In this thesis, we study three emerging applications of OR/MS, namely, (i) disease spread modeling, intervention strategies, and food supply chain management during an influenza pandemic, (ii) the practical applications of production planning and scheduling in the commercial lithographic printing industry, and (iii) packing/placement problems in chip design in the semiconductor industry. In the first part of the thesis, we study an emergency response planning problem motivated by discussions with the American Red Cross, which has taken on a responsibility to feed people in case of an influenza pandemic. During an emergency such as an influenza pandemic or a bioterror attack, regular distribution channels of critical products and services including food and water may be disrupted, or some of the infected individuals may not be able to go to grocery stores. We analyze the geographical spread of the disease and develop solution approaches for designing the food distribution supply chain network in case of an influenza pandemic. In addition, we investigate the effect of voluntary quarantine on the disease spread and food distribution supply chain network. Finally, we analyze the effect of influenza pandemic on the workforce level. In the second part, we study a real life scheduling/packing problem motivated by the practices in the commercial lithographic printing industry which make up the largest segment of the printing industry. We analyze the problem structure and develop efficient algorithms to form cost effective production schedules. In addition, we propose a new integer programming formulation, strengthen it by adding cuts and propose several preprocessing steps to solve the problem optimally. In the last part of the thesis, motivated by the chip design problem in the semiconductor industry, we study a rectangle packing/placement problem. We discuss the hardness of the problem, explore the structural properties, and discuss a special case which is polynomially solvable. Then, we develop an integer programming formulation and propose efficient algorithms to find a ``good' placement.

T lymphocytes are an essential component of the adaptive immune response and are highly versatile in function. Each T cell has a unique T cell receptor that can recognize an antigenic peptide in the context of the major his to compatibility complex (MHC) encoded molecules, thus offering a high degree of specificity to the immune response. T cells play a central role in the development of an effective host immune response and the quantitative and qualitative regulation of the T cell response is critical. T cells develop in the thymus, an important primary immune organ, where immature thymocytes undergo differentiation and maturation. Through the process of thymic differentiation, immature cluster of differentiation (CD)4-CD8- thymocytes progress to a CD4+CD8+ stage and are subjected to positive and negative selection to give rise to MHC restricted, single positive CD4+ or CD8+ naive T cells that emigrate from the thymus and populate the peripheral lymphocyte pool. Thymic atrophy is well known to occur naturally during the process of aging with thymocyte depletion and reduced thymic output. Along with age associated changes leading to atrophy, the thymus is exquisitely sensitive to starvation and several stresses. In addition, thymic atrophy is a characteristic feature during several viral, bacterial and parasitic infections. Egress of immature thymocytes, loss of thymic populations due to sensitivity to glucocorticoids and cytokine modulation, etc. have been variously proposed to be involved in this process. However there is limited understanding on the numerous mechanisms involved and the crosstalk between these diverse pathways. In this study, a model for thymic atrophy during acute Salmonella enterica serovar Typhimurium (S. typhimurium) infection was developed. S. typhimurium is a Gram negative bacterium that resides and grows in intracellular compartments within host cells. It causes gastroenteritis in humans but leads to typhoid like disease in mice, similar to that caused by S. typhi in humans. Initially, it was established that acute infection of C57BL/6 mice with 108 CFU S. typhimurium, via the oral, i.e. the physiological, route of infection leads to extensive depletion (8-10 fold) of thymocytes in an infection-dependent manner. Infected mice had higher CFU burden in the Peyer’s patches, spleen, liver, and mesenteric lymph node (MLN) as compared to the thymus. The thymic atrophy was dependent upon the infection caused by live S. typhimurium since oral feeding of mice even with higher doses (1010 CFU) of heat-killed bacteria did not lead to thymic atrophy. The susceptible populations in the thymus were identified by staining for expression of CD4 and CD8 on cell surface using specific monoclonal antibodies tagged to fluorophores, e.g. Fluorescein isothiocyanate (FITC) and phycoerythrin (PE), respectively. The