Advances in childhood immunisation in South Africa: where to now? Programme managers’ views and evidence from systematic reviews.

Background: The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals. Methods: Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus. Results: Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents’ understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored. Conclusion: In line with the Millennium Development Goals, we have to ensure that our children’s right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders

Immunoproteasome Overexpression Underlies the Pathogenesis of Thyroid Oncocytes and Primary Hypothyroidism: Studies in Humans and Mice

BACKGROUND:Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS:Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE:In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism

Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis

BACKGROUND: Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-TB therapy (ATT) and relationship with mortality. METHODS: We established a microscopy method for direct visualisation of M. tuberculosis bacilli in blood using a novel lysis-concentration protocol and the fluorescent probe, 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). We tested blood using GeneXpert® MTB/RIF-Ultra (Xpert-ultra) and Myco/F lytic culture after processing blood through lysis-wash steps to remove PCR inhibitors and anti-microbial drug carry-over. HIV-positive patients predicted to have MTBBSI gave blood samples 0, 4, 24, 48 and 72 h after ATT initiation. Bacillary loads were quantified using microscopy, Xpert-ultra cycle threshold, and culture time-to-positivity. Pharmacodynamics were modelled using these measures combined on an ordinal scale, including association with 12-week mortality. FINDINGS: M. tuberculosis was detected in 27 of 28 recruited participants; 25 (89%) by blood Xpert-ultra, 22 (79%) by DMN-Tre microscopy, and 21 (75%) by Myco/F lytic blood culture. Eight (29%) participants died by 12-week follow-up. In a combined pharmacodynamic model, predicted probabilities of negative DMN-Tre microscopy, blood Xpert-ultra, or blood culture after 72 h treatment were 0·64, 0·27, and 0·94, respectively, in those who survived, compared with 0·23, 0·06, and 0·71 in those who died (posterior probability of slower clearance of MTBBSI in those that died >0·99). DMN-Tre microscopy of blood demonstrated heterogenous bacillary morphologies, including microcolonies and clumps. Bacillary cell-length varied significantly with ATT exposure (mean cell-length increase 0·13 log-µm/day; 95%CrI 0·10-0·16). INTERPRETATION: Pharmacodynamics of MTBBSI treatment can be captured using DMN-Tre microscopy, blood Xpert-ultra and culture. This could facilitate interventional trials in severe HIV-associated TB. FUNDING: Wellcome Trust, NIH Fogarty International Center, South African MRC, NIHR(UK), National Research Foundation of South Africa

Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry

BACKGROUND: The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease

Genetic variation in TLR genes in Ugandan and South African populations and comparison with HapMap data

Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts

Alcohol use and extramarital sex among men in Cameroon

<p>Abstract</p> <p>Background</p> <p>The spread of HIV in sub-Saharan Africa is believed to be driven by unsafe sex, and identification of modifiable risk factors of the latter is needed for comprehensive HIV prevention programming in the region. Some previous studies suggest an association between alcohol abuse and unsafe sexual behaviour, such as multiple concurrent sexual partnerships and inconsistent condom use in sex with non-spousal non-cohabiting partners. However, most of these studies were conducted in developed countries and the few studies in Africa were conducted among well-defined social groups such as men attending beer halls or sexually transmitted infection clinics. We therefore examined the association between alcohol and extramarital sex (a sign of multiple concurrent sexual partnerships) among men in a population-based survey in Cameroon; a low-income country in sub-Saharan Africa with a high rate of alcohol abuse and a generalised HIV epidemic.</p> <p>Methods</p> <p>We analyzed data from 2678 formally married or cohabiting men aged 15 to 59 years, who participated in the 2004 Cameroon Demographic and Health Survey, using a multivariate regression model.</p> <p>Results</p> <p>A quarter of the men (25.8%) declared having taken alcohol before their last sexual intercourse and 21% indicated that the last sex was with a woman other than their wife or cohabiting partner. After controlling for possible confounding by other socio-demographic characteristics, alcohol use was significantly associated with having extramarital sex: adjusted odds ratio (OR) 1.70, 95% confidence intervals (CI) 1.40 to 2.05. Older age (30–44 years: OR 3.06, 95%CI 2.16–4.27 and 45–59 years: OR 4.10, 95%CI 2.16–4.27), higher education (OR 1.25, 95%CI 1.10–1.45), and wealth (OR 1.71, 95%CI 1.50–1.98) were also significantly associated with higher odds of having extramarital sex. The men were more likely to have used a condom in their last sex if it was extramarital (OR 10.50, 95%CI 8.10–13.66). Older age at first sex (16–19 years: OR 0.81, 95%CI 0.72–0.90 and > 19 years: OR 0.74, 95% CI 0.65–0.87) and being the head of a household (OR 0.17, 95%CI 0.14–0.22) significantly decreased the odds of having sex outside of marriage. Religion and place of residence (whether urban or rural) were not significantly associated with extramarital sex.</p> <p>Conclusion</p> <p>Alcohol use is associated with having multiple concurrent non-spousal sexual partnerships among married men in Cameroon. We cannot infer a causal relationship between alcohol abuse and unsafe sex from this cross-sectional study, as both alcohol use and unsafe sexual behaviour may have a common set of causal personal and social factors. However, given the consistency with results of studies in other settings and the biologic plausibility of the link between alcohol intake and unsafe sex, our findings underscore the need for integrating alcohol abuse and HIV prevention efforts in Cameroon and other African countries with similar social profiles.</p

A survey of knowledge, attitudes and practice of emergency contraception among university students in Cameroon

<p>Abstract</p> <p>Background</p> <p>Unsafe abortion is a major public health problem in low-and-middle income countries. Young and unmarried women constitute a high risk group for unsafe abortions. It has been estimated that widespread use of emergency contraception may significantly reduce the number of abortion-related morbidity and mortality. The purpose of this study was to evaluate the knowledge, attitudes and experiences on emergency contraceptive pills by the university students in Cameroon in order to develop and refine a national health programme for reducing unwanted pregnancies and their associated morbidity and mortality.</p> <p>Methods</p> <p>A convenient sample of 700 students of the University of Buea (Cameroon) was selected for the study. Data was collected by a self-administered, anonymous and pre-tested questionnaire.</p> <p>Results</p> <p>The response rate was 94.9% (664/700). General level of awareness of emergency contraceptive pills was 63.0% (418/664). However, knowledge of the general features of emergency contraceptive pills was low and misinformation was high among these students. Knowledge differed according to the source of information: informal source was associated with misinformation, while medical and informational sources were associated with better knowledge. Although the students generally had positive attitudes regarding emergency contraceptive pills, up to 65.0% (465/664) believed that emergency contraceptive pills were unsafe. Those with adequate knowledge generally showed favourable attitudes with regards to emergency contraceptive pills (Mann-Whitney U = 2592.5, p = 0.000). Forty-nine students (7.4%) had used emergency contraceptive pills themselves or had a partner who had used them.</p> <p>Conclusion</p> <p>Awareness of emergency contraception pills by Cameroonian students is low and the method is still underused. Strategies to promote use of emergency contraception should be focused on spreading accurate information through medical and informational sources, which have been found to be reliable and associated with good knowledge on emergency contraceptive pills.</p

Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.

Tuberculous pericarditis is one of the most severe forms of extrapulmonary tuberculosis, causing death or disability in a substantial proportion of affected people.1,2 In Africa, the incidence of tuberculous pericarditis is rising as a result of the HIV epidemic.3 The effect of HIV infection on survival in patients with tuberculous pericarditis is unknown.2,4 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have a similar outcome to non-infected cases,5 others have shown that there may be an increase in mortality in HIV associated with tuberculous pericarditis.2,6,7 We established a prospective observational study, the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry, to obtain current information on the diagnosis, management and outcome of patients with presumed tuberculous pericarditis living in sub-Saharan Africa, where the burden of HIV infection is the greatest in the world.4,8-10 In this paper, we report the mortality rate and its predictors during the 6 months of antituberculosis treatment among patients enrolled in the regis