@Oxford Publications 2013

Glover M, Bosman A, Wagemakers A, Kira A, Paton C, Cowie N. 2013. An innovative team-based stop smoking competition among Māori and Pacific Island smokers: rationale and method for the study and its evaluation. BMC Public Health, 13 (1), pp. 1228. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Māori and Pacific Island people have significantly higher smoking rates compared to the rest of the New Zealand population. The main aim of this paper is to describe how knowledge of Indigenous people's practices and principles can be combined with proven effective smoking cessation support into a cessation intervention appropriate for Indigenous people. METHODS/DESIGN: A literature review was conducted to identify what cultural principles and practices could be used to increase salience, and what competition elements could have an impact on efficacy of smoking cessation. The identified elements were incorporated into the design of a cessation intervention. DISCUSSION: Cultural practices incorporated into the intervention include having a holistic family or group-centred focus, inter-group competitiveness, fundraising and ritual pledging. Competition elements included are social support, pharmacotherapy use, cash prize incentives and the use of a dedicated website and iPad application. A pre-test post-test will be combined with process evaluation to evaluate if the competition results in triggering mass-quitting, utilisation of pharmacotherapy and in increasing sustained smoking cessation and to get a comprehensive understanding of the way in which they contribute to the effect. The present study is the first to describe how knowledge about cultural practices and principles can be combined with proven cessation support into a smoking cessation contest. The findings from this study are promising and further more rigorous testing is warranted.

Abdulla S, Alonso P, Binka F, Graves P, Greenwood B, Leke R, Malik E, Marsh K, Meek S, Mendis K et al. 2013. Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of September 2013 meeting MALARIA JOURNAL, 12 (1), pp. 456-456. | Citations: 1 (Web of Science Lite) | Read more

Nguyen KV, Thi Do NT, Chandna A, Nguyen TV, Pham CV, Doan PM, Nguyen AQ, Thi Nguyen CK, Larsson M, Escalante S et al. 2013. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health, 13 (1), pp. 1158. | Citations: 37 (Scopus) | Show Abstract | Read more

BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.

Achan J, Adam I, Arinaitwe E, Ashley EA, Awab GR, Ba MS, Barnes KI, Bassat Q, Borrmann S, Bousema T et al. 2013. The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data PLOS MEDICINE, 10 (12), pp. e1001564-e1001564. | Citations: 38 (Scopus) | Show Abstract | Read more

Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p < 0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions:DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.Please see later in the article for the Editors' Summary. © 2013 Price et al.

Crosnier C, Wanaguru M, McDade B, Osier FH, Marsh K, Rayner JC, Wright GJ. 2013. A library of functional recombinant cell-surface and secreted P. falciparum merozoite proteins. Mol Cell Proteomics, 12 (12), pp. 3976-3986. | Citations: 32 (Scopus) | Show Abstract | Read more

Malaria, an infectious disease caused by parasites of the Plasmodium genus, is one of the world's major public health concerns causing up to a million deaths annually, mostly because of P. falciparum infections. All of the clinical symptoms are associated with the blood stage of the disease, an obligate part of the parasite life cycle, when a form of the parasite called the merozoite recognizes and invades host erythrocytes. During erythrocyte invasion, merozoites are directly exposed to the host humoral immune system making the blood stage of the parasite a conceptually attractive therapeutic target. Progress in the functional and molecular characterization of P. falciparum merozoite proteins, however, has been hampered by the technical challenges associated with expressing these proteins in a biochemically active recombinant form. This challenge is particularly acute for extracellular proteins, which are the likely targets of host antibody responses, because they contain structurally critical post-translational modifications that are not added by some recombinant expression systems. Here, we report the development of a method that uses a mammalian expression system to compile a protein resource containing the entire ectodomains of 42 P. falciparum merozoite secreted and cell surface proteins, many of which have not previously been characterized. Importantly, we are able to recapitulate known biochemical activities by showing that recombinant MSP1-MSP7 and P12-P41 directly interact, and that both recombinant EBA175 and EBA140 can bind human erythrocytes in a sialic acid-dependent manner. Finally, we use sera from malaria-exposed immune adults to profile the relative immunoreactivity of the proteins and show that the majority of the antigens contain conformational (heat-labile) epitopes. We envisage that this resource of recombinant proteins will make a valuable contribution toward a molecular understanding of the blood stage of P. falciparum infections and facilitate the comparative screening of antigens as blood-stage vaccine candidates.

Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, Gundle R, Berendt A. 2013. Erratum to One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): Antibiotic duration and outcome [J Antimicrob Chemother, 63, (2009), 1264-71] Journal of Antimicrobial Chemotherapy, 68 (12), pp. 2964-2965. | Read more

Rono J, Osier FHA, Olsson D, Montgomery S, Mhoja L, Rooth I, Marsh K, Färnert A. 2013. Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria. Clin Infect Dis, 57 (10), pp. 1409-1416. | Citations: 29 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Elucidating the mechanisms of naturally acquired immunity to Plasmodium falciparum infections would be highly valuable for malaria vaccine development. Asymptomatic multiclonal infections have been shown to predict protection from clinical malaria in a transmission-dependent manner, but the mechanisms underlying this are unclear. We assessed the breadth of antibody responses to several vaccine candidate merozoite antigens in relation to the infecting parasite population and clinical immunity. METHODS: In a cohort study in Tanzania, 320 children aged 1-16 years who were asymptomatic at baseline were included. We genotyped P. falciparum infections by targeting the msp2 gene using polymerase chain reaction and capillary electrophoresis and measured antibodies to 7 merozoite antigens using a multiplex assay. We assessed the correlation between the number of clones and the breadth of the antibody response, and examined their effects on the risk of malaria during 40 weeks of follow-up using age-adjusted multivariate regression models. RESULTS: The antibody breadth was positively correlated with the number of clones (RR [risk ratio], 1.63; 95% confidence interval [CI], 1.32-2.02). Multiclonal infections were associated with a nonsignificant reduction in the risk of malaria in the absence of antibodies (RR, 0.83; 95% CI, .29-2.34). The breadth of the antibody response was significantly associated with a reduced risk of malaria in the absence of infections (RR, 0.25; 95% CI, .09-.66). In combination, these factors were associated with a lower risk of malaria than they were individually (RR, 0.14; 95% CI, .04-.48). CONCLUSIONS: These data suggest that malaria vaccines mimicking naturally acquired immunity should ideally induce antibody responses that can be boosted by natural infections.

