Activation and proliferation of antigen-specific T cells is the hallmark of an anti-viral immune response. Effector T cells generated during an immune response are heterogeneous in regards to their ability to populate the memory pool once the immune response has resolved. Initial T cell activation takes place in the lymphoid organs, after which T cells migrate into the non-lymphoid tissues. The presence of memory T cells at non-lymphoid tissue sites has been shown to be critical for protection against secondary virus challenge. Our lab has previously demonstrated that during and after the resolution of the immune response to Lymphocytic choriomeningitis virus (LCMV) CD8+T cells in the nonlymphoid tissues are more resistant to apoptosis than those in the lymphoid organs. This stability of T cells in the non-lymphoid tissues may be critical in ensuring protection against a secondary virus challenge. Mechanisms regulating tissue-dependent differences in CD8+T cell apoptosis were studied in an acute LCMV infection model. Virus-specific CD8+T cells from lymphoid (spleen, mesenteric lymph nodes (MLN), inguinal lymph nodes (ILN)) and non-lymphoid tissues (peritoneal exudate cells (PEC), fat-pads) were compared for expression of surface antigenic markers known to correlate with a memory phenotype. Non-lymphoid tissues were enriched in IL-7Rhi, KLRG-1lo, CD27hi and CXCR3hi virus-specific CD8+ T cells, and the presence of these antigenic markers correlated with increased memory potential and survival. Transcription factors in addition to cell surface antigens were assessed as correlates of resistance to apoptosis. Virus-specific CD8+T cells in the nonlymphoid tissues were enriched in cells expressing T cell factor-1 (TCF-1), which correlated with increased memory potential and survival. CD8+T cells in the peritoneum of TCF-1-deficient mice had decreased survival during resolution of the immune response to LCMV, suggesting a role for TCF-1 in promoting survival in the non-lymphoid tissues. As an additional mechanism, I investigated whether apoptosis-resistant CD8+T cells migrate to non-lymphoid tissues and contribute to tissue-dependent apoptotic differences. CXCR3+ CD8+T cells resisted apoptosis and accumulated in the lymph nodes of mice treated with FTY720, which blocks the export of lymph node cells into the peripheral tissues. The PECs expressed increased amounts of CXCR3 ligands, CXCL9 and CXCL10, which may have recruited the non-apoptotic cells from the lymph nodes. By adoptively transferring splenic T cells into the spleen or PEC environment I showed that the peritoneal environment through a yet undefined factor promoted survival of CD8+T cells. In this study I have elucidated the mechanisms by which CD8+T cells preferentially survive in the non-lymphoid tissues. I found that non-lymphoid tissues were enriched in memory-phenotype CD8+T cells which were intrinsically resistant to apoptosis irrespective of the tissue environment. Furthermore, apoptosisresistant CD8+T cells may preferentially migrate into the non-lymphoid tissues where the availability of tissue-specific factors may enhance memory cell survival. Few transcription factors have been identified that regulate CD8+T cell effector-memory differentiation during an immune response. In this thesis, I have also studied the mechanism by which the transcription factor Blimp-1 regulates the generation of effector and memory CD8+T cells. Blimp-1 is known to repress a large number of target genes, and ChIP (chromatin immunoprecipitation) sequencing analysis done by Dr. HyunMu Shin in the lab of Dr. Leslie J. Berg identified CD25 (IL-2Rα) and CD27 as potential targets of Blimp-1. I found that Blimp-1-deficient CD8+T cells had sustained expression of CD25 (IL-2Rα) and CD27 during peak and resolution of the immune response to LCMV. By performing adoptive transfers of CD25hi and CD27hi CD8+T cells I showed that CD25 and CD27 expression on CD8+T cells during resolution of the immune response correlates with enhanced survival. Silencing Il2rα and Cd27 expression reduced the Blimp-1-deficient CD8+T cell response, suggesting that sustained expression of CD25 and CD27 was in part responsible for the enhanced CD8+T cell response seen in the Blimp-1-deficient mice. Furthermore, our collaborator Dr. HyunMu Shin showed that CD25 and CD27 are direct targets of Blimp-1, and that Blimp-1 recruits histone modifying enzymes to Il2rα and Cd27 loci to suppress their expression during the peak of the anti-viral immune response. This study identifies one of the mechanisms by which Blimp-1 regulates the balance between generation of effector and memory CD8+T cells. In this thesis work I also studied the function of the transcription factor ROG (Repressor of GATA-3) in regulating in vivo T cell responses during both acute and chronic LCMV infection. ROG-deficient mice had increased CD8+T cell responses during an acute LCMV infection. ROG deficiency also led to the generation of memory T cells with an enhanced recall response compared to WT controls. By using LCMV-specific P14+ TCR transgenic ROG-deficient CD8+T cells these defects were shown to be T cell intrinsic. ROG-deficient mice had enhanced CD8+T cell responses and viral clearance during a persistent high dose LCMV Clone 13 infection. During chronic LCMV infection ROG-deficient mice also had increased lung pathology and mortality. The results indicate that ROG negatively regulates T cell responses and memory generation during both acute and chronic LCMV infection. The studies highlighted in this thesis elucidate the mechanisms promoting CD8+T cell survival in non-lymphoid tissues as well as transcription factormediated regulation of memory CD8+T cell differentiation. Knowledge of this will help us better understand T cell immunity after infections and may eventually help develop better vaccines.

