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1.  The Genetic Regulation of Infant Immune Responses to Vaccination 
A number of factors are recognized to influence immune responses to vaccinations including age, gender, the dose, and quality of the antigen used, the number of doses given, the route of administration, and the nutritional status of the recipient. Additionally, several immunogenetic studies have identified associations between polymorphisms in genes encoding immune response proteins, both innate and adaptive, and variation in responses to vaccines. Variants in the genes encoding Toll-like receptors, HLA molecules, cytokines, and cytokine receptors have associated with heterogeneity of responses to a wide range of vaccines including measles, hepatitis B, influenza A, BCG, Haemophilus influenzae type b, and certain Neisseria meningitidis serotypes, amongst others. However, the vast majority of these studies have been conducted in older children and adults and there are very few data available from studies conducted in infants. This paper reviews the evidence to date that host genes influencing vaccines responses in these older population and identifies a large gap in our understanding of the genetic regulation of responses in early life. Given the high mortality from infection in early life and the challenges of developing vaccines that generate effective immune responses in the context of the developing immune system further research on infant populations is required.
PMCID: PMC4313718
SNPs; transcriptional profiling; candidate gene; GWAS
2.  Epidemiology and individual, household and geographical risk factors of podoconiosis in Ethiopia: results from the first nationwide mapping 
Although podoconiosis is one of the major causes of tropical lymphoedema and is endemic in Ethiopia its epidemiology and risk factors are poorly understood. Individual level data for 129,959 individuals from 1,315 communities in 659 woreda (districts) were collected for nationwide integrated survey of lymphatic filariasis and podoconiosis. Blood samples were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests. A clinical algorithm was used to reach a diagnosis of podoconiosis by excluding other potential causes of lymphoedema of the lower limb. Bayesian multilevel models were used to identify individual and environmental risk factors. Overall, 8,110 of 129,959 (6.2%, 95% confidence interval [CI] 6.1 - 6.4%) surveyed individuals were identified with lymphoedema of the lower limb, of whom 5,253 (4.0%, 95% CI 3.9 - 4.1%) were confirmed to be podoconiosis cases. In multivariable analysis, being female, older, unmarried, washing the feet less frequently than daily, and being semiskilled or unemployed were significantly associated with increased risk of podoconiosis. Attending formal education and living in a house with a covered floor were associated with decreased risk of podoconiosis. Podoconiosis exhibits marked geographical variation across Ethiopia, with variation in risk associated with variation in rainfall, enhanced vegetation index and altitude.
PMCID: PMC4288951  PMID: 25404069
podoconiosis; mapping; non-filarial elephantiasis; lymphoedema; Ethiopia
3.  The Global One Health Paradigm: Challenges and Opportunities for Tackling Infectious Diseases at the Human, Animal, and Environment Interface in Low-Resource Settings 
Zoonotic infectious diseases have been an important concern to humankind for more than 10,000 years. Today, approximately 75% of newly emerging infectious diseases (EIDs) are zoonoses that result from various anthropogenic, genetic, ecologic, socioeconomic, and climatic factors. These interrelated driving forces make it difficult to predict and to prevent zoonotic EIDs. Although significant improvements in environmental and medical surveillance, clinical diagnostic methods, and medical practices have been achieved in the recent years, zoonotic EIDs remain a major global concern, and such threats are expanding, especially in less developed regions. The current Ebola epidemic in West Africa is an extreme stark reminder of the role animal reservoirs play in public health and reinforces the urgent need for globally operationalizing a One Health approach. The complex nature of zoonotic diseases and the limited resources in developing countries are a reminder that the need for implementation of Global One Health in low-resource settings is crucial. The Veterinary Public Health and Biotechnology (VPH-Biotec) Global Consortium launched the International Congress on Pathogens at the Human-Animal Interface (ICOPHAI) in order to address important challenges and needs for capacity building. The inaugural ICOPHAI (Addis Ababa, Ethiopia, 2011) and the second congress (Porto de Galinhas, Brazil, 2013) were unique opportunities to share and discuss issues related to zoonotic infectious diseases worldwide. In addition to strong scientific reports in eight thematic areas that necessitate One Health implementation, the congress identified four key capacity-building needs: (1) development of adequate science-based risk management policies, (2) skilled-personnel capacity building, (3) accredited veterinary and public health diagnostic laboratories with a shared database, and (4) improved use of existing natural resources and implementation. The aim of this review is to highlight advances in key zoonotic disease areas and the One Health capacity needs.
