Thesis (Dr.P.H.)--Boston University / The recently classified neglected tropical diseases (NTD), -- onchocerciasis, lymphatic filariasis, schistosomiasis, and soil-transmitted helminthiasis -- are all coendemic in Nigeria. The World Health Organization recommended strategy for addressing these diseases is preventive chemotherapy through annual mass drug administration (MDA) with ivermectin, albendazole, and praziquantel. Integrated delivery of these medicines has become the de facto strategy advocated for in the literature as a means of reducing costs through shared resources. Little empirical evidence, however, exists to support this. This paper explores these diseases and the concept of integration in the context of the global strategies for their control. A literature review was conducted using PubMed to identify articles published containing any of the disease names and costs. Of the 2,028 articles returned, only 14 published between 1998 and 2011 met the criteria for review. All costs were adjusted for inflation. Overall, the mean cost of MDA by any means was 0.83 cents. No data comparing separate MDA to integrated MDA were found. To examine this, a model was created comparing MDA programs with similar distribution strategies and targeting similar diseases. Data from separate articles presenting stand alone MDA were combined to give a mean cost of 0.42 cents to deliver two medicines in two rounds. This was compared with articles showing integrated MDA, which gave a mean cost of 0.25 cents to deliver two medicines in a single round. This suggests a cost savings of 40 percent. To verify this, data from a NTD program in Nigeria that transitioned to integrated MDA was examined in detail. In 2008, eight districts received a single round of ivermectin with albendazole followed at least 1 week later by a single round of praziquantel to school-aged children. The following year, a single round of all three drugs was co-administered. The number of treated individuals was essentially unchanged during both years (1,301,864 in 2008 and 1,297,509 in 2009). The total programmatic costs for the MDA, not including drug and overhead costs, reduced by 41% from $123,624 to $72,870, similar to savings seen in the literature review. Cost savings were attributed largely to transportation and personnel costs. Integrated delivery of medicines is recommended for mature programs targeting these diseases.

Leptospirosis, a zoonotic disease caused by pathogenic spirochete bacteria (family Leptospiraceae, genus Leptospira), is endemic in developing tropical regions of the world. It occurs in epidemics and is endemic in Ecuador where environmental conditions are ideal for maintenance. The role of soil as a long term reservoir has been previously been documented. Geographic Information System (GIS) and Remote Sensing (RS) technology was used in our study to further explore the role of soil as an environmental reservoir and its potential use as a static risk indicator for disease. Red, Green, Blue (RGB) spectral band data from known leptospire positive soil sites were extracted from high resolution satellite images and used to construct the first ever remotely dependent soil-based model. The soil co-variates failed to demonstrate statistical significance; however, elevation was found to be statistically significant. The soil type most associated with soil samples where leptospire DNA was detected using real-time PCR analysis was cambisol, a soil type with a common distribution in Ecuador and Africa. This exploratory analysis presented a novel idea of combining environmental microbiological sampling and GIS/RS technology to better examine static risk indicators such as soil. Further analysis is warranted based on spatial relationships noted.