Vitiligo is an autoimmune skin disease in which the pigment producing cells of the epidermis, melanocytes, are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma-shared antigens. Previous work has identified IFNg as the central cytokine driving disease pathogenesis in both human patients and in our mouse model of vitiligo. IFNg signaling induces production of the chemokines CXCL9 and CXCL10, which trigger autoreactive T cell migration into the epidermis where effector T cells can target and destroy melanocytes. However, both IFNg and type I IFN signaling through activation of STAT1 proteins can induce transcription of the chemokines CXCL9 and CXCL10. Therefore, it seems reasonable that type I IFN signaling may also contribute to disease pathogenesis. The role of type I IFN in vitiligo is still unclear. Genome wide association studies identified multiple genes within the type I IFN pathway including TICAM1 and IFIH1 as susceptibility loci in vitiligo. One additional study reported increased epidermal staining of CD123, a marker expressed by pDCs, and the type I IFN induced gene MX1 in vitiligo patient skin. However, this study did not show any functional data to support the role of type I IFN signaling in vitiligo pathogenesis. Since the role of type I IFN in vitiligo is ill-defined, we used two different mouse models of vitiligo to functionally determine the role of type I IFN in disease by inducing vitiligo in hosts which lack the type I IFN receptor (IFNaR). In the first model, we induced vitiligo by adoptive transfer of melanocyte-specific CD8 T cells, which are activated in vivo by infection with recombinant vaccinia virus (VACV) expressing their cognate antigen. Vitiligo induction in IFNaR-deficient mice led to the development of severe disease compared to wild type mice. Acceleration and severity of disease was characterized by increased early recruitment of melanocyte-specific CD8 T cells to the skin, increased production of effector cytokines TNFa and IFNg, and reduced PD-1 expression. Increased production of IFNg by CD8 T cells in the skin of IFNaR-deficient mice led to increased expression of the chemokines CXCL9 and CXCL10 driving disease progression. IFNaR-deficient mice also displayed significantly increased VACV titters compared to wild type hosts. This data reveals a role of type I IFN in the clearance of recombinant VACV. This data also suggests that persistent VACV infection and prolonged antigen exposure in IFNaR deficient hosts is likely driving enhanced activation of melanocyte specific CD8 T cells and the subsequent development of severe vitiligo. Since melanocytes and melanoma cells express shared antigens that can be recognized by CD8 T cells, and because the development of vitiligo after melanoma immunotherapy is a positive prognostic factor for patients, we asked whether VACV vaccine therapy in IFNaR deficient mice would enhance the anti-tumor response to melanoma. B16-F10 inoculated wild type and IFNaR-deficient mice received adoptive transfer of melanocyte-specific CD8 T cells in combination with vaccinia virus expressing their cognate antigen to activate the cells in vivo. Treatment of adoptive T cell transfer and infection with VACV in IFNaR-deficient mice revealed significantly reduced tumor burden compared to wild type mice. Improved tumor regression in IFNaR-deficient hosts was characterized by increased infiltrating cytotoxic T lymphocytes and reduced PD-1 expression. These results further demonstrate that in the absence of type I IFN, hosts mount a robust cytotoxic CD8 T cell response against melanocyte/melanoma antigens and this is likely a result of persistent VACV that leads to prolonged CD8 T cell priming. As a result, IFNaR deficient hosts kill tumor cells more efficiently. To determine whether type I IFN regulates disease pathogenesis in the absence of virus infection, we generated a model of vitiligo in which bone marrow derived dendritic cells (BMDCs) pulsed with the cognate antigen were used to prime melanocyte-specific T cells in place of the viral vector. Induction of vitiligo in IFNaR-deficient hosts using BMDCs revealed no significant differences in disease score compared to wild type hosts. This data clearly demonstrates that type I IFN, in contrast to IFNg, is not required during the effector stage of vitiligo pathogenesis in mice. However, since we intentionally activate transferred melanocyte-specific CD8 T cells with VACV or BMDCs expressing their cognate antigen, our mouse models may circumvent the role of type I IFNs in initiating activation of autoreactive cells and driving autoimmunity. Type I IFN is critical for providing innate immune signals that drive the priming of autoreactive T cells through maturation of DCs by inducing antigen presentation, co-stimulatory molecule expression, and migration to the lymph nodes to encounter naïve T cells. Our mouse models of vitiligo may not capture this process. We have addressed this question by using a TLR ligand to activate BMDCs before transfer into hosts. In fact, activation of BMDCs before transfer leads to significantly enhanced vitiligo in mice and this is partially a result of type I IFN signaling on host cells. Thus, we provide evidence that type I IFNs can enhance the activation of melanocyte-specific CD8 T cells and drive autoimmunity. Collectively, our results show that type I IFN signaling has disparate effects on autoreactive T cell priming in a context dependent manner. We reveal that although type I IFN is not required for the effector phase of vitiligo in mice, maturation of DCs and subsequent type I IFN production can enhance the priming of autoreactive T cells and enhance vitiligo severity. Our studies also reveal that type I IFN is required to clear recombinant attenuated VACV infection and vaccine administration in IFNaR deficient hosts led to a robust autoreactive and anti-tumor response. These insights describing the role of type I IFN in autoimmunity and tumor immunology could have important implications for T cell dependent tumor immunotherapy.

