VictorJuiz/thesis huggingface dataset:
Cardiovascular Disease Risk Markers in Young Adults: 9p21 Genotype, Plasma Proteomics and Dietary Patterns
Keywords: Cardiovascular-Disease
Dietary Patterns
Genomics
Nutrigenomics
Personalised-Medicine
Proteomics

Background: 9p21single nucleotide polymorphisms (SNPs) have been associated with cardiovascular disease (CVD) and to a lesser extend insulin sensitivity. Mechanisms by which 9p21 contributes to CVD development remain unknown since no annotated proteins are present. Previous studies have been in older, diseased-populations, and few have examined gene-diet interactions or the plasma proteome. Objective: To determine the association of 9p21 SNPs with traditional and emerging biomarkers of CVD risk in a diverse ethnocultural group of young-adults and assess if habitual dietary patterns modify these associations. Methods: Subjects were 1,639 young adults, from the Toronto Nutrigenomics and Health Study. Five 9p21 SNPs were genotyped. Traditional and emerging biomarkers of CVD risk were assessed from fasting blood. Dietary patterns were determined using principal components analysis with a 196-item food frequency questionnaire. Linear regression was used to assess all associations. Results: 9p21 high-risk alleles were associated with higher fasting insulin, especially in women not on hormonal contraceptives (HC). Consuming a Prudent diet was associated with a lower mean fasting insulin in homozygous carriers of risk alleles, but no associations were found with diet in non-risk alleles carriers. Gene-diet interactions were associated with lower HOMA-IR with five SNPs and lower HOMA-Beta with one SNP. When analyzing the plasma proteome; in Caucasians, risk alleles from four SNPs were associated with higher Apolipoprotein-E and two with higher Haptoglobin; while in East Asians, three SNPs were associated with higher α-1b-Glycoprotein concentrations; two with higher Apolipoprotein-B-100 and one with higher Apolipoprotein-E and Haptoglobin and in South Asians, one was associated with higher Apolipoprotein-B-100. Conclusion: 9p21 genotypes were associated with markers of insulin sensitivity and plasma proteins, which varied by ethnicity, sex and HC use. The 9p21 genotype associations with insulin markers were modifiable by a Prudent dietary pattern in the high-genetic risk group only.
Bilateral Auditory Development and Function in Children with Asymmetric Hearing Loss Who Listen with Electric and Acoustic Hearing
Keywords: Bimodal hearing
Cochlear implant
Deafness
Development
Electroencephalography
Hearing loss

This thesis aimed to determine whether treating children who have asymmetric hearing loss with two different, but appropriate auditory prostheses promotes bilateral auditory development and bilateral hearing abilities. Unilateral deafness during development drives extensive reorganization in bilateral auditory pathways, limiting spatial hearing and putting children at risk for social and educational challenges. Providing electric cochlear implant hearing to the deaf ear and acoustic sound through a hearing aid or normal hearing in the other ear (bimodal hearing) restores bilateral access to sound. But it remains unclear how the two very different auditory signals can be processed by the auditory system to prevent abnormal neurophysiological changes from occurring. Hearing development in bimodal users was assessed by measuring evoked electrophysiological changes in the brainstem and cortex, as well as behavioural perception of important differences in sounds between the two ears. Even though electrical and acoustic hearing are unique and stimulate the auditory system in different ways, symmetric neural conduction in bilateral brainstem pathways and the expected representation of each ear in the auditory cortex were achieved in children who had sufficient residual hearing in their non-implanted ear. Moreover, most children experienced a bilateral advantage for speech perception over wearing either device alone, benefited from spatial hearing and could detect changes in binaural inter-aural level cues. These findings suggest that bilateral hearing does not need to be restricted to one modality and that the auditory system can integrate bimodal hearing to some extent. However, prolonged experience with asymmetric hearing during development extensively and persistently reorganizes the auditory system, limiting future efforts to restore bilateral and spatial hearing with bimodal devices. These findings are highly relevant to the clinical treatment of asymmetric hearing loss and support the recommendation to provide the most appropriate bilateral auditory prostheses as soon as possible to children who have significant hearing loss.
Correlation Model Risk and Non-Gaussian Factor Models
Keywords: correlation
factor model
option
prices
weak GARCH

