Thesis (PhD)--Stellenbosch University, 2012. / Includes bibliography / ENGLISH ABSTRACT: Tuberculosis (TB) has been declared a global health emergency by the World Health Organisation, and consequently there is an urgency to develop improved methods of diagnosis and treatment. Despite the current TB epidemic, the disease can be treated effectively using isoniazid (INH) in combination with other antibiotics. However, INH is inactivated in the body by certain drug metabolising enzymes, which may reduce the efficacy of TB treatment. The activity of these drug metabolising enzymes, called NAT, are in turn reduced by nucleotide changes (SNPs) in the gene. These genetic variants (alleles) have been correlated with the rapid- (FA), intermediate- (IA), and slow acetylation (SA) enzymatic activity, and one is therefore able to investigate potential phenotypic effects via genotypic analyses. We investigated these genetic changes in the NAT1 and NAT2 genes in individuals from the local Coloured community (SAC) since this group has one of the highest TB incidences in the country. NAT2 is primarily responsible for the inactivation of INH, whilst NAT1 metabolises para-aminosalicyclic acid (PAS) which is used in the treatment of drug resistant TB. The NAT2 results indicated that the NAT2 alleles were not equally represented in three local ethnic groups studied, and subsequently the rapid, intermediate and slow acetylation activity reflected these differences. However, the relative frequency of these variants in the SAC and Caucasian groups were relatively low. These differences require further investigation to determine their overall relevance to the NAT2 activity differences between groups. In the case of the NAT1 analysis we also observed differences in the relative frequency of various NAT1 alleles between Caucasian and SAC individuals. However, many of these NAT1 SNPs and alleles have not as yet been characterised, so effects of these variants are currently unknown. Interestingly, the NAT1*4 and NAT1*10 alleles were the most prevalent NAT1 alleles in both Caucasians and SAC. The NAT1*4 allele exhibits the rapid NAT1 activity, whilst the activity of the NAT1*10 allele is currently subject to ongoing debate. In this respect, the analysis of NAT1 continues to be a topic for ongoing research. These results, observed for the NAT genes, underscore the importance of doing genetic analyses in local ethnic groups, since these differences may vary significantly between the groups. / AFRIKAANSE OPSOMMING: Tuberkulose (TB) is deur die Wêreldgesondheidsorganisasie (WGO) tot 'n globale gesondheidsnood verklaar en derhalwe is dit noodsaaklik dat nuwe, verbeterde diagnostiese metodes ontwikkel word, wat tot meer effektiewe behandeling kan lei. Ten spyte van die huidige TB-epidemie, kan die siekte doeltreffend behandel word deur middel van isoniasied (INH), in kombinasie te met ander antibiotika. INH kan egter geïnaktiveer word deur sekere ensieme in die liggaam, met die gevolg dat INH nie meer effektief is nie in die behandeling van TB. Die aktiwiteit van hierdie ensiem, die sogenaamde NAT2 (Arielamien N-asetieltransferase 2) ensiem, word op sy beurt beïnvloed deur sekere nukleotied veranderings (SNPs) in die geen. Hierdie genetiese veranderings gekorreleer met ensiemaktiwiteitsveranderings (geklassifiseer as vinnig (FA) Intermediêr (IA) en stadig (SA)), wat mens in staat stel om potensiële fenotipiese effekte te ondersoek deur middel van genotipiese analise. Ons het hierdie genetiese veranderings ondersoek in die NAT1 en NAT2 gene in individue van die Kleurling-gemeenskap (SAC) omdat díe bevolkingsgroep die hoogste voorkoms van TB in die land het. NAT2 is primêr verantwoordelik vir die inaktivering van INH, terwyl NAT1 para-amienosalisilaat (PAS) inaktiveer, wat gebruik word in die behandeling van midel-weerstandige TB. Die NAT2 resultate dui daarop dat die allele van die NAT2 geen nie eweredig verteenwoordig wasin die drie etniese groepe nie en derhalwe word die vinnige (FA), intermediêre (IA) en stadige (SA) ensiemaktiwiteite deur hierdie verskille weerspieël. Hoewel die teenwoordigheid van hierdie variante relatief laag was in die SAC en Koukasiër gemeenskappe, is verdere studies nodig om die omvang van hierdie verskille te bepaal ten onsigte van NAT2 aktiwiteit tussen groepe. In die geval van die NAT1 analise het ons verskille waargeneem in die voorkoms van verskeie NAT1 allele tussen Koukasiese en SAC individue. Baie van hierdie NAT1 SNPs is egter nog nie gekarakteriseer nie, en derhalwe is die effek van hierdie NAT1 variante onbekend. Die NAT1*4 en NAT1*10 allele was die prominentste NAT1 alleel in beide Koukasiërs en SAC. Die NAT1*4 is betrokke by vinnige NAT1 aktiwiteit, terwyl die effek van die NAT1*10 alleel nog onderhewig is aan aktiefwe debat. In hierdie verband, is die studie van NAT1 steeds 'n onderwerp vir toekomstige navorsing. Hierdie resultate, wat vir die NAT gene waargeneem is, beklemtoon die belangrikheid van verdere genetiese analises in plaaslike etniese groepe, aangesien hierdie verskille beduidend kan wees tussen die verskillende groepe.

