Veterinarians often perform controlled experiments in which they inoculate animals with infectious diseases. They then monitor the transmission process in infected animals. The aim of such experiments can be to assess vaccine effects. The fitting of individual-level models (ILMs) to the infectious disease data, typically achieved by means of Markov Chain Monte Carlo (MCMC) methods, can be computationally burdensome. Here, we want to see if a vaccination effect can be identified using simpler regression-type models rather than the complex infectious disease models. We examine the use of various logistic growth curve models, via a series of simulated experiments in which the underlying true model is a mechanistic model of infectious disease spread. We want to investigate whether a vaccination effect can be identified when only partial epidemic curves are observed, and to assess the performance of these models when experiments are run with various sets of observational times.

The thesis investigates how Agent-Based Modeling and Simulation (ABMS) and Queueing Theory (QT) techniques help manage mass gathering (MG) crowds. The techniques are applied to Hajj MG, which is one of the most complex annual MG, with a focus on its challenging Tawaf ritual. The objective is to develop a Tawaf Decision Support System (DSS) to better understand Tawaf crowd dynamics and discover decisions that lead to superior performance. TawafSIM is an ABMS model in the DSS, which simulates macro-level Tawaf crowd dynamics through micro-level pilgrim modeling to explore the impact of crowd characteristics, facility layout, and management preferences on emergent crowd behaviours with respect to throughput, satisfaction, health, and safety. Whereas, TawafQT is a QT model in the DSS to explore the impact of pilgrim arrival rate and Tawaf throughput on expected arrival, departure, and waiting times along with average queue length in the Tawaf waiting area. The thesis provides several contributions, including the following. First, it is the only Tawaf research to use a hybrid ABMS and QT approach. Second, TawafSIM is a comprehensive Tawaf simulator. It incorporates features for pilgrim characteristics, facility design, and management preferences. It calculates eight metrics for Tawaf performance, which includes one for throughput, three for satisfaction, one for health, and three for safety. It is the only Tawaf simulator to estimate satisfaction and spread of infectious disease. It conducts 42 simulation experiments in 12 categories. It generates observations for emergent, tipping point, expected, and counter intuitive behaviours. It recommends a default scenario as the best decision along with a small subset of alternative scenarios, which provide above average Tawaf performance. It generates a Tawaf Crowd Management Guide to better understand Tawaf crowd dynamics and how to pursue above average Tawaf performance under different conditions. Third, TawafQT is the only study of the Tawaf waiting area. It uses an accurate queueing model with finite source, single service, and PH type distribution, which is not only applicable to the Tawaf and other Hajj related queueing systems but also to any queueing system, which has finite population and single service characteristics.

Neurons in the spinal cord do not spontaneously regenerate, which often leads to debilitating injuries. One method proposed to promote axonal regeneration is the injection of viruses carrying genes for growth factors into the injured spinal cord. One such virus, the adeno-associated virus (AAV), has shown promise in gene therapy medical research. However, injecting AAV into rhesus macaques with C7 spinal cord hemisection lesions actually leads to motor neuron loss in the gray matter of the spinal cord, rather than contributing to the preservation or regeneration of axons. This unexpected result highlights the necessity of further testing with therapeutic approaches for axon regeneration in nonhuman primate models before moving into clinical trials. It is possible that an immune-related T cell response to the AAV-transfected cells causes this motor neuron loss. T cells are white blood cells that play a role in attacking cells infected with viruses. It is unknown whether such a response of the immune system to respond with an up-regulation of T cells may be taking place over a relatively short period (weeks) or over many months. This question was tested here: T cells were stained in spinal cord sections caudal (below) the lesion in the spinal cord and near AAV injection sites to determine whether there was a greater quantity of T cells in these areas compared to the subject’s baseline levels. Subjects that had AAV therapeutic injections and that were examined 6 months after the injection were found to have greater quantities of T cells than those who did not have injections containing AAV. It was also found that the AAV-injected subjects examined only 6 weeks post injection did not have greater quantities of T cells than control subjects. These results suggest that there may be a delayed immune response to the AAV injections in nonhuman primates with spinal cord injury, which occurs over a period of months. Pinpointing the mechanism that causes this cell death would allow researchers to create a safer therapeutic that could promote axonal growth in people with spinal cord injuries.

