VictorJuiz/thesis huggingface dataset:
Sodium Glucose co-Transporter 2 (SGLT2) Inhibitors for Type 2 Diabetes Mellitus: Assessing their Safety and Effectiveness using Real-world Data

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of medications for adults with type 2 diabetes mellitus. While their efficacy has been well established, less is known about their effectiveness and safety in routine care. The three studies for this thesis include: (1) To compare the cardiovascular effectiveness of SGLT2-inhibitors compared to metformin for people with diabetes who are treatment-naive; (2) To compare the risk of fracture with SGLT2-inhibitors compared to GLP1 agonists; and (3) To identify predictors of SGLT2-related diabetic ketoacidosis using Machine Learning. Methods: All three studies utilized routinely collected data from large healthcare databases in the United States and applied the new-user cohort design. Study 1 and 2 applied propensity-score matching and a Cox proportional hazards model to estimate the hazard ratios for the primary outcome. Study 3 utilized two popular machine learning techniques: least absolute shrinkage and selection operator regression and gradient boosted trees. Results: In Study 1, the primary outcome of stroke, myocardial infarction, or heart failure occurred in 198 individuals (32 events per 1,000 person-years) newly prescribed an SGLT2, compared to 223 individuals (31 events per 1,000 person-years) among 10,549 PS-matched new-users of metformin (HR = 1.02, 95% CI: 0.84, 1.23). In Study 2, 79,964 patients initiating canagliflozin who were propensity score matched to 79,964 patients initiating a GLP1-agonist. The primary outcome of hip fracture, pelvic fracture, humeral fracture, or wrist fracture was similar for canagliflozin (2.2 events per 1,000 person-years) compared to GLP1-agonists (2.3 events per 1,000 person-years). In Study 3, 111,597 adults newly prescribed an SGLT2 were identified. The following variables had strong associations with an inpatient diagnosis of diabetic ketoacidosis: prior DKA (OR = 4.62, 95% CI 1.06 – 20.14), digoxin use (OR = 4.38, 95% CI 1.98, 8.56), and a baseline hemoglobin A1C above 10% (OR = 3.10, 95% CI 1.93,4.98). Discussion: This thesis provides timely data to understand the safety and effectiveness of SGLT2-inhibitors in routine care. This was achieved through advanced pharmacoepidemiologic methods and machine-learning techniques. With the aid of open-source statistical packages, this body of work also provides a methodologic framework for conducting similar studies.

Advisor: Redelmeier, Donald
Investigation of Vascular Function and its Modulation in a Mouse Model of Amyloidosis

Vascular integrity and function is critical for maintaining homeostasis of the central nervous system. Compromises in vascular structure and function are observed in Alzheimer’s disease (AD) and associated with amyloid pathology. Vascular dysfunction affects cerebral blood flow (CBF), including vascular reactivity which can be regulated by arachidonic acid (AA) and nitric oxide (NO). This thesis investigates vascular dysfunction and response to challenges in the TgCRND8 mouse model of amyloidosis. Biochemical and functional vascular characteristics were evaluated to better understand the extent of vascular dysfunction in this mouse model. With the goal of evaluating vascular plasticity and vascular response to challenges in presence of amyloid, we disrupted the blood-brain barrier (BBB) with focused ultrasound (FUS) in TgCRND8 and non-transgenic mice. We then used Vasculotide (VT), which was previously characterized as a Tie2 agonist to assess the effects of a 3-month VT treatment on vascular integrity and repair. VT-treated TgCRND8 mice required less pressure to induce permeability and demonstrated an accelerated restoration of the BBB after FUS. Using functional MRI, hippocampal, but not cortical, vascular hyporeactivity was found in TgCRND8 mice at 7.5 months, at which point there is significant vascular pathology. A higher cerebral amyloid angiopathy burden was identified in the hippocampus, compared to the cortex. At the mRNA level, we identified increased expression of cyclooxygenase (COX)-1, essential for AA metabolism, in the hippocampus and increased expression of endothelial and neuronal NO synthases (NOS) in the cortex of TgCRND8 mice. These results indicate modulation of AA and NOS enzymes in the brain of TgCRND8 mice that may be relevant to the observed vascular dysfunction. In conclusion, these results provide evidence of cerebrovascular dysfunction in presence of amyloidosis and they characterize potential regulators of vascular dysfunction, such as AA, NOS and CAA, in the mouse brain, which could be engaged for plasticity and repair. Lastly, the combined use of VT and FUS suggests that VT enhances vascular plasticity, which is promising for its future use in combating insults to the BBB. Overall, a better understanding of cerebrovascular dysfunction in the context of AD pathologies is critical for the understanding and treatment of AD.

