VictorJuiz/thesis huggingface dataset:
Towards Automated Toxicity Testing Using Novel Technologies to Reduce Spectral Overlap and Address Sensitivity Limitations in Environmental In-Vivo NMR
Keywords: Daphnia magna
Digital Microfluidics
Environmental Toxicity
In-Vivo Metabolomics
Nuclear Magnetic Resonance Spectroscopy
Pulse Sequences

Toxicity testing of living organisms has been undergoing a paradigm shift over the last decade. Focus has moved from examining apical endpoints such as death or reproduction, to measuring sub-lethal impacts from a biochemical perspective, with future aspirations to automate the approach. One of the ways this is examined is through metabolomics, the study of the impacts to an organism’s metabolic system as a result of an external stressor, such as a potential toxin. Recently, the field of in-vivo nuclear magnetic resonance (NMR) spectroscopy to study metabolomics has provided breakthroughs in toxicity testing information. Much of this work has been done with the aquatic organism Daphnia magna, a model organism for aquatic toxicity studies. While robust, NMR suffers from a lack of sensitivity and heavy spectral overlap in complex systems, such as living organisms. Thus, this thesis introduces novel technologies which help address sensitivity limitations and remove overlap in in-vivo NMR while working towards creating an automated dosing platform in line with the paradigm shift of toxicity testing. First, a new holistic approach to testing is examined which uses three NMR techniques in tandem, providing complementary information of toxin interactions including binding, physical partitioning, and biochemical response inside living organisms. Binding with the organism’s outer shell and metabolic oxidative stress responses were measured, which could not have been examined independently. Additionally, two new NMR pulse sequences are introduced. The first examines new bond formation between different nuclear isotopes (13C-12C), and food incorporation into living biomass of D. magna was examined. In the second sequence, suites of molecules chosen by the user can be isolated from an unchanged matrix, while focusing increases sensitivity over traditional 1H NMR. Four metabolites indicative of oxidative stress were monitored in D. magna simultaneously, while the unselected signals were filtered out. Finally, an automated dosing platform was created by the combination of digital microfluidics (DMF) and NMR to keep D. magna alive for prolonged periods using automated movement of food and water. Moving forward, these four new approaches could be used in tandem to increase sensitivity, reduce overlap, and automate the toxicity testing process.
Development of a Human Precision Cut Intestinal Slice Model of Acute IgE-Mediated Food Allergy
Keywords: Allergy
Allergy model
Food allergy
Intestine

Food allergy is a potentially life-threatening disorder that affects both children and adults. There are no definitive prevention strategies in place, and treatments remain limited. Models of food allergy are needed to further understand the cause and underlying cellular mechanisms of this disorder, and to develop and test preclinical therapeutics. Current models of food allergy are limited in their ability to reflect the complexity of this disease in human mucosal tissue. Therefore, the aim of this thesis project was to generate a novel model of IgE-mediated food allergy using precision cut intestinal slices (PCIS). PCIS are live pieces of intestinal tissue of a fixed thickness that maintain the cellular diversity and function of the organ. We optimized the generation of PCIS using intestinal tissue from mice, rats, pigs, and humans. Viability and metabolic activity were maintained for up to 24h. Rodent and human PCIS were passively sensitized using plasma or serum from allergic donors and the smooth muscle contraction reactions that occurred following stimulation with allergen or controls were filmed. These contractions functioned as a readout of the allergic response. To quantify these responses, a novel video analysis software was created that measured muscle contraction in free-floating PCIS. We verified these responses were due to mast cell-derived mediator release by measuring allergen-specific increases in tryptase concentration in the culture supernatant. We showed that treating rodent and human PCIS with commonly used antihistamines could block contraction responses. We also found that plasma from peanut allergic patients who were successfully desensitized by oral immunotherapy could suppress allergen-specific contraction responses in human PCIS. Using single nucleus RNA sequencing we confirmed the presence of all expected cell subsets including stromal cells, epithelial cells, and key immune cell populations. We demonstrated that human PCIS can be used to observe tissue-specific changes in gene expression patterns following stimulation with allergen or controls. Through this thesis research, we established PCIS as a novel complementary tissue-based model to study acute, IgE-mediated food allergic responses, to assess current and preclinical therapeutics, and to investigate the complex network of reactions that occurs within intestinal tissues during an allergic reaction.
Carving Space for Staff Agency in a Faculty of Medicine: A Foucauldian-inspired Discourse Analysis of Administrative Staff and Faculty Relations
Keywords: administrative staff
critical theory
Foucault
health professions education
higher education
power

