Reactivation of latent infection is the major cause of tuberculosis (TB). Cholesterol is a critical carbon source during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the sterol-ring degradation and is essential for intracellular survival. NAT from M. tuberculosis (TBNAT) can utilise propionyl-CoA and therefore was proposed as a target for TB-drug development. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. NAT inhibitors, including the piperidinol class, were identified by high-throughput screening. The insolubility of recombinant TBNAT has been a major limitation in pursuing it as a drug target. Subcloning tbnat into a pVLT31 vector resulted in a yield of 6-16 mg/litre-bacterial-culture of pure-soluble recombinant TBNAT. The increased yield allowed for extensive screening for crystallisation conditions. However, since a structure was not obtained, the model NAT from M. marinum (MMNAT) was employed to further understand NAT as a target. Screening against a panel of Acyl-CoA cofactors showed that MMNAT can also utilise propionyl-CoA. The MMNAT structure in complex with the high affinity substrate hydralazine was determined (2.1 Å) and the architecture of the arylamine pocket was delineated. A novel mechanism for the acetylation reaction of hydralazine has emerged. It is proposed that the acetyl group is transferred from acetyl-CoA to the heterocyclic aromatic nitrogen of hydralazine, which explains the immediate cyclisation of the acetylated metabolite into an N-methyltriazolophthalazine. By employing mass spectroscopy, enzyme assays, computational docking and structural studies, a covalent mechanism of inhibition by the piperidinol class was established, and the inhibitor-binding pocket was identified. Inhibitors with new scaffolds were identified using the in silico 3D-shape screening and thermal shift assay.

Thesis (MScMedSc (Pathology. Medical Microbiology))--Stellenbosch University, 2008. / The genus Mycobacterium is a group of acid–fast, aerobic, slow- growing organisms which include more than 90 different species. A member of this genus, Mycobacterium tuberculosis, belonging to the Mycobacterium tuberculosis complex (MTB), is the causative agent of tuberculosis (TB). This disease is currently considered a global emergency, with more than 2 million deaths and over 8 million new cases annually. TB is the world’s second most common cause of death after HIV/AIDS. About one-third of the world’s population is estimated to be infected with TB. This catastrophic situation is further compounded by the emergence of Multi Drug Resistant tuberculosis (MDR-TB) and in more recent times, Extensive Drug Resistant tuberculosis (XDR-TB). Early diagnosis is critical to the successful management of patients as it allows informed use of chemotherapy. Also, early diagnosis is also of great importance if the menace of MDR-TB and XDR-TB is to be curbed and controlled. As MTB is highly infectious for humans, it is of paramount importance that TB be diagnosed as early as possible to stop the spread of the disease. Traditional conventional laboratory procedures involving microscopy, culture and sensitivity tests may require turnaround times of 3-4 weeks or longer. Tremendous technological advancement over the years such as the advent of automated liquid culture systems like the BACTEC® 960 and the MGITTM Tube system, and the development of a myriad of molecular techniques most of which involves nucleic acid amplification (NAA) for the rapid identification of mycobacterial isolates from cultures or even directly from clinical specimens have contributed immensely to the early diagnosis of tuberculosis. Most of these NAA tests are nevertheless fraught with various limitations, thus the search for a rapid, sensitive and specific way of diagnosing tuberculosis is still an active area of research. The search has expanded to areas that would otherwise not have been considered ‘conventional’ in diagnostic mycobacteriology. One of such areas is mass spectrometry. This study joins the relatively few studies of its kind encountered in available literature to establish the ground work for the application of mass spectrometry, specifically Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-ToF MS) in the field of diagnostic mycobacteriology. This is an area which is in need of the speed, sensitivity and specificity that MALDI-ToF technique promises to offer. Since this technology is still in its infancy, the use of utmost care in the preparation of reagents, and the handling and storage of the organisms used to generate reference mass spectra for the database cannot be overemphasized. Similarly, the optimization of certain crucial experimental factors such as inactivating method and choice of matrix is of paramount importance. The main aim of this thesis was to generate a database of reference mass spectra fingerprints of selected (repository) Mycobacterium species. This necessitated the standardization of an experimental protocol which ensured that experimental factors and the various instrument parameters were optimized for maximum spectra generation and reproducibility. A standard operating procedure (SOP) for generating the database of reference mass spectra finger print of selected Mycobacterium species was developed and used to investigate the ability of the database to differentiate between species belonging to the same clinical disease complex as well as the nontuberculosis complex. The findings of this study imply that if the defined protocol is followed, the database generated has the potential to routinely identify and differentiate (under experimental conditions) more species of Mycobacterium than is currently practical using PCR and its related techniques. It is therefore a realistic expectation that when the database is clinically validated and tested in the next phase of the study, it will contribute immensely to the diagnosis of tuberculosis and other mycobacterioses. It will also aid in the identification of emerging pathogens particularly amongst the non-tuberculous mycobacteria.

