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Quantitative Volumetric Analysis Using 3D Ultrasound Tomography for Breast Mass Characterization
Get PDFBreast cancer detection remains a significant challenge, with traditional mammography presenting barriers such as discomfort, radiation exposure, high false-positive rates, and financial burden. Moreover, younger women frequently fall outside routine mammographic screening guidelines, leaving critical gaps in early detection. Objectives: This study investigates the potential of quantitative transmission breast acoustic computed tomography scanner imaging (QT3D) as an innovative, non-invasive imaging modality for characterizing and evaluating breast masses. Methods: A comparative analysis between QT3D imaging and magnetic resonance imaging (MRI) was conducted in a cohort of patients with biopsy-proven benign or malignant breast lesions, comparing key metrics in quantifying breast masses for the purposes of breast mass characterization. Results: The findings in this study highlight its capability in identifying relatively small tumors, multiple lesions, satellite lesions, intraductal extensions, and calcifications, in addition to offering valuable diagnostic insights. Conclusions: This work is a first step toward studies essential for confirming its clinical feasibility, establishing its role in breast cancer tumor characterization, and potentially improving patient outcomes
To Stop or Not to Stop: Response After Nucleos(t)ide Analogue Withdrawal Among Patients With Chronic Hepatitis B
Get PDFHepatitis B virus (HBV) infection is a major global public health concern with high morbidity and mortality due to progression of liver disease to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Nucleos(t)ide analogues (NAs) are highly effective in viral suppression however, most patients require lifelong treatment, and hepatitis B surface antigen (HBsAg) loss, or “functional cure” is rare on therapy. NA withdrawal results in higher rates of HBsAg loss but remains controversial because of the possibility of HBV flares. This thesis aims to investigate long-term outcomes after NA cessation and determine prognostic factors among virally supressed chronic hepatitis B (CHB) patients who were hepatitis B e antigen (HBeAg)-negative at end of therapy. The first study found that Caucasians with HBsAg levels 30%, although the risk of hepatic decompensation and HCC persisted. The second study found that patients who remained off-therapy without HBsAg loss for one year had mildly active disease, even if they did not meet the criteria for retreatment. The third study found that there were no significant differences in the rates of HBsAg loss between patients who discontinued tenofovir disoproxil fumarate (TDF) compared with entecavir (ETV) however, virological relapse occurred earlier in the TDF-treated group and rates of clinical relapse were also relatively higher in this group. The fourth study showed that the risk of hepatic decompensation was higher among cirrhotics and patients who were HBeAg-positive at the start of therapy. The fifth study described patients who were referred for liver transplantation (LT) after NA cessation. The fourth and fifth studies collectively highlighted that patients should be very carefully assessed prior to NA discontinuation and timely re-initiation of treatment is crucial to avoid adverse outcomes. In conclusion, NA withdrawal can lead to HBsAg loss, but virological relapse is universal and a sustained response off therapy may not be comparable to on-therapy viral suppression. Thus, if NA withdrawal is considered, strict and frequent monitoring is critical to prevent severe complications and liver-related deaths. Non-cirrhotic, Caucasian patients with low HBsAg levels are likely the best candidates for NA withdrawal.Ph.D
The Contribution of AIDA (Artificial Intelligence Dystocia Algorithm) to Cesarean Section Within Robson Classification Group
Get PDFGlobal cesarean section (CS) rates continue to rise, with the Robson classification widely used for analysis. However, Robson Group 2A patients (nulliparous women with induced labor) show disproportionately high CS rates that cannot be fully explained by demographic factors alone. This study explored how the Artificial Intelligence Dystocia Algorithm (AIDA) could enhance the Robson system by providing detailed information on geometric dystocia, thereby facilitating better understanding of factors contributing to CS and developing more targeted reduction strategies. The authors conducted a comprehensive literature review analyzing both classification systems across multiple databases and developed a theoretical framework for integration. AIDA categorized labor cases into five classes (0–4) by analyzing four key geometric parameters measured through intrapartum ultrasound: angle of progression (AoP), asynclitism degree (AD), head–symphysis distance (HSD), and midline angle (MLA). Significant asynclitism (AD ≥ 7.0 mm) was strongly associated with CS regardless of other parameters, potentially explaining many “failure to progress” cases in Robson Group 2A patients. The proposed integration created a combined classification providing both population-level and individual geometric risk assessment. The integration of AIDA with the Robson classification represented a potentially valuable advancement in CS risk assessment, combining population-level stratification with individual-level geometric assessment to enable more personalized obstetric care. Future validation studies across diverse settings are needed to establish clinical utility
