Cardio-thoracic ratio is stable, reproducible and has potential as a screening tool for HIV-1 related cardiac disorders in resource poor settings

BACKGROUND: Cardiovascular disorders are common in HIV-1 infected persons in Africa and presentation is often insidious. Development of screening algorithms for cardiovascular disorders appropriate to a resource-constrained setting could facilitate timely referral. Cardiothoracic ratio (CTR) on chest radiograph (CXR) has been suggested as a potential screening tool but little is known about its reproducibility and stability. Our primary aim was to evaluate the stability and the inter-observer variability of CTR in HIV-1 infected outpatients. We further evaluated the prevalence of cardiomegaly (CTR≥0.5) and its relationship with other risk factors in this population. METHODOLOGY: HIV-1 infected participants were identified during screening for a tuberculosis vaccine trial in Khayelitsha, South Africa between August 2011 and April 2012. Participants had a digital posterior-anterior CXR performed as well as history, examination and baseline observations. CXRs were viewed using OsiriX software and CTR calculated using digital callipers. RESULTS: 450 HIV-1-infected adults were evaluated, median age 34 years (IQR 30-40) with a CD4 count 566/mm 3 (IQR 443-724), 70% on antiretroviral therapy (ART). The prevalence of cardiomegaly was 12.7% (95% C.I. 9.6%-15.8%). CTR was calculated by a 2 nd reader for 113 participants, measurements were highly correlated r = 0.95 (95% C.I. 0.93-0.97) and agreement of cardiomegaly substantial κ = 0.78 (95% C.I 0.61-0.95). CXR were repeated in 51 participants at 4-12 weeks, CTR measurements between the 2 time points were highly correlated r = 0.77 (95% C.I 0.68-0.88) and agreement of cardiomegaly excellent κ = 0.92 (95% C.I. 0.77-1). Participants with cardiomegaly had a higher median BMI (31.3; IQR 27.4-37.4) versus 26.9; IQR 23.2-32.4); p<0.0001) and median systolic blood pressure (130; IQR 121-141 versus 125; IQR 117-135; p = 0.01). CONCLUSION: CTR is a robust measurement, stable over time with substantial inter-observer agreement. A prospective study evaluating utility of CXR to identify cardiovascular disorder in this population is warranted

Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different alpha subunit partners of beta2 (i.e., alpha4 and alpha6), the homo-pentameric alpha7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 microg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta2, alpha4, alpha6 and alpha7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, beta2-VEC mice with the beta2 subunit re-expressed exclusively in the VTA, alpha4-VEC mice with selective alpha4 re-expression in the VTA, alpha6-VEC mice with selective alpha6 re-expression in the VTA, and alpha7-KO mice promptly self-administer nicotine intravenously, whereas beta2-KO, beta2-VEC in the substantia nigra, alpha4-KO and alpha6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha4beta2- and alpha6beta2-subunit containing nicotinic receptors (alpha4beta2*- and alpha6beta2*-nAChRs), but not alpha7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mic

A Recent HIV Diagnosis Is Associated with Non-Completion of Isoniazid Preventive Therapy in an HIV-Infected Cohort in Cape Town

Introduction: Despite high rates of successful treatment TB incidence in South Africa remains high, suggesting ongoing transmission and a large reservoir of latently infected persons. Isoniazid preventive therapy (IPT) is recommended as preventive therapy in HIV-infected persons. However, implementation has been slow, impeded by barriers and challenges including the fear of non-adherence. Objective and Methods: The aim was to evaluate predictors of IPT non-completion. One hundred and sixty four antiretroviral therapy (ART)-naïve HIV-infected patients with tuberculin skin test ≥5 mm were recruited from Khayelitsha day hospital and followed up monthly. A questionnaire was used to collect demographic information. Results: The overall completion rate was 69%. In multivariable analysis, there was a 29% decrease in risk of non-completion for every year after HIV diagnosis (OR 0.81; 95% C.I. 0.68–0.98). Self-reported alcohol drinkers (OR 4.05; 95% C.I. 1.89–9.06) also had a four-fold higher risk of non-completion, with a strong association between alcohol drinkers and smoking (χ2 27.08; p<0.001). Conclusion: We identify patients with a recent HIV diagnosis, in addition to self-reported drinkers and smokers as being at higher risk of non-completion of IPT. The period of time since HIV diagnosis should therefore be taken into account when initiating IPT. Our results also suggest that smokers and alcohol drinkers should be identified and targeted for adherence interventions when implementing IPT on a wider scale

Detection of tuberculosis in HIV-infected and-uninfected African adults using whole blood RNA expression signatures: a case-control study

Background: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test. Methods and Findings: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI [80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI [84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group. Conclusions: In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions

Urban health in Africa: a critical global public health priority.

The African continent is predicted to be home to over half of the expected global population growth between 2015 and 2050, highlighting the importance of addressing population health in Africa for improving public health globally. By 2050, nearly 60% of the population of the continent is expected to be living in urban areas and 35-40% of children and adolescents globally are projected to be living in Africa. Urgent attention is therefore required to respond to this population growth - particularly in the context of an increasingly urban and young population. To this end, the Research Initiative for Cities Health and Equity in Africa (RICHE Africa) Network aims to support the development of evidence to inform policy and programming to improve urban health across the continent. This paper highlights the importance of action in the African continent for achieving global public health targets. Specifically, we argue that a focus on urban health in Africa is urgently required in order to support progress on the Sustainable Development Goals (SDGs) and other global and regional public health targets, including Universal Health Coverage (UHC), the new Urban Agenda, and the African Union's Agenda 2063. Action on urban public health in Africa is critical for achieving global public health targets. Four key research and training priorities for improving urban health in Africa, are outlined: (1) increase intersectoral urban health literacy; (2) apply a healthy urban governance and systems approach; (3) develop a participatory and collaborative urban health planning process; and, (4) produce a new generation of urban health scholars and practitioners. We argue that acting on key priorities in urban health is critical for improving health for all and ensuring that we 'leave no-one behind' when working to achieve these regional and global agendas to improve health and wellbeing

