VictorJuiz/thesis huggingface dataset:
On the Development of High-frequency Phased Array Systems for Transcranial Ultrasound Delivery in Small Animals

Transcranial focused ultrasound (FUS) combined with contrast agent microbubbles can transiently and selectively increase the permeability of the blood–brain barrier (BBB) to enable targeted agent delivery to the central nervous system. Despite the recent progress made toward clinical translation of FUS-mediated BBB permeabilization, small animal preclinical studies (e.g., mouse and rat models) remain critical for the continued development of disease-specific treatment strategies. Existing systems for applying transcranial focused ultrasound in small animals produce large focal volumes relative to the size of cerebral structures available for interrogation. The use of high ultrasonic frequencies can improve targeting specificity; however, the aberrations induced by rodent calvaria at megahertz frequencies severely distort the acoustic fields produced by single-element focused transducers. In this thesis, we present the design, fabrication, and characterization of high-frequency phased array systems for transcranial FUS delivery in small animals. Initially, we designed and constructed a 3.3 MHz transducer array of 64 independent elements with equal surface area. The acoustic field generated by the phased array was measured at various target locations using a fiber-optic hydrophone, both in free-field conditions as well as through ex vivo rat skull caps with and without hydrophone-assisted phase aberration corrections. Insertion of a rat skullcap resulted in substantial distortion of the acoustic field; however, phase corrections restored partial focal quality. However, hydrophone-based transcranial aberration corrections are impractical for in vivo experimentation. Next, we investigated the feasibility of using an acoustic measurement library for non-invasive trans-rodent skull ultrasonic focusing at high frequency. Phase corrections calculated from the acoustic measurement library restored partial transcranial focal quality relative to that recovered using the hydrophone-based technique. Our results suggest that a measurement library of skull-induced phase differences can facilitate non-invasive transcranial focusing in rodents at high frequencies. Finally, the design and construction of a 10 MHz phased array transducer for FUS-induced BBB opening in a mouse model is investigated. The high-frequency phased array transducers developed over the course of this thesis are expected to play a role in future in-vivo BBB opening studies in small animals.

Advisor: Hynynen, Kullervo
An Adjoint Approach to Aerodynamic Shape Optimization for Unsteady Flows with Application to Laminar and Transonic Turbulent Flows

An adjoint approach to aerodynamic shape optimization has been developed, implemented, applied, and investigated for several deterministic unsteady flow problems. The optimization framework integrates a robust geometry parameterization and geometry control strategy, a mesh-movement technique based on linear elasticity theory, and a high-fidelity parallel Newton-Krylov flow algorithm to evaluate the forward problem needed to compute the optimization objective function. A gradient-based algorithm is used to solve the optimization problems, and the objective gradients are computed using the discrete adjoint methodology. The aerodynamic shape optimization framework is applied to a range of unsteady flow problems. For the two-dimensional optimization problems, three objectives based on the mean aerodynamic quantities were considered: a lift-constrained drag minimization, lift-to-drag ratio maximization, and lift maximization. For the drag minimization and lift-to-drag ratio maximization problems, the optimizer improved the performance of the baseline airfoil primarily by keeping the flow on the upper surface attached as long as possible and introduced an aft-camber to maintain or increase the lift coefficient. This novel aft-camber feature is consistent with results seen in the literature for ultra-low Reynolds number flows. A first attempt at studying the multi-modality of optimization problems driven by unsteady flows indicated that the lift-maximization problem is likely to be multimodal, while the other design objectives are likely to be unimodal. For the three-dimensional laminar flow studies, a mean drag minimization at a fixed mean coefficient of lift was considered. The optimizer exploited the section shape, chord length, and twist geometric freedoms given to improve the design objective, and introduced a significant aft-camber throughout the sections similar to the two-dimensional studies. Finally, a first attempt at optimizing aerodynamic shapes in the presence of transonic buffet was undertaken using the unsteady Reynolds-averaged Navier-Stokes equations. The mean coefficient of drag was minimized at a fixed mean lift coefficient using the NASA Common Research Model wing-only geometry. These preliminary optimization results showed that the optimization framework is capable of solving such a design problem, thus enabling such an optimization framework to include buffet conditions considered in a multi-point optimization of wings and aircraft under transonic flow conditions.

