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simulation data and code of project 39 as suggested by one reviewer
No full textThis code was created in Dec 2024 to verify that the method used to calculate represented positions and headings, including the selection of environments, target buildings, and the algorithm based on Cosine similarity, does not introduce systematic biases, such as adding more noise to position estimates than to heading estimates. Please read readme.docx
Improving the diagnosis and cascade of care for prenatal, infant, and priority populations infected with hepatitis C virus (HCV) in Alberta, Canada
No full textHepatitis C virus (HCV) is a bloodborne pathogen that causes chronic liver disease and can be cured with highly effective direct-acting antivirals (DAAs). In 2016, the World Health Organization (WHO) aimed to eliminate viral hepatitis as a public health threat and Canada has committed to meeting this goal. In 2019, the Canadian Network on Hepatitis C released the Blueprint to Inform Hepatitis C Elimination Efforts in Canada, which provides elimination targets across the HCV cascade of care (testing and diagnosis, linkage to care, treatment, and achievement of a sustained virologic response (SVR), and proposes priority populations for elimination efforts, including people who inject drugs (PWID), people who are incarcerated (PWAI), and the birth cohort (those born between 1945 and 1975). Although pregnant women and children were not defined as priority populations, they were outlined as being underserved across elimination initiatives. Achieving HCV elimination in Canada will require a combination of population and cohort-specific programming across the care cascade. However, every province/territory is responsible for their own healthcare services and reaching elimination will rely on each jurisdiction to optimize their HCV programs and policies.
This thesis presents the evaluation of three new HCV healthcare programs in Alberta: a universal prenatal HCV screening program, a call-out system for linking prenatal HCV positive patients to care, and a novel HCV reflex testing algorithm.
Canadian guidelines currently recommend risk-based HCV screening for pregnant women. In February 2020, a pilot universal prenatal HCV screening program was implemented across Alberta by amending the provincial prenatal screening program to include HCV testing. Screening rates, prevalence, and risk factors among diagnosed pregnant women were compared between risk-based and universal programs. Compared to the risk-based program, the universal program had significantly higher HCV screening rates (99.9% versus 8.8%) and prevalence (0.10% versus 0.06%), translating to an additional 21 HCV-positive individuals diagnosed annually, particularly among those engaging in high-risk sexual behaviours/sex work, unstably housed, and previously undiagnosed. Programs were also assessed for downstream effects on follow-up testing in perinatally HCV-exposed infants. Follow-up testing was lower among infants born to mothers diagnosed through universal versus risk-based programs (29.5% versus 54.2%), however, adherence to screening guidelines for infants was higher (69.2% versus 46.2%).
A new call-out system for linking first-time HCV positive pregnant women to specialty care was implemented across Alberta in January 2021. Prior to implementation, ordering providers were responsible for linking patients to specialty care. With the new call-out system, ordering providers are still responsible for linking patients to specialty care, but are guided through result comment notifications and phone calls with virologists. After implementation, a higher proportion of pregnant women were linked to follow-up care compared to before (76.5% versus 59.4%), but median turnaround times between diagnosis and linkage to care were longer (50 days versus 38 days) and were associated with a gravidity ≥1.
HCV testing across Alberta previously used a two-sample testing method, where one blood sample was collected to screen individuals for HCV antibodies, and if positive, a second sample was collected for RNA confirmation. A reflexive HCV diagnostic algorithm on a single blood sample was assessed for test-method and clinical validation and found to have high sensitivity (99.3%) and specificity (100.0%), low contamination rates from the serological instrument (3.29%), led to a definitive diagnosis for ~97% of individuals, and decreased average diagnostic turnaround times from 39 days to 4 days. Downstream, individuals diagnosed through reflex versus two-sample testing were significantly more likely to be linked to care (92.8% versus 57.6%), leading to improved retention in the care cascade and improving overall turnaround times to treatment and SVR. Reflex testing was also associated with increased odds of PWID and the birth cohort achieving all downstream cascade of care milestones and PWAI being diagnosed and linked to care. However, the emergence of first-wave COVID-19 restrictions in April 2020 significantly decreased HCV antibody and RNA testing rates by 98.39 and 1.78 tests per 100,000, and testing levels remained below pre-restriction levels at the end of 2022.