PMCID: PMC4230840  PMID: 25393303
4.  Perceptions of consent, permission structures and approaches to the community: a rapid ethical assessment performed in North West Cameroon 
BMC Public Health  2014;14(1):1026.
Understanding local contextual factors is important when conducting international collaborative studies in low-income country settings. Rapid ethical assessment (a brief qualitative intervention designed to map the ethical terrain of a research setting prior to recruitment of participants), has been used in a range of research-naïve settings. We used rapid ethical assessment to explore ethical issues and challenges associated with approaching communities and gaining informed consent in North West Cameroon.
This qualitative study was carried out in two health districts in the North West Region of Cameroon between February and April 2012. Eleven focus group discussions (with a total of 107 participants) were carried out among adult community members, while 72 in-depth interviews included health workers, non-government organisation staff and local community leaders. Data were collected in English and pidgin, translated where necessary into English, transcribed and coded following themes.
Many community members had some understanding of informed consent, probably through exposure to agricultural research in the past. Participants described a centralised permission-giving structure in their communities, though there was evidence of some subversion of these structures by the educated young and by women. Several acceptable routes for approaching the communities were outlined, all including the health centre and the Fon (traditional leader). The importance of time spent in sensitizing the community and explaining information was stressed.
Respondents held relatively sophisticated understanding of consent and were able to outline the structures of permission-giving in the community. Although the structures are unique to these communities, the role of certain trusted groups is common to several other communities in Kenya and Ethiopia explored using similar techniques. The information gained through Rapid Ethical Assessment will form an important guide for future studies in North West Cameroon.
PMCID: PMC4195877  PMID: 25277694
5.  Integrated mapping of lymphatic filariasis and podoconiosis: lessons learnt from Ethiopia 
Parasites & Vectors  2014;7(1):397.
The World Health Organization (WHO), international donors and partners have emphasized the importance of integrated control of neglected tropical diseases (NTDs). Integrated mapping of NTDs is a first step for integrated planning of programmes, proper resource allocation and monitoring progress of control. Integrated mapping has several advantages over disease specific mapping by reducing costs and enabling co-endemic areas to be more precisely identified. We designed and conducted integrated mapping of lymphatic filariasis (LF) and podoconiosis in Ethiopia; here we present the methods, challenges and lessons learnt.
Integrated mapping of 1315 communities across Ethiopia was accomplished within three months. Within these communities, 129,959 individuals provided blood samples that were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests (ICT). Wb123 antibody tests were used to further establish exposure to LF in areas where at least one ICT positive individual was detected. A clinical algorithm was used to reliably diagnose podoconiosis by excluding other potential causes of lymphoedema of the lower limb.
A total of 8110 individuals with leg swelling were interviewed and underwent physical examination. Smartphones linked to a central database were used to collect data, which facilitated real-time data entry and reduced costs compared to traditional paper-based data collection approach; their inbuilt Geographic Positioning System (GPS) function enabled simultaneous capture of geographical coordinates. The integrated approach led to efficient use of resources and rapid mapping of an enormous geographical area and was well received by survey staff and collaborators. Mobile based technology can be used for such large scale studies in resource constrained settings such as Ethiopia, with minimal challenges.
This was the first integrated mapping of podoconiosis and LF globally. Integrated mapping of podoconiosis and LF is feasible and, if properly planned, can be quickly achieved at nationwide scale.
Electronic supplementary material
The online version of this article (doi:10.1186/1756-3305-7-397) contains supplementary material, which is available to authorized users.
