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1.  The H3Africa policy framework: negotiating fairness in genomics 
Trends in genetics : TIG  2015;31(3):117-119.
Human Heredity and Health in Africa (H3Africa) research seeks to promote fair collaboration between scientists in Africa and those from elsewhere. Here, we outline how concerns over inequality and exploitation led to a policy framework that places a firm focus on African leadership and capacity building as guiding principles for African genomics research.
PMCID: PMC4471134  PMID: 25601285
Africa; genomics; ethics; fairness; H3Africa
2.  Effect of distance to health facility on the maintenance of INR therapeutic ranges in rheumatic heart disease patients from Cape Town: no evidence for an association 
Lack of adherence to international normalised ratio (INR) monitoring in rheumatic heart disease (RHD) patients is a contributor to cardio-embolic complications. This population-based observational study investigated whether the distance between home and an INR clinic affects the maintenance of therapeutic INR in RHD patients on warfarin.
Residential addresses, INR clinics, and INR results of patients with RHD were extracted from the Cape Town component of the Global Rheumatic Heart Disease Registry (REMEDY) database. Addresses of homes and INR clinics were converted to geographical coordinates and verified in ArcGIS 10®. ArcGIS 10® and Google Maps® were used for spatial mapping and obtaining shortest road distances respectively. The travel distance between the home and INR clinic was correlated with time within therapeutic range (TTR) using the Rosendaal linear interpolation method, and with the fraction of INR within range, based on an average of three INR readings of patients and compared with recommended therapeutic ranges.
RHD patients (n = 133) resided between 0.2 km and 50.8 km (median distance, 3.60 km) from one of 33 INR clinics. There was no significant difference in the achievement of the therapeutic INR between patients who travelled a shorter distance compared to those who travelled a longer distance (in range = 3.50 km versus out of range = 3.75 km, p = 0.78). This finding was the same for patients with mechanical valve replacement (n = 105) (3.50 km versus 3.90 km, p = 0.81), and native valves (3.45 km versus 2.75 km, p = 0.84).
There is no association between the maintenance of INR within therapeutic range amongst RHD patients in Cape Town and distance from patients’ residence to the INR clinic.
PMCID: PMC4456049  PMID: 26041470
GIS; INR; RHD; Distance decay
3.  Common variation in the CD36 (fatty acid translocase) gene is associated with left-ventricular mass 
Journal of hypertension  2011;29(4):690-695.
Genetic variation in the fatty acid translocase (CD36) gene has been shown in animal models to affect several risk factors for the development of left-ventricular hypertrophy, but this phenotype has not, thus far, been investigated in humans. We examined the relationship between common genetic polymorphisms in the CD36 gene and left-ventricular mass.
Methods and results
We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Seven single-nucleotide polymorphisms which together tagged common genetic variation in the CD36 gene were genotyped using a SEQUENOM MALDI-TOF instrument. There was evidence of association between the rs1761663 polymorphism in intron 1 of the CD36 gene and left-ventricular mass determined either by echocardiography (P = 0.003, N = 780) or electrocardiography (P = 0.001, N = 814). There was also association between rs1761663 genotype and body mass index (P < 0.001, N = 1354). Genotype was associated with between 2 and 8% differences in these phenotypes per allele. After adjustment for the effect of body mass index, there remained significant associations between genotype and left ventricular mass measured either by echo (P = 0.017) or ECG (P = 0.007).
Genotype at the rs1761663 polymorphism has independent effects both on body mass index and left-ventricular mass. Genes with such pleiotropic effects may be particularly attractive therapeutic targets for interventions to modify multiple risk factors for cardiovascular events.
PMCID: PMC4454277  PMID: 21346626
CD36; genetics; left-ventricular mass; obesity
4.  A Cost-Effectiveness Analysis of a Program to Control Rheumatic Fever and Rheumatic Heart Disease in Pinar del Rio, Cuba 
PLoS ONE  2015;10(3):e0121363.
Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) persist in many low- and middle-income countries. To date, the cost-effectiveness of population-based, combined primary and secondary prevention strategies has not been assessed. In the Pinar del Rio province of Cuba, a comprehensive ARF/RHD control program was undertaken over 1986 – 1996. The present study analyzes the cost-effectiveness of this Cuban program.
