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Master of Public Health - MPH / Background: As South Africa’s HIV programme increases in size, increasingly complex HIV/TB cases occur that are often beyond the clinical scope of primary health care clinicians. In the Eastern Cape (EC) province, health facilities are geographically widespread, with a discrepancy of specialist availability outside of academic/tertiary institutions. The use of WhatsApp, a Mobile Instant Messaging (MIM) application, could facilitate learning and mentoring of primary healthcare clinicians in peripheral facilities. The aim of this study is to describe this app and its use as an alternative learning tool to improve clinician access to specialized management of complicated HIV/TB cases, as part of Continuing Medical Education (CME). Method: A an observational, descriptive cross-sectional study was conducted among a group of clinicians from the EC province that formed part of a Wits RHI WhatsApp HIV/TB clinical discussion group from January 2016 to July 2017. Data was collected using a structured anonymous internet questionnaire, distributed to the clinicians that formed part of the WhatsApp group, informed consent being obtained from participants prior to completion. Data was analysed with Epi Info, using descriptive and analytic statistics. Frequency distributions and cross tabulations were generated and bi-variate analysis was done to determine significant associations between relevant variables.

MSc (Med), Epidemiology and Biostatistics, Faculty of Health Sciences, University of the Witwatersrand / Introduction: Tuberculosis (TB) persists as a serious global public heath problem of a magnitude requiring urgent attention. The increase in new cases of TB in African countries where the prevalence of HIV is relatively low has been associated with other host and environmental factors. There is little or no comparable data on the association between host and environmental related factors and TB incidence in low HIV prevalence regions of South Africa. Objectives: This study aims to investigate host and environmental factors associated with incident TB in one region of South Africa. Methods: 3493 TB-free participants were recruited, and baseline data collected at the beginning of 2003 in the Lung Health Study in Ravensmead and Uitsig, Cape Town, South Africa. The TB register was used to identify new cases among the 3493 participants between 2003 and 2007. Results: Of the 3493 study participants, 109 developed TB; i.e. 57 males and 52 females. The incidence of TB in the Ravensmead and Uitsig study population was 632 per 100 000. Cohabiting, OR= 2.09 (95% CI= 1.05 - 4.17), smoking, OR= 2.19 (95% CI= 1.48 - 4.14), and history of imprisonment OR= 1.88 (95% CI= 1.09 - 3.23) were all statistically associated with TB incidence in multiple logistic regression models. The summary population attributable fraction for these three factors was 53.2%. Conclusions: TB incidence was high in this community. Cigarette smoking was one of the most important predictors of TB incidence, and the proportion of smokers in this population was relatively high. TB control and prevention strategies need to focus on interventions which will reduce or limit the impact of TB risk factors.

Abstract Introduction: Tuberculosis carries a high mortality in the days immediately after treatment. It is also the commonest cause of adrenal insufficiency in the developing world. Rifampicin is a potent hepatic enzyme inducer, and may contribute to adrenal insufficiency by accelerating cortisol breakdown. The aim of the study was to determine whether rifampicin induced accelerated catabolism of corticosteroids. Methods: A prospective, randomised study comparing adrenal function in 20 patients with pulmonary tuberculosis in the first five days treated with two different antituberculosis regimens, one containing rifampicin, and the other ciprofloxacin. Results: Demographic, clinical and laboratory results were similar in both groups. Both groups showed a statistically significant and similar decrease in morning cortisol, with similar responses to ACTH stimulation at both 30 and 60 minutes before and after four days of treatment. In the entire cohort, 40% demonstrated an incremental cortisol rise of <250nmol/l after ACTH stimulation on day 1. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol:DHEA-S ratio. No patient demonstrated overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any electrolytes, hormones or calculated serum osmolality. Conclusions: Rifampicin did not additionally impair adrenocortical function during the initial period of therapy.

