VictorJuiz/thesis huggingface dataset:
The Role of Myeloid Peroxisome Proliferator-activated Receptor Delta in Experimental Autoimmune Encephalomyelitis
Keywords: dendritic cells
experimental autoimmune encephalomyelitis
microglia

Peroxisome proliferator-activated receptor δ (PPAR-δ) is a nuclear receptor that regulates whole body metabolic homeostasis, cell growth and differentiation. Previously our lab reported that mice lacking PPAR-δ (Ppardmut) developed more severe experimental autoimmune encephalomyelitis (EAE), with more proinflammatory T helper (Th) cells and macrophages. To elucidate the role of peripheral myeloid cells to this disease phenotype, EAE was induced in mice with a myeloid-specific PPAR-δ-deficiency (LysMCre:Ppardfl/fl). These mice developed more severe EAE compared to Ppardfl/fl controls, with an increased accumulation of pathogenic IL-17+CD4+ T cells in the CNS at the peak of EAE. Adoptive transfer studies and radiation bone marrow chimeras pointed to peripheral myeloid cells as the driver of this disease phenotype, substantiated by enhanced splenic myelin-specific Th1 and Th17 responses in LysMCre:Ppardfl/fl mice. Using a CD11b+:Th cell coculture system, CD11b+ cells from LysMCre:Ppardfl/fl mice were found to better at priming myelin-specific Th cells relative to Ppardfl/fl CD11b+ cells. The driver of this effect was predominantly increased expression of IL-12p40 and higher secretion of IL-12p40 homodimer and IL-23 by LysMCre:Ppardfl/fl CD11b+CD11c+ cells. These results thus identified a novel role for PPAR-δ in DCs in the regulation of Th cell priming during EAE. To evaluate the contribution of PPAR-δ in microglia in EAE, we used mice with a microglia-specific PPAR-δ-deficiency (Cx3cr1CreERT2:Ppardfl/fl), where tamoxifen (TAM)-treated mice exhibited microglial specific Ppard knockdown at 30 days. TAM-treated Cx3cr1CreERT2:Ppardfl/fl mice experienced worse EAE relative to TAM-treated Ppardfl/fl controls. Histopathology and magnetic resonance studies revealed increased Iba-1 immunoreactivity, axonal injury, and CNS atrophy in TAM-treated Cx3cr1CreERT2:Ppardfl/fl mice compared to controls. In early EAE, Cx3cr1CreERT2: Ppardfl/fl and Ppardfl/fl groups, Ppard-deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length, lower expression of microglial genes associated with homeostasis, and higher expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and inflammation. Our results therefore suggest that PPAR-δ is important in limiting the pro-inflammatory activities of microglia during EAE. Together, these studies expand upon the existing understanding of PPAR-δ in the immune system and are the first studies to evaluate the cell-specific roles of PPAR-δ in EAE.
Understanding the Drivers of Low-value Care and De-implementation Processes: A Multi-methods Study
Keywords: Choosing Wisely
De-implementation
Low-value care
Qualitative
Scoping review
Theory

Low-value care (LVC) are tests, treatments, medications or procedures which have been deemed, through evidence, to be ineffective, harmful or unnecessary. It is estimated that 30% of current healthcare dollars are spent on these practices (Canadian Institute for Health Information, 2017). The de-implementation of low-value care is widely recognized as critical for patient safety, healthcare resources and health system sustainability. In recent years, a number of initiatives, such as Choosing Wisely, have targeted the de-implementation of low-value practices in healthcare. The de-implementation of LVC is an important endeavour that poses challenging conceptual and practical questions. This dissertation explores the conceptual and practical aspects of LVC and de-implementation through three complementary studies. In the first study, I conducted a comprehensive scoping review of the literature on the use of theory to understand or explain efforts to reduce LVC. This review offers four key findings: 1. De-implementation is still largely atheoretical, but the use of theory is increasing; 2. TDF is the most commonly used framework; 3. Theory was most commonly used to identify determinants or inform data analysis; and 4. The lack of studies examining the impact of patients on efforts to de-implement LVC. In the second study, I developed the Implementation Process Model (IPM) using a modified Delphi approach. This study, to advance understanding of de-implementation processes and explicate the elements of implementation processes, identified four critical elements important to implementation processes: 1. Stakeholder engagement throughout the process; 2. Iterative nature of implementation processes; 3. Importance of context; and 4. Importance of using guiding theories or frameworks. The third study used the knowledge and tools produced in the first two studies to conduct a qualitative exploration of factors which impact LVC and de-implementation processes. The findings of this study explicated the drivers of LVC, the magnitude of the problem of LVC and unique influences on de-implementation processes. Understanding LVC and de-implementation processes is critical to improving patient care, reducing waste and improving the healthcare system. The results of these studies provide insights into theoretical approaches, implementation processes, and factors which influence LVC and de-implementation applicable to both research and practice.
Medication Errors in Critically Ill Children: Evidence, Event Rate, Harm Analysis
Keywords: adverse drug events
critical care
medication errors
pediatrics
pharmacoepidemiology

