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Countries on the African continent have varying capacities to regulate medical products, although all 54 countries, except one, have a regulatory authority or department within the ministry of health responsible for the regulation of medicines. These challenges in capacity have led to protracted timelines delaying access to quality assured medicines as well as the problem of substandard and falsified medicines. To mitigate these challenges, regulatory harmonisation and collaboration through the pooling of expertise and resources of the regulatory authorities in the regional economic communities (RECs) has been implemented through the African Medicines Registration Harmonisation Initiative (AMRH), established in 2009. One such collaboration is the Southern African Development Community work sharing initiative, ZaZiBoNa. The aim of this research programme was to evaluate the regulatory review system in the ZaZiBoNa initiative with a view to enhancing the review process and ensuring patients' access to medicines. This was achieved through a review of the history of the ZaZiBoNa initiative focusing on what had been realised in its eight years of operation and what still needed to be achieved. The registration process of the agency responsible for coordinating ZaZiBoNa, MCAZ, was evaluated and compared with mature regulatory authorities of comparable size in order to benchmark best practices. The regulatory review processes of the individual participating countries that contribute to the ZaZiBoNa reviews and GMP inspections were evaluated and strategies for alignment proposed. Lastly, the applicants' and regulatory authorities' views on the effectiveness and efficiency of the ZaZiBoNa initiative were evaluated. A mixed methods research design, incorporating both quantitative and qualitative methods was selected. A purposive sampling technique was used for data collection using techniques such as narrative literature review, self-administered questionnaires and semi-structured interviews. The results of the evaluation of the MCAZ indicated that the agency successfully implemented the three review models and was largely able to achieve comparable timelines to mature regulatory agencies by using reliance. However, the results also showed that in its current capacity the MCAZ was not able to achieve its target timelines due to issues related to Covid-19 pandemic. The results of the evaluation and comparison of the regulatory review processes of the individual participating countries showed that although the processes were similar, there was great variation among the countries in the target timelines set for key milestones and the frequency of expert committee meetings which contributed to the differences in the implementation of ZaZiBoNa recommendations by member countries. The results of the evaluation of the ZaZiBoNa initiative by regulatory authorities and pharmaceutical companies documented the successes and challenges of this initiative as well as measures that might improve its effectiveness and efficiency. The benefits and challenges to regulators, applicants and patients were also identified. Overall, the results of these studies culminated in the development of a proposed improved model for the ZaZiBoNa initiative. This research programme has provided insight into the regulatory review processes of low-and-middle income countries in the SADC region and how these impact the ZaZiBoNa initiative. The evaluation of the initiative by regulatory agencies and pharmaceutical industry provides valuable stakeholder feedback which if implemented will enhance the review process and patients' access to medicines. This programme of research has presented, in a vital piece of work, key recommendations for the improvement of the regulatory review system in ZaZiBoNa including a proposed improved new model.

This PhD research focuses on understanding a maternal pregnancy condition known as pre-eclampsia. This condition contributes to around 14 % of the global burden of maternal mortality and fivefold of perinatal mortality in developing countries. Genetic, environmental, nutritional and socioeconomic factors are thought to disproportionately affect the burden of pre-eclampsia in low and middle-income countries (LMIC). The first chapter gives an overview; it introduces pre-eclampsia and outlines its contribution to the burden of maternal and infant mortality and morbidity. It summarises all chapters in this thesis. The second chapter gives the background of the literature review. This chapter describes pre-eclampsia in the context of hypertensive disorders of pregnancy. It then explains some of the risk factors of pre-eclampsia, the natural history of the disease and the health system response: current modalities in screening, the evolution of the definition pre-eclampsia, diagnosis, prevention and management. The third chapter describes the scoping study, which aims at summarising explored risk factors in Africa, to identify potential gaps and the feasibility of conducting a systematic review. Its