Convincing evidence that activated macrophages play a critical role in control of mycobacterial diseases has been clearly established from animal and in-vitro studies. Macrophages produce a variety of molecules upon appropriate stimulation, which act in concert towards eventual killing of bacteria. People with SUb-optimal macrophage activation are more susceptible to infection with intracellular pathogens. My project aims to answer two questions relating to genetic regulation of macrophage activation in tuberculosis: do macrophage genes regulate microbial-induced responses and do macrophage genes influence susceptibility to tuberculosis? A whole blood assay was used to investigate IFN-y responsiveness in healthy individuals and those who develop tuberculosis in The Gambia. Cytokine responses to lipopolysaccaride (LPS), Lipoarabinomanan (LAM) and the enhancing effect of IFN-y on these stimulants were measured. LPS induced IL-l 0 levels was higher in recovered TB cases than in controls (p=0.02). LPS and LAM induced cytokines were highly correlated (p<0.0001) similarly, levels of IL-IB and TNF were highly correlated (P<O.OOOl). Ten new polymorphisms were detected by sequencing specific regions within the promoter of IFNG and IFNGRI genes. One, a double deletion of TT in the promoter of IFNGR1, abolishes a GAS binding site at position -470 and another, a CIT transition, is close to a putative NF-kappa B binding site at position -56 in the IFNGRI gene (positions are relative to the transcription start site). These along with published polymorphisms at some macrophage candidate gene loci were genotyped. Comparisons were made to determine whether different alleles at candidate gene loci influence macrophage cytokine responses. TNFA-863 , LTA NeaL lL1RN and NRAMPl (469+14) polymorphisms were shown to influence macrophage cytokine levels significantly. TNFA-863 was associated with LPS induced TNF (P < 0.05), LTA was associated with LAM and LPS induced TNF and 1L-~ levels (p < 0.01). NRAMPI (469+14) was associated with LAM induced 1L-I0 (P<O.OI) and fL1RN was associated with LAM and LPS induced 1L-l 0 (P<0.05). Alleles 1 (G) of TNFA-308, 2 (A) of TNFA-238, 1 (T) of fL1B-511 and 2 (ddeVT) of fFNGR1 were significantly associated with TB in the panel of samples studied. For the microsatellite markers, allele 5 of fL9 (TG)n repeat in intron 4 and allele 3 of the Z DNA promoter polymorphism NRAMP 1, were significantly associated with TB. NRAMP 1 !NT 4 variant was significantly associated with both TB and LAM induced 1L-I0 secretion.

Master of Public Health - MPH / Background: As South Africa’s HIV programme increases in size, increasingly complex HIV/TB cases occur that are often beyond the clinical scope of primary health care clinicians. In the Eastern Cape (EC) province, health facilities are geographically widespread, with a discrepancy of specialist availability outside of academic/tertiary institutions. The use of WhatsApp, a Mobile Instant Messaging (MIM) application, could facilitate learning and mentoring of primary healthcare clinicians in peripheral facilities. The aim of this study is to describe this app and its use as an alternative learning tool to improve clinician access to specialized management of complicated HIV/TB cases, as part of Continuing Medical Education (CME). Method: A an observational, descriptive cross-sectional study was conducted among a group of clinicians from the EC province that formed part of a Wits RHI WhatsApp HIV/TB clinical discussion group from January 2016 to July 2017. Data was collected using a structured anonymous internet questionnaire, distributed to the clinicians that formed part of the WhatsApp group, informed consent being obtained from participants prior to completion. Data was analysed with Epi Info, using descriptive and analytic statistics. Frequency distributions and cross tabulations were generated and bi-variate analysis was done to determine significant associations between relevant variables.

