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Zar H.J.,University of Cape Town | Madhi S.A.,South African National Institute for Communicable Diseases | Madhi S.A.,University of Witwatersrand | Aston S.J.,Malawi Liverpool Wellcome Trust Clinical Research Programme
Thorax | Year: 2013

Pneumonia remains the leading cause of childhood mortality and the most common reason for adult hospitalisation in low and middle income countries, despite advances in preventative and management strategies. In the last decade, pneumonia mortality in children has fallen to approximately 1.3 million cases in 2011, with most deaths occurring in low income countries. Important recent advances include more widespread implementation of protein-polysaccharide conjugate vaccines against Haemophilus influenzae type B and Streptococcus pneumoniae, implementation of case-management algorithms and better prevention and treatment of HIV. Determining the aetiology of pneumonia is challenging in the absence of reliable diagnostic tests. High uptake of new bacterial conjugate vaccines may impact on pneumonia burden, aetiology and empiric therapy but implementation in immunisation programmes in many low and middle income countries remains an obstacle. Widespread implementation of currently effective preventative and management strategies for pneumonia remains challenging in many low and middle income countries.


Moxon C.A.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Grau G.E.,University of Sydney
British Journal of Haematology | Year: 2011

Residence in the human erythrocyte is essential for the lifecycle of all Plasmodium that infect man. It is also the phase of the life cycle that causes disease. Although the red blood cell (RBC) is a highly specialized cell for its function of carrying oxygen to and carbon dioxide away from tissues, it is devoid of organelles and lacks any cellular machinery to synthesize new protein. Therefore in order to be able to survive and multiply within the RBC membrane the parasite needs to make many modifications to the infected RBC (iRBC). Plasmodium falciparum (P. falciparum) also expresses parasite-derived proteins on the surface of the iRBC that enable the parasite to cytoadhere to endothelial and other intravascular cells. These RBC modifications are at the root of malaria pathogenesis and, in this ancient disease of man, have formed the epicentre of a genetic 'battle' between parasite and host. This review discusses some of the critical modifications of the RBC by the parasite and some of the consequences of these adaptations on disease in the human host, with an emphasis on advances in understanding of the pathogenesis of severe and cerebral malaria (CM) from recent research. © 2011 Blackwell Publishing Ltd.


Chipeta M.G.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Ngwira B.,University of Malawi | Kazembe L.N.,University of Namibia
PLoS Neglected Tropical Diseases | Year: 2013

Background: Urinary Schistosomiasis infection, a common cause of morbidity especially among children in less developed countries, is measured by the number of eggs per urine. Typically a large proportion of individuals are non-egg excretors, leading to a large number of zeros. Control strategies require better understanding of its epidemiology, hence appropriate methods to model infection prevalence and intensity are crucial, particularly if such methods add value to targeted implementation of interventions. Methods: We consider data that were collected in a cluster randomized study in 2004 in Chikhwawa district, Malawi, where eighteen (18) villages were selected and randomised to intervention and control arms. We developed a two-part model, with one part for analysis of infection prevalence and the other to model infection intensity. In both parts of the model we adjusted for age, sex, education level, treatment arm, occupation, and poly-parasitism. We also assessed for spatial correlation in the model residual using variogram analysis and mapped the spatial variation in risk. The model was fitted using maximum likelihood estimation. Results and discussion: The study had a total of 1642 participants with mean age of 32.4 (Standard deviation: 22.8), of which 55.4 % were female. Schistosomiasis prevalence was 14.2 %, with a large proportion of individuals (85.8 %) being non-egg excretors, hence zero-inflated data. Our findings showed that S. haematobium was highly localized even after adjusting for risk factors. Prevalence of infection was low in males as compared to females across all the age ranges. S. haematobium infection increased with presence of co-infection with other parasite infection. Infection intensity was highly associated with age; with highest intensity in school-aged children (6 to 15 years). Fishing and working in gardens along the Shire River were potential risk factors for S. haematobium infection intensity. Intervention reduced both infection intensity and prevalence in the intervention arm as compared to control arm. Farmers had high infection intensity as compared to non farmers, despite the fact that being a farmer did not show any significant association with probability of infection. These results evidently indicate that infection prevalence and intensity are associated with risk factors differently, suggesting a non-singular epidemiological setting. The dominance of agricultural, socio-economic and demographic factors in determining S. haematobium infection and intensity suggest that disease transmission and control strategies should continue centring on improving socio-economic status, environmental modifications to control S. haematobium intermediate host snails and mass drug administration, which may be more promising approaches to disease control in high intensity and prevalence settings. © 2013 Chipeta et al.


