VictorJuiz/thesis huggingface dataset:
Clustered Protocadherins: A Molecular Barcode for Neuronal Wiring and Survival

Neuronal branch patterns influence connectivity and function, with dendrites elaborating complex but non-overlapping distributions. One developmental process that regulates branch spacing is dendrite self-avoidance, in which dendrites originating from the same cell (self-dendrites) minimize overlap and contacts. Little is known of the cellular or molecular mechanism that underpins self-avoidance. It is hypothesized that immense extracellular diversity establishes unique molecular repertoires that confer single neuron identity, and signal for neurite avoidance. Studies suggest the clustered Protocadherins (cPcdhs) provide the molecular diversity required for these processes. The mouse cPcdh locus encodes 58 transmembrane recognition molecules in three clusters: Pcdh-alpha (Pcdha), Pcdh-beta (Pcdhb), and Pcdh-gamma (Pcdhg). cPcdhs extracellular domains vary, but isoforms within clusters share a common intracellular domain. Binding property studies showed cPcdhs engage in strict homophilic trans interactions and expression studies suggest that cPcdhs generate single neuron identity through expression of unique isoform subsets in individual neurons. In the retina, the Pcdhg cluster regulates two distinct processes: developmental apoptosis, and self-avoidance. Retinas lacking Pcdhgs display enhanced programmed cell death, and a loss of self-avoidance. However, whether Pcdhgs cooperate with other cPcdhs, or if Pcdha or Pcdhb diversity is required in cell survival or self-avoidance was unknown. Additionally, the dynamic process of dendrite self-avoidance was unknown. In my thesis I use the retina to investigate the role of cPcdh cluster diversity in cell survival and dendrite patterning. My analysis of double Pcdha; Pcdhg mutants showed cell death and self-avoidance defects are exacerbated, revealing cooperative functions between Pcdha and Pcdhg and a role for cPcdh molecular diversity. I established a novel live-imaging method to capture videos of Starburst Amacrine Cells arbour development. Through quantitative video analysis I determined that dendrite self-avoidance is a contact-dependent process. In Pcdhg knockouts, filopodia fail to retract after self-contact. Interestingly, non self-contacting filopodia dynamics are unaffected. This shows Pcdhgs are required for retraction after self-contact but dispensable for non self-contacting interactions. My work is the first study to show cooperative functions for the Pcdhas and Pcdhgs in circuit development and to directly image vertebrate dendrite self-avoidance, revealing it to be a contact-dependent and Pcdhg-mediated process.

Keywords: dendrite development
dendrites
protocadherins
self-avoidance
starburst amacrine cell
Advisor: Lefebvre, Julie L
A Diagnostic Evaluation of Physical Restraint Practices in An Adult Intensive Care Unit: A Mixed Method Study

Background: Evidence indicates that physical restraints (PR) are associated with adverse physical, emotional and psychological sequelae and do not consistently prevent intensive care unit (ICU) patients from removing medical devices. Guidelines advocate for minimization of PR use in ICUs. Nevertheless, PRs continue to be used extensively in ICUs both in Canada and internationally. Aim: To identify the baseline (i.e., pre-implementation) factors that could influence the successful implementation of PR minimization interventions using the integrated–Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. Design: A convergent parallel mixed qualitative and quantitative methods study in a 20-bed mixed medical, surgical and trauma ICU in Toronto, Canada Methods: The qualitative component comprised one-on-one semi structured interviews with fourteen ICU staff. The quantitative component comprised a 12-week prospective observational study of 102 restrained patients. Results: The integration of findings revealed a risk-averse culture where prophylactic application of PR for intubated patients was used to prevent unplanned extubation, thereby avoiding blame from colleagues. Interviewees shared a perception of a lack of routine communication about PR from intensivists in daily team discussions. Similarly, the quantitative data showed that in only 10% (3/30) of interprofessional rounds was PR use discussed by the ICU team. The interviewed participants demonstrated poor awareness of current local PR rates of use, which echoes the observation that PR was poorly documented in medical records. While most interviewees recommended nurse facilitation to minimize PR use, nurse leaders were not actively involved in PR discussion during the interprofessional team rounds. Interviewees recommendations regarding strategies to minimize restraint use included availability of restraint alternatives and guidance on situations for applying and removing restraints. Conclusion: This analysis of contextual influences on PR practices and minimization using the i-PARIHS framework revealed potentially modifiable barriers to successful PR minimization, including a lack of leadership involvement, gaps in practice monitoring and collaborative decision-making processes, and sometimes conflicting priorities in terms of patient safety. The establishment of an interprofessional facilitation team that addresses risk-averse culture and promotes collaboration among ICU stakeholders will be crucial to the success of any approach to restraint minimization in this context.