Methods and Findings
We developed a decision tree model based on the natural history of ARF/RHD, comparing the costs and effectiveness of the 10-year Cuban program to a “do nothing” approach. Our population of interest was the cohort of children aged 5 – 24 years resident in Pinar del Rio in 1986. We assessed costs and health outcomes over a lifetime horizon, and we took the healthcare system perspective on costs but did not apply a discount rate. We used epidemiologic, clinical, and direct medical cost inputs that were previously collected for publications on the Cuban program. We estimated health gains as disability-adjusted life years (DALYs) averted using standard approaches developed for the Global Burden of Disease studies. Cost-effectiveness acceptability thresholds were defined by one and three times per capita gross domestic product per DALY averted. We also conducted an uncertainty analysis using Monte Carlo simulations and several scenario analyses exploring the impact of alternative assumptions about the program’s effects and costs. We found that, compared to doing nothing, the Cuban program averted 5051 DALYs (1844 per 100,000 school-aged children) and saved $7,848,590 (2010 USD) despite a total program cost of $202,890 over 10 years. In the scenario analyses, the program remained cost saving when a lower level of effectiveness and a reduction in averted years of life lost were assumed. In a worst-case scenario including 20-fold higher costs, the program still had a 100% of being cost-effective and an 85% chance of being cost saving.
A 10-year program to control ARF/RHD in Pinar del Rio, Cuba dramatically reduced morbidity and premature mortality in children and young adults and was cost saving. The results of our analysis were robust to higher program costs and more conservative assumptions about the program’s effectiveness. It is possible that the program’s effectiveness resulted from synergies between primary and secondary prevention strategies. The findings of this study have implications for non-communicable disease policymaking in other resource-limited settings.
PMCID: PMC4358951  PMID: 25768008
5.  Increasing the value of health research in the WHO African Region beyond 2015—reflecting on the past, celebrating the present and building the future: a bibliometric analysis 
BMJ Open  2015;5(3):e006340.
To assess the profile and determinants of health research productivity in Africa since the onset of the new millennium.
Bibliometric analysis.
Data collection and synthesis
In November 2014, we searched PubMed for articles published between 2000 and 2014 from the WHO African Region, and obtained country-level indicators from World Bank data. We used Poisson regression to examine time trends in research publications and negative binomial regression to explore determinants of research publications.
We identified 107 662 publications, with a median of 727 per country (range 25–31 757). Three countries (South Africa, Nigeria and Kenya) contributed 52% of the publications. The number of publications increased from 3623 in 2000 to 12 709 in 2014 (relative growth 251%). Similarly, the per cent share of worldwide research publications per year increased from 0.7% in 2000 to 1.3% in 2014. The trend analysis was also significant to confirm a continuous increase in health research publications from Africa, with productivity increasing by 10.3% per year (95% CIs +10.1% to +10.5%). The only independent predictor of publication outputs was national gross domestic product. For every one log US$ billion increase in gross domestic product, research publications rose by 105%: incidence rate ratio (IRR=2.05, 95% CI 1.39 to 3.04). The association of private health expenditure with publications was only marginally significant (IRR=1.86, 95% CI 1.00 to 3.47).
There has been a significant improvement in health research in the WHO African Region since 2000, with some individual countries already having strong research profiles. Countries of the region should implement the WHO Strategy on Research for Health: reinforcing the research culture (organisation); focusing research on key health challenges (priorities); strengthening national health research systems (capacity); encouraging good research practice (standards); and consolidating linkages between health research and action (translation).
PMCID: PMC4360830  PMID: 25770227
6.  Genomic medicine in Africa: promise, problems and prospects 
Genome Medicine  2014;6(2):11.
PMCID: PMC3979013  PMID: 25031612
7.  Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner 
BMC Genetics  2014;15:136.
The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression.
We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies.
ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0136-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4301889  PMID: 25539802
Expression QTL mapping; Trans-ethnic mapping; Atrial fibrillation; Genome-wide association study
8.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Murray, Christopher J L | Ortblad, Katrina F | Guinovart, Caterina | Lim, Stephen S | Wolock, Timothy M | Roberts, D Allen | Dansereau, Emily A | Graetz, Nicholas | Barber, Ryan M | Brown, Jonathan C | Wang, Haidong | Duber, Herbert C | Naghavi, Mohsen | Dicker, Daniel | Dandona, Lalit | Salomon, Joshua A | Heuton, Kyle R | Foreman, Kyle | Phillips, David E | Fleming, Thomas D | Flaxman, Abraham D | Phillips, Bryan K | Johnson, Elizabeth K | Coggeshall, Megan S | Abd-Allah, Foad | Ferede, Semaw | Abraham, Jerry P | Abubakar, Ibrahim | Abu-Raddad, Laith J | Abu-Rmeileh, Niveen Me | Achoki, Tom | Adeyemo, Austine Olufemi | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie Elisabet | Akena, Dickens | Al Kahbouri, Mazin J | Alasfoor, Deena | Albittar, Mohammed I | Alcalá-Cerra, Gabriel | Alegretti, Miguel Angel | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Alla, Francois | Allen, Peter J | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzman, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Anderson, Benjamin O | Antonio, Carl Abelardo T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Banerjee, Amitava | Basu, Sanjay | Beardsley, Justin | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku Jibat | Bhala, Neeraj | Bhalla, Ashish | Bhutta, Zulfiqar A | Abdulhak, Aref Bin | Binagwaho, Agnes | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Brainin, Michael | Breitborde, Nicholas | Castañeda-Orjuela, Carlos A | Catalá-López, Ferrán | Chadha, Vineet K | Chang, Jung-Chen | Chiang, Peggy Pei-Chia | Chuang, Ting-Wu | Colomar, Mercedes | Cooper, Leslie Trumbull | Cooper, Cyrus | Courville, Karen J | Cowie, Benjamin C | Criqui, Michael H | Dandona, Rakhi | Dayama, Anand | De Leo, Diego | Degenhardt, Louisa | Del Pozo-Cruz, Borja | Deribe, Kebede | Jarlais, Don C Des | Dessalegn, Muluken | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Driscoll, Tim R | Durrani, Adnan M | Ellenbogen, Richard G | Ermakov, Sergey Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Forouzanfar, Mohammad H | Paleo, Urbano Fra. | Gaffikin, Lynne | Gamkrelidze, Amiran | Gankpé, Fortuné Gbètoho | Geleijnse, Johanna M | Gessner, Bradford D | Gibney, Katherine B | Ginawi, Ibrahim Abdelmageem Mohamed | Glaser, Elizabeth L | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rajeev | Gupta, Rahul | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Haro, Josep Maria | Havmoeller, Rasmus | Hay, Simon I | Hedayati, Mohammad T | Pi, Ileana B Heredia | Hoek, Hans W | Hornberger, John C | Hosgood, H Dean | Hotez, Peter J | Hoy, Damian G | Huang, John J | Iburg, Kim M | Idrisov, Bulat T | Innos, Kaire | Jacobsen, Kathryn H | Jeemon, Panniyammakal | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kan, Haidong | Kankindi, Ida | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Keren, Andre | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Khonelidze, Irma | Kinfu, Yohannes | Kinge, Jonas M | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, S | Defo, Barthelemy Kuate | Kulkarni, Veena S | Kulkarni, Chanda | Kumar, Kaushalendra | Kumar, Ravi B | Kumar, G Anil | Kwan, Gene F | Lai, Taavi | Balaji, Arjun Lakshmana | Lam, Hilton | Lan, Qing | Lansingh, Van C | Larson, Heidi J | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Yichong | Li, Yongmei | De Lima, Graça Maria Ferreira | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | Lotufo, Paulo A | Machado, Vasco Manuel Pedro | Maclachlan, Jennifer H | Magis-Rodriguez, Carlos | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Masci, Joseph R | Mashal, Mohammad Taufiq | Mason-Jones, Amanda J | Mayosi, Bongani M | Mazorodze, Tasara T | Mckay, Abigail Cecilia | Meaney, Peter A | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Melaku, Yohannes Adama | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Mori, Rintaro | Moturi, Wilkister Nyaora | Mukaigawara, Mitsuru | Murthy, Kinnari S | Naheed, Aliya | Naidoo, Kovin S | Naldi, Luigi | Nangia, Vinay | Narayan, K M Venkat | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nowaseb, Vincent | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pervaiz, Aslam | Pesudovs, Konrad | Petzold, Max | Pourmalek, Farshad | Qato, Dima | Quezada, Amado D | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad Ur | Raju, Murugesan | Rana, Saleem M | Razavi, Homie | Reilly, Robert Quentin | Remuzzi, Giuseppe | Richardus, Jan Hendrik | Ronfani, Luca | Roy, Nobhojit | Sabin, Nsanzimana | Saeedi, Mohammad Yahya | Sahraian, Mohammad Ali | Samonte, Genesis May J | Sawhney, Monika | Schneider, Ione J C | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Shivakoti, Rupak | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Simard, Edgar P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soneji, Samir | Soshnikov, Sergey S | Sreeramareddy, Chandrashekhar T | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Swaminathan, Soumya | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thomson, Alan J | Thorne-Lyman, Andrew L | Towbin, Jeffrey A | Traebert, Jefferson | Tran, Bach X | Dimbuene, Zacharie Tsala | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Uzun, Selen Begüm | Vallely, Andrew J | Vasankari, Tommi J | Venketasubramanian, N | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Waller, Stephen | Wallin, Mitchell T | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | White, Richard A | Wilkinson, James D | Williams, Thomas Neil | Woldeyohannes, Solomon Meseret | Wong, John Q | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | El Sayed Zaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Vos, Theo
Lancet  2014;384(9947):1005-1070.
