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Bovine viral diarrhea virus (BVDV) is an important viral pathogen affecting all ages of cattle, resulting in significant economic losses worldwide. BVDV infection is associated with a diverse array of symptoms including gastrointestinal disorder, respiratory distress, fetal malformation, stillbirth, abortions, and mucosal disease (MD). Transplacental infections of fetuses between 42 and 125 days of gestation can result in immune-tolerance and the surviving fetuses become persistently infected (PI). PI animals are major reservoir of BVDV and it becomes problematic to control the disease. The objectives of this dissertation were to: 1) develop a cost-effective testing scheme to detect BVDV PI animals from exposed herds, 2) characterize two virulent BVDV-2 Mississippi isolates associated with severe hemorrhagic diseases, and 3) perform phylogenetic analysis based on sequences of 5'UTR, E2, and NS5B regions. First, we developed a BVDV testing scheme by combining pooled real-time RT-PCR with antigen capture enzyme-linked immunosorbent assay (ACE) to screen cattle herds. From positive pools individual positives were identified using ACE. Data from a three year period indicated that 92.94% PI animals were infected with BVDV-1, 3.53% with BVDV-2, and 3.53% with both BVDV-1 and BVDV-2. Analysis of the 5'UTR of 22 isolates revealed the predominance of BVDV-1b followed by BVDV-2a. Second, two virulent BVDV isolates, M10-3432 and M10-5347, were successfully recovered from an adult beef breeding cow and feedlot calf respectively. When compared to the reference strain BVDV-2 125c, five and three unique amino acids in E2 regions were different from M10-5347 and M10-3432 respectively. Phylogenetic analysis of E2 region grouped both Mississippi isolates in BVDV-2a, a subtype containing high virulent strains. M10-3432 was clustered with high virulent strain 890 while M10-5347 was clustered with high virulent strain CD87. Third, we compared the phylogenetic analyses of BVDV based on the sequences of 5'UTR, E2, and NS5B at either nucleotides or amino acids level. Although slight differences were observed, the virulent BVDV isolates were consistently classified into BVDV-2a cluster regardless of region of sequences used. Furthermore, phylogenetic tree constructed using combined two or more regions had higher posterior probability and bootstrap value than phylogenetic trees constructed using a single region

Human rotavirus (HRV) is a major causative agent of acute gastroenteritis (AGE), which causes severe dehydrating diarrhea in children under the age of five and results in up to 215,000 deaths worldwide each year. There are two live oral attenuated vaccines licensed for use in the United States that are highly effective in high-income countries but much less so in low-and middle-income countries (LMICs). Several factors contributing to decreased efficacy in these areas include chronic malnutrition, gut dysbiosis, and concurrent viral infection. Along with this, currently used vaccines require constant cold-chain storage to maintain vaccine stability, and those resources can be scarce in LMICs. These areas continue to maintain a high burden of HRV morbidity and mortality, and more efficacious vaccines are needed. The gnotobiotic (Gn) pig model of HRV infection and diarrhea has long been used in the evaluation of novel HRV vaccines due to Gn pigs' susceptibility to HRV infection, development of clinical signs, histopathological changes in the intestine, and the infection kinetics that mimic those seen in human infants. The first project in this dissertation used the Gn pig model to evaluate a thermostable live oral attenuated vaccine administered as a dissolvable film. Two doses of the tetravalent dissolvable film vaccine conferred significant protection from virus shedding by delaying its onset and reducing peak titers in feces. It also significantly delayed the onset of diarrhea and reduced the duration and area under the curve (AUC) of diarrhea. The dissolvable film was highly immunogenic, inducing high titers of serum virus neutralizing (VN) antibodies specific to each of the four G-types included in the vaccine formulation, HRV-specific serum IgA and IgG, and intestinal IgA. These data confirm the thermostable platform as a useful alternative to liquid vaccines that require cold-chain. The second project evaluated three mRNA-based nonreplicating vaccine candidates in the Gn pig model. All three mRNA candidates encoded a universal CD4+ T cell epitope, P2, derived from tetanus toxoid, fused with the encoded VP8* from P[4], P[6], and P[8] HRVs. Two candidates also encoded for a lumazine synthase (LS) domain fused with the P2-VP8*. A dose response study of the LS-P2-VP8* candidates was conducted simultaneously. Significant protection against virus shedding was induced by all three candidates, with