Administrative staff in higher education have been described as invisible (Eveline, 2004; Szekeres, 2004) and often characterized as being “non-academic, non-faculty, non-teaching, [and] non-professional” (Losinger, 2015, p. 157). These characterizations manifest within health professions education (HPE) contributing to the undervaluing of staff and staff contributions. While administrative staff are present on campuses or within the virtual workspace, staff often remain absent when it comes to HPE documents, literature, and reports. With few exceptions, if staff appear in the HPE literature it is as a passive object, often as a resource, a possession, or a liability. If staff appear in institutional reports, it is often within an acknowledgement section rather than a list of authors. These absences are also felt in the everyday staff experience: staff are sometimes overlooked in meetings, may not feel comfortable contributing knowledge, and may feel devalued or invisible in their roles. At the same time, the neoliberal university system has led to the increasing professionalization of staff roles, occurring as health professionals experience their own shifts in power and prestige. These changes affect staff and faculty relationships in the health professions education space at times, leading to tensions if not toxicity. Throughout this thesis I build and examine an archive of published literature, archival documents, interview data, and my reflections and lived experience as a staff member to conduct a Foucauldian-inspired discourse analysis. Specifically, I conduct a “history of the present” (Foucault, 1977; Garland, 2014) to identify discourses that regulate the work of and power relations between administrative staff and faculty in a faculty of medicine. I discuss what these discourses make possible for staff to do, be, or say and what these discourses now make impossible. I explore the material effects of discourse, very purposefully centering staff voices within this text. Using feminist and decolonial critical theories throughout my analysis, I engage with the historic and hierarchical structure of academic medicine that constructs the largely feminized administrative staff cohort as having limited agency in HPE. To navigate the tensions produced by discourses and structure, I work to rebuild agency through staff voices, resistance, and recommendations for practice.
Ecology and Sensitivity to Environmental Change of a Northern Population of Spotted Salamander, Ambystoma maculatum
Keywords: Algonquin Provincial Park
amphibian
climate change
demography
ecology
salamander

Amphibians perform numerous ecological roles—as predators and prey, as connectors of energy flow between aquatic and terrestrial landscapes, and as sizable contributors to vertebrate biomass—in wetland and forest ecosystems. Amphibians are also modern “canaries in the coal mine”, serving as a barometer for assessing environmental health. The Spotted Salamander (Ambystoma maculatum) is geographically widespread in eastern North America and is well-studied. This research arises from long-term monitoring of Spotted Salamanders at Bat Lake in Algonquin Provincial Park, Ontario, Canada, approaching the species northern climatic range edge. In 2008, monitoring efforts were formalized into a capture-mark-recapture study, collecting morphological, reproduction, and population data. The long-term aims of this project are to monitor baseline population vital rates and assess the effects of climate (change) on a northern salamander population. Chapter One introduces salamanders as research subjects and the ecology of Bat Lake. Chapter Two presents a synthesis of Spotted Salamander biology based on 15-years of monitoring data, including phenology of spring breeding and post-metamorphic dispersal, operational sex ratio, early life survival, body size of adults and metamorphic juveniles, age and size at maturity, longevity, and spatial habitat use. These findings are paired with a literature review to compare the natural and life history of Bat Lake salamanders to other populations. Chapter Three estimates population vital rates, including adult survival and abundance, and provides suggestions on how to sample the Bat Lake salamander population to inform continued long-term ecological and demographic study. Chapter Four investigates the influence of seasonal climate on body condition, reproductive output, and breeding phenology. Breeding body condition declined over a 12 year monitoring period (2008–2019) with warmer summer temperatures at least partly responsible for the observed decline in body condition, highlighting the vulnerability of fossorial taxa and subterranean environments amid accelerating climate change. This dissertation contributes to our understanding of salamander ecology and begins to address a knowledge gap about the consequences of climate (change) for amphibian populations.
Inverse Design of Metasurfaces Using Machine Learning Techniques
Keywords: machine learning
metasurfaces
optimization
polarizers
wave transformation