Thesis (MSc MedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background The QuantiFERON In-Tube (QFT IT) assay is an Interferon-gamma release assay (IGRA) which is currently used to detect Mycobacterium tuberculosis (M. tb) infection. It however cannot differentiate between latent infection and active tuberculosis (TB) disease. In an attempt to improve this tool to accurately diagnose active TB, the release of a variety of markers should be assessed in combination with Interferon gamma (IFN- γ). Luminex analysis was previously done on QFT plasma and promising candidates were identified which could be of great value in treatment response studies. IFN-γ ELISpot, are not only used to detect M.tb infection, but is also implicated in vaccine trails to assess immunogenicity. The IFN-γ ELISpot and flow cytometry are the most common assays to assess these phenomena during clinical trials. Our aim therefore was to develop a multi platform immune analysis assay using the QFT IT system. Study design and method The first approach of this study was to optimize the QFT IT assay for flow cytometry applications. The following questions formed part of the optimization study: How does the QFT whole blood assay (QFT-WBA) compare to the currently used WBA? Is antigen re-stimulation required after the initial incubation time and for how long should cells be re-stimulated in the presence of Brefeldin A? The second approach was to use the optimized QFT-WBA for community controls (CTRL), household contacts (HHC) and TB cases, which were recruited from the high TB incidence areas Ravensmead, Uitsig and Elsies River. The infection status of each participant was determined by IFN-γ ELISA and Luminex analysis was performed to measured wide range of cytokine expression. In addition immune cell markers like CD14, CD4, CD8, CD19, and T cell receptor gamma delta (TCRγδ) were characterized; polyfunctional characteristics (IFN-γ, Tumor necrosis factor-alpha (TNF-α) and Interleukin-2 (IL-2)) and proliferation (Ki-67+) of T cells determined by flow cytometry. Results After stimulating the whole blood of the study participants for 22 hours with the M. tb specific antigens, early secreted antigenic target 6 kDa (ESAT-6), culture filtrate protein-10 kDa (CFP-10) and TB7.7 the levels of TNF-α producing CD4 T cells were elevated in TB cases compared to HHCs. After stimulating the whole blood for 6 days TNF-α producing T cells declined in TB cases and HHC showed a higher expression. CD40L+CD4+ (p=0.0225) was increased in HHC while IL-9+CD8+ (0.3230) was decreased in HHC compared to TB cases. Other markers such as IL-5(AG-NIL), IL-13(Ag- NIL), FGF basicAg, GM-CSFNIL, VEGFNIL/(Ag-NIL), MIP-1βAg and MCP-1Ag/(Ag-NIL) showed significant differences between HHC and TB cases. Conclusions The responses in the QFT-based assay were generally comparable to the WBA that is routinely used. The differences of TNF-α expression seen in QFT-WBA and QFTLPA could be explained by the fact that effector T cell responses were measured in the short term assay and the central memory T cell responses in the long term assay. Our study therefore shows that the QFT-based tests can be used to simultaneously