Neglected Tropical Diseases (NTDs) are both causes and manifestations of poverty in developing countries. Recent advocacy efforts have increased the profile of NTDs, and led to bold new control and elimination targets set for 2020 by the World Health Organisation. However there are multifaceted challenges in effectively implementing NTD interventions in resource-poor contexts that need to be understood and engaged. While there is a growing call by researchers and international agencies for a science of global health delivery to understand these complexities, the exact nature of this science remains contested. This thesis contributes to these debates by advancing a critical social science perspective on the factors that mediate intervention effectiveness for NTD control. Grounded in a social constructivist approach using mixed methods, it critiques prevailing orthodoxies by unpacking the nature, processes and outcomes of three large-scale NTD prevention programmes in Eastern Africa. Focused on different diseases, these case studies represent different types of intervention approaches: top-down, participatory and public-private partnership. The thesis traces the social, technical and environmental processes that mediate the delivery, adoption and use of particular health technologies, such as pit latrines, insecticides and vaccination. Together, these case studies reveal surprisingly similar reasons for why many interventions do not perform according to expectations. Despite new approaches that claim to overcome stereotypical challenges of top-down planning, narrow technocratic perspectives continue to play a defining role in maintaining disjunctions between global aspirations, local realities and intervention outcomes. New perspectives and changes in orientation are needed that emphasise flexibility, learning and adaptability to local contexts. Towards this end, the thesis outlines a conceptual framework based on a comparative analysis of the case studies that highlights five interrelated domains where effectiveness is determined: geographical/livelihood variation, local agency, incentives, the socio-materiality of technology and planning/governance. I argue that addressing the shortcomings of contemporary interventions requires that programme planners actively engage these domains by seeking to “order complexity.” Greater integration of social science perspectives into the management of NTD programmes would provide significant benefit. In these ways, the thesis contributes to wider debates about the nature of global health interventions and the influence of local contexts in mediating efforts to improve the health and wellbeing of the world’s poor and marginalised.

BACKGROUND: Chagas disease, a parasitic infection caused by Trypanosoma cruzi, is a neglected disease endemic to Latin America. Currently, approximately 6–7 million people worldwide are infected. Although Chagas disease is not considered endemic to the United States (US), official estimates put the number of cases at about 300,000 people. However, screening for Chagas disease is not common in the US. This project assessed the barriers, challenges, and opportunities to implementing screening for Chagas disease in primary care settings. METHODS: This project consisted of: 1) a literature review comparing and contrasting Chagas disease screening programs in endemic and non-endemic countries, and 2) semi-structured individual and group interviews with 43 healthcare providers (HCPs) who care for patients at-risk for Chagas disease. Interviews included questions around feasibility of implementing Chagas disease screening in their professional settings and probed on preferences for professional education such as format, length, and mode. Interviews were carried out between April 2021 and January 2022. RESULTS: According to the literature review, no single program for Chagas disease screening works perfectly. However, analyzing both endemic and non-endemic country programs revealed successful components that could be applied to the US context. From the interviews, the majority of participants reported knowing little about Chagas disease, matching the current literature. Most HCPs interviewed were interested in incorporating screening for Chagas disease into their practice but had some concerns. For example, HCPs are already required to screen for several diseases so Chagas disease screening would need to be incorporated into existing workflows. Finally, many HCPs reported that official guidelines from the Centers for Disease Control and Prevention or professional organizations would be enough for them to begin screening. The results informed the creation of a handbook for implementing Chagas disease screening. CONCLUSION: There are many barriers and challenges to implementing routine screening for Chagas disease in primary care settings in the US. However, there is also interest among HCPs in learning more and addressing the gap in screening. Advocacy is also needed to address the lack of national and professional guidelines around screening for Chagas disease.