results showed that there were twenty studies done in Africa that had explored relatively few risk factors. These studies had methodological limitations of size and rigour, hence produced conflicting and inconclusive associations between pre-eclampsia outcome and most explored risk factors, including malaria infection. They also showed a gap in the literature regarding models built by risk factors that attempted to classify pre-eclampsia outcome in African populations. The fourth chapter describes the systematic review that explores the relationship between malaria infection and gestational hypertension (GH) with proteinuria (pre-eclampsia) or without. It considers two pathways that malaria possibly exert its effect on causing gestational hypertension. One pathway being through a dysfunctional placenta and the other pathway is by endothelial inflammation of blood vessels from malaria toxins. The result of the meta-analysis was a pooled odds ratio (OR) of 2.6, 95 % confidence interval (CI) 1.5 to 4.5. The odds of pre-eclampsia among pregnant women with malaria infection were 2.6 times than pregnant women without malaria infection. The fifth chapter describes the analysis of secondary data from Tanzania. This data analysis has four objectives. The sixth chapter describes the results of the four objectives, while chapter Seven presents the discussions of the four objectives. This data analysis used data from two sources: a hospital maternity register from northern Tanzania and a clinical trial in Dar es Salaam, Tanzania. The data analysis had four objectives; objective one determined the incidence pre-eclampsia to be 1.9 %, 95 % CI 1.3 % to 2.2 % in Dar es Salaam city, Tanzania. Objective two describes the sociodemographic characteristics of women with pre-eclampsia compared with those without pre-eclampsia in northern Tanzania population. Preeclampsia was more frequent among women with age above 35 years, single and tertiary level education. Objective three aimed to identify biomedical risk factors for pre-eclampsia among women in northern Tanzania. Then, I used these identified risk factors to build prediction models for pre-eclampsia. I later assessed the ability of these models to classify women with and without pre-eclampsia. Maternal age, weight before pregnancy, contraceptive intrauterine device (IUD) use, a diagnosis of malaria, diagnosis of infections, history of hypertension and HIV treatment were statistically significant predictors in some of my models. My final models in predicting pre-eclampsia in all deliveries, term and preterm delivery subgroups produced an area under the curve of 69.4 %, 71.2 % and 66.9 % respectively. The points of maximum sensitivity and specificity produced sensitivity values of 65 %, 65 % and 59 % respectively, while also producing specificity values of 63 %, 65 % and 66 % respectively. The risk factors and the prediction models were developed on a hospital-based register where the incidence of pre-eclampsia was 3.5%. Since hospital estimates tend to overestimate the incidence compared to population survey, the results of my prediction models will differ in women populations with a high risk of pre-eclampsia. The fourth objective describes the pregnancy outcome of women with preeclampsia compared to women without pre-eclampsia. The results showed there were more stillbirths among women with pre-eclampsia. The odds of stillbirth were 4.8 (95 % CI 3.7 – 6.3) times among women with preeclampsia than women without pre-eclampsia in all deliveries. Upon stratifying by term and preterm deliveries the odds were 2.6 (95 % CI 1.6 – 4.3) and 2.9 (95 % CI 2.0 – 4.1) respectively. The surviving offspring have worse developmental indicators compared to their counterparts in terms of low a Apgar score at 1-minute, low birth weight, small head circumference and short birth length. The odds of a low Apgar score (0 – 3) baby was 4.3 times (95 % CI 3.4 - 5.4) among pre-eclampsia women in all deliveries compared to normal Apgar score (4 – 10) babies. The association was maintained in the subgroups of term and preterm delivery (OR = 2.3, 95 % CI 1.5 – 3.5 and 2.8, 95 % CI 2.0 - 3.9 respectively). Chapter Eight covers the conclusion and recommendations of this thesis, which are: (i) Few studies that explored risk factors in Africa, more studies are needed to resolve conflicting and inconclusive findings from these studies. (ii) Malaria infection is associated with pre-eclampsia and gestational hypertension in malaria endemic regions. Malaria control should be intensified among pregnant women and further studies should explore the causal mechanisms. (iii) The incidence of pre-eclampsia should be tracked to observe changes in its trends in the evolving urban populations of LMIC. (iv) Affordable and feasible prediction models for pre-eclampsia should be developed and assessed for performance to enable identification and provision of prevention services on women with a high risk of developing preeclampsia. (v) Women with pre-eclampsia should receive appropriate treatment to mitigate the negative impact on their pregnancy outcome.

