Open Theses and Dissertations
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- ItemOpen AccessThree-Dimensional Transvaginal Ultrasound for Intracavitary and Interstitial Gynecologic High-Dose-Rate Brachytherapy(2023-05-23) Van Elburg, Devin John; Meyer, Tyler; Roumeliotis, Michael; Plume, Rene; Phan, Tien; Thind, Kundan; Hoover, Doug; Stosky, JordanUltrasound is prominent in prostate brachytherapy treatment workflows. While ultrasound is commonly used for applicator insertion guidance, limitations in conventional 2D ultrasound imaging restrict adoption into gynecologic brachytherapy workflows which favour MRI/CT planning. However, recent advances in 3D ultrasound imaging overcome many limitations and have more utility in gynecologic brachytherapy. In this work, we investigate clinical utility of a 3D transvaginal ultrasound (3DTVUS) in both intracavitary and interstitial gynecologic high-dose-rate brachytherapy (HDRBT) workflows. The primary limitation of ultrasound imaging is shadowing beyond inserted applicators. To overcome this, ultrasound-compatible vaginal cylinders made of sonolucent material TPX have been previously developed for 3DTVUS guidance of interstitial HDRBT implants; the cylinder was subsequently removed for the clinical vaginal cylinder for treatment. More streamlined ultrasound-based workflows are possible if treatment cylinders were ultrasound-compatible. We investigated dosimetry of TPX versus conventional materials and conclude the uncertainties introduced by TPX cylinders are clinically acceptable in gynecologic HDRBT. We developed a surrogate vaginal cylinder (SVC) which is sonolucent and geometrically matched to the multi-channel vaginal cylinder (MCVC) for intracavitary HDRBT. In theory, SVC-3DTVUS images are anatomically representative MCVC-inserted images. Therefore, the MCVC may be digitized in SVC-3DTVUS images, effectively replacing CT in the standard clinical workflow. We commissioned the SVC for MCVC intracavitary HDRBT and showed that geometric and dosimetric uncertainties are within accepted tolerances. We then implement 3DTVUS-guidance into the clinical workflow, guiding 20 combined needles across seven template interstitial HDRBT implants. The primary benefit of 3DTVUS imaging is 3D visualization of the target allowing for intraoperative assessment of implants. We qualitatively and quantitatively show that 3DTVUS impacts needles most important for target coverage and share clinician perspectives on 3DTVUS utility. Part of evaluating 3DTVUS-guided interstitial implants is assessment of vaginal dose. Despite extensive multi-institutional studies, there lacks vaginal dose metrics that reasonably correlate to toxicities due to small volume evaluation in very high dose gradient regions. We investigated small volume vaginal dose metrics and show vaginal dose metrics are reliable across different dose calculation methods when metric volumes are ≥2 cm3 and when the target volume is removed from the vaginal contour.
- ItemOpen AccessDeveloping a Non-aureus Staphylococcus Intramammary Probiotic as a Preventative Measure for Bovine Mastitis(2023-05-11) Vu, Dennis; De Buck, Jeroen; Storey, Douglas; Barkema, HermanBovine mastitis is the most common and economically important disease affecting the dairy industry. Intramammary infection (IMI) with Staphylococcus aureus is the leading cause of contagious mastitis. Interestingly, non-aureus staphylococci (NAS) are frequently found in cows with subclinical mastitis, but with a severity less than with S. aureus. Antibiotics are the main method for preventing and treating mastitis. Misuse and overuse of antibiotics have resulted in the emergence of antimicrobial-resistant bacteria, and thus, alternative treatments are required. Bacteriocins, antimicrobial peptides produced by bacteria, are a promising alternative. We hypothesized that by creating a NAS probiotic through genetically engineering a bacteriocin gene cluster into its genome, it will be able to inhibit S. aureus and prevent mastitis. To achieve this, we needed to find a persistent and non-inflammatory NAS strain that can colonize cow mammary glands by using an experimental mammary infusion model. After finding a persistent and non-inflammatory NAS, we will perform a bacteriocin gene cluster knock-in using allelic replacement. Finally, the probiotic will then be characterized through gene expression and killing assays. This thesis aimed to create an alternative treatment to prevent the growth of mastitis pathogens during the dry period. Ultimately, this will lower the usage of antibiotics and give us another preventative tool against mastitis. We identified S. warneri 2993 as the most persistent and non-inflammatory NAS but unfortunately, we were not able to perform our bacteriocin gene knock-in. Instead, we recommend future studies to re-attempt this gene knock-in but with a different bacteriocin gene cluster for an increased likelihood of success. The probiotic will then need testing in ¬in vivo¬ IMI experiments in mice and then in cows following the protocols we have designed.
