M. Pharm., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Background: According to the 2010 edition of the UNAIDS Report on the global AIDS epidemic, an estimated 320 000 (20%) fewer people died of AIDS-related causes in South Africa in 2009 than in 2004 due to the increase in availability of anti-retroviral medicines.(2) With this positive trend, the mindset should be shifted towards reducing adverse effects of ART. The need for permanent ART treatment and the significant increase in life expectancy have led to the observation of new, frequent, and sometimes severe drug-related adverse effects.(4) One of the most challenging and potentially dangerous side-effects is hyperlactataemia (Hlac) that may evolve to lactic acidosis (LA)(5) ART–associated Hlac may be asymptomatic, or symptomatic which in the extreme case can progress to life threatening acidosis. The latter, i.e. lactic acidosis is a fairly frequent and often misdiagnosed or under diagnosed and potentially fatal side effect of ARTs. (6) Objectives: To explore the relationship between Hlac/LA and gender, weight, dosage CD4 and regimen alterations in HIV patients on ARTs and to compare the earlier regimens to the revised regimens as independent risk factors for Hlac and LA. Sample size would be based on the hypothesis that newer regimens would reduce the incidence of Hlac and LA. Methods: A Retrospective study was conducted by reviewing 3 741 patient files from August 2004 to December 2007. This study was to assess the incidence and risk factors of Hlac/LA. Hlac was defined as a venous lactate measurement of ≥2.3mmol/L and LA was ≥5mmol/L. Immunological, virological, haemotological and biochemical results were recorded for all the patients. A second phase involved a Prospective study. Patients who were on treatment for >12 months were randomly selected from the queue at the clinic between the September 2008 and December 2009. Immunological, virological, haematological and biochemical information was recorded for all patients selected. Analysis involved descriptive statistics, comparison of means, frequency analysis and multivariate analysis. Results: Two-hundred and thirty two patients were identified with elevated lactate levels in the retrospective study. The incidence was 6.2% in this population, with gastro-intestinal symptoms, peripheral neuropathy, abdominal tenderness, rash and upper respiratory tract infection being the significant symptoms. The major risk factor was a low CD4 count. The prospective study included 292 patients with 24.3% with Hlac/LA with peripheral neuropathy (p 0.209), gastrointestinal symptoms (nausea, vomiting) (p 0.148) and abdominal tenderness (p 0.214) were the most significant symptoms. In terms of the hypothesis that newer regimens would lower the incidence of elevated lactate levels by 50%, the observed incidence of 24.3% is no different from previously reported rates. This therefore shows that although regimen changes have been implemented the overall incidence of Hlac appears to be unchanged but the LA rate was found to be significantly lower than before, 6.8 cases per 1000 patient years vs ±19 cases per 1000 person years.(16) Gastro-intestinal symptoms but not peripheral iv neuropathy; with low CD4 count, weight loss and low weight on entry were the significant risk factors, which is most likely representative of advanced disease. Conclusions: Although newer regimens have been introduced, Hlac/LA still exist. Healthworkers need to be on high alert for Hlac/LA particularly if a patient enters into the ART program with a low CD4 count and a low weight

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Masters of Public Health in the field of Health Measurement 22nd February, 2012 / Introduction: Barriers associated with good adherence to Antiretroviral Therapy (ART) among human immunodeficiency virus (HIV) infected adolescents are multiple and complex. Those barriers contribute to low adherence levels putting infected adolescents at risk of developing resistance and decreasing their survival time. Patients care givers psychosocial and demographic variables, medication related factors and health care delivering factors are among the barriers that correlate with non adherence to antiretroviral drugs (ART’s) among HIV infected adolescents. Those barriers vary across individuals within the same population of adolescents. This study was conducted to determine the level of adherence among HIV infected adolescents on ART and to identify barriers associated with non adherence among this population attending the Botswana Baylor Children’s Clinical Center of Excellence (COE) in Gaborone, Botswana. Materials and methods: A cross sectional analytical study using quantitative data was performed. A structured, self administrated questionnaire adapted from the AIDS Clinical Trials Group (ACTG) was used to identify the barriers while the socio-demographic and clinical data were retrieved from study participants’ medical records. The adherence level was estimated using the pharmacy pill count technique. The adolescents aged 13 to 18 years receiving ART for more than 6 months and attending the ART National Program at the time of the study and who did assent and had their care givers consent to participate in the study were included in the analysis. Results: A high adherence level (75.6%) was reported among the study participants. Besides gender, no other socio-demographic and clinical variables showed association with non adherence. Male adolescents were found to be 70% less likely to adhere to their medication than their counterpart females [p= 0.020, OR=0.30, 95% CI (0.10 – 0.85)]. Furthermore adolescents v who missed a dose because their pills were not collected from the pharmacy either by themselves or by their care givers were 77 % less likely to adhere to their ART medication than those who did not miss a dose because they had their medication collected [p= 0.019, OR= 0.23, 95%CI (0.064 – 0.837)]. Conclusion: A high proportion of HIV infected adolescents attending the Baylor Center of Excellence ART National Program were adherent to their medication. Despite the high level adherence to ART among this age group, interventions to improve adherence level should be designed with a focus on male adolescents and to reinforce counseling of care givers and adolescents about the hazards of poor adherence to treatment. Further research is however, needed to elucidate more about the two main barriers that were found to be significantly associated with non adherence among adolescents at Botswana Baylor Children’s Clinical Center of Excellence: male-gender and medication collection from the pharmacy.