Flegg JA, Guérin PJ, Nosten F, Ashley EA, Phyo AP, Dondorp AM, Fairhurst RM, Socheat D, Borrmann S, Björkman A et al. 2013. Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives. Malar J, 12 (1), pp. 411. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The emergence of Plasmodium falciparum resistance to artemisinins in Southeast Asia threatens the control of malaria worldwide. The pharmacodynamic hallmark of artemisinin derivatives is rapid parasite clearance (a short parasite half-life), therefore, the in vivo phenotype of slow clearance defines the reduced susceptibility to the drug. Measurement of parasite counts every six hours during the first three days after treatment have been recommended to measure the parasite clearance half-life, but it remains unclear whether simpler sampling intervals and frequencies might also be sufficient to reliably estimate this parameter. METHODS: A total of 2,746 parasite density-time profiles were selected from 13 clinical trials in Thailand, Cambodia, Mali, Vietnam, and Kenya. In these studies, parasite densities were measured every six hours until negative after treatment with an artemisinin derivative (alone or in combination with a partner drug). The WWARN Parasite Clearance Estimator (PCE) tool was used to estimate "reference" half-lives from these six-hourly measurements. The effect of four alternative sampling schedules on half-life estimation was investigated, and compared to the reference half-life (time zero, 6, 12, 24 (A1); zero, 6, 18, 24 (A2); zero, 12, 18, 24 (A3) or zero, 12, 24 (A4) hours and then every 12 hours). Statistical bootstrap methods were used to estimate the sampling distribution of half-lives for parasite populations with different geometric mean half-lives. A simulation study was performed to investigate a suite of 16 potential alternative schedules and half-life estimates generated by each of the schedules were compared to the "true" half-life. The candidate schedules in the simulation study included (among others) six-hourly sampling, schedule A1, schedule A4, and a convenience sampling schedule at six, seven, 24, 25, 48 and 49 hours. RESULTS: The median (range) parasite half-life for all clinical studies combined was 3.1 (0.7-12.9) hours. Schedule A1 consistently performed the best, and schedule A4 the worst, both for the individual patient estimates and for the populations generated with the bootstrapping algorithm. In both cases, the differences between the reference and alternative schedules decreased as half-life increased. In the simulation study, 24-hourly sampling performed the worst, and six-hourly sampling the best. The simulation study confirmed that more dense parasite sampling schedules are required to accurately estimate half-life for profiles with short half-life (≤ three hours) and/or low initial parasite density (≤ 10,000 per μL). Among schedules in the simulation study with six or fewer measurements in the first 48 hours, a schedule with measurements at times (time windows) of 0 (0-2), 6 (4-8), 12 (10-14), 24 (22-26), 36 (34-36) and 48 (46-50) hours, or at times 6, 7 (two samples in time window 5-8), 24, 25 (two samples during time 23-26), and 48, 49 (two samples during time 47-50) hours, until negative most accurately estimated the "true" half-life. For a given schedule, continuing sampling after two days had little effect on the estimation of half-life, provided that adequate sampling was performed in the first two days and the half-life was less than three hours. If the measured parasitaemia at two days exceeded 1,000 per μL, continued sampling for at least once a day was needed for accurate half-life estimates. CONCLUSIONS: This study has revealed important insights on sampling schedules for accurate and reliable estimation of Plasmodium falciparum half-life following treatment with an artemisinin derivative (alone or in combination with a partner drug). Accurate measurement of short half-lives (rapid clearance) requires more dense sampling schedules (with more than twice daily sampling). A more intensive sampling schedule is, therefore, recommended in locations where P. falciparum susceptibility to artemisinins is not known and the necessary resources are available. Counting parasite density at six hours is important, and less frequent sampling is satisfactory for estimating long parasite half-lives in areas where artemisinin resistance is present.

Marsh V, Kombe F, Fitzpatrick R, Molyneux S, Parker M. 2013. Managing misaligned paternity findings in research including sickle cell disease screening in Kenya: 'consulting communities' to inform policy. Soc Sci Med, 96 pp. 192-199. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

The management of misaligned paternity findings raises important controversy worldwide. It has mainly, however, been discussed in the context of high-income countries. Genetic and genomics research, with the potential to show misaligned paternity, are becoming increasingly common in Africa. During a genomics study in Kenya, a dilemma arose over testing and sharing information on paternal sickle cell disease status. This dilemma may be paradigmatic of challenges in sharing misaligned paternity findings in many research and health care settings. Using a deliberative approach to community consultation to inform research practice, we explored residents' views on paternal testing and sharing misaligned paternity information. Between December 2009 and November 2010, 63 residents in Kilifi County were engaged in informed deliberative small group discussions, structured to support normative reflection within the groups, with purposive selection to explore diversity. Analysis was based on a modified framework analysis approach, drawing on relevant social science and bioethics literature. The methods generated in-depth individual and group reflection on morally important issues and uncovered wide diversity in views and values. Fundamental and conflicting values emerged around the importance of family interests and openness, underpinned by disagreement on the moral implications of marital infidelity and withholding truth. Wider consideration of ethical issues emerging in these debates supports locally-held reasoning that paternal sickle cell testing should not be undertaken in this context, in contrast to views that testing should be done with or without the disclosure of misaligned paternity information. The findings highlight the importance of facilitating wider testing of family members of affected children, contingent on the development and implementation of national policies for the management of this inherited disorder. Their richness also illustrates the potential for the approach adopted in this study to strengthen community consultation.

Mulaku M, Opiyo N, Karumbi J, Kitonyi G, Thoithi G, English M. 2013. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries Archives of Disease in Childhood, 98 (11), pp. 908-914. | Citations: 11 (Scopus) | Show Abstract | Read more

Hydroxyurea is widely used in high-income countries for the management of sickle cell disease (SCD) in children. In Kenyan clinical guidelines, hydroxyurea is only recommended for adults with SCD. Yet many deaths from SCD occur in early childhood, deaths that might be prevented by an effective, disease modifying intervention. The aim of this review was to summarise the available evidence on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in children below 5 years of age to support guideline development in Kenya. We undertook a systematic review and used the Grading of Recommendations Assessment, Development and Evaluation system to appraise the quality of identified evidence. Overall, available evidence from 1 systematic review (n=26 studies), 2 randomised controlled trials (n=354 children), 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels, reduced rates of hospitalisation, reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD. However, it is associated with adverse events (eg, neutropenia) when high to maximum tolerated doses are used. Evidence is lacking on whether hydroxyurea improves survival if given to young children. Majority of the included studies were of low quality and mainly from high-income countries. Overall, available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in settings able to provide consistent haematological monitoring.

Le MQ, Lam HM, Cuong VD, Lam TT-Y, Halpin RA, Wentworth DE, Hien NT, Thanh LT, Phuong HVM, Horby P, Boni MF. 2013. Migration and persistence of human influenza A viruses, Vietnam, 2001-2008. Emerg Infect Dis, 19 (11), pp. 1756-1765. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Understanding global influenza migration and persistence is crucial for vaccine strain selection. Using 240 new human influenza A virus whole genomes collected in Vietnam during 2001-2008, we looked for persistence patterns and migratory connections between Vietnam and other countries. We found that viruses in Vietnam migrate to and from China, Hong Kong, Taiwan, Cambodia, Japan, South Korea, and the United States. We attempted to reduce geographic bias by generating phylogenies subsampled at the year and country levels. However, migration events in these phylogenies were still driven by the presence or absence of sequence data, indicating that an epidemiologic study design that controls for prevalence is required for robust migration analysis. With whole-genome data, most migration events are not detectable from the phylogeny of the hemagglutinin segment alone, although general migratory relationships between Vietnam and other countries are visible in the hemagglutinin phylogeny. It is possible that virus lineages in Vietnam persisted for >1 year.

Coia JE, Ritchie L, Adisesh A, Makison Booth C, Bradley C, Bunyan D, Carson G, Fry C, Hoffman P, Jenkins D et al. 2013. Guidance on the use of respiratory and facial protection equipment. J Hosp Infect, 85 (3), pp. 170-182. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

Infectious micro-organisms may be transmitted by a variety of routes, and some may be spread by more than one route. Respiratory and facial protection is required for those organisms that are usually transmitted via the droplet/airborne route, or when airborne particles have been artificially created, such as during 'aerosol-generating procedures'. A range of personal protective equipment that provides different degrees of facial and respiratory protection is available. It is apparent from the recent experiences with severe acute respiratory syndrome and pandemic (H1N1) 2009 influenza that healthcare workers may have difficulty in choosing the correct type of facial and respiratory protection in any given clinical situation. To address this issue, the Scientific Development Committee of the Healthcare Infection Society established a short-life working group to develop guidance. The guidance is based upon a review of the literature, which is published separately, and expert consensus.

Franzen SRP, Chandler C, Atashili J, Angus B, Lang T. 2013. Barriers and enablers of locally led clinical trials in Ethiopia and Cameroon: a prospective, qualitative study LANCET, 382 pp. 14-14. | Citations: 1 (Web of Science Lite)

Lang T, Marsh K, Peeling R, Farrar J. 2013. Sharing methods for global health research: an assessment of methodology LANCET, 382 pp. 5-5.