These days, devices employing electromagnetic waves, such as antennas, have been intertwined with everyday life such that they are now unrecognizable by a general user. Despite the advancement of these technologies in the past few decades, in recent years, electromagnetic metasurfaces have introduced an unprecedented potential to not only tackle the problems of the conventional systems, but also create new applications for them. These engineered two-dimensional materials offer complete and intimate control over the electromagnetic fields involved through their constituent, judiciously designed meta-atoms. In recent years, in response to emerging applications for these surfaces, there have been tens of proposed meta-atoms that compete in performance, while the search for new applications is ongoing to date. Considering the revolution caused by these structures in different fields, ranging from micro-sized cameras to intelligent buildings, the significance of automated and efficient approaches to design and discover new metasurfaces is undeniable. Inspired by the breakthrough of machine and deep learning methods in other fields, generative machine learning networks such as variational autoencoders and generative adversarial networks are employed to explore the high-dimensional solution space of the meta-atoms composed of metallic and/or dielectric scatterers. Based on the presented generative methods, periodic and quasi-periodic single-layer and multilayer transverse-electric and transverse-magnetic metasurfaces are designed for different applications, including but not limited to frequency selectivity and wideband linear-to-circular polarization conversion. An end-to-end approach involving predicting the dispersive properties of bianisotropic meta-atoms via machine learning surrogate models for a beam-splitting metasurface is also presented. The functionalities of the presented metasurfaces are validated through full-wave simulation tools and experimental measurements. Lastly, future opportunities and design considerations are outlined. While the presented machine learning methods for the design of metasurfaces in this thesis serve as early attempts to tackle the problem, the achieved results demonstrate the capability and versatility of data-driven techniques for different applications of metasurfaces. Due to these remarkable abilities, machine learning will undoubtedly become an indispensable tool for solving increasingly challenging electromagnetic metasurface problems in the near future.
Contributions to Minimax Statistical Theory
Keywords: Adaptivity
Causal
Density estimation
Log loss
Minimax
Sequential

Complex statistical methods are regularly deployed in high-stakes settings. Examples include policy making informed by epidemiological and economic models, and medical diagnoses and autonomous driving informed by machine learning algorithms. These settings demand an understanding of the risks associated with statistical methods, both when optimistic modelling assumptions are correct and when they fail. One way to quantify these risks is through theoretical guarantees, yet statistical theory often relies on unverifiable assumptions and therefore fails to explain performance in real-world settings. This dissertation provides methods and theoretical guarantees without such limitations across a wide range of statistical tasks, including inference, prediction, and decision making. We study these problems using minimax analysis, determining the best possible performance against worst-case data and distributions, where the notion of worst-case is problem-specific. The considerable flexibility of this approach facilitates, for example, characterizing statistical optimality separate from concrete algorithms, obtaining a precise, non-asymptotic dependence on all relevant features of various decision problems, and establishing results that apply in generality across modelling assumptions. The main contributions of this dissertation are (i) tight bounds on the minimax performance of contextual probabilistic forecasting without any assumptions; (ii) the minimax rates of conditional density estimation for all parametric and nonparametric classes with i.i.d. data; and (iii) the introduction of adaptivity to sequential experiments, including the first algorithm that adaptively exploits causal structure.
Advanced Diagnostic Imaging and Differentiated Thyroid Cancer in Ontario: Detection, Incidence, Access, and Patient Outcomes
Keywords: Diagnostic Imaging
Epidemiology
Incidence
Incidental Findings
Regression Analysis
Thyroid neoplasms

Overdetection of thyroid cancer from increasing use of diagnostic imaging is a leading hypothesis to explain worldwide incidence rate increases in the context of low and relatively stable mortality rates. In this dissertation, I present three studies that investigate factors and outcomes related to use of advanced diagnostic imaging in the incidence of differentiated thyroid cancer (DTC) in Ontario. In the first study, I classified pre-diagnostic pathways with advanced diagnostic imaging procedures as incidentally detected cases (IDCs) (otherwise non-incidentally detected, non-IDCs). I found that a up to 20% and 30% of female and male DTCs were IDCs, and that incidence rate ratios (IRR) for these cases (IRR, females: 3.45, 95% CI 3.00-3.96; males: 3.21, 95% CI 2.65-3.90) increased more rapidly than non-IDCs (IRR, females: 2.49, 95% CI 1.22-5.08; males: 2.38, 95% CI: 2.20-2.58) in the most recent period (2013-2017) compared to earliest (1998-2002). In the second study, I evaluated standardized imaging capacity and geographic access to imaging facilities associated with increasing incidence of IDCs. I found that CT and MRI imaging capacity were associated with higher odds of IDCs among males (odds ratio, OR: 1.26, 95% CI 1.01-1.57) and females (OR: 1.44, 95% CI 1.10-1.85), respectively. Drivetime (per 10 minutes) from patient residence to imaging facility was associated with higher odds of incidental detection of DTC outside rural areas (OR range: 1.06, 95% CI 1.02-1.12 in urban areas to 1.44, 95% CI 1.25-1.66 in large urban areas). In the third study, I used instrumental variable methods to compare five-year mortality and recurrence between IDCs and non-IDCs. While I did not identify a strong instrument—causing imprecise results—the findings show confounding by prognostic and clinical factors which are unavailable in the administrative data. Sensitivity analyses support the design and approach upon identification of a strong instrument. These findings show that use of advanced diagnostic imaging contributes to Ontario’s increases in DTC incidence. As use of advanced diagnostic imaging increases, incidence rates of patients with IDCs will continue increasing. Overall, these findings provide a foundation to conduct future epidemiological, clinical, and health services research of the burden of DTC in Ontario.
Characterization of T Cell Responses to SARS-CoV-2 following Infection and Vaccination
Keywords: adaptive immunity
COVID-19
infectious diseases
SARS-CoV-2
T cells
vaccines

