The world's population is expected to grow from 6 billion to about 10 billion by 2050. The greatest population increase is expected to occur in Africa, Latin America, and Asia. To feed a world with huge increases in population and to sustain the well-being of humans, a large increase in food production must be achieved. The projected increase in food production must be accomplished on the existing cultivated areas because the expansion of new land is limited by environmental concerns, urbanization and increasing water scarcity. Different compounds have been developed for the "immunization" of plants against several pathogens. These compounds induce systemic acquired resistance (SAR) in plants, leading to broad-based, long-lasting resistance to a wide range of pathogens. The salicylic acid binding protein 2 (SABP 2) has been identified as a key enzyme in the salicylic acid mediated pathogen resistance pathway, converting methyl salicylate (MeSA) to salicylic acid (SA), a key compound responsible for SAR . S-methyl benzo [1, 2, 3,] thiadiazole-7-carbothiate (BTH) was the first commercial compound used for plant immunization. We have synthesized and characterized some new salicylic acid derivatives [methyl-2-(2-hydroxy benzoyl thio) acetate and derivatives], and we have studied the in-vitro activity with SABP2 of BTH by HPLC analysis.

Objective: Little is known about the parental perception of usage and delivery of Vaccine Information Statements (VISs), the timing of VIS delivery, parent opportunity to read VISs, and time for discussing content of VISs with providers. Parental reports of dissemination and use of VISs are explored in this study, including parental use, experience, and perceptions. Method: Data for this pilot cross-sectional descriptive study were collected via an online survey. The instrument consisted of 21questions including five demographic questions, 11 questions about VIS distribution, four questions about parental use and understanding of VISs, and one open-ended question about finding information about immunizations (see appendix A). The questionnaire was available in both English and Spanish. Results: Responses from 130 parents in one school district were used for analysis. Most participants (67.7%) reported getting vaccine information from a pediatric healthcare provider. A large majority of participants (71.5%) said VISs were included as part of the vaccination process and that they received a paper copy (64.6%). About a third of participants (37.7%) said they read some or all of the VIS before their child was vaccinated and over half (59.3%) said they read some or all of the VIS after their child was vaccinated. Discussion: While it is promising that many parents reported receiving the federally mandated vaccine information, over a quarter of parents reported they did not receive a VIS. Similar to findings in the literature, a majority of parents read all or part of the VIS after an immunization appointment. Limited time to read and understand the information on the VIS before an immunization was administered may lead to limited parental understanding. Although some parents reported struggling to understand VISs, more than half of the parents in our study said that VISs were helpful and would read another in the future. Nursing Implications: Without appropriate use of VISs and other vaccine education material, providers miss the opportunity to educate parents on the risks and benefits of vaccinating their children. Conclusion: Since their implementation in 1986, there has been little research on VIS use for vaccine education and parental perception. Providers must be aware of literacy levels and vaccine attitudes and create appropriate opportunities for parents to read and learn about vaccines. VISs are a valuable tool to educate patients and parents on the benefits and risks of vaccines. Improvements are needed to improve the clarity of the VIS messaging and dissemination practices.

