While the molecular defect that cause sickle cell disease has well been established, the cause of vaso-occlusive crisis remains elusive and largely debated upon. Majority of studies have linked the painful episodes to polymerization of sickle hemoglobin following its deoxygenation. The variability of the disease symptoms among patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator of Hb F induction and a widely used treatment, has ameliorated the complication of SCD but it is only effective in 50% of the patients. Expression of Hb F lowers the content of Hb S in blood and hence reduces oxidative stress caused by Hb S denaturation. Sickle cell disease severity depends on several factors. Most importantly, the ability of red cell to sickle dominates all other determinants. While deoxygenation of sickle hemoglobin may be inevitable, the duration with which the red cell remains in the deoxygenated state can be manipulated. Deoxygenation is a transient process that when compared to the time taken to develop the long filaments of deoxyhemoglobin to causes severe sickling, the red cell would have been cycled back to the lungs and re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle cells would flow as fast as healthy erythrocytes, the detrimental impacts of sickling such as vaso-occlusive crisis, would not be a concern for this disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation through auto-oxidation, which imposes oxidative stress to the cells. The oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which subsequently impair their constitutive action against the tyrosine kinases. In the end, a net tyrosine phosphorylation state in the red cell membrane proteins, most notably the transmembrane protein band 3, succeeds. Band 3 tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage to the membrane thus engendering membrane destabilization. A destabilized erythrocyte sheds membrane fragments in form of microvesicles/microparticles and discharges free hemoglobin into the extra cellular matrix. In consequence, the microparticles power initiation of coagulation cascade through activation of thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is necessary for vasodilation and induces further oxidative stress within the microvasculature, and activates expression of adhesion receptors on the endothelium. Taken together, these events culminate in entrapment of red cells (not naming leucocytes and platelets) in the microvasculature, blockade of blood vessels and further damage of erythrocytes through prolonged deoxygenated state thus terminating in tissue injury, strokes, and organ damage, amid vaso-occlusive episodes which always require hospitalization and extensive medical care for survival. Band 3 tyrosine phosphorylation and membrane weakening is not unique just to SCD, but also a druggable target for malaria. Malaria, a disease that is touted as the evolutionary cause of sickle cell disease, surprisingly thrives through the same mechanism. Briefly, malaria parasite consumes hemoglobin for its DNA synthesis, and in the process generate reactive oxygen species from denatured hemoglobin that feeds into the oxidative stress which triggers band 3 tyrosine phosphorylation. In this case however, a destabilized membrane offers perfect conditions for merozoites’ (malaria daughter parasites) egress/exit out of the cell to begin infecting other red cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s death. Treatment of diseased cells with imatinib and other Syk inhibitors effectively reversed membrane weakening. A stabilized membrane not only survives longer in circulation to alleviate SCD symptoms but also traps and starves malaria parasite leading to termination of the parasitic infection. With band 3 tyrosine phosphorylation at center stage, this dissertation explores the above events in an effort to unveil a novel therapy for sickle cell and malaria diseases. First, the therapeutic strategy regarding SCD is discussed in detail beginning with non-transfused patients and ending in additional mechanistic study on inactivation of the principal erythrocyte’s protein tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial proof of concept on efficacy of imatinib in treatment of malaria as a monotherapy and its efficacy when used in a triple combination therapy with the standard of care treatment. Finally, I outline an alternative possible mechanism of action of quinine against malaria.

Health Management Information System (HMIS) in developing countries lags seriously behind as compared to the developed countries; and the existing HMIS in many countries is insufficient to support health management functions. The purpose of this study was to describe the implementation of Anti-retroviral Therapy (ART) pharmacy management information system in public health facilities. Quantitative, descriptive research was conducted at 38 public health facilities. The participants of the study were Pharmacists and Druggists those are working at ART Pharmacy. Data collection was done by using structure questionnaire. 76 respondents were recruited to participate in the study. The participants ages ranged from 26-50 years and all had more than 2 years’ work experience. The study indicated that even if there is a system at most health facilities their utilization of information technology (IT) for pharmacy practice were not appreciated. The findings indicated that the need for creating awareness among professionals in giving more skill oriented and also a formal in-service information technology related trainings for the professionals. To achieve better utilization of information technology at health care delivery system particularly pharmacy practice, government and stakeholder should consider capacity building activities through proper training and it should also viewed as a long term socio-cultural and technical development process. / Health Studies / M.A. (Public Health with specialization in Medical Informatics)