assess a wide range of immunological markers and not only IFN-γ expression. / AFRIKAANSE OPSOMMING: Agtergrond Die QuantiFERON In Tube (QFT IT) toets is ‘n Interferon-gamma vrystellingstoets (IGRA) wat huidiglik dien as ‘n maatstaf van Mycobacterium tuberculosis (M. tb) infeksie. Hierdie toets kan egter nie onderskei tussen latente infeksie en aktiewe tuberkulose (TB) nie. ‘n Noemenswaardige verbetering in die vermoë van hierdie toets om aktiewe TB te diagnoseer, berus op die studie van ‘n verskeidenheid vrygestelde merkers, insluitend Interferon gamma (IFN-γ). In vorige Luminex studies op QFT plasma, is belowende kandidate geïdentifiseer wat van groot waarde kan wees vir studies wat fokus op die reaksie tot behandeling. Die IFN-γ ELISpot dien nie net as ‘n maatstaf van M.tb infeksie nie, maar word ook in vaksienproewe betrek om die aard van immuniteit te ondersoek. Die IFN-γ ELISpot toets sowel as vloeisitometriese toetse, is van die mees algemene toetse om hierdie verskynsels te meet, tydens kliniese proewe. Die doel van hierdie studie was dus om die QFT IT sisteem te ontwikkel as ‘n basis vir ‘n multiplatform immunologiese analiseringstoets. Studie ontwerp en metode Die inleidende benadering van hierdie studie was die optimisering van die QFT IT toets, vir vloeisitometrie doeleindes. Die volgende vrae het deel uitgemaak van die optimiseringstudie: Hoe vergelyk die QFT heelbloedtoets (QFT-WBA) met huidige WBAs wat in gebruik is? Word meermalige antigeenstimulasies benodig na die oorspronklike inkubasieperiode en hoe lank moet die tydperk wees vir sellulêre opvolgstimulasie, in die teenwoordigheid van Brefeldin A? As ‘n tweede benadering, was om die geoptimiseerde QFT-WBA te gebruik vir gemeenskapskontroles (CTRL), huishoudelike kontakte (HHC) en TB gevalle. Al drie hierdie groepe was opgeneem uit Ravensmead, Uitsig en Elsies Rivier, areas met betreklik hoë vlakke van TB infeksie. Elke persoon in die studie se vlak van infeksie is vasgestel met behulp van die IFN-γ ELISA en Luminex analiese was uitgevoer, om ‘n wye verskeidenheid uitdrukkingsvlakke van sitokiene te meet. Dies meer, was immuunselmerkers soos CD14, CD4, CD8, CD19 en T sel reseptor gamma delta (TCRγδ) gekarakteriseer. Meervuldige funskionele karakteristieke (IFN-γ, Tumor nekrose faktor-alpha (TNF-α) en Interleukin-2 (IL-2)) en vermenigvuldiging van T-selle, was vasgestel deur middel van vloeisitometrie. Resultate Nadat die heelbloed van studiedeelnemers gestimuleers was met M. tb spesifieke antigene, vroeë afskeidings antigeniese teiken 6kDa (ESAT-6), kultuurfiltraatproteïn 10kDa (CFP-10) en TB7.7, vir 22 uur, was gevind dat vlakke van TNF-α produserende CD4 T selle hoër was in TB pasïente, in vergelyking met HHCs. Nadat die heelbloed vir 6 dae gestimuleer was, het die vlak van TNF-α produserende T-selle afgeneem in TB pasïente, terwyl dit hoër was in HCC. CD40L+CD4+ (p=0.0225) het hoër vlakke bereik in HHC, terwyl IL-9+CD8+ (0.3230) vlakke afgeneem het, in vergelyking met TB pasïente. Ander merkers soos,onder andere, IL-5(AG-NIL), IL-13(Ag-NIL), FGF basicAg, GMCSFNIL, VEGFNIL/(Ag-NIL), MIP-1βAg and MCP-1Ag/(Ag-NIL), het noemenswaardige verskille geopenbaar tussen HHC en TB pasïente.

