VictorJuiz/thesis huggingface dataset:
The Costs and Clinical Consequences of Rheumatoid Arthritis: Applying Novel Causal Attribution Methods to a Complex Chronic Disease

Rheumatoid arthritis (RA) is a lifelong chronic disease affecting about 300,000 Canadians (1% of the population). The complicated treatment pathways and patterns of care for rheumatoid arthritis combined with a high burden of disease make RA a fascinating candidate for testing new methodological approaches to measure the clinical and economic impact of chronic diseases. The treatment pathway for RA involves patients presenting with potentially non-specific symptoms (fatigue, unspecified joint pain etc.), receiving a diagnosis, then being treated with 1 of 4 conventional synthetic disease modifying anti rheumatic drugs (csDMARDS) or 1 of 10 biologics (bDMARDs). Treatment changes in drug regimens are common when medications fail to control disease activity, or initially control disease activity but eventually fail to control disease activity. The treatment structure is unique because csDMARDS (500-900 CAD/yr), can be prescribed in combination with each other or biologics (15,000-30,000 CAD/yr) which can only be prescribed 1 biologic at a time, resulting in thousands of potentially unique treatment pathways. Furthermore, the clinical paradigm of RA has shifted to target inflammation reduction to reduce the direct effects of RA and the systemic inflammatory effects of the disease through adequate control with medications. This unique clinical pathway has led to several important questions. These questions centre around what the true costs and comorbidities attributable to RA are, what proportion of costs and comorbidities are attributable to RA related inflammation, and how have the introduction of biologic medications affected costs and comorbidities over time. This thesis applies causal attribution methods that have not been used in the field of RA, while also utilizing best-practice methods in longitudinal study1-4 design by carefully considering the selection of matched case-control cohorts over time. We used all available follow-up and disease history and available covariates to implement a data-driven approach to case-control matching. Using the population of Ontario RA cases, we applied these methods to determine the associated attribution RA to the acquisition of health care costs and comorbid conditions over a 22-year time horizon.

Keywords: chronic diseases
computational methods
data driven analysis
mahalanobis distance
rheumatoid arthritis
statistical methods
Advisor: Bombardier, Claire
Modeling, Designing and Evaluating Fully Dilutable Self Microemulsifying Delivery System for Hydrophobic Pharmaceuticals and Nutraceuticals

Many newly discovered drugs and nutraceuticals are hydrophobic in nature. When these drugs and nutraceuticals are ingested, their low aqueous solubility limits their ability to dissolve in intestinal fluid and eventually permeate the intestinal membrane to become bioavailable. To overcome this limitation, various delivery systems have been developed to enhance the solubility and absorption of active ingredients. Lipid-based delivery systems (LBDS) such as microemulsions (μE) and self-microemulsifying delivery systems (SMEDS) are among the most advanced systems. However, there are multiple technological challenges in the design and applications of SMEDS. Using lecithin as the main surfactant and hydrophilic and lipophilic linkers as co-surfactants, a platform was developed to produce food-grade, fully dilutable microemulsions containing hydrophobic solutes. The in vitro and in vivo experiments showed a high solubilization capacity for hydrophobic solutes. For ibuprofen, used as a model solute a significant improvement in absorption and bioavailability was observed. The results also showed a shorter absorption time and a longer drug circulation time when ibuprofen was formulated in fully dilutable system. The main tool used to design the fully dilutable SMEDS was the hydrophilic-Lipophilic –Difference (HLD) framework. HLS was used to predict the phase inversion point of surfactant-oil-water (SOW) systems as a function of formulation composition. The HLS was further coupled with Net-Average0Curveture (NAC) model to predict the minimum surfactant required to produce fully dilutable systems. The same tool was also used to characterize the effect of the solute on the formulation and design reformulation strategies to maintain the fully dilutable path. To explore the potential for controlled release with SMEDS, the idea of integrating the concepts of SMEDS and organogels was explored. This novel self-dispersing organogel provides 1-4 days release, which is a substantial improvement over the improved release obtained with SMEDS alone.