PMCID: PMC4153915  PMID: 25164687
Integrated; Mapping; Lymphedema; Elephantiasis; Lymphatic filariasis; Podoconiosis; Ethiopia
6.  Modelling environmental factors correlated with podoconiosis: a geospatial study of non-filarial elephantiasis 
The precise trigger of podoconiosis — endemic non-filarial elephantiasis of the lower legs — is unknown. Epidemiological and ecological studies have linked the disease with barefoot exposure to red clay soils of volcanic origin. Histopathology investigations have demonstrated that silicon, aluminium, magnesium and iron are present in the lower limb lymph node macrophages of both patients and non-patients living barefoot on these clays. We studied the spatial variation (variations across an area) in podoconiosis prevalence and the associated environmental factors with a goal to better understanding the pathogenesis of podoconiosis.
Fieldwork was conducted from June 2011 to February 2013 in 12 kebeles (administrative units) in northern Ethiopia. Geo-located prevalence data and soil samples were collected and analysed along with secondary geological, topographic, meteorological and elevation data. Soil data were analysed for chemical composition, mineralogy and particle size, and were interpolated to provide spatially continuous information. Exploratory, spatial, univariate and multivariate regression analyses of podoconiosis prevalence were conducted in relation to primary (soil) and secondary (elevation, precipitation, and geology) covariates.
Podoconiosis distribution showed spatial correlation with variation in elevation and precipitation. Exploratory analysis identified that phyllosilicate minerals, particularly clay (smectite and kaolinite) and mica groups, quartz (crystalline silica), iron oxide, and zirconium were associated with podoconiosis prevalence. The final multivariate model showed that the quantities of smectite (RR = 2.76, 95% CI: 1.35, 5.73; p = 0.007), quartz (RR = 1.16, 95% CI: 1.06, 1.26; p = 0.001) and mica (RR = 1.09, 95% CI: 1.05, 1.13; p < 0.001) in the soil had positive associations with podoconiosis prevalence.
More quantities of smectite, mica and quartz within the soil were associated with podoconiosis prevalence. Together with previous work indicating that these minerals may influence water absorption, potentiate infection and be toxic to human cells, the present findings suggest that these particles may play a role in the pathogenesis of podoconiosis and acute adenolymphangitis, a common cause of morbidity in podoconiosis patients.
PMCID: PMC4082615  PMID: 24946801
Podoconiosis; Spatial analysis; Epidemiology; Soil; Ethiopia
7.  A mixed-methods study on perceptions towards use of Rapid Ethical Assessment to improve informed consent processes for health research in a low-income setting 
BMC Medical Ethics  2014;15:35.
Rapid Ethical Assessment (REA) is a form of rapid ethnographic assessment conducted at the beginning of research project to guide the consent process with the objective of reconciling universal ethical guidance with specific research contexts. The current study is conducted to assess the perceived relevance of introducing REA as a mainstream tool in Ethiopia.
Mixed methods research using a sequential explanatory approach was conducted from July to September 2012, including 241 cross-sectional, self-administered and 19 qualitative, in-depth interviews among health researchers and regulators including ethics committee members in Ethiopian health research institutions and universities.
In their evaluation of the consent process, only 40.2% thought that the consent process and information given were adequately understood by study participants; 84.6% claimed they were not satisfied with the current consent process and 85.5% thought the best interests of study participants were not adequately considered. Commonly mentioned consent-related problems included lack of clarity (48.1%), inadequate information (34%), language barriers (28.2%), cultural differences (27.4%), undue expectations (26.6%) and power imbalances (20.7%). About 95.4% believed that consent should be contextualized to the study setting and 39.4% thought REA would be an appropriate approach to improve the perceived problems. Qualitative findings helped to further explore the gaps identified in the quantitative findings and to map-out concerns related to the current research consent process in Ethiopia. Suggestions included, conducting REA during the pre-test (pilot) phase of studies when applicable. The need for clear guidance for researchers on issues such as when and how to apply the REA tools was stressed.
