The 2009 H1N1 pandemic caused serious concerns worldwide due to the novel biological feature of the virus strain, and the high morbidity rate for youth. The urban scale is crucial for analyzing the pandemic in metropolitan areas such as the Greater Toronto Area (GTA) of Canada because of its large population. The challenge of exploring the spatial dynamics of H1N1 is exaggerated by data scarcity and the absence of an immediately applicable methodology at such a scale. In this study, a stepwise methodology is developed, and a retrospective spatial statistical analysis is conducted using the methodology to estimate the spatial dynamics of the 2009 H1N1 pandemic in the GTA when the data scarcity exists. The global and local spatial autocorrelation analyses are carried out through the use of multiple spatial analysis tools to confirm the existence and significance of spatial clustering effects. A Generalized Linear Mixed Model (GLMM) implemented in Statistical Analysis System (SAS) is used to estimate the area-specific spatial dynamics. The GLMM is configured to a spatial model that incorporates an Intrinsic Gaussian Conditionally Autoregressive (ICAR) model, and a non-spatial model respectively. Comparing the results of spatial and non-spatial configurations of the GLMM suggests that the spatial GLMM, which incorporates the ICAR model, proves a better predictability. This indicates that the methodology developed in this study can be applied to epidemiology studies to analyze the spatial dynamics in similar scenarios. / Thesis (Master, Geography) -- Queen's University, 2012-10-30 17:41:28.445

Niña de dos años con fiebre y síntomas catarrales que presenta convulsiones focales de hemicuerpo derecho, las cuales persisten adicionándose signos de hipertensión endocraneana. Se identifica Influenza AH1N1 mediante reacción de cadena de polimerasa en hisopado nasofaríngeo. Paciente evoluciona favorablemente con medidas de soporte. No recibió Oseltamivir.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Wenjun Ma / Influenza A virus (IAV) is a negative sense, single-stranded, segmented RNA virus with eight gene segments. It is an important respiratory pathogen which causes annual epidemics and occasional pandemics worldwide in humans and leads to considerable economic problems for the livestock industry. To control and prevent this significant disease, understanding the pathogenesis of IAVs is critical. Although some molecular mechanisms regarding virulence have been determined, IAV pathogenesis is not completely understood and is difficult to predict. The eight viral gene segments of IAV were thought to encode for 10 viral proteins. Since 2001, eight additional viral proteins have been identified, including PB1-F2, PB1-N40, PA-X, NS3, PA-N155, PA-N182, M42, and PB2-S1. However, the functions of these novel proteins in influenza virus replication as well as pathogenesis have not been fully elucidated. Although PB1-F2 protein is an important virulence factor of IAV, the effects of this protein on viral pathogenicity of swine influenza virus (SIV) remain unclear. In Chapter 2, we investigated the contribution of the PB1-F2 protein to viral pathogenicity of a virulent triple-reassortant (TR) H1N1 SIV in different hosts, pigs and mice. Our data indicate that PB1-F2 expression in virulent TR H1N1 SIV modulates virus replication and pathogenicity in the natural host, pigs, but not in mice. In addition, single amino acid (aa) substitution at position 66 (N/S) in the PB1-F2 has a critical role in virulence in mice but no effect was found in pigs. A novel IAV protein, PA-X consists of the N-terminal 191aa of PA protein and a unique C-terminal 41 (truncated form) or 61 (full-length form) aa residues encoded by +1 ribosomal frameshifting. Although several studies have demonstrated the PA-X protein as an important immune modulator and virulence factor, the impact of different expressions of PA-X protein including full-length, truncated or PA-X deficient forms on viral pathogenicity and host response remains unclear. In Chapter 3, we showed that expression of either truncated or full-length PA-X protein in 2009 human pandemic H1N1 (pH1N1) viruses suppresses host antiviral response by host shutoff activity which promotes viral growth and virulence in mice when compared to loss of PA-X expression. Furthermore, full-length PA-X expression displayed stronger impact on viral pathogenicity and host immune response compared to truncated PA-X expression. Taken together, our results provide new insights into the impact of PB1-F2 and PA-X proteins on virus replication, pathogenicity and modulation of host immune responses. This knowledge is important for better understanding of IAV pathogenesis.