African trypanosomes are protozoan parasites that cause African trypanosomiasis, diseases that affect humans and their livestock. Not only has trypanosomiasis had an overwhelming effect on the development of tropical Africa in the past, but it also constitutes one of the most significant present economic problems of the continent. Trypanosomes alternate between a mammalian host and a tsetse vector using a complex life cycle. In the mammalian host the trypanosomes live as bloodstream forms (BSFs) that are so proficient at antigenic variation, and thus host immune system evasion, that no suitable vaccine candidates have yet been identified. In contrast, the lifecycle stages that exist in the tsetse vector do not undergo antigenic variation. This potentially makes the vector-occupying trypanosomes much better targets for control if strategies can be devised to disrupt their lifecycle in the vector or to interfere with their transmission to mammalian hosts. The primary impediment to developing strategies for disruption of trypanosome life cycles in tsetse is a lack of understanding of the molecular basis of trypanosome-tsetse interactions. Although several major surface molecules have been identified on insect form trypanosomes, these have not been well studied due to a lack of appropriate antibody probes and to the difficulty in obtaining sufficient quantities of the different parasite life cycle stages required for such molecular studies. My thesis research was focused on developing and using monoclonal antibody probes for analysis of expression of major surface molecules of Trypanosoma congolense, a serious pathogen of cattle in Africa. I used this species of trypanosome since in addition to being a socioeconomically important parasite, all four of its major life cycle stages can be grown in vitro in amounts sufficient for immunochemical analysis. I successfully derived and characterized monoclonal antibodies that were useful for detecting the three major surface proteins of T. congolense insect forms: glutamic acid/alanine rich protein (GARP), the T. congolense heptapeptide repeat protein (TcHRP) and congolense epimastogote specific protein (CESP). Selected monoclonal antibody probes were then employed for expression analysis of these molecules throughout the parasite life cycle using in vitro grown trypanosomes and parasites taken directly from infected tsetse. In addition, I determined the peptide epitopes for two of my GARP-specific monoclonal antibodies and in collaboration with Dr. Martin Boulanger and Jeremy Mason was able to localize the epitopes on a high resolution three-dimensional structure obtained by X-ray crystallography. This allowed us to derive a model that describes the orientation of GARP in the trypanosome surface membrane and explains the possible structure-function relationships involved in replacement of the bloodstream form variant surface glycoprotein (VSG) by GARP as trypanosomes differentiate in the tsetse vector after a bloodmeal.

Carrion’s disease is a neglected tropical disease caused by Bartonella bacilliformis, a vector-borne pathogen restricted to the Andean valleys of Peru, Ecuador and Colombia. Carrion’s disease is a biphasic illness; in the acute phase the case-fatality rate can be as high as 88 %, related to high parasitemia, arriving to almost all erythrocytes, and secondary bacterial infections close related with the development of transient immunosuppression in the earlier illness phases. In addition, there are an undefined number of asymptomatic carriers that are reservoirs of the etiological agent of Carrion’s disease in endemic areas, they make take into account due to they are the perpetuators of this disease. The actual scenario of Carrion’s disease, in which the illness is arriving to new areas, due to the expansion of the vector’s distribution, suggests that now may be a crucial time to design a strategy focusing on its elimination.

This dissertation contrasts Hong Kong’s and the International Settlement’s management of malaria and of leprosy from the 1880s through the 1940s. This dissertation has two main objectives. Firstly it examines the historical management of malaria and leprosy within specific geo-political contexts. By focusing on British possessions in coastal China, this project explores the production of colonial medical knowledge within a transnational context, presents new and original analyses of the local history of the disease, and bridges the historiography of the British Empire and that of modern China. Secondly this dissertation contrasts Hong Kong’s and the International Settlement’s management of each of these two diseases. By focusing specifically on these two British possessions in coastal China, this project provides insights into the Imperial conceptualisation and management of Chinese bodies and Chinese environments, sheds light on broader historiographical debates regarding the role of colonial medicine, and complicates modern debates about the nature of colonialism in China.

Female genital schistosomiasis (FGS) is a chronic manifestation of schistosomiasis, a waterborne parasitic infection, and is estimated to impact 56 million women predominantly in Sub-Saharan Africa. Currently, there is scarce literature on FGS and related health-seeking behaviour (HSB) among at-risk women. The objective of this mixed-method study is to understand the socio-cultural determinants of HSB and the health information trust networks for women at-risk of FGS in Ghana. A cross-sectional survey and twelve focus group discussions (FGDs) were conducted in the North Tongu and Weija Districts of Ghana. A total of 863 cross-sectional surveys and 12 FGDs were administered in both districts. There was an overall lack of awareness of FGS among adult women (38.9%). Only 48.8% of women reported HSB from the 86 women who choose to talk about their FGS-related symptoms. HSB was significantly associated with monthly steady income (p-value: 0.036) and level of education (p-value: 0.15,0.27), when controlling for age group and source of trusted health information. Some of the determining themes for HSB included: environmental and systemic context, shared norms, and apprehensions. Active and passive health information-seeking behaviour also emerged through the FGDs. Taking a mixed-method approach allowed for the appraisal of both methodologies and provided validity to the results. The lack of awareness of FGS indicates the need for tailored health information campaigns in endemic communities. More research is required on the FGS diagnostic and treatment capabilities of health facilities to understand their impact on HSB of women. This investigation finds that social, environmental, and cultural determinants are involved in the HSB of women at-risk for FGS, in North Tongu and Weija.

