VictorJuiz/thesis huggingface dataset:
The Impact of Psychosocial Factors on the Outcome of Surgical Repair for Rotator Cuff Tears – A Prospective Cohort (IMPROVE Study)
Keywords: Psychosocial factors
Rotator cuff tears
Surgical outcomes

Rotator cuff tears are a common cause of pain and reduced function in the shoulder. The impact of psychosocial factors on patient outcomes following rotator cuff repair (RCR) surgery is unclear. The main goal of this thesis was to determine the association of psychosocial factors and outcomes in patients undergoing RCR surgery. Objectives: (1) To determine if psychosocial factors are associated with post-operative outcomes one-year after RCR surgery. (2) To determine if psychosocial factors are associated with disease severity at baseline. (3) To determine if psychosocial measures improve in patients one-year after RCR surgery. (4) To determine if treating surgeons are able to accurately assess patient’s mental health status at the baseline visit. Methods: A multi-centre, prospective, cohort study was performed where patients with a full-thickness rotator cuff tear were enrolled prior to RCR surgery. Patients completed multiple validated questionnaires to measure psychosocial functioning (symptoms of depression, anxiety, pain catastrophizing, treatment expectations and social support) at the pre-operative visit. Patients were followed for one year after their surgery. The primary outcome was the patient-reported Western Ontario Rotator Cuff Index (WORC) completed at one-year. The secondary outcomes were the Constant Murley Score (Constant) and the EQ-5D-5L. A multivariable regression analysis was performed. Results: 244 patients were enrolled, and 137 patients have completed a one-year follow-up. When controlling for other key variables, a multiple linear regression analysis did not demonstrate an independent association between any of the psychosocial factors and WORC scores at one year. Patients with higher levels of pain catastrophizing prior to surgery presented with worse WORC scores, Constant scores, and EQ-5D-5L health index scores at baseline and worse Constant scores at one-year. The remaining psychosocial factors were not associated with worse WORC scores at baseline. Scores on all of the psychosocial questionnaires improved between baseline and the one-year follow-up visit. The surgeons’ rating of patient’s mental health did not agree with the scores from the questionnaires. Conclusion: In this patient population, we found a low rate of clinically significant psychological symptoms and when controlling for other variables, psychosocial factors did not have a significant impact on outcomes after RCR.
The Effect of Hemodynamics on Endothelial Cell Gene Expression: The Interaction between Cis-DNA Elements and Chromatin-based Pathways
Keywords: Atherosclerosis
DNA methylation
Endothelial cells
Epigenetics
Hemodynamics
Shear stress

Endothelial cells (ECs) are professional sensors of shear stress (SS), the frictional force of blood flow. Endothelial nitric oxide synthase (eNOS) is an EC-specific gene predominantly expressed in arterial regions of atheroprotective laminar flow with high SS. This prototypic arterial EC gene contains two distinct flow-responsive cis-DNA elements in the promoter, the Shear Stress Response Element (SSRE) and the Krüppel-Like Factor (KLF) element. To investigate the in vivo function of these cis-DNA elements, insertional transgenic mice with a mutation at each element were generated using a murine eNOS promoter-β-galactosidase reporter. Surprisingly, the SSRE mutation abolished eNOS transcription and was associated with aberrant hypermethylation at the eNOS proximal promoter. The KLF mutation demonstrated an integration site-specific decrease in eNOS transcription, again with marked promoter methylation. Together, this indicated that both elements are necessary for a transcriptionally permissive, hypomethylated eNOS promoter and neither element alone is sufficient for eNOS transcription in vivo. We also examined the genome-wide DNA methylation profiles in arterial ECs exposed to different flow conditions. Global methylation and hydroxymethylation levels showed no changes in vivo between the aortic arch and the descending thoracic aorta in mice, as well as in human ECs in vitro under distinct arterial flow patterns, suggesting that flow-mediated changes in DNA methylation are gene-specific. Two arterial EC genes, namely eNOS and C-X-C motif chemokine receptor 4 (CXCR4), showed differential endothelial responses to SS that were associated with changes in proximal promoter DNA methylation. Laminar flow induced eNOS expression but repressed CXCR4 expression. Conversely, disturbed flow repressed eNOS expression but induced CXCR4 expression. Methylation levels at the proximal promoter region of each gene were significantly correlated with its repressed gene expression in a flow-dependent manner, indicating a mechanistic role of promoter DNA methylation in flow-mediated endothelial gene regulation. In conclusion, we describe the in vivo function of flow-responsive cis-DNA elements for the first time and present evidence for biological interplay between these elements and chromatin-based pathways, particularly DNA methylation. Moreover, we demonstrate that the expression of arterial EC genes, eNOS and CXCR4, is regulated by flow-dependent epigenetic mechanisms, offering new mechanism-based therapeutic strategies for cardiovascular diseases.
Synthesis and Surface Modification of NaLnF4 Nanoparticles Toward Applications in Mass Cytometry
Keywords: lanthanide nanoparticles
silica coating
surface modification
upconversion nanoparticles