This thesis looks at the social, political, and military effects of epidemic polio on America's war effort during World War II. The primary sources consulted include newspapers, military medical reports, photographs, memoirs, speeches, and archival collections. It looks at the effects of polio on the home front, more specifically how epidemics and the rising rates of polio were a detriment to the civilian war effort. It also focuses on the American military's preparation for and response to polio outbreaks among troops both at home and abroad. Finally, it discusses the experiences of the servicemen who contracted polio during the war. This work fills a major hole in the historiography of the disease and highlights the overlapping interests of the public, the medical community, and the military during a time of war.

HIV infection persists in Swaziland with the highest prevalence of the disease globally – 1 in 4 Swazis aged 15-49 are HIV-positive. Women have a higher rate of infection than men (31.1% of women are HIV-positive, whereas 19.7% of men are HIV-positive). The difference in prevalence between the sexes raises some concerns, particularly due to the possibility of vertical transmission from mothers to infants because the average number of children ever born per woman is 2.28 for all women and 3.58 children for married women. This research aimed to determine if there was a significant difference regarding the knowledge and personal beliefs about HIV transmission between men and women. Obtaining correct knowledge regarding the transmission of HIV and where to get tested for HIV is vital to preventing further transmission of the disease. The Demographic and Health Surveys Program (DHS) gathered data in 2006-2007 to determine the baseline knowledge of individuals about the transmission of HIV. Comparisons of data collected from Swazi men (n = 4,156) and women (n = 4,987) concerning their knowledge and beliefs about HIV were made in order to obtain descriptive statistics, including chi-square to determine the presence or absence of significance (p-values) and percent differences between the sexes. Statistical Package for the Social Sciences (SPSS) software was utilized to perform all statistical analyses using both the chi-square and percent difference functions. Data was weighted accordingly prior to analyses being run in SPSS. Questions regarding the individuals’ personal beliefs about the transmission of HIV were included on surveys for both sexes, specifically addressing the following: 1) the outward appearance of those who are HIV-positive (96.1% of women and 95.7% of men believed healthy-looking individuals can be infected with HIV; p = 0.336, % difference = 0.3999, χ2 = 0.926), 2) the role (or lack thereof) of mosquitoes in transmitting HIV (65.7% of women and 66.1% of men believed mosquitoes cannot transmit HIV; p = 0.688, % difference = 0.3999, χ2 = 0.161), 3) supernatural involvement in the transmission of HIV (92.3% of women and 91.7% of men believed supernatural means do not contribute to the spread of HIV; p = 0.292, % difference = 0.5999, χ2 = 1.112), 4) and the ability of HIV to be spread via food intake (82.2% of women and 82.3% of men believe they cannot becoming infected with HIV by sharing food with an HIV-positive individual; p = 0.901, % difference = 0.0999, χ2 = 0.016). Despite no statistically significant differences between the beliefs about HIV transmission held by both men and women, the data indicated only 51.9% of women and 51.4% of men possess comprehensively correct knowledge about the transmission of HIV. Furthermore, although 91.8% of women knew where to get tested for HIV, only 78.1% of men knew where to get tested for HIV. However, an encouraging 73.8% of women and 71.8% of men between the ages of 18 and 19 stated they believed adolescents between the ages of 12 and 14 should be taught proper condom use to prevent HIV infection. Comprehensive adolescent and adult sex education programs are indicated to ensure all adolescents and sexually active men and women possess correct knowledge about the transmission of HIV and where to seek assistance for HIV testing and treatment.

