David Patrick

Introduction: The angiotensin converting enzyme two (ACE2) protein serves as the host receptor for the severe acute respiratory syndrome coronavirus two (SARS-CoV-2). We aim to understand if transcription of ACE2 can be reliably detected in diagnostic specimens collected by nasopharyngeal swab and if a relationship exists between availability of ACE2 in the upper human respiratory tract, SARS-CoV-2 viral load, and secondary transmission.Methods: Measurements of ACE2 transcription and SARS-CoV-2 viral load were taken by targeted ribonucleic acid sequencing (RNA-Seq) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Alternative measures of ACE2 transcription were compared using bivariate statistical analysis to quantify instrument bias. Viral load was only measured by RT-qPCR. A cross-sectional study of n = 424 people who tested positive (n = 212) or negative (n = 212) for SARS-CoV-2 was performed to observe the association between ACE2 transcription and SARS-CoV-2 viral load. Statistical analysis involved bivariate testing and multivariable linear regression. To assess involvement of ACE2 in transmission of SARS-CoV-2, nasopharyngeal ACE2 transcription was measured in confirmed cases from hospital associated outbreaks. An infection tracing transmission network and multivariable Poisson/Negative Binomial regression was used for analysis. Results: No instrument bias was detected. In COVID-19 negative participants nasopharyngeal ACE2 transcription had no relationship with biological sex (P = 0.832) or age (P = 0.092), in adults over the age of 18. Regardless, nasopharyngeal ACE2 transcription varied greatly between SARS-CoV-2 negative participants indicating inter-individual heterogeneity. In COVID-19 positive participants the association between ACE2 transcription and SARS-CoV-2 viral load differed by isoform. Transmembrane ACE2 transcription positively correlated (β = 0.89, 95%CI: [0.59 to 1.18]) while the putative soluble transcript had a negative association (β = -0.099, 95%CI: [-0.18 to -0.022]). The infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. High ACE2 transcription was observed in 98.6% of transmission events. In patients, ACE2 transcription was associated with an increased in the number of secondary cases (β = 0.187 (95% CI: 0.0101 to 0.370) adjusting for viral load.Conclusion: ACE2 expression in the upper respiratory tract may differentiate an individual’s risk of SARS-CoV-2 infection and likelihood of transmission.

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Avian influenza virus (AIV) is a wildlife-origin pathogen with potential for causing disease in multiple species but challenges in sampling directly from wild bird hosts means the diversity of circulating viruses is often incompletely understood. This dissertation evaluated if indirect sampling of wild waterfowl birds through viruses excreted into their wetland environment—combined with probe capture sequencing—could provide an alternative to conventional AIV surveillance. Our project collected both conventional bird swabs (n = 1,290) and environmental wetland sediment samples (n = 2,090) between September 2016 and August 2018 in southwestern British Columbia, Canada. To facilitate selection of environmental sample collection locations, we characterized the spatial clustering of AIV positivity in wetland using Kulldorff's spatial scan statistic and identified ecological variables associated with detection of AIV through a Bernoulli generalized additive regression model with the R-INLA program. Evaluating the use of environmental samples as a proxy for conventional surveillance was done by comparing the AIV subtype diversity found in wetland sediment with that from direct bird sampling. The temporal dynamics of AIV subtype diversity in wetland sediment follows the seasonality of waterfowl migration. Furthermore, it suggests that extended persistence of AIV in the wetland sediment was possible but unlikely to extend over the summer months in our study area. Compared to direct bird surveillance, environmental surveillance provided higher subtype detection rates, detected subtypes at more times of the year, and detected a higher maximum number of subtypes per sample. We developed a methodology to incorporate both the fragmented RNA detected in the environment and complete AIV sequences from wild birds into the same Bayesian phylogenetic trees. Within a subtype, we found that only a small number of AIV sequences from sediment were considered genetically equivalent to AIV from study birds; however, many were genetically similar. Overall, this dissertation demonstrates that while environmental surveillance can provide similar trends to conventional surveillance, greater genetic diversity is detected at more locations and more times of year when using both programs together. Combining multiple surveillance data sources provides the best context for decision makers in a complex and incompletely understood disease landscape.