Marsh V, Kombe F, Fitzpatrick R, Williams TN, Parker M, Molyneux S. 2013. Consulting communities on feedback of genetic findings in international health research: sharing sickle cell disease and carrier information in coastal Kenya. BMC Med Ethics, 14 (1), pp. 41. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: International health research in malaria-endemic settings may include screening for sickle cell disease, given the relationship between this important genetic condition and resistance to malaria, generating questions about whether and how findings should be disclosed. The literature on disclosing genetic findings in the context of research highlights the role of community consultation in understanding and balancing ethically important issues from participants' perspectives, including social forms of benefit and harm, and the influence of access to care. To inform research practice locally, and contribute to policy more widely, this study aimed to explore the views of local residents in Kilifi County in coastal Kenya on how researchers should manage study-generated information on sickle cell disease and carrier status. METHODS: Between June 2010 and July 2011, we consulted 62 purposively selected Kilifi residents on how researchers should manage study-generated sickle cell disease findings. Methods drew on a series of deliberative informed small group discussions. Data were analysed thematically, using charts, to describe participants' perceptions of the importance of disclosing findings, including reasoning, difference and underlying values. Themes were derived from the underlying research questions and from issues emerging from discussions. Data interpretation drew on relevant areas of social science and bioethics literature. RESULTS: Perceived health and social benefits generated strong support for disclosing findings on sickle cell disease, but the balance of social benefits and harms was less clear for sickle cell trait. Many forms of health and social benefits and harms of information-sharing were identified, with important underlying values related to family interests and the importance of openness. The influence of micro and macro level contextual features and prioritization of values led to marked diversity of opinion. CONCLUSIONS: The approach demonstrates a high ethical importance in many malaria endemic low-to-middle income country settings of disclosing sickle cell disease findings generated during research, alongside provision of effective care and locally-informed counselling. Since these services are central to the benefits of disclosure, health researchers whose studies include screening for sickle cell disease should actively promote the development of health policy and services for this condition in situations of unmet need, including through the prior development of collaborative partnerships with government health managers and providers. Community consultation can importantly enrich ethical debate on research practice where in-depth exploration of informed views and the potential for difference are taken into account.

Bayoumi AM, Barnett PG, Joyce VR, Griffin SC, Sun H, Bansback NJ, Holodniy M, Sanders G, Brown ST, Kyriakides TC et al. 2013. Cost-effectiveness of newer antiretroviral drugs in treatment-experienced patients with multidrug-resistant HIV disease. J Acquir Immune Defic Syndr, 64 (4), pp. 382-391. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: Newer antiretroviral drugs provide substantial benefits but are expensive. The cost-effectiveness of using antiretroviral drugs in combination for patients with multidrug-resistant HIV disease was determined. DESIGN: A cohort state-transition model was built representing treatment-experienced patients with low CD4 counts, high viral load levels, and multidrug-resistant virus. The effectiveness of newer drugs (those approved in 2005 or later) was estimated from published randomized trials. Other parameters were estimated from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of 2 newer drugs and 1 conventional drug, compared with 3 conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness. RESULTS: Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared with conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting 3 newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued. CONCLUSIONS: In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost-effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior.

Le MQ, Horby P, Fox A, Nguyen HT, Le Nguyen HK, Hoang PMV, Nguyen KC, de Jong MD, Jeeninga RE, Rogier van Doorn H et al. 2013. Subclinical avian influenza A(H5N1) virus infection in human, Vietnam. Emerg Infect Dis, 19 (10), pp. 1674-1677. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam.

Participants in the Community Engagement and Consent Workshop , Kilifi, Kenya , March 2011. 2013. Consent and community engagement in diverse research contexts. J Empir Res Hum Res Ethics, 8 (4), pp. 1-18. | Citations: 25 (Scopus) | Show Abstract | Read more

Consent and community engagement (CE) in health research are two aspects of a single concern-that research is carried out in a respectful manner where social value is maximized. There are important overlaps and interdependencies between consent and CE; for example, CE can provide insights into how best to tailor consent to context and can be an important component of consent processes. Engaging communities can also have intrinsic and instrumental value beyond consent; for example, as a means of showing respect and identifying appropriate ways of working respectfully. In this paper we critically examine how CE and consent processes are characterized, conducted, and evaluated in diverse health research contexts, and propose a preliminary research agenda to support future learning in these critical areas.

Nair M, Ariana P, Ohuma EO, Gray R, De Stavola B, Webster P. 2013. Effect of the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA) on malnutrition of infants in Rajasthan, India: a mixed methods study. PLoS One, 8 (9), pp. e75089. | Citations: 5 (Scopus) | Show Abstract | Read more

OBJECTIVES: Analyse the effect of the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA), a wage-for-employment policy of the Indian Government, on infant malnutrition and delineate the pathways through which MGNREGA affects infant malnutrition. HYPOTHESIS: MGNREGA could reduce infant malnutrition through positive effects on household food security and infant feeding. METHOD: Mixed methods using cross-sectional study and focus group discussions conducted in Dungarpur district, Rajasthan, India. PARTICIPANTS: Infants aged 1 to <12 months and their mothers/caregivers. Final sample 528 households with 1056 participants, response rate 89.6%. Selected households were divided into MGNREGA-households and non-MGNREGA-households based on participation in MGNREGA between August-2010 and September-2011. OUTCOMES: Infant malnutrition measured using anthropometric indicators - underweight, stunting, and wasting (WHO criteria). RESULTS: We included 528 households with 1,056 participants. Out of 528, 281 households took part in MGNREGA between August'10, and September'11. Prevalence of wasting was 39%, stunting 24%, and underweight 50%. Households participating in MGNREGA were less likely to have wasted infants (OR 0·57, 95% CI 0·37-0·89, p = 0·014) and less likely to have underweight infants (OR 0·48, 95% CI 0·30-0·76, p = 0·002) than non-participating households. Stunting did not differ significantly between groups. We did 11 focus group discussions with 62 mothers. Although MGNREGA reduced starvation, it did not provide the desired benefits because of lower than standard wages and delayed payments. Results from path analysis did not support existence of an effect through household food security and infant feeding, but suggested a pathway of effect through low birth-weight. CONCLUSION: Participation in MGNREGA was associated with reduced infant malnutrition possibly mediated indirectly via improved birth-weight rather than by improved infant feeding. Addressing factors such as lack of mothers' knowledge and inappropriate feeding practices, over and above the social and economic policies, is key in efforts to reduce infant malnutrition.

Tanomsing N, Imwong M, Sutherland CJ, Dolecek C, Hien TT, Nosten F, Day NPJ, White NJ, Snounou G. 2013. Genetic marker suitable for identification and genotyping of Plasmodium ovale curtisi and Plasmodium ovale wallikeri. J Clin Microbiol, 51 (12), pp. 4213-4216. | Citations: 9 (Scopus) | Show Abstract | Read more

We present a seminested PCR method that specifically discriminates between Plasmodium ovale curtisi and P. ovale wallikeri with high sensitivity. The test is based on species-specific amplification of a size-polymorphic fragment of the tryptophan-rich antigen gene, potra, which also permits discrimination of intraspecific sequence variants at this locus.

Flegg JA, Metcalf CJE, Gharbi M, Venkatesan M, Shewchuk T, Hopkins Sibley C, Guerin PJ. 2013. Trends in antimalarial drug use in Africa. Am J Trop Med Hyg, 89 (5), pp. 857-865. | Citations: 10 (Scopus) | Show Abstract | Read more

Resistance to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) led the World Health Organization (WHO) to recommend changes in national drug policies. The time between policy changes and their implementation profoundly affects program impact. We developed a model based on data on antimalarial treatments, extracted from household surveys and national antimalarial policy information from the literature. Drug use in each country during the time period 1999-2011 and the trend in reduction of CQ use after policy change were estimated. The SP use estimates were correlated with the prevalence of a molecular marker associated with SP resistance. There was no spatial pattern in the country-level rate of reduction of CQ use, after policy change. In East Africa SP drug use was strongly correlated to resistance. If artemisinin resistance spreads to, or emerges in, Africa this methodology will be a valuable tool to estimate actual drug use and its impact on changes in drug efficacy.

