This dissertation describes the development and application of a new mathematical model for simulating the progression of Plasmodium falciparum infections in individuals with no malarial acquired immunity. The model allows for stochastic simulation of asexual and sexual parasitemias as well as the onset of fever and human to mosquito infectivity on a daily time scale. The model components for the asexual and sexual stages were developed elsewhere but are here extended to allow for simulation of the full range of dynamics observed in a subset of malaria therapy patients. As a first application of the model, I calculate the human component of malarial R0, the basic reproductive number. I then compare this value to those from three other models and describe how this quantity can be used to model malaria transmission. The second application of the model incorporates the effects of drug treatment on progression of infection by utilizing modeled pharmacokinetic and pharmacodynamic properties of a variety of antimalarials. I utilize a stage specific proportional killing model for sexual stages, informed from recent in vitro data. The relationship of effect sizes to treatment coverage and type of treatment in both early and late treatment seeking settings is calculated. In the third chapter, I consider the economic and epidemiological ramifications of antimalarial and rapid diagnostic subsidization for malaria control. For the epidemiological modeling I utilize a semi-mechanistic model of the spread of drug resistance parameterized from historical malaria mortality data; for the economic model I consider the effect of rapid diagnostics on the intensive and extensive margins of antibiotics and antimalarials, as well as the benefits to improved targeting of both. I find that rapid diagnostic testing is justified given our baseline assumptions for areas with low proportions of malarious individuals among all treatment-seekers, but that caution is necessary before deployment worldwide. For antimalarial subsidization, we find that this is a cost-effective method for reducing mortality in developing countries, though efforts to delay the onset and slow the spread of resistance are urgently needed.

MSc (Mathematics) / Department of Mathematics and Applied Mathematics

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Master of Science June, 30, 2015 / The world suffers under a serious threat of malaria with about 584 000 deaths reported each year and most of these fatalities being children under five years of age. Malaria is caused by the protozoan parasite of the genus Plasmodium. Five different malaria species infect humans and cause disease: P. vivax, P. malariae, P. ovale, P. knowlesi and the cause of most malaria deaths, P. falciparum. The main reason for this disturbing situation is the emergence of drug resistance which reduces the effectiveness of most antimalarials. Hence, there is an urgent need for new drugs that will possibly be effective against both wild type and mutant strains of Plasmodium species. Pyrimethamine, a dihydrofolate reductase (DHFR) inhibitor, has been used most widely as an antimalarial antifolate drug for the treatment of malaria. However, rapid development of parasite resistance to this drug occurred because of its rigidity. Parasitic resistance to antimalarial antifolates arises from single mutations at various amino acid residues surrounding the PfDHFR active site. In this project, we aimed to design and synthesise a novel series of flexible pyrimidine analogues of a dihydrotriazine hit compound prepared in a previous study. These compounds were designed to target folate metabolism in the malaria parasite. The initial series of compounds prepared in this project were synthesised over 5 steps in an overall yield of 10%. The flexible pyrimidine analogues were screened for antimalarial activity in an in vitro P. falciparum screen on the Gambian FCR-3 strain (chloroquine and cycloguanil resistant strain) with dihydroartemisinin, methotrexate and quinine as controls. 5-(3-(3,5-Dichlorophenoxy)propyl)-6-phenylpyrimidine-2,4-diamine displayed the best antimalarial activity (IC50 = 0.09 μM) of the compounds in this series. Surprisingly; this was the only compound prepared in this series that proved to be as effective as our original hit dihydrotriazine (IC50 ~50 nM). In the second generation of compounds prepared in this study, we used a multicomponent coupling approach to synthesise three flexible pyrimidines bearing a non-aromatic side chain at the 6-position of the pyrimidine ring. For comparison, two analogues bearing a phenyl group at the 6-position of the pyrimidine ring were also prepared. Once again; only one compound of this series [5-((4-chlorophenethylamino)methyl)-6-cyclopropylpyrimidine-2,4-diamine, (IC50 = 0.03 μM)] showed activity comparable with our original hit compound. iv Finally, ten substituted pyrimidines bearing a flexible side chain at the 6-position of the pyrimidine ring, were prepared. These compounds are structurally similar to P65, [6-methyl-5-(3-(2,4,5-trichlorophenoxy)propoxy)pyrimidine-2,4-diamine] an analogue of a potent antifolate, WR99210, found to have good oral bioavailability in rats. Once again, the antimalarial activity of the compounds prepared was assessed in an in vitro P. falciparum screen on the Gambian FCR-3 strain. The most promising compound of this series was 6-(3-(3,4-dichlorophenoxy)propoxy)pyrimidine-2,4-diamine, which exhibited antimalarial activity in the low micromolar range (IC50 = 4.46 μM).