<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>

The outcome of an infection is often determined by the qualitative nature of the immune response generated against the infectious agent. Various intracellular pathogens, including those that cause leprosy, tuberculosis, leishmaniasis, and most probably malaria and AIDS appear to require a predominant cell-mediated, Th1, response for effective containment, whereas the generation of a mixed Th1/Th2 or predominantly Th2 response is associated with progressive disease. Therefore, any attempt to develop universally efficacious vaccination against these pathogens must generate an immunological imprint that ensures a strong and stable cell-mediated response upon natural infection with the relevant pathogen. We report here critical tests of a strategy designed to achieve such an imprint using Bacille-Calmette-Guérin (BCG) vaccine. BCG vaccine is an attenuated form of M. bovis, the causative agent of tuberculosis in cattle, and is the most widely used vaccine in humans. However, considerable uncertainty still surrounds its efficacy against tuberculosis both in man and animals. As the protective dose is not known, BCG has been given at the maximum tolerable dose. However, recent studies in mice and other animals have shown that the dose of an antigen can be a critical factor in determining the type of immune response generated. I tested the general hypothesis that low dose vaccination would preferentially induce cell-mediated immune response and generate a Th1 imprint that can protect the host against intracellular pathogens in the particular case of mycobacteria. To this end, both adult and newborn mice were vaccinated with different doses of BCG or saline and cell-mediated and humoral immune responses were assessed at different times post-vaccination. Several weeks after vaccination, mice from each group were challenged with a dose of BCG that induces a mixed Th1/Th2 response in naïve mice, and the T-cell and antibody responses were assessed using ELISPOT and ELISA assays, respectively. The splenic bacterial burden was also determined using colony formation on agar plates. <p>Our results show that the class of immunity induced by BCG depends on the dose employed for vaccination, independent of the route of administration and the age and strain of mice used. In all cases, lower doses induce an exclusive cell-mediated, Th1, response with no antibody production, while higher doses induce either a mixed Th1/Th2 response or a predominantly Th2, humoral response, with higher titers of both IgG1 and IgG2a antibodies. Following intravenous high dose BCG challenge, all mice in the vaccinated groups developed a Th1 response associated with a more efficient clearance of BCG from the spleen. The greatest clearance of mycobacteria was generated following vaccination with lower doses, as low as 33 cfu of BCG. In addition, our findings demonstrate that newborn mice are not inherently biased towards generating Th2 responses, but they can generate Th1 responses and Th1 imprints if appropriate vaccination protocols (dose, route and time) are employed. Furthermore, subcutaneous exposure of young mice to environmental mycobacteria can induce a mixed Th1/Th2 response that can abrogate the potential to generate Th1 responses and Th1 imprints upon vaccination with low doses of BCG vaccine. Low dose neonatal BCG vaccination can circumvent the interference caused by impingement of environmental mycobacteria on the immune system. Therefore, our observations strongly support a neonatal low dose BCG vaccination strategy to provide universally efficacious protection against infections by pathogenic mycobacteria.