Two problems are considered in this thesis. The ﬁrst is concerned with correlation model risk and the second with non-Gaussian factor modelling of asset returns. A fundamental problem in the application of mathematical ﬁnance results in a real world setting, is the dependence of mathematical models on parameters that are hard to observe in markets. The common term for this problem is model risk. The ﬁrst part of this thesis studies the sensitivity of mathematical objects (prices) to correlation inputs. In high dimensions, computational complexities increase faster than exponentially. A typical way to deal with this problem is to introduce a principal component approach for dimension reduction. We consider the price of portfolios of options and approximations obtained by modifying the eigenvalues of the covariance matrix, then proceed to ﬁnd analytical upper bounds on the magnitude of the difference between the price and the approximation, under different assumptions. In the second part of this thesis, the assumptions and estimation methods of four different factor models with time-varying parameters are discussed. These models are based on Sharpe’s single index model. The ﬁrst model assumes that residuals follow a Gaussian white noise process, while the other three approaches combine the structure of a single factor model with time-varying parameters, with dynamic volatility (GARCH) assumptions on the model components. The four approaches then are used to estimate the time-varying alphas and betas of three different hedge fund strategies. Results are compared.
How Principals Manage their Emotions
Keywords: emotional regulation
emotions
managing emotions
principals
principals' work
work intensification

This study examines how secondary school principals manage their emotions at work. Specifically, this study used key informant interviews with 13 secondary school principals to identify conditions that lead to emotion-generating situations in their work, and to better understand the strategies they use to manage their emotions. This study also inquired about the supports secondary school principals access to mitigate emotion-generating situations. Gross’ (1998, 2001, 2002, 2010, 2013, 2014) process model for emotional regulation (ER) provides the conceptual framework for this study. The process model includes five families of ER: situation selection, situation modification, attentional deployment, cognitive change, and response modulation. The interview sample included a broad range of principals representing the diverse contexts in which contemporary principals in Ontario work. Several trends emerged when collecting and analyzing the data. For example, principals use several strategies to manage their emotions beyond those previously reported in the literature. Further, participating principals also reported using strategies associated with all five families of ER found in Gross’ process model to manage their emotions. Principals in this study also described facing conditions that can lead to emotion-generating situations, including encountering barriers when advocating for students, system-based challenges, media attention, a lack of support, and managing crises or tragedies in the school community. Although principals in this study did not describe accessing formal professional supports to help them manage their emotions, they did seek out supports within their schools, often through members of their administrative teams. This study and its findings contribute to the current research base on principals and their work, and to the emergent line of inquiry exploring the emotional nature of educational leadership. This study also discusses the implications this research could have for secondary school principals’ professional practice, provincial education policies, and administrative theory. Further, this study also provides a solid foundation for several next steps in the research process, including exploring how ER strategies influence perceptions of principal professionalism, further examining the kinds of situations that incite positive emotional responses, and determining the impact of work intensification on how principals manage their emotions.
Molecular Analysis of Phenotypic Diversity in Human Fungal Pathogens
Keywords: Cystic fibrosis
Drug resistance
Fungal microbiome
Fungal pathogen
Mycobiome

Fungal pathogens are a leading cause of human mortality, in part due to their ability to thwart therapeutic regimens by rapidly evolving resistance to antifungal drugs, and their ability to readily adapt to the hostile conditions experienced in a mammalian host. Candida species can colonize various niches in the human body making them common commensals of the mucosal microbiota, where the maintenance of a stable host-fungus relationship is presumably critical for avoiding disease. However, the importance of fungi is only beginning to be appreciated in context of the human microbiome. My doctoral research focuses on two aspects of how Candida species influence human health and disease. First, I characterized fungal communities of 28 cystic fibrosis patients by coupling high-throughput ITS1 sequencing with phenotypic analyses of fungal isolates from sputum samples. Fungal communities were not determined by clinical characteristics, but considerable phenotypic variation in traits such as antifungal resistance and morphogenesis was identified within Candida species. Notably, filamentation in the absence of inducing cues was observed in 28 Candida isolates from six patients, with most isolates harboring mutations in a transcriptional repressor of filamentation, NRG1. These mutants were resistant to the filament inhibitory effects of Pseudomonas aeruginosa, implicating interkingdom interactions as the driver of adaptation. Second, I characterized the role of the molecular chaperone Hsp90 in drug resistance and morphogenesis in an emerging fungal pathogen, Candida auris. I showed that fluconazole resistance of C. auris was independent of HSP90 expression, but in part mediated by the ABC transporter CDR1. Further, I showed that C. auris is capable of filamentous growth in response to Hsp90 depletion or inhibition. Transcriptomic analysis upon HSP90 depletion showed that filamentous growth is associated with upregulation of putative cell wall associated genes. Overall, my research provides key insights into mechanisms governing phenotypic diversity in human fungal pathogens.
Asymmetries and Ill-Being
Keywords: Axiology
Ill-being
Normative ethics
Well-being