A Thesis Submitted to the Faculty of Health Sciences, University of the Witwatersrand in partial fulfilment of the requirements for the Degree of Master of Science in Epidemiology Major Area-Subject: Biostatistics and Epidemiology November 2014 / Background: Malaria is a serious public health challenge in sub-Saharan Africa with children under five being the most vulnerable, and a child dies every 30 seconds from it. Therefore, it is important to investigate malaria’s direct and indirect determinants in specific sub-Saharan populations as well as identifying malaria hotspots in order to have informed and targeted preventative interventions. Rationale: Given the extent and seriousness of malaria in Southern Africa, understanding fully the factors associated with malaria is important in successfully fighting it. Therefore, understanding the determinants of malaria in children under five is important in working towards eliminating malaria in sub-Saharan populations. Objectives: This study’s objectives were:  To describe demographic, behavioral and environmental determinants (factors) associated with malaria episodes in under fives in households in Malawi in the year 2012  To investigate the determinants of malaria episodes in children under five years in Malawi in 2012  To compare spatial distribution of malaria episodes in households in Malawi in 2012. Methods: This study was a secondary data analysis based on data from the Malawi 2012 Malaria Indicator Survey (MIS) obtained from Demographic and Health Survey (DHS) program website. The outcome variable was positive blood smear result for malaria in children less than five years, after an initial positive rapid malaria diagnostic test done at the homestead. We controlled for confounders after propensity score matching in order to reduce selection bias. Cases and controls were matched based on their propensity scores. Statistical modelling was done using logistic regression as well as generalized structural equation modeling (G-SEM) to model direct and indirect effects on the outcome. Poisson regression was done to determine associations between the outcome (positive blood smear malaria result) and selected explanatory variables at household level and we then introduced a structured and unstructured random effect to measure spatial effects if any of malaria morbidity in children under the age of five. Results: The matched data had 1 325 children with 367 (24.3%) having blood smear positive malaria. Female children made up approximately 53% of the total study participants. Child related variables (age, haemoglobin and position in household) as well as wealth index were significant (directly and indirectly) with p values <0.001. Socio-economic status (SES) [Odds ratio (OR) = 0.96, 95% Confidence interval (CI) = 0.92, 0.99] and primary level of education [OR = 0.50, 95%CI = 0.32, 0.77] were important determinants. The spatially structured effects accounted for more than 90% of random effects as these had a mean of 1.32 (95% Credible Interval (CI) =0.37, 2.50) whilst spatially unstructured had a mean of 0.10(CI=9.0x10-4, 0.38). The spatially adjusted significant variables on malaria morbidity were; type of place of residence (Urban or Rural) [posterior odds ratio (POR) =2.06; CI = 1.27, 3.34], not owning land [RR=1.77; CI= 1.19, 2.64], not staying in a slum [RR=0.52; CI= 0.33, 0.83] and enhanced vegetation index [RR=0.02; CI= 0.00, 1.08]. A trend was observed on usage of insecticide treated mosquito nets [POR=0.80; CI= 0.63, 1.03]. Conclusion: Socio-economic status (directly and indirectly) and education are important factors that influence malaria control. The study showed malaria as a disease of poverty with significant results in slum, type of place of residence as well as ownership of land. It is important that these factors be taken into consideration when planning malaria control programs in order to have effective programs. Direct and indirect effect modelling can also provide an alternative modelling technique that incorporates indirect effects that might not be of significance when modeled directly. This will help in improving malaria control. Enhanced vegetation index was also an important factor in malaria morbidity but precipitation and temperature suitability index were not significant factors.