Thesis (MCurr)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Taking into consideration the long duration of standard treatment for Mycobacterium tuberculosis (TB), the high prevalence of HIV co-infection and the growing prevalence of drug-resistant TB, there is an urgent need for improved treatment approaches for TB and HIV. However, there is inadequate information regarding the burden being placed on the Department of Health (DOH) systems by the current treatment of patients established on Antiretroviral Therapy (ART) who are newly diagnosed with TB, and by their clinical management. The aim of the study was to determine what proportion of patients established on ART were newly diagnosed with TB, and what their clinical and treatment outcomes were in different public sector settings in the eThekwini Region, KwaZulu-Natal (KZN). Approval for the study was obtained from the Human Research Committee of Stellenbosch University and from the Biomedical Research Committee, KZN. The study used a retrospective, quantitative, cohort technique at both TB and ART clinics at three sites in the eThekwini region, KZN. These sites were DOH clinics and were selected as they all had a TB clinic and a DOH-registered ART clinic. The study focused on a period of one year prior to a patient established on ART developed TB. The study population comprised all TB patients who attended the selected DOH clinics. A data collection tool was developed and pilot-tested. A small sample of patient files (n=15, representing 2% of the study population) was randomly selected; five from each site. The files and data were excluded from the main study. A total of 1824 files (579 from the TB clinics and 1245 from the ART clinics) were reviewed. The data were captured into an electronic database (EpiData Version 3.3) and analyzed using STATA (Version 11.0) with the assistance of a statistician. The findings show that of the study sample from the TB clinics (N=579), 78% (454/579) were newly diagnosed with TB. Of the new TB cases, 90% (409/454) had pulmonary TB and 71% (413/579) were HIV-positive. Nearly 50% (68/137) of the patients had commenced ART prior to TB diagnosis and treatment, and 14% (19/137) had commenced ART after TB. Of those who commenced ART prior to TB diagnosis and treatment, 29% (20/68) had commenced ART more than three months prior to acquiring TB. The findings from the ART clinics show that of the files (N=1245) reviewed, 40% (501/1245) had TB, and of these 8% (42/501) developed TB after three months or more of ART. Missing data in the patient medical files was a major challenge. The lack of recorded data about ART in the TB clinics and about TB in the ART clinics suggests suboptimal clinical management and poor integration of HIV and TB services. It was therefore not possible to derive a combined HIV-TB outcome measure. Recommendations to promote and implement the integration of TB and HIV services included policy changes and implementation, management and practice suggestions, education and training to integrate TB/HIV services and increase research to identify gaps in clinical management and to improve integration of services. / AFRIKAANSE OPSOMMING: Met inagneming van die lang duur van die standaard behandeling vir Mycobacterium tuberkulose (TB), hoë voorkoms van MIV-infeksie en die groeiende voorkoms van dwelmweerstandige TB, is daar ’n dringende behoefte aan verbeterde behandelingbenaderings vir TB en MIV. Daar is egter ’n gebrek aan inligting oor die las geplaas op die Departement van Gesondheid (DvG) se stelsels deur die huidige behandeling van pasiënte op antiretrovirale terapie (ART) wat gediagnoseer is met TB en deur hul kliniese bestuur. Die doel van die studie was om vas te stel watter persentasie van pasiënte wat op ART gevestig is, wel met TB gediagnoseer is, en wat hul kliniese en behandeling-uitkomste was in verskillende openbare-sektorinstellings in die eThekwini-streek, KwaZulu-Natal (KZN). Goedkeuring vir die studie is verkry van die Menslike Navorsingskomitee van die Universiteit van Stellenbosch en van die Biomediese Navorsingskomitee, KZN. Die studie het gebruik gemaak van ’n retrospektiewe, kwantitatiewe ‘cohort’-tegniek by beide TB en ARB-klinieke op drie plekke in die eThekwini-streek, KZN. Hierdie terreine was DvG-klinieke en is gekies omdat hulle almal oor ’n TB-kliniek en 'n DvGgeregistreerde ART-kliniek beskik. Die studie het gefokus op ’n tydperk van een jaar voor ’n pasiënt wat op ART is, TB ontwikkel het. Die studiepopulasie bestaan uit alle TBpasiënte wat die geselekteerde DvG-klinieke bygewoon het. ’n Data-insamelinginstrument is ontwikkel en getoets. ’n Klein voorbeeld van die pasiëntlêers (n = 15, 2% van die studie bevolking verteenwoordig) is ewekansig gekies: vyf uit elke plek, en die data is vervat in ’n elektroniese databasis (EpiData Version 3,3). ’n Totaal van 1824 lêers (579 in die TB-klinieke en 1245 lêers in die ART-klinieke) is ondersoek. Die data is ontleed deur gebruik te maak van Stata (weergawe 11,0) met die hulp van ’n statistikus. Die bevindinge