VictorJuiz/thesis huggingface dataset:
Associations between Allopurinol and Cardiovascular and Renal Outcomes in Diabetes
Keywords: allopurinol
clinical epidemiology
diabetes
gout
pharmacoepidemiology

Diabetes is a leading cause of cardiovascular and kidney disease, and novel therapies to reduce these adverse diabetes outcomes are urgently required. Allopurinol, a uric acid-lowering therapy traditionally used for the treatment of gout, may reduce mortality and cardiovascular and kidney disease through reductions in oxidative stress and improved endothelial function, but this has not been well-studied in diabetes. Through three related projects, this thesis examines the associations between allopurinol and all-cause mortality, cardiovascular and renal outcomes in individuals with diabetes using population-based administrative health care data in Ontario, Canada. The first project examined patterns of allopurinol use and their predictors, to inform the design of subsequent studies. In 38,416 individuals with diabetes newly prescribed allopurinol, discontinuation and interruption of allopurinol were common. Female sex and greater severity of gout were associated with worse adherence. The second project evaluated the association between allopurinol-exposed time and all-cause mortality and cardiovascular outcomes in 38,416 new allopurinol users with diabetes. Allopurinol-exposed time was associated with a reduced risk of the primary composite outcome of all-cause mortality, atherothrombotic cardiovascular events (myocardial infarction, revascularization, stroke), or heart failure, which was primarily driven by a reduction in all-cause mortality. However, healthy user bias could not be completely excluded. The third project evaluated the association between allopurinol use and progression of chronic kidney disease (CKD) or development of end-stage renal disease (ESRD). In 5937 individuals with a gout flare and Stages 1 to 3 CKD at baseline (1911 with diabetes), renal outcomes did not differ between allopurinol users and non-users after weighting by the inverse probability of treatment. Based on the thesis results, allopurinol may reduce mortality and atherothrombotic cardiovascular events in individuals with diabetes, but does not appear to reduce heart failure, CKD progression, or development of ESRD. Defining allopurinol exposure in pharmacoepidemiology studies is challenging due to frequent interruptions and discontinuation. Thus, study designs incorporating time-varying exposure and time-varying confounders may be more robust. A clinical trial designed to evaluate the effect of allopurinol on atherothrombotic cardiovascular events in individuals with diabetes and hyperuricemia is strongly justified.
Andante, Allegro o Silenzio: An Examination of Background Music Tempo on Facial Emotions, Electrodermal Responses, and Reading Task Performance
Keywords: Educational psychology
Emotion
Emotion regulation
Music cognition

Current literature has established that learner’s emotions are an integral part of the learning experience (Pekrun Perry, 2014) and have significant effects on learning processes that optimize performance (Cunningham, Dunfield, Stillman, 2013), and attentional responses (Kärner Kögler, 2016). This present study examines the psycho-emotional and psychophysiological effects that variations in the tempo of background music have on learners who are completing reading comprehension tasks. To accomplish this, the present study examines how learning performance is modulated through the expressed emotions and bodily responses of participants and how our understanding of the relationship between the emotional experience and cognitive functions in learning tasks. A total of seventy-four (N= 74) participants studied in this project indicated that the tempo condition that participants were exposed to while competing their reading comprehension task did have a significant effect of predicting their performance outcome, emotional expressions, and psychophysiological responses. Results indicated that participants were more likely to have lower performance scores accompanied with the likelihood of greater expressions of fear, joy and contempt, along with greater skin conductance responses when listening to fast tempo music (150bpm). These results can suggest that a combined regulatory mechanism may be at play that helps indicate the combined effect that music may have on cognitive performance, attention allocation, and emotion regulation.
Noncoding Mechanisms in NF-κB Driven Vascular Endothelial Cell Inflammation
Keywords: CCL2
endothelial cells
epigenetics
long noncoding RNA
NF-kB
super-enhancer