Influenza virus is one of the major respiratory pathogens of humans as well as animals, including equines. There is an increasing evidence that bacterial infections are the most common cause of the death during influenza. In horses also, secondary bacterial pneumonia can lead to death, and surviving horses may take up to six months for the complete recovery resulting in heavy economic loss to the equine industry. Interleukin (IL)-23 mediated innate immune response has been shown to protect the host from various respiratory bacterial infections. However, studies to investigate the role of host and viral factors in the regulation of IL-23 are limited. Endoplasmic reticulum (ER) stress-induced transcription factor CHOP-10 and IFN-β has been shown to participate in the regulation of IL-23. Primary hypothesis for the current study was that influenza A virus (IAV) NS1 protein downregulates the IL-23 expression via inhibition of CHOP-10. In order to test our hypothesis, we infected the RAW264.7 cells - a murine macrophage cell line, and primary murine alveolar macrophage cells either with the wild type Influenza A virus (PR/8/34, PR8) or isogenic mutant virus lacking NS1 (delNS1). Quantitative analysis of mRNA expression revealed a significantly higher mRNA expression of IL23p19, IFN-β and CHOP-10 in delNS1 virus infected cells as compared the PR8 virus infected cells. Additionally, overexpression of CHOP-10 partially restored the expression of IL-23p19 in PR8 virus infected cells and knockdown of CHOP-10 resulted in downregulated expression of IL-23p19 in delNS1 infected cells. Taken together, these results suggest that IAV NS1 protein mediated inhibition of CHOP-10 expression leads to downregulation of IL-23 expression in macrophage cells in-vitro. Similar results were also observed in-vivo using IAV and Streptococcus zoooepidemicus (S. ze) co-infection model. In a co-infection mouse model delNS1 virus co-infection resulted in significantly higher expression of the IL-23 and IL-17. Considering the role of IL-23 in protection against respiratory bacterial pathogens, effect of exogenous supplementation of IL-23 was also investigated in the influenza and S. ze co-infection mouse model. We found that a single intranasal dose of recombinant murine IL-23 significantly improved the survival of mice co-infected with PR8 and S .ze. Overall, our study suggests that IAV infection subverts the IL-23 mediated respiratory innate immune response and restoration of IL-23 could protect from influenza-associated respiratory bacterial infections.

The thesis investigates how Agent-Based Modeling and Simulation (ABMS) and Queueing Theory (QT) techniques help manage mass gathering (MG) crowds. The techniques are applied to Hajj MG, which is one of the most complex annual MG, with a focus on its challenging Tawaf ritual. The objective is to develop a Tawaf Decision Support System (DSS) to better understand Tawaf crowd dynamics and discover decisions that lead to superior performance. TawafSIM is an ABMS model in the DSS, which simulates macro-level Tawaf crowd dynamics through micro-level pilgrim modeling to explore the impact of crowd characteristics, facility layout, and management preferences on emergent crowd behaviours with respect to throughput, satisfaction, health, and safety. Whereas, TawafQT is a QT model in the DSS to explore the impact of pilgrim arrival rate and Tawaf throughput on expected arrival, departure, and waiting times along with average queue length in the Tawaf waiting area. The thesis provides several contributions, including the following. First, it is the only Tawaf research to use a hybrid ABMS and QT approach. Second, TawafSIM is a comprehensive Tawaf simulator. It incorporates features for pilgrim characteristics, facility design, and management preferences. It calculates eight metrics for Tawaf performance, which includes one for throughput, three for satisfaction, one for health, and three for safety. It is the only Tawaf simulator to estimate satisfaction and spread of infectious disease. It conducts 42 simulation experiments in 12 categories. It generates observations for emergent, tipping point, expected, and counter intuitive behaviours. It recommends a default scenario as the best decision along with a small subset of alternative scenarios, which provide above average Tawaf performance. It generates a Tawaf Crowd Management Guide to better understand Tawaf crowd dynamics and how to pursue above average Tawaf performance under different conditions. Third, TawafQT is the only study of the Tawaf waiting area. It uses an accurate queueing model with finite source, single service, and PH type distribution, which is not only applicable to the Tawaf and other Hajj related queueing systems but also to any queueing system, which has finite population and single service characteristics.

Francisella tularensis is a highly infectious. Gram-negative coccobacillus that is the etiological agent of the acute. febrile. zoonotic disease tularemia. A ca. 35 kb Francisella pathogenicity island (FM) was previously discovered. Two genes. pdpA and pdpD were shown to be required for virulence. The FP1 gene pdpC encodes a protein that has no significant similarities to any motifs, domains, or homologues of known bacterial proteins. This gene of unknown function may encode a novel virulence factor involved in Francisella infection. The role of PdpC in F. novicida intracellular growth was investigated. Results from this study demonstrated that the erythromycin allelic replacement mutant of pdpC was more attenuated in intracellular growth in the murine macrophage-like J774A.1 cells than in bone marrow-derived macrophages from BALB/c mice and that complementation in trans partially complements this mutation. To further investigate the role of pdpC in virulence. partial deletion mutagenesis in the C-terminus of PdpC was performed which resulted in four mutants that showed slight attenuation in J774A.1 intramacrophage growth but behaved like wildtype F, novicida in bone marrow-derived macrophages. Chicken embryos were infected to evaluate the virulence of these pdpC mutants. The virulence of the Em allelic replacement mutant was significantly more attenuated than wildtype F. novicida and complementation partially restored virulence. Partial deletion mutants of pdpC exhibited greater virulence than the EmR mutant in chicken embryos and were able to cause 100% mortality at day 6. Furthermore, eukaryotic expression of triple FLAG-tagged PdpC in chicken embryo fibroblasts resulted in cells that exhibited different morphologies than uninfected fibroblasts which suggests that PdpC may play a role in cytoskeletal rearrangements by altering host cell signaling pathways.