toon dat van die studiemonster in die TB-klinieke (N = 579), 78% (454/579) met TB gediagnoseer is. Van die nuwe TB-gevalle, het 90% (409/454) pulmonêre TB gehad en was 71% (413/579) MIV-positief. Byna 50% (68/137) van die pasiënte het ART begin vóór hulle TB-diagnose en -behandeling, en 14% (19/137) ART ná TB. Van dié wat ART voor TB-diagnose en -behandeling begin het, het 29% (20/68) meer as drie maande voor die opdoen van TB met ART begin. Die bevindinge van die ART-klinieke toon dat van die lêers (N = 1245) wat bestudeer is, 40% (501/1245) TB het, en hiervan het 8% (42/501) TB na drie of meer maande van ART ontwikkel. Ontbrekende data in die pasiënt se mediese lêers was ’n groot uitdaging. Die gebrek aan aangetekende data oor ART in die TB-klinieke en oor TB in die ART-klinieke dui op suboptimale kliniese bestuur en swak integrasie van MIV- en TB-dienste. Dit was dus nie moontlik om ’n gesamentlike MIV-TB uitkomsmaatreël af te lei nie. Aanbevelings om die integrasie van TB- en MIV-dienste te bevorder en te implementer, het beleidveranderinge en -implementering ingesluit, asook bestuur- en praktykvoorstelle, onderwys en opleiding om TB-/MIV-dienste by DvG-vlak te integreer en meer navorsing om gapings in die kliniese bestuur te identifiseer en die integrasie van dienste te verbeter.

Thesis (PhD (Molecular Biology and Human Genetics))--University of Stellenbosch, 2005. / 157 leaves single sided printed, preliminary pages i-xvii and numbered pages 1-141. Includes bibliography, and abbreviations and a list of figures. / ENGLISH ABSTRACT: A gene coding for Arylaminie N-acetyltransferase (NAT) has been found in Mycobacterium tuberculosis, the casual agent of tuberculosis (TB). N-acetyltransferase acetylates and inactivates isoniazid (INH), which is a front line drug used in TB therapy. A guanine to adenine SNP at basepair 619 (G619A) has previously been identified in this gene, which results in a glycine to arginine change at amino acid 207 (G207R) (Upton et al. 2001). In this study the nat gene was further characterised. The frequency of the G619A SNP was analysed in 37 M tuberculosis strain families found in the Western Cape Province of South Africa, and it was found that the G619A SNP is conserved in two strain families (strain family 3 and strain family 28). Further sequence analysis identified a new thymine to cytosine SNP at base-pair 529 (T529C) resulting in a tyrosine to histidine change at amino acid 177 (Yl77H). This SNP was found only in isolates from strain family 3. These results imply that these SNPs may be used in epidemiology studies to classify isolates into these strain families. Using Real Time PCR, the expression of nat in M bovis BCG and M tuberculosis (reference strain H37Rv) was determined over a 7 and 28 day growth cycle, respectively. Using 16S rRNA as an endogenous control, the nat gene was shown to be expressed early during the growth curve and reach its maximum expression level at approximately mid-log phase. The expression of nat was induced in drug susceptible M tuberculosis isolates (reference strain H37Rv and isolate 1430 containing both SNPs) exposed to INH at a concentration of O.Oll-lg/ml, but minimal change in expression was observed in resistant isolates (isolate 816) exposed to INH at the same concentration. Mycobacterium bovis BCG cultures exposed to INH, at a final concentration of 0.28I-lg/ml, showed an increase in protein production. The increase of nat mRNA and NAT protein in M tuberculosis and M bovis BCG, respectively, implies that INH affects the expression of NAT. The NAT protein was localised to all fractions of the cell in Mycobacterium smegmatis, M bovis BCG and M tuberculosis, using the Western blot technique. However, protein fractions from the cell envelope region showed a protein (detected with specific NAT antibodies) that ran at a higher molecular weight (MW). This implies that the cytosolic hydrophilic NAT undergoes some type of post-translational process that may make it hydrophobic, and enable it to pass into the cell envelope region. These results show for the first time how nat is expressed during the entire growth cycle of M tuberculosis and M. bovis BeG. It was shown that nat is expressed early during the growth cycle of the bacterium reaching maximum expression levels at mid-log phase. These results are in concordance with those obtained using M. smegmatis nat mutants, which taken together, show that early expression of nat is important for early growth and development of mycobacteria. The results in this study also showed that NAT appeared to be translocated into the cell envelope of the bacterium, implying that NAT may be involved in one of the pathways needed for complete formation of the cell envelope. These results suggest that NAT may be an important target for drug development, as inhibitors of NAT could result in hindered growth and hence spread of the bacterium within its host. Inhibitors may also result in the incomplete development of the cell wall, enabling the host to combat the disease using its own immune system.