double labelled samples were analyzed by flow cytometry. Interestingly, significant death of CD4+CD8+, the major population of thymocytes, but not single positive thymocytes or peripheral lymphocytes (MLN and spleen cells), was observed at later stages during infection. To gain greater understanding of the processes involved, the mechanisms leading to thymic atrophy were investigated. To this purpose, small molecule inhibitors and mice lacking key molecules important for the immune response were utilized. Also, various assays to assess death of thymocytes, including analysis of death markers such as Annexin V based detection of membrane flipping and caspase activation were performed. I. The extrinsic death pathway involving Fas/FasL interactions is a major death pathway. Therefore, the expression and functional role of the components of the pathway in this model of thymocyte death was investigated. It was observed that thymocytes from infected mice expressed more Fas and Fas ligand (FasL) on their surface than cells from uninfected mice. To address the role of the death receptor, Fas, infection studies were performed with lpr mice that lack functional Fas expression. The depletion of CD4+CD8+ thymocytes in lpr mice was comparable to that in C57BL/6 mice indicating that it was independent of the Fas pathway. However, extensive loss of mitochondrial membrane potential was observed upon analysis with mitochondrial potential specific dyes MitoTracker Red and DiOC6. Most likely, the intrinsic death pathway involving mitochondrial depolarization is involved in this model of thymic atrophy. II. Since thymocytes are known to be sensitive to glucocorticoids both in vitro and in vivo, the involvement of the same in this model of thymic atrophy was assessed. The amounts of cortisol, a glucocorticoid, as detected by ELISA, were elevated during infection. To investigate the functional implication of the increase in cortisol, studies were performed using RU486, a glucocorticoid receptor antagonist. RU486 did not modulate cortisol amounts and treatment of mice with RU486 did not affect CFU burden or survival of mice. However there was a moderate rescue in the number of viable CD4+CD8+ thymocytes, with only a 3-4 fold drop as compared to the 8-10 fold drop in vehicle treated infected mice. III. As glucocorticoids appeared to play a partial role in this model, it was reasonable to assume that other pathways were also involved in the thymic atrophy. The quantitative and qualitative modulation of the cytokine milieu has a profound effect upon the thymus. In fact, inflammatory cytokines, Tnfα and Ifnγ, increased upon infection. In order to study the role of Ifnγ mediated inflammatory responses in this model, infection studies with Ifnγ-/- mice were performed. Ifnγ-/- mice had higher CFU and lower survival; however the drop in thymocyte numbers was 3-4 fold as compared to the 8-10 fold drop in the infected C57BL/6 mice, again indicating a partial involvement of the Ifnγ mediated pathways. In order to study the interactions, if any, between the two pathways mentioned above, corticosteroid signaling was blocked in the Ifnγ-/- mice with RU486. Upon infection, the number of CD4+CD8+ thymocytes was significantly higher in Ifnγ-/- mice treated with RU486 (~1.5 fold drop in viable thymocyte numbers) along with lower caspase 3 activity and mitochondrial damage. Importantly, cortisol amounts in infected Ifnγ-/- mice were comparable to those in infected C57BL/6 mice and the administration of RU486 did not modulate Tnfα and Ifnγ cytokine amounts in sera. Thus, the glucocorticoid and Ifnγ mediated pathways are parallel but synergize in an additive manner to induce death of CD4+CD8+ thymocytes during S. typhimurium nfection. IV. Although thymic atrophy is known to occur, a detailed characterization of cell surface changes in thymocyte populations has not been performed. To investigate this aspect, thymocytes and MLN cells from uninfected and infected animals were stained for cell surface expression of CD3, CD4, CD5, CD8, CD24, CD25, CD44, CD69, MHC I and MHC II. This analysis was initially performed by studying the changes in expression of these molecules within the total thymocyte and MLN populations. Although there was no change in the expression of CD25 and MHC II in the total thymocyte population upon infection, CD24 expression reduced, whereas, the expression of CD3, CD5, CD44, CD69 and MHC I increased. Notably, changes in the frequency of expression of CD3, CD69 and MHC I were observed before the development of extensive thymic atrophy. The depletion of majority of the CD4+CD8+ thymocytes enriches the mature CD4+ or CD8+ thymocyte population This was corroborated with the observation that, upon in vitro stimulation with PMA and Ionomycin (pharmacological agents used to activate T cells) the residual thymocytes from infected mice produced more IL2 compared to thymocytes from uninfected mice. Subsequently, cells were