LS-P2-VP8* candidates inducing significantly higher VP8*-specific serum IgG. All three candidates induced significantly higher numbers of P[8]-VP8*-specific IgG antibody-secreting cells (ASCs) and IFN-γ-producing T cells in the ileum, spleen and blood. These data provide guidance for further development of the relatively new mRNA-based technology for use in HRV vaccine development. In the final study of this dissertation, we used the Gn pig model of both P[8] and P[6] HRV infection to evaluate a cocktail nanoparticle-based HRV vaccine. This vaccine was made up of an S60 nanoparticle, self-assembled from the S domain of the human norovirus capsid protein. The exposed C-termini on the S60 nanoparticle were utilized as an antigen display platform, where VP8* from P[4], P[6] and P[8] HRVs was fused. This vaccine was tested as both a two-dose intramuscular (IM) regimen, or as an IM booster preceded by an oral priming immunization with commercial monovalent Rotarix®. Pigs were challenged with either P[6] or P[8] HRV to evaluate cross-protection of the nanoparticle vaccine. Both regimens were highly immunogenic, inducing high titers of serum VN, IgG and IgA antibodies. Furthermore, the prime-boost regimen conferred significant protection against virus shedding in P[8] HRV-challenged pigs as evidenced by the shortened duration of fecal virus shedding. There was also significant protection in P[6] HRV-challenged pigs vaccinated with the prime-boost regimen, as evidenced by the shortened duration, reduced mean peak titer and AUC of virus shedding. Prime-boost-vaccinated pigs challenged with P[8] HRV had significantly higher P[8]-specific IgG ASCs in the spleen post-challenge. Prime-boost-vaccinated pigs challenged with P[6] HRV had significantly higher numbers of P[6] and P[8]-specific IgG ASCs in the ileum, as well as significantly higher numbers of P[8]-specific IgA ASCs in the spleen post-challenge. Oral priming followed by parenteral boosting appears to be a promising vaccination strategy for HRV and these data warrant further investigation into this regimen. Through these studies, we improved our understanding of the effect of different vaccination routes and formulations in the effectiveness of conferring protection against an enteric virus. The knowledge will facilitate the development of more effective vaccination strategies against HRV, the leading cause of infantile diarrhea in LMICs, as well as other enteric viruses. / Doctor of Philosophy / Human rotavirus (HRV) is a major causative agent of acute gastroenteritis (AGE) in children under the age of five. Acute gastroenteritis is characterized by nausea, vomiting, and potentially deadly dehydrating diarrhea. There are two highly effective vaccines licensed for use in the United States; however, these vaccines are much less effective in low- and middle-income countries (LMICs), where HRV disease burden is the highest. There are several reasons thought to be responsible for the decrease in effectiveness seen in these areas, including chronic malnutrition and gut dysbiosis. Non-biological reasons for decreased efficacy may include the breakdown of cold-chain storage for these vaccines, which require constant low temperature storage that is often unavailable in LMICs. Thermostable vaccines are necessary for increasing vaccine distribution and efficacy in these areas. Because many of the biologic factors thought to interfere with the effectiveness of these vaccines appear to be confined to the gastrointestinal tract, development of next generation HRV vaccines has focused on the parenteral route of administration. The gnotobiotic (Gn) pig model is a highly relevant animal model that has been used for decades to evaluate novel HRV vaccine efficacy. Our first study evaluated a thermostable, dissolvable live oral vaccine administered as a dissolvable film in our Gn pig model. Two doses of this vaccine significantly reduced the severity of diarrhea and virus shedding in the stool. Our second study evaluated three mRNA-based intramuscular (IM) vaccines in the Gn pig model. Three doses of all mRNA candidates provided significant protection from virus shedding in the stool, as well as inducing the production of strong HRV-specific antibodies in the serum and high numbers of virus-specific T cells in the tissues. In our final study, we evaluated a nanoparticle-based vaccine as a two-dose IM regimen or as an IM booster preceded by an oral immunization using the commercially available Rotarix® vaccine. The prime-boost regimen significantly shortened the duration and severity of virus shedding in the stool. We also detected more cross-strain HRV-specific antibody-secreting cells in the tissues. All three vaccines evaluated in this dissertation offer differing novelty in the field of HRV vaccine development, and the Gn pig model has been instrumental in the evaluation of these vaccines.