No description available.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves 52-53). Also available on the Internet.

Introduction: Malaria is one of the leading causes of morbidity and mortality in developing countries, with sub-Saharan Africa carrying the highest per capita burden of this disease in the world. In line with the World Health Organisation's Global Strategy for Malaria Control, which emphasises the empowerment of local communities in health decision making and positive health seeking behaviour, the KwaZulu-Natal Department of Health developed two malaria health education materials. These health education materials have since never been systematically evaluated in terms of their content, the target groups reached, and the appropriateness of the health education messages provided. The aim of this project was thus to evaluate these existing malaria health education printed materials, including their efficacy in communicating appropriate, understandable and relevant messages at community level in the malarias region of Jozini in northern KwaZulu-Natal. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2007.

Nearly half of the world's population lives in tropical and temperate climates where they may be at risk from one or more vector borne diseases. Approximately 2.1 billion people, living in more than 100 countries are at risk from malaria. While the malaria situation has improved in some places, the overall prevalence in Africa, Asia and the Americas continues to deteriorate. This has led nations, institutions, organisations and agencies including the World Health Organisation to call for development of new and innovative approaches to its surveillance and control. In nature, maintenance of malaria transmission involves a complex interaction between the mosquito vector, the human host, the disease organism, and both the internal and external environments. An understanding of this complex relationship is the key to the prevention, control and eventual eradication of malaria. Malaria prevention and control programmes do not only have to be based on sound knowledge of how these factors interrelate, but also on an application of the political will of the concerned authorities. This study attempts to identify some determinants of malaria and to characterise it in epidemiological zones in Zambia. The study aims at contributing to the body of knowledge that would support implementation of an evidence-based national malaria programme. This study has come at an opportune time when there is renewed focus on malaria prevention and control globally. It is hoped that these aspects of the malaria programme in Zambia will not have to be rewritten in the foreseeable future, instead will be improved upon in order to progress to the delivery of quality assured malaria services as close to the family as possible based on the principles of community-health partnerships. The study is presented in a series of chapters; each developed as a follow up to the previous one and forms a bridge to the next. In this way, it enables the reader to build a relatively complete picture of the malaria situation in the country. However, some repetitions could not be avoided with regard to descriptions of study sites. In the chapters dealing with health systems and quantification of malaria risk, the country (Zambia) is taken as the study site. The remaining sections are based on specific sites, selected on the basis of their representing different aspects of the malaria situation in the country. Mapping of households and other referral points provided the basis upon which a Malaria Information System would in future be built. One of the two study sites was special because most of the previously conducted malaria research in Zambia has been conducted at this site. While the other was not only new in terms of malaria research, it also represented locations in the high rainfall zone in Zambia. The introductory chapter sets out the general principles of Geographical Information System (GIS), malariology, entomology, and health systems. The chapter reviews the current global burden of malaria including its implications for economic development of endemic subSaharan African countries, and discusses progress made in the light of drug and insecticide resistance and the changing global weather patterns. This section examines the position of the African continent in relation to the global malaria eradication era and the possible reasons why it was excluded from the global malaria eradication campaign of 1956-1969. It goes on to analyse new obstacles being faced in rejuvenating global interest in malaria programmes, starting with Primary Health Care through to the principles of Roll Back Malaria (RBM). It also emphasizes special Africa-specific initiatives related to malaria, such as the MARA/ARMA collaboration which (through the use of GIS) is providing a basis for evidence-based decision making. The fist chapter deals with the historical aspects of malaria control in Zambia. It traces how malaria was successfully controlled over a period of 46 years. It starts with a rural set up where copper mineral deposits were discovered. From there it traces the history of malaria control spanning almost eight decades to the present day. It outlines the major milestones in both the malaria programme and in the political history of the country; from a British protectorate , through Federation to the present day nation, Zambia. The chapter demonstrates how malaria can be controlled in an intense transmission situation, using a combination of simple and relatively cost-effective interventions. It also demonstrates that political will is an essential element to disease control. The second chapter examines the role of health systems in the delivery of quality, efficient and cost-effective services to the population. It examines the adequacy of health services in the light of time-limited Roll Back Malaria goals, according to the Abuja Declaration of 2000. This chapter analyses the capacity of the local health system to deliver on its health vision of taking quality assured health services (Malaria services) as close to the family as possible. Together, these goals are examined in terms of population accessing the facilities within 30 minutes' walking distance. Chapter three focuses on identifying factors that facilitate or hinder households acquiring and using Insecticide Treated Nets (ITNs) in the same locality. Specifically, distance of households to some reference points is examined. Also the effects of social, economic and educational status of heads of households are analysed. Together all parameters are analysed statistically to isolate the important reasons why some homes acquire ITNs while others do not. The study concludes with an analysis of the importance of ITN s in averting malaria among users. Some anecdotal evidence resented on the value of ITN s in reducing malaria incidence in the general population is presented. GIS is employed in the fourth chapter to produce a malaria endemicity risk map for the country. It employs population Plasmodjum faldparum infection rates. It proposes stratification and compares it with existing expert opinions and the climate-based Fuzzy Logic predictive model. The resultant malaria risk map is verified against existing maps and expert opinions. The chapter then discusses application for local decision making on policy and action. Chapter number five is dedicated to identifying and studying the bionomics of malaria vectors at two sites. It reviews existing literature on this subject, from 1929 to date. It identifies possible malaria vectors, their behaviour and ecology at two sites representing two extreme situations of malaria endemicity in the country. The combination of Anopheles vector densities and their reliance on temperature and rainfall are analysed and the implications discussed. The chapter also looks at possible ways forward for the country in the light of the paucity of information in this respect. P. faldparum infection rates are estimated together with their entomological inoculation rates and possible implications for malaria transmission potential. The final section (chapter six), highlights the major lessons and their implications for global goals and local health policies. It also outlines the way forward chapter by chapter. / Thesis (Ph.D.)-University of Natal, Durban, 2003.