No description available.

Les kinétoplastidés sont des protozoaires flagellés responsables de maladies tropicales négligées mortelles telles que la leishmaniose viscérale (L. donovani et L. infantum) ou la trypanosomiase humaine africaine (T. brucei), pour lesquelles les traitements disponibles sont très limités. Depuis quelques années, on observe un regain d'intérêt pour le développement de nitrohétérocycles aromatiques anti-infectieux tels que le delamanide et le féxinidazole. De récentes études indiquent que l'activité anti-kinétoplastidés de ces dérivés repose sur leur bioactivation sélective par des nitroréductases parasitaires, conduisant à la formation de métabolites réduits électrophiles, fortement cytotoxiques. Suite à des études préliminaires réalisées dans notre équipe en série 8-nitroquinoléin-2(1H)-one, ces travaux de thèse portent sur la synthèse et l'étude in vitro de l'activité antiparasitaire de 80 dérivés notamment fonctionnalisés en positions 3 et 6 du pharmacophore par divers motifs, notamment via la mise au point de réactions d'halogénation sélective et de couplages pallado-catalysés. Ainsi, 5 nouvelles molécules hits (4 anti-kinétoplastidés et 1 sélective de T. brucei) ont été identifiées (0,01 µM ≤ CI50 ≤ 7 µM et 13 < IS < 1500), trois d'entre-elles étant des substrats sélectifs des nitroréductases parasitaires de type I. Afin de préciser les relations structure-activité, une étude des potentiels de réduction a également été menée. Des études physico-chimiques (solubilité, test de perméabilité PAMPA) et pharmacocinétiques in vitro (stabilité microsomale et fixation à l'albumine humaine) sont venues compléter ce travail. Enfin, des évaluations de la mutagénicité et de la génotoxicité de ces hits sur des cellules procaryotes et humaines ont été conduites, dans le but de statuer sur leur potentiel pharmaceutique antiparasitaire humain et vétérinaire. / Kinetoplastids are flagellated protozoan parasites responsible for lethal neglected tropical diseases, such as visceral leishmaniasis (L. donovani and L. infantum) or sleeping sickness (T. brucei brucei), for which very few drugs are available. Nowadays, nitroheterocyclic compounds present a renewed interest as anti-infective agents, as illustrated by the development of fexinidazole and delamanid. Some recent studies demonstrated that the antikinetoplastid activity of these derivatives involves their selective bioactivation by parasitic nitroreductases, leading to the formation of electrophilic reduced metabolites, highly cytotoxic. Based on preliminary studies conducted in our team in 8-nitroquinolin-2(1H)-one series, this PhD work is about the synthesis and in vitro antiparasitic study of 80 derivatives mainly functionalized at positions 3 and 6 of the pharmacophore by various substituents, especially via the optimization of selective halogenation and pallado-catalyzed cross coupling reactions. Thereby, 5 new hit compounds (4 antikinetoplastid and 1 selective of T. brucei) were identified (0.01 µM ≤ IC50 ≤ 7 µM and 13 < SI < 1500), three of them being selective substrates of type I parasitic nitroreductases. In order to refine the structure-activity relationship studies, an analysis of reduction potentials was also conducted. In vitro physicochemical (solubility, PAMPA permeability assay) and pharmacokinetic (microsomal stability and human albumin binding) experiments completed this work. Finally, the mutagenicity and genotoxicity evaluations of these new hit compounds toward prokaryotic and human cells were realized, in order to assess their human and veterinary antiparasitic pharmaceutical potential.