Doctor Educationis / Ototoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).

[pt] TV Digital é um dos assuntos mais discutidos na atualidade, devido ao grau de influência que ela exerce sobre toda população, pelas inovações propostas que conseqüentemente trarão novas e interessantes facilidades aos espectadores, e pela corrida tecnológica que ela está desenvolvendo. O objetivo deste trabalho é o desenvolvimento de uma ferramenta de análise de desempenho do padrão de TV Digital japonês ISDB-T. Através dela é possível identificar as características positivas e negativas do sistema, fazer uma análise mais detalhada do padrão e identificar os benefícios que esta nova tecnologia trás para os telespectadores. Ainda, o desempenho da transmissão é avaliado através dos resultados gerados pela ferramenta, sob forma de gráficos, que servem como método comparativo entre as diversas configurações possíveis no sistema. Estas comparações permitem a identificação da configuração ótima para cada tipo do canal. / [en] Digital TV is one of the most discussed subjects nowadays, due to the influence they exerce in population, the services offered by innovations and the technological race developed. A tool which has been developed to asses the quality of ISDB-T system trough the simulation will be discussed in this work. This tool enable us to test the data transmission performance of all ISDB-T system configuration. Situations simulated involves AWGN channel and, to evaluate one most disturbing interference on television signal, AWGN plus multipath channel is also under consideration. The results are shown in graphics, which allow comparisons among all possible configurations and to know the performance of this system.

Despite decades of the implementation of the directly observed therapy short-course (DOTS), Sierra Leone is ranked among the 30 highest TB-burdened countries. Several factors account for unfavorable treatment outcomes, among which are patient characteristics. Previous studies have only focused on treatment compliance without any consideration for the factors that lead to noncompliance to treatment. The purpose of this study was to investigate patient characteristics that are associated with treatment noncompliance (treatment not completed) among TB patients undergoing the DOTS program in Sierra Leone. A retrospective longitudinal quantitative design was used to analyze secondary data from the completed records of 1,633 TB patients, using the Andersen's behavioral model of health services utilization as a theoretical framework work. Descriptive statistics and bivariate and multivariate logistic regressions were used to analyze the data. The results show that there was no significant association between treatment completion and age, gender, and TB-case category. On the other hand, being HIV-positive decreases the odds of treatment completion. Also, the educational level, geographic location, and year of treatment were significantly associated with treatment completion. Overall, program performance improved as the number of dropouts decreased significantly between 2013 and 2015. The social change implication of this study was that it identified HIV-positive patients and rural communities as areas needing specific attention such as the assignment of case managers to ensure compliance thereby improve DOTS program performance, thereby reducing the incidence and transmission of TB

Tuberculosis (TB) is a major public health problem in many parts of the world. Nigeria is one of the 30 countries in the world that has the highest burden of TB. Private medical practitioners in Nigeria play an important role in health care delivery. Motivating them to adhere to TB treatment guidelines in managing persons suspected of having TB or diagnosed with the disease is one of the strategies employed by the National Tuberculosis Program to Reduce the Burden of TB. Few studies were identified which used qualitative study approaches to study the perceptions of these practitioners towards the TB treatment guidelines. The overarching question asked the study participants centered on eliciting their perceptions towards the guidelines. Guided by the theory of planned behavior, this qualitative narrative study explored the perceptions of private medical practitioners in Anambra State, Nigeria towards the Nigerian National TB Treatment Guidelines. To elicit these perceptions, in-depth interviews were conducted on 11 purposefully selected practitioners. Data analysis comprised coding of data obtained and extracting themes from them. The QSR Nvivo 11 helped to manage data. The main finding of the study was that the practitioners perceived the treatment guidelines to be adequate to meet most of their needs in the diagnosis and treatment of TB patients. Other key findings were that provision of financial incentives and regular training will motivate collaboration with the TB program and adherence to the guidelines. Positive social change may occur by insight being gained into how private medical practitioners view the treatment guidelines and how this knowledge will lead to improved management of TB patients. This may in turn result in the reduction in the morbidity and mortality associated with TB in Nigeria.