The study findings clearly indicated that there are perceived to be correctable gaps in the consent process of medical research in Ethiopia. REA is considered relevant by researchers and stakeholders to address these gaps. Exploring further the feasibility and applicability of REA is recommended.
PMCID: PMC4055294  PMID: 24885049
Rapid ethical assessment; Ethiopia; Research ethics; Consent
8.  Individual Correlates of Podoconiosis in Areas of Varying Endemicity: A Case-Control Study 
Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls.
Methods/principal findings
This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: ‘low’ (prevalence <1%), ‘medium’ (1–5%) and ‘high’ (>5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6–4.6) and had lower income (t = −4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in ‘high’ and ‘medium’ endemicity kebeles were less likely than people in ‘low’ endemicity areas to ‘ever’ have owned shoes (OR = 0.5, 95% CI = 0.4–0.7).
Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis.
Author Summary
Podoconiosis is a neglected tropical disease that results in swelling of the lower legs and feet. It is common among barefoot individuals within defined areas due to the geochemical characteristics of the soil in these areas. Presence of podoconiosis and its huge burden among the affected people in north Ethiopia has previously been documented. Moreover, difference in the occurrence of the disease by area and among individuals had been observed. In the present study, we investigated individual factors for the occurrence of podoconiosis, by comparing individuals with podoconiosis and without podoconiosis that live in three areas with varying disease prevalence. We found that individuals with the disease, particularly women, were less educated, with lower income and less likely to be married, compared to healthy individuals. Moreover, more than one individual was found in most of the affected households. Podoconiosis-affected individuals started wearing shoes at later ages than healthy individuals, and their feet were observed to be more cracked and dirty. There is a recent increase in shoe-wearing among all study subjects. We concluded that intervention efforts should focus to address late age shoe-wearing and inequalities in education, income and marriage, between podoconiosis affected individuals, and particularly among female patients. In addition, the presence of more than one patient per household helps for targeted case identification for intervention.
PMCID: PMC3854961  PMID: 24340109
9.  Genetic variants of MARCO are associated with susceptibility to pulmonary tuberculosis in a Gambian population 
BMC Medical Genetics  2013;14:47.
The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear.
To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case–control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee.
We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPs in MARCO (rs4491733, Mantel-Haenszel 2x2 χ2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 χ2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 χ2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 χ2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis.
These findings identify MARCO as a potentially important receptor in the host response to tuberculosis.
PMCID: PMC3652798  PMID: 23617307
Scavenger receptors; Mycobacterium tuberculosis; Single nucleotide polymorphisms; Case control study; MARCO
10.  HLA Class II Locus and Susceptibility to Podoconiosis 
The New England Journal of Medicine  2012;366(13):1200-1208.
Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%).
We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls.
We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P = 1.42×10−9; and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P = 3.44×10−8), and suggestive associations (P<1.0×10−5) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701–DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis.
Association between variants in HLA class II loci with podoconiosis (a noncommuni-cable disease) suggests that the condition may be a T-cell–mediated inflammatory disease and is a model for gene–environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.)
PMCID: PMC3350841  PMID: 22455414
11.  Correction: Prediction of HLA Class II Alleles Using SNPs in an African Population 
PLoS ONE  2012;7(7):10.1371/annotation/3529a6a2-4ba2-47dc-929e-399d441b0afa.
PMCID: PMC3393640
12.  Prediction of HLA Class II Alleles Using SNPs in an African Population 
PLoS ONE  2012;7(6):e40206.
Despite the importance of the human leukocyte antigen (HLA) gene locus in research and clinical practice, direct HLA typing is laborious and expensive. Furthermore, the analysis requires specialized software and expertise which are unavailable in most developing country settings. Recently, in silico methods have been developed for predicting HLA alleles using single nucleotide polymorphisms (SNPs). However, the utility of these methods in African populations has not been systematically evaluated.