Keywords: Drug Delivery system
Microemulsion
Nanoencapsulation
Nutraceuticals
SMEDDS
Advisor: Diosady, Levente
Acosta, Edgar
The Threat of Small Things: Patterns of Repression and Mobilization against Micro-sized Groups in Indonesia

Why do very small groups become targets of mobilization and repression? Given their economic and political insignificance, most theories of ethnic and religious conflict expect groups that are less than 1 percent of the population—what I call micro-sized groups—to be ignored. Yet, micro-sized groups like the Jehovah’s Witnesses in Eastern Europe and the Baha’i in Iran have been targets of high levels of state repression and collective mobilization. I argue that the threat of micro-sized groups is linked to fears about group boundaries in flux. When micro-sized groups challenge the institutions, routines, and practices that form the foundations of group belonging through the marking of public space (“visible constitutive threat”), it is seen as a danger to the larger group’s continued existence. Micro-sized groups thus become seen as a perceived threat to the larger ethnic, religious, or national group when: 1) they present a visible constitutive threat; and 2) political entrepreneurs are incentivized to amplify these visible constitutive threats for their own interests. Using archival data, a geo-coded events dataset, and over 135 interviews collected over 17 months of fieldwork, I develop my argument through a study of the Ahmadiyah sect in Indonesia. I show that Ahmadis were a constitutive threat to Muslims in Indonesia because their practices challenged those that allowed a diverse people to belong to a single category. However, Ahmadis were only seen as threatening when these constitutive challenges were publicly visible. When electoral reforms increased the relevance of local clientelist networks, political entrepreneurs were incentivized to exploit and amplify the Ahmadiyah threat. Rates of anti-Ahmadiyah activity consequently multiplied. By identifying why and how micro-sized groups come to be seen as threats, my work challenges longstanding assumptions about the necessary material dimensions of threat. It instead suggests that threat construction and perception is not just driven by concerns around access to resources, but is shaped by a group’s public visibility. Broadly, understanding how visible constitutive threats operate can shed light on political phenomena that appear to be costly, inefficient, and irrational. Finally, my work speaks to the burgeoning literature linking clientelism to conflict.

Keywords: Ethnic Conflict
Indonesia
Qualitative Methods
Religious Conflict
Southeast Asia
Symbolic Politics
Advisor: Bertrand, Jacques
Performing Invisible Labour: The Globalization of Care in Aesthetic and Everyday Practice

This thesis examines how labour associated with the reproductive sphere—labour historically consigned to women and continually undervalued yet needed to sustain and reproduce daily life—is politicized or made visible through aesthetic and social practices. Tracing the transformation of reproductive work from an unpaid and unrecognized duty shouldered by housewives to a feminized, racialized, and globalized form of waged labour performed by migrant women, I explore the entanglements between labour, gender, migration, and performance in the context of post-Fordist, neoliberal, advanced capitalism. Through close analysis of artistic production, political struggles, commercial interests, market forces, and urban practices that reveal distinct ways of rendering the private public, I show how domestic labour has changed in site, character, and value, and argue that current efforts to theorize, analyze, and valorize such work must respond to shifting divisions of labour and changing social relations of value production. This project begins with social feminist and artistic efforts to visibilize and politicize women’s hidden labour at key moments in the development of global capitalism. It is followed by close readings of gendered labour and durational performance in narrative films that query cinema’s capacity to render visible the otherwise invisible labour of women through its explorations in extended duration and everyday spaces. Next, I explore the affective performances of transnational domestic workers captured in audition videos by online employment agencies. I argue that mobility for these migrant women is dependent on their performances of servility, and that the circulation of these videos on YouTube reproduces the ‘foreign maid’ as a global commodity. I then turn to Filipina domestic workers occupying public spaces in Hong Kong. Considering their increased visibility, their community-building efforts, and their growing awareness of the social and economic value of their labour, I explore the possibilities of transnational domestic labour as a site from which political subjectivities might be constituted. These various case studies, while operating along different aesthetic categories, social registers, and geopolitical contexts, are key sources of analysis for understanding social reproduction and provide distinct perspectives from which to theorize care work, its value and meaning, in the twenty-first century.

Keywords: affective labour
gender
migration
performance studies
social reproduction
transnational domestic workers
Advisor: Quayson, Ato
Rights to Settle? —Comparing Migrant Care Worker Policies in Taiwan and South Korea

Industrialized countries around the world are facing rapid demographic changes, including declining fertility rates, greater longevity, and an aging population, and these are creating unprecedented challenges in care provision. Many East Asian countries have used migrant care workers to solve the challenges of labour shortages in the social welfare sector. The purpose of this dissertation is to understand why East Asian countries have adopted different policy approaches to recruit migrant care workers. Specifically, it investigates why Taiwan’s policies are designed to recruit “household care workers with a temporary contract” while South Korea’s policies focus on “institutional care workers with access to long-term settlement”? The dissertation explores this question by probing the politics of eldercare and care migration and tracing the development of migrant care worker policies. By employing a framework that intersects care, employment and migration regimes, it highlights the institutional contexts that shape how a country designs its migrant care worker policies. It argues that migrant care worker policies manifest how care work, citizenship, and gender equality are defined and contested by the receiving society. It also demonstrates how the development of migrant care worker policies reflects the legacies of earlier policy decisions, by illuminating the political actors with access to the policymaking process. Based on archival research and 53 personal interviews with government bureaucrats, policymakers and migrant worker activists, the dissertation maps out the political mechanisms that determine the levels of rights, labour mobility, and access to membership rights for migrant care workers in Taiwan and South Korea. It challenges conventional understandings of policy as formal and static and posits the formation of migrant care worker policy as an organic process which is modified and contested as part of a political process.