Advisor: Johnston, Linda
Dale, Craig
Contemporary Interventional Management of Peripheral Artery Disease in Ontario

Introduction: Despite increasing international recognition of the morbidity associated with peripheral artery disease (PAD), our understanding of PAD epidemiology and management outcomes in the province of Ontario remains based on studies of limited contemporary external validity. The overarching objective of this thesis was to characterize contemporary interventional management of PAD in Ontario. Methods: Using Ontario administrative databases, we first performed a time series analysis of the trends in hospitalization for PAD. Second, we performed a validation study to estimate the positive predictive value (PPV) of diagnostic, procedure and physician claims coding to identify lower extremity open and endovascular revascularization for PAD in Ontario administrative databases. Third, we evaluated temporal trends of lower extremity revascularizations and amputation for PAD, in the context of a rising diabetes prevalence. Finally, in a cohort study, we compared the long-term effectiveness of open and endovascular revascularization approaches with respect to amputation-free survival (AFS) and related outcomes.Results: Hospitalizations for PAD have not significantly declined (decline of 0.068/100,000 Ontarians per quarter from 2006 to 2019, p=0.10). Open and endovascular revascularization for PAD can be reliably identified in Ontario administrative databases (PPV 83% to 96%). As the prevalence of diabetes has increased, the use of revascularization for PAD has increased (from 75.1 in 2002 to 90.7/100,000 person-years in 2019; unadjusted rate ratio (RR) [95% CI]=1.11 [1.08-1.14]; diabetes-adjusted RR [95% CI]=1.00 [0.98-1.03]), and a decrease in amputations for PAD has been attenuated (from 49.5 in 2002 to 45.4/100,000 person-years in 2019; unadjusted RR [95% CI]=0.81 [0.78-0.84]; diabetes-adjusted RR [95% CI]=0.65 [0.63-0.67]). Endovascular compared to open revascularization was associated with better AFS (HR [95% CI]= 0.94 [0.91-0.98]) in the full cohort, but not among subgroups with diabetes, tissue loss or isolated infrainguinal disease. Conclusions: Hospitalizations for PAD have not significantly decreased. Ontario databases can be reliably used to identify revascularization for PAD. The rising prevalence of diabetes has influenced the temporal trends in revascularization and amputation for PAD. Open revascularization may not offer a long-term benefit over endovascular revascularization. These data answer a need for real-world evidence to guide decision-making around PAD care.

Keywords: Comparative effectiveness
Ontario
Peripheral artery disease
Revascularization
Temporal trends
Validation
Advisor: Al-Omran, Mohammed
de Mestral, Charles
Deciding to Play: Exploring Why Adolescent Athletes Under-report Sport-related Concussions using a Mixed Methods Approach

Sport participation offers several benefits for adolescent athletes but is not without limitations, including risk of injury. Sport-related concussions (SRC) leave adolescents vulnerable to significant health, physical, social, and educational disruptions. Current recommendations emphasize SRC education and removal from play upon suspicion of concussion. However, many adolescents under-report SRC symptoms, but the scope of under-reporting for this population is not well understood, nor are the underlying motivations for (under)reporting. It is necessary to interrogate the relationship between SRC knowledge and reporting and invite athletes to share their decision-making processes. In consideration of developmental, educational, psychosocial and sport cultural findings, the objective of the current research was to understand why adolescents under-report sport-related concussions. Using a mixed methods approach, two studies were developed. The purpose of Study 1 was to assess the current literature on SRC under-reporting in adolescent athletes 13-18 years old through a systematic review. In total, 26 articles were included in the review. All studies found evidence for athletes failing to disclose concussion symptoms; both male and female athletes were found to under-report, with limited evidence suggesting male athletes under-report SRC more frequently. Prior concussion knowledge does not appear to predict sustained improvements in under-reporting behaviours, highlighting the complexity of under-reporting decision-making. The purpose of Study 2 was to understand how athletes’ attitudes, experiences and beliefs regarding concussions influence their under-reporting decisions and behaviours. This research employed a constructivist grounded theory approach. Participants included 17 elite athletes, 16-18 years old, from a variety of sports. A substantive theoretical model demonstrates personal, social, cultural, and biophysical processes that contribute to under-reporting decisions. The model identifies multiple interconnected processes that contribute to ‘high-risk’ situations of under-reporting. Findings implicate the collective responsibility of under-reporting and the use of risk profiles as a novel approach to understand and consequently improve under-reporting behaviours. Overall, this research synthesizes evidence on adolescent under-reporting, challenges the reliance on concussion education as the primary tool for improving behaviours, and provides a theoretical foundation for how to support adolescent athlete decision-making for improved reporting outcomes.