Disentangling the silence : endarkened explorations of Punjabi Canadian feminine hair narratives
Get PDFThis dissertation was completed and submitted at Nipissing University, and is made freely accessible through the University of Toronto’s TSpace repositoryThrough a methodology of Endarkened Narrative Inquiry (McClish-Boyd & Bhattacharya, 2021, 2023) and a postcolonial post-structural feminist theoretical framework, this study examined the hair experiences of a Punjabi Sikh woman living in the Canadian diaspora, seeking to help fill the gaps in existing scholarship around Sikh female hair experiences in Canada. By exploring the hair experiences of the research participant, this study yielded a number of insights about how she negotiated the tension between (a) patriarchal Punjabi Sikh hair dictates that she felt mandated she follow religio-cultural imperatives to keep her body and head hair uncut in order to support a distinct identity for the community, and (b) racist beauty hair standards of colonial Canadian culture that prized infantile hairlessness in women as a way of reinforcing racial hierarchy. Findings of this study provide insights into the nuances of racist and sexist colonial hair norms of Canada, and the effects of patriarchal Punjabi Sikh hair culture on women. This study also reveals the many ways the Punjabi Canadian female research participant’s internalization of these hair narratives had the effect of silencing self-determined hair expressions. However, moments of hope, in which she was able to self-construct alternate meanings for her hair were also evident. This study helps dispel some of the academic silence around Punjabi Canadian female hair expressions, reveals the habitual racism and sexism inherent in hair dictates and makes space for further research on this topic.Ph.D
Evaluation of the Role of Endogenous Factor XIII as a Determinant of Bleeding-Related Outcomes and Death Among Severely Injured Patients
Get PDFUncontrolled bleeding is the number one preventable cause of death after traumatic injuries. The body limits blood loss by reducing clot destruction with coagulation factors such as factor XIII (FXIII). Lower serum FXIII levels can cause reduced clot stability and premature clot breakdown. We hypothesize that lower FXIII levels result in worse bleeding-related outcomes and death. To test the hypothesis, we first examined the available evidence concerning FXIII levels and its supplementation and adverse outcomes. Then, we evaluated whether lower FXIII concentration was associated with bleeding-related outcomes and death in severely injured patients. Lastly, in a cohort of severely bleeding patients, we sought to ascertain whether lower baseline FXIII levels were associated with massive transfusion and whether they were different FXIII trajectories within the first 24 hours post-injury.
We found that the available evidence concerning FXIII is scarce, low-quality, and prone to confounding bias. We also identified key knowledge gaps that should be addressed in future research endeavours, such as defining the target population, improving the quality of evidence, and addressing FXIII treatment uncertainties (transfusion trigger, doses, testing modality, etc.). Furthermore, we found that baseline FXIII levels had an inconsistent association with bleeding-related outcomes in severely injured patients and were not associated with a composite of massive transfusion or death due to bleeding in severely bleeding patients. Lastly, we identified distinct FXIII trajectories within 24 hours post-trauma; the group of patients with initial low FXIII levels and an early increase within 4 hours post-injury had lower 24-hours and mortality due to bleeding than the remaining groups despite a high-injury severity clinical profile.
Overall, this thesis work found that reduced FXIII levels do not appear to be a key driver of hemorrhagic risk in severely injured patients; however, we were limited by generally small sample sizes, few FXIII measurements, and cohorts of patients where tranexamic acid was not consistently provided. Future research is needed in the form of a prospective international longitudinal cohort study to determine the natural history and potential clinical relevance of FXIII in a large, contemporary and diverse patient population of severely injured patients.Ph.D
Essays on the Economics of Traditional Chinese Medicine
Get PDFObjectiveThe objectives of this thesis are to study whether Traditional Chinese Medicine (TCM) and Modern medicine (MM) are complementary or substitute goods, the factors associated with TCM use among middle-aged and elderly Chinese adults, and the lifetime economic impact of acupuncture in migraine prevention.