Keywords: Care Migration
East Asia
Eldercare
Migrant Care Workers
Migration Policy
Welfare State
Advisor: Wong, Joseph
Peng, Ito
Homelessness and the Commons: A Theory of Expressively Egalitarian Regulation

This doctoral thesis examines homelessness and the regulation of public property from the perspective of the republican theory of freedom (or republicanism). Republicanism construes freedom as non-domination, meaning the absence of others’ power to interfere with an individual’s actions and purposes. Expressive egalitarianism is a political ideal whereby the state expresses equal respect for individuals. This doctoral thesis advances A Theory of Expressively Egalitarian Regulation. Its central claim is that republicanism provides new insight into the reality of homelessness and how the regulation of public property undermines homeless people’s liberty in ways that existing theories ignore. Republicanism also serves as the foundation for a theory of how laws that govern public property in Canada and the U.S. can operate in a more expressively egalitarian manner, by mitigating domination and treating homeless people with greater respect. This project culminates with concrete proposals that aim to eliminate the most egregious forms of domination that homeless people experience from those laws. A Theory of Expressively Egalitarian Regulation elucidates why laws that govern public property subject homeless people to two distinct forms of domination. First, others can exert control over homeless people’s opportunities to obey laws that regulate public property. Second, homeless people must make non-egalitarian sacrifices to their basic interests to obey laws that manage public property. A core tenet of A Theory of Expressively Egalitarian Regulation is that the justifications for regulating public property result in two fundamental problems for homeless people that are elucidated by the republican theory of freedom: the non-egalitarianism and entrenchment problems. The non-egalitarianism problem implies that the state has a greater capacity to regulate and police homeless people’s basic human acts (e.g.: urinating, defecating, sitting, sleeping, etc.), whereas people with access to housing are meaningfully protected against such regulation and its enforcement. The entrenchment problem implies that the state possesses the power to entrench people in the condition of homelessness, where individuals will continue to be subject to domination that stems from the non-egalitarianism problem. Certain practical limitations (both constitutional and political), however, currently stand in the way of eliminating the domination to which homeless people are subject exclusively through the allocation of resources and entitlements by the state. For that reason, it is necessary to consider how laws that govern public property can subject homeless people to less domination and express greater respect for homeless people. This thesis concludes by offering concrete proposals for how the state can strive to achieve those aims.

Keywords: Homelessness
Law
Legal theory
Poverty law
Public property
Advisor: Thorburn, Malcolm
Impacts of Perinatal High Fat Diet and Prenatal Stress Exposure on the Programming of the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-like Behaviour in Rats

The maternal environment has a profound effect on the development of offspring, including responses to stress mediated by the hypothalamic-pituitary-adrenal (HPA) axis. Maternal diet and stress are two environmental factors that program the HPA axis in a manner that persists throughout adulthood, however there are no reports of their joint effect on the development of the HPA axis and anxiety-like behaviour. The objective of this thesis was to examine the effects of maternal obesity in the form of high fat diet (HFD) consumption and maternal stress in the form of exposure to chronic variable stress (CVS) on stress-related behavioural, endocrine, and molecular measures in neonatal and adult offspring in rats. I hypothesized that combined effects perinatal HFD and prenatal CVS would have synergistic effects on programming of stress-related phenotypes. I observed strong main effects of perinatal HFD on offspring anxiety-like behaviours and HPA axis physiological responses. Interestingly, CVS normalized the effects of perinatal HFD on anxiety-like behaviour in adult female offspring and physiological stress response in neonate offspring. I also characterized maternal physiological and behavioural responses to HFD consumption and CVS exposure and found increased sensitivity to CVS in HFD dams. Further, examining the interaction between the dam and neonatal offspring using maternal behaviour and pup ultrasonic vocalization (USVs) characteristics, I found impaired pup retrieval in HFD dams and altered USV characteristics in HFD neonates. Finally, due to the main effects of perinatal HFD on behavioural and physiological phenotype, I examined differential effects of maternal HFD consumption on offspring gene expression and the epigenome in brain regions that regulate the HPA axis. I observed increased Crh expression in the PVN and decreased Nr3c1 expression in the ventral hippocampus in neonates along with differential methylation of genes involved in neuronal development in the amygdala. In adulthood, HFD induced differential DNA methylation in genes involved in protein phosphorylation, specifically GTPase related genes. Findings in this thesis provides several avenues for future studies in both mother and offspring, including possible intervention studies targeting dam-pup interaction and molecular mechanism underlying the programming effects of perinatal HFD in offspring.