Van Kerkhove MD, Hirve S, Koukounari A, Mounts AW, H1N1pdm serology working group. 2013. Estimating age-specific cumulative incidence for the 2009 influenza pandemic: a meta-analysis of A(H1N1)pdm09 serological studies from 19 countries. Influenza Other Respir Viruses, 7 (5), pp. 872-886. | Citations: 80 (Scopus) | Show Abstract | Read more

BACKGROUND: The global impact of the 2009 influenza A(H1N1) pandemic (H1N1pdm) is not well understood. OBJECTIVES: We estimate overall and age-specific prevalence of cross-reactive antibodies to H1N1pdm virus and rates of H1N1pdm infection during the first year of the pandemic using data from published and unpublished H1N1pdm seroepidemiological studies. METHODS: Primary aggregate H1N1pdm serologic data from each study were stratified in standardized age groups and evaluated based on when sera were collected in relation to national or subnational peak H1N1pdm activity. Seropositivity was assessed using well-described and standardized hemagglutination inhibition (HI titers ≥ 32 or ≥ 40) and microneutralization (MN ≥ 40) laboratory assays. The prevalence of cross-reactive antibodies to the H1N1pdm virus was estimated for studies using sera collected prior to the start of the pandemic (between 2004 and April 2009); H1N1pdm cumulative incidence was estimated for studies in which collected both pre- and post-pandemic sera; and H1N1pdm seropositivity was calculated from studies with post-pandemic sera only (collected between December 2009-June 2010). RESULTS: Data from 27 published/unpublished studies from 19 countries/administrative regions - Australia, Canada, China, Finland, France, Germany, Hong Kong SAR, India, Iran, Italy, Japan, Netherlands, New Zealand, Norway, Reunion Island, Singapore, United Kingdom, United States, and Vietnam - were eligible for inclusion. The overall age-standardized pre-pandemic prevalence of cross-reactive antibodies was 5% (95%CI 3-7%) and varied significantly by age with the highest rates among persons ≥ 65 years old (14% 95%CI 8-24%). Overall age-standardized H1N1pdm cumulative incidence was 24% (95%CI 20-27%) and varied significantly by age with the highest in children 5-19 (47% 95%CI 39-55%) and 0-4 years old (36% 95%CI 30-43%). CONCLUSIONS: Our results offer unique insight into the global impact of the H1N1 pandemic and highlight the need for standardization of seroepidemiological studies and for their inclusion in pre-pandemic preparedness plans. Our results taken together with recent global pandemic respiratory-associated mortality estimates suggest that the case fatality ratio of the pandemic virus was approximately 0.02%.

Mulaku M, Opiyo N, Karumbi J, Kitonyi G, Thoithi G, English M. 2013. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries. Arch Dis Child, 98 (11), pp. 908-914. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

Hydroxyurea is widely used in high-income countries for the management of sickle cell disease (SCD) in children. In Kenyan clinical guidelines, hydroxyurea is only recommended for adults with SCD. Yet many deaths from SCD occur in early childhood, deaths that might be prevented by an effective, disease modifying intervention. The aim of this review was to summarise the available evidence on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in children below 5 years of age to support guideline development in Kenya. We undertook a systematic review and used the Grading of Recommendations Assessment, Development and Evaluation system to appraise the quality of identified evidence. Overall, available evidence from 1 systematic review (n=26 studies), 2 randomised controlled trials (n=354 children), 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels, reduced rates of hospitalisation, reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD. However, it is associated with adverse events (eg, neutropenia) when high to maximum tolerated doses are used. Evidence is lacking on whether hydroxyurea improves survival if given to young children. Majority of the included studies were of low quality and mainly from high-income countries. Overall, available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in settings able to provide consistent haematological monitoring.

Warimwe GM, Fletcher HA, Olotu A, Agnandji ST, Hill AVS, Marsh K, Bejon P. 2013. Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data. BMC Med, 11 (1), pp. 184. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. METHODS: Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling. RESULTS: The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset. CONCLUSION: The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00380393 and NCT00436007.

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P, Tajar A, Piechnik SK et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients Circulation, 128 (8), pp. 814-822. | Citations: 50 (Scopus) | Show Abstract | Read more

BACKGROUND - : HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS - : Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P < 0.003) and 74% higher median plasma triglyceride levels (both P < 0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P < 0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS - : Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV. © 2013 American Heart Association, Inc.

Tarning J, Kloprogge F, Dhorda M, Jullien V, Nosten F, White NJ, Guerin PJ, Piola P. 2013. Pharmacokinetic properties of artemether, dihydroartemisinin, lumefantrine, and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in Uganda. Antimicrob Agents Chemother, 57 (10), pp. 5096-5103. | Citations: 19 (Scopus) | Show Abstract | Read more

Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.

Clutton G, Yang H, Hancock G, Sande N, Holloway C, Angus B, von Delft A, Barnes E, Borrow P, Pellegrino P et al. 2013. Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection. Eur J Immunol, 43 (11), pp. 2875-2885. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

Flegg JA, Patil AP, Venkatesan M, Roper C, Naidoo I, Hay SI, Sibley CH, Guerin PJ. 2013. Spatiotemporal mathematical modelling of mutations of the dhps gene in African Plasmodium falciparum. Malar J, 12 (1), pp. 249. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum has repeatedly evolved resistance to first-line anti-malarial drugs, thwarting efforts to control and eliminate the disease and in some period of time this contributed largely to an increase in mortality. Here a mathematical model was developed to map the spatiotemporal trends in the distribution of mutations in the P. falciparum dihydropteroate synthetase (dhps) gene that confer resistance to the anti-malarial sulphadoxine, and are a useful marker for the combination of alleles in dhfr and dhps that is highly correlated with resistance to sulphadoxine-pyrimethamine (SP). The aim of this study was to present a proof of concept for spatiotemporal modelling of trends in anti-malarial drug resistance that can be applied to monitor trends in resistance to components of artemisinin combination therapy (ACT) or other anti-malarials, as they emerge or spread. METHODS: Prevalence measurements of single nucleotide polymorphisms in three codon positions of the dihydropteroate synthetase (dhps) gene from published studies of dhps mutations across Africa were used. A model-based geostatistics approach was adopted to create predictive surfaces of the dhps540E mutation over the spatial domain of sub-Saharan Africa from 1990-2010. The statistical model was implemented within a Bayesian framework and hence quantified the associated uncertainty of the prediction of the prevalence of the dhps540E mutation in sub-Saharan Africa. CONCLUSIONS: The maps presented visualize the changing prevalence of the dhps540E mutation in sub-Saharan Africa. These allow prediction of space-time trends in the parasite resistance to SP, and provide probability distributions of resistance prevalence in places where no data are available as well as insight on the spread of resistance in a way that the data alone do not allow. The results of this work will be extended to design optimal sampling strategies for the future molecular surveillance of resistance, providing a proof of concept for similar techniques to design optimal strategies to monitor resistance to ACT.

Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, Pinoges L, Dhorda M, Boum Y, Sundaygar T, Zolia YM et al. 2013. Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial. Malar J, 12 (1), pp. 251. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce. METHODS: An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured. RESULTS: The day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017). CONCLUSIONS: Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended. TRIAL REGISTRATION: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.

Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, Pinoges L, Sundaygar T, Zolia YM, Jones JJ, Comte E et al. 2013. Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia. Malar J, 12 (1), pp. 250. | Citations: 20 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal. METHODS: Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28. RESULTS: Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis). CONCLUSION: Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT. TRIAL REGISTRATION: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).

Mbindyo P, Blaauw D, English M. 2013. The role of Clinical Officers in the Kenyan health system: a question of perspective. Hum Resour Health, 11 (1), pp. 32. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: Despite the increasing interest in using non-physician clinicians in many low-income countries, little is known about the roles they play in typical health system settings. Prior research has concentrated on evaluating their technical competencies compared to those of doctors. This work explored perceptions of the roles of Kenyan non-physician clinicians (Clinical Officers (COs). METHODS: Qualitative methods including in-depth interviews (with COs, nurses, doctors, hospital management, and policymakers, among others), participant observation and document analysis were used. A nomothetic-idiographic framework was used to examine tensions between institutions and individuals within them. A comparative approach was used to examine institutional versus individual notions of CO roles, how these roles play out in government and faith-based hospital (FBH) settings as well as differences arising from three specific work settings for COs within hospitals. RESULTS: The main finding was the discrepancy between policy documents that outline a broad role for COs that covers both technical and managerial roles, while respondents articulated a narrow technical role that focused on patient care and management. Respondents described a variety of images of COs, ranging from 'filter' to 'primary healthcare physician', when asked about CO roles. COs argued for a defined role associated with primary healthcare, feeling constrained by their technical role. FBH settings were found to additionally clarify CO roles when compared with public hospitals. Tensions between formal prescriptions of CO roles and actual practice were reported and coalesced around lack of recognition over COs work, role conflict among specialist COs, and role ambiguity. CONCLUSIONS: Even though COs are important service providers their role is not clearly understood, which has resulted in role conflict. It is suggested that their role be redefined, moving from that of 'substitute clinician' to professional 'primary care clinician', with this being supported by the health system.