<p><font face="Times New Roman" size="3"><font face="Times New Roman" size="3"> <p align="left">The aim of the study is to explore the barriers associated with low VCT uptake by the TB patients attending primary health care clinics within the Buffalo City municipality. <font face="Times New Roman" size="3"><font face="Times New Roman" size="3">The study population was drawn from TB patients attending the primary health care facilities in Buffalo city municipality in the Eastern Cape Province. Eight participants were purposively selected to include those who had accepted VCT as well as those who did not.</font></font></p> </font></font></p>

In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model.

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

<p><font face="Times New Roman" size="3"><font face="Times New Roman" size="3"> <p align="left">The aim of the study is to explore the barriers associated with low VCT uptake by the TB patients attending primary health care clinics within the Buffalo City municipality. <font face="Times New Roman" size="3"><font face="Times New Roman" size="3">The study population was drawn from TB patients attending the primary health care facilities in Buffalo city municipality in the Eastern Cape Province. Eight participants were purposively selected to include those who had accepted VCT as well as those who did not.</font></font></p> </font></font></p>

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model.

Magister Public Health - MPH (Public Health) / Over the past two decades, despite a growing tuberculosis (TB) epidemic, the South African health system and National TB Programme (NTP) have taken significant steps to ensure improved clinical awareness, early diagnosis, prompt treatment initiation and follow-up of treatment outcomes in cases of TB. The effects of these programmatic measures over time on changes in the severity of disease and presenting clinical profile of patients with pulmonary TB have not been studied. Doing so may provide another window on the impact of TB control initiatives in South Africa.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2017-03-24T11:22:47Z No. of bitstreams: 2 Dissertação - Tatiana Marlene Galvez Sánchez - 2017.pdf: 3124839 bytes, checksum: 942aa6d4fa9aa30babb4eb0d7e04a805 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-03-24T12:39:25Z (GMT) No. of bitstreams: 2 Dissertação - Tatiana Marlene Galvez Sánchez - 2017.pdf: 3124839 bytes, checksum: 942aa6d4fa9aa30babb4eb0d7e04a805 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-03-24T12:39:25Z (GMT). No. of bitstreams: 2 Dissertação - Tatiana Marlene Galvez Sánchez - 2017.pdf: 3124839 bytes, checksum: 942aa6d4fa9aa30babb4eb0d7e04a805 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-02-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Outro / Tuberculin skin test (TST) identifies a previous exposed to M. tuberculosis (Mtb) using an intradermal inoculation of purified protein derivates (PPD) that result in a delayed hypersensitivity reaction (DTH). Interferon-gamma release assay (IGRA) was suggested to replace TST. The IGRA uses antigens, ESAT-6 and CFP-10, absent in all BCG strains and some non tuberculous mycobacteria (NTM). However, reproducibility and high cost were limitations for endemic countries. For this reason, the development of new diagnose test for latent TB is necessary. Fusion proteins developed by our group has been recognized by the immune response generated by the infection with Mycobacterium tuberculosis. Thus the aim of this work was to evaluate the capacity of CMX or ECMX to be used in a Skin test for tuberculosis. BALB/c mice infected with Mtb were euthanized forty-five days after infection. Spleens, lungs and draining lymph nodes of infected mice were processed and evaluated by flow cytometry Both CD4 and CD8 IFN+ cells were able to recognize rCMX and rECMX. The skin test followed an evaluation of thickness/swelling ≥ PPD 2UT (positive control) to consider positive DTH. Based on