Methodology/Principal Findings
In the present study, we investigate prediction of HLA class II (HLA-DRB1 and HLA-DQB1) alleles using SNPs in the Wolaita population, southern Ethiopia. The subjects comprised 297 Ethiopians with genome-wide SNP data, of whom 188 had also been HLA typed and were used for training and testing the model. The 109 subjects with SNP data alone were used for empirical prediction using the multi-allelic gene prediction method. We evaluated accuracy of the prediction, agreement between predicted and HLA typed alleles, and discriminative ability of the prediction probability supplied by the model. We found that the model predicted intermediate (two-digit) resolution for HLA-DRB1 and HLA-DQB1 alleles at accuracy levels of 96% and 87%, respectively. All measures of performance showed high accuracy and reliability for prediction. The distribution of the majority of HLA alleles in the study was similar to that previously reported for the Oromo and Amhara ethnic groups from Ethiopia.
We demonstrate that HLA class II alleles can be predicted from SNP genotype data with a high level of accuracy at intermediate (two-digit) resolution in an African population. This finding offers new opportunities for HLA studies of disease epidemiology and population genetics in developing countries.
PMCID: PMC3386230  PMID: 22761960
13.  Population differences in immune responses to BCG in infancy1 
The Journal of infectious diseases  2009;199(6):795-800.
BCG vaccination induces a marked increase in the IFNγ response to M.tb PPD in UK, but not Malawian adolescents. We hypothesized that PPD-induced IFNγ following BCG vaccination would be similar in infants in the two countries. Infants were BCG-vaccinated in the first 3-13 weeks of life. Three months post-BCG, 100% (51/51) of UK infants made an IFNγ response to M.tb PPD, compared to 53% of Malawian infants in whom responses varied by season of birth.
We conclude that population differences in immune responses following BCG vaccination are observed in infants, as well as in young adults.
PMCID: PMC3276835  PMID: 19434928
BCG vaccination; Infant immune responses; IFNγ
14.  BCG Vaccination Induces Different Cytokine Profiles Following Infant BCG Vaccination in the UK and Malawi 
The Journal of Infectious Diseases  2011;204(7):1075-1085.
Background. BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants.
Methods. Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses.
Results. We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants.
Conclusions. Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.
PMCID: PMC3164434  PMID: 21881123
15.  Report on the 6th African Society of Human Genetics (AfSHG) Meeting, March 12–15, 2009, Yaoundé, Cameroon 
The African Society of Human Genetics (AfSHG), founded in 2003 with its inaugural meeting in Accra, Ghana,1 has the stated missions of (1) disseminating information about human genetics research in Africa, (2) establishing a mentorship network providing educational resources, including the development of appropriate technology transfer, (3) providing advocacy for human genetic research in Africa, and (4) encouraging collaborative research. Despite its young age, the AfSHG has developed a strong cadre of active researchers, both within and outside of Africa, with more than 400 members (from 16 countries across Africa as well as 8 other countries), and has held six successful meetings, five in Africa and one in the United States.
PMCID: PMC2911163  PMID: 20682860
16.  Evaluation of a Prediction Protocol to Identify Potential Targets of Epigenetic Reprogramming by the Cancer Associated Epstein Barr Virus 
PLoS ONE  2010;5(2):e9443.
Epstein Barr virus (EBV) infects the majority of the human population, causing fatal diseases in a small proportion in conjunction with environmental factors. Following primary infection, EBV remains latent in the memory B cell population for life. Recurrent reactivation of the virus occurs, probably due to activation of the memory B-lymphocytes, resulting in viral replication and re-infection of B-lymphocytes. Methylation of the viral DNA at CpG motifs leads to silencing of viral gene expression during latency. Zta, the key viral protein that mediates the latency/reactivation balance, interacts with methylated DNA. Zta is a transcription factor for both viral and host genes. A sub-set of its DNA binding sites (ZREs) contains a CpG motif, which is recognised in its methylated form. Detailed analysis of the promoter of the viral gene BRLF1 revealed that interaction with a methylated CpG ZRE (RpZRE3) is key to overturning the epigenetic silencing of the gene.