Objective: 2009 H1N1 influenza was first detected in the Northern Hemisphere in April 2009. National data have suggested that the novel influenza virus disproportionately causes severe illness in children and young adults, a somewhat different presentation from traditional seasonal flu which normally strikes hardest in the very young and older adults. This may or may not be the case in Virginia, which, if it is different, may suggest a need to alter flu prevention messages and vaccine policy as the outbreak continues through the fall 2009-10 influenza season. This report examined the early presentation of the new influenza virus in Virginia, compared with the seasonal flu presentation. Methods: Surveillance data of influenza-like illness (ILI) visits to hospital emergency departments and urgent care centers for the period Oct. 2008 to Aug. 2009 were obtained from the Virginia Department of Health. The period from Oct. 2008-March 2009 was considered to be the normal flu season, while April-Aug. 2009 was considered as the 2009 (novel) H1N1 flu season. Descriptive statistics looked for differences by age, region and sex with respect to the proportion of visits that were for influenza-like illness compared to all reported illness for the normal and H1N1 flu seasons. Chi square and p-values were used to assess the level and significance of differences between flu seasons. Results: While the 2009 H1N1 influenza was a novel virus that, like all influenza viruses, could mutate and change into a form causing more severe illness, during the early months of the epidemic/pandemic, the virus did not appear to cause more illness as a percent of all illness compared to the preceding months of influenza in Virginia. Though it was unexpected to have influenza-like illness in the amount seen during April-August 2009, with several exceptions the level of flu-like illness compared to all illness was not higher than during the normal flu season immediately preceding the appearance of the 2009 H1N1 influenza. Conclusion: During the early months of the novel influenza H1N1 epidemic/pandemic in Virginia, the novel influenza virus caused levels of illness that were lower than levels of illness seen during the preceding normal flu season. Further study that examines the novel influenza virus through the end of the 2009-10 season may help to quantify the impact of the new virus. Flu-like illness reports spiked, for instance, as schools and colleges returned for fall 2009 semesters.

abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Given that pandemic swine flu outbreak led to substantial admission in intensive care unit, extracorporeal membrane oxygenation has been increasingly applied to those who suffered from H1N1 infection induced acute respiratory distress syndrome. This review is going to evaluate the effectiveness of using ECMO based on five related observational studies. The result, discussion and policy implication in Hong Kong are discussed. Since the ECMO system has been technological improved in recent years, there are less complications when applying ECMO. In view of evidence of reviewed studies, application of ECMO in Hong Kong can be considered as cost effective. And since only a few hospitals in Hong Kong can offer ECMO application, retrieval teams are needed to ensure safety transfer between hospitals. / published_or_final_version / Public Health / Master / Master of Public Health

Mannose-binding lectin (MBL) functions as pattern recognition molecule to mediate first-line host defense against invading pathogens. Although MBL is well-known for its anti-bacterial action, its role towards virus infection is less comprehensively understood. In 2009, the pandemic H1N1 2009 (pdmH1N1) influenza A virus caused more than 18,000 deaths worldwide and is still circulating in human community as a seasonal strain. In this study, the role of MBL in pdmH1N1 infection was investigated. Using in vitro microtiter capture assay, MBL was found to bind to pdmH1N1 virus via its carbohydrate recognition domain. Under transmission electron microscope (TEM), MBL was clearly visible on the surface of pdmH1N1 virus. By infecting C57B6/J wild-type (WT) and MBL knockout (KO) mice with a sub-lethal dose of pdmH1N1 virus, WT mice displayed greater weight loss and more severe lung damage than MBL KO mice. Using flow cytometry-based profiling analysis of the lung homogenates isolated from infected mice, a variety of proinflammatory cytokines and chemokines were found to be significantly up-regulated. These results indicate that the presence of MBL can cause excess proinflammatory cytokine production and result in a more severe pdmH1N1 infection. To provide physiologically relevant insight into the immunomodulating role of MBL, the investigation was further extended to the use of human cell line model. Infection of A549 cells, which is a human lung epithelial cell line, with MBL-bound pdmH1N1 virus elevated the production of MCP1, RANTES and IL-8 significantly more than unbound pdmH1N1 infection. The increased production of chemokines also enhanced recruitment of monocytes as demonstrated by transwell migration assay. Interestingly, MBL did not affect viral entry or replication kinetics. TEM and confocal imaging revealed the presence of MBL-bound pdmH1N1 inside infected A549 cells, suggesting that the endocytosed MBL may interact with intracellular components to promote the release of cytokines and chemokines. To this end, expressions of Toll-like receptors were examined (TLR3, TLR7, TLR8 and TLR9) and found that TLR3 expression was dramatically enhanced upon pdmH1N1 infection. Interestingly, in MBL-bound pdmH1N1 infection, TLR3 mRNA and protein expression was significantly higher than unbound pdmH1N1 infection in A549 cells. In addition, the NF-κB signaling was further activated in the presence of MBL-bound pdmH1N1. A novel physical interaction between MBL and TLR3 was also delineated as evidenced by MBL’s capability to bind to TLR3 in vitro; and their colocalization in the endosomes of the infected A549 cells. In summary, MBL can bind to pdmH1N1 virus but fails to inhibit its infection in human lung epithelial cell line. Upon pdmH1N1 infection, MBL is internalized with the virus into the cell, where it may associate with TLR3 to further amplify the NF-κB signaling and augment the cytokine production in the human lung epithelial cells. The present findings advocate the adverse immunomodulating role of MBL during pdmH1N1 infection. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

During the 2009 H1N1 influenza pandemic, public health nurses (PHNs) were called upon to protect their communities against a deadly influenza virus. Currently, there appears to be no literature that describes the experience of Canadian PHNs responding to the first influenza pandemic of the 21st century. A qualitative research study was conducted and the data were analyzed by using content analysis. Thirteen nurses were interviewed from an Urban, Rural and Northern health region in Manitoba. Focus groups were conducted for the Urban and Rural nurses while Northern nurses were interviewed by telephone. Communication and dissemination of information, personal and professional challenges, personal face of the pandemic, regional support and lessons learned were themes generated from the data analysis. Communication and information flow was a major theme that impacted the overall PHNs’ response experience. Practice, administration, research and education implications and the limitations of the study are presented in the study.