Keywords: Adjoint
Aerodynamics
Flows
Laminar
Optimization
Unsteady
Advisor: Zingg, David W
Rhodium-catalyzed Asymmetric Addition/Aldol Cascades and Studies towards the Synthesis of Aconitine

Asymmetric synthesis is a powerful tool often used in the synthesis of natural products and pharmaceutical compounds. The rhodium-catalyzed asymmetric conjugate addition is one of the most robust reactions widely employed for this purpose. We sought to harness the reactivity of the rhodium enolate intermediate generated through this process for the synthesis of stereochemically complex (hetero)cyclic scaffolds. Chapter 1 of this thesis details a rhodium-catalyzed asymmetric conjugate alkynylation/aldol cascade to generate densely functionalized chiral cyclic α-propargyl-β-hydroxyketones bearing three new contiguous stereocenters. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations. Chapter 2 expands upon our previous findings and describes a rhodium-catalyzed asymmetric conjugate addition/aldol/spirocyclization cascade to generate enantioenriched spiro-oxiranes. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. Chapter 3 reviewed reported total syntheses of C19-diterpenoid alkaloids. Chapter 4 describes the preliminary studies towards the synthesis of the C19-diterpenoid alkaloid aconitine, proposing the use of a pinacol reaction, a Mannich reaction, and aldol reactions as key steps. Routes to access the A-, C- and D-ring fragments were developed, and the fragments were successfully coupled. The next steps require the formation of the C-ring via an intramolecular aldol reaction.

Keywords: Aconitine
Asymmetric Catalysis
Epoxides
Total Synthesis
Advisor: Lautens, Mark
Development of a Generic Emergency Department Discrete Event Simulation Model

Emergency Departments’ (EDs') critical role in patient care and their complex process flow contribute to them being one of the most frequently modelled systems in healthcare Operations Research (OR). The goal of this research was to develop a simulation model flexible enough to be applicable to any ED, that could be easily applied to diagnose bottlenecks and evaluate performance improvement approaches. We used Discrete Event Simulation (DES) to create a single input-driven generic model and validated it against limited de-identified datasets belonging to nine sites in Canada, U.S.A, and U.K. in such metrics as length of stay and key wait times (e.g., time to initial assessment). The validation results indicate performance on par with existing site-specific DES designs. We gain additional insights into the effects of resource and process duration changes on model performance and conclude that the model is slightly more sensitive to resource amounts than to granular process durations. The key benefit of the model is its flexibility and the speed with which it can be implemented at any hospital in need of a DES study. The model can be used to evaluate performance and preview the effects of staffing and flow changes before committing to the improvement measures.

Keywords: discrete event simulation
generic simulation
industrial engineering
operations research
simulation modelling
Advisor: Carter, Michael
Walter Benjamin's Weak Force of Study and Counter-traditional Education

My dissertation re-evaluates the potential of a seemingly unpromising moment in the incomplete project of university reform: Walter Benjamin’s attempt to reorient the German youth movement towards the question of the student. Current scholarship does not address Benjamin’s theoretical project for student reform, his creative reception of canonical texts in philosophy of education, or the impact of the youth movement’s alignment with the national war effort on his view of the relationship between state power, education, and violence. I set Benjamin’s educational writings into conversation with nineteenth-century German philosophy in order to bring out the philosophical core of a corpus that has usually been relegated to biography. The productive autonomy of study is the core of Benjamin’s program for educational reform. He proposes that the reciprocal determination of scientific principles and existential commitments shapes each student’s capacity to become a teacher. He argues that this transformed concept of study can ground the organization of the university and alter its working conditions. In opposition to the progressive consolidation of the university system around a nation-building program advancing an unified cultural state, Benjamin proposes that study can be a way of mediating between scientific discourses in the university and emerging problems in civil society. Staging a speculative encounter between Benjamin’s concept of study and Kant’s exposition of the right to philosophical critique, I contend that this expansive vision for freedom of learning has the power to contest the predetermined scope of the right to education granted by the state. Benjamin’s account of student autonomy makes use of the idealist principle of the transcendental subject who identifies with the idea of its study in creating its form of life. He also reactivates the destructive energies in Nietzsche’s critique of educational institutions to unbind the revolutionary kernel of idealism from the ideal of a cultural state. This twofold retrieval resists the reduction of the idealist legacy to administrative rationality and rescues the radical moment of critique that can intervene in the disputed trajectory of educational institutions. My interpretation demonstrates the contemporary actuality of Benjamin’s educational writings and their critical force for pedagogical experiments today.