stained with anti-CD4-FITC, anti-CD8-PE and a third biotinylated antibody, which was detected by a streptavidin-APC conjugate, against one of the remaining six markers. This three colour analysis made it possible to determine the changes in the expression of the third marker in each of the CD4-CD8-, CD4+CD8+, CD4+ and CD8+ populations upon infection. Distinct differences were observed in the phenotypes of uninfected and infected CD4+CD8+ thymocytes and the latter were CD3high, CD5high, CD24low, CD69high and MHC Ihigh indicating that the surviving population had a possibly more mature phenotype. Also, the changes in the phenotypes of the thymocyte populations were dependent upon the extent of thymic atrophy as indicated by time course and CFU studies with C57BL/6 and BALB/c mice respectively. Finally, the roles of glucocorticoids, Ifnγ and Nos2 in modulation of expression of these markers during infection were addressed. Interestingly, the expression of CD3, CD24 and MHC class I significantly correlated with increase in the number of surviving thymocytes upon inhibition of glucocorticoids signaling and in Ifnγ-/- mice. The implications of these changes in the thymocyte surface phenotype during thymic atrophy are discussed. V. Finally, the roles of downstream signalling molecules in S. typhimurium induced thymic atrophy were studied. Although the MAP kinase family members, Erk, Jnk and p38 have been implicated to play a role in the positive and/or negative selection of thymocytes during development, their role in infection induced thymocyte depletion has not been studied. Interestingly, the amounts of Jnk and pJnk, but not p38, increased in thymocytes upon infection. Importantly, pJnk amounts increased predominantly in CD3-/low thymocytes during infection. Furthermore, inhibition of Jnk signalling, using a specific inhibitor SP600125, lead to an increase in survival of CD4+CD8+ thymocytes during infection due to multiple reasons: lowering of cortisol, Tnfα and Ifnγ amounts, and better maintenance of thymic architecture. Thus, inhibition of Jnk mediated signaling protected CD4+CD8+ and CD3-/low thymocytes from death during S. typhimurium infection. Overall, the main conclusions of this study are as follows: First, extensive analysis of the surface phenotype of cells during thymic atrophy throws light on the sensitive and resistant thymocyte populations, thus offering a potential predictive marker profile. Second, glucocorticoids, Ifnγ and, importantly, Jnk mediated signaling play functional roles in the death of immature CD4+CD8+ thymocytes during S. typhimurium infection. The mechanistic details uncovered in this study may be important in designing effective strategies for reducing thymic atrophy during other infections. In fact, enhancement of thymic output may lead to greater numbers and diversity of thymic T cell emigrants in the periphery which is likely to enhance host responses during infections.

Mannheimia haemolytica is the principal bacterial agent associated with bovine respiratory disease (BRD). It has a significant economic impact on the beef feedlot industry. The current methods for BRD prevention and treatment have various problems and limitations, especially with reports of increased antimicrobial resistance in M. haemolytica. Bacteriophage therapy presents a novel method to mitigate M. haemolytica. This study aimed to isolate strictly lytic M. haemolytica-specific bacteriophages from bovine nasopharyngeal swabs and feedlot trough water. This was accompanied by an extensive characterization of temperate bacteriophages induced from representative strains of a M. haemolytica collection. Phage morphology, host specificity, genomic diversity, and comparative genomics were determined. Even though temperate bacteriophages are not ideal candidates for phage therapy, they can be engineered or modified to serve this function. Genome sequences of selected temperate bacteriophages also provide a foundation for future studies on the biology of these microorganisms. / viii, 107 leaves : ill. ; 29 cm

The purpose of this study is to examine how the health care system in Babati meets the increasing need for control, treatment and prevention of diabetes and hypertension. By defining what kind of specific problems and obstacles that exists in this area, the result of the research can contribute to creation and adoption of improved policies and interventions. Field studies were conducted in Babati, Tanzania for three weeks in February and March 2014. This is a qualitative study with data collected through semi-structured interviews with informants from different levels of the health system, based on the pyramidal structure of Tanzania's health care system. The theoretical framework for the study is based on aspects that corresponding to critical functions of health systems. The type of problem being treated affects the adoption and diffusion of new health interventions and the extent to which they