Malaria is one of the most serious human infectious diseases. To date, the collection of studies suggest that the disease is determined by transmission dynamics and host age altogether with host genetics and immunological responses. The precise and direct contribution of parasite components to the activation of such immunological responses has not been fully unravelled. In addition to a role proposed for plasmodial GPI, different lines of evidence suggest that hemozoin (HZ) could also be a potential inflammatory agent. The role of HZ in the modulation of immune responses has remained a polemic subject, making it difficult to describe the contribution of this molecule in pathogenesis of malaria. However, our previous laboratory studies, suggest that HZ has a pro-inflammatory role. For this reason, our study was designed to further define the contribution of HZ to the pro-inflammatory events related to malaria immunopathology, and to identify the intracellular signals underlying the up-regulatory effects of HZ in the macrophage, one of the major sources of inflammatory mediators in malaria. In order to do that, we used a chemically characterized synthetic version of the native PfHZ, rcHZ; and evaluated its effects on macrophage nitric oxide (NO) production. Our first approach was to compare the effects of rcHZ with other morphologically different versions of this molecule (aHZ and scHZ) alone or in combination with IFN-gamma on macrophage NO production. In a second approach, we evaluated if the presence of serum proteins plays a role in the increased IFN-gamma induced-NO production by rcHZ. In the third part of our study, we explored if rcHZ is able to increase NO production by macrophages when incubated in combination with a molecule from another pathogen, such as gram-negative bacteria lipopolysaccaride (LPS). The present study is a functional study that uses a synthetic and morphologically identical version of the native PfHZ. Our results suggests that intrinsic physical characteristics, such as shape and size; presence of host serum proteins, and presence of other pathogenic molecules, are important determinants for the macrophage response to HZ in the context of NO production. Besides, it describes part of the signaling pathways that are involved, which may contribute in the future, not only to understand mechanisms of regulation; but also, to find new therapeutic targets against malaria.

Typescript. / Thesis (Ph. D.)--University of Hawaii at Manoa, 1990. / Includes bibliographical references (leaves 122-133) / Microfiche. / xvi, 133 leaves, bound ill. 29 cm