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Bill & Melinda Gates Foundation.
PMCID: PMC4202387  PMID: 25059949
9.  HIV-1 Subtype C Unproductively Infects Human Cardiomyocytes In Vitro and Induces Apoptosis Mitigated by an Anti-Gp120 Aptamer 
PLoS ONE  2014;9(10):e110930.
HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.
PMCID: PMC4201581  PMID: 25329893
12.  Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study 
BMC Medicine  2014;12:101.
Tuberculous pericarditis (TBP) is associated with high morbidity and mortality, and is an important treatable cause of heart failure in developing countries. Tuberculous aetiology of pericarditis is difficult to diagnose promptly. The utility of the new quantitative PCR test (Xpert MTB/RIF) for the diagnosis of TBP is unknown. This study sought to evaluate the diagnostic accuracy of the Xpert MTB/RIF test compared to pericardial adenosine deaminase (ADA) and unstimulated interferon-gamma (uIFNγ) in suspected TBP.
From October 2009 through September 2012, 151 consecutive patients with suspected TBP were enrolled at a single centre in Cape Town, South Africa. Mycobacterium tuberculosis culture and/or pericardial histology served as the reference standard for definite TBP. Receiver-operating-characteristic curve analysis was used for selection of ADA and uIFNγ cut-points.
Of the participants, 49% (74/151) were classified as definite TBP, 33% (50/151) as probable TBP and 18% (27/151) as non TBP. A total of 105 (74%) participants were human immunodeficiency virus (HIV) positive. Xpert-MTB/RIF had a sensitivity and specificity (95% confidence interval (CI)) of 63.8% (52.4% to 75.1%) and 100% (85.6% to 100%), respectively. Concentration of pericardial fluid by centrifugation and using standard sample processing did not improve Xpert MTB/RIF accuracy. ADA (≥35 IU/L) and uIFNγ (≥44 pg/ml) both had a sensitivity of 95.7% (88.1% to 98.5%) and a negative likelihood ratio of 0.05 (0.02 to 0.10). However, the specificity and positive likelihood ratio of uIFNγ was higher than ADA (96.3% (81.7% to 99.3%) and 25.8 (3.6 to 183.4) versus 84% (65.4% to 93.6%) and 6.0 (3.7 to 9.8); P = 0.03) at an estimated background prevalence of TB of 30%. The sensitivity and negative predictive value of both uIFNγ and ADA were higher than Xpert-MT/RIF (P < 0.001).
uIFNγ offers superior accuracy for the diagnosis of microbiologically confirmed TBP compared to the ADA assay and the Xpert MTB/RIF test.
PMCID: PMC4073812  PMID: 24942470
Tuberculous pericarditis; Adenosine deaminase; Interferon γ; Xpert MTB/RIF test; Diagnosis
13.  Reference intervals for the echocardiographic measurements of the right heart in children and adolescents: a systematic review 
Transthoracic echocardiography is the primary imaging modality for the diagnosis of right ventricular (RV) involvement in congenital and acquired heart diseases. There is increasing recognition of the contribution of RV dysfunction in heart diseases affecting children and adolescents, but there is insufficient information on reference intervals for the echocardiographic measurements of the right heart in children and adolescents that represent all the continental populations of the world.
The aim of this systematic review was to collate, from published studies, normative data for echocardiographic evaluation of the right heart in children and adolescents, and to identify gaps in knowledge in this field especially with respect to sub-Saharan Africans.