are integrated into critical health systems functions. The study shows that diabetes and hypertension is an increasing problem in Babati. In relation to the burden, resources are lacking at all investigated levels. Therefore it is difficult to meet the increasing needs for diabetes and hypertension. To meet the future challenges, a number of cost effective strategies with focus to improve the prevention, control and reduce modifiable risk factors is suggested. / Syftet med studien är att undersöka hur hälso-och sjukvården i Babati möter det ökande behovet för kontroll, behandling och förebyggande åtgärder för diabetes och högt blodtryck. Genom att definiera vilka typer av specifika problem och hinder som finns, kan resultat från studien bidra till att skapandet och antagandet av förbättrade strategier och åtgärder. Fältstudier genomföres i Babati, Tanzania under tre veckor i februari och mars 2014. Detta är en kvalitativ studie med data insamlat genom semistrukturerade intervjuer med informanter från olika nivåer inom sjukvårdsystemet baserat på den pyramidala struktur Tanzanias sjukvårdssystem bygger på. Det teoretiska ramverket för studien baseras på aspekter som motsvarar kritiska funktioner för sjukvårdssystem. Antagandet och spridning av nya hälsointerventioner och i vilken mån de är integrerade i kritiska hälso- systemfunktioner påverkas av den typ av problem som behandlas. Studien visar att diabetes och högt blodtryck är ett ökande problem i Babati. I relation till hur sjukdomsbördan ser ut, saknas det resurser på samtliga undersökta nivåer. Därför är det svårt att möta de ökande behov som finns för att hantera diabetes och högt blodtryck. För att möta de framtida utmaningarna i Babati har ett antal kostnadseffektiva strategier med fokus att förbättra förebyggande, kontroll och minska påverkbara riskfaktorer föreslagits.

The main aim of this study was to investigate how effective School Management Teams were in the management of healthy school environments in the Gert Sibande District. This was a qualitative study which employed two data collection strategies: face to face interviews and photographs. A literature review on this study revealed vital aspects, that a healthy school environment: can directly improve children’s health and effective learning; the school is strategically positioned to reach large numbers of the population to teach them to understand the importance of investing in health. Literature indicated collaboration and synergy as essential aspects, and policies as cornerstones that underpin the health promotion initiatives. Selection of sites was purposefully done as three of the four schools in this study were part of the Eco Schools programme. The study revealed that there was disconnect between the SMTs and committees that were involved in health promotion: in coordinating plans; and monitoring and evaluating the implementation of programmes. This therefore, means that there was no support for the committees from the SMT. It was also found that there were committees that: did not have plans; did not sit for meetings and the reluctance of the SMT to address these challenges compounded the situation and contributed to some committees being dysfunctional. The failure of the SMT to guide and provide leadership in their engagement with community members who provided assistance in terms of basic needs to learners indicated a need for the development of a cadre of leaders that are capable of working beyond the borders of schools. In all the committees that were interviewed, the Environmental Committee came up to be more effective and organized than others in three schools. The health committee was lacking in the area of training especially in the prevention of communicable diseases. The study provided recommendations to assist the SMT in their endeavors to promote healthy environments in their schools. / MEd, Education Management, North-West University, Vaal Triangle Campus, 2012

Delivering health care services in an efficient and effective way has become a great challenge for many countries due to the aging population worldwide, rising health expenses, and increasingly complex healthcare delivery systems. It is widely recognized that models and analytical tools can aid decision-making at various levels of the healthcare delivery process, especially when decisions have to be made under uncertainty. This thesis employs stochastic models to improve decision-making under uncertainty in two specific healthcare settings: inpatient flow management and infectious disease modeling. In Part I of this thesis, we study patient flow from the emergency department (ED) to hospital inpatient wards. This line of research aims to develop insights into effective inpatient flow management to reduce the waiting time for admission to inpatient wards from the ED. Delayed admission to inpatient wards, also known as ED boarding, has been identified as a key contributor to ED overcrowding and is a