Background Children in Intensive Care Units (ICUs) are at high-risk group of healthcare associated harm. We used pharmaco-epidemiologic methods to estimate drug error, and patient associated harm using a large drug administration dataset. The objectives of this doctoral dissertation were to describe the: [1] Evidence for the effect of electronic strategies on medication errors and harm, [2] Incidence of acetaminophen dosing errors; [3] Patient specific harm associated with acetaminophen errors. Methods Objective 1: A systematic review was used to evaluate the impact of electronic strategies on medication errors, adverse drug events and harmful medication errors in hospitalized patients. For objectives 2 3, we used a large database of drug administrations from 2004 to 2017. Objective 2: An algorithm to identify acetaminophen dosing errors was created. The nature of errors was described as well as the characteristics of affected patients. Objective 3: A Generalized estimating equations regression study was then conducted on the acetaminophen dataset, with cumulative dosing error of acetaminophen as the exposure of interest. Outcomes were changes in liver enzymes (ALT, AST, GGT) as a marker for acetaminophen organ induced toxicity. Results Objective 1: This systematic review found that, amongst 38 prospective interventional studies identified, electronic prescribing strategies reduced medication errors (13 studies), and adverse drug events (n=4 studies), compared to no electronic strategy. Evidence was low-quality and studies had high risk of bias. Objective 2: In the evaluation of 14 146 admissions, having received 147 485 doses of acetaminophen, under- and over- dosing were common in the pediatric intensive care unit; with a rate of 1 in 19 and 1 in 20 doses administered respectively. Cumulative 24-hour overdosing occurred in 1 in every 9 patient days, (> 82.5 mg/kg/day). Objective 3: Cumulative acetaminophen dosing (>82.5mg/kg/day) was not associated with an increase in ALT, AST and GGT in the 24h -72h after the cumulative overdose, nor was a sensitivity analysis with higher cumulative dosing (>100 mg/kg/day). Conclusion Electronic strategies reduce medication errors and adverse drug events. This finds does not include preventable adverse drug events, and no studies involve children. Although acetaminophen dosing errors may be common, they are not always associated with harm.
Rethinking the Division of Tax Room in Fiscal Federalism
Keywords: federalism
fiscal federalism
tax competition
tax room
taxation

The division of tax room for shared tax bases, such as income taxation in Canada and the United States, is a frequent cause of political conflict between national and sub-national governments. Economists and legal scholars have developed a normative theory that sets out an optimal division of tax room, but federal nations often substantially depart from this prescription by allocating too much or too little tax room to national governments. This thesis argues that the divergence between the normative theory and actual practice can be partially explained by three incentive problems that afflict the division of tax room: 1) a “credit assignment” problem; 2) a contract enforcement problem; and 3) a vertical tax competition problem. In combination, these problems produce an incentive structure that discourages the optimal division of room and invites high levels of political conflict. To illustrate, this thesis develops a model of tax room allocation, which it then applies to the four oldest constitutional federations: the United States, Switzerland, Canada, and Australia. The thesis argues that law can be used to improve the allocation of tax room in two ways. First, a number of non-tax legal doctrines, including rules addressing conditional grants, concurrent expenditure jurisdiction, direct cash transfers to individuals, and parliamentary sovereignty, should be revised to encourage consensual and welfare-maximizing exchanges of tax room between national and sub-national governments. Second, when consensual exchanges fail, law should be used to regulate vertical tax competition, so that the competitive process tends toward welfare-maximizing outcomes. This thesis examines a number of competition-regulating measures, including intergovernmental anti-discrimination rules and conflict-of-law rules. The thesis concludes by briefly considering whether and how these approaches can be applied to two other contexts in which vertical relationships are relevant: regional-local tax room allocation and international tax room allocation.
Understanding Recovery Reactions Following Balance Loss: The Effect of Age and Handrail Cross-sectional Design
Keywords: Balance recovery
Biomechanics
Fall prevention
Handrail design
Stair ambulation