Vascular inflammation is an integral step in the initiation and progression of atherosclerosis.Mediated primarily by the nuclear factor kappa B (NF-κB) signaling pathway, vascular endothelial cells (EC) produce pro-inflammatory cytokines and adhesion molecules which facilitate monocyte recruitment and their subsequent transmigration through the endothelium. Noncoding mechanisms at the chromatin and noncoding RNA levels have been implicated in the development of atherosclerosis. Understanding these noncoding processes is imperative as they can provide ways to control and fine-tune aberrant vascular inflammation. Therefore, this dissertation aimed to elucidate how EC inflammation is regulated by long noncoding RNAs (lncRNAs) and NF-κB-chromatin interactions. LncRNAs are a heterogeneous class of noncoding transcripts >200 base pairs in length, many of which have been reported to act in cis to regulate the expression of their neighboring genes. Work in this dissertation has identified interleukin-1β (IL-1β) regulated neighboring mRNA-lncRNA pairs which were defined based on localization on the same topologically associated domains (TADs), divergent transcription, and shared regulatory elements. This approach led to the discovery of lncRNA-CCL2 which is transcribed divergently to CCL2, encoding a chemokine that is involved in monocyte recruitment. Moreover, lncRNA-CCL2 was found to positively regulate CCL2 transcript levels via interaction with RNA binding proteins. The second half of the dissertation used evolutionary conservation and NF-κB chromatin interaction status as a way to delineate which NF-κB binding sites are likely to regulate gene expression. It was found that accessible chromatin regions bound by NF-κB prior to tumor necrosis factor alpha (TNFα) treatment showed the highest degree of evolutionary conservation and were enriched near TNFα up-regulated genes. Furthermore, deletion of several TNFα pre-bound and conserved NF-κB sites, particularly within the CCL2 super-enhancer, showed them to be important for gene regulation. Altogether, these findings increase our understanding of the noncoding mechanisms implicated in vascular inflammation and in the future could be targeted to selectively fine-tune the EC inflammatory response.
Flipping the Paradigm: The Conceptualization and Practice of Mental Healthcare in Ontario Prisons
Keywords: Health
Incarceration
Mental Healthcare
Mental Illness
Prison
Social Policy

This dissertation focuses on understandings of mental illness and on the organization and delivery of mental healthcare in Ontario prisons. In the process, I identify a nascent model of correctional medicine in Ontario prisons. Having interviewed both medical professionals and correctional personnel, I give a voice to those who deliver care in prisons in Ontario, a voice that has been rarely heard. Although my focus is on the provision of mental healthcare, the study offers a window into the workings of provincial prisons more generally. Multiple reports, commissions, and ombudspersons have called for improvements to mental healthcare for people in custody. Missing in these discussions is clarity about who and what is being talked about. I start to answer these questions and describe what care is being provided and for whom. I also show that the current practices define people out of the category of mentally ill rather than in. ‘Defining out’ perpetuates the inadequacy of care. Moreover, the inherent subjectivity of mental health diagnoses and treatment is not being mediated by appropriate communication among those delivering care in prisons. I discuss how prisons are becoming de facto mental health facilities; how institutional responses vary across the province of Ontario; and how everyone dealing with mentally ill individuals has to improvise – sometimes just to get everyone through the day as safely as possible. My findings indicate that correctional officers operate with insufficient understandings of mental illness to effectively carry out their current roles as central gatekeepers to mental healthcare. As a result, medical professionals have limited access to the people who would benefit from that expertise. I show how practitioners perceive the patterns of mental healthcare delivery in correctional settings and expose an emerging model of medicine that is distinct from both community medicine and forensic medicine. Throughout the dissertation, I argue for the need to flip the paradigm of mental healthcare from one with a singular focus on illness to one that focuses on wellness in order to better address the mental health needs of all people in prison, including those experiencing forms of ‘un-wellness’.
Recombination Restriction, Degeneration and Population Divergence on Plant Sex Chromosomes
Keywords: haploid selection
recombination
sex chromosomes
speciation

This dissertation investigates patterns of sex chromosome evolution in the dioecious plant Rumex hastatulus, an annual species with two distinct largely allopatric sex chromosome cytotypes (females XX and males XY or XYY). My thesis addresses three general observations often associated with sex chromosome evolution, which are summarized in Chapter 1: i) the degeneration of the Y chromosome, ii) the lower rates of recombination between the X and Y chromosomes compared with the rest of the genome, and iii) the finding that sex chromosomes contribute disproportionately to population genetic divergence. In Chapter 2, I demonstrate that in R. hastatulus the loss of gene expression precedes gene deletion from the Y, suggesting that the loss of constraint allowed by lowered expression is a prerequisite for gene loss on the Y chromosome. In Chapter 3, I show that pollen-expressed genes are significantly less likely to be lost from the Y chromosome during degeneration with important implications for selection during the haploid phase of the life cycle. In Chapter 4, construction of a linkage map revealed that the sex chromosomes probably arose in a pericentromeric region and population-level analyses estimated very low rates of recombination across this region prior to sex chromosome evolution. These findings are consistent with the hypothesis that low rates of recombination predate the origin of sex chromosomes and likely facilitated their evolution. In Chapter 5, my studies of demographic history revealed that during a historic period of reduced gene flow between the cytotypes of R. hastatulus, both the X and Y played a more significant role in genetic divergence than autosomes. My demographic modelling also suggests an X-A fusion event occurred at roughly the same time as the loss of gene flow between the cytotypes. Finally, in Chapter 6, I detect reduced gene flow around the fused region of the X chromosome in R. hastatulus and show biased segregation of the fused X in an F2 cross implicating the presence of a selfish transmission advantage. My thesis research highlights that even in plants, where sex chromosomes are rare, the sex chromosomes are of outsized evolutionary importance in species that bear them.
A Class Full of Class Clowns: A Case Study On The Education of Aspiring Comedians
Keywords: Comedy
Education
Humour