This study examines the "Spanish" influenza pandemic of 1918-1919 in the U.S. South, using case-studies of Jacksonville, Savannah, New Orleans, and Nashville to sculpt a "Southern flu" more identical to the Global South and the developing world than the rest of the U.S. I examine poverty and political and economic paralysis in the years between the end of Reconstruction and 1918, and the poor results of political indifference on public health and disease control. I also analyze the social and institutional racism against persons of color that defined high infectious disease mortality in Southern cities. I argue that Southerners faced higher flu mortality than other parts of the country due to the regional poverty and public health underdevelopment that defined previous diseases and made the South distinct in the national epidemiological narrative, namely through yellow fever, malaria, hookworm, and pellagra. I also challenge the conventional orthodoxy by arguing that within the South, African Americans faced exorbitant mortality rates compared to whites. I argue against the myth of a democratic killer flu, but rather, the existence of deep social inequalities and inequities that furthered mortality among the impoverished and marginalized. I argue that the pandemic was like most epidemics and pandemics in Western history, in that it disproportionately killed minorities and those without access to medical care and social services due to conducive social architecture. While pestilence shapes societies, societies simultaneously shape the course of pestilence. This study is divided into five chapters. An introductory chapter examines the scholarship and Southern public health before 1918. The second chapter addresses the pandemic in Jacksonville and Savannah, the third chapter examines New Orleans, and the fourth chapter assesses Nashville. A concluding chapter compares the U.S. South with the Global South, tethering the U.S. South to the global pandemic.

No description available.

<p><strong>Background.</strong> As disease patterns change, healthcare facilities have had to adapt and create new strategies. Little is known about the impact of infectious disease on the changing nature of work for frontline nurses, healthcare executives laboratory staff, and infection control practitioners (ICPs), in these disciplines in community hospitals. In the past seven years, there has been an increase in the incidence of infectious disease in Ontario (MRSA, VRE, C. difficile). As a result, there has been implementation of new infection control policies and practices, and transparency in the public reporting systems (Ministry of Health and Long-Term Care [MOHLTC], 2008). However, no research has focused on how these changes have impacted the work of health professionals.</p> <p><strong>Purpose.</strong> The purpose of this study is to explore the impact of hospital-acquired infections (HAIs) on the changing nature of work of frontline nurses, healthcare executives, laboratory staff, and infection control practitioners. Methods. The study uses an exploratory descriptive case study design and is situated in South Eastern Ontario (Niagara Health System). The methodology includes document analysis, demographic workforce questionnaires, and semi-structured interviews.</p> <p><strong>Findings.</strong> The findings demonstrate that work has changed for all health professionals because of (1) the continued increase in infectious diseases, (2) the proliferation of infection control policies and practices, (3) the increase in data management and data-based decisions, and (4) increased communication and connectivity required across disciplines.</p> <p><strong>Conclusion.</strong> Implications for future research include the need to address streamlining changes at the healthcare system, institutional, and clinical level. There needs to be an evaluation of the evidence supporting existing institutional policies and procedures, and of the care structures in the management of infectious diseases.</p> / Master of Science (MSc)