The outcome of an infection is often determined by the qualitative nature of the immune response generated against the infectious agent. Various intracellular pathogens, including those that cause leprosy, tuberculosis, leishmaniasis, and most probably malaria and AIDS appear to require a predominant cell-mediated, Th1, response for effective containment, whereas the generation of a mixed Th1/Th2 or predominantly Th2 response is associated with progressive disease. Therefore, any attempt to develop universally efficacious vaccination against these pathogens must generate an immunological imprint that ensures a strong and stable cell-mediated response upon natural infection with the relevant pathogen. We report here critical tests of a strategy designed to achieve such an imprint using Bacille-Calmette-Guérin (BCG) vaccine. BCG vaccine is an attenuated form of M. bovis, the causative agent of tuberculosis in cattle, and is the most widely used vaccine in humans. However, considerable uncertainty still surrounds its efficacy against tuberculosis both in man and animals. As the protective dose is not known, BCG has been given at the maximum tolerable dose. However, recent studies in mice and other animals have shown that the dose of an antigen can be a critical factor in determining the type of immune response generated. I tested the general hypothesis that low dose vaccination would preferentially induce cell-mediated immune response and generate a Th1 imprint that can protect the host against intracellular pathogens in the particular case of mycobacteria. To this end, both adult and newborn mice were vaccinated with different doses of BCG or saline and cell-mediated and humoral immune responses were assessed at different times post-vaccination. Several weeks after vaccination, mice from each group were challenged with a dose of BCG that induces a mixed Th1/Th2 response in naïve mice, and the T-cell and antibody responses were assessed using ELISPOT and ELISA assays, respectively. The splenic bacterial burden was also determined using colony formation on agar plates. <p>Our results show that the class of immunity induced by BCG depends on the dose employed for vaccination, independent of the route of administration and the age and strain of mice used. In all cases, lower doses induce an exclusive cell-mediated, Th1, response with no antibody production, while higher doses induce either a mixed Th1/Th2 response or a predominantly Th2, humoral response, with higher titers of both IgG1 and IgG2a antibodies. Following intravenous high dose BCG challenge, all mice in the vaccinated groups developed a Th1 response associated with a more efficient clearance of BCG from the spleen. The greatest clearance of mycobacteria was generated following vaccination with lower doses, as low as 33 cfu of BCG. In addition, our findings demonstrate that newborn mice are not inherently biased towards generating Th2 responses, but they can generate Th1 responses and Th1 imprints if appropriate vaccination protocols (dose, route and time) are employed. Furthermore, subcutaneous exposure of young mice to environmental mycobacteria can induce a mixed Th1/Th2 response that can abrogate the potential to generate Th1 responses and Th1 imprints upon vaccination with low doses of BCG vaccine. Low dose neonatal BCG vaccination can circumvent the interference caused by impingement of environmental mycobacteria on the immune system. Therefore, our observations strongly support a neonatal low dose BCG vaccination strategy to provide universally efficacious protection against infections by pathogenic mycobacteria.

In order to investigate the distribution and burden of tuberculosis (TB) in Stockholm County during the period 1989 to 1996, a descriptive study was conducted. The TB cases registered in the central TB register during that period were studied.  Demographic profiles, geographic distribution, disease presentation and diagnosis of registered TB cases were described. During 1989 to 1996, 1022 TB cases were registered in Stockholm County accounting for 23% (1022/4487) of all TB cases in Sweden during that period.  The crude annual incidence was stable, oscillating between 7,1 and 8,1 per 100 000 population. Stratification by national origin showed a decrease of the annual incidence from 4,3 to 3,3 cases per 100 000 in the Swedish born population and an increase from 149,4 to 238,9 among the Africa borns. The overall age distribution of 1022 cases showed a bimodal pattern, peaking among young adults aged 25 to 44 years and among the elderly above 64 years. Stratification by age showed a declining trend in the age group above 64 years. In this age group the proportion of Swedish born was 85%. An increasing trend was observed in the age group 18 to 24 years. In this age group 91% were foreign born. The median age declined from 61 years during 1989 to 37 during 1996. The average annual incidence varied in the different municipalities between 1,3 (Ekerö) and 10,7 (Sundbyberg)per 100 000 population. The highest average annual incidence was found in Spånga parish. Due to an increased number of Africa born TB cases, the annual incidence in Spånga increased three-fold from 18,1 to 48,0 per 100 000 population. Nearly two-thirds (63) of the cases had pulmonary TB, 16% had lymphatic TB and 21 % had other extra –pulmonary lesions. The site of disease showed gender and ethnic differences. Lymphatic TB was more common in females, while pulmonary and other extra- pulmonary TB were more common in males. The highest proportion (42%) of lymphatic TB was found among Asian female cases compared to 4% in the Swedish male cases. Crude county incidence does not reveal geographic and ethnic clustering of TB cases. Clinical manifestations of TB vary depending on sex and ethnic differences. As being a low-incidence county, Sweden could be well suitable for TB eradication. To achieve such goal, the national TB control program need to be restructured in order to facilitate cluster oriented interventions.