Keywords: Alzheimer's disease
Amyloidosis
Focused Ultrasound
Tie2
Vasculature
Vasculotide
Advisor: Aubert, Isabelle
Visions and Shadows: A Socio-history of the Mental-health Policy Reform Agenda in Canada

This dissertation offers a critical, contextualizing analysis of government policy and discourse pertaining to mental-health reform in Canada, with a focus on the province of Ontario. It represents my attempt to craft an analysis and contextual history of government policy visions pertaining to mental disorder and wellness. I define the study’s problematic broadly, as an attempt to understand how problems are defined and solutions enacted through institutions organized under the auspices of government, insofar as problems and solutions in public discourse are depicted as pertaining to mental disorder. My investigation proceeds through an analysis of government texts and their social, political and historical context, influenced by Dorothy Smith’s contributions to institutional ethnography and political economy, Arthur Frank’s project of socio-narratology, and, (in a more complicated way), the historical and methodological works of Michel Foucault. My history of reform is in many respects a history of how problems have been constructed and understood, and my deconstruction of discourses of recovery and reform is in many ways an exploration of institutional developments (as well as certain concrete policy proposals that authorized discourse seems to preclude, actively or implicitly). Drawing on literature from policy studies related to policy subsystems and state capacity, I interpret actual policy developments and visionary discourse pertaining to mental-health policy as the vanguard movement of neoliberalism within the Canadian social-welfare state. I suggest that a biomedical era of mental-health discourse may be usefully thought of as giving way to, and merging with, an ascendant economic understanding of disorder itself – the antecedents of which are well-described in Foucault’s analysis in the 1970s of the then-nascent political implications of neoliberalism.

Keywords: Critical studies
Discourse analysis
Health services
Mental health
Policy studies
Ruling Relations
Advisor: Webster, Fiona
Heck Fun Ya! (Let's Eat!) An Autoethnographic Cookbook: Memories of a Chinese-Canadian Upbringing Beyond

This dissertation emerges out of the conceit that food, more than mere sustenance, is significant cultural artifact. Rooted in the premise that there is educative value in life story as research, Heck Fun Ya! (Let’s Eat!) An Autoethnographic Cookbook: Memories of a Chinese-Canadian Upbringing Beyond is a performative text using food as a vehicle to discuss culture, identity, and otherness. Blending academic analyses, life story writing, and multi-media, its creative format is an expression of the uniqueness of this process. Thematically organized, the cookbook structure of starters, mains, and desserts is comprised of food experiences punctuated by recipe in a variety of narrative forms. Narratives will be analyzed through interdisciplinary lenses that explore how food shapes various identities in order to ask: What role does food play in identity construction? And how can storying and/or re-storying food experiences be used to live a good life? In approaching this, the work aims to recalibrate my understanding of past experiences to create resonance with new ones, and thus, deepen knowledge. Starters offers two opposing effects of food experience: one that considers food shame and stigma through a psychoanalytic lens (Kristeva, 1982; Goffman, 1963), and the other that explores the role of disgust in igniting imagination (Korsmeyer, 2011). Mains will address the part food plays in the identities that emerge from having a sense of home and belonging. Narratives serve as entry points for discussions that emphasize the home, food, eating, and family connection (Bell Valentine, 1997; Blunt Dowling, 2006). Food’s role in identities that evolve out of the things we do are also considered: teaching and food writing including the physiology of taste, impact of hunger and whether it sharpens one’s descriptive abilities (Brillat-Savarin, 1949/2009; Hemingway, 1964/2009; Zola, 1873/2009). Desserts, the last cookbook section, takes a dramatic turn to consider the non-alimentary ways of food and feeding; this discussion explores music, yoga, meditation, and narrative medicine as expressions of “nourishment” (Pretorius, 2017; McGonigal, 2008; Lazar et al., 2005; Charon, 2008). Finally, the significance of the study and implications for next steps will be presented.