The work in this dissertation focused on delivering a nipple shield drug delivery device that is ready for clinical trials with the hope of making a positive impact on the health of neonates, infants, and paediatrics five and younger worldwide. In order to do that, the tools and techniques necessary to understand the hydrodynamics of the system needed to be developed, and then used, to fully grasp the impact of the number of effluent holes, the size and positioning of those effluent holes, and the shape and form factor of the nipple shield and any potential internal geometry contained within. Next, it was essential to understand the landscape of potential use cases for the device, including the populations of neonates, infants and paediatrics five and younger worldwide, but particularly in low- and middle-income countries, where the impact and burden of disease and mortality is highest. This involved collecting and analyzing data on such infant mortality and incidence of disease globally, and then determining and compiling a list of the highest impact medications that could be used within the nipple shield drug delivery device. Finally, it was essential to test real-world impact of the device, so three of the highest impact medications were selected for testing. Tablet dissolution and disintegration was studied using NMR spectroscopy, and a breastfeeding mimic simulation was created to test delivery of the three designated medications within the temporal and volumetric constraints of a single average breastfeeding session. Conclusions based on the results of each set of experiments were drawn, leading to an analysis of the evaluated nipple shield designs and features in preparation for clinical trials.

Abstract: Background and Rationale: Obstetric ultrasounds have become a routine practice in pregnancy management globally. Evidence, however, suggests that while obstetric scans in high-income countries are associated with positive experiences to mothers, the technology may not be having similar positive impact in low-and middle- income countries. Available evidence shows the detrimental impact of obstetric ultrasounds on fetal sex identification and consequent abortions of female fetuses in India. Studies from Vietnam, Tanzania and Uganda suggest some women have started perceiving ultrasound scans as the entirety of antenatal care. Other studies suggest mothers are overestimating the diagnostic abilities of ultrasound technology to the point where they are not receiving the appropriate care. The concerning nature of the current evidence available in the literature indicates the need for a detailed, qualitative investigation that examines both women and providers’ understandings and practices of obstetric ultrasound use. Objective: To explore the impact of ultrasound technology on both the biomedical, and lay, cultural management of pregnancy in Rural Pakistan. Method: Data were drawn from two qualitative research projects conducted in Pakistan between 2009 and 2015. The first study, entitled “Are community midwives addressing the inequities in access to skilled birth attendance in Pakistan? Gender, class, and social exclusion”, used a mixed methods approach - an institutional ethnography and a cross-sectional survey to explore whether a new cadre of midwives were improving access to skilled maternity care for poor and socially excluded women in two districts – Layyah and Jhelum in Punjab. Qualitative data were collected using in-depth interviews with 83 health care providers and 139 community members, and 180 formal and informal observations of patient-provider interactions in health facilities. The survey interviewed 1457 women who had given birth in the two years prior. The second project, “Addressing disparities in maternal health care in Pakistan: gender, class and exclusion” is a critical ethnography of maternal health services in a village in Chakwal, Punjab. Data were generated over the course of 10-months using 134 observations, 94 in-depth interviews, and 11 focus group discussions. Transcripts were selected if they contained the term “ultrasound” and related terms, e.g., “scan”. Qualitative data were organized using Quirkos software and analyzed through thematic analysis. The survey data were analysed using STATA 14. Results: Our findings revealed that an obstetric ultrasound was a common procedure for pregnant women in rural Pakistan as part of their pregnancy management. In fact, the data suggests women perceived the scan as synonymous with antenatal care and assumed it was an integral part of their antenatal visit, irrespective of any stated medical indication. It was sometimes the only care they sought during pregnancy, with 80% reporting a scan while only 49% reported receiving a blood test, blood pressure measurement or a urinalysis. A common reason underlying these patterns of use was the mothers’ strong trust in ultrasound technology’s abilities to diagnose ill-health broadly and believing it alone would ensure a healthy pregnancy and healthy baby. So strong was this trust in the powers of ultrasound technology, that mothers expected delivery dates and fetal sex reports to be precise. Any deviations were unacceptable. Wider societal level forces – a highly privatized health care sector and strong son-preference - are driving a mutually reinforcing supplydemand cycle of potentially unnecessary scans during a healthy pregnancy. Researchers observed the providers, mostly in the private sector implementing different strategies to market their ultrasound services including prioritizing ultrasound scans during appointments over other elements of antenatal care, encouraging monthly scans, and offering special discounts. A desire to ensure birth of a son is driving pregnant women’s demand for repeat scans in the hope of either expecting a different ‘diagnosis’ if a female fetus is suspected or repeatedly confirming a male fetus. Conclusions: Obstetric ultrasound has become the preferred method of surveillance to women during healthy pregnancies to the extent that its use is understood as synonymous and equivalent to antenatal care. It appears that both providers, particularly those in the profit-driven private sector, and patients have mutually reinforced the demand for un-necessary ultrasound scans during pregnancy. Given the limited role of obstetric ultrasound in pregnancy surveillance, it is important to ensure that the technology does not replace routine elements of antenatal care. While a culture that prizes sons is not going to be easily amenable to change, health policy makers can address the market forces underlying the for-profit private health care sector to the limit unscrupulous use of ultrasound technology. Measures must be taken to ensure that health care provision for women during pregnancy is driven not by profit, but by medical recommendation.