Methods
Guided by Grossman’s Model of investments in health capital and using administrative data from Taiwan's National Health Insurance Research Database (NHIRD), the Almost Ideal Demand System (AIDS) was applied to calculate the elasticity of demand for TCM and MM across medical conditions to determine if TCM complements or substitutes for MM. To address my second research question, data were drawn from the China Health and Retirement Longitudinal Study (CHARLS) and the Taiwan Longitudinal Study on Aging (TLSA) to study the factors associated with TCM use through the lens of Grossman’s model. The primary outcomes assessed were the propensity to use (i.e., whether respondents visited a TCM hospital) and the intensity of use (i.e., the number of TCM hospital visits) by a random-effect Heckit selection model. Finally, a cost-benefit evaluation was constructed to compare acupuncture with drug prophylaxis and with no active treatment among patients with episodic migraine and chronic migraine over their lifetime from both a Taiwanese healthcare payer and a societal perspective.
Results
Across all conditions, TCM is complementary to MM, and MM is complementary to TCM. The demand for both TCM and MM was inelastic, but the demand for TCM was less responsive to price changes than MM's. In addition, increasing age, living in rural China, higher self-rated health status, and being a woman were significantly associated with TCM use. Last but not least, acupuncture was associated with greater lifetime net economic gains in migraine prevention compared to no active treatment or drug prophylaxis.
Conclusion
Our study shed light on policies in price setting for efficient allocation of healthcare resources when TCM and MM co-exist in the formal healthcare market. Decision-makers should consider increasing TCM out-of-pocket payments at large medical institutions, increasing the supply of TCM hospitals, and reimbursements for acupuncture sessions to meet healthcare demand.Ph.D
HER2-targeted Theranostic Radioimmunoconjugates for SPECT Imaging and α-particle Radioimmunotherapy of HER2-positive Breast Cancer
Get PDFThe human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–20% of breast cancer (BC) patients. HER2-targeting antibody trastuzumab IgG and its smaller molecular weight fragments trastuzumab F(ab′)2 and Fab were modified with the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) and radiolabeled with γ-emitting 111In for SPECT imaging and α-emitting 225Ac for radioimmunotherapy (RIT) as theranostic 225Ac/111In pairs. [111In]In-DOTA-trastuzumab IgG exhibited saturable and specific binding to HER2-overexpressing BC cells in vitro (KD = 1.2 ± 0.3 × 10–8 mol/L). [225Ac]Ac-DOTA-trastuzumab IgG significantly reduced clonogenic survival and induced DNA DSBs in HER2-overexpressing BC cells in vitro. SPECT/CT and biodistribution at 48 h p.i. revealed high and HER2-specific tumour uptake of [111In]In-DOTA-trastuzumab IgG in NRG mice with HER2-overexpressing human BC xenografts. [111In]In-DOTA-trastuzumab F(ab′)2 and Fab demonstrated saturable and specific binding to HER2-overexpressing BC cells in vitro (KD = 1.2 ± 0.3 × 10–7 and 1.4 ± 0.3 × 10–7 mol/L, respectively). Tumours of NRG mice with HER2-overexpressing human BC xenografts were well-visualized on SPECT/CT images at 2 d p.i. with [111In]In-DOTA-trastuzumab IgG and F(ab′)2, but not at 18 h p.i. using [111In]In-DOTA-trastuzumab Fab. Radiation absorbed doses in the tumour was highest for [225Ac]Ac-DOTA-trastuzumab F(ab′)2 (2.88 ± 0.12 Gy), while [225Ac]Ac-DOTA-trastuzumab IgG and Fab deposited 0.84–1.32 Gy when estimated at a therapeutic total dose of 6 kBq. [225Ac]Ac-DOTA-trastuzumab IgG and Fab were characterized by a high spleen dose (17.4 ± 2.4 Gy) and high kidney dose (7.92 ± 0.48 Gy), respectively. Administration of 2 and 4 kBq of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab′)2, and Fab separated by 8 d in mice with HER2-overexpressing human BC xenografts equivalently inhibited tumour growth, but [225Ac]Ac-DOTA-trastuzumab F(ab′)2 demonstrated the strongest survival advantage. In healthy NRG mice, [225Ac]Ac-DOTA-trastuzumab IgG induced acute hematopoietic toxicity, but not [225Ac]Ac-DOTA-trastuzumab F(ab′)2 and Fab. CED of 1.5 kBq of [225Ac]Ac-DOTA-trastuzumab F(ab′)2 in the tumours of mice with HER2-overexpressing human BC xenografts in the brain deposited high doses of 11.1 Gy, with low activities observed in normal tissues. CED of [225Ac]Ac-DOTA-trastuzumab F(ab′)2 induced significant tumour growth inhibition and prolonged survival. These results suggest that theranostic HER2-targeting radioimmunoconjugates for SPECT imaging and α-particle RIT are promising for detection and treatment of HER-positive BC.Ph.D