- ItemOpen AccessElectrokinetic Control of Interfacial Instabilities(2023-05-17) Nwani, Benedicta Nkenchor; Benneker, Anne Maria; Gates, Ian Donald; Hassanzadeh, Hassan; Hejazi, Hossein; Bryant, Steven; Docoslis, AristidesInterfacial instabilities have significant impact on the efficiency of various processes that are present in our surroundings. These instabilities occur due to fluid-fluid interfacial perturbations which could be driven electrically, magnetically, via pressure, surface tension, etc. One of the most frequent occurrences of interfacial instabilities is the displacement of a more viscous fluid by a less viscous one which results in an instability known as ‘viscous fingering’. Controlling viscous fingering is challenging since it occurs at the onset of the displacement and affects the overall displacement pattern observed. Nevertheless, researchers have proposed passive and active control methods to address this issue. The objective of this thesis is to extensively explore the use of electric fields for actively controlling viscous fingering in both miscible and immiscible fluid systems. A combination of experimental and numerical techniques are employed to investigate this phenomenon. The first fluid system examined is immiscible, in which the resident fluid is a perfect dielectric fluid with a preferential wetting on the substrate and no notable fluid-fluid and fluid-wall interfacial charges. The second fluid system involves both miscible and conducting fluids with electro-neutral fluid-fluid interface. The immiscible third fluid system has significant interfacial charges between fluids due to added ionic surfactants in the invading brine, leading to preferential substrate wetting. The results of the first study conducted experimentally, indicated that viscous fingering can be effectively controlled even when one of the fluids is completely non-conductive. Regardless of the magnitude of the applied electric field, positive values stabilized the displacement, while negative values destabilized it. For the miscible fluid system, numerical simulations revealed that the effect of positive or negative electric fields on the displacement (de)-stabilization depended on whether the resident fluid experienced a higher or lower electroosmotic flow under the influence of an electric field. The third study’s experimental results revealed that the presence of the combination of electric field and ionic surfactants dramatically altered the system’s behavior, due to the presence of fluid-fluid interfacial charges that induced electro-Marangoni stresses at the interface when acted upon by an external electric field, which ultimately destabilized the displacement in most cases.
- ItemOpen AccessSynthesis and Characterization of Novel Piezoelectric Solid Solutions(2023-05-18) Rowe, Thomas Michael; Dolgos, Michelle; Thangadurai, Venkataraman; Trudel, Simon; Ménard, Gabriel; Brennecka, GeoffThis thesis presents three studies in the synthesis and characterization of three ferroelectric solid solutions that were hypothesized to be viable replacements for the lead-based industry standard material Pb(Zr,Ti)O3 (PZT), due to both environmental concerns and physical property limitations. The first chapter is an introduction to ferro and piezoelectricity along with the perovskite structure. It also describes how element selection and structural deviation can be utilized to design novel materials with targeted properties. The first research chapter involves the (1-x) Na0.5Bi0.5TiO3 – (x)BaTiO3 (NBT-BT) system doping in group 13 elements onto the B-site in order to improve the ferroelectric properties. The third chapter explores the idea of using a polarization extension to form a Morphotropic Phase Boundary (MPB) between paraelectric and ferroelectric phases through compositional changes. The solid solution (1-x) NaNbO3 – (x)BaZrO3 (NN-BZ) was synthesized, and the electromechanical properties were measured in order to see if there was in increase in the piezoelectric response. Chapter four describes the synthesis of a ferroelectric solid solution that improves on PZT’s Curie temperature. Due to this research, a new solid solution (1-x)Bi(Fe2/8Ti3/8Mg3/8)O3 – (x)PbTiO3 (BFTM-PT) was synthesized, and the electromechanical properties were measured.
- ItemOpen AccessDeficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses(2023-05-11) Wachoski-Dark, Emily Mary Ann; Greenway, Steven; Shutt, Timothy; Braun, JaniceThe dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare autosomal recessive mitochondrial disease that results from mutations in the poorly characterized DNAJC19 gene and is frequently associated with premature death in children. DNAJC19 is a component of the TIM23 complex which imports proteins into mitochondria but has also been implicated in cardiolipin maturation. Better understanding of the role of DNAJC19 will provide insight into the mechanism of disease. Since previous work did not identify abnormalities in cardiolipin content within patient cells, I hypothesized that deficiency of DNAJC19 would negatively impact mitochondrial protein homeostasis. To address my hypothesis, I quantified the impact of DNAJC19 deficiency on the proteome of DCMA patient dermal fibroblasts. I identified an increase in mitochondrial fission, confirming previous observations. Pathway analysis predicted an upregulation of eukaryotic translation initiation factor 2 (EIF2) signaling in patient cells, indicating increased cellular stress. I identified significant increases in gene expression for key genes involved in the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). Activation of these stress responses was not accompanied by increases in apoptosis, potentially indicating that patient cells can mitigate the cellular stress they face. I then tested two potential therapeutics: SS-31, which reduces oxidative stress, and tauroursodeoxycholic acid (TUDCA), which refolds proteins in the cytosol. Both compounds prevented upregulation of the ISR and the UPRmt. In conclusion, I have identified a novel upregulation of two key cellular stress response pathways in DCMA patient fibroblasts. This work also identified TUDCA as a potentially novel treatment for DCMA and supports the classification of DCMA as a disease of mitochondrial proteostasis.