Performing health surveys in developing countries and humanitarian emergencies can be challenging work because the resources in these settings are often quite limited and information needs to be gathered quickly. The Expanded Program on Immunization (EPI) sampling method provides one way of selecting subjects for a survey. It involves having field workers proceed on a random walk guided by a path of nearest household neighbours until they have met their quota for interviews. Due to its simplicity, the EPI sampling method has been utilized by many surveys. However, some concerns have been raised over the quality of estimates resulting from such samples because of possible selection bias inherent to the sampling procedure. We present an algorithm for obtaining the probability of selecting a household from a cluster under several variations of the EPI sampling plan. These probabilities are used to assess the sampling plans and compute estimator properties. In addition to the typical estimator for a proportion, we also investigate the Horvitz-Thompson (HT) estimator, an estimator that assigns weights to individual responses. We conduct our study on computer-generated populations having different settlement types, different prevalence rates for the characteristic of interest and different spatial distributions of the characteristic of interest. Our results indicate that within a cluster, selection probabilities can vary largely from household to household. The largest probability was over 10 times greater than the smallest probability in 78% of the scenarios that were tested. Despite this, the properties of the estimator with equally weighted observations (EQW) were similar to what would be expected from simple random sampling (SRS) given that cases of the characteristic of interest were evenly distributed throughout the cluster area. When this was not true, we found absolute biases as large as 0.20. While the HT estimator was always unbiased, the trade off was a substantial increase in the variability of the estimator where the design effect relative to SRS reached a high of 92. Overall, the HT estimator did not perform better than the EQW estimator under EPI sampling, and it involves calculations that may be difficult to do for actual surveys. Although we recommend continuing to use the EQW estimator, caution should be taken when cases of the characteristic of interest are potentially concentrated in certain regions of the cluster. In these situations, alternative sampling methods should be sought. / Thesis / Master of Science (MSc)

Currently available VR-diversion solutions for vaccination lack key features for delivering an immersive and pleasurable experience. A tailor-made diversionary semi-interactive VR-experience software for vaccination procedures has been developed using mainly the game engine Unity and programmed in C#. The software aims to reduce or prevent anxiety, fear, and pain during these procedures. It is predominantly intended to be used by children as a tool for prevention. The narrative of the experience runs in parallel with the different steps and events of a vaccination procedure on the left arm. The interactions from the patient are only made using head gestures and no other controllers or movements of the body are used. The sequence can be initiated, restarted, and followed by a healthcare professional using a controller. The software is in a testable and applicable state but can be improved upon and polished in various areas. / Nuvarande VR-avledningslösningar för vaccination saknar viktiga funktioner för att leverera en immersiv och trevlig upplevelse. En skräddarsydd avledande semi-interaktiv VR-upplevelseprogramvara för vaccinationsprocedurer har utvecklats med huvudsakligen spelmotorn Unity och programmerats i C#. Programvaran syftar till att minska eller förebygga ångest, rädsla och smärta under dessa procedurer. Den är främst avsedd att användas av barn som ett förebyggande verktyg. Berättelsen i upplevelsen löper parallellt med de olika stegen och händelserna i en vaccinationsprocedur på vänster arm. Interaktionerna från patienten görs endast med hjälp av huvudgester och inga andra kontroller eller rörelser av kroppen används. Sekvensen kan initieras, startas om och följas av sjukvårdspersonal som använder en handkontroll. Programvaran är i ett testbart och tillämpligt tillstånd men kan förbättras och poleras inom olika områden.

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The Expanded Program on Immunization Sampling Method (known simply as EPI sampling) is a two-stage sampling procedure originally intended for quick estimation of disease prevalence in large geographical regions. The method was developed in the 1970s and all the subsequent assessments of its performance have been conducted by simulation. In her master's thesis, Reyes (2016) studied in detail the second-stage sampling of the method by developing formulas for the exact calculation of the household inclusion probabilities when sectors are used to identify the initial household to generate the EPI samples. The inclusion probabilities were used in turn to obtain exact mean, bias, variance and mean square error of any estimator of disease prevalence in the population. Thus, no extensive simulations are required and the results are exact rather than just estimates. This thesis is an extension of Reyes' (2016) work. The extension is two-fold; (a) employing strips rather than sectors because they narrow the geographic area for field workers and to use strips to select the first household for the EPI sample at the secondary stage, and (b) carrying out an analysis on simulated population and sampling plans, using both stages of the EPI method. Analyzing the simulated populations showed that equal weight estimator that samples primary units with replacement with probability proportional to size (EW1) should be used when the target characteristic is thought to be spread randomly throughout the population, and the Horvitz-Thompson estimator that samples primary units systematically with replacement (HTSYS) should be used when the disease is believed to spread from a central location or through pocketing. Comparing the strip and sector sampling methods at the secondary stage using their effective areas leads to a comparative basis in which the inclusion probabilities are identical for both methods. / Thesis / Master of Science (MSc)