Belita A, Mbindyo P, English M. 2013. Absenteeism amongst health workers--developing a typology to support empiric work in low-income countries and characterizing reported associations. Hum Resour Health, 11 (1), pp. 34. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

The contribution of inadequate health worker numbers and emigration have been highlighted in the international literature, but relatively little attention has been paid to absenteeism as a factor that undermines health-care delivery in low income countries. We therefore aimed to review the literature on absenteeism from a health system manager's perspective to inform needed work on this topic. Specifically, we aimed to develop a typology of definitions that might be useful to classify different forms of absenteeism and identify factors associated with absenteeism. Sixty-nine studies were reviewed, only four were from sub-Saharan Africa where the human resources for health crisis is most acute. Forms of absenteeism studied and methods used vary widely. No previous attempt to develop an overarching approach to classifying forms of absenteeism was identified. A typology based on key characteristics is proposed to fill this gap and considers absenteeism as defined by two key attributes, whether it is: planned/unplanned, and voluntary/involuntary. Factors reported to influence rates of absenteeism may be broadly classified into three thematic categories: workplace and content, personal and organizational and cultural factors. The literature presents an inconsistent picture of the effects of specific factors within these themes perhaps related to true contextual differences or inconsistent definitions of absenteeism.

Persson KEM, Fowkes FJI, McCallum FJ, Gicheru N, Reiling L, Richards JS, Wilson DW, Lopaticki S, Cowman AF, Marsh K, Beeson JG. 2013. Erythrocyte-binding antigens of Plasmodium falciparum are targets of human inhibitory antibodies and function to evade naturally acquired immunity. J Immunol, 191 (2), pp. 785-794. | Citations: 33 (Scopus) | Show Abstract | Read more

Abs that inhibit Plasmodium falciparum invasion of erythrocytes form an important component of human immunity against malaria, but key target Ags are largely unknown. Phenotypic variation by P. falciparum mediates the evasion of inhibitory Abs, contributing to the capacity of P. falciparum to cause repeat and chronic infections. However, Ags involved in mediating immune evasion have not been defined, and studies of the function of human Abs are limited. In this study, we used novel approaches to determine the importance of P. falciparum erythrocyte-binding Ags (EBAs), which are important invasion ligands, as targets of human invasion-inhibitory Abs and define their role in contributing to immune evasion through variation in function. We evaluated the invasion-inhibitory activity of acquired Abs from malaria-exposed children and adults from Kenya, using P. falciparum with disruption of genes encoding EBA140, EBA175, and EBA181, either individually or combined as EBA140/EBA175 or EBA175/EBA181 double knockouts. Our findings provide important new evidence that variation in the expression and function of the EBAs plays an important role in evasion of acquired Abs and that a substantial amount of phenotypic diversity results from variation in expression of different EBAs that contributes to immune evasion by P. falciparum. All three EBAs were identified as important targets of naturally acquired inhibitory Abs demonstrated by differential inhibition of parental parasites greater than EBA knockout lines. This knowledge will help to advance malaria vaccine development and suggests that multiple invasion ligands need to be targeted to overcome the capacity of P. falciparum for immune evasion.

Newton PN, Stepniewska K, Dondorp A, Silamut K, Chierakul W, Krishna S, Davis TME, Suputtamongkol Y, Angus B, Pukrittayakamee S et al. 2013. Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand. Malar J, 12 (1), pp. 229. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Severe malaria remains a major cause of death and morbidity amongst adults in the Asiatic tropics. METHODS: A retrospective analysis of the clinical and laboratory data of 988 adult patients, hospitalized with Plasmodium falciparum malaria and prospectively recruited to malaria studies in western Thailand between 1986 and 2002, was performed to assess the factors associated with a fatal outcome. Different severity scores and classifications for defining severe malaria were compared and, using multiple logistic regression, simple models for predicting mortality developed. RESULTS: The proportion of patients fulfilling the WHO 2000 definition of severe malaria was 78.1%, and their mortality was 10%. Mortality in patients given parenteral artesunate or artemether (16/317, 5%) was lower than in those given parenteral quinine (59/442, 13%) (P < 0.001). Models using parameter sets based on WHO 1990, 2000 and Adapted AQ criteria plus blood smear parasite-stage assessment gave the best mortality prediction. A malaria prognostic index (MPI), derived from the dataset using five clinical or laboratory variables gave similar prognostic accuracy. CONCLUSIONS: The mortality of severe malaria in adults has fallen and the switch from quinine to artesunate has probably been an important contributor. Prognostic indices based on WHO 2000 definitions, and other simpler indices based on fewer variables, provide clinically useful predictions of outcome in Asian adults with severe malaria.

Mugyenyi CK, Elliott SR, McCallum FJ, Anders RF, Marsh K, Beeson JG. 2013. Antibodies to polymorphic invasion-inhibitory and non-Inhibitory epitopes of Plasmodium falciparum apical membrane antigen 1 in human malaria. PLoS One, 8 (7), pp. e68304. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: Antibodies to P. falciparum apical membrane protein 1 (AMA1) may contribute to protective immunity against clinical malaria by inhibiting blood stage growth of P. falciparum, and AMA1 is a leading malaria vaccine candidate. Currently, there is limited knowledge of the acquisition of strain-specific and cross-reactive antibodies to AMA1 in humans, or the acquisition of invasion-inhibitory antibodies to AMA1. METHODOLOGY/FINDINGS: We examined the acquisition of human antibodies to specific polymorphic invasion-inhibitory and non-inhibitory AMA1 epitopes, defined by the monoclonal antibodies 1F9 and 2C5, respectively. Naturally acquired antibodies were measured in cohorts of Kenyan children and adults. Antibodies to the invasion-inhibitory 1F9 epitope and non-inhibitory 2C5 epitope were measured indirectly by competition ELISA. Antibodies to the 1F9 and 2C5 epitopes were acquired by children and correlated with exposure, and higher antibody levels and prevalence were observed with increasing age and with active P. falciparum infection. Of note, the prevalence of antibodies to the inhibitory 1F9 epitope was lower than antibodies to AMA1 or the 2C5 epitope. Antibodies to AMA1 ectodomain, the 1F9 or 2C5 epitopes, or a combination of responses, showed some association with protection from P. falciparum malaria in a prospective longitudinal study. Furthermore, antibodies to the invasion-inhibitory 1F9 epitope were positively correlated with parasite growth-inhibitory activity of serum antibodies. CONCLUSIONS/SIGNIFICANCE: Individuals acquire antibodies to functional, polymorphic epitopes of AMA1 that may contribute to protective immunity, and these findings have implications for AMA1 vaccine development. Measuring antibodies to the 1F9 epitope by competition ELISA may be a valuable approach to assessing human antibodies with invasion-inhibitory activity in studies of acquired immunity and vaccine trials of AMA1.

Karumbi J, Mulaku M, Aluvaala J, English M, Opiyo N. 2013. Topical umbilical cord care. Pediatr Infect Dis J, 32 (7), pp. 801-802. | Citations: 1 (Web of Science Lite) | Read more

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P, Tajar A, Piechnik SK et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. Circulation, 128 (8), pp. 814-822. | Citations: 51 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS: Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS: Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

Saira K, Lin X, DePasse JV, Halpin R, Twaddle A, Stockwell T, Angus B, Cozzi-Lepri A, Delfino M, Dugan V et al. 2013. Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. J Virol, 87 (14), pp. 8064-8074. | Citations: 42 (Scopus) | Show Abstract | Read more

Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.