Identify and answer the commonly asked questions by families prior to international travel Recognize and list the vaccines that are required and recommended against preventable infections in the pediatric international traveler Discuss preventive measures useful against insect borne diseases such as malaria and yellow fever Discuss the epidemiology, presentation and treatment of Traveler’s diarrhea

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The study conducted in the rural area of the province of Imbabura included a total of 518 families that when compared with the estimated sample of 96%, 42.7 % corresponding to the indigenous ethnic group, 28.15% to Black and 25% to mixed-race ethnic groups, these differences of involvement between ethnic groups is due to the fact that the indigenous population is greater than the two remaining populations. Of the 518 families studied they were able to obtain a total of 794 children younger than 5, in which 48.5% pertaining to the male sex and 51.4% to the female sex. In linking the number of participating families and the number of children studied we were able to find that mothers have 1 to 2 children younger than the age of 5 in every family. In evaluating the nutritional state of the 794 studied children, 47.09% were found to have global malnutrition (P/E), 67.26% presented a chronic malnutrition that is to say a lower height for their age, whereas 13.97% presented an acute malnutrition, a percentage that doesn’t attract attention due to what I have already noted previously with children presenting low height and weight for their age when using the indicated weight/height, the nutritional state of the children is appropriate. The nutritional state of children under the age of 5, by considering the indicators of weight/age and height/age, identified the indigenous ethnicity having major problems of malnutrition (54% and 80.97%) respectively, while the two remaining ethnic groups have presented similar percentages. The opposite occurs with the indicator of weight/height, which detected that the Black ethnic group presented a major nutritional deterioration (24%) unlike the other two ethnic groups, we believe that this difference is due to indigenous children presenting a diminished height, consequently when we use the indicator of weight/height, an adequate weight for height is presented. According to the magnitude of diarrheal processes we find that 28.34% of children presented EDA, the indigenous ethnicity being that with the highest percentage (12.84%) in relation to the other two ethnic groups. According to the severity of the diarrheal processes, light EDA presents the highest percentage with 62.67%, with the indigenous ethnicity being affected the most, moderate EDA presents a 34.22% similarly affecting the indigenous ethnicity and severe EDA presents a 3.11% with the mixed-race ethnicity being the most affected. Relating the nutritional state with acute diarrheal illnesses, considering the indicators of weight/age and height/age, we find that the indigenous population is mostly affected in nutritional state as well as in the presence of EDA. Malnourished children present a higher number of diarrheal processes. Considering the indicator of weight/height, diarrhea is more frequent in children with a normal nutritional state, with the Black ethnicity that which presents the greater percentage of EDA in normal and malnourished children. For this reason, it is urgent that national programs of health and alimentation are defined and implemented in order to combat the nutritional problem and ensure an adequate supply of food for the whole population, improving the conditions of health and environmental sanitation in order to reduce the high rates of malnutrition, diarrhea and acute respiratory infections.