The successful elimination of vaccine-preventable diseases is contingent on high-vaccine coverage rates in targeted populations. The proliferation of vaccine misinformation on social media has led to vaccine hesitancy in the past two decades. A highly contextual phenomenon, areas with an increased prevalence of vaccine hesitancy and vaccine exemption have been shown to correlate with decreased immunization coverage and intermittent vaccine-preventable disease outbreaks worldwide. Although the Canadian government has recommended the use of social media to increase public confidence in vaccines, little documentation exists regarding the perceptions of advisors and decision-makers in policy and communications for immunization towards vaccine hesitancy on social media, and the use of social media to increase public confidence in vaccines in the context of Ontario, Canada’s largest province. This thesis employed 3 unique mixed-methods studies to explore the role of social media in addressing the problem of vaccine hesitancy facilitated through misinformation about childhood vaccines in Ontario. The first study is a social network analysis that incorporates sentiment analysis to demonstrate that pro-vaccine and anti-vaccine communities operate in siloes with little interaction with one another. Those interactions that do occur are most commonly facilitated by sentiment and geographic location, rather than profession or affiliation of the social media user. The second study is a mixed methods content analysis illustrating significant differences in user attributes (emotion, medium shared in tweets, direction of information-sharing, and use of Twitter functions) among pro-, neutral, and anti-vaccine Twitter users, suggesting different motivations underlying Twitter use. Qualitative inquiry of links and reasons for negative vaccine sentiment illustrate the proliferation of pseudo-experts occupying social media, as well as concerns about vaccine safety and mistrust towards the government. The third study complements the first two studies, and uses documents and in-depth interviews with 23 advisers and decisionmakers in policy and communications to illustrate that although vaccine hesitancy is of concern, the use of social media to increase public confidence in vaccines is met with resistance due to a myriad of barriers at all levels of immunization policy and program delivery in the Province of Ontario. Implications for policy and practice of this study include the recognition that a multi-pronged approach is needed to increase the public’s confidence in vaccines. Elements of this multi-pronged approach could include: i) commitments to investing in understanding social media’s use in informing immunization at all levels of governance and decision-making; ii) the active surveillance of public sentiment and the public’s concerns about vaccines on social media using network analysis and content analysis; and iii) the fostering of interdisciplinary collaboration to design interventions that facilitate connectivity between siloes. The implications for future research include the need for continued commitment to the design, implementation, and evaluation of public health interventions on social media in the Ontario context. This study points to the need to pay attention to the behavioral attributes and affordances of social media in order to develop policies, communicative strategies, and programmatic designs that comprehensively address public concerns towards vaccines and, in turn, promote increased confidence in them. / Thesis / Doctor of Philosophy (PhD) / Immunization efforts are integral to maintaining herd immunity. Over the past two decades, it has been observed that vaccine hesitancy brought forth by vaccine misinformation has led to reduced confidence in vaccines, contributing to declining vaccination rates that have subsequently led to outbreaks of vaccine-preventable diseases. Vaccine misinformation on social media has played a crucial role in exacerbating vaccine hesitancy. Limited research has explored the use of social media in the Canadian context in relation to how vaccine information is communicated, what is being discussed and with whom. The extent to which decision-makers working in the immunization policy arena in Canada consider the role of social media as a tool for addressing vaccine hesitancy in order to increase vaccine uptake is also unclear. Using a mixed methods approach, this study, carried out in Ontario, Canada, illustrates that communities supporting and opposing vaccines operate in silos that do not necessarily communicate with each other through social media. Although decision-makers acknowledge the role of social media in the salience of vaccine hesitancy, they consider social media to be a less feasible method to increase vaccine confidence. By exploring the networks and conversations about vaccination on social media, and by understanding decision-makers’ perceptions towards vaccine hesitancy and social media, this study identified gaps between the recommendations for addressing vaccine hesitancy, provincial decision-makers’ preference for addressing immunization, and concerns of the vaccine hesitant on social media. These findings can inform the design of public health messaging to increase the public’s confidence in vaccines in Ontario.