Interpretable and Constrained Machine Learning via Combinatorial Optimization
Get PDFRecent transformative advances in machine and deep learning have enabled the recognition of complex patterns from vast data, with or without human supervision. These advances have catalyzed the application of machine learning techniques to a diversity of problem settings, from healthcare to robotics. Unfortunately, sophisticated machine learning techniques can result in the construction of domain models that are challenging for humans to understand and in which it is difficult to enforce user-specified constraints. This lack of interpretability, as well as the inability to impose further constraints, has become a major obstacle to human trust in machine learning models and a challenge to the broad adoption of machine learning-based systems.
While one of the goals of artificial intelligence is, arguably, to extend its reasoning beyond the cognitive capabilities of humankind, such a pursuit should not disregard human-compatibility. Interpretable machine learning aims to develop human-understandable models and to explain so-called black-box models. Constrained machine learning addresses the problem by enforcing expert knowledge and formal requirements on solutions.
In this dissertation we introduce methods to produce machine learning models/artifacts that are interpretable and amenable to human-specified constraints. We do so through the exploitation of techniques for solving combinatorial optimization problems.
In particular, we propose novel formulations to learn inherently interpretable models such as decision trees. Our work includes encoding a variety of solution formats and objectives. We further propose frameworks and encodings for the integration of constraints during or after training. We show that our approaches successfully produce high-quality interpretable and constrained solutions in short runtimes, solving new problems and improving the state of the art in others. Our collective work shows that interpretability does not necessarily come at the expense of quality and, in fact, sometimes improves it. Utilizing constraints can also improve accuracy despite reducing the space of feasible solutions. Lastly, we discuss how the work presented in this dissertation can be extended in several interesting directions and inspire new approaches for using combinatorial optimization problems in machine learning.Ph.D
Evaluation of the Bioinductive Effects of a Novel Antibiotic Eluting Cardiac Implantable Electronic Device Envelope
Get PDFBackground: Subcutaneous pocket infection is a common morbidity associated with the integration of cardiac implantable electronic devices (CIEDs). A new antibiotic-eluting CIED bioenvelope has been developed as a prophylactic measure to mitigate infection and skin erosion caused by device migration. This study investigated the envelope’s regulatory properties in scar formation and vascularization. Methods: Fibroblasts were seeded on either plastic (n = 6) or small intestine submucosal extracellular matrix (SIS-ECM) (n = 6) for 24 h. The culture media were analyzed for proangiogenic and proinflammatory proteins with multiplex. Sham (n = 8) or SIS-ECM (n = 8) was randomly implanted into the dorsal subcutaneous pocket of mice. The implants were excised on day 7, cultured for 24 h, and the media analyzed. Rabbit models were implanted with either synthetic polymer HDPE (n = 12) or SIS-ECM (n = 11). The treatments were excised at weeks 2, 10, and 26 and then stained for analysis. Results: SIS-ECM significantly increased the fibroblasts’ paracrine release of proangiogenic and proinflammatory factors like VEGF-A (p < 0.05) and IL-6 (p < 0.05) compared with plastic. The murine tissue interacting with SIS-ECM released significantly more angiogenic proteins like VEGF-A (p < 0.05) than the sham. The histology analysis of rabbit subcutaneous tissue revealed a decreasing level of inflammation and fibrosis over time with SIS-ECM. Conclusions: The CIED bioenvelope elicited proangiogenic paracrine signaling and reduced fibrotic response in fibroblasts and animal models. Clinical translation of the CIED bioenvelope as an adjunct to regular prophylactic practice may be warranted in the future