Feasey N.A.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Feasey N.A.,University of Liverpool | Dougan G.,Wellcome Trust Sanger Institute | Kingsley R.A.,Wellcome Trust Sanger Institute | And 3 more authors.
The Lancet | Year: 2012

Invasive strains of non-typhoidal salmonellae have emerged as a prominent cause of bloodstream infection in African adults and children, with an associated case fatality of 20-25%. The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent. The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children. A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause invasive disease in human beings. Multidrug-resistant ST313 has caused epidemics in several African countries, and has driven the use of expensive antimicrobial drugs in the poorest health services in the world. Studies of systemic cellular and humoral immune responses in adults infected with HIV have revealed key host immune defects contributing to invasive non-typhoidal salmonella disease. This emerging pathogen might therefore have adapted to occupy an ecological and immunological niche provided by HIV, malaria, and malnutrition in Africa. A good understanding of the epidemiology of this neglected disease will open new avenues for development and implementation of vaccine and public health strategies to prevent infections and interrupt transmission.


Nair S.,The Texas Institute | Nkhoma S.C.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Serre D.,Cleveland Clinic Lerner Research Institute | Zimmerman P.A.,Case Western Reserve University | And 6 more authors.
Genome Research | Year: 2014

Most malaria infections contain complex mixtures of distinct parasite lineages. These multiple-genotype infections (MGIs) impact virulence evolution, drug resistance, intra-host dynamics, and recombination, but are poorly understood. To address this we have developed a single-cell genomics approach to dissect MGIs. By combining cell sorting and whole-genome amplification (WGA), we are able to generate high-quality material from parasite-infected red blood cells (RBCs) for genotyping and next-generation sequencing. We optimized our approach through analysis of >260 single-cell assays. To quantify accuracy, we decomposed mixtures of known parasite genotypes and obtained highly accurate (>99%) single-cell genotypes. We applied this validated approach directly to infections of two major malaria species, Plasmodium falciparum, for which long term culture is possible, and Plasmodium vivax, for which no long-term culture is feasible. We demonstrate that our single-cell genomics approach can be used to generate parasite genome sequences directly from patient blood in order to unravel the complexity of P. vivax and P. falciparum infections. These methods open the door for large-scale analysis of within-host variation of malaria infections, and reveal information on relatedness and drug resistance haplotypes that is inaccessible through conventional sequencing of infections. © 2014 Nair et al.


Govindasamy D.,University of Witwatersrand | Meghij J.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Negussi E.K.,World Health Organization | Baggaley R.C.,World Health Organization | And 2 more authors.
Journal of the International AIDS Society | Year: 2014

Introduction: Several approaches have been taken to reduce pre-antiretroviral therapy (ART) losses between HIV testing and ART initiation in low- and middle-income countries, but a systematic assessment of the evidence has not yet been undertaken. The aim of this systematic review is to assess the potential for interventions to improve or facilitate linkage to or retention in pre-ART care and initiation of ART in low- and middle-income settings. Methods: An electronic search was conducted on Medline, Embase, Global Health, Web of Science and conference databases to identify studies describing interventions aimed at improving linkage to or retention in pre-ART care or initiation of ART. Additional searches were conducted to identify on-going trials on this topic, and experts in the field were contacted. An assessment of the risk of bias was conducted. Interventions were categorized according to key domains in the existing literature. Results: A total of 11,129 potentially relevant citations were identified, of which 24 were eligible for inclusion, with the majority (n = 21) from sub-Saharan Africa. In addition, 15 on-going trials were identified. The most common interventions described under key domains included: health system interventions (i.e. integration in the setting of antenatal care); patient convenience and accessibility (i.e. point-of-care CD4 count (POC) testing with immediate results, home-based ART initiation); behaviour interventions and peer support (i.e. improved communication, patient referral and education) and incentives (i.e. food support). Several interventions showed favourable outcomes: integration of care and peer supporters increased enrolment into HIV care, medical incentives increased pre-ART retention, POC CD4 testing and food incentives increased completion of ART eligibility screening and ART initiation. Most studies focused on the general adult patient population or pregnant women. The majority of published studies were observational cohort studies, subject to an unclear risk of bias. Conclusions: Findings suggest that streamlining services to minimize patient visits, providing adequate medical and peer support, and providing incentives may decrease attrition, but the quality of the current evidence base is low. Few studies have investigated combined interventions, or assessed the impact of interventions across the HIV cascade. Results from on-going trials investigating POC CD4 count testing, patient navigation, rapid ART initiation and mobile phone technology may fill the quality of evidence gap. Further high-quality studies on key population groups are required, with interventions informed by previously reported barriers to care. © 2014 Govindasamy D et al; licensee International AIDS Society.