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BACKGROUND: Streptococcus pneumoniae causes substantial health and economic burden. Two vaccines available to combat pneumococcal disease are the 23-valent pneumococcal polysaccharide vaccine (PPV23) for adults and the 13-valent pneumococcal conjugate vaccine (PCV13) for children. This thesis evaluated changes in health and economic burden from pneumococcal disease following the PCV13 introduction in the infant immunization program in British Columbia (BC), Canada.METHODS: A literature search and meta-analyses determined the indirect effect of the PCV13 childhood immunization on invasive pneumococcal disease (IPD) among adults worldwide. Then, pneumococcal disease, i.e., IPD, and acute otitis media (AOM), acute sinusitis (AS), and community-acquired pneumonia (CAP) cases and associated healthcare costs were identified using administrative databases for the years 2000-2018. Costs were adjusted to 2018 Canadian dollars. Changes in the incidence, annual healthcare utilization, and associated costs for pneumococcal disease were evaluated across vaccine eras (pre-PCV13 era: 2000-2010, PCV13 era: 2011-2018) using generalized linear models and adjusted for the PCV7 program (2004-2010). RESULTS: A substantial decline in overall IPD (18%), PCV7 (55%), and PCV13 (40%) serotype IPD were observed among adults following the PCV13 vaccine use in the infant immunization program globally. However, a concurrent 112% increase in non-vaccine serotype IPD occurred during the PCV13 period. Similar declines in overall IPD (18%), PCV7-related (70%), and PCV13-related (24%) vaccine serotype IPD among adults and increase in non-vaccine serotype (NVT) IPD (154%) were noted in BC. A substantial rate reduction in AOM (30%) and AS (15%) across all ages was recorded. Although CAP incidence decreased among young children aged 0-2 years (9%), there was a modest increase in the older age groups: 50-64 years (7%), and ≥65 years (5%). As such, temporal declines in total annual cost were observed in the PCV13 era for IPD (27%), AOM (30%), and AS (32%) compared to the pre-PCV13 era, but not CAP, where an increase of 4% in total costs was seen across all ages. CONCLUSIONS: Increasing NVT IPD and pneumonia rates in the post-PCV13 necessitates a need for newer vaccines and stresses the importance of improving public health messaging to increase the PPV23 uptake rates.

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Background: West Nile Virus (WNV) is a zoonotic arbovirus that has caused significant diseasein Canada, yet remains rare in British Columbia (BC). WNV is spread between avian reservoirsby Culex mosquitoes, and incidental transmission to humans can occur. Understanding temporal and spatial changes in WNV risk is di cult because of the complexity of the transmissioncycle. Nonetheless, public health agencies require decision support in order to guide resourceallocation. Understanding the climate and ecological drivers of WNV disease can help with thedevelopment of such tools.Methods: Descriptive analyses were used to compare ecological and climate conditions in yearswith and without WNV transmission in BC from 2009 to 2015. Generalized linear mixed modelswere used to evaluate associations between WNV incidence in Saskatchewan (2003-2007) and:1) total irrigated landscape, and 2) avian community structure. Results were combined witha literature review to develop a WNV decision-support tool for BC which was evaluated via auser survey.Results: WNV activity in BC between 2009-2015 was limited to select locations during hot summers when temperatures remained above key temperature thresholds during the amplificationperiod. In Saskatchewan, human incidence was positively associated with irrigated landscapesin 2003 but not 2007. Non-passerine species richness and abundance was positively associatedwith incidence from 2003-2007, and the dilution hypothesis was not supported. Heat was consistently associated with incidence, but other predictors had varying effects between years andmodels. The resulting decision support tool contained seven surveillance inputs and three hazard levels. Survey results supported the choice of surveillance inputs and the recommendedprevention measures.Discussion: Ecological complexity challenges quantitative risk prediction for WNV and necessitates the use of simpler tools for public health decision support. Public health agenciesin low-incidence areas should invest public health resources in improving situational awarenessand preparedness instead of risk prediction. The decision support tool created here provides ageneral estimate of WNV amplification as a proxy of WNV hazard. Continued refinement ofthe tool as more is learned about the ecology of WNV would increase its utility

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The discovery of antibiotics was one of the most significant advances in modern medicine; however, our reliance on antibiotics is threatened by the spread of resistance. Antibiotic resistance is a natural phenomenon that is exacerbated by selection pressure from antibiotic use. Where prescriptions are required for antibiotics, understanding prescribing behaviour is paramount. Guidelines recommend antibiotics for respiratory tract infections (RTIs) only when pneumonia or other serious complications are suspected. Urine cultures are recommended for complicated, but not uncomplicated, urinary tract infections (UTIs). The objectives of this thesis were to identify factors related to patients, physicians, and geographic regions associated with antibiotic use for RTIs, and urine culturing for UTI; and to explore the extent of variations in these practices across physicians.A systematic review of the literature was conducted to assess factors that have previously been empirically associated with antibiotic prescribing. Then, using linked administrative datasets, factors associated with antibiotic prescriptions for paediatric respiratory tract infection were analyzed. Urine culture data was subsequently linked in, to explore urine culturing practices. These analyses demonstrated that observed physician characteristics had a stronger influence on practice patterns that did differences in patient characteristics. In particular, physicians who had been in practice for longer tended to be more likely to prescribe antibiotics, and to order urine cultures. Physicians trained outside of Canada were more likely to prescribe, but less likely to order a urine culture. Female physicians were less likely to prescribe antibiotics, and more likely to order urine cultures. The variation between physicians that remained after accounting for observed characteristics was substantial. This research demonstrates some common features of physicians that are associated with antibiotic prescribing and urine culture use. However, the variation between physicians in practice styles is greater than the effects of these characteristics. These findings have implications for the design and implementation of antibiotic stewardship efforts to improve antibiotic use. For example, audit and feedback interventions and academic detailing have shown some promise, and may be particularly effective if targeted to physicians with higher prescribing or culturing practices. This thesis demonstrates the utility of administrative datasets in identifying such physicians.