Keywords: critical pedagogy
philosophy of education
study
university
Walter Benjamin
youth
Advisor: Comay, Rebecca
Smart Hospital Applications

Recent technological advancements (i.e., internet of things [IoT]), radio-frequency identification technology, electronic medical records/electronic health records) and new achievements in machine learning have provided hospitals the platform necessary to invest in data-driven modern technologies to enhance care delivery and therefore to reduce cost and increase revenue generation. Therefore, this Ph.D. research identifies the impacts and demonstrates the applications of these advanced technologies to shape the current hospital system by accomplishing three projects: (i) Evaluate the impacts of IoT on the quality of care domains and staff requirements of a hospital unit, (ii) Design a validation framework and apply it to evaluate the impact of a smart privacy auditing tool on operational excellence, and (iii) Predict the number of beds to clean within the next few hours as well as foresee the staff requirements in the emergency department (ED) applying machine learning algorithms and discrete-event simulation (DES) modeling to facilitate decision-making and reduce ED crowding. To identify the impacts of IoT on quality care domains (e.g., patient safety, efficiency, timeliness), a pre-/post-intervention analysis of patient falls and length of stay as well as a post-intervention analysis on hand hygiene compliance rate and call response time has been conducted using interrupted time series and other statistical analyses. Additionally, semi-structured interviews to find staff experiences have been performed. A favorable impact of IoT on these outcome measures is reported. The black box method of user acceptance testing has been adopted to design the evaluation framework for the automated privacy auditing tools, considering several scenarios on appropriate and inappropriate behavior. Validation of the framework with one hospital’s data shows that the effectiveness of one such tool is 98.09%. Poisson regression performs the best for predicting the number of beds to clean at the ED. Prediction model results are used as the input for a DES model to identify staff requirements and to assist in decision-making. This data-driven Ph.D. research unfolds the evidence of the consequences of smart hospital applications and solves the current complex problems related to decision making. Thus, this research informs hospital management and policymakers about the effectiveness of smart hospital applications.

Keywords: Big data
Discrete event simulation
Hospital
Internet of things
Machine learning
Privacy auditing
Advisor: Carter, Michael MC
The Natural History of Ductal Carcinoma In Situ and Early-stage Breast Cancer

Ductal carcinoma in situ (DCIS) is described as a noninvasive form of breast cancer (stage 0) which cannot metastasize without first progressing to invasive cancer, whereas small stage I cancers are considered de facto breast cancers with the ability to metastasize and cause death. This thesis consists of four papers dealing with various aspects of the early stages of breast cancer and an extensive literature review. I attempt to get a better understanding of the relationship between local invasion and distant metastases in small cancers. In Paper 1, I examined the relationship between local recurrence and distant metastasis/death among women with early-stage (DCIS, stage I or stage II) breast cancer in the Henrietta Banting Breast Database at Women’s College Hospital. There was little correlation between the 15-year rates of local recurrence and of breast cancer mortality across the three stages. Factors predicting local recurrence were different from factors predicting mortality. In Paper 2, I examined the impact of microinvasion on breast cancer mortality in patients with DCIS, using the SEER database. In terms of 20-year survival, DCIS with microinvasion (0.1 cm or less) was distinct from pure DCIS and similar to small invasive breast cancer (0.2 to 1.0 cm). In Paper 3, I examined the relationship between tumour size and risk of metastases among patients with invasive breast cancer in the SEER database. Metastasis risk had little correlation with the number of tumour cells (based on calculated tumour volume). The potential for metastasis decreased with increasing tumour size. In Paper 4, I examined the prognostic impact of a prior history of DCIS among women with early-stage invasive breast cancer in the SEER database. Invasive breast cancer post-DCIS was indistinguishable from primary invasive cancer in terms of prognosis. Together, these studies and the literature review suggest that the invasive in-breast tumour, nodal and distant metastases are independent events which originate from an upstream cause. The prevention of invasive recurrence post-DCIS does not impact on breast cancer mortality. This knowledge is important to optimize strategies for early detection and treatment.