New survey data indicate that injection drug users (IDU) in Victoria, BC who share syringes do so with a single person. These partnerships pose an obvious health risk to IDU, as blood borne illnesses are transmitted through the sharing of injection equipment. Here we formulate an ordinary di erential equation (ODE) model of pair formation and separation. Susceptible-infectious (SI) disease dynamics are built into this model so as to describe the syringe-mediated transmission of human immune de ciency virus (HIV) and hepatitis C virus (HCV) among IDU. We utilize a novel parameter estimation approach, and t the distribution of partnership durations observed in Victoria. The basic reproduction number is derived, and its qualitative behavior explored with both analytical and numerical techniques.

Mandatory notification of disease forms the backbone of disease surveillance in New Zealand and overseas. Notification data is used by public health professionals and academics to identify cases requiring public health control, monitor disease incidence and distribution, and in epidemiological research. However, there is emerging evidence that notification rates do not accurately reflect the true extent of notifiable diseases within the community, resulting in the underascertainment of many notifiable cases. While adequate surveillance does not necessarily require that all cases of notifiable disease be captured, the systematic underascertainment of disease can have significant implications for perceived spatial and demographic trends in disease prevalence; potentially threatening the credibility of spatial epidemiological research by under or overestimating the burden of disease in different populations. There is evidence that systematic underascertainment occurs as a result of the differential actions of laboratories and general practitioners. It has also been recognised that that underascertainment can be influenced by a patient's willingness to seek medical attention and participate in laboratory tests. However, few studies have investigated whether these factors systematically influence notification either in New Zealand or overseas. Furthermore, the discipline of health geography has been slow to engage with this topic of public health importance, despite the inherently spatial nature of the processes involved, and the close ties to the geographic literature on health service utilization and healthcare provision. This thesis explores the spatial and temporal variation in notification rates in New Zealand for the period 1997-2005 and the potential relationships between notification rates and different variables. Unlike many underascertainment studies, which have used individual data and capture-recapture methods, data constraints inspired a unique ecological approach to investigating the factors which may be associated with notification in New Zealand. Variables were divided into categories based on Anderson's behavioural model for healthcare utilization and the influence of these variables on notification was determined through multiple regression analyses. The main findings of this research indicate that in New Zealand notification rates have increased during the period 1997-2005 and that there is a north-south gradient in notifications, with substantially lower rates in the North Island than in the South Island. Furthermore, it is also evident that the variables associated with notification vary according to disease, spatial aggregation and spatial scale. Notification rates are significantly associated with a range of predisposing and enabling factors which might influence patient choice to consult for many frequently underascertained diseases. More variation in enteric diseases is explained by the independent variables analysed than the variation in non-enteric diseases. However, further research into these relationships, and underascertainment in general, is required before firm conclusions can be drawn.

Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 239 pages. Includes vita. Includes bibliographical references.

Francisella tularensis is a highly infectious. Gram-negative coccobacillus that is the etiological agent of the acute. febrile. zoonotic disease tularemia. A ca. 35 kb Francisella pathogenicity island (FM) was previously discovered. Two genes. pdpA and pdpD were shown to be required for virulence. The FP1 gene pdpC encodes a protein that has no significant similarities to any motifs, domains, or homologues of known bacterial proteins. This gene of unknown function may encode a novel virulence factor involved in Francisella infection. The role of PdpC in F. novicida intracellular growth was investigated. Results from this study demonstrated that the erythromycin allelic replacement mutant of pdpC was more attenuated in intracellular growth in the murine macrophage-like J774A.1 cells than in bone marrow-derived macrophages from BALB/c mice and that complementation in trans partially complements this mutation. To further investigate the role of pdpC in virulence. partial deletion mutagenesis in the C-terminus of PdpC was performed which resulted in four mutants that showed slight attenuation in J774A.1 intramacrophage growth but behaved like wildtype F, novicida in bone marrow-derived macrophages. Chicken embryos were infected to evaluate the virulence of these pdpC mutants. The virulence of the Em allelic replacement mutant was significantly more attenuated than wildtype F. novicida and complementation partially restored virulence. Partial deletion mutants of pdpC exhibited greater virulence than the EmR mutant in chicken embryos and were able to cause 100% mortality at day 6. Furthermore, eukaryotic expression of triple FLAG-tagged PdpC in chicken embryo fibroblasts resulted in cells that exhibited different morphologies than uninfected fibroblasts which suggests that PdpC may play a role in cytoskeletal rearrangements by altering host cell signaling pathways.