This thesis describes the synthesis, surface modification and characterization of lanthanide nanoparticles (NaLnF4 NPs) designed to be used as high sensitivity reagents in mass cytometry. In the first part of my thesis, I describe my work preparing a library of single-lanthanide NaLnF4 NPs (Ln = Pr, Nd, Sm, Eu, Tb, Ho) and NaLuF4:Gd,Yb,Er upconversion nanoparticles (UCNPs) of varying diameters. From these studies, I found that identical reaction conditions led to different cubic-to-hexagonal phase change behaviors for different NaLnF4 NPs. I also observed a correlation between the phase transformation, average diameter, and size distribution of the resulting NPs. For NaLuF4:Gd.Yb,Er UCNPs, I found that in the absence of Lu, Gd promotes direct nucleation of NPs in the hexagonal phase, while the presence of Lu promotes initial nucleation in the cubic phase. I also discuss the batch-to-batch reproducibility of several reactions. Here, I found that some reactions (eg. 4 and 12 nm NaLuF4:Gd,Yb,Er UCNPs) were more reproducible than others (eg. 13 nm NaTbF4 NPs). I also present a method to troubleshoot a particular problem encountered with the NaLnF4 NP reaction, whose signature was the colour of the reaction mixture becoming brown. In the second part of this thesis, I describe my work on the surface modification NaLnF4 NPs. First, I present the work on silica coating NaLnF4 NPs (SiO2@NaLnF4 NPs) using the reverse microemulsion method. I found that by adjusting the purification method used to isolate NaLnF4 NPs from the original reaction mixture, NaLnF4 NPs of a variety of compositions, and prepared using different reaction conditions, can be coated with a thin silica shell. Dynamic light scattering experiments were carried out to better understand the silica coating process, however these results were difficult to interpret. Finally, I functionalized SiO2@NaTbF4 NPs with azide-functionalized PEG polymers. Considerable effort was spent trying to characterize the grafting density of the PEG polymers. Unfortunately, I found that these NPs had limited long-term colloidal stability in PBS buffer, and further work is required to improve the colloidal stability and to test these NPs in MC experiments.
Real-time Delay Prediction and Quality of Service Assurance for Traffic Management in Service Systems
Keywords: Quality of service
queueing
Reinforcement learning
service systems

Ensuring quality of service (QoS) is one of the important challenges facing service providers. A key metric of the QoS is the experienced delay by the customers, which can depend on various factors such as the demand patterns, service capacity and the scheduling discipline. In this thesis, we study delay distribution prediction in service networks and propose novel QoS assurance methods which target the mentioned factors. In particular, the proposed methods require no knowledge of the system model or parameters, which is an important feature for real-world applications. We first consider the delay distribution prediction problem in tandem and acyclic queueing networks. Our analytical results suggest that the Gaussian mixture model can be a good candidate for estimating the end-to-end delay distribution in these systems. Motivated by this result, we use mixture density networks to propose a delay distribution predictor based on queue length information, which requires no knowledge of the system model or parameters. As the next step, we take a reinforcement learning (RL) approach and propose an admission controller with the goal of providing probabilistic upper-bounds on the end-to-end delay of the accepted jobs, while minimizing the probability of unnecessary rejections. Since admission control might not be a viable solution in some applications, we propose a deep RL-based service-rate controller as an alternative, which is capable of providing probabilistic upper-bounds on the end-to-end delay of the system by dynamic adjustment of the service rates. In the last part of this thesis, we study urban traffic management, as another important example of service systems. Specifically, we introduce two notions of fairness in this context, which are concerned with the delay of the vehicles and throughput of the traffic flows at an intersection. This is particularly important asneglecting fairness can lead to situations where some vehicles experience unacceptable long delays, or where the throughput of a particular traffic flow is highly impacted by the fluctuations of another conflicting flow. Finally, we propose two traffic signal control methods for implementing these fairness notions, which also consider the efficiency of the system at the same time.
The Effects of Intelligence, Personality Traits, L1 Fluency, and L2 proficiency on L2 Spoken Fluency
Keywords: English
French
intelligence
language learning
personality
second language