High prevalence of subclinical tuberculosis in HIV-1-infected persons without advanced immunodeficiency: implications for TB screening

Background The prevalence of asymptomatic tuberculosis (TB) in recently diagnosed HIV-1-infected persons attending pre-antiretroviral therapy (ART) clinics is not well described. In addition, it is unclear if the detection of Mycobacterium tuberculosis in these patients clearly represents an early asymptomatic phase leading to progressive disease or transient excretion of bacilli. Objective To describe the prevalence and outcome of subclinical TB disease in HIV-1-infected persons not eligible for ART. Methods The study was conducted in 274 asymptomatic ART-naive HIV-1-infected persons in Khayelitsha Day Hospital, Cape Town, South Africa. All participants were screened for TB using a symptom screen and spoligotyping was performed to determine genotypes. Results The prevalence of subclinical TB disease was 8.5% (95% CI 5.1% to 13.0%) (n = 18; median days to culture positivity 17 days), with 22% of patients being smear-positive. Spoligotyping showed a diverse variety of genotypes with all paired isolates being of the same spoligotype, effectively excluding cross-contamination. 56% of patients followed up developed symptoms 3 days to 2 months later. All were well and still in care 6-12 months after TB diagnosis; 60% were started on ART. A positive tuberculin skin test (OR 4.96, p = 0.064), low CD4 count (OR 0.996, p = 0.06) and number of years since HIV diagnosis (OR 1.006, p = 0.056) showed trends towards predicting TB disease. Conclusion This study found a high prevalence but good outcome (retained in care) of subclinical TB disease in HIV-1-infected persons. The results suggest that, in high HIV/TB endemic settings, a positive HIV-1 test should prompt TB screening by sputum culture irrespective of symptoms, particularly in those with a positive tuberculin skin test, longer history of HIV infection and low CD4 count. Operational difficulties in resource-constrained settings with respect to screening with TB culture highlight the need for rapid and affordable point-of-care tests to identify persons with clinical and subclinical TB disease.Immunogenetics and cellular immunology of bacterial infectious disease

Tuberculosis, Human Immunodeficiency Virus, and the Association With Transient Hyperglycemia in Periurban South Africa

Abstract Background Diabetes mellitus (DM) increases tuberculosis (TB) risk. We assessed the prevalence of hyperglycemia (DM and impaired glucose regulation [IGR]) in persons with TB and the association between hyperglycemia and TB at enrollment and 3 months after TB treatment in the context of human immunodeficiency virus (HIV) infection. Methods Adults presenting at a Cape Town TB clinic were enrolled. TB cases were defined by South African guidelines, while non-TB participants were those who presented with respiratory symptoms, negative TB tests, and resolution of symptoms 3 months later without TB treatment. HIV status was ascertained through medical records or HIV testing. All participants were screened for DM using glycated hemoglobin and fasting plasma glucose at TB treatment and after 3 months. The association between TB and DM was assessed. Results Overall DM prevalence was 11.9% (95% confidence interval [CI], 9.1%–15.4%) at enrollment and 9.3% (95% CI, 6.4%–13%) at follow-up; IGR prevalence was 46.9% (95% CI, 42.2%–51.8%) and 21.5% (95% CI, 16.9%–26.3%) at enrollment and follow-up. TB/DM association was significant at enrollment (odds ratio [OR], 2.41 [95% CI, 1.3–4.3]) and follow-up (OR, 3.3 [95% CI, 1.5–7.3]), whereas TB/IGR association was only positive at enrollment (OR, 2.3 [95% CI, 1.6–3.3]). The TB/DM association was significant at enrollment in both new and preexisting DM, but only persisted at follow-up in preexisting DM in patients with HIV-1 infection. Conclusions Our study demonstrated high prevalence of transient hyperglycemia and a significant TB/DM and TB/IGR association at enrollment in newly diagnosed DM, but persistent hyperglycemia and TB/DM association in patients with HIV-1 infection and preexisting DM, despite TB therapy. This work was supported by the Wellcome Trust (grant numbers 084323, 104873, and 203135), a Carnegie Corporation Postdoctoral Fellowship, and a Harry Crossley Senior Clinical Fellowship. R. J. W. is supported by the Francis Crick Institute, which receives funding from Cancer Research UK (grant number FC001010218), Research Councils UK (grant number FC0010218), and the Wellcome Trust (grant number FC0010218). He also receives support from the National Institutes of Health (NIH) (grant number U1 AI115940), NIH (grant number WILK116PTB), and European and Developing Countries Clinical Trials Partnership (grant number SRIA 2015–1065). M. K. is supported by the South African Centre for Epidemiological Modelling and Analysis, the International Epidemiology Databases to Evaluate AIDS, and the NIH (grant number U01AI069924)

New venture evolution of migrants under institutional voids: Lessons from Shonga Farms in Nigeria

This article inductively builds theory on how transaction costs may be alleviated and institutional voids bridged in developing economies, based on the case study of successful migrant entrepreneurial involvement in Nigerian agriculture: Shonga Farms. We argue that the iterative process of building conditions of trust through long-term commitment, involvement of regional government, appropriate modes of financial contracts and the gradual transitioning of controlling interests to private actors are factors of success. We draw additional lessons by contrasting our case study with other similar migrant schemes that have failed