Falls on stairs are a common cause of injury and hospitalizations, particularly for older adults. To recover balance after a destabilization, fast, accurate and appropriate balance recovery strategies must be employed to arrest a fall. While handrails have been shown to decrease the likelihood of falls, it is unknown how handrail shape and size affect the ability to support successful balance recovery. With a lack of guiding data to support design, national and international standards and regulations permit a variety of handrail cross-sectional sizes and shapes. This thesis aims to better understand balance recovery on stairs and how the design of handrails affects the reach-to-grasp balance recovery responses. I conducted four experimental studies to address the overall research objective. In the first two studies, I characterized the demands of balance recovery during stair descent. Novel methods were used to induce unexpected forward and backward balance loss during stair descent in younger adults. To recover from both forward and backward balance loss, participants used a variety of strategies, including compensatory stepping, counter-balancing trunk and arm movement and grasping environmental features. Of those participants who grasped the handrail, participants applied a range of forces, from light touch to 30% of their body weight. Many participants also had errors in grasping, particularly in backward balance loss. Building on this work, Studies 3 and 4 aimed to further understand the effect of handrail shape and size on the speed and accuracy of reach-to-grasp reactions and ability to generate necessary forces to arrest a fall for older and younger adults. A ramp-up perturbation protocol was used to induce balance loss that was repeatable and demanding for all handrail cross-sections. Of the seven handrails tested, the 1.5” round handrails allowed participants to apply the highest forces and to withstand the greatest magnitudes of perturbation with the fewest errors for both younger and older adults. In contrast, large complex handrails resulted in reduced forces, lower withstood perturbations with more errors. This research provides empirical evidence that can be used to guide standard development and clinical recommendations for safer stairways.
Human Physiology and Acheulean Handaxe Design
Keywords: Acheulean handaxe
Balance
Geometric morphometrics
Physiology
Symmetry
Weber fractions

Acheulean handaxes have played a leading role in our understanding of the cognitive and behavioural abilities of early hominins. An enormous amount of scholarly attention has been dedicated to better understanding the role these tools played in human evolution. Since the 1960’s, experimental archaeology and increasingly sophisticated quantitative analyses have brought us much closer to answering many fundamental questions about their true nature. Nonetheless, uncertainty remains about morphological differences, symmetry, and the meaning behind Acheulean handaxes’ remarkable longevity and spatial distribution. This dissertation presents the results of a series of experiments designed to study handaxe design and sources of shape variation using novel methodological approaches. The main goal is to examine their shape variation from a physiological perspective since most studies focus on functional and/or cultural aspects of handaxe manufacture and use. This is accomplished in two ways, one by looking at limitations in humans’ visual perception, and the second by examining how mass is distributed in Acheulean handaxes. The first goal examines limitations in humans’ visual perceptive abilities for distinguishing size differences between three-dimensional (3D) objects by using a series of different sized 3D printed models which were presented to participants who were asked to iii differentiate the size differences. The results indicate that our ability to distinguish size differences drops significantly below 3%. As such, it is suggested that this physiological limitation would introduce shape variation in handaxe assemblages. The second goal examines the role that balance played in handaxe design and manufacturing since neuroscience studies indicate that humans manipulate handheld tools according to their center of mass (CM) location and well-balanced tools reduce stresses and injuries in the hands, arms, and shoulders. Therefore, a novel methodology was developed that turns the CM location into a ratio that can be compared between handaxes. The results indicate that the CM location was tightly controlled and is less variable than any other shape trait and is relatively independent from symmetry. Furthermore, 3D geometric morphometrics and K-means clustering analysis was conducted on South African and British handaxe handaxes in order to examine shape variation at the assemblage level.
A Systematic Analysis of Argonaute Proteins in Caenorhabditis elegans
Keywords: Argonaute
C. elegans
RNA interference
small RNA