Ayieko P, Griffiths UK, Ndiritu M, Moisi J, Mugoya IK, Kamau T, English M, Scott JAG. 2013. Assessment of health benefits and cost-effectiveness of 10-valent and 13-valent pneumococcal conjugate vaccination in Kenyan children. PLoS One, 8 (6), pp. e67324. | Citations: 25 (Scopus) | Show Abstract | Read more

BACKGROUND: The GAVI Alliance supported 10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the 13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects. METHODS: The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose. FINDINGS: The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26-103) and US$ 1,958 (95% CI 866-3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43-56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively. CONCLUSIONS: Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.

Murungi LM, Kamuyu G, Lowe B, Bejon P, Theisen M, Kinyanjui SM, Marsh K, Osier FHA. 2013. A threshold concentration of anti-merozoite antibodies is required for protection from clinical episodes of malaria. Vaccine, 31 (37), pp. 3936-3942. | Citations: 25 (Web of Science Lite) | Show Abstract | Read more

Antibodies to selected Plasmodium falciparum merozoite antigens are often reported to be associated with protection from malaria in one epidemiological cohort, but not in another. Here, we sought to understand this paradox by exploring the hypothesis that a threshold concentration of antibodies is necessary for protection. We analyzed data from two independent cohorts along the Kenyan coast, one in which antibodies to AMA1, MSP-2 and MSP-3 were associated with protection from malaria (Chonyi) and another in which this association was not observed (Junju). We used a malaria reference reagent to standardize antibody measurements across both cohorts, and applied statistical methods to derive the threshold concentration of antibodies against each antigen that best correlated with a reduced risk of malaria (the protective threshold), in the Chonyi cohort. We then tested whether antibodies in Junju reached the protective threshold concentrations observed in the Chonyi cohort. Except for children under 3 years, the age-matched proportions of children achieving protective threshold concentrations of antibodies against AMA1 and MSP-2 were significantly lower in Junju compared to Chonyi (Fishers exact test, P<0.01). For MSP-3, this difference was significant only among 4-5 year olds. We conclude that although antibodies are commonly detected in malaria endemic populations, they may be present in concentrations that are insufficient for protection. Our results have implications for the analysis and interpretation of similar data from immuno-epidemiological studies.

Abdulla S, Alonso P, Binka F, Graves P, Greenwood B, Leke R, Malik E, Marsh K, Meek S, Mendis K et al. 2013. Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting MALARIA JOURNAL, 12 (1), pp. 213-213. | Read more

South East Asia Infectious Disease Clinical Research Network. 2013. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ, 346 (may30 2), pp. f3039. | Citations: 49 (Scopus) | Show Abstract | Read more

OBJECTIVE: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. DESIGN: Double blind randomised trial. SETTING: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. PARTICIPANTS: Patients aged ≥ 1 year admitted to hospital with confirmed severe influenza. INTERVENTIONS: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). MAIN OUTCOME MEASURE: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. RESULTS: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. CONCLUSIONS: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. REGISTRATION: Clinical Trials NCT00298233.

Horby PW, Pfeiffer D, Oshitani H. 2013. Prospects for emerging infections in East and southeast Asia 10 years after severe acute respiratory syndrome. Emerg Infect Dis, 19 (6), pp. 853-860. | Citations: 22 (Scopus) | Show Abstract | Read more

It is 10 years since severe acute respiratory syndrome (SARS) emerged, and East and Southeast Asia retain a reputation as a hot spot of emerging infectious diseases. The region is certainly a hot spot of socioeconomic and environmental change, and although some changes (e.g., urbanization and agricultural intensification) may reduce the probability of emerging infectious diseases, the effect of any individual emergence event may be increased by the greater concentration and connectivity of livestock, persons, and products. The region is now better able to detect and respond to emerging infectious diseases than it was a decade ago, but the tools and methods to produce sufficiently refined assessments of the risks of disease emergence are still lacking. Given the continued scale and pace of change in East and Southeast Asia, it is vital that capabilities for predicting, identifying, and controlling biologic threats do not stagnate as the memory of SARS fades.

Alexander N, Fox A, Lien VTK, Dong T, Lee LY-H, Hang NLK, Mai LQ, Horby P. 2013. Defining ELISpot cut-offs from unreplicated test and control wells JOURNAL OF IMMUNOLOGICAL METHODS, 392 (1-2), pp. 57-62. | Citations: 3 (Scopus) | Show Abstract | Read more

In the absence of replication of wells, empirical criteria for enzyme-linked immunospot (ELISpot) positivity use fixed differences or ratios between spot forming units (SFU) counts between test and control. We propose an alternative approach which first identifies the optimally variance-stabilizing transformation of the SFU counts, based on the Bland-Altman plot of the test and control wells. The second step is to derive a positivity threshold from the difference in between-plate distribution functions of the transformed test and control SFU counts. This method is illustrated using 1309 assay results from a cohort study of influenza in Vietnam in which some, but not all, of the peptide pools have clear tendencies for SFU counts to be higher in test than control wells. © 2013 Elsevier B.V.

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection Journal of Immunological Methods, 391 (1-2), pp. 174-178. | Citations: 7 (Scopus) | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a co nventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10 -2 to 8×10 -5 , and by nearly two-fold (p < 0.001) at the optimal MOI tested (10 -2 ). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs. © 2013 Elsevier B.V.

Gathara D, Irimu G, Kihara H, Maina C, Mbori-Ngacha D, Mwangi J, Allen E, English M. 2013. Hospital outcomes for paediatric pneumonia and diarrhoea patients admitted in a tertiary hospital on weekdays versus weekends: a retrospective study. BMC Pediatr, 13 (1), pp. 74. | Show Abstract | Read more

BACKGROUND: Quality of patient care in hospitals has been shown to be inconsistent during weekends and night-time hours, and is often associated with reduced patient monitoring, poor antibiotic prescription practices and poor patient outcomes. Poorer care and outcomes are commonly attributed to decreased levels of staffing, supervision and expertise and poorer access to diagnostics. However, there are few studies examining this issue in low resource settings where mortality from common childhood illnesses is high and health care systems are weak. METHODS: This study uses data from a retrospective cross-sectional study aimed at "evaluating the uptake of best practice clinical guidelines in a tertiary hospital" with a pre and post intervention approach that spanned the period 2005 to 2009. We evaluated a primary hypothesis that mortality for children with pneumonia and/or dehydration aged 2-59 months admitted on weekends differed from those admitted on weekdays. A secondary hypothesis that poor quality of care could be a mechanism for higher mortality was also explored. Logistic regression was used to examine the association between mortality and the independent predictors of mortality. RESULTS: Our analysis indicates that there is no difference in mortality on weekends compared to weekdays even after adjusting for the significant predictors of mortality (OR = 1.15; 95% CI 0.90 -1.45; p = 0.27). There were similarly no significant differences between weekends and weekdays for the quality of care indicators, however, there was an overall improvement in mortality and quality of care through the period of study. CONCLUSION: Mortality and the quality of care does not differ by the day of admission in a Kenyan tertiary hospital, however mortality remains high suggesting that continued efforts to improve care are warranted.

Liverani M, Waage J, Barnett T, Pfeiffer DU, Rushton J, Rudge JW, Loevinsohn ME, Scoones I, Smith RD, Cooper BS et al. 2013. Understanding and managing zoonotic risk in the new livestock industries. Environ Health Perspect, 121 (8), pp. 873-877. | Citations: 17 (Scopus) | Show Abstract | Read more

BACKGROUND: In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock. OBJECTIVES: Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem. DISCUSSION: We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management. CONCLUSION: Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences.