big challenge for many hospitals. Part I consists of three main chapters. In Chapter 2 we present an extensive empirical study of the inpatient department at our collaborating hospital. Motivated by this empirical study, in Chapter 3 we develop a high fidelity stochastic processing network model to capture inpatient flow with a focus on the transfer process from the ED to the wards. In Chapter 4 we devise a new analytical framework, two-time-scale analysis, to predict time-dependent performance measures for some simplified versions of our proposed model. We explore both exact Markov chain analysis and diffusion approximations. Part I of the thesis makes contributions in three dimensions. First, we identify several novel features that need to be built into our proposed stochastic network model. With these features, our model is able to capture inpatient flow dynamics at hourly resolution and reproduce the empirical time-dependent performance measures, whereas traditional time-varying queueing models fail to do so. These features include unconventional non-i.i.d. (independently and identically distributed) service times, an overflow mechanism, and allocation delays. Second, our two-time-scale framework overcomes a number of challenges faced by existing analytical methods in analyzing models with these novel features. These challenges include time-varying arrivals and extremely long service times. Third, analyzing the developed stochastic network model generates a set of useful managerial insights, which allow hospital managers to (i) identify strategies to reduce the waiting time and (ii) evaluate the trade-off between the benefit of reducing ED congestion and the cost from implementing certain policies. In particular, we identify early discharge policies that can eliminate the excessively long waiting times for patients requesting beds in the morning. In Part II of the thesis, we model the spread of influenza pandemics with a focus on identifying factors that may lead to multiple waves of outbreak. This line of research aims to provide insights and guidelines to public health officials in pandemic preparedness and response. In Chapter 6 we evaluate the impact of seasonality and viral mutation on the course of an influenza pandemic. In Chapter 7 we evaluate the impact of changes in social mixing patterns, particularly mass gatherings and holiday traveling, on the disease spread. In Chapters 6 and 7 we develop agent-based simulation models to capture disease spread across both time and space, where each agent represents an individual with certain socio-demographic characteristics and mixing patterns. The important contribution of our models is that the viral transmission characteristics and social contact patterns, which determine the scale and velocity of the disease spread, are no longer static. Simulating the developed models, we study the effect of the starting season of a pandemic, timing and degree of viral mutation, and duration and scale of mass gatherings and holiday traveling on the disease spread. We identify possible scenarios under which multiple outbreaks can occur during an influenza pandemic. Our study can help public health officials and other decision-makers predict the entire course of an influenza pandemic based on emerging viral characteristics at the initial stage, determine what data to collect, foresee potential multiple waves of attack, and better prepare response plans and intervention strategies, such as postponing or cancelling public gathering events.

Aphanomyces invadans is the pathogen that causes epizootic ulcerative syndrome (EUS), an economically devastating fish disease in southern Asia. The present thesis considered possible improvements to current methods of monitoring EUS, and examined the mechanisms of the host immune response to A. invadans in order to establish whether they could be enhanced to reduce the impact of EUS on aquaculture. Monoclonal antibody (MAb) technology was considered as a possible improvement to the histopathological methods currently used in diagnosis of EUS. Five MAbs were raised to day-old A. invadans germlings. Four gave weak reactions to A. invadans and cross-reacted with other Aphanomyces spp, though they may be useful for future studies on A. invadans. The other, designated MAb 3gJC9, only cross-reacted with the crayfish plague pathogen, A. astaci, and was used for the development of an immunohistochemistry protocol that may be of use in diagnosis. Immunohistochemistry with MAb 3gJC9, which recognised an extracellular product (ECP) of A. invadans, was specific to A. invadans in fish tissue, although it also recognised A. astaci in plague-infected crayfish. It also recognised the mycelium in fish infected with ulcerative mycosis, indicating that ulcerative mycosis is synonymous with EUS. Preliminary observations indicated that both ECPs and what appeared to be a hitherto unreported early stage of the mycelium are important in the