RNA interference (RNAi) pathways, consisting of Argonaute proteins and small RNAs that provide sequence specificity, play key roles in gene regulation across all domains of life. Studies of Argonautes in many species have revealed that they impact gene expression at nearly every stage in the life cycle of a transcript—from transcription to translation. Due to their central role in RNAi and profound impact on development and differentiation in numerous organisms, uncovering new and conserved molecular mechanisms of Argonautes advances our fundamental knowledge of cellular function and has the potential to provide more precise means to manipulate gene expression, relevant for biotechnology and therapeutics.The C. elegans genome encodes an expanded family of 27 ago genes, 19 of which produce functional proteins. In this thesis I have undertaken a systematic study of every functional C. elegans Argonaute to develop a comprehensive portrait of the molecular mechanisms of these mostly uncharacterized proteins throughout development. Using CRISPR/Cas9 genome-editing, I epitope-tagged each Argonaute with GFP::3xFLAG. I used confocal microscopy to characterize the expression patterns of each Argonaute throughout development and defined the tissue specific and subcellular localizations of each Argonaute. High-throughput sequencing of 1) small RNAs associated with each Argonaute, and 2) total small RNA pools from argonaute mutants versus wild type uncovered the stratification of subsets of Argonautes into distinct gene regulatory modules. Directed by the localization and small RNA sequencing data, I employed phenotypic analyses of argonaute mutants under normal and stressful conditions. These revealed previously unappreciated phenotypes, including a transgenerational loss of fertility known as the Mortal Germline (mrt) defect, and resistance to the bacterial pathogen Pseudomonas aeruginosa. Overall, my systematic and pioneering studies provide an unprecedented view of the small RNA regulatory landscape throughout the development of a complex animal.
Engaging Indigenous Voices in the Academy: Indigenizing Music in Canadian Universities
Keywords: Decolonization
higher music education
Indigenization
Indigenization of higher music education
Indigenization of the academy
reconciliation

Canadian universities are under increasing pressure to address systemic exclusions of Indigenous peoples and knowledges, exclusions that have been perpetrated by residential schools, day schools, and universities. Canadian universities have, increasingly, begun to engage in Indigenization efforts; however, engagement in Indigenization efforts has been inconsistent and uneven within institutions and across the sector. Higher music education, in particular, has done little in terms of engaging in Indigenization, and this research seeks to address this gap. This research engages with six Indigenous musicians who each hold at least one university degree in music in order to hear their experiences in higher music education and to envision an Indigenized higher music education in Canadian universities. This research is, in part, a response to the Truth and Reconciliation Commission of Canada’s 94 Calls to Action (2015c), specifically Call 62, ii.: We call upon the federal, provincial, and territorial governments, in consultation and collaboration with Survivors, Aboriginal peoples, and educators, to: ii. Provide the necessary funding to post-secondary institutions to educate teachers on how to integrate Indigenous knowledge and teaching methods into classrooms (p. 331). Call to Action 62, ii provides a framework for thinking about and envisioning what higher music education—or post-secondary music programs—can do to respond to the TRC’s Calls to Action (2015c) in meaningful ways in collaboration with Indigenous peoples, communities, and Nations. This research engages with Ermine’s (2007) conceptualization of the ethical space and McCallum and Perry’s (2018) structures of indifference in order to conceptualize higher music education as structures of difference whereby Indigenous musics, musicians, knowledges, and musical practices are valued and included in ways that go well beyond Indigenous inclusion (Gaudry Lorenz, 2018). The final chapter includes a lengthy list of recommendations, informed by the participants’ stories, for all stakeholders in higher music education, including deans and senior leadership, chairs, faculty, staff, students, patrons and donors, and audience members. The academy has undergone very little structural change (Ottmann, 2013) and the magnitude of what will be required of higher music education in the work of Indigenization will necessitate visionary and courageous leadership. Keywords: music, higher music education, Indigenization, decolonization, reconciliation, post-secondary music education, university, Indigenization of the academy, Indigenization of higher music education
Jobs, Homes, and the Right to Exist: Neighbourhood Activism in Deindustrializing Toronto and Montreal, 1963-1989
Keywords: Archives
Canada
Gentrification
Neighbourhood
Quebec
Urban

AbstractThis dissertation explores the points of tension between dominant histories of neighbourhood activism in Toronto and Montreal between 1963-1989 and the lived experiences of locally embedded activists who organized for access to safe jobs, homes, and the right to exist in their neighbourhoods. It demonstrates how material conditions, determined by the overlapping processes of deindustrialization, post-industrial development, and the movement of capital from Montreal to Toronto, shaped how neighbourhood activists organized, who they organized with, what they organized for, and how they recorded what they were doing. Dominant narratives of neighbourhood activism during this period over-emphasize the perspectives white, middle-class, and cis-gendered male activists who benefitted from the world the sixties made. Their upward mobility, made possible through the expansion of public spending and their involvement in gentrification, gave them the time and resources to document what they were doing, elevating their perspectives in the historical record. At the same time, embedded poor and working-class, racialized, disabled, and trans activists who continued to experience the ongoing structural violence of the capitalist city also continued to collectively resist that violence. Unfortunately, their ongoing precarity denied them of the resources necessary to produce historical records to the same degree as their upwardly mobile contemporaries. By historicizing how uneven material conditions shaped what activists were doing and how they recorded what they were doing, this thesis demonstrates how power shaped the production of neighbourhood activism history. It also presents opportunities to contest this power in the historical record.