This research presents a mathematical model for the transportation and distribution of COVID-19 vaccine, a simulation model for fleet optimization, and a measurement model for "Healthcare 4.0." Essay 1 examines the development of a distribution model using mixed integer programming (MIP) with the objective of maximizing the number of vaccinated individuals, minimizing transportation costs across the entire network, and ensuring widespread access. This research primarily focuses on the distribution aspect of the vaccine and accordingly devises a model for transportation and distribution that ensures swift and efficient delivery of the COVID-19 vaccine. Essay 2 provides a simulation-based model to enhance logistics performance by including drones along with vaccine trucks and air cargo in the vaccine distribution fleet. The simulation model focuses on minimization of the overall cost of distribution of medical supplies. This second study shows that the types of vehicles utilized have an impact on overall system performance. The selection of the appropriate mix for the mode of transportation impacts transportation costs and lead time. To increase the responsiveness and cost-effectiveness of the logistics system for delivery of the vaccine a proper fleet configuration is required. The model developed in this study is validated via application in Telangana, India as well as through confirmation about the applicability of the model with healthcare executives. Essay 3 introduces a measurement model and constructs for Healthcare 4.0, specifically tailored for implementation by healthcare service providers. While the concept of Healthcare 4.0 and its various components have been explored in the literature, the existing body of research primarily consists of conceptual and theoretical studies, indicating that Healthcare 4.0 is still a relatively nascent research domain. In order to facilitate practical and theoretical advancements in this field, it is imperative to refine the constructs and establish a consensus on perspectives and definitions. To address this need, the items pertaining to Healthcare 4.0 for healthcare service organizations were developed through an extensive literature review and interviews conducted with practitioners in the field. The resulting theoretical model was further validated by surveying experienced professionals from the healthcare industry, utilizing Mturk as a platform.

The Heath-Jarrow-Morton (HJM) model represents the latest in powerful arbitrage-free technology for modeling the term structure and managing interest rate risk. Yet risk management strategies in the form of immunization portfolios using duration, convexity, and M-square are still widely used in bond portfolio management today. This study addresses the question of how traditional risk measures and immunization strategies perform when the term structure evolves in the HJM manner. Using Monte Carlo simulation, I analyze four HJM volatility structures, four initial term structure shapes, three holding periods, and two traditional immunization approaches (duration-matching and duration-and-convexity-matching). I also examine duration and convexity measures derived specifically for the HJM framework. In addition I look at whether portfolios should be constructed randomly, by minimizing their M-squares or using barbell or bullet structures. I assess immunization performance according to three criteria. One of these criteria corresponds to active portfolio management, and the other two correspond to passive portfolio management. Under active portfolio management, an asset portfolio is successfully immunized if its holding period return is greater than or equal to the holding period return of the liability portfolio. Under passive portfolio management, the closer the returns of the asset portfolio to the returns of the liability portfolio, the better the immunization performance. The results of the study suggest that, under the active portfolio management criterion, and with the duration matching strategy, HJM and traditional duration measures have similar immunization performance when forward rate volatilities are low. There is a substantial deterioration in the immunization performance of traditional risk measures when there is high volatility. This deterioration is not observed with HJM duration measures. These results could be due to two factors. Traditional risk measures could be poor risk measures, or the duration matching strategy is not the most appropriate immunization approach when there is high volatility because yield curve shifts would often be large. Under the active portfolio management criterion and with the duration and convexity matching strategy, the immunization performance of traditional risk measures improves considerably at the high volatility segments of the yield curve. The improvement in the performance of the HJM risk measures is not as dramatic. The immunization performance of traditional duration and convexity measures, however, deteriorates at the low volatility segments of the yield curve. This deterioration is not observed when HJM risk measures are used. Overall, with the duration and convexity matching strategy, the immunization performance of portfolios matched with traditional risk measures is very close to that of portfolios matched with the HJM risk measures. This result suggests that the duration and convexity matching approach should be preferred to duration matching alone. Also the result shows that the underperformance of traditional risk measures under high