Overall, all three novel HCV healthcare programs improved patient outcomes. However, programs across the care cascade should continue to be optimized, expanded, and prioritized if HCV elimination is to be achieved in Alberta by 2030
GrEX-Success Begets Success
No full textPrécis of select award-winning Insight Grants (IG) (2012-2022) and Partnership Development Grants (PDG) (2015-2020) for varying disciplines detailing the strengths of their proposals along with a list of key databases for accessing successful grant applications and some tips for research grants
Onîkihikomâwiwin (Parenthood): Researching and Understanding Approaches to Raising Children in Alexander First Nation
Full text linkTo be evidence-based, practices, programs, decisions, and policies aimed at supporting parents and families must be based on the best existing evidence on parenting within the context of individual factors, including culture. Parenting research has a history of being positivist and based on Eurocentric and Western samples, conceptualizations, theories, ways of knowing, and ways of being. Although research suggests that some aspects of parenting are universal, the form and function of parenting behaviours and dimensions have been found to vary across cultures. In Canada, Indigenous peoples, families, communities, and cultures have persisted through and been impacted by historical and ongoing colonization, forced assimilation, cultural genocide, and systemic racism. Indigenous children and families are overrepresented in child welfare systems and there are few culturally safe parenting programs whose effectiveness has been researched, thereby perpetuating these cycles of harm. Although high-quality research on Indigenous parenting that avoids deficit-theorizing and blanket statements is growing, more research is needed to build our understanding of the unique parenting approaches, strengths, and needs in diverse Indigenous communities. Such research can help inform and reform existing practices, programs, decisions, and policies affecting Indigenous families. However, to ensure the research and its results are valid, meaningful, and ethical, the research must itself be culturally safe by being done with, by, and for Indigenous communities based on their epistemologies, ontologies, axiologies, and methodologies.
This dissertation consists of two papers describing the processes and results of an Indigenous community-based participatory research (CBPR) study on child-rearing in Alexander First Nation (AFN) from the perspective of eleven community members. The overarching purpose of this dissertation is to share the community’s approach to research and child-rearing, with the hope that (a) the knowledge generated in this study can be used by AFN to support the children, youth, and families in their community, (b) the research processes can provide a case example to parenting researchers of how research understanding Indigenous child-rearing can be conducted, and (c) the knowledge can add to a literature base on Indigenous child-rearing that can play a role in changing harmful and systemically racist practices, programs, decisions, and policies.
The first of the two papers focuses on the processes of the research study. It provides an overview of the history of research done on Indigenous peoples, including in parenting research, followed by a brief review of CBPR and Indigenous approaches to research. Then the processes (including successes, challenges, and reflections) of the current Indigenous CBPR study are described including building relationship with the Alexander Research Committee (ARC) and AFN community, designing the study, recruitment, data generation, Indigenous thematic analysis processes, and knowledge mobilization.
The second paper focuses on the results of the study. The study aimed to answer the following three research questions:
1. What are the cultural and traditional beliefs, values, and practices related to child-rearing and child development held and used by the people in AFN?
2. How do these beliefs, values, and practices reflect strengths and developmentally-supportive child-rearing in AFN?
3. How has colonization and intergenerational trauma impacted the intergenerational transmission of traditional child-rearing practices in AFN?
Tipi teachings received from people within AFN were used as the study’s guiding Indigenous theorizing. The Indigenous CBPR approach included relational sampling, interviews with each of the 11 participating individuals (all of whom identified as women) based in the conversational method, and Indigenous thematic analysis. Four themes emerged, thematically represented by a tipi: (a) Defining Tipi Pole Roles (Mothering); (b) Cooperation Between the Poles, the Environment, and the Land (Community Approach to Raising Children); (c) The Hide (Supporting Child Development); and (d) Maintaining a Sturdy Tipi (Healing Intergenerational Trauma). These findings capture the strengths and developmental support present in the approaches to child-rearing in AFN, which will be mobilized to benefit the community in partnership with the ARC
Alternative Design of Column Web Doubler Plates in Steel Pipe Rack Modules
No full textPipe rack modules are non-building structures used mostly in refineries, chemical plants, and oil sands facilities. They often consist of steel braced frames in the direction of pipes and steel moment-resisting frames in the perpendicular direction. Moment frames are designed to resist a variety of loads, which often makes their connections complex and expensive. Doubler plates are often required the in beam-to-column connection panel zone. A groove weld is typically used to
weld the doubler plate to the column web. Groove welds are known to be more complex, expensive, and take more time than fillet welds. This report proposes a new doubler plate detail involving a reduced-size plate welded to the column web, for beam-to-column moment connections in pipe rack modules, and presents a new design method to size such doubler plates under shear induced in the column panel zone. To investigate the effect of reducing the doubler plate and using fillet welds in pipe rack module connections, a full-scale experimental test setup was developed. The experimental study consisted of twelve moment connections, where each six specimens represented a different beam-to-column W-section. Six used W250×58 beams and columns and the rest used W410×60 columns and W410×100 beams. The proposed detail consisted of a reduced doubler plate fillet-welded to the
column web in the panel zone area of the connection instead of a doubler plate that is groove welded. The tests showed that a reduced-size doubler plate with a fillet weld could be used in pipe rack module connections, but with certain thresholds in place. A new design method was developed to size doubler plate dimensions taking into account potential limit states and limiting shear deformation in the panel zone beyond yielding. It was validated based on the experimental results and performed on two beam-to-column moment connection examples
Mechanisms of Collateral Failure and Neutrophil-Mediated Microvascular Obstruction in Ischemic Stroke: Therapeutic Interventions Targeting Reperfusion and Neuroprotection
Full text linkIschemic stroke triggers complex and interrelated vascular and immune responses that dictate recovery outcomes, yet demographic factors such as age and sex introduce variability in these responses, complicating treatment strategies. This thesis investigates the underlying mechanisms driving post-stroke microvascular dysfunction that drives ‘futile recanalization’, and explores targeted interventions to mitigate ischemic damage and promote recovery. Using a mouse MCAo model to mimic successful recanalization but poor outcome (i.e. futile recanalization), high-resolution in vivo imaging, and molecular assays, this research highlights critical influences of vascular dynamics, neutrophil activity, and pharmacological intervention on stroke outcome across demographic groups.