The COVID-19 pandemic caused by the SARS-CoV-2 virus continues to be a global health crisis. There is an urgent need to understand immune responses against SARS-CoV-2 to develop effective therapeutics and vaccine strategies for controlling infection. While antibodies prevent infection, T cells are critical for controlling and resolving infection. Memory T cell responses are necessary to limit re-infections. While there was a race to probe antibody responses after infection during the early stages of the pandemic, there was notable lack of focus on cellular immunity. This thesis sought to characterize the T cell memory response after SARS-CoV-2 infection and vaccination. In the weeks after symptom onset, I show that all study subjects develop SARS-CoV-2-specific CD4+ T cell responses. However, CD4+ T cells exhibited unusual cytokine profiles characterized by high IL-2 and reduced IFN-γ expression across two separate convalescent cohorts, especially when compared with responses against the more common influenza virus. I demonstrated that SARS-CoV-2 T cell responses persist up to 9 months after symptom onset in most convalescent subjects, and that the atypical cytokine profile that was initially observed is maintained over time. With the advent of COVID-19 vaccines, it became crucial to examine vaccine immunogenicity in immunocompromised individuals who were overlooked during vaccine trials despite being more vulnerable to severe outcomes of COVID-19. Here, I followed a cohort of 124 patients with immune-mediated inflammatory diseases on various immunosuppressive therapies after successive mRNA vaccinations. In this study, I provide compelling evidence that these patients have diminished and less durable vaccine-induced antibody and T cell responses against SARS-CoV-2. In particular, patients on TNF inhibitor therapy exhibited lower levels of virus-specific antibody and decreased T cell responses compared to healthy controls, especially with respect to neutralization responses against variants of concern. Thus, vaccine strategies need to be optimized for this patient population. Altogether, the work in this thesis contributes to our current understanding of immune responses against SARS-CoV-2 by highlighting skewed antiviral T cell responses and reduced vaccine immunogenicity in immunocompromised individuals.
John Duns Scotus on Cognitive Acts: Their Causes, Ontological Nature, and Intentional Character
Keywords: cognition
concepts
Duns Scotus
Intentionality
objective being
Quodlibet

How do we acquire our cognitive acts? What is their ontological status? How are they related to the extramental world? These are only a few of the major questions concerning cognitive acts that puzzled late medieval thinkers, forming one of the most exciting philosophical debates that took place between the second half of the thirteenth and the first half of the fourteenth century. John Duns Scotus (d. 1308) is considered a leading figure in this debate; scholars believe that he “wrought a revolution in the philosophy of mind” by offering “startling new ideas about cognition, making a radical break with his predecessors and contemporaries” (King). Modern scholars of medieval philosophy have devoted much attention to Scotus’s view on the intentionality of cognitive acts, but little on issues such as their origin and ontological status. My dissertation fills this gap. First, I examine Scotus’s new idea of an essential order between object and intellect in the co-causation of the cognitive act (intellectio). Scotus argues that this essential order is required to ensure both the reliability of our cognition as well as the freedom of the knower in the cognitive process. Second, I discuss the theoretical implications of Scotus’s idea that cognitive acts are a special sort of activity (operatio) in the Aristotelian category of “quality” and not of “action.” According to Scotus this explains the intentionality of cognitive acts, that is, how and why cognitive acts are about their objects, and why only the cognition of an existent and actually present object can fully perfect the human intellect, through what Scotus calls a “relation of contact.” This second step will also involve a study of the peculiar terminology Duns Scotus uses, such as the distinction between “objective being” and “subjective being,” as well as the expression “diminished being” (esse diminutum). I conclude that Scotus’s view on the ontological nature of the cognitive act provides a more plausible explanation than the one offered by his predecessors about how the cognitive faculty cognizes the extramental world and gives a more reliable epistemological foundation to human cognition. Finally, I provide a critical edition of question 13 of Scotus’s Quaestiones quodlibetales, his last and most important work on the ontology of cognitive acts and how they relate to the extramental world. A critical edition is indispensable because the best Latin text that is currently availableis very difficult to understand due to textual flaws and omitted passages.