Background: Diarrhea is the passage of 3 or more loose or liquid stools per day. Globally, it is the second-leading cause of death among under-five children, accounting for 9% of all under-five deaths, and kills more young children than Acquired Immunodeficiency Syndrome (AIDS), malaria and measles combined. In developing countries, an estimated 1.8 million people die annually due to diarrheal diseases, and more than 80% of them are children under 5 years, while 88% of these deaths are in South Asia and Sub-Saharan Africa (SSA). There are limited studies that investigate the prevalence and factors associated with diarrhea in SSA despite the health burden. Method: The Demographic and Health Survey (DHS) children’s recode dataset of 2015 for Chad was used for this study. The predictor variables were; age of child, source of drinking water, maternal highest level of education, drank from bottle with nipple, and the outcome variable was diarrhea recently. Descriptive statistics for all variables were completed, and Chi-square analyses were conducted to determine associations between predictor variables and the outcome, diarrhea recently. Simple and multiple logistic regressions were completed to determine factors that predict diarrhea in the last two weeks. Odds ratios, 95% confidence intervals, and p-values were reported. Results: The total sample size was (N=16,710). About 3292 (19.70%) children had diarrhea, 13418 (80.30%) children had no diarrhea. A high prevalence of diarrhea in under-five children was observe particularly in those who drink water from unprotected well (1070 cases), had mothers with only primary level of education (796 cases), and did not drink from bottles with nipple (2961 cases). Based on the age of child, the odds of having diarrhea were over 60% lower in children 3 years old and below [aOR = 0.39, C.I (0.279-0.538), p <.0001] compared to 4 years old and above. Based on the source of drinking water, children that drank from a protected spring were 74% less likely to have diarrhea [0.26, 0.084-0.827, p=0.0223] compared to those that drank from other sources. The study also showed that children that drank from bottles with nipple were 16% less likely of having diarrhea [0.84, 0.726-0.968, p=0.0166] compared to those that did not drink from bottles with nipple. However, maternal highest level of education had no significant association with the odds of having diarrhea in these children. Conclusion: Caregivers should ensure absolute hygiene and provide safe drinking water to under-five children, especially those above 3 years who may easily access contaminated water sources themselves. We also encourage the use of bottles with nipple heads for drinking in children. Further studies are needed in SSA on other factors influencing diarrhea risk in those under five.

The P2Y inhibitor, ticagrelor, has been shown to prevent thrombotic events and hence, improve morbidity and mortality in patients with acute coronary syndrome following coronary artery stent placement. Despite many clinical benefits, ticagrelor has been associated with several adverse effects, including dyspnea, easy bruising, and gastrointestinal bleeding. We report the case of a 67-year-old patient with an acute coronary artery syndrome requiring percutaneous coronary artery intervention with stenting who developed ticagrelor-induced diarrhea. The patient's ticagrelor medication was replaced with clopidogrel, and his diarrhea completely resolved within one week with no complications observed at his one-month follow-up visit. Clinicians should be aware of this adverse effect of ticagrelor so as to guide them toward possible underlying etiologies and appropriate workup of chronic diarrhea.

Problem/Purpose: Antibiotic associated diarrhea (AAD) and clostridium-difficile diarrhea (CDAD) are the most common forms of infectious diarrhea in long-term care facilities. The purpose of this study was to determine the effectiveness of probiotics in preventing AAD and CDAD in the long term care geriatric population, and to identify interventions that can be used to improve clinical practice. Background/Significance: Prophylactic use of probiotics have been purported to decrease the incidences of AAD and CDAD. Previous studies have yielded contradictory results on the efficacy of probiotics. The objective of this study was to evaluate the impact of administration of probiotics on the rate of infectious diarrhea in the Long Term Care (LTC) population Method: This was a retrospective cohort study. The charts of residents of a LTC facility who were 65 years of age and older, and were administered antibiotic therapies, with or without co-administration of probiotics were reviewed. A data collection instrument was created for this study and piloted prior to its utilization. A chi-square test of independence was calculated to obtain the results. Results: Forty-four residents received probiotics with antibiotics, five cases of diarrhea were reported; no cases of CDAD were reported. In 39 residents who received antibiotics without probiotics, two cases of diarrhea and one case of CDAD were reported. Conclusion: The study showed no statistically significant evidence to support the effectiveness of probiotic use in the prevention of AAD and CDAD in a long term care facility. The incidence of AAD was higher in the group with probiotics