Chapter 3 examines the impact of age and sex on cerebral perfusion after stroke induction. Advanced imaging techniques reveal that aged mice experience rapid collateral failure and sustained microvascular obstructions within 24 hours post-recanalization, accompanied by reduced vessel diameter, RBC flux, and microvascular volume. Younger mice, however, show improved collateral recruitment and microvascular restoration. Elevated inflammatory markers, including Angiopoietin-2 and TNF-α, were particularly pronounced in aged mice, indicating an intensified inflammatory response. These findings identify mechanisms for increased futile recanalization with older age, and underscore age- and sex-specific vulnerabilities that highlight the need for therapies targeting vascular and inflammatory pathways.
Chapter 4 explores neutrophils' dual role in stroke pathology, with a focus on how neutrophil-driven capillary blockages and inflammation impede perfusion. High-resolution imaging reveals significant microvascular disruptions due to neutrophil stalls as early as 3 hours post-recanalization, leading to prolonged no-reflow in the penumbra. Neutrophil depletion through anti-Ly6G treatment partially restores microvascular function. Molecular profiling shows that neutrophil depletion dampens pro-inflammatory signaling while supporting immune pathways that facilitate recovery, illustrating neutrophils' complex involvement in ischemic damage and inflammation. These findings position neutrophils as pivotal targets for post-stroke interventions aimed at reducing futile recanalization by enhancing perfusion and reducing inflammation.
Chapter 5 evaluates the therapeutic potential of Ibudilast in stroke outcome after recanalization, focusing on its effects on cerebral blood flow and inflammation. By enhancing collateral circulation and reducing neutrophil adhesion, Ibudilast preserves perfusion and lowers pro-inflammatory cytokines, creating a protective anti-inflammatory environment. Significant reductions in infarct size observed at 24 hours post-recanalization, particularly in younger mice and females, underscore the potential of Ibudilast to mitigate ischemic injury and enhance recovery by strengthening microvascular integrity and managing inflammation within specific demographic groups.
Collectively, this thesis elucidates the vascular and immune mechanisms driving ischemic stroke outcomes, emphasizing the importance of demographic considerations in stroke recovery and futile recanalization. The insights gained on neutrophil modulation and therapeutic efficacy of Ibudilast highlight promising avenues for targeted treatments that can enhance microvascular function and reduce inflammatory damage, offering potential improvements in stroke recovery across diverse populations
PNKP is Involved in DNA Replication and Protects Nascent DNA from Degradation at Stalled Replication Forks in Response to Replication Stress
No full textThe process of DNA replication is essential for all living cells and occurs in two forms: leading and lagging strands, also known as Okazaki fragments. Okazaki fragment maturation is a crucial DNA metabolic process that is vital for maintaining genome integrity and cell viability. Recent studies have shown that LIG3-XRCC1 operates in an alternative pathway to the canonical FEN1-LIG1 pathway. Chapter 2 of this thesis presents data indicating that polynucleotide kinase phosphatase (PNKP) is another important participant in DNA replication, similar to LIG3-XRCC1. Through functional experiments, we demonstrate PNKP's enrichment at DNA replication forks and its association with PCNA and LIG3, suggesting its involvement in the alternative Okazaki fragment maturation pathway. Depletion of PNKP in cells leads to defects observed in OFMrelated proteins, highlighting its significance in replication fork dynamics.
We also identify PNKP as a substrate for cyclin-dependent kinase (CDK), which phosphorylates PNKP at multiple residues. Mutation analysis of these phosphorylation sites underscores the importance of CDK-mediated PNKP phosphorylation in DNA replication. The uncontrolled degradation and collapse of stalled replication forks are primary sources of genomic instability, yet the molecular mechanisms for protecting forks from degradation and collapse are not fully understood. Chapter 3 explores the involvement of PNKP in the replication stress response. Our research shows that PNKP protects stalled forks from excessive degradation. Loss of PNKP results in EXO1-dependent nucleolytic degradation of nascent DNA at stalled
replication forks. This mechanism is different from the BRCA2-dependent fork protection pathway, which safeguards stalled forks from excessive MRE11-dependent nucleolytic degradation