Keywords: Autoethnography
Culture
Food
Identity
Otherness
Writing
Advisor: Trifonas, Peter P
Elastin-derived Peptides in the Pathogenesis of Kawasaki Disease

Kawasaki disease (KD) is an acute multisystem vasculitis that predominantly targets the coronary arteries in children. The immunopathogenesis of KD is characterized by systemic inflammation localizing to the coronary arteries and production of pro-inflammatory cytokines. Local cytokines induce the upregulation of MMP-9, a key elastolytic protease in KD. MMP-9 activity leads to elastin degradation and aneurysm formation. Elastin breakdown is a hallmark of aneurysms. Interestingly, the degradation of elastin generates fragments referred to as elastin-derived peptides (EDPs). EDPs can bind directly to elastin-binding protein (EBP), a subunit of the elastin receptor complex. Through EBP-mediated signaling, EDPs regulate diverse cellular events including the upregulation of elastolytic MMPs. EBP is an inactive splice variant of -galactosidase that retains the ability to bind galactosugars at its galactolectin binding site. Unlike EDPs, the binding of galactosugars by EBP induces dissociation of the elastin receptor complex and inhibits EDP-mediated signaling. The overarching theme of this thesis is the role of EDPs in modulating the immunobiology of KD. Firstly, EDPs are elevated in the Lactobacillus casei cell wall extract (LCWE) murine model of KD in which diseased mice have greater EDPs compared to non-diseased mice. We demonstrate that EDPs are bioactive in vitro and induce ERK phosphorylation, MMP-9 expression, and cell migration in both a murine (MOVAS) and human aortic smooth muscle cell line. More importantly, EDP-induced signaling and cellular functions are inhibited in the presence of galactosugars. We show that intravenous immunoglobulin (IVIG), the primary treatment for KD, is also a source of galactosugars. The Fc domain of IgG in IVIG is glycosylated and these glycans can terminate in galactose or sialic acid attached to penultimate galactose. Thus, desialylation cleaves sialic acid and exposes terminal galactose. Desialylated IVIG inhibits EDP-induced signaling and cellular functions in MOVAS, whereas sialylated IVIG has no effect. Furthermore, in vivo administration of galactosugars attenuates disease, decreasing coronary arteritis severity and reducing EDPs in the LCWE model of KD. Taken together, these results further our understanding of the immunopathogenesis of KD, identify EDPs as a potential biomarker of disease, and provide insights into potential therapeutic approaches and targets for KD treatment.

Advisor: Yeung, Rae SM
Anselm of Laon, the Glossa Ordinaria, and the Tangled Web of Twelfth-century Psalms-Exegesis

This thesis studies the textual relationships between a group of related early scholastic commentaries on the Psalms. At the centre of the discussion stands the commentary which is often said to epitomize the developments in teaching which emerged within the cathedral schools in the twelfth century, namely the so-called Glossa ordinaria on the Bible, and its association with Anselm of Laon, one of the most celebrated theologians of the period. Despite its central place in twelfth-century intellectual culture, relatively little has been able to be conclusively established regarding the origins of the Gloss. Likewise, the authorship of many of the early scholastic Psalms-commentaries related in some way to the Gloss remains uncertain. A great many suggestions have been put forward by modern scholars, but rather than looking only at one or two of the attributions, this thesis broadens the scope of the question and takes a comprehensive view of a larger group of these commentaries, showing that this is necessary if we want to be able to say anything conclusive about their authorship. The first chapter examines the latest scholarship on the Gloss on some other books of the Bible, showing how this bears on the question of Anselm’s authorship of the Gloss on the Psalms. The second chapter analyses the relationship of the Gloss on the Psalms to its two closest relatives and attempts to settle conclusively the question of the direction of influence. The third chapter examines the evidence and arguments for the attribution of one of the other Psalms-commentaries to Anselm, arguing, on the basis of the expanded scope of the examination, against the attribution. Chapter Three also begins to examine the relationships that exist within the larger group and introduces a new hypothesis for the place of the Gloss in the family tree and for Anselm’s involvement in its creation. The fourth chapter analyses the relationships of the group as a whole, demonstrating how they are all related to one another, but that none can be the sole source of the rest of the group, and arguing further for the hypotheses introduced in Chapter Three.