Methodology and Principal Findings
Here we question whether we can use this information to identify which host genes contain promoters with similar response elements. A computational search of human gene promoters identified 274 targets containing the 7-nucleotide RpZRE3 core element. DNA binding analysis of Zta with 17 of these targets revealed that the flanking context of the core element does not have a profound effect on the ability of Zta to interact with the methylated sites. A second juxtaposed ZRE was observed for one promoter. Zta was able to interact with this site, although co-occupancy with the RpZRE3 core element was not observed.
This research demonstrates 274 human promoters have the potential to be regulated by Zta to overturn epigenetic silencing of gene expression during viral reactivation from latency.
PMCID: PMC2829078  PMID: 20195470
17.  Impact of social stigma on the process of obtaining informed consent for genetic research on podoconiosis: a qualitative study 
BMC Medical Ethics  2009;10:13.
The consent process for a genetic study is challenging when the research is conducted in a group stigmatized because of beliefs that the disease is familial. Podoconiosis, also known as 'mossy foot', is an example of such a disease. It is a condition resulting in swelling of the lower legs among people exposed to red clay soil. It is a very stigmatizing problem in endemic areas of Ethiopia because of the widely held opinion that the disease runs in families and is untreatable. The aim of this study was to explore the impact of social stigma on the process of obtaining consent for a study on the genetics of podoconiosis in Southern Ethiopia.
We adapted a rapid assessment tool validated in The Gambia. The methodology was qualitative involving focus-group discussions (n = 4) and in-depth interviews (n = 25) with community members, fieldworkers, researchers and staff of the Mossy Foot Treatment and Prevention Association (MFTPA) working on prevention and treatment of podoconiosis.
We found that patients were afraid of participation in a genetic study for fear the study might aggravate stigmatization by publicizing the familial nature of the disease. The MFTPA was also concerned that discussion about the familial nature of podoconiosis would disappoint patients and would threaten the trust they have in the organization. In addition, participants of the rapid assessment stressed that the genetic study should be approved at family level before prospective participants are approached for consent. Based on this feedback, we developed and implemented a consent process involving community consensus and education of fieldworkers, community members and health workers. In addition, we utilized the experience and established trust of the MFTPA to diminish the perceived risk.
The study showed that the consent process developed based on issues highlighted in the rapid assessment facilitated recruitment of participants and increased their confidence that the genetic research would not fuel stigma. Therefore, investigators must seek to assess and address risks of research from prospective participants' perspectives. This involves understanding the issues in the society, the culture, community dialogues and developing a consent process that takes all these into consideration.
PMCID: PMC2736170  PMID: 19698115
18.  Tailoring Consent to Context: Designing an Appropriate Consent Process for a Biomedical Study in a Low Income Setting 
Currently there is increasing recognition of the need for research in developing countries where disease burden is high. Understanding the role of local factors is important for undertaking ethical research in developing countries. We explored factors relating to information and communication during the process of informed consent, and the approach that should be followed for gaining consent. The study was conducted prior to a family-based genetic study among people with podoconiosis (non-filarial elephantiasis) in southern Ethiopia.
Methodology/Principal Findings
We adapted a method of rapid assessment validated in The Gambia. The methodology was entirely qualitative, involving focus-group discussions and in-depth interviews. Discussions were conducted with podoconiosis patients and non-patients in the community, fieldworkers, researchers, staff of the local non-governmental organisation (NGO) working on prevention and treatment of podoconiosis, and community leaders. We found that the extent of use of everyday language, the degree to which expectations of potential participants were addressed, and the techniques of presentation of information had considerable impact on comprehension of information provided about research. Approaching podoconiosis patients via locally trusted individuals and preceding individual consent with community sensitization were considered the optimal means of communication. Prevailing poverty among podoconiosis patients, the absence of alternative treatment facilities, and participants' trust in the local NGO were identified as potential barriers for obtaining genuine informed consent.
Researchers should evaluate the effectiveness of consent processes in providing appropriate information in a comprehensible manner and in supporting voluntary decision-making on a study-by-study basis.