Thesis (M. Pharm) --University of Limpopo, 2013 / Tuberculosis (TB) threatens the public health all over the world. South Africa is ranked fifth on the list of 22 high burden countries. SA has not achieved the international targets for cure rate and default rate yet. This is attributed to high HIV/AIDS prevalence and emergence of multi- drug resistant TB. Limpopo Province experiences poor TB treatment outcome, in spite of the adoption of strategies that proved globally that they can improve the outcome. The factors affecting treatment outcome in Limpopo Province are as yet undocumented. The specific objectives of this study were to determine the demographic profile of TB patients in the Limpopo Province; to investigate the treatment outcomes and to establish the relationship between age, gender, HIV status, treatment regimen and health facility level and the treatment outcomes in patients diagnosed with pulmonaryTB for period between 2006- 2010, inclusive, in Limpopo Province. Method Retrospective data for the period between 2006 and 2010 (inclusive) were reviewed, and 1200 records of cases of confirmed TB patients were sampled from the ETR.net provincial database. All these patients were diagnosed and treated according to guidelines adopted by the national TB control programme. Standard WHO definitions were used to classify the TB treatment outcome. Chi squire test was used to investigate the association between age, gender, diagnostic category and treatment regimen and treatment outcome. Results Of the 1200 TB cases sampled, 656 (54%) were male. Most of them fell within the age group 22- 55 years (n=871; 72.5%)). According to diagnostic category, 1035 (86.2%) were new cases; 962 (80.1%) cases received regimen I (two months of rifampicin [R], isoniazid [H], pyrazinamide [Z} and ethambutol [E] followed by four months of rifampicin and isoniazid, 2RHZE+ 4RH); 893 (74.4%) cases had successful treatment; 118 (9.8%) defaulted on treatment; 26 (2.2%) had treatment failure, and 163 (13.6%) died. There was a strong association between age (P <0.001), diagnostic category (P < 0.001), treatment regimen (P < 0.001), and health facility level (P< 0.001) and treatment outcome. The success treatment was highly significant (P <0.001) for the cases that fell within the age group 3- 6 years, those that were diagnosed as new cases, those that received treatment at mine health facilities or were treated with regimen III (2RHZ + 4RH). While the default rate was highly significant (P< 0.05) for the cases aged 7- 12 or 22- 55 years, patients that had history of defaulting, and those that received treatment at a community health centre or village health facilities –. treatment failure was highly significant (P< .05) for Those fell within age group 22-55 or 56- 74 years, those had initial treatment failure, those that received treatment at hospital or mobile health facilities or treated with regimen II (3RHZES + 5RH) while the death rate was highly significant (P< 0.05) for the cases either fall within age group 0-2, 22- 55 or 56- 74 years, had initial failure, received treatment at hospital or village health facilities or treated with regimen). The un success rate was very highly significant (P< 0.001) for those either characterized by; fall within age group 22- 55 years, had initial failure, received treatment at hospital or village health facilities or treated with regimen II. Conclusion TB treatment outcome are poor in the Limpopo Province, particularly among patients with previous history of TB treatment, those receiving treatment in hospitals, or those being treated with first line regimen II. This situation requires that the TB control programme and other relevant programmes be strengthened, for instance through integration at facility level, towards more effective response to the challenges which hamper progress towards international targets on TB. Further studies are needed to address the effect of HIV status and AIDS, CD4+ cell counts, anti-retroviral therapy (ART), cotrimoxazole preventive therapy (CPT) and radiological presentation, and their effect on TB treatment outcome in Limpopo Province. Those data are not routinely captured on ETR.net, hence were not included in the present study.