Keywords: Adolescents
Concussion
Decision-Making
Injury
Reporting
Sports
Advisor: Mainwaring, Lynda
A Six-Case Comparative Study to Identify Systems Thinking in Government-designed Public Health Strategies

Governments around the world are grappling with increasingly complex and hard to solve public health problems, such as the rise in chronic diseases and increasing health inequity. Complexity is a significant challenge for policy makers who design large-scale interventions for several reasons: the interconnected dynamics of a system might lead policy design to overlook potential synergies, the heterogeneity of factors and the nonlinearity of processes in a system make causal links difficult to determine, and prediction is difficult because multiple forces shape the future behaviour of the system. Traditional theoretical frameworks, such as the biomedical or behavioural health models, are based on a reductionist paradigm that holds that all phenomena can be understood by reducing them to their smallest components and studying their interactions. This reductionist stance is inadequate for dealing with increasing complexity in public health. In this dissertation, I explore the use of systems thinking as a theoretical framework for understanding complex public health issues and designing government-led public health strategies. A systems thinking framework considers how dynamic feedback, unpredictability, and interconnected elements impact the overall structures and patterns in a system. I use a multiple case study analysis to investigate the extent to which systems thinking concepts and social determinants of health approaches are present in the design processes of three federal and three provincial strategies in Canada. Each case applies an original analytical framework to policy documents and interviews with senior strategy design leaders (n=18). Through comparative analysis, I find that that although no cases formally applied systems thinking to strategy design, the concepts are present to a significant, moderate, or limited extent. The analysis also presents a set of contextual factors in the policy environment that help or hinder the use of systems thinking. Contextual factors include the evidence-base of the strategy topic and theory of change, the policy environment and policy levers available, the specifics of the strategy design process and operational resources, and the leadership, culture, and skills of the workforce. This study contributes to the calls for evidence of applied systems thinking in public health policy and systems research.

Keywords: Complex Adaptive Systems
Governance
Public Health
Public Policy
Strategy Design
Systems Thinking
Advisor: Schwartz, Robert
Sensitivity of Hostile Hemodynamics to Intracranial Aneurysm Geometry

An intracranial aneurysm (IA) is an abnormal outpouching of an artery in the brain and is thought to be present in about 1 in 30 adults. Rupture of an IA is a devastating event leading to death or disability in most cases. To supplement clinical treatment decisions, researchers have turned to hemodynamics, which are thought to contribute to the growth and rupture of IAs. Simulations using medical-image-based computational fluid dynamics (CFD) yield patient-specific risk parameters, but these parameters are often highly uncertain due to modelling limitations, limiting their clinical utility. Recent CFD studies have shown IA rupture to be associated with wall shear stress (WSS) and jet impingement, but these studies may be overlooking turbulent-like flow instabilities. This thesis investigates the nature of these flow instabilities and risk parameters in the context of uncertainty due to geometry. To characterize these instabilities, this thesis highlights the novel use of spectrograms as an interpretable summary of the flow field (Chapter 2) and demonstrates their variation in a cohort of 50 IAs (Chapter 3). Based on these spectrograms, I developed a novel marker to quantify harmonic flow features and demonstrated that this marker was a better predictor of rupture than popular WSS-based metrics in our cohort of 50 high-fidelity IA simulations (Chapter 4). Overestimation of the IA neck is a widespread issue among IA CFD researchers, which could selectively promote or inhibit the development of flow instabilities. To overcome this issue, I devel- oped a novel technique for improving IA segmentation from 3D imaging (Chapter 5) and showed that hemodynamic parameters including flow instabilities can be sensitive to these common segmentation errors, potentially muddling efforts toward rupture prediction (Chapter 6). Hemodynamic parameters are ultimately only useful if they are robust to modelling error and provide useful diagnostic information that is not more-easily extracted from geometry alone. Lever- aging a recent deep neural network for unsupervised 3D shape interpolation, I created plausible interpolations between patient-derived geometries and demonstrated the hemodynamic sensitivity to these broad changes in geometry (Chapter 7). This research exposes limitations inherent to reduced risk indices and could help researchers identify better risk markers.