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Background: Although there have been major advances in acute care following spinal cord injury (SCI), individuals surviving the acute period experience a reduced life expectancy. Historically, acute respiratory and renal dysfunction were the most prevalent complications, and remain important contributors to mortality. However, all-cause cardiovascular disease (CVD) has now emerged as the leading cause of mortality in chronic SCI. Although it has been long speculated that individuals with SCI may be at a higher risk of complications such as CVD, quantitative data are currently limited. Furthermore, the inter-relationships among secondary complications are currently unknown, as is the relationship with changes in neurological function.Objectives: to examine the risk of secondary complications among individuals with SCI; to examine the relationships among secondary complications in individuals with SCI; to examine the relationship among secondary complications and neurological outcomes. Methods: Data were compiled from the Canadian Community Health Survey, the SCI Community Health Survey, the European Multi-Centre Study on Spinal Cord Injury dataset, and the Simon Fraser University SCI dataset. Several methods were employed for analysis of these data, including: multivariable logistic and linear regression, mixed effects models, and unbiased recursive partitioning.Results: Findings identified elevated odds of heart disease, stroke, Type 2 diabetes, chronic respiratory conditions, and chronic pain among individuals with SCI when compared with non-SCI individuals. Complex correlations were also identified among secondary complications following SCI. These include positive associations between neuropathic pain and CVD, and between blood pressure fluctuations and CVD. Lastly, secondary complications (specifically neuropathic pain) following SCI were positively correlated with neurological decline in chronic phases of injury, and neurological motor recovery in acute phases. These relationships may be partly related through treatments for the secondary complications rather than the secondary complications themselves. Implications: These novel findings update current knowledge of secondary complications among individuals with SCI. These data are useful in guiding the prospective collection of data elements within SCI-specific registries, as well as the design/analysis of studies (i.e., issues of confounding in multivariable analyses). These epidemiological data will also be useful for refined, hypothesis-driven physiological studies exploring precise biological mechanisms.

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Urban rats (Rattus spp.) are an important source of zoonotic pathogens, yet there is a paucity of integrated, interdisciplinary, ecosystem-based research on rat-associated zoonoses (RAZ). The goal of this project was to begin to characterize the public health risks associated with rats by studying the ecology of rat populations and the zoonotic pathogens that they carry in an inner-city neighbourhood of Vancouver, Canada. By characterizing rat populations within our study area, we were able to identify a number of factors which could influence the ecology of RAZ. We were also able to design a tool to predict rat abundance based on characteristics of the urban microenvironment, which may be useful for predicting RAZ prevalence in the future. Although we found that L. interrogans (a common RAZ) was present in our study area, other zoonoses thought to be endemic in rat populations worldwide (Seoul hantavirus, Rickettsia typhi, and Bartonella spp.) were conspicuously absent. However, rats were found to carry other potentially zoonotic organisms (Clostridium difficile and methicillin-resistant Staphylococcus aureus) for which they are not the ‘traditional’ reservoir. Finally, we found that by integrating data regarding rat ecology and RAZ, we were able to gain a more comprehensive picture of how these pathogens circulate within rat populations. Overall, this research illustrates the importance of a comprehensive and holistic approach for obtaining a better understanding of RAZ, and highlights the need for ongoing research and surveillance.

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Infectious agents transmitted between animals and humans (zoonoses) are important causes of emerging infectious diseases with major societal, economic, and public health implications. In order to prevent and control emerging zoonotic diseases (EZDs), they should ideally be identified in animals before they affect the human population. The utility of animal data for public health EZD surveillance was investigated in this thesis in four studies: a systematic literature review of current EZD surveillance systems and three critical examinations of pilot agricultural animal health surveillance systems. The first critical examination used expert-elicited criteria of EZD surveillance needs to evaluate a sentinel clinical pre-diagnostic system. The other two studies used statistical modeling to assess the ability of a laboratory-based system and an integrated system with both human and animal data to detect known patterns and outbreaks. The systematic review identified few evaluated surveillance systems, hence an evidence base for successful systems could not be obtained. Experts identified diagnostic data from laboratories and information on potential human exposures as important for public health action. While the sentinel animal surveillance system was not deemed useful on its own, identified gaps and biases in laboratory submissions suggest that sentinel veterinarians could inform animal laboratory surveillance. Seasonal trends and expected events of public health importance were identified in animal diagnostic laboratory data, however, statistical surveillance in either pre-diagnostic or diagnostic data streams did not provide adequate early warning signals for action. While the integrated surveillance for Salmonella bacteria allowed for the examination of the relationship between human and animal data, statistical alerts did not correlate with expert-identified investigations. Laboratory surveillance is likely the best candidate for EZD surveillance in animals, however, this information needs to be supplemented with potential human exposure information, as well as knowledge of data gaps and biases inherent in the data. Without this additional risk information to convert the animal data into risk for humans, the best use of animal laboratory data at this time is to help generate hypotheses in epidemiological investigations and in helping evaluate programs by examining longer-term trends.

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