We performed a systematic literature search to identify studies of reference intervals for right heart measurements as determined by transthoracic echocardiography in healthy children and adolescents of school-going age. Articles were retrieved from electronic databases with a combination of search terms from the earliest date available until May 2013.
Reference data were available for a broad range of variables. Fifty one studies out of 3096 publications were included. The sample sizes of the reference populations ranged from 13 to 2036 with ages varying from 5 to 21 years. We identified areas lacking sufficient reference data. These included reference data for determining right atrial size, tricuspid valve area, RV dimensions and areas, the RV % fractional area change, pulmonary artery pressure gradients and the right-sided haemodynamics, including the inferior vena cava dimensions and collapsibility. There were no data for sub-Saharan African children and adolescents.
Reliable reference data are lacking for important echocardiographic measurements of the RV in children and adolescents, especially for sub-Saharan Africans.
PMCID: PMC3922696  PMID: 24476413
Echocardiography; Reference ranges; Normal values; Right ventricle; Right atrium; Tricuspid; Pulmonary; Vena cava; Paediatric
14.  Prevalence, Hemodynamics, and Cytokine Profile of Effusive-Constrictive Pericarditis in Patients with Tuberculous Pericardial Effusion 
PLoS ONE  2013;8(10):e77532.
Effusive constrictive pericarditis (ECP) is visceral constriction in conjunction with compressive pericardial effusion. The prevalence of proven tuberculous ECP is unknown. Whilst ECP is distinguished from effusive disease on hemodynamic grounds, it is unknown whether effusive-constrictive physiology has a distinct cytokine profile. We conducted a prospective study of prevalence and cytokine profile of effusive-constrictive disease in patients with tuberculous pericardial effusion.
From July 2006 through July 2009, the prevalence of ECP and serum and pericardial levels of inflammatory cytokines were determined in adults with tuberculous pericardial effusion. The diagnosis of ECP was made by combined pericardiocentesis and cardiac catheterization.
Of 91 patients evaluated, 68 had tuberculous pericarditis. The 36/68 patients (52.9%; 95% confidence interval [CI]: 41.2-65.4) with ECP were younger (29 versus 37 years, P=0.02), had a higher pre-pericardiocentesis right atrial pressure (17.0 versus 10.0 mmHg, P<0.0001), serum concentration of interleukin-10 (IL-10) (38.5 versus 0.2 pg/ml, P<0.001) and transforming growth factor-beta (121.5 versus 29.1 pg/ml, P=0.02), pericardial concentration of IL-10 (84.7 versus 20.4 pg/ml, P=0.006) and interferon-gamma (2,568.0 versus 906.6 pg/ml, P=0.03) than effusive non-constrictive cases. In multivariable regression analysis, right atrial pressure > 15 mmHg (odds ratio [OR] = 48, 95%CI: 8.7-265; P<0.0001) and IL-10 > 200 pg/ml (OR=10, 95%CI: 1.1, 93; P=0.04) were independently associated with ECP.
Effusive-constrictive disease occurs in half of cases of tuberculous pericardial effusion, and is characterized by greater elevation in the pre-pericardiocentesis right atrial pressure and pericardial and serum IL-10 levels compared to patients with effusive non-constrictive tuberculous pericarditis.
PMCID: PMC3796485  PMID: 24155965
15.  Prevalence of myocarditis and cardiotropic virus infection in Africans with HIV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients: a pilot study 
Cardiovascular Journal of Africa  2013;24(6):218-223.
The prevalence of myocarditis and cardiotropic viral infection in human immunodeficiency virus (HIV)-associated cardiomyopathy is unknown in Africa.
Between April 2002 and December 2007, we compared the prevalence of myocarditis and cardiotropic viral genomes in HIV-associated cardiomyopathy cases with HIV-negative idiopathic dilated cardiomyopathy patients (i.e. negative controls for immunodeficiency) and heart transplant recipients (i.e. positive controls for immunodeficiency) who were seen at Groote Schuur Hospital, Cape Town, South Africa. Myocarditis was sought on endomyocardial biopsy using the imunohistological criteria of the World Heart Federation in 33 patients, 14 of whom had HIV-associated cardiomyopathy, eight with idiopathic dilated cardiomyopathy and 11 heart transplant recipients.