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Thesis(MSc(Med)(Pharmacy))--University of Limpopo (Medunsa Campus), 2011. / High levels of adherence to ART are essential for maximal suppression of viral replication and avoidance of drug resistance. Pill counts are an indirect, objective method of assessing adherence. Patients can invalidate pill counts by manipulating the number of tablets returned. This paper describes a pilot study which investigated the ability of ‘mixed’ pill counts to detect deliberate masking of non-adherence to ART at a public sector ARV Clinic in Pretoria, South Africa. Seventy-eight adult patients on a first line regimen of ART were recruited. At the first return visit, a standard pill count was performed and adherence (% of tablets taken) was calculated. For the repeat prescription, three days’ extra supply was dispensed without the patients’ knowledge. At the second return visit, a ‘mixed’ pill count was performed and adherence was calculated. Patients were grouped into three categories based on calculated adherence: truthfully non-adherent (<100% adherence), adherent (100% adherence) and ‘over-compliant’ (>100% adherence, i.e. returning to the clinic with fewer tablets than required). Exploratory interviews were conducted with truthfully nonadherent and over-compliant patients to obtain explanations for discrepancies in pill counts. Twenty-nine (37%) patients completed the study. Reasons for drop-out or discontinuation from the study included the issue of prescriptions for 2-3 months’ ARV supply, missed appointments, regimen changes and failure to return remaining tablets to the clinic. Eleven patients (38%) were identified as over-compliant in one or more of the ARVs in their regimen. Nine of these patients agreed to be interviewed, of which three admitted to manipulating their tablet numbers. Reasons for manipulation included: being ’fine now’ and not in need of ARVs; changes in body shape; possibility of the social grant being terminated if non-adherent; getting a new supply and no need for remaining ARVs; knowing that the tablets would be counted for the study. This pilot study indicated that the ‘mixed’ pill count method is capable of detecting deliberate masking of non-adherence. Applying this method to a larger sample may better estimate the frequency of pill count manipulation by patients and help gain insight to reasons for this behaviour and the extent of actual non-adherence. Key words: dumping, manipulation, masking, over-compliance, HAART

Thesis (MPH)University of Limpopo (Medunsa Campus), 2011. / INTRODUCTION: Antiretroviral therapy (ART) has been proven to significantly improve the quality and quantity of lives of patients infected with HIV. However, several barriers exist that prevent children from being initiated on treatment on time. Studies in adults have shown that the timing of treatment influence outcomes of ART; but little is known about this in children. Hence, the need for this study. The purpose of this study was to characterize the outcomes of late initiation of ART in HIV- positive children seen at the Mildmay Jajja Home center. METHODOLOGY: The study was a cross-sectional survey involving all children who were initiated at the Mildmay Jajja Home in 2005 and had had been on ART for at least 18 months. Two sets of data were collected, for the children on ART: their age and sex were recorded. In addition, based on the Ugandan clinical guidelines for ART, children were grouped into two groups; those 6 six years and below; and those above 6 years. Clinical variables recorded were baseline and repeated measurements of bodyweights, and CD4 counts; weight and CD4 counts at the time of initiation of ART, at 12 months and at 18 months. For the care providers: their age, gender, education level, relationship to the child was recorded. Three outcomes of treatment were assessed, adherence level by the 12th month on treatment; hospitalisation by the 12th month (during the first 12 months of treatment); and survival or death at by the 12th and 18th month on treatment. RESULTS: In total, 114 children were included in the sample. Among them, 54.4% of children were initiated late. Based on age, children 6 years old and younger were more likely and significantly initiated late as compared to those over 6 years old as about 70% of them were actually initiated late. Based on sex, female children older than 6 years were significantly initiated late as compared to boys. The characteristics of care providers that were associated with children being initiated late were being male, less than 40 years old, with a primary school level of education, and not knowing their own HIV status. With regard to outcomes of the treatment, adherence, hospitalisation, and survival were assessed. Overall, 59.4% of children achieved an adherence level of 90% or more; 17.3% of children had been hospitalised at least once; and the mortality was 17.5% during the 2 year period covered by the study. Adherence was influenced slightly by the timing of the start of the treatment since less than half (46.34%) of those initiated late achieved an adherence level of 90% or more as compared to over 53% among those initiated timely. Though there was not statistically significant difference, adherence was slightly better in children whose care providers were biological parents, whose HIV status was known as positive, and female. With regard to hospitalisation, children less than 6 years were significantly more hospitalised than the older ones; their care providers were relatives, not educated, and of unknown HIV status. Those initiated late were significantly more hospitalised than those initiated timely (63.15% versus 36.84%, p=0.03). With regard to survival, the majority of children who died were over 6 years old, and female. The majority of their care providers were female, under 40 years old, and known HIV-positive. In children initiated late, the mortality was 50% (n=14) and 83.3% (n=6) respectively by the 12th and 18th month of treatment as compared to those initiated timely. In conclusion, 54.4% of children were initiated late. Late initiation was associated with negative outcomes such as low adherence to treatment as less than half of them achieved a adherence level of 90% or more; hospitalisation as those initiated late were significantly more hospitalised than those initiated timely; and high mortality since among those who died, 50% and 83.3% of deaths occurred respectively by the 12th and 18th month of treatment among those initiated late. In order to minimize the probability that the majority of children are initiated late, a general awareness campaign should be directed at the general public so that they can be sensitized to the need to bring children to medical attention as soon as possible