Keywords: aneurysm
cfd
fluids
geometry
imaging
Advisor: Steinman, David A
Using the Nanoparticle Protein Corona to Build Nanomaterials

Nanoparticles are used to carry medical agents to diseased sites for treatment and diagnosis. When nanoparticles are administered in biological environments, hundreds of proteins rapidly adsorb onto their surface and form a protein layer known as the protein corona. These adsorbed proteins cover up the original surface of the nanoparticle and form a new interface that interacts with cell and tissues. Strategies to use targeting or blocking molecules on the nanoparticle to circumvent or abolish protein corona formation have been unsuccessful. The protein corona forms regardless of the material composition, surface chemistry, size and shape. Consequently, it is necessary to understand how the protein corona directs interactions with cells and tissues to design effective nanoparticles. In this thesis, I developed methods to understand and use the protein corona as a nanomaterial for delivery. In aim 1, I developed a workflow combining mass spectrometry, genome-wide screens and bioinformatic analysis to identify interactions between specific proteins in the protein corona and receptors on the cell surface. This approach allows us to systematically discover the molecular interactions formed between the protein corona and cells. Given that the protein corona dictates biological fate rather than the underlyingnanoparticle, I turned the protein corona into a standalone nanomaterial in aim 2. This eliminated the need for the underlying nanoparticle which is often foreign to the body. Altogether, this thesis provides researchers with the foundational tools needed to understand the biological behavior of the protein corona and to use it as a nanomaterial for effective and predictable delivery. This thesis has broad implications because it presents a paradigm shift away from preventing the protein corona and towards exploiting it for delivery.

Keywords: Genome-wide screen
Nanoparticles
Protein corona
Protein nanomaterials
Receptors
Advisor: Chan, Warren C.W.
A Discriminating Memory: Learning and Chemosensation in C. elegans

Animals receive information about the external world through their senses, which feed this information into the nervous system where it’s processed, stored, and subsequently influences behaviour. In this work, I describe both how the first steps of chemosensory processing occur in the sensory neurons of the nematode Caenorhabditis elegans, and how the information provided by this chemosensory input, in conjunction with previous sensory information and the internal satiety state of the animal, act to modulate subsequent behaviour. In the first part of this work, I provide an analysis of the phenomenon of Kamin Blocking in C. elegans, in which past learning about sensory cues can modulate the ability of subsequent cues to form memories, and offer a molecular analysis of Kamin Blocking in the worm which challenges a common interpretation of it in mammals. In the second part of this work, I focus on the very initial steps occurring during chemosensation in C. elegans chemosensory neurons, and find that discrimination between different olfactory stimuli which are sensed within the same neuron relies on β-arrestin mediated desensitization of ligand-bound receptors. I provide a model for how desensitization acts to enable intraneuronal olfactory discrimination in the paradigm being tested, offering a resolution to a longstanding question in the field, and test several predictions of this model. In sum, the research presented in this work describes both the earliest mechanisms of chemosensory biology in the worm, and examines how chemosensation acts to create memories and modulate subsequent behaviour. By exploiting the simplicity and genetic tractability of C. elegans, the research described here deepens our understanding of the mechanisms underlying (and linking) the most fundamental aspects of sensation and learning in animals.

Keywords: arrestin
c. elegans
discrimination
kamin blocking
learning
olfaction
Advisor: van der Kooy, Derek
Women’s Prisons and the Politics of Punishment in Nazi and Postwar Germany

This dissertation is a new line of inquiry in the history of gender, crime, and punishment in modern Germany and during the Holocaust, illuminating the degree to which conventional prisons confined and often terrorized women during and after the Third Reich. Prisons in twentieth-century Germany are largely overlooked, while studies of concentration camps and Soviet forced labor camps have understandably drawn the attention of historians, but their history provides an important and rich template for critical understandings of carceral systems and their enduring power in the modern age. This project has two main objectives: first, to analyze how conceptions of gender shaped the lives of women prisoners and informed the administration of penal institutions, and second, to shed light on the position of prisons in relation to the Holocaust and to better understand the role of prisons in nascent postwar East and West German societies. The ways in which the “outside world” had concrete effects on the “inside world” of prisons are explored throughout this research, with the following interest groups at the core of the narrative: people in prison, staff in prison, families of people in prison, political actors, and broader society. The primary characteristics of the female prisoner population changed with the political, social, and economic climates of the times, as did the methods of punishment and rehabilitation, but the overarching function of prisons as sites of state power was constant. This study reveals that the criminalization of women’s sexuality and class did not falter even as the criminalization of women and their intersections with race, religion, and politics fluctuated enormously from one German administration to another. Underpinning twentieth-century German women’s prisons was a paradox of invisibility and visibility. Although women were not deemed important enough to warrant substantial sex and gender-specific treatment, they were dangerous enough to confine. Women were also the legal system’s afterthought, except for when the government sought to control their sexuality and exploit their labor. Despite the repressive conditions to which women prisoners were subjected, many found ways to resist the isolating and demoralizing effects of incarceration.

Keywords: Cold War
Germany
Holocaust
Nazi
Prisons
Women
Advisor: Bergen, Doris L.