Background: Poor access to and uptake of mental health interventions by adults and even adolescents has been highlighted in Nigeria and other low- and middle-income countries (LMICs). The literature indicates that less than 10% of Nigerians including the adolescent population access mental health intervention (Federal Ministry of Health (FMoH), 2013). The dearth of human and infrastructural resources among other resources have been highlighted as the predisposing factors to poor access. For instance, published findings have revealed that there are only eight psychiatric hospitals and 36 mental health units (in the general hospitals located across the 36 states of the country) that provide mental health interventions to over 214 million Nigerians (World Health Organisation, 2014b). This study was undertaken to develop a school based mental health programme (SBMHP) that will help to improve access to and uptake of mental health interventions by the adolescent population. Methods: A multiphase qualitative case study design was adopted to undertake this study. In Phase I, the researcher undertook a systematic literature review to identify the modules of SBMHPs that have been implemented in LMICs. A total of 11 articles were reviewed to elicit seven modules that were used as baseline data to guide phase II data collection. Phase II was done to generate culturally sensitive modules from participants drawn from diverse disciplines. 10 modules were generated from the 26 key informant interviews that were conducted. In Phase III, the researcher carried out triangulation of the findings from Phases II and III, to develop a hybrid programme. 10 modules were generated from this process. Phase IV involved the conduct of focus group discussions (FGD) with parents and teachers to confirm the applicability of the modules of the proposed hybrid programme and to subsequently modify the programme. A total of nine modules and three facilitators were generated from this Phase. 36 focus group discussants were involved in this Phase. Finally in Phase V, the researcher undertook member checking of the findings of the study to ensure rigour or trustworthiness of the study. The data were analysed using the five phases of analysis highlighted by Blanche et al. (2006). Results: The study findings were documented in four chapters. A total of seven modules, namely, an introduction module, a communication and relationship module, a psychoeducation module, a cognitive skills module, a behavioural skills module, a module on establishing social networks for recovery and help seeking behavioural activities, and a conclusion module were revealed from Phase I (Chapter Three). Five themes were generated from Phase II (Chapter Four). These themes were knowledge of mental health; adolescence and mental health; mental health institutions; access to mental health interventions; and the range of mental health interventions. In Chapter Five (Phase III), ten modules were reported as findings. The modules were as follows: introduction; life skills; social support; behavioural skills; mental health literacy; early diagnosis, treatment, and referral; creating and maintaining a healthy school environment; developing vocational skills; an overarching element and conclusion. Finally, nine modules and three facilitators were reported in Chapter Six (Phase IV). The modules include introduction; mental health literacy; life skills; behavioural skills; vocational skills; early diagnosis, treatment, and referral; social support; religious and traditional support; and conclusion. The facilitators included healthy environment; advocacy on resources (both human and capital); and training of teachers, parents, and other stakeholders. Other findings included the cultural sensitivity of the modules, recognising that spiritual and religious healers are part of the first line of contact, a concern with mental health problems in primary school children, and factors influencing the help seeking behaviour of parents and their children. Conclusion: This is the first study to generate culturally sensitive modules in LMICs. The findings of this study identified implications for policy development and deployment, the practice of child and adolescent mental health in schools and future studies. Some of the implications were as follows: advocacy for the inclusion of the contents of the developed school-based programme in the school curriculum; the development of some basic child and adolescent documents that will guide provision of mental health interventions in Plateau State; development of a protocol that can be used to provide mental health first aid in schools; and if applicable early identification and treatment. This study also produced a baseline programme that can be used to provide a myriad of interventions (mental health promotion, prevention, and early diagnosis and treatment) in schools in Plateau State, Nigeria and possibly other LMICs.