Band G, Le QS, Jostins L, Pirinen M, Kivinen K, Jallow M, Sisay-Joof F, Bojang K, Pinder M, Sirugo G et al. 2013. Imputation-based meta-analysis of severe malaria in three African populations. PLoS Genet, 9 (5), pp. e1003509. | Citations: 35 (Web of Science Lite) | Show Abstract | Read more

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.

Miotto O, Almagro-Garcia J, Manske M, Macinnis B, Campino S, Rockett KA, Amaratunga C, Lim P, Suon S, Sreng S et al. 2013. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet, 45 (6), pp. 648-655. | Citations: 219 (Scopus) | Show Abstract | Read more

We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist in its elimination.

Horby P. 2013. H7N9 is a virus worth worrying about. Nature, 496 (7446), pp. 399. | Citations: 34 (Web of Science Lite) | Read more

Woodrow CJ, Dahlström S, Cooksey R, Flegg JA, Le Nagard H, Mentré F, Murillo C, Ménard D, Nosten F, Sriprawat K et al. 2013. High-throughput analysis of antimalarial susceptibility data by the WorldWide Antimalarial Resistance Network (WWARN) in vitro analysis and reporting tool. Antimicrob Agents Chemother, 57 (7), pp. 3121-3130. | Citations: 20 (Scopus) | Show Abstract | Read more

Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50s) were determined by a modified sigmoid Emax model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC50s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs.

Das D, Price RN, Bethell D, Guerin PJ, Stepniewska K. 2013. Early parasitological response following artemisinin-containing regimens: a critical review of the literature. Malar J, 12 (1), pp. 125. | Citations: 15 (Scopus) | Show Abstract | Read more

BACKGROUND: Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented. METHODS: The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire. RESULTS: In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3-95, IQR=30.5-69.2] on Day 1, 6% [range 0-65.9, IQR=2-11.5] on Day 2 and 0 [range 0-12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours. CONCLUSIONS: These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

Douglas AD, Edwards NJ, Duncan CJA, Thompson FM, Sheehy SH, O'Hara GA, Anagnostou N, Walther M, Webster DP, Dunachie SJ et al. 2013. Comparison of modeling methods to determine liver-to-blood inocula and parasite multiplication rates during controlled human malaria infection. J Infect Dis, 208 (2), pp. 340-345. | Citations: 21 (Scopus) | Show Abstract | Read more

Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasite's liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.

Angwenyi V, Kamuya D, Mwachiro D, Marsh V, Njuguna P, Molyneux S. 2013. Working with Community Health Workers as 'volunteers' in a vaccine trial: practical and ethical experiences and implications. Dev World Bioeth, 13 (1), pp. 38-47. | Citations: 11 (Scopus) | Show Abstract | Read more

Community engagement is increasingly emphasized in biomedical research, as a right in itself, and to strengthen ethical practice. We draw on interviews and observations to consider the practical and ethical implications of involving Community Health Workers (CHWs) as part of a community engagement strategy for a vaccine trial on the Kenyan Coast. CHWs were initially engaged as an important network to be informed about the trial. However over time, and in response to community advice, they became involved in trial information sharing and identifying potential participants; thereby taking on roles that overlapped with those of employed fieldworkers (FWs). While CHWs involvement was generally perceived as positive and appreciated, there were challenges in their relations with FWs and other community members, partly related to levels and forms of remuneration. Specifically, payment of CHWs was not as high as for FWs and was based on 'performance'. This extrinsic motivation had the potential to crowd out CHWs intrinsic motivation to perform their pre-existing community roles. CHWs remuneration potentially also contributed to CHWs distorting trial information to encourage community members to participate; and to researchers encouraging CHWs to utilize their social connections and status to increase the numbers of people who attended information giving sessions. Individual consent processes were protected in this trial through final information sharing and consent being conducted by trained clinical staff who were not embedded in study communities. However, our experiences suggest that roles and remuneration of all front line staff and volunteers involved in trials need careful consideration from the outset, and monitoring and discussion over time.

Marsh V, Mocamah G, Mabibo E, Kombe F, Williams TN. 2013. The "difficult patient" conundrum in sickle cell disease in Kenya: complex sociopolitical problems need wide multidimensional solutions. Am J Bioeth, 13 (4), pp. 20-22. | Citations: 1 (Web of Science Lite) | Read more

Ahmed OH, Sullivan SJ, Schneiders AG, Anderson L, Paton C, McCrory PR. 2013. Ethical considerations in using Facebook for health care support: a case study using concussion management. PM R, 5 (4), pp. 328-334. | Citations: 10 (Scopus) | Show Abstract | Read more

Social networking sites (SNS) are now part of everyday life, and SNSs such as Facebook, YouTube, and Twitter are among the most accessed Web sites on the Internet. Although SNSs are primarily used for staying in touch with friends and family, they are increasingly being used for health-related purposes for a variety of conditions, including concussion awareness. As health interventions begin to be more commonly provided through SNSs (particularly Facebook), ethical issues have been raised with regard to confidentiality, privacy, and trust; these issues need to be addressed. This article outlines some of the key considerations when providing a concussion intervention through Facebook and discusses potential solutions to these issues.

English M. 2013. Designing a theory-informed, contextually appropriate intervention strategy to improve delivery of paediatric services in Kenyan hospitals. Implement Sci, 8 (1), pp. 39. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: District hospital services in Kenya and many low-income countries should deliver proven, effective interventions that could substantially reduce child and newborn mortality. However such services are often of poor quality. Researchers have therefore been challenged to identify intervention strategies that go beyond addressing knowledge, skill, or resource inadequacies to support health systems to deliver better services at scale. An effort to develop a system-oriented intervention tailored to local needs and context and drawing on theory is described. METHODS: An intervention was designed to improve district hospital services for children based on four main strategies: a reflective process to distill root causes for the observed problems with service delivery; developing a set of possible intervention approaches to address these problems; a search of literature for theory that provided the most appropriate basis for intervention design; and repeatedly moving backwards and forwards between identified causes, proposed interventions, identified theory, and knowledge of the existing context to develop an overarching intervention that seemed feasible and likely to be acceptable and potentially sustainable. RESULTS AND DISCUSSION: In addition to human and resource constraints key problems included failures of relevant professionals to take responsibility for or ownership of the challenge of pediatric service delivery; inadequately prepared, poorly supported leaders of service units (mid-level managers) who are often professionally and geographically isolated and an almost complete lack of useful information for routinely monitoring or understanding service delivery practice or outcomes. A system-oriented intervention recognizing the pivotal role of leaders of service units but addressing the outer and inner setting of hospitals was designed to help shape and support an appropriate role for these professionals. It aims to foster a sense of ownership while providing the necessary understanding, knowledge, and skills for mid-level managers to work effectively with senior managers and frontline staff to improve services. The intervention will include development of an information system, feedback mechanisms, and discussion fora that promote positive change. The vehicle for such an intervention is a collaborative network partnering government and national professional associations. This case is presented to promote discussion on approaches to developing context appropriate interventions particularly in international health.

Olotu A, Fegan G, Wambua J, Nyangweso G, Awuondo KO, Leach A, Lievens M, Leboulleux D, Njuguna P, Peshu N et al. 2013. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N Engl J Med, 368 (12), pp. 1111-1120. | Citations: 137 (Scopus) | Show Abstract | Read more

BACKGROUND: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited. METHODS: For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria. RESULTS: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, -11.0 to 36.4). CONCLUSIONS: The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.).

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection. J Immunol Methods, 391 (1-2), pp. 174-178. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10(-2) to 8×10(-5), and by nearly two-fold (p<0.001) at the optimal MOI tested (10(-2)). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs.