Myocarditis was present in 44% of HIV-associated cardiomyopathy cases, 36% of heart transplant recipients, and 25% of participants with idiopathic dilated cardiomyopathy. While myocarditis was acute in 50% of HIV- and heart transplant-associated myocarditis, it was chronic in all those with idiopathic dilated cardiomyopathy. Cardiotropic viral infection was present in all HIV-associated cardiomyopathy and idiopathic dilated cardiomyopathy cases, and in 90% of heart transplant recipients. Multiple viruses were identified in the majority of cases, with HIV-associated cardiomyopathy, heart transplant recipients and idiopathic dilated cardiomyopathy patients having an average of 2.5, 2.2 and 1.1 viruses per individual, respectively.
Acute myocarditis was present in 21% of cases of HIV-associated cardiomyopathy, compared to none of those with idiopathic dilated cardiomyopathy. Infection with multiple cardiotropic viruses may be ubiquitous in Africans, with a greater burden of infection in acquired immunodeficiency states.
PMCID: PMC3767940  PMID: 23775037
HIV-associated cardiomyopathy; myocarditis; dilated cardiomyopathy; cardiotropic virus
17.  The Pan-African Society of Cardiology (PASCAR) in 2013 and beyond 
Cardiovascular Journal of Africa  2013;24(5):151-153.
The biennial Congress of the Pan-African Society of Cardiology (PASCAR) was held in Dakar from 16 to 19 May 2013 under the patronage of his Excellency, Macky Sall, president of the Republic of Senegal. This meeting was remarkable in the diversity of its 700 participants from English-, French- and Portuguese-speaking Africa. Important aspects of cardiovascular disease in Africa were presented in 195 abstracts and numerous talks; the topics were hypertension, obesity, diabetes, heart failure, cardiomyopathies, coronary heart disease, stroke and rheumatic heart disease. The general assembly meeting was marked by the review and adoption of a new constitution and elections of a new PASCAR governing council that will be in office for the next four years. The new leadership of PASCAR has committed itself to strengthening the administrative infrastructure of the organisation, developing programmes to address education and training needs of African cardiovascular practitioners, developing a pan-African multi-national research platform, and ensuring that ministries of health implement national programmes for the prevention and control of cardiovascular and other non-communicable diseases.
PMCID: PMC3748447  PMID: 24217160
19.  Common Variation Neighbouring Micro-RNA 22 Is Associated with Increased Left Ventricular Mass 
PLoS ONE  2013;8(1):e55061.
Previous genome-wide linkage analysis has suggested that chromosomal region 17p13.3 may harbour genes influencing left ventricular mass (LVM) in man. To date, the genetic factors accounting for LVM variability remain largely unknown but a non-coding RNA gene within this region, micro-RNA 22 (miR-22), has been implicated in cardiac hypertrophy and heart failure in animal models. We thus investigated the relationship between common genetic polymorphisms surrounding miR-22 and left ventricular mass in a family-based association study.
Methods and Results
We studied a cohort of 255 families comprising 1,425 individuals ascertained via a hypertensive proband. Ten single nucleotide polymorphisms which together tagged common genetic variation surrounding the miR-22 gene were genotyped. There was evidence of association between the rs7223247 polymorphism, which lies within the 3′UTR of a gene of unknown function, TLCD2, immediately downstream from miR-22, and left ventricular mass determined by Sokolow-Lyon voltage (Bonferroni corrected p-value = 0.038). The T allele at rs7223247 was associated with an 0.272 standard deviation higher Sokolow-Lyon voltage. Genotype was responsible for ∼1% of the population variability in LVM.
Genotype at the rs7223247 polymorphism affects left ventricular mass determined by Sokolow-Lyon voltage. The neighbouring genes miR-22 and TLCD2 are strong candidates to account for this observation.
PMCID: PMC3555935  PMID: 23372812
20.  Current status and future prospects of epidemiology and public health training and research in the WHO African region 
Background To date little has been published about epidemiology and public health capacity (training, research, funding, human resources) in WHO/AFRO to help guide future planning by various stakeholders.
Methods A bibliometric analysis was performed to identify published epidemiological research. Information about epidemiology and public health training, current research and challenges was collected from key informants using a standardized questionnaire.