Despite the significant attention that has been given to developing and defending theories of intrinsic prudential value, or what makes us well off, far less attention has been given to explaining what makes us intrinsically badly off. In Chapter 1, I argue that theories of prudential badness, or ill-being, do not trivially follow from theories of well-being, yet an account of ill-being is necessary for a complete theory of prudential value. In the remaining chapters, I investigate how well the major theories of well-being extend to ill-being. Considering ill-being also makes possible asymmetries between the good and the bad. I show that there are many such asymmetries, involving both structure, such as when a condition of welfare does not apply to illfare, and value, such as when the disvalue of a bad outweighs the value of its counterpart good. Chapter 2 concerns pain as the counterpart to pleasure. I argue that, in equal intensities, pain is a greater bad than pleasure is a good. Chapter 3 is on ‘adjusted subjective theories’, which adjust the value of pleasure or happiness based on other factors. I show how one theory—L.W. Sumner’s theory of welfare as authentic happiness—fails as an account of ill-being. In Chapter 4, I argue that the most common account of ill-being for the desire theory, that frustrated desires contribute disvalue, should be replaced by an aversion account, according to which there is a negative counterpart to desires. In Chapter 5, I consider two objective goods, autonomy and knowledge. I argue that autonomy has no negative counterpart, while knowledge has many counterparts, only some of which are intrinsically bad. In Chapter 6, I argue that, insofar as achievement is a plausible objective prudential good, there is a state of anti-achievement that is intrinsically bad. Finally, in Chapter 7 I show how the hybrid theory of well-being produces an implausible account of ill-being.
Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency
Keywords: ceramidase
ceramide
lysosome
sphingolipid

Farber disease (FD) is a devastating Lysosomal Storage Disorder (LSD) caused by mutations in ASAH1, resulting in acid ceramidase (ACDase) deficiency. ACDase deficiency manifests along a broad spectrum but in its classical form patients die during early childhood. Due to the scarcity of cases FD has largely been understudied. To circumvent this, our lab previously generated a mouse model that recapitulates FD. In some case reports, patients have shown signs of visceral involvement, retinopathy and respiratory distress that may lead to death. Beyond superficial descriptions in case reports, there have been no in-depth studies performed to address these conditions. To improve the understanding of FD and gain insights for evaluating future therapies, we performed comprehensive studies on the ACDase deficient mouse. In the visual system, we reported presence of progressive uveitis. Further tests revealed cellular infiltration, lipid buildup and extensive retinal pathology. Mice developed retinal dysplasia, impaired retinal response and decreased visual acuity. Within the pulmonary system, lung function tests revealed a decrease in lung compliance. Mice developed chronic lung injury that was contributed by cellular recruitment, and vascular leakage. Additionally, we report impairment to lipid homeostasis in the lungs. To understand the liver involvement in FD, we characterized the pathology and performed transcriptome analysis to identify gene and pathway changes. We revealed progressive liver injury, inflammation and fibrosis. RNAseq analyses on hepatocytes revealed activation of pathways in inflammation response and cellular recruitment and deactivation of pathways related to lipid metabolism. MCP-1 is an inflammatory chemokine that is dramatically elevated in ACDase deficient mice and humans. To understand the role of MCP-1 in FD, we created and characterized the Asah1P361R/P361R;MCP-1-/- double mutant mice. Ablation of MCP-1 attenuated disease and provided a modest extension of life from ~9 weeks to ~14 weeks of age. The greatest reduction in inflammation was detected in the lung. Decreased inflammation in the Asah1P361R/P361R;MCP-1-/- mice also resulted in less ceramide accumulation in the lung and liver. Taken together, targeting MCP-1 though not effective in all organs may provide a benefit in combination with other therapies until a cure is available for this debilitating disorder.
Economic Aspects of Reimbursement of Drugs for Rare Diseases
Keywords: Drug Reimbursement
Orphan Drugs
Rare Diseases