Corbett E.L.,London School of Hygiene and Tropical Medicine | Corbett E.L.,Malawi Liverpool Wellcome Trust Clinical Research Programme | MacPherson P.,Malawi Liverpool Wellcome Trust Clinical Research Programme
International Journal of Tuberculosis and Lung Disease | Year: 2013

Twenty years of sky-high tuberculosis (TB) incidence rates and high TB mortality in high human immunodeficiency virus (HIV) prevalence countries have so far not been matched by the same magnitude or breadth of responses as seen in malaria or HIV programmes. Instead, recommendations have been narrowly focused on people presenting to health facilities for investigation of TB symptoms, or for HIV testing and care. However, despite the recent major investment and scale-up of TB and HIV services, undiagnosed TB remains highly prevalent at community level, implying that diagnosis of TB remains slow and incomplete. This maintains high transmission rates and exposes people living with HIV to high rates of morbidity and mortality. More intensive use of TB screening, with broader definitions of target populations, expanded indications for screening both inside and outside of health facilities, and appropriate selection of new diagnostic tools, offers the prospect of rapidly improving population-level control of TB. Diagnostic accuracy of suitable (high throughput) algorithms remains the major barrier to realising this goal. In the present study, we review the evidence available to guide expanded TB screening in HIV-prevalent settings, ideally through combined TB-HIV interventions that provide screening for both TB and HIV, and maximise entry to HIV and TB care and prevention. Ideally, we would systematically test, treat and prevent TB and HIV comprehensively, offering both TB and HIV screening to all health facility attendees, TB households and all adults in the highest risk communities. However, we are still held back by inadequate diagnostics, financing and paucity of population-impact data. Relevant contemporary research showing the high need for potential gains, and pitfalls from expanded and intensified TB screening in high HIV prevalence settings are discussed in this review. © 2013 The Union.


Rylance J.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Rylance J.,International Health Group | Pai M.,McGill University | Lienhardt C.,WHO | Garner P.,International Health Group
The Lancet Infectious Diseases | Year: 2010

Reliable and relevant research can help to improve tuberculosis control worldwide. In recent years, various organisations have assessed research needs and proposed priorities for tuberculosis. We summarise existing priority statements and assess the rigour of the methods used to generate them. We found 33 documents that specifically outline priorities in tuberculosis research. The top priority areas were drug development (28 articles), diagnosis and diagnostic tests (27), epidemiology (20), health services research (16), basic research (13), and vaccine development and use (13). The most focused questions were on the treatment and prevention of multidrug-resistant tuberculosis in people co-infected with HIV. Methods used to identify these priorities were varied. Improvements can be made to ensure the process is more rigorous and transparent, and to use existing research or systematic reviews more often. WHO, Stop TB Partnership, and other organisations could adopt an incremental process of priority development, building on the existing knowledge base. © 2010 Elsevier Ltd.


Ferreira D.M.,Respiratory Infection Group | Jambo K.C.,Respiratory Infection Group | Jambo K.C.,Malawi Liverpool Wellcome Trust Clinical Research Programme | Gordon S.B.,Respiratory Infection Group
Trends in Microbiology | Year: 2011

Pneumococcal conjugate vaccines have had unprecedented success in controlling vaccine-type invasive pneumococcal disease. As serotype replacement and the complexity of designing vaccines to multiple capsular polysaccharides ultimately pose a threat to these vaccines, the development of alternative protein vaccines is important. Protein vaccines offer the promise of extended serotype coverage, reduced cost, and improved protection against otitis media and pneumococcal pneumonia. As placebo-controlled trials are not currently ethically justifiable, human pneumococcal challenge models using prevention of carriage as a test endpoint offer an attractive link between preclinical studies and clinical efficacy trials. Experimental human pneumococcal carriage studies offer a means of describing mechanisms of protection against carriage and a clinical tool to choose between vaccine candidates. © 2011 Elsevier Ltd.


MacPherson E.E.,Malawi Liverpool Wellcome Trust Clinical Research Programme
Journal of the International AIDS Society | Year: 2012

In Southern Malawi, the fishing industry is highly gendered, with men carrying out the fishing and women processing, drying and selling the fish. Research has shown that individuals living in fishing communities in low-income countries are particularly vulnerable to HIV infection. One of the key drivers of HIV in fishing communities is transactional sex. In the fishing industry this takes the form of "fish-for-sex" networks where female fish traders exchange sex with fishermen for access to or more favourable prices of fish. By controlling the means of production, the power dynamics in these exchanges favour men and can make it more difficult for women to negotiate safe sex. Qualitative methods were used to collect data on gendered drivers of transactional sex in the fishing community and how different groups perceive HIV risk in these transactions. Observation, focus group discussions and semi-structured interviews were undertaken with members of the fishing communities, including men and women directly and indirectly involved in fishing. In fishing communities transactional sex was prevalent across a spectrum ranging from gift giving within relationships, to sex for fish exchanges, to sex worker encounters. Power differences between couples in transactional sexual encounters shape individual's abilities to negotiate condom use (with women being at a particularly disadvantaged negotiating position). The context and motivations for transactional sex varied and was mediated by economic need and social position both of men and women. Female fish traders new to the industry and boat crew members who travelled for work and experienced difficult living conditions often engaged in transactional sex. Transactional sex is common in Malawian fishing communities, with women particularly vulnerable in negotiations because of existing gendered power structures. Although knowledge and understanding of the HIV risk associated with transactional sex was common, this did not appear to result in the adoption of risk reduction strategies. This suggests that specially targeted strategies to increase women's economic empowerment and tackle the structural drivers of women's HIV risk could be important in fishing communities.

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