Author Summary
Informed consent to biomedical research in developing countries is a highly topical issue. When consent forms and processes are simply borrowed from developed countries, obtaining genuine informed consent becomes extremely challenging. This paper examines how a quick and relatively simple intervention (Rapid Assessment) can influence the design and implementation of informed consent processes in the context of biomedical research involving poor, socially stigmatized and illiterate communities in a developing country. The paper goes on to discuss the effect of social, cultural, and economic factors identified by the intervention in a particular context and demonstrates how knowledge of these influences helped to develop a socially relevant and practical consent process prior to conducting a programme of community-based genetic research. The paper concludes that this intervention is an effective and economical means by which to ensure the efficacy and ethical integrity of consent processes when recruiting participants to new research sites, even within countries with which researchers are already acquainted.
PMCID: PMC2705797  PMID: 19621067
19.  Natural Variation in Immune Responses to Neonatal Mycobacterium bovis Bacillus Calmette-Guerin (BCG) Vaccination in a Cohort of Gambian Infants 
PLoS ONE  2008;3(10):e3485.
There is a need for new vaccines for tuberculosis (TB) that protect against adult pulmonary disease in regions where BCG is not effective. However, BCG could remain integral to TB control programmes because neonatal BCG protects against disseminated forms of childhood TB and many new vaccines rely on BCG to prime immunity or are recombinant strains of BCG. Interferon-gamma (IFN-γ) is required for immunity to mycobacteria and used as a marker of immunity when new vaccines are tested. Although BCG is widely given to neonates IFN-γ responses to BCG in this age group are poorly described. Characterisation of IFN-γ responses to BCG is required for interpretation of vaccine immunogenicity study data where BCG is part of the vaccination strategy.
Methodology/Principal Findings
236 healthy Gambian babies were vaccinated with M. bovis BCG at birth. IFN-γ, interleukin (IL)-5 and IL-13 responses to purified protein derivative (PPD), killed Mycobacterium tuberculosis (KMTB), M. tuberculosis short term culture filtrate (STCF) and M. bovis BCG antigen 85 complex (Ag85) were measured in a whole blood assay two months after vaccination. Cytokine responses varied up to 10 log-fold within this population. The majority of infants (89–98% depending on the antigen) made IFN-γ responses and there was significant correlation between IFN-γ responses to the different mycobacterial antigens (Spearman's coefficient ranged from 0.340 to 0.675, p = 10−6–10−22). IL-13 and IL-5 responses were generally low and there were more non-responders (33–75%) for these cytokines. Nonetheless, significant correlations were observed for IL-13 and IL-5 responses to different mycobacterial antigens
Cytokine responses to mycobacterial antigens in BCG-vaccinated infants are heterogeneous and there is significant inter-individual variation. Further studies in large populations of infants are required to identify the factors that determine variation in IFN-γ responses.
PMCID: PMC2567029  PMID: 18941532
20.  On the pathway to better birth outcomes? A systematic review of azithromycin and curable sexually transmitted infections 
The WHO recommends the administration of sulfadoxine-pyrimethamine (SP) to all pregnant women living in areas of moderate (stable) to high malaria transmission during scheduled antenatal visits, beginning in the second trimester and continuing to delivery. Malaria parasites have lost sensitivity to SP in many endemic areas, prompting the investigation of alternatives that include azithromycin-based combination (ABC) therapies. Use of ABC therapies may also confer protection against curable sexually transmitted infections and reproductive tract infections (STIs/RTIs). The magnitude of protection at the population level would depend on the efficacy of the azithromycin-based regimen used and the underlying prevalence of curable STIs/RTIs among pregnant women who receive preventive treatment. This systematic review summarizes the efficacy data of azithromycin against curable STIs/RTIs.
PMCID: PMC3906303  PMID: 24191955
azithromycin; bacterial vaginosis; Chlamydia; gonorrhea; malaria; pregnancy; reproductive tract infections; sexually transmitted infections; sub-Saharan Africa; syphilis; trichomoniasis

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