Telecommunication service providers have recently begun to offer ubiquitous access to packetised data. As a result, the Internet is not limited to computers that are physically connected but is also available to users that axe equipped with mobile devices. This ubiquitous access fuels the growth and the usage of the Internet even further, and thus the realisation of dynamic Internet. With the realisation of the dynamic Internet, increasing support is needed for Internet protocol (IP) and transmission control protocol (TCP) over wireless/mobile networks.Two areas of interest in this thesis are unicast and multicast routing in connectionless and connection-oriented networks. To address the problems of routing protocols in mobile computing environments, the active networks (ANs) paradigm is employed. ANs provide an alternative paradigm to solving network problems and comprise programmable network elements that allow enhancement of existing protocols and the execution of active protocols which run for the duration of the communication session.This thesis investigates the viability and advantages of ANs when applied to routing in mobile communications. Two new AN-based protocols, for IP and asynchronous transfer mode (ATM) networks, that address the problems of multicast routing with mobile group members are outlined. The Internet Engineering Task Force (IETF) mobile IP has been augmented with active programs in order to enhance its operation further. Also, a novel model for rerouting connections in ATM networks is presented.Results of extensive simulation studies comparing performances of conventional as well as some recently proposed protocols with those of AN-based protocols are presented. The results obtained from these simulation studies show that AN-based protocols have the following benefits: (i) efficient adaptation to mobility, (ii) reduced signaling overheads, ++ / (iii) high reuse of allocated network states, (iv) extensibility, (v) network topology independence, and (vi) scalability. The aforementioned points are crucial in mobile environments where states at routers (switches) are frequently updated due to mobility. It was shown that ANs provide the most benefits to protocols that maintain states within the network, for example connection-oriented and multicast protocols. AN-based protocols enable fast and efficient update of the states maintained at the routers/switches without incurring excessive signaling overheads. Moreover, part of a connection or multicast tree can be updated iteratively with the use of ANs, resulting only in modifications to routers (switches) that are affected by host migration. A model for deploying active programs that is coupled with the protocol operation is also demonstrated. Implementation of such a model eliminates the need for strategic positioning of active services.