Keywords: Anselm of Laon
Biblical Commentary
Cathedral Schools
Glossa Ordinaria
Psalms
Twelfth Century
Advisor: Andrée, Alexander
Per una metodologia di studio del protogiallo: i casi di Giulio Piccini e Carolina Invernizio

Since the 1980s Italian crime fiction has enjoyed international mass popularity, and has drawn critics towards a genre neglected for decades. Studies have almost exclusively focussed on texts written after 1929, the publication year of the first volume of Mondadori’s ‘Libri Gialli’, a series that made giallo synonymous with the crime novel and which is considered as the birth of modern Italian crime fiction. In fact, texts dealing with mysteries, criminals, police, trials and detection contributed to developing a modern conception of the genre from the 1850s onward. As it does not conform to a recognizable genre-structure, the pre-1929 period has been defined as the “prehistory of Italian crime fiction” or protogiallo, and to date only a few scholars have studied early crime fiction writers, approaching them as exceptions of an undignified lowbrow genre. Going against this critical trend, the purpose of my research is to identify a methodological approach to study the protogiallo, which is instrumental to understand the development of the genre in a diachronic perspective as well as to synchronically explore its phases. To achieve this, I relate protogiallo’s heterogeneous corpus to canonical crime fiction by applying Jacques Derrida’s genre conception, which distinguishes ‘participation’ in a genre from the stricter ‘belonging’. Moreover, after determining the fundamental influence of Anglo-American and French crime fiction in the protogiallo’s development, I propose a comparative typology that allows critics to effectively approach early Italian crime fiction texts by identifying their foreign models. I then apply such typological approach to two case-studies: Giulio Piccini’s crime novels published in the 1880s and featuring the first serial detective in Italian literature; and a selection of fin-de-siècle feuilletons by Carolina Invernizio who, from my research, emerges as a proto-feminist crime fiction writer. While highlighting the international interconnectedness of crime fiction, this study pinpoints characteristics that differentiate the protogiallo from its foreign models, including the mutual impact between Italian popular literature and the society of the time. Thus, it emerges how this work does not only speak to scholars invested in literary criticism, but to anyone interested in a wider socio-cultural portrayal of Italian crime fiction.

Keywords: comparative literature
crime fiction
popular literature
Post-Unification and fin-de-siècle Italy
Advisor: Somigli, Luca
Transscalar Critique: Crisis and Form in the Anthropocene Contemporary

“Transscalar Critique” proposes a new model of literary criticism for reading in the Anthropocene. I argue that contemporary literature and literary criticism are defined by a problem of scale. Critics and novelists have sought to capture the expansiveness of a larger and more connected world while simultaneously contracting inwards, refocusing on smaller units of analysis. By looking at representations of specific crises and foregrounding scale as a central analytic, my dissertation develops a mode of critique that is at once discursive, geologic, political, and ontological. “Transscalar Critique” offers a survey of the Anthropocene contemporary to suggest that paying attention to questions of the micro-scale of the word is just as important as the macro-scale of the world. In the first half of this dissertation, I argue that the 2008 Financial Crisis and climate change have been represented as monoscalar. Existing literary and critical accounts of these events only attend to their human scale, imaging crisis as the result of specific individuals and a momentary interruption in a teleological narrative of technological and economic expansion. “Transscalar Critique” reveals the way that these very specific crises in fact result from the co-constitutional convergence of human and nonhuman life. In the second half of the dissertation, I read two authors I understand as specifically transscalar, Ben Lerner and Paul Beatty. Lerner develops an ambient mode of literary fiction and critique that dissolves the distinction between text and world, rescaling the relationship between audience, author, and work of art. Beatty uses satire as a way to both represent and critique the divergent scales of the contemporary, writing fiction that is just as concerned with environmental and economic issues as it is with questions of race and aesthetic value. It is between these scales, “Transscalar Critique” argues, that we can understand what it means to live in a contemporary backlit by the perennial crisis of the Anthropocene.