Few studies have assessed the optimum second line highly active anti-retroviral therapy (HAART) regimen in patients who had failed on the first-line HAART in resource-limited settings. This study aimed to compare the Protease inhibitor (PI)-based second line HAART regimens used in one clinic in Trinidad by comparing immunological, virological and clinical outcomes of patients on the different second line HAART regimens. The records of 35 treatment-experienced patients, over 21years of age and on PI-based regimens for at least six months, were analysed using SPSS version 20. The regimen containing TDF/FTC/AZT/LPV/r proved to produce superior outcomes compared to the other second line regimens. Due the small number of usable patients’ records, the findings cannot be generalised but indicate directions for future studies attempting to compare the treatment outcomes of different second line HAART regimens / Health Studies / M. A. (Public Health)

Indiana University-Purdue University Indianapolis (IUPUI) / Graft-versus-host disease (GVHD) remains the major complication after allogeneic hematopoietic stem cell transplantation (HSCT), resulting from immunological attack on target organs such as gastrointestinal (GI) tract, liver and skin from donor allogeneic T cells. The most common treatment for GVHD is immunosuppressive drugs such as corticosteroids, which may result in many side effects including the loss of the beneficial graft-versus-leukemia (GVL) effect and increased infection rates. However, GVHD-specific drugs have yet to be implemented. Here we show that by targeting on a novel pathogenic CD4+ T cell subpopulation that our lab previously found in patients with GI GVHD, we can develop new avenues to treat GVHD. This novel population is characterized as CD146+CCR5+ T cells, co-expressing IL-17A and IFN-γ. We found that the inducible T-cell costimulator (ICOS), which has been reported to be important for human Th17 differentiation in vitro, is critical for the development of this nonconventional T Helper 1 (Th1*)-polarized CD146+CCR5+ conventional T cells (Tconvs) population. Furthermore, we found that ICOS can induce the generation of Th1*-polarized CD146+CCR5+ regulatory T cells (Tregs) population, lowering the frequencies of phenotypic markers of functional Tregs. Our data also showed that inhibiting the major transcriptional factor of Th17, RAR-related orphan receptor gamma t (RORγt), could prevent the development of CD146+CCR5+ Tconvs in vitro. Our results demonstrate how pathogenic CD146+CCR5+ T cells are induced through ICOS or RORγt, suggesting new targets for GVHD treatment. We anticipate our assay to be a starting point for the development of novel GVHD-specific drugs. For example, the treatments that focus on inhibiting RORγ would have fewer side effects than general immunosuppressive drugs that GVHD patients use today and inhibit GVHD while sparing the GVL effect. Furthermore, we expect the CD146+CCR5+ Tconvs and/or Tregs can be used as GVHD biomarkers. These biomarkers may guide preemptive treatments such as RORγt inhibitor.

This study analysed data obtained from respondents and their medical records to determine the barriers and motivators for good adherence to ART. Respondents' records were also reviewed together with their pharmacy refill records to identify any correlation between .CD4 cell counts, viral load, VL and adherence to antiretroviral drugs at extension 15 ARV clinic in Gaborone, Botswana. The study investigated whether the combination of pharmacy refills and pill counts adherence measurement methodologies could predict immunological recovery and virologic response through increased CD4 cell counts and suppressed VL. . There was a positive relationship between adherence, CD4 cell counts and VL. Pharmacy refills and pill counts adherence measurement methodologies scored high on sensitivity, specificity, and positive predictive values but low on negative predictive values. / Health Studies / M.A. (Public Health)

Uganda has experienced 1.6 million deaths to HIV/AIDS related illness. Introduction of free-ART in rural hospitals that bear the burden od AIDS reduces adults morbidity and mortality. The study design was a quantitative, retrospective and descriptive design through data mining of medical records. In the six years, hospital admissions decreased by 16.7% and the median age at death increased by seven years. Hospital admissions decreased from three to seven deaths per 100 admissions per month. Male and female mortality was 1:1.6 and females in the 15-34 age group had a 37% higher likeliness of dying in hospital compared to males. Deaths from sub-countries with an ART site reduced by 4% to 8.6%. The data revealed that despite ART coverage of 60%, mortality rates showed a rising trend. Free access to ART's over three years did not make any observable changes to overall mortality. Therefore, ART access contributed to a decline in overall hospital admissions, an increase in median age at time of death and a reduction in deaths from sub-counties with an ART site. There was no reduction in overall hospital mortality rate. / M.A. (Public Health) / Health Studies