Stand-up comedy is not just for entertainment. It is a platform that many comedians have used to question hierarchies, critique social injustice and inspire change (Chattoo, 2019; Gilbert, 2004; Bingham Hernandez, 2009). For this reason, it is important to understand the education and progression of aspiring comedians as they embark on their journey as social influencers. The purpose of this study was to examine the comedy principles that students learned and how they applied these to their own practice. This study also examined the instructional approaches of stand-up comedy instructors as they guided students with their professional expertise. To inform my case studies, I observed two stand-up comedy classes over a sixteen week period. My results showed that instructors used a balance of different feedback and modeling techniques to create a safe space for their students to explore their comedic creativity. For the students, the classes were a practice on self-reflection, as they learned the importance of drawing on their own experiences to create authentic stage personas. Through their writing and their performances, they also had to negotiate ways to be relatable to their audience. However, one of the major challenges that students encountered was finding the right balance in showing and sharing their vulnerable sides. Some students had difficulties navigating “the hurtline” (Perez, 2013), while others over-relied on negative self-deprecating humour. This study supports the idea that being a comedian is much more than “being funny” and telling jokes. It also highlights the importance of the self and drawing on lived experiences in the composition and performance of comedy. The implications of this study go beyond the stand-up comedy profession, as the resulting instructional themes can be applied to arts education. Additionally, the principles of being a comedian can be applied to everyday social interaction as humour plays a significant role in our lives.
Postgraduate Medical Education (PGME) Selection and Admissions: Intentions and Perceptions
Keywords: Admissions
Intentions
Medical Education
Perceptions
PGME
Selection

This study explores residents’ and faculty members’ experiences of the selection and admissions process in postgraduate medical education (PGME). The purpose of the study is to understand how postgraduate residency programs make selection and admissions decisions and how residents believe those decisions are made. Faculty and residents from a Family Medicine program and a Paediatrics program at a large university were interviewed to determine the potential degree of alignment between the programs’ intended selection and admissions processes and the residents’ perceptions of these processes. This research provides an opportunity for participants to reflect on their experiences in their role as an applicant, a committee member, a file reviewer, an interviewer and/or an administrator in the PGME selection and admissions process. Gaining a better understanding of the intentions and perceptions of the PGME selection and admissions process from both faculty and residents has the potential to enhance the PGME selection and admissions process through increased transparency and common understanding of faculty members’ and residents’ experiences. Individual interviews were conducted with faculty to understand how postgraduate residency programs make admissions decisions. Individual interviews were conducted with residents to determine how they believe those decisions are made. Borrowing elements from a phenomenological methodological approach within an interpretivist research paradigm allowed for flexibility in the way data were collected and analyzed Both faculty and residents viewed the process as complex and difficult to navigate. The two groups differed in their perceptions of the characteristics of the ideal applicant, the relative weights of selection criteria, possible biases of the selection committee, red flags, the best methodologies for selecting applicants, and common vulnerabilities in the process. The discussion highlights the importance of faculty members’ and residents’ development of their individual and professional identity through the PGME selection and admissions process. Findings of this study can inform future decisions in refining the process and communications about the process.
Understanding How Minoritized Female Legal Professionals Negotiate Extra-corporate Commitments and Legal Practice
Keywords: Equity
Higher Education
Law
Professional Education
Race
Sociology

ABSTRACT This thesis examines the experiences of minoritized female legal professionals working in law and aims to explore how minoritization is reproduced in the legal profession. How lawyers, law clerks and legal assistants navigate legal practice as well as practices in social justice throughout their careers is revealed through professional and personal narrative. The study documents their struggle to “fit” in the profession filling in the everyday/everynight reality of working in law, and reveals there is negotiation at every stage of their careers. Methodologically, I have chosen an anti-racist theoretical analysis as well as Clarke and Smith's theories. Using institutional ethnography, I start with the broad question of what is the lived experience of minoritized women working in corporate law? I employed a mixed method design using interviews to examine the experiences of 12 minoritized female legal professionals, including myself, at various stages in their legal careers. I also analyze certain “texts” used and relied upon by the legal community to understand how they are informed by the ruling relations and how they in turn, inform governance and social relations. The study reveals there is systemic discrimination and disadvantage in the profession and the story of disadvantage for minoritized female legal professionals working in law is one of cumulative inequity and trauma.
Rearing Autonomous Children in Cold War Korea: Transnational Formations of a Liberal Order, 1950s-1960s
Keywords: cultural Cold War
history of childhood
liberalism
modern Korea
postwar reconstruction
transnational history