thickness, at 24 h, rCMX 25μg (0.37±0.02) and rECMX 15-25μg (0.38±0.03/0,62±0,12) induced a positive DTH response. At 48h, rCMX 25μg (0.28±0.03) and rECMX 25μg (0.5±0.04) induced also a positive DTH reaction. In conclusion, fusion proteins rCMX and rECMX are recognized by infected mice with Mtb and skin test using rECMX 25μg induced better DTH response that of conventional PPD. / A prova tuberculínica (PT) é um teste cutâneo que identifica a exposição prévia ao M. tuberculosis (Mtb), mediante a inoculação via intradérmica do derivado protéico purificado (PPD) de Mtb, o que resulta em uma reação de hipersensibilidade do tipo tardia (DTH). O ensaio de liberação de IFN-γ (IGRA) foi indicado para substituir a PT. O IGRA usa os antígenos ausentes na BCG e algumas micobactérias não causadoras de TB (MNT), ESAT-6 e CFP-10. Porém, apresenta falta de reprodutibilidade e alto custo quando usado em populações endêmicas para TB. Diante disso, o desenvolvimento de novos testes de diagnóstico é necessário. Nosso grupo desenvolveu proteínas de fusão que são reconhecidas por linfócitos gerados pela infecção com Mtb. Assim, o trabalho propõe avaliar a utilização das proteínas rCMX e rECMX no desenvolvimento de um teste cutâneo de diagnóstico para tuberculose. Camundongos BALB/c foram infectados com Mtb H37Rv. Após 45 dias, a infecção induziu linfócitos T CD4+ e CD8+ produtores de IFN-γ específicos para rCMX e rECMX no baço, pulmões e linfonodos drenantes. Enquanto ao teste cutâneo realizado 45 dias após a infecção, a leitura de espessura/inchaço ≥ PPD 2UT (controle positivo) indicou uma reação de DTH positiva. Avaliando a espessura 24h após o inóculo, rCMX 25μg (0.37±0.02) e rECMX 15-25μg (0.38±0.03/0,62±0,12) induziram reação de DTH positiva. As 48h, rCMX 25μg (0.28±0.03) e rECMX 25μg (0.5±0.04) também apresentaram reação positiva. Enquanto o inchaço as 24h, só a rECMX apresentou DTH positiva. Em conclusão, este trabalho mostra que as proteínas rCMX e rECMX são reconhecidas pela resposta celular de camundongos infectados com Mtb, e quando usadas no teste cutâneo induziram reação de DTH positiva comparável e até superior ao PPD convencional. Dessa forma, é recomendada a avaliação das proteínas de fusão em outros modelos animais e posteriormente em humanos.

Thesis (MPH.) -- University of Limpopo, 2019 / Background: Tuberculosis still continues to be a global public health problem and leads to many deaths. In an effective TB control strategy, TB patients are allocated to community care workers who provide care to these patients in their homes. It is important to understand the experiences of community care workers in order to strengthen TB control in the country. Objective(s): The purpose of this study was to explore lived experiences of community care workers of supporting patients taking Tuberculosis treatment. Methods: The design of the study was phenomenological, exploratory, descriptive, and contextual. The study site was Hlogotlou area in Limpopo Province. The target population was all community care workers supporting patients on Tuberculosis treatment. Purposive sampling was used with a sample of 13 participants, which was determined by the saturation of data. Semi-structured interviews were conducted using an interview guide and all sessions were audio recorded. The data were analysed using Interpretative Phenomenological Analysis. Results: The results highlighted certain challenges met by community care workers. Patients thought that community care workers are there to kill them with treatment, they had mood swings during treatment and this caused them to use vulgar words and become aggressive to their community care workers. Most community care workers did not have enough information about Tuberculosis. This made it difficult for them to support patients on tuberculosis treatment. Conclusions: A good relationship with patients enhances treatment compliance. The researcher recommends that intensive training about tuberculosis should be provided to community care workers.