Globally, drowning is the second largest cause of death by injury in children aged 1-14 years old. Risk factors for child drowning include poor supervision, lower socioeconomic status, poor swimming and rescue skills, and the proximity of open water near homes. These are more prevalent in low-and middle-income countries(LMICs). The WHO has developed recommended interventions for drowning prevention in rural LMIC contexts, such as the provision of supervised childcare to prevent access to nearby water bodies. This thesis explores the process of developing and evaluating drowning prevention programs in two high-risk LMIC regions: the Sundarbans in India and the Barishal Division in Bangladesh. As no previous research on drowning burden and prevention has been conducted in India, the main aims were to: (1) Identify the burden of child drowning in the Sundarbans, and (2) identify implementation strategies for drowning prevention programs. Conversely, drowning prevention programs have been implemented in Bangladesh, but evaluation of their implementation remains. The Anchal program provides supervised childcare to younger children, while SwimSafe provides swim training to older children. The main aims in Bangladesh were to: (1) Understand implementation implications and best practices, and (2) understand the impact of gender norms on implementation. The findings from the Sundarbans mortality survey showed a significant burden of drowning, with a rate of 243.8/100 000 for 1-4-year-old children, and 38.8/100 000 for 5-9-year-old children. Common circumstances were the lack of effective adult supervision, no physical barriers against water, and proximity of open water to homes. Findings from the analysis of relevant government policy and interviews with community-based stakeholders identified three existing government programs that could be leveraged for the implementation of drowning interventions. In Bangladesh, the mixed-methods process evaluation of the Anchal program showed that while the program was acceptable in the community, geographical barriers to access, cultural beliefs and inadequate resources reduced attendance, limiting effectiveness. The gender analyses of both Anchal and SwimSafe programs revealed opportunities to ensure equitability. Fewer older girls enrolled in SwimSafe classes compared to boys due to cultural concerns. Female community-based staff found that employment in the programs improved social status, physical mobility and access to resources.

Abstract: Trauma registries are an anonymized, systematic, prospective data banks for trauma patients that may include details on demographics, injury details, hospital processes, and outcomes. They are an important component of trauma care systems and a tool for improving outcomes in trauma. Given the high rates of morbidity and mortality from trauma in low- and middle-income countries (LMICs), the implementation of trauma registries in LMICs is a growing area of interest; however, while many pilot trauma registries have been demonstrated to be feasible in LMICs, very few are sustainable in the long term. In this thesis, a trauma registry established in 2017 in Mbarara Regional Referral Hospital (MRRH), Uganda is examined. Since the establishment of this registry, data for over 3000 trauma patients has been collected, however, the registry faces questions of how to achieve long-term viability without the financial support of external partnerships. The aim of this thesis is therefore to evaluate several aspects of sustainability of trauma registries for low-income settings. First, the ethical importance of sustainability in global surgery was established through a scoping review on the literature on the ethics of global surgery. A grounded theory content analysis was completed to identify themes and gaps in the existing literature. Four major ethical domains in global surgery were identified: clinical care and delivery; education and exchange of trainees; research, monitoring, and evaluation; and engagement in collaborations and partnerships. While the literature on ethics in global surgery was sparse, mostly in the form of commentaries or editorials, and largely published by authors in high-income countries (HICs), the importance of including LMIC authors in the conversation on ethics in global surgery and the value of building sustainable collaborations and partnerships were key findings of this scoping review. Next, a literature review of considerations for the implementation of ethical and sustainable trauma registries in LMICs was completed. A number of practical challenges were identified for the development of trauma registries in LMICs and included funding sources, personnel requirements, technology access, and quality assurance mechanisms. Ethical considerations for trauma registry development were also identified, and included concerns of patient confidentiality, informed consent, and sustaining the registry. Strategies for these ethical and practical considerations for trauma registry development in LMICs are discussed, and opportunities for future research opportunities are explored. The widespread nature and accessibility of mobile phones in most low- and middle-income countries, including Uganda, makes the use of mobile phone technology in health a potential avenue for inexpensive health