This study argues that the liberal project to raise children into autonomous subjects in 1950s and 1960s South Korea was crucial to transnational formations of a new Cold War liberal order. The study explores four realms of childhood — bedrooms, children’s literature, infant feeding, and children’s psychology — in order to illustrate how the seemingly apolitical issue of rearing children operated as a nexus for the construction of an anti-communist, capitalist society. In particular, the liberal ideas of autonomy, freedom, and individuality as a shared value system enabled the transnational circulation and coproduction of a Cold War liberal order. The disavowal of the political nature of rearing autonomous children was fundamental to the everyday practices of transnational anti-communism, in which people in multivalent roles such as mothers, children, home architects, psychologists, and educators actively participated. With sources ranging from children’s literature, women’s magazines, infant formula advertisements, home designs, psychological advice for children, and government publications, this study takes an interdisciplinary approach to the history of childhood, the sociocultural history of the Cold War, and modern Korean history. Chapter 1 examines how home architects and planners advocated for the “independence” of children’s rooms as necessary in cultivating children’s autonomy. Chapter 2 explores the children’s magazine Sonyŏn segye (Boys’/Children’s World) as a site of transnational Cold War modernism, insisting that children should cultivate their own autonomous creativity based on “child-like” experiences and expressions. Chapter 3 examines the complex ways in which children were highly gendered and racialized along multiple lines of ethnicity, nation, and region through infant formula market campaigns targeting mothers. Finally, Chapter 4 examines how the psychological testing of children reproduced the ideology of capitalist competition as a form of freedom and equality and rendered the inequalities created by gender, class, and other variables as purely individual differences to be psychologically managed by the liberal individual. Taken as a whole, this study treats childhood as a fulcrum through which many enduring questions of national sovereignty, decolonization, postwar reconstruction, and anti-communism were contested within the Cold War milieu.
Functional Genomics identify Novel Therapeutic Vulnerabilities in Retinoblastoma
Keywords: cancer
drug combination
functional genomics
retinoblastoma
therapeutic target
therapy

Retinoblastoma is a pediatric cancer caused by loss of the RB1 tumor suppressor gene or, in rare cases, amplification of the MYCN oncogene. Improved treatments are required to salvage the eye, retain vision, and reduce chemotherapeutic toxicity. Here, we utilized network analysis to identify perturbed protein-protein interaction hubs, and in vivo RNAi screens to expose essentiality. Top hits, in both RB1null and MYCNamp tumors, included BRCA1 and RAD51, which promote DNA repair via homologous recombination. Targeting RAD51 with siRNA or a small molecule inhibitor, B02, selectively killed retinoblastoma cells, and B02 synergized in vivo with topotecan (TPT), standard-of-care chemotherapy. Synergy operated via increased DNA damage, activation of CHK kinases, and engagement of the p53-BAX pro-apoptotic pathway. We also identified a tumor insensitive to B02+TPT, paradoxically exhibiting elevated DNA damage. In this case, a subset of cells was spared due to preferential activation of the p53-p21 axis and cell cycle arrest. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53-BAX axis, and synergized with B02, TPT or both to overcome resistance. In addition, the in vivo screens confirmed essentiality of SKP2, a component of the multi-subunit Cullin Ring Ligases (CRLs) that ubiquitylate and target proteins for degradation. CRLs rely on Cullin neddylation for their activity, and we found the neddylation inhibitor MLN4924 mimicked many of the effects of SKP2-depletion. Moreover, intravitreal MLN4924 shrunk orthotopic retinoblastoma xenografts, and CRISPR/Cas9 screens linked hypersensitivity to DNA damage, p53 and E2F3 signaling. MLN4924 also synergized with standard-of-care therapies, which we linked to enhanced DNA damage, but also amplified transcription and nucleolar stress. In the latter, CRISPR/Cas9 screens revealed that ribosomal proteins, MYCN, p53, E2F3, and p21 mediated drug synergy. These data expose the first example in which amplified transcription is used to drive cancer cell death. Finally, a clinically relevant schedule of dual MLN4924/TPT led to 100% complete responses while preserving vision. In summary, this work provides mechanistic and preclinical evidence that inhibiting HR and NEDD8 are promising new retinoblastoma therapeutic strategies. The many new synergistic combinations identified in this thesis could lead to improved therapies for retinoblastoma and potentially other RB1-deficient cancers.