Public health screening plays an important role in the overall healthcare system. As an example, consider newborn screening, a state-level initiative that screens newborns for life-threatening genetic disorders for which early treatment can substantially improve health outcomes. Another topical example is in the realm of infectious disease screening, e.g., screening for COVID-19. The common features of both public health screening problems include large testing populations and resource limitations that inhibit screening efforts. Cost is a major barrier to the inclusion of genetic disorders in newborn screening, and thus screening must be both highly accurate and efficient; and for COVID-19, limited testing kits, and other shortages, have been major barriers to screening efforts. Further, for both newborn screening and infectious disease screening, equity (reducing health disparities among different sub-populations) is an important consideration. We study the testing process design for newborn screening for genetic diseases, considering cystic fibrosis as a model disorder. Our optimization-based models take into account disease-related parameters, subject risk factors, test characteristics, parameter uncertainty, and limited testing resources so as to design equitable, accurate, and robust screening processes that classify newborns as positive or negative for cystic fibrosis. Our models explicitly consider the trade-off between false-negatives, which lead to missed diagnoses, and the required testing resources; and the trade-off between the accuracy and equity of screening. We also study the testing process design for infectious disease screening, considering COVID-19 as a model disease. Our optimization-based models account for key subject risk factors that are important to consider, including the likelihood of being disease-positive, and the potential harm that could be averted through testing and the subsequent interventions. Our objectives include the minimization of harm (through detection and mitigation) or maximization of testing coverage. These are complex problems. We develop novel mathematical models and characterize key structural properties of optimal solutions. This, in turn, allows the development of effective and efficient algorithms that exploit these structural properties. These algorithms are either polynomial- or pseudo-polynomial-time algorithms, and are able to solve realistic-sized problems efficiently. Our case studies on cystic fibrosis screening and COVID-19 screening, based on realistic data, underscore the value of the proposed optimization-based approaches for public health screening, compared to current practices. Our findings have important implications for public policy. / Doctor of Philosophy / Public health screening plays an important role in the overall healthcare system. As an example, consider newborn screening, a state-level initiative that screens newborns for life-threatening genetic disorders for which early treatment can substantially improve health outcomes. Another topical example is in the realm of infectious disease screening, e.g., screening for COVID-19. The common features of both public health screening problems include large testing populations and resource limitations that inhibit screening efforts. Cost is a major barrier to the inclusion of genetic disorders in newborn screening, and thus screening must be both highly accurate and efficient; and for COVID-19, limited testing kits, and other shortages, have been major barriers to screening efforts. Further, for both newborn screening and infectious disease screening, equity (reducing health disparities among different sub-populations) is an important consideration. We study the testing process design for newborn screening for genetic diseases, considering cystic fibrosis as a model disorder. Our optimization-based models take into account disease-related parameters, subject risk factors, test characteristics, parameter uncertainty, and limited testing resources so as to design screening processes that classify newborns as positive or negative for cystic fibrosis. Our models explicitly consider the trade-off between false-negatives, which lead to missed diagnoses, and the required testing resources; and the trade-off between the accuracy and equity of screening. We also study the testing process design for infectious disease screening, considering COVID-19 as a model disease. Our optimization-based models account for key subject risk factors that are important to consider, including the likelihood of being disease-positive, and the potential harm that could be averted through testing and the subsequent interventions. Our objectives include the minimization of harm (through detection and mitigation) or maximization of testing coverage. These are complex problems. We develop novel mathematical models and characterize key structural properties of optimal solutions. This, in turn, allows the development of effective and efficient algorithms that exploit these structural properties. Our case studies on cystic fibrosis screening and COVID-19 screening, based on realistic data, underscore the value of the proposed optimization-based approaches for public health screening, compared to current practices. Our findings have important implications for public policy.

The pandemic produced by the COVID-19 virus has resulted in an estimated 6.4 million deaths worldwide and a rise in unemployment rates, notably in the UK. Healthcare monitoring systems encounter several obstacles when regulating and anticipating epidemics. The study aims to present the AF-HIDOP model, an artificial neural network Fast Fourier Transform hybrid technique, for the early identification and prediction of the risk of Covid-19 spreading within a specific time and region. The model consists of the following five stages: 1) Data collection and preprocessing from reliable sources; 2) Optimal machine learning algorithm selection, with the Random Forest tree (RF) classifier achieving 94.4% accuracy; 3) Dimensionality reduction utilising principal components analysis (PCA) to optimise the impact of the data volume; 4) Predicting case numbers utilising an artificial neural network model, with 52% accuracy; 5) Enhancing accuracy by incorporating Fast Fourier Transform (FFT) feature extraction and ANN, resulting in 91% accuracy for multi-level spread risk classification. The AF-HIDOP model provides prediction accuracy ranging from moderate to high, addressing issues in healthcare-based datasets and costs of computing, and may have potential uses in monitoring and managing infectious disease epidemics.

This study using a quantitative, descriptive design with a questionnaire investigated cultural, religious and social factors that might impact on ARV treatment in HIV/AIDS-infected women in Botswana. The study found that the majority never missed any doses, a few missed doses once or twice, and a small minority missed more than three times. The respondents’ perception of cultural influence on treatment of HIV/AIDS in women revealed that the majority (70%) believe culture has an influence on the treatment. Social factors also impacted on ARV adherence. A few of the respondents indicated that side effects and the number of pills prevented ARV medication adherence. The main reason for non-adherence, however, was forgetfulness. There had been an improvement in the majority of the respondents’ health status and quality of life. Maximizing adherence is essential. Providers and patients both have responsibilities in this regard. / Health Studies / M.A.(Health Studies)