHF) 8 T MRI systems deemed to …

Protective Benefits Of Hydrogen Sulfide Treatment During Renal Transplantation, Ian Lobb

Electronic Thesis and Dissertation Repository

Ischemia/reperfusion injury (IRI) is inherent to renal transplantation (RTx) and is initiated when blood supply is necessarily removed during organ procurement (ischemia) and subsequently restored upon engraftment (reperfusion). During renal ischemia, ATP depletion causes tubular epithelial cell (TEC) injury and subsequent release of pro-inflammatory mediators. Upon reperfusion, influx of O₂ causes reactive oxygen species (ROS) production and infiltration of innate immune cells which release damaging ROS and proteases. Prolonged periods of IRI are associated with increased risk of delayed graft function (DGF) and decreased long-term graft survival. The endogenously produced gasotransmitter, hydrogen sulfide (H₂S), has recently been …

Detection Of Circulating Thyroid Tumor Dna In Patients With Thyroid Nodules, Krupal Bhupendrabhai Patel

Electronic Thesis and Dissertation Repository

This study was conducted to determine the feasibility of detecting BRAF(V600E) circulating tumor DNA (ctDNA) in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. Plasma samples from patients undergoing thyroid surgery for thyroid nodules were obtained prospectively pre-operatively and one month post-operatively, and quantitative-PCR was used determine the presence of BRAF(V600E) ctDNA. These were compared to formalin fixed paraffin embedded samples from the index nodule. Thirty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. 6/18 (33.3%) patients with classical PTC and 0/8 (0%) patients with nodular hyperplasia had …

Contribution Of Enhanced Intrinsic Apoptosis To Renal Ischemia Reperfusion Injury In The Absence Of Ripk3 And Caspase-8 Dependent Regulated Cell Death, Ron Sung

Electronic Thesis and Dissertation Repository

Ischemia-reperfusion injury (IRI) contributes to reduced long term organ transplant survival. IRI is a complex process related to multiple mechanisms including regulated forms of cell death such as apoptosis and necroptosis. We have previously shown that preventing necroptosis by genetic elimination of the key molecule (RIPK3) or apoptosis inhibition through caspase-8 silencing are of benefit in kidney IRI. As these pathways of regulated cell death are unique, we tested the hypothesis that deletion of both RIPK3 and caspase-8 activity in kidneys would synergistically improve renal IRI, compared to inhibition of individual pathways. Interestingly we found that IRI was not improved …

High Throughput Screening For Drug Discovery In Head And Neck Squamous Cell Carcinoma, Morgan D. Black

Electronic Thesis and Dissertation Repository

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and despite advancements in traditional therapies, the survival rate of ~40% remains unchanged, thus highlighting the need for novel treatments in HNSCC. High throughput robotic screening of a panel of HNSCC cell lines was carried out against 1,505 compounds, where drug activity was measured using metabolic agent alamarBlue and quantified by percent activity. Initial screening found that the majority of active compounds could be grouped based upon their cellular target(s) and/or function including: cell cycle regulation, cytoskeleton disruption, and DNA topoisomerase function. Potency was confirmed with …

A Clinically Relevant Relevant Post-Traumatic Osteoarthritis Mouse Model, Chantel P. Arce

Electronic Thesis and Dissertation Repository

Osteoarthritis affects 13-20% of Canadians with the majority being under 65years of age. Post-traumatic osteoarthritis (PTOA) is of great concern in young athletes following knee injury. Current research attempts at modeling the disease fall short. This study aimed to incorporate two important aspects of injury, the nature of the injury and the post-injury standard of care in humans, to a model of PTOA in mice. The study validated a non-invasive protocol to elicit an anterior cruciate ligament (ACL) injury at varying loading speeds addressing the closed capsule nature of an ACL injury that occurs in humans. Secondly, we proposed a …

Quantifying The Effects Of Systematic Stn-Dbs Programming On Rest And Postural Tremor In Idiopathic Parkinson Disease Patients, Kristina Ognjanovic

Electronic Thesis and Dissertation Repository

Parkinson’s disease (PD) is a complex neurodegenerative disorder that encompasses both motor and non-motor symptoms. These symptoms and their severity are typically assessed by scale based measures in a clinical setting. Scale- based assessments of PD patients undergoing bilateral subthalamic nucleus deep brain stimulation surgery (STN-DBS) such as the Unified Parkinson Disease Rating Scale (UPDRS) are commonly used in a clinical setting to assess symptom severity and progression. However, the subjective nature of these and other clinical scales call into question both the sensitivity and accuracy of patient assessment over time. An objective quantification of rest and postural tremor of …