care innovation. A mobile application trauma registry was designed and implemented to minimize workload and contribute to sustainability of the registry. Healthcare workers involved in trauma then completed a validated questionnaire known as the Unified Theory of Acceptance and Use of Technology (UTAUT) for evaluating the usability of the mobile application trauma registry and predicting future use behaviours. Healthcare workers scored the mobile application highly, indicating a high potential for ongoing use. The UTAUT was also identified as a method for other trauma registries to predict future use and opportunities for sustainability. Finally, a potential means of financial self-sustainability for trauma registries in low-income countries was evaluated. In many public hospitals in low-income settings, government funding for patients seen is dependent on documentation of those patients. This study evaluated the improvements to patient documentation following the implementation of a trauma registry and concurrent patient registration system at MRRH. A significant improvement in patient documentation was found, with a 20-fold increase in trauma patients documented following the implementation of patient registration and a trauma registry. This more accurate documentation could then be used to apply for increased government funding for trauma patients and for sustaining the trauma registry in the long-term. The concurrent implementation of a patient registration system with a trauma registry therefore could be an avenue for financial viability for other trauma registries in low-income contexts. Taken together, these studies represent a compelling picture for the ethical imperative to develop sustainable trauma registries in LMICs and some of the strategies that may be undertaken to achieve this. By combining these techniques, we hope to achieve a sustainable, long-term trauma registry at MRRH that can serve as a model for other trauma registries in LMICs going forward.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with contemporary therapy resulting in a 90% survival in high-income countries (HIC). However, an estimated 89% of the world’s children live in low- and middle-income countries (LMIC) where survival is much lower. Lack of access to essential chemotherapy contributes significantly to the decreased survival rates for LMIC, and inaccurate forecasting of chemotherapy needed may lead to stockouts or oversupply. This chapter describes a simple forecasting system with population and patient-based multipliers for each drug used in the treatment of pediatric ALL, thus estimating the essential chemotherapy quantities needed for a single patient, facility, region, or country. We described a forecasting model for estimating essential chemotherapy in the treatment of childhood ALL to multipliers. Multipliers were obtained from a reference population of 10 million children evenly distributed (2.5 million each) across four age cohorts at 5-year intervals (0-4, 5-9, 10-14, and 15-19 years). The forecasting model and multipliers were applied to 171 countries with age-specific population data available in the United Nations 2017 World Populations Prospects. Results from the forecasting model and multipliers were compared to determine differences for each country and for countries with extreme population distributions across the pediatric age range. The multipliers produced results no greater than 15% of those obtained using the forecasting model. Multipliers allow healthcare providers, cancer centers, hospitals, countries, and drug manufacturers to accurately estimate the essential chemotherapy needs for a patient, facility, region, or country. This practical tool can be applied to other cancer diagnoses and treatment protocols.

The onset of Alzheimer’s Disease (AD) may begin up to 20 years before clinical symptoms are apparent. It is a challenge for clinicians to treat, as the best medical outcome is temporarily slowing the onset of the disease before it becomes ultimately fatal. Due to economic and social pressure AD places on the affected individual and their families, it is particularly burdensome to low-to-middle income countries (LMCIs). Thankfully, cutting-edge deep learning (DL) models are being developed to predict the diagnosis of AD before clinical symptoms manifest. These DL models most commonly use the biomarker fluorodeoxyglucose (FDG), although amyloid-PET (florbetapir) has also become prevalent. FDG is the more accessible and affordable biomarker, whereas, florbetapir detects the amyloid plaque that is theorized to be directly responsible for the neuronal death in AD and may be the better detector of the disease. To determine the most practical biomarker for LMICs, we utilized low-resolution datasets of FDG-PET and amyloid-PET provided by the Alzheimer’s Disease Neuroimaging Initiative to train two DL models with a 3D image classification framework. The FDG-PET and amyloid-PET models resulted in AUCs of 0.919 and 0.891 on their respective test sets. We conclude the difference of DL performance between the two biomarkers trained on low-resolution PET data is negligible. Thereby, as the modestly priced and universal biomarker, FDG-PET is the practical option for LMICs and other financially vulnerable communities for the prediction of a future AD diagnosis.