volatility is not due to their being poor risk measures, but rather due to the reason that the duration matching strategy is not an appropriate immunization approach when there is high volatility in the market. Under the passive portfolio management criteria, the performances of traditional and HJM measures are similar with the duration matching strategy. Less than 29% of the duration matched portfolios have returns within one basis point of the target yield, whereas almost all are within 100 basis points of the target yield. These results suggest that the duration matching strategy might not be sufficient to generate cash flows close to those of the target bond. The duration measure assumes a linear relation between the bond price and the yield change, and the nonlinearities that are not captured by the duration measure might be important. When the duration and convexity matching strategy is used, more than 36% of the portfolios are within one basis point of the target with HJM risk measures. This dramatic improvement in the immunization performance of HJM measures is not guaranteed for traditional risk measures. In fact, there are certain cases in which the performance of traditional risk measures deteriorates with the duration and convexity matching strategy. In this respect, choosing the correct risk measure is more important than the immunization strategy when passive portfolio management is pursued. Under active portfolio management criterion, there is no significant difference among bullet, barbell, minimum M-square, and random portfolios with both duration matching and duration and convexity matching strategies. Under the passive portfolio management criterion, bullet portfolios produce closer returns to the target for short holding periods when the duration matching strategy is used. With the duration and convexity matching strategy, bullet, barbell and minimum M-square portfolios produce closer returns to the target for short holding periods. Random portfolios perform as well as bullet, barbell and minimum M-square portfolios for medium to long holding periods. These results suggest that when the duration matching strategy is used, bullet portfolios are preferable to other portfolio formation strategies for short holding periods. When the duration and convexity matching strategy is used, no portfolio formation strategy is better than the other. Under the active portfolio management criterion, minimum M-square portfolios are successfully immunized under each yield curve shape and volatility structure considered. Under the passive portfolio management criterion, minimum M-square portfolios perform better for short holding periods, and their performance deteriorates as the holding period increases, irrespective of the volatility level. This suggests that the performance of minimum M-square portfolios is more sensitive to the holding period rather than the volatility. Therefore, minimum M-square portfolios would be preferred in the markets when there are large changes in volatility. Overall, the results of the study suggest that, under the active portfolio management criterion and with the duration matching strategy, traditional duration measures underperform their HJM counterparts when forward rate volatilities are high. With the duration and convexity matching strategy, this underperformance is not as dramatic. Also no particular portfolio formation strategy is better than the other under the active portfolio management criterion. Under the passive portfolio management criterion, the duration matching strategy is not sufficient to generate cash flows closer to those of the target bond. The duration and convexity matching strategy, however, leads to substantial improvement in the immunization performance of the HJM risk measures. This improvement is not guaranteed for the traditional risk measures. Under the passive portfolio management criterion, bullet portfolios are preferred to other portfolio formation strategies for short holding periods. For medium to long holding periods, however, the portfolio formation strategy does not significantly affect immunization performance. Also, the immunization performance of minimum M-square portfolios is more sensitive to the holding period rather than the volatility. / Ph. D.

Human rotavirus (HRV) and human norovirus (HuNoV) are the most common causative agents of acute gastroenteritis- (AGE) related morbidity and mortality around the world. Gnotobiotic (Gn) pigs are the ideal large-animal model that allows for accurate, and precise, preclinical evaluation of vaccine efficacy. Similarities in gastrointestinal anatomy, physiology, and immune system allows for direct translation of results from Gn pigs to humans. Commercially available HRV vaccines perform significantly poorer in low- and middle- income countries as compared with developed countries. Non-replicating rotavirus vaccines (NRRVs) have been proposed as a viable solution to the problems facing currently available live-, attenuated oral vaccines and evaluation of a NRRV was the first research project in this dissertation. Three doses of a novel parenterally administered nanoparticle-based RV vaccine, P24-VP8*, adjuvanted with Al(OH)3 adjuvant, was able to prime VP8*-specific mucosal and systemic T cell responses (IFN-γ producing CD4+ and CD8+ T cells), and to induce strong systemic B cell responses (IgA, IgG and serum neutralizing antibodies). A significant reduction in the mean diarrhea duration, fecal virus shedding titers, and significantly lower fecal cumulative consistency scores