Keywords: breast cancer
cancer invasion
cancer metastasis
cancer progression
DCIS
natural history
Advisor: Narod, Steven A
Partakers in Paideia: Representations of Literacy in the Epigraphy of Christians in Central Asia Minor

My dissertation examines the epigraphic practices of Christians living in central Asia Minor in the second to fourth centuries CE. Christians living in an area known as Phrygia as well as the bordering region of Lycaonia produced the earliest epigraphic remains of Christians in the Greek East. Many of these inscriptions are in verse and seek to represent the deceased as literate. I argue that the compulsion to produce verse epitaphs representing the deceased as literate stems from two coinciding ancient traditions. The first influence was literary valorization that was present in the earliest documents and material culture of the Christian tradition. This trend portrayed Christians and their early heroes as capable readers and writers. The second is the proliferation of Greek epigram that was popularized after the year 250 CE. Civic and imperial officials used this poetic genre to represent themselves as eloquent, educated rulers who legitimately possessed their posts based on their paideia or education. Through an examination of technologies of paideia in the epitaphs of Phrygian Christians, I argue that Christians in Asia Minor capitalized on this trend to accrue social capital. In doing so, they could portray themselves as skilled with Greek literature that was representative of an elite class of rulers. Capitalizing on literate self-representation, Christians could openly display aspects of their faith, so long as they were couched in the language of paideia. Using a practice-based theory of literacy, my dissertation asks not how early Christians became literate but what did literate representation do for their individual and corporate identity in the socio-cultural and political context of late Roman Asia Minor.

Keywords: Asia Minor
Christianity
Epigraphy
Poetry
Advisor: Kloppemborg, John
Adapting Automated Vehicles as Assistive Technologies for Older Adults through Intelligent Features

Automated Vehicles (AVs) are expected to cause a paradigm shift in transportation systems with promises of enhancing road safety and access to transportation among populations whose non-automated driving is restricted. Among such populations are those living with age-related declines and medical conditions such as dementia. While utilizing AVs to promote older adults’ safe driving can provide potential life-changing benefits to this populations, the topic has received relatively limited attention from the research community and automated vehicle manufacturers alike. At this time when the race to bring AVs to the market continues and many of the AV features are still in development, it is the appropriate time to ask, \textit{“How can we adapt AVs as assistive technologies for older adults?” } This thesis attempts to answer this question through a combination of (A) mixed-method usability studies to uncover insights about the interactions of older adults with AVs and (B) applying the experimental findings of the usability studies towards designing intelligent features for AVs that can ultimately help adapt AVs as assistive technologies for older adults. Correspondingly, the first three usability studies in Chapters 2-4 respectively assess the views of three groups of stakeholders including healthy older adults, people with dementia, and their family care-partners on using AVs as assistive technologies. These usability studies highlight the shortfalls of current AV designs in meeting the needs and preferences of older adults, especially those living with dementia and highlight the merits of AV customization in promoting older adults’ acceptance of AVs. Building upon the findings of the usability studies, Chapters 5 and 6 describe studies on designing intelligent features that could be used for the ultimate adaptation of AVs for older adults. Chapter 5 introduces a design to predict older drivers’ baseline fitness to operate an AV and Chapter 6 introduces a design to monitor older drivers for signs of confusion about the AV’s operating mode. The combination of usability and design studies advances our understanding of the interaction of older adults with AVs and strives to design an intelligent system that could potentially bridge the usability gap between current AV designs and older adults.

Keywords: Assistive Technologies
Automated Vehicles
Dementia
Human-AI Interaction
Older Adults
Advisor: Mihailidis, Alex AM
Campos, Jennifer JC
Development of Oral Amino Acid Tracer Models to Study Muscle and Whole-body Anabolism in Humans

Traditional stable isotope infusion methods to study muscle and whole-body anabolic responses to feeding and exercise can be invasive and logistically challenging and generally do not provide insight into the metabolic fate of ingested amino acids. Therefore, this thesis aimed to develop oral amino acid tracer models to comprehensively study muscle and whole-body anabolism in humans. In Chapter 2, we demonstrated that oral L-[1-13C]leucine and L-[ring-2H5]phenylalanine ingestion resulted in greater dietary amino acid incorporation after feeding and exercise as compared to feeding and fasting at rest, resulting in greater rates of myofibrillar protein synthesis. In Chapter 3, we demonstrated that a non-invasive breath test based on oral L-[1-13C]leucine ingestion can detect reduced dietary leucine oxidation and enhanced net leucine balance after feeding and exercise as compared to feeding at rest. And finally, in Chapter 4 we demonstrated that amino acid transporter expression was not influenced by acute feeding and/or resistance exercise and did not positively influence the incorporation of dietary amino acids for myofibrillar protein synthesis. Collectively, these findings represent viable methods and models to allow greater flexibility in testing anabolic sensitivity under a range of physiological conditions and within a wider variety of study populations.

Keywords: amino acids
dietary protein
muscle protein synthesis
resistance exercise
stable isotopes
Advisor: Moore, Daniel R