Keywords: Behaviour
Epigenetics
HPA Axis
Maternal Programming
Obesity
Stress
Advisor: McGowan, Patrick O
Functional Annotation of Uncharacterized Enzymes in Saccharomyces cerevisiae

In the post-genomic era, clinicians and scientists are increasingly reliant on interpretation of variants in metabolic genes for determining pathogenicity. These interpretations depend on functional annotation of the roles genes provide in metabolism, annotation which is far from complete. I embarked on a journey of enzyme discovery to fill gaps in our knowledge of metabolism in the budding yeast, Saccharomyces cerevisiae. I carried out a genetic and metabolomic screen of 120 uncharacterized candidate enzyme encoding genes that comprised my MSc. This dissertation describes my work in ascribing function to two distinct enzymes, Das2 and Tda5. Throughout my study I have found that Das2 is a novel uridine/cytidine kinase that functions in concert with a second minor uridine kinase, Urk1. These two enzymes are interdependent and in turn depend on a third enzyme, the major uracil phosphoribosyl transferase, Fur1 for stability. These three enzymes form a complex that is essential to wild-type pyrimidine salvage. As I aimed to elucidate the function of Tda5, I discovered that this uncharacterized enzyme is essential to growth. Loss of function mutations in TDA5 are alleviated by de-repression of its sporulation specific paralog, Ydl114w, and when YDL114W is deleted, tda5Δ is rescued by hypomorphic mutations in the ergosterol biosynthetic pathway. Analysis of metabolite levels in hand with nutritional sensitivities and genetic interaction data support the essential role of Tda5 in lipid homeostasis. Together, these studies assign new functions to previously uncharacterized genes and reveal functional interdependence of enzymes that sheds light on metabolic interpretations of genetic data.

Keywords: Enzyme
Functional Genomics
Metabolism
Metabolomics
Saccharomyces cerevisiae
Advisor: Caudy, Amy A
Exosomal microRNAs in Cerebrospinal Fluid as Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons from the brain, brain stem, and spinal cord, resulting in progressive paralysis and death. Patients with frontotemporal dementia (FTD) usually present with either behavioural or language impairment secondary to atrophy of the frontal and/or temporal lobes. Recent evidence suggests that about 15% of patients with ALS develop FTD and about 15% of patients with FTD develop ALS. ALS and FTD are typically diagnosed months to years after symptom onset. Hence, there is an unmet need to enhance the diagnostic process. The overlap in clinical presentation and the recent discovery of shared genetic and pathological features have changed our view of ALS and FTD, which are now often thought of diseases on a spectrum, rather than two distinct disease entities. Aberrant RNA processing causing dysfunction of vital cellular processes has emerged as a common theme in ALS and FTD research. There is increasing evidence that alterations in the expression of non-coding RNAs, such as microRNAs (miRNA or miR-), occur in ALS and FTD. In human biofluids, miRNAs have been found enriched in small vesicles termed exosomes, providing an opportunity for miRNA biomarker profiling in ALS and FTD with the goal to identify miRNAs that have diagnostic value. Studies presented here have identified dysregulated exosomal miR-204-5p and miR-632 in cerebrospinal fluid (CSF) as diagnostic biomarker candidates for genetic FTD and miR-632 also for sporadic FTD. For ALS, we provide evidence for altered exosomal 16-5p, miR-376c-3p, miR-451a, miR- 632, and miR-2110 expression in CSF. In silico analysis uncovered targets of these miRNAs in biological pathways associated with ALS and FTD. TAR DNA-Binding Protein 43 (TDP-43), a hallmark protein of ALS and FTD pathology, has been shown to be implicated in different steps of miRNA biogenesis and data presented here further supports the role of TDP-43 in the dysregulation of exosomal miRNA. As such, exosomal miRNAs may represent disease-relevant biomarkers with potential to improve the diagnostic process resulting in earlier and more accurate diagnosis of ALS and FTD.

Keywords: Amyotrophic lateral sclerosis
Frontotemporal dementia
microRNA
Advisor: Robertson, Janice