Influenza type A is associated with most severe complications to humans and is historically recognized to cause pandemics. If a new subtype replicates well in humans it might upsurge in a new pandemic strain, one such example is the Influenza A (A/H1N1). The A/H1N1 pandemic in 2009/2010 was not as severe in Sweden as expected. Criticism has targeted the fact that authorities having misjudged the need for vaccination, concerns have been raised regarding the effect of the campaign on people’s willingness to be vaccinated in the future. This study aims to investigate if there are significant differences in attitudes towards the vaccination of A/H1N1 among different population groups in Stockholm, Sweden. The main groups explored are risk groups and non- risk groups, defined by objective definitions. A quantitative method was approached using questionnaires. The result indicates that people in a risk group and vaccinated had more favorable attitudes towards the vaccine compared to other groups. They also expressed less troubled concerns regarding vaccine safety and were more likely to immunize referring to inadequate health. It is evident that people at risk also define themselves as more vulnerable, in which vaccination is more acceptable. The expressed attitudes are in such dependent on risk-perceptions and vaccine status.

On June 11, 2009, the World Health Organization declared a global influenza pandemic due to a novel influenza A virus subtype of H1N1. Public health emergencies, such as an influenza pandemic, can potentially impact disadvantaged populations disproportionately due to underlying social factors. Canada???s First Nation population was severely impacted by the 2009 H1N1 influenza pandemic. Most First Nation communities suffer from poor living conditions, impoverished lifestyles, lack of access to adequate health care, and uncoordinated health care delivery. Also, there are vulnerable populations who suffer from co-morbidities who are at a greater risk of falling ill. Moreover, First Nation communities that are geographically remote (nearest service center with year-round road access is located over 350 kilometers away) and isolated (only accessible by planes year-round) face additional challenges. For example, transportation of supplies and resources may be limited, especially during extreme weather conditions. Therefore, remote and isolated First Nation communities face unique challenges which must be addressed by policy planners in order to mitigate the injustice that may occur during a public health emergency. The Assembly of First Nations noted that there has been very little inclusion of First Nations??? input into current federal and provincial pandemic plans. Disadvantaged groups know best how they will be affected by a public health emergency and are able to identify barriers and solutions. Therefore, the objective of my research was to gain retrospective insight into the barriers faced by three remote and isolated First Nation communities of sub-arctic Ontario (i.e., Fort Albany, Attawapiskat, and Kashechewan) during their 2009 H1N1 pandemic response. Culturally-appropriate community-based suggestions for improvement of existing community-level pandemic plans were also elicited. Collected data informed modifications to community-level pandemic plans, thereby directly applying research findings. Being a qualitative community-based participatory study, First Nation community members were involved in many aspects of this research. Semi-directed interviews were conducted with adult key informants (n=13) using purposive sampling of participants representing the three main sectors responsible for health care services (i.e., federal health centers, provincial hospitals, and Band Councils). Data were manually transcribed and coded using deductive and inductive thematic analysis to reveal similarities and differences experienced within and between each community (and government body) regarding their respective pandemic response. Another round of semi-directed interviews (n=4) and community pandemic committee meetings were conducted to collect additional information to guide the modifications to the community-level pandemic plans. Reported barriers due to being geographically remote and isolated included the following: overcrowding in houses, insufficient human resources, and inadequate community awareness. Primary barriers faced by government bodies responsible for health care delivery were reported as follows: receiving contradicting governmental guidelines and direction from many sources, lack of health information sharing, and insufficient details in community-level pandemic plans. Suggested areas for improvement included increasing human resources (i.e., nurses and trained health care professionals), funding for supplies, and community awareness. Additionally, participants recommended that complementary communication plans should be developed. As suggested by participants, community-specific information was added to update community-level pandemic plans. Remote and isolated First Nation communities faced some barriers during their 2009 H1N1 health sector pandemic response. Government bodies should focus efforts to provide more support in terms of human resources, monies, and education. In addition, various government organizations should collaborate to improve housing conditions, timely access to resources, and the level of coordination regarding health care delivery. Furthermore, as pandemic plans are dynamic, government bodies should continue to aide First Nation communities with updating their community-level pandemic plans to satisfy their evolving needs. These recommendations should be addressed so that remote and isolated western James Bay First Nation communities and other similar communities can be better prepared for the next public health emergency.