pathology of EUS. Studies in vitro on the macrophages of EUS-susceptible giant gourami Osphronemus gouramy and silver barb Barbodes gonionotus, and EUS-resistant Nile tilapia Oreochromis niloticus, found that their macrophages were able to inhibit the growth of A. invadans. The macrophages of striped snakehead Channa striata did not inhibit A. invadans, which may account for their high EUS-susceptibility, especially as A. invadans strongly inhibited the respiratory burst of snakehead macrophages. Studies on humoral immune responses revealed that complement inhibited A. invadans in the case of snakeheads, gourami and barbs but not tilapia or swamp eels Monopterus albus. The humoral responses of the latter were very different to the four other species, and not elucidated. Low levels of anti A. invadans antibodies were found in tilapia and gourami from an EUS-endemic region, and high levels in snakehead. Snakehead antibodies appeared to be able to inhibit A. invadans even when complement was removed, but lower levels were produced at the low temperatures typically associated with EUS. A range of potential immunostimulants were screened for the ability to enhance resistance to EUS. The two successful products were administered as feed supplements to snakeheads and barbs that were subsequently injected intramuscularly with A. invadans. One, the algal extract Ergosan, showed some beneficial effects on snakeheads although the challenge was inconclusive. The other, the vitamin supplement Salar-bec, accelerated the cellular immune response and reduced mortality in snakeheads and barbs, and enhanced antibody production in snakeheads. The antibody response of snakeheads was further studied by comparing the anti- A. invadans antibody level, inhibitory activity of sera in vitro and protective capacity of sera from EUS-naïve snakeheads to that of snakeheads recently exposed to EUS and those subject to long term EUS-exposure. Sera of populations recently exposed to EUS showed an increased level of antibodies, but little improvement in inhibitory or protective activity. Sera from snakeheads that had endured long term exposure showed a wide range of antibody levels, but marked increases in inhibitory and protective activity. Antibodies cross-reacted with non-pathogenic Aphanomyces spp. in all cases.

Revised and extended version of the author's doctoral thesis. / Includes bibliographical references and index.

Thesis (Ph.D)--Industrial and Systems Engineering, Georgia Institute of Technology, 2010. / Committee Chair: Keskinocak, Pinar; Committee Member: Ergun, Ozlem; Committee Member: Goldsman, David; Committee Member: Hupert, Nathaniel; Committee Member: Swann, Julie. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Brucellosis is one of the neglected diseases in Nigeria. In Lagos, the commercial capital of Nigeria with about twenty one million people, a descriptive cross-sectional study was carried out in order to determine the sero-prevalence of brucellosis among people at risk in some selected abattoirs and secondary health care facilities (hospitals) in the state. Mixed sampling method was employed at the abattoir while convenient sampling method was used in sampling the respondents at the hospitals. Sera samples from three hundred and one (n=301) abattoir-based workers and traders; and one hundred and twenty one (n=121) hospital-based individuals which include people with febrile illnesses and blood donors were tested for brucellosis using Rose Bengal Plate test (RBPT), with indirect ELISA being used as a confirmatory test. Of the 301 abattoir-based workers and traders, 27 (8.97%) were sero-positive to the infection when Rose Bengal Plate test antigen was used. The twenty seven individuals consists of fifteen (15) butchers; four (4) veterinarians; two (2) meat transporters and bone/cow horn dealers each as well as one each of blood meal producer, abattoir engineer, water seller and meat supplier. When blood samples from the sero-positive individuals were subjected to ELISA, 3 (11.1%) were sero-positive to the brucellosis, while one is equivocal. These results confirm that agglutination observed on RBPT might be related to unknown cross-reactions and confirmation with a different test was necessary. None of the hospital-based respondents is sero-positive to the infection. The clinical signs significant for the infection in this study were fever, joint pain, lower backache, regular headache and miscarriage. Brucellosis awareness level among the respondents was very low. Data was analysed using (SPSS) version 20.0 at α0.05 significant level. The significant risk factors for human brucellosis according to this research are consumption of fura (unpasteurized milk) and wara (fresh cheese). The study revealed that brucellosis is not only an occupational disease but can also affect people who trade or live in proximity with infected animals. / Agriculture, Animal Health and Human Ecology / M. Sc. (Agriculture)