This dissertation explores the underlying structure of second language (L2) fluency by investigating inter-learner variability via a comparison of the relative contributions of two understudied variables, intelligence and personality traits (extraversion, neuroticism, openness to experience, conscientiousness, agreeableness) versus known L2 fluency predictors, namely, first language (L1) fluency, and L2 lexical and grammatical proficiency. Previous research has rarely considered the effects of intelligence and personality on L2 fluency, despite their omnipresence in psychology studies. Two exceptions are Dewaele (1999) and Dewaele Furnham (2000) who found positive correlations between extraversion and L2 fluency measures, suggesting that personality may contribute to L2 fluency variation. However, this previous research failed to control for L1 fluency and L2 proficiency, known corelates of L2 fluency (e.g., Hilton, 2008; Riazantseva, 2001), lacked comprehensive fluency analyses, and relied on univariate analyses that cannot compare the effect sizes of multiple fluency predictors.In the present study, L1 and L2 speech data were elicited from 73 advanced Anglophone learners of French via a picture description task and analyzed for seven standard fluency measures. The Big Five Aspect Scales test (DeYoung, Quilty, Peterson, 2007) and a short form of Raven’s Standard Progressive Matrices (Bilker, Hansen, Brensinger, Richard, Gur Gur, 2012) evaluated personality and intelligence. A Vocabulary Levels Test and a sentence scramble test (Department of French Studies, 2020) measured lexical and grammatical proficiency. Correlational analyses demonstrated significant relationships between L2 fluency and L1 fluency, L2 lexical and grammatical proficiency, and openness to experience. Sequential regressions revealed that L1 fluency explained more L2 fluency variance than proficiency. Openness to experience was not a significant predictor after accounting for L1 fluency. This dissertation contributes to our understanding of the relative importance of L2 fluency predictors including personality and intelligence and makes a methodological contribution via its use of multivariate statistics.
A General Study of Genetic Association Tests and the Test of Hardy-Weinberg Equilibrium
Keywords: Allele-based
Correlation
Genetic association studies
Hardy-Weinberg equilibrium
Multiple phenotypes
Robustness

A great number of statistical methods have been developed to test genetic association between a heritable trait and a genetic marker. However, no single existing method can deal with multiple analytical challenges that include, for example, evaluating multiple (binary and continuous) traits simultaneously, being robust to departure from Hardy-Weinberg equilibrium (HWE), and analyzing correlated data from pedigrees. Further, there is much confusion about the analytical differences and similarities between the different association tests. This thesis work fills in this gap by developing a new analytical framework, which also unifies some of the existing methods for simple yet commonly seen settings. Chapter 1 provides the scientific motivation and genetic background. Chapter 2 focuses on genotype- based approaches, introduces a new ‘reverse’ or retrospective regression model that tests association in related samples with adjustment to Hardy-Weinberg disequilibrium (HWD), and shows the theoretical link between the proposed genotype-based test and the existing ones. Chapters 3 and 4 expand the genotype-based retrospective regression to a robust allele-based (RA) alternative, and generalize the locally most powerful allelic association test to accommodate complex data scenarios. Chapter 5 takes a fresh look at the role of HWD in association analysis, and proposes a RA joint test that leverages the HWD attributed to true association to increase testing power yet remains robust to HWD attributed to genotyping error. Finally, Chapter 6 revisits all the tests introduced in the earlier chapters, and provides additional insights on the analytical connections between the prospective and retrospective regression frameworks, between regression-based and non-parametric methods, and between genotype-based and allele-based association tests.
Evaluating the Therapeutic Potential of Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Drosophila Alzheimer's Disease Models
Keywords: Alzheimer's Disease
amyloid
Drosophila
memory
presenilin
renin angiotensin system

Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, I used a genetic and pharmacological approach to evaluate the beneficial effects of Angiotensin Converting Enzyme-inhibitors (ACE-Is) and Angiotensin Receptor Blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. I show that captopril, an ACE-I, and losartan, an ARB, can suppress brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Ab42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of C99 and Ab42. Moreover, neither drug rescued brain cell death in Drosophila expressing human Tau suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, I also observed reduced cell death and a complete rescue of memory deficits when I crossed a null mutation in Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is ACER. In addition, I also found that knockdown of an ACER interactor, CG2233, in flies expressing human Ab42 recapitulated the beneficial effects by Acer null mutationand captopril, suggesting an ACER-CG2233 pathway underlying the captopril-driven beneficial effects. Altogether, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in Drosophila.
Bioretention Systems for Stormwater Management: Assessment, Performance and Changes Over Time
Keywords: bioretention
green infrastructure
green stormwater infrastructure
low impact development
stormwater

Bioretention systems function to mimic natural hydrology, by retaining stormwater runoff from routine rain events and returning it to infiltration and evapotranspiration, instead of runoff. This thesis consists of four studies which answer these research questions: How do we assess performance, and how does bioretention performance change over time? A systematic scoping review of 320 studies found that bioretention performance is defined in terms of hydrologic controls, while investigations into mechanisms of contaminant transport and fate are overlooked. Bioretention field research has been primarily conducted by a small number of institutions (26 institutions were responsible for 50% of the research) located mainly in high income countries, and primarily on new systems for a short period of time. Following the definition of performance, a field survey of mature systems (>3 years operation) was conducted on bioretention cells across Ontario, Canada. Saturated hydraulic conductivity (KSat) (a measure of hydrologic performance) was above minimum guidelines for all sites, and KSat improved for 6 of 9 sites. Soil-water interaction properties, such as plant available water and wilting point, more closely resembled loam soils than sandy soils, which may be due to the development of a soil structure over time. A more in-depth analysis of bioretention performance was conducted using a bioretention cell located in Vaughan, Ontario. The hydrologic and water quality performance was compared over two monitoring periods: new (immediately post-construction) and mature (4-5 years post-construction). The hydrologic performance was maintained in the mature system (median volume reductions of 100%) and mature effluent water quality was improved compared to the new condition for some parameters (e.g., dissolved solids, nitrogen species). A complete water balance of the system was performed using inflow, outflow and evapotranspiration data (via a weighing lysimeter). The water balance was further broken down by event size, where the event size was determined by rainfall frequency analysis. Recharge was the largest component of the water balance overall (86 % of inflow), and evapotranspiration was the next largest water balance component (7 % of inflow overall). Evapotranspiration was a significant component of inflow (21 %) when considering small events with a 50% chance of occurrence.
Development of an Automated Computational Cell Tracking Tool for High-throughput Screening of Cellular Migration in Exosome-stimulated Wnt-PCP Signaling
Keywords: Algorithm
Cell tracking/methods
High-throughput screening
Planar cell polarity
WNT

Intercellular delivery of WNT ligands across tissues is required for development, regeneration and is also involved in many pathologies. One method of this transport is facilitated by being carried on exosomes, which are small, stable extracellular vesicles. Exosomes released by cancer associated fibroblasts (CAFs) interact with various types of cancer cells to stimulate motility through transport of WNT11 to promote WNT-PCP signaling. This model system presented a unique opportunity to identify new regulators of exosome-based WNT-PCP signaling. However manual measurement of the motility is slow, thus greatly inhibiting our ability to screen large number of candidate regulators. As such, I devised a method to automate the measurement and analysis of cell motility by tracking cells over a time course using live cell imaging. The algorithm I developed was able to accurately and precisely measure the movements of 100s of cells in a multi-well format. Additionally, my approach considers possible track fragmentations to ensure that the majority of tracks encompass the entire time course. I also expanded the algorithm to measure changes in cell morphology and cell death. High-throughput screening of kinase inhibitor tool compounds in a proof-of-concept screen identified various kinases with putative roles in exosome-stimulated motility. One such kinase I chose to focus on was RET, a receptor tyrosine kinase, that is closely linked to migration and morphogenesis in development and is often mutated or overexpressed in cancer. RET loss showed loss of motility in both MDA-MB-231 triple negative breast cancer cells and T24 bladder cancer cells as well as morphological changes that led to increased cell aspect ratios. Furthermore, RET and WNT11 interactions in the embryonic kidney are required to promote branching morphogenesis. I inhibited the release of exosomes in ex vivo E11.5 kidneys through treatment with Manumycin A, which resulted in a reduction in branching. My work describes an efficient, automated method to screen for regulators of WNT-PCP associated cell motility and illustrates a potential role for RET and WNT11 interaction in exosome-stimulated cell migration.