Results From 1991 to 2010, epidemiology and public health research output in the WHO/AFRO region increased from 172 to 1086 peer-reviewed articles per annum [annual percentage change (APC) = 10.1%, P for trend < 0.001]. The most common topics were HIV/AIDS (11.3%), malaria (8.6%) and tuberculosis (7.1%). Similarly, numbers of first authors (APC = 7.3%, P for trend < 0.001), corresponding authors (APC = 8.4%, P for trend < 0.001) and last authors (APC = 8.5%, P for trend < 0.001) from Africa increased during the same period. However, an overwhelming majority of respondents (>90%) reported that this increase is only rarely linked to regional post-graduate training programmes in epidemiology. South Africa leads in publications (1978/8835, 22.4%), followed by Kenya (851/8835, 9.6%), Nigeria (758/8835, 8.6%), Tanzania (549/8835, 6.2%) and Uganda (428/8835, 4.8%) (P < 0.001, each vs South Africa). Independent predictors of relevant research productivity were ‘in-country numbers of epidemiology or public health programmes’ [incidence rate ratio (IRR) = 3.41; 95% confidence interval (CI) 1.90–6.11; P = 0.03] and ‘number of HIV/AIDS patients’ (IRR = 1.30; 95% CI 1.02–1.66; P < 0.001).
Conclusions Since 1991, there has been increasing epidemiological research productivity in WHO/AFRO that is associated with the number of epidemiology programmes and burden of HIV/AIDS cases. More capacity building and training initiatives in epidemiology are required to promote research and address the public health challenges facing the continent.
PMCID: PMC3535755  PMID: 23283719
Epidemiology; public health; training; Africa; capacity building; retention; research; WHO/AFRO
22.  Quantification of echodensities in tuberculous pericardial effusion using fractal geometry: a proof of concept study 
The purpose of this study was to quantify the heterogeneous distribution of echodensities in the pericardial fluid of patients with tuberculous pericarditis using echocardiography and fractal analysis, and to determine whether there were differences in the fractal dimensions of effusive-constrictive and effusive non-constrictive disease.
We used fractal geometry to quantify the echocardiographic densities in patients who were enrolled in the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry. Sub-costal and four chamber images were included in the analysis if a minimum of two clearly identified fibrin strands were present and the quality of the images were of a standard which allowed for accurate measurement of the fractal dimension. The fractal dimension was calculated as follows: Df = limlog N(s)/[log (l/s)], where Df is the box counting fractal dimension of the fibrin strand, s is the side length of the box and N(s) is the smallest number of boxes of side length s to cover the outline of the object being measured. We compared the fractal dimension of echocardiographic findings in patients with effusive constrictive pericarditis to effusive non-constrictive pericardial effusion using the non-parametric Mann–Whitney test.
Of the 14 echocardiographs from 14 participants that were selected for the study, 42.8% (6/14) of images were subcostal views while 57.1% (8/14) were 4-chamber views. Eight of the patients had tuberculous effusive constrictive pericarditis while 6 had tuberculous effusive non-constrictive pericarditis. The mean fractal dimension Df was 1.325 with a standard deviation (SD) of 0.146. The measured fibrin strand dimension exceeded the topological dimension in all the images over the entire range of grid scales with a correlation coefficient (r2) greater than 0.8 in the majority. The fractal dimension of echodensities was 1.359 ± 0.199 in effusive constrictive pericarditis compared to 1.330 ± 0.166 in effusive non-constrictive pericarditis (p = 0.595).
The echocardiographic densities in tuberculous pericardial effusion have a fractal geometrical dimension which is similar in pure effusive and effusive constrictive disease.
PMCID: PMC3464936  PMID: 22838492
Pericardial effusion; Tuberculosis; Fractal dimension; Effusive constrictive pericarditis; Effusive non-constrictive pericarditis
23.  The 12-lead ECG in peripartum cardiomyopathy 
Cardiovascular Journal of Africa  2012;23(6):322-329.
The value of the 12-lead electrocardiogram (ECG) to provide prognostic information in the deadly and disabling syndrome peripartum cardiomyopathy (PPCM) is unknown.
To determine the prevalence of major and minor ECG abnormalities in PPCM patients at the time of diagnosis, and to establish whether there are ECG correlates of persistent left ventricular dysfunction and/or clinical stability at six months of follow up, where available.
Twelve-lead ECGs were performed at the point of diagnosis on 78 consecutive women presenting with PPCM to two tertiary centres in South Africa and 44 cases (56%) at the six-month follow up. Blinded Minnesota coding identified major ECG abnormalities and minor ECG changes.