This quantitative study sought to identify and describe factors influencing HIV disclosure and sexual practices among 340 PLWHA on ART at Mbabane National Referral VCT/ART Centre, Swaziland. Data were collected using a structured questionnaire. A high general HIV disclosure rate (94.1%; f=320; N=340) was observed of which 57.5% (f=184; n=320) was to sexual partners. X2 procedures indicate an association with gender, residential region, religion, and period of being on ART. The majority (70.2%; f=179; n=255) of the respondents used condoms all the time to avoid infecting their sexual partners (99.2%; f=243; n=245) and to avoid contracting STIs (99.2%; f=243; n=245). X2 procedures indicate an association with gender, residential region, marital status, number of sexual partners, knowledge of the HIV status of sexual partners and period of being on ART. The single leading reason for not using the condom was sexual partners’ refusal to use condoms (85.7%; f=54; n=63). / Health Studies / M.A.(Health Studies)

The objectives of the study were (1) to quantify adherence rate among the study participants in the ART unit and (2) to identify factors that contribute to non-adherence. This cross sectional study was carried out at Nekemete referral clinic. Data was collected using a self-developed structured questionnaire where a total of 338 participants grouped into adherent and non-adherent based on a score derived from an adherence assessment were interviewed. Data was analysed using the Statistical Package for Social Sciences (SPSS) version 17.0. By using multivariate analysis of variables identified as correlates of adherence, non-adherence was common among those; with age between 18-30 yrs, with no education, who were not married, who had no pipe water supply, those with no electricity in the house, who perceived had no access to assistance from providers, who perceived the health care providers (HCPs) did not keep information confidentially, who had a language barrier with providers, and who were treated with a psychiatric illness. The study concludes that adherence is multi-factorial and varies significantly by individual and care setting. Psychosocial factors were found to impact adherence and should be analysed in more detail by further studies. Three psychosocial factors were independently associated with poor adherence: the study found that patients perceiving poor access; those perceiving problems in information confidentiality (and possibly experiencing stigmatisation); and having psychiatric morbidity (and possibly with less social support) are more likely to be non-adherent. Furthermore, individuals without electricity and those without piped water supply, implying low income, are at risk for non-adherence / Health Studies / M.A. (Public Health)

M.A. (Public Health) / Anti-Retroviral Therapy (ART) adherence is a crucial component of the patient management framework for people living with Human Immune Deficiency Virus (HIV). Trait emotional intelligence is “the constellation of behavioural-dispositions and self-perceived abilities to recognise, process, and utilise emotion-laden information”. The purpose of the study was to determine whether there was a correlation between ART adherence behaviour and behavioural-dispositions related to trait emotional intelligence among HIV/AIDS infected people receiving ART at the regional public hospitals in Addis Ababa. The study used observational, analytical, and cross-sectional research design. The participants were selected through a proportionally stratified systematic random sampling method. Data collection was through a structured self-report questionnaire format. The findings showed that 79.1% had optimal ART adherence behaviour; 84.4% had average trait emotional intelligence. The research finding showed a statistically significant positive correlation between ART adherence behaviour and behavioural-dispositions related to trait emotional intelligence at (r =0.417, n=392, P<0.001). / Health Studies

The purpose of this study was to determine factors affecting non-adherence to Anti-retroviral therapy among AIDS patients. A cross sectional quantitative survey, was used. Structured interviews were conducted with 300 ART patients. Data were analysed using SPSS version 13 and presented in charts, graphs and frequency tables. Motivators of good adherence were identified as disclosure of HIV positive status to more than one person, frequent adherence counselling, self-efficacy to adhere to ART, positive interactions between patients and healthcare providers; and using an adherence partner. Barriers to adherence were forgetfulness, transportation costs to and from the clinic, time away from work and side effects. There was a strong positive correlation between adherence, CD4 counts and viral load. Adherence was closely tied to immunologic and virologic improvements. Respondents with poor adherence were likely to have unsuppressed viral loads (OR 12.98, 95%, CI 4.9-34). / Health Studies / Masters of Public Health