The reimbursement of drugs that treat rare diseases, also known as orphan drugs, have been the topic of much debate in the last few years presenting a problem to decision makers who are challenged by increasing drug budgets. This thesis covers three main objectives: 1. Are the Incremental Cost Effectiveness Ratios (ICERs) for rare diseases different from ICERs for non-rare diseases? Although it is believed that ICERs for drugs assessing rare diseases are higher than those of drugs assessing common diseases, no studies to date have formally examined the evidence for this belief. Our objective in this chapter was to assess whether there are differences in ICERs for rare and common cancers using published data. 2. What is the estimated cost of drug development for orphan drugs? Research and Development (R) costs associated with orphan drug development have not been well characterized in the published literature. The objective of this chapter was to identify the differences in clinical trial characteristics between orphan and non-orphan drugs and use that information to estimate the clinical R costs for both groups using publicly available data. 3. What country-specific economic and institutional factors can explain the variability in the reimbursement of orphan drugs in OECD (Organization for Economic Co-operation and Development) countries? It is known that there are differences in the approval and access of drugs across countries. Country-specific factors that lead to these variances have not been studied for orphan drugs. This chapter aims to better understand the differences in the approvals, launch and reimbursement of orphan drugs among 20 OECD countries and determine which economic and institutional factors can explain these differences. The results from these three chapters shed light on three different aspects of reimbursement of orphan drugs including cost-effectiveness, cost of drug development and access to orphan drugs. This research can be essential when developing orphan drug related policies across the world.
Neural Correlates of Pain and its Associated Clinical and Psychological Correlates in the Dynamic Pain Connectome in Patients with Ankylosing Spondylitis
Keywords: brain
fMRI
MRI
neuroscience
pain

Chronic pain is a major public health issue. Despite its prevalence, the brain and behavioural mechanisms underlying chronic pain are not well understood, hampering effective treatment. Both individual factors (such as how we adapt in response to stressors), and brain function contribute to variability in pain perception. Abnormalities in brain and behaviour may indicate (mal)adaptive response or functioning in chronic pain patients. The overall goal of this thesis is to elucidate brain and behavioral mechanisms involved in pain. I first explore brain communication within and between networks of the dynamic pain connectome (default mode network; DMN, salience network; SN, sensorimotor network; SMN) that reflect chronic pain symptoms. Second, I examine how resilience – an individual’s ability to adapt well in response to stress – contributes to individual differences in pain perception. Finally, I investigate the intersection of brain communication and resilience and how this relationship is altered in chronic pain. My participants included healthy controls and patients with ankylosing spondylitis (AS) experiencing chronic pain. Participants underwent a resting state fMRI scan and psychophysical testing, and completed questionnaires probing resilience and other factors. I found that 1) AS patients exhibit abnormal, heightened DMN-SN cross-network functional connectivity, 2) cross-network connectivity between the DMN, SN, SMN, and descending pain system tracks AS pain-related outcomes, 3) resilience, anxiety, and their interaction predict pain-related affect in response to experimental pain stimuli, 4) AS patients reporting high pain intensity and disease activity are less resilient, 5) Chronic pain intensity is related to (heightened) DMN – SMN cross network connectivity, and 6) within-DMN connectivity tracks resilience in healthy individuals and patients reporting minimal pain. This thesis demonstrates that AS patients have chronic pain-related abnormalities between brain networks of the dynamic pain connectome, and that resilience plays a role in the pain experience and its representation in the brain.
Flexible Shape-memory Scaffold for Minimally Invasive Delivery of Functional Tissues
Keywords: biomaterials
cardiac tissue engineering
shape-memory
soft-lithography

Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold’s shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm × 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved. Engineering mature tissues requires a guided assembly of cells into organized three-dimensional (3D) structures with multiple cell types. The assembly of individual units into functional 3D tissues is often time-consuming, relying on cell ingrowth and matrix remodeling, whereas disassembly requires an invasive method that includes either matrix dissolution or mechanical cutting. We invented Tissue-Velcro, a bio-scaffold with a microfabricated hook and loop system. The assembly of Tissue-Velcro preserved the guided cell iii alignment realized by the topographical features in the 2D scaffold mesh and allowed for the instant establishment of coculture conditions by spatially defined stacking of cardiac cell layers or through endothelial cell coating. The assembled cardiac 3D tissue constructs were immediately functional as measured by their ability to contract in response to electrical field stimulation. Facile, on-demand tissue disassembly was demonstrated while preserving the structure, physical integrity, and beating function of individual layers.