Intracellular dNTP pool sizes are highly asymmetric, with dGTP usually comprising 5 to 10% of the sum of the dNTP pools. The work presented in this dissertation addresses the question of whether the underrepresentation of dGTP is related to its potential to be oxidized by reactive oxygen species. 8-oxo-guanine is important in oxidative mutagenesis, and current evidence indicates that this lesion arises in DNA partly through oxidation of dGTP, followed by incorporation of 8-oxo-dGTP into DNA. The bacterial MutT protein and its mammalian homolog catalyze the hydrolysis of 8-oxo-dGTP to 8-oxo-dGMP in vitro. It is a widely accepted premise that the primary function of these enzymes is to remove 8-oxo-dGTP from the nucleotide pool of cells so that it cannot be used as a substrate for DNA synthesis. However, this model has been called into question by observations that some mutT strains of E. coli display a mutator phenotype when grown anaerobically, and by kinetic studies that showed 8-oxo-dGTP to be a poor DNA polymerase substrate. In this study, the dNTP pools of mammalian cells cultured in varying oxygen conditions were measured, with the expectation that the dGTP pool would expand under low oxygen conditions if it were a target for damage by reactive oxygen species. HeLa cells cultured in 2% 0��� showed no change in the dGTP pool when compared to cells cultured in 20% 0���; however, in V79 cells, the dGTP pool did expand in 2% 0���. This result was not specific to the dGTP pool, as pools of dATP and dTTP also increased when V79 cells were cultured at 2% 0���. These results suggest that there may be increased turnover of the dGTP pool when cells are cultured in high oxygen, but these experiments did not address the reason for this oxygen-dependent change. In order to determine whether 8-oxo-dGTP accumulates to levels that are sufficient to cause mutagenesis in cells, an analytical method for the measurement of 8-oxo-dGTP from cell extracts was developed. By use of this method, which involves reversed-phase high performance liquid chromatography coupled with electrochemical detection, no 8-oxo-dGTP was detected in mutT E. coli cells, even when they were cultured in the presence of H���0���. The estimated upper limit of 8-oxo-dGTP in these cells is about 240 molecules per cell, which corresponds to an intracellular concentration of approximately 0.34 ��M. When 8-oxo-dGTP was added at this concentration to an in vitro DNA replication system in which replication errors could be scored as mutations, along with the four normal dNTPs at their estimated intracellular concentrations, there was no detectable effect on the frequency of mutation. Therefore, the presence of 8-oxo-dGTP at physiologically relevant concentrations does not appear to be significantly mutagenic. The results presented in this dissertation suggest that the mechanism by which the MutT enzyme counteracts mutagenesis should be reevaluated. / Graduation date: 2003

With the increased attention on high efficiency and energy savings, power electronic energy conversion equipment is increasingly incorporated in all levels of the power system. The drawback of such equipment is the generation of nonsinusoidal currents in the power distribution network due to the nonlinear operation. Harmonic currents may distort the line voltages and lead to several unwanted effects including equipment overheating, system failure, interference with communication systems, etc. In response to these concerns, this research presents an active filter for the cancellation of harmonic line current distortion. The active filter used in this research is connected in parallel with the nonlinear load and is designed for a three-phase three-wire industrial power system. The filter consists of a voltage source inverter connected through a coupling inductor to the terminals of the ac-source. The inverter is controlled via a space vector-pulse width modulation (SVPWM) algorithm that is generated using a digital signal processor (DSP). In order to reduce the distortion resulting from the switching nature of the active filter inverter, a switching ripple filter is connected in parallel. The control algorithm of the active filter is based on the rotating reference frame theory. For each harmonic which is to be cancelled, a corresponding synchronous reference frame is generated to extract the harmonic phase and magnitude. With this information, each harmonic current component can be separately controlled and the proposed algorithm can therefore compensate for hardware effects such as measuring delays and component transfer functions. For the extraction of the harmonic components, a finite impulse response filter is used in order to quickly react to changing load currents. An adapting algorithm is implemented to compensate for slowly varying system parameters. Simulations under varying load and transient conditions are performed. The results show nearly perfect cancellation performance for the proposed active filter control algorithm. / Graduation date: 2001

Active technology in database management systems (DBMS) enables the movement of behaviour dependent on the system’s state, from the application software to a rule base in the DBMS. With active technology in database systems, the problem of how to design active behaviour has become an important issue. Modelling processes do not foresee support for design of active rules which can lead to conflicts between the event-condition-action (ECA) rules representing the active behaviour and the application systems, using the active DBMS. The unified modelling language (UML) is a widely used notation language and is the main subject in this project. Its features will be investigated to acknowledge to what extend UML modelling diagrams provide information that can be used to formulate ECA rules. To achieve this, two methods where developed. One of the methods was applied on use-case UML modelling diagrams. The use-case models were developed by means of reflecting a real-life organisation. The results from applying the method on the use-case models were that there are features in UML that can be expressed with ECA rules. Active technology in database management systems (DBMS) enables the movement of behaviour dependent on the system’s state, from the application software to a rule base in the DBMS. With active technology in database systems, the problem of how to design active behaviour has become an important issue. Modelling processes do not foresee support for design of active rules which can lead to conflicts between the event-condition-action (ECA) rules representing the active behaviour and the application systems, using the active DBMS. The unified modelling language (UML) is a widely used notation language and is the main subject in this project. Its features will be investigated to acknowledge to what extend UML modelling diagrams provide information that can be used to formulate ECA rules. To achieve this, two methods where developed. One of the methods was applied on use-case UML modelling diagrams. The use-case models were developed by means of reflecting a real-life organisation. The results from applying the method on the use-case models were that there are features in UML that can be expressed with ECA rules.