Keywords: Anthropocene
Contemporary Literature
Crisis
Postcritique
Advisor: Downes, Paul
Functions of Discoidin Domain Receptor 1 in Diabetic Vascular Calcification and Regulation of Obesity and Type 2 Diabetes in High-fat Fed Mice

The extracellular milieu is a critical component of tissue structure and organization. The collagen-binding receptor tyrosine kinase Discoidin Domain Receptor 1 (DDR1) is an important sensor of the extracellular milieu that has been implicated in the pathogenesis of fibrosis, certain cancers, and atherosclerosis and vascular calcification. Due to its recent discovery, much remains to be learned about DDR1’s role in health and disease. In the present thesis, I describe a mechanism by which DDR1 promotes diabetic vascular calcification. In vivo, DDR1 deletion ameliorated diabetic vascular calcification and suppressed osteogenic transcription factor RUNX2. In vitro, DDR1 potentiated RUNX2 by the PI3K/Akt signaling axis. Downstream of Akt, GSK3β is an inhibitor of microtubule assembly and RUNX2. Microtubule organization was perturbed in DDR1 deficient cells and microtubule stabilization rescued nuclear RUNX2 translocation in DDR1-deficient cells. These findings demonstrate a novel pathway by which DDR1 promotes diabetic vascular calcification and implicate DDR1 in the regulation of microtubule assembly. Additionally, I discovered a novel function for DDR1 in the development of obesity-associated hyperglycemia and metabolic dysfunction. High fat feeding induced DDR1 expression in adipose tissue. Conversely, DDR1 deficient mice were leaner and were protected against metabolic dysfunction and had increased energy expenditure and UCP-1 expression in subcutaneous adipose tissue. In vitro, DDR1 inhibition blunted adipogenic differentiation of C3H10T1/2 cells and increased UCP-1 expression, whereas DDR1 overexpression suppressed UCP-1. These findings suggest that DDR1 deletion promotes beige fat formation whereas DDR1 suppresses it. Adipose tissue fibrosis is a known suppressor of beige fat formation and DDR1 has known functions in mediating fibrosis. Consistent with this, DDR1 deficient mice had decreased adipose tissue fibrosis, implicating DDR1 in the regulation of adipose tissue remodeling and whole-body energy metabolism, possibly by suppressing beige fat formation while concurrently promoting adipose tissue fibrosis. In conclusion, the research presented in this thesis demonstrates a signaling mechanism by which DDR1 promotes vascular calcification and uncovers a novel function of DDR1 in the regulation of adipogenesis, beige fat formation, and adipose tissue fibrosis. Taken together, these observations suggest that DDR1 is an important matrix sensor and determinant of cellular differentiation.

Keywords: atherosclerosis
brown fat
diabetes
energy expenditure
obesity
vascular calcification
Advisor: Bendeck, Michelle P
Mountains of Time: Historical Consciousness and Sacred Mountains in Japan

This dissertation presents an ethnographic account of mountain asceticism and pilgrimage in Dewa Sanzan, a sacred mountain range in Yamagata Prefecture, Japan. I argue that the space of Dewa Sanzan, like that of other sacred mountains in Japan, stands not only in topographical contrast with the urban sprawl in valleys below, but also in temporal contrast with a culturally and historically unique form of capitalist modernity. For contemporary practitioners, mountain ascetic rituals and pilgrimage bend the linear, clock-time of capitalist modernity into a premodern-like cyclical time of annual rebirth in the mountain’s symbolic womb and of ancestral return on mountain summits. Each chapter of this dissertation explores different ways in which Mount Haguro, Gassan, and Mount Yudono, the three mountains of Dewa Sanzan, constitute a spatiotemporal alterity in modern Japanese society. Dewa Sanzan is a place that evokes modes of historical consciousness for visitors, some of which are contested, but all of which reach into the past as imagined. Engagements with the spatialized past of Dewa Sanzan enable modern people to fashion themselves anew, reconnect with ancestors, and gain a critical perspective of society.

Keywords: Historical Consciousness
Japan
Place
Religion
Time
Advisor: Boddy, Janice
Sanders, Todd