The cohort mainly comprised young women of black African ancestry (90%) [mean age 29 ± 7 years and median body mass index 24.3 (IQR: 22.7–27.5) kg/m2]. The majority of cases (n = 70; 90%) presented in sinus rhythm (mean heart rate 100 ± 21 beats/min). At baseline, at least one ECG abnormality/variant was detected in 96% of cases. Major ECG abnormalities and minor changes were detected in 49% (95% CI: 37–60%) and 62% (95% CI: 51–74%) of cases, respectively; the most common being T-wave changes (59%), p-wave abnormality (29%) and QRS-axis deviation (25%).
Of the 44 cases (56%) reviewed at six months, normalisation of the 12-lead ECG occurred in 25%; the most labile ECG features being heart rate (mean reduction of 27 beats/min; p < 0.001) and abnormal QRS axis (36 vs 14%; p = 0.014). On an adjusted basis, major T-wave abnormalities on the baseline 12-lead ECG were associated with lower left ventricular ejection fraction (LVEF) at baseline (average of –9%, 95% CI: –1 to –16; p = 0.03) and at six months (–12%; 95% CI: –4 to –24; p = 0.006). Similarly, baseline ST-segment elevation was also associated with lower LVEF at six months (–25%; 95% CI: –0.7 to –50; p = 0.04).
In this unique study, we found that almost all women suffering from PPCM had an ‘abnormal’ 12-lead ECG. Pending more definitive studies, the ECG appears to be a useful adjunctive tool in both screening and prognostication in resource-poor settings.
PMCID: PMC3734749  PMID: 22337203
peripartum cardiomyopathy; ECG; baseline; follow up; comparative study; South Africa
24.  The prevalence and outcome of effusive constrictive pericarditis: a systematic review of the literature 
Cardiovascular Journal of Africa  2012;23(5):281-285.
There is sparse information on the epidemiology of effusive constrictive pericarditis (ECP). The objective of this article was to review and summarise the literature on the prevalence and outcome of ECP, and identify gaps for further research. The prevalence of ECP ranged from 2.4 to 14.8%, with a weighted average of 4.5% [95% confidence interval (CI) 2.2–7.5%]. Sixty-five per cent (95% CI: 43–82%) of patients required pericardiectomy regardless of the aetiology. The combined death rate across the studies was 22% (95% CI: 4–50%). The prevalence of ECP is low in non-tuberculous pericarditis, while pericardiectomy rates are high and mortality is variable. In this review, of 10 patients identified with tuberculous ECP, only one presumed case had a definite diagnosis of ECP. Appropriate studies are needed to determine the epidemiology of ECP in tuberculous pericarditis, which is one of the leading causes of pericardial disease in the world.
PMCID: PMC3721892  PMID: 22240903
effusive constrictive pericarditis; prevalence; pericardiectomy and death
25.  The burden of antenatal heart disease in South Africa: a systematic review 
Maternal mortality in South Africa is rising, and heart conditions currently account for 41 per cent of indirect causes of deaths. Little is known about the burden of heart disease in pregnant South Africans.
We systematically reviewed the contemporary epidemiology and peripartum outcomes of heart disease in South African women attending antenatal care. Searches were performed in PubMed, ISI Web of Science, the EBSCO Africa-Wide database, the South African Union Catalogue, and the Current and Completed Research database (South Africa). References of included articles were also hand-searched. Studies reporting epidemiologic data on antenatal heart disease in South Africa were included. Data on morbidity and mortality were also collected.
Seven studies were included in the systematic review. The prevalence of heart disease ranged from 123 to 943 per 100,000 deliveries, with a median prevalence of 616 per 100,000. Rheumatic valvular lesions were the commonest abnormalities, although cardiomyopathies were disproportionately high in comparison with other developing countries. Peripartum case-fatality rates were as high as 9.5 per cent in areas with limited access to care. The most frequent complications were pulmonary oedema, thromboembolism, and major bleeding with warfarin use. Perinatal mortality ranged from 8.9 to 23.8 per cent, whilst mitral lesions were associated with low birth weight. Meta-analysis could not be performed due to clinical and statistical heterogeneity of the included studies.
Approximately 0.6 per cent of pregnant South Africans have pre-existing cardiac abnormalities, with rheumatic lesions being the commonest. Maternal and perinatal morbidity and mortality continue to be very high. We conclude this review by summarising limitations of the current literature and recommending standard reporting criteria for future reports.
PMCID: PMC3340323  PMID: 22463484

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