The World Health Organization acknowledges that single-use medical devices (SUDs) are commonly reprocessed and reused beyond their intended life to deliver patient care in low-resource settings. SUDs originally intended for use on one patient for one procedure are “reprocessed” in such cases, which involves cleaning, disinfection or sterilization, and functional testing before they are reused in hospitals. Studies have shown that reuse of SUDs in countries where reprocessing is unregulated can be safe if stringent standard operating procedures are followed. The broad objective of this thesis was to validate a reprocessing protocol for the bag-valve-mask (BVM), a single-use device commonly reused in low- and middle-income countries. This device is critical for supporting neonatal resuscitation in low- and middle-income countries, where neonatal mortality due to failure to establish breathing has a prevalence of roughly 19%. This was accomplished by documenting reprocessing practices in a tiered healthcare system in Tanzania and assessing cleaning markers and functional performance parameters for BVM exposed to a bleach-based reprocessing protocol under simulated worst-case conditions and by defining human factors affecting BVM reprocessing. Tanzanian hospital personnel interviews revealed variations in reprocessing practices and demonstrated a need for validated reprocessing protocols and screening methods for single-use devices. The bleach-based protocol was validated to meet disinfection targets established by the FDA, and its efficacy was unaffected by simulated worst-case conditions including high organic load, low hypochlorous acid presence (pH ~11), and prolonged drying of bioburden following simulated use. The BVM met performance targets even after multiple reprocessing cycles and simulated abrasive wear. Finally, the usability study defined human factors relevant to user compliance with the validated bleach-based protocol. This body of work ultimately provides a comprehensive framework for validating reprocessing protocols for single-use medical devices such as the BVM. The approaches outlined in this thesis support the safe reuse of medical devices through reprocessing validation using protocols that are suitable for clinical or laboratory settings.

Background: Globally, there are 10 million new cases of tuberculosis (TB) disease annually and 95% of cases occur in low- and middle-income countries (LMIC). More than 1 billion people use tobacco, and 80% of tobacco users reside in LMIC. Smoking approximately doubles the risk of TB disease and is associated with excess mortality during TB treatment. We aimed to estimate the proportion of annual incident TB cases and TB mortality attributable to tobacco smoking in high burden TB countries. Methods: To estimate population attributable fractions (PAF), we obtained country specific estimates of TB incidence and TB mortality rates from the WHO 2015 Global TB Report. Country specific smoking prevalence was estimated from WHO 2015 tobacco surveillance reports and the Tobacco Atlas. Risk ratios for the effect of smoking on TB incidence and TB mortality were obtained from previously published meta-analyses. Country specific PAF of smoking for TB disease were age and sex adjusted. Results: In high burden countries during 2014, an estimated 4.5 million adults developed TB disease and 163,000 people died from TB. An estimated 740 million adult smokers lived in those high burden countries in 2014. We estimated that tobacco smoking was attributable for 17.7% (95% confidence interval [CI] 8.6-21.9%) of TB cases and 15.0% (95% CI 1.9-31.6%) of TB mortality. Of the high burden countries, Russia had the highest proportion of smoking attributable TB disease (31.8%, 95% CI 16.0-37.8%) and death (28.1%, 95% CI 3.8-51.3%). India had the greatest absolute number of TB cases (233,000) and TB deaths (7,400) attributable to smoking. Men (30.5%, 95% CI 14.9%-36.9%) had a greater proportion of TB cases attributable to smoking than women (4.7%, 95% CI 1.9%-6.2%). Conclusion: In high-burden TB countries, nearly one-sixth of all TB cases and TB deaths were attributable to smoking. Our findings highlight the need for tobacco control in high TB burden regions and specifically among patients with TB. Reaching key populations and integrating smoking cessation efforts into TB programs will be essential to achieve global TB control goals.