was observed among vaccinated pigs demonstrating the efficacy of the vaccine against RV infection and diarrhea. Next, we determined the median infectious dose (ID50) and median diarrhea dose (DD50) of the GII.4/2003 Cin-1 variant of HuNoV in Gn pigs to better standardize the pig model for HuNoV vaccine evaluation. Gn pigs were inoculated with 7 different doses of Cin-1 at 33-34 days of age. Pigs were monitored daily from post-inoculation day (PID) 1 to 7, for fecal virus shedding and fecal consistency to evaluate the virus infectiousness and associated diarrhea. The Log10 ID50 and DD50 were determined based on various mathematical models to be between 3.11 to 3.76, and 3.37 to 4.87 RNA copies, respectively. The Beta-Poisson was identified to be the best-fitting statistical model for estimating both the ID50 and DD50 of Cin-1. Determining the ID50 of the challenge virus strain is crucial for identifying the true infectiousness of HuNoVs and for accurate evaluation of protective efficacies in pre-clinical studies of therapeutics, vaccines and other prophylactics using this reliable animal model. The lack of an easily reproducible cell culture model for HuNoV has significantly delayed the development of effective vaccines. There is still no HuNoV vaccine available. Currently, the vaccine development efforts are mostly based on genetically engineered virus-like particles (VLPs) comprised of the major HuNoV capsid protein VP1. We tested the immunogenicity of a novel tetravalent VLP vaccine containing 4 major HuNoV genotypes (GI.1, GII.3, GII.4 and GII.17) using Gn pigs and evaluated its protective efficacy when challenged with GII.4 Cin-1 HuNoV. Three doses of the VLP vaccine with Al(OH)3 adjuvant administered to Gn pigs intramuscularly (IM), induced high levels of VLP-specific serum IgA and IgG antibody and hemagglutination inhibition antibody responses in the vaccinated pigs. VLP-specific IFN-γ producing CD4+ and CD8+ T cells were also elevated among vaccinated pigs at post-challenge day (PCD) 7 in the spleen and blood, but not in the ileum. However, the vaccinated pigs were not protected from infection and diarrhea when challenged with any one of the three different doses (2 x 105, 8 x 104, and 2 x 104 genome RNA copies) of Cin-1 HuNoV. These results indicated that the IM tetravalent VLP vaccine was highly immunogenic, but the presence of high levels of immune effectors induced by the vaccine were not sufficient for protecting the Gn pigs from Cin-1 challenge. Amino acid (aa) sequence analysis showed that the GII.4 Sydney 2012 strain which was included in the VLP vaccine, had 23 aa substitutions in the major receptor binding domain (P2) compared to the Cin-1, a GII.4 Farmington Hills 2002 strain. Our findings, for the first time, provided in vivo experimental evidence for the total lack of cross-genogroup, cross-genotype and cross-variant protection among HuNoV. This finding has importance implications for HuNoV vaccine development. HuNoV vaccines have to include multiple variants and have to be routinely updated in order to ensure sustained protection among the population. Together these three studies in this dissertation demonstrate the versatility of Gn pigs as a reliable large animal model for studying the pathogenesis and immunity of enteric viruses and the evaluation of immunogenicity and protective efficacy of novel enteric viral vaccines. / Doctor of Philosophy / People of all age groups are susceptible to acute gastroenteritis (AGE), a condition characterized by sudden onset of diarrhea, nausea and abdominal cramps. The two most important viral pathogens responsible for causing AGE are rotavirus (RV) and norovirus (NoV). Gnotobiotic (Gn) pigs have been valuable in helping us understand the mechanism of infection, pathogenesis, immunity and have played a key role in the expediting development of novel vaccines and therapeutics against both of these viruses. Live oral RV vaccines are available but they are not very effective in low income countries where the vaccines are needed the most. Next generation parenteral vaccines are proposed to improve the RV vaccine efficacy. Our first study showed that a nanoparticle-based intramuscular (IM) RV vaccine effectively reduced the duration and severity of human RV infection and diarrhea in Gn pigs. Secondly, we examined in detail the infectivity of HuNoV and identified accurately using different mathematical models on how much virus would be required to infect and cause diarrhea in naïve Gn pigs. This knowledge would greatly help in the accurate assessment of the efficacy of NoV vaccines. Third, we evaluated the immunogenicity and protective efficacy of a tetravalent IM NoV vaccine in Gn pigs. Although the vaccine was highly immunogenic, it did not confer any protection against infection and diarrhea upon challenge with the NoV at different doses. NoVs are so diverse that one year we might be infected with one strain and a few years later, we might be infected again with another strain, even though they belong to the same genotype, and experience the same symptoms. This is because, changes brought about due to mutation in the virus capsid protein allow the viruses to hide from neutralizing antibodies induced by previous infection or vaccination as we have revealed in this study. NoV diversity and lack of cross protection need to be taken into consideration during vaccine development. This thesis shows how Gn pigs can be used to study these components in order to further maximize our ability to understand and combat enteric viral diseases.