Smith R, Lagarde M, Blaauw D, Goodman C, English M, Mullei K, Pagaiya N, Tangcharoensathien V, Erasmus E, Hanson K. 2013. Appealing to altruism: an alternative strategy to address the health workforce crisis in developing countries? J Public Health (Oxf), 35 (1), pp. 164-170. | Show Abstract | Read more

BACKGROUND: Recruitment and retention of health workers is a major concern. Policy initiatives emphasize financial incentives, despite mixed evidence of their effectiveness. Qualitative studies suggest that nurses especially may be more driven by altruistic motivations, but quantitative research has overlooked such values. This paper adds to the literature through characterizing the nature and determinants of nurses' altruism, based on a cross-country quantitative study. METHODS: An experimental 'dictator game' was undertaken with 1064 final year nursing students in Kenya, South Africa and Thailand between April 2007 and July 2008. This presents participants with a real financial endowment to split between themselves and another student, a patient or a poor person. Giving a greater share of this financial endowment to the other person is interpreted as reflecting greater altruism. RESULTS: Nursing students gave over 30% of their initial endowment to others (compared with 10% in similar experiments undertaken in other samples). Respondents in all three countries showed greater generosity to patients and the poor than to fellow students. CONCLUSIONS: Consideration needs to be given to how to appeal to altruistic values as an alternative strategy to encourage nurses to enter the profession and remain, such as designing recruitment strategies to increase recruitment of altruistic individuals who are more likely to remain in the profession.

Gikonyo C, Kamuya D, Mbete B, Njuguna P, Olotu A, Bejon P, Marsh V, Molyneux S. 2013. Feedback of research findings for vaccine trials: experiences from two malaria vaccine trials involving healthy children on the Kenyan Coast. Dev World Bioeth, 13 (1), pp. 48-56. | Show Abstract | Read more

Internationally, calls for feedback of findings to be made an 'ethical imperative' or mandatory have been met with both strong support and opposition. Challenges include differences in issues by type of study and context, disentangling between aggregate and individual study results, and inadequate empirical evidence on which to draw. In this paper we present data from observations and interviews with key stakeholders involved in feeding back aggregate study findings for two Phase II malaria vaccine trials among children under the age of 5 years old on the Kenyan Coast. In our setting, feeding back of aggregate findings was an appreciated set of activities. The inclusion of individual results was important from the point of view of both participants and researchers, to reassure participants of trial safety, and to ensure that positive results were not over-interpreted and that individual level issues around blinding and control were clarified. Feedback sessions also offered an opportunity to re-evaluate and re-negotiate trial relationships and benefits, with potentially important implications for perceptions of and involvement in follow-up work for the trials and in future research. We found that feedback of findings is a complex but key step in a continuing set of social interactions between community members and research staff (particularly field staff who work at the interface with communities), and among community members themselves; a step which needs careful planning from the outset. We agree with others that individual and aggregate results need to be considered separately, and that for individual results, both the nature and value of the information, and the context, including social relationships, need to be taken into account.

Gharbi M, Flegg JA, Hubert V, Kendjo E, Metcalf JE, Bertaux L, Guérin PJ, Le Bras J, Members of the French National Reference Centre for Imported Malaria Study, Aboubaca A et al. 2013. Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000-2011. Malar J, 12 (1), pp. 35. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. METHODS: The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. RESULTS: A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = -0.3, p < 10-3). CONCLUSIONS: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011 and they correlated to the decrease of the drug pressure.

Koh GCKW, Schreiber MF, Bautista R, Maude RR, Dunachie S, Limmathurotsakul D, Day NPJ, Dougan G, Peacock SJ. 2013. Host responses to melioidosis and tuberculosis are both dominated by interferon-mediated signaling. PLoS One, 8 (1), pp. e54961. | Citations: 34 (Scopus) | Show Abstract | Read more

Melioidosis (Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Northeast Thailand and northern Australia. B. pseudomallei is a soil saprophyte endemic to Southeast Asia and northern Australia. The clinical presentation of melioidosis may mimic tuberculosis (both cause chronic suppurative lesions unresponsive to conventional antibiotics and both commonly affect the lungs). The two diseases have overlapping risk profiles (e.g., diabetes, corticosteroid use), and both B. pseudomallei and Mycobacterium tuberculosis are intracellular pathogens. There are however important differences: the majority of melioidosis cases are acute, not chronic, and present with severe sepsis and a mortality rate that approaches 50% despite appropriate antimicrobial therapy. By contrast, tuberculosis is characteristically a chronic illness with mortality <2% with appropriate antimicrobial chemotherapy. We examined the gene expression profiles of total peripheral leukocytes in two cohorts of patients, one with acute melioidosis (30 patients and 30 controls) and another with tuberculosis (20 patients and 24 controls). Interferon-mediated responses dominate the host response to both infections, and both type 1 and type 2 interferon responses are important. An 86-gene signature previously thought to be specific for tuberculosis is also found in melioidosis. We conclude that the host responses to melioidosis and to tuberculosis are similar: both are dominated by interferon-signalling pathways and this similarity means gene expression signatures from whole blood do not distinguish between these two diseases.

Roetynck S, Olotu A, Simam J, Marsh K, Stockinger B, Urban B, Langhorne J. 2013. Phenotypic and functional profiling of CD4 T cell compartment in distinct populations of healthy adults with different antigenic exposure. PLoS One, 8 (1), pp. e55195. | Citations: 12 (Scopus) | Show Abstract | Read more

BACKGROUND: Multiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully. METHODOLOGY/PRINCIPAL FINDINGS: We developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for "Th1" type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures. CONCLUSION/SIGNIFICANCE: These findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.

Opiyo N, Shepperd S, Musila N, Allen E, Nyamai R, Fretheim A, English M. 2013. Comparison of alternative evidence summary and presentation formats in clinical guideline development: a mixed-method study. PLoS One, 8 (1), pp. e55067. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Best formats for summarising and presenting evidence for use in clinical guideline development remain less well defined. We aimed to assess the effectiveness of different evidence summary formats to address this gap. METHODS: Healthcare professionals attending a one-week Kenyan, national guideline development workshop were randomly allocated to receive evidence packaged in three different formats: systematic reviews (SRs) alone, systematic reviews with summary-of-findings tables, and 'graded-entry' formats (a 'front-end' summary and a contextually framed narrative report plus the SR). The influence of format on the proportion of correct responses to key clinical questions, the primary outcome, was assessed using a written test. The secondary outcome was a composite endpoint, measured on a 5-point scale, of the clarity of presentation and ease of locating the quality of evidence for critical neonatal outcomes. Interviews conducted within two months following completion of trial data collection explored panel members' views on the evidence summary formats and experiences with appraisal and use of research information. RESULTS: 65 (93%) of 70 participants completed questions on the prespecified outcome measures. There were no differences between groups in the odds of correct responses to key clinical questions. 'Graded-entry' formats were associated with a higher mean composite score for clarity and accessibility of information about the quality of evidence for critical neonatal outcomes compared to systematic reviews alone (adjusted mean difference 0.52, 95% CI 0.06 to 0.99). There was no difference in the mean composite score between SR with SoF tables and SR alone. Findings from interviews with 16 panelists indicated that short narrative evidence reports were preferred for the improved clarity of information presentation and ease of use. CONCLUSIONS: Our findings suggest that 'graded-entry' evidence summary formats may improve clarity and accessibility of research evidence in clinical guideline development. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN05154264.

Warimwe GM, Murungi LM, Kamuyu G, Nyangweso GM, Wambua J, Naranbhai V, Fletcher HA, Hill AVS, Bejon P, Osier FHA, Marsh K. 2013. The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. PLoS One, 8 (2), pp. e57320. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum malaria remains a major cause of illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention. METHODS AND FINDINGS: Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR)  =  2.7 (95% CI 1.42, 5.01, P  =  0.002) but not in those without detectable parasitaemia (HR  =  1.0 (95% CI 0.74, 1.42, P  =  0.9). CONCLUSIONS: We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual's capacity to mount an effective immune response to P. falciparum infection.

Kamuya DM, Marsh V, Kombe FK, Geissler PW, Molyneux SC. 2013. Engaging communities to strengthen research ethics in low-income settings: selection and perceptions of members of a network of representatives in coastal Kenya. Dev World Bioeth, 13 (1), pp. 10-20. | Show Abstract | Read more

There is wide agreement that community engagement is important for many research types and settings, often including interaction with 'representatives' of communities. There is relatively little published experience of community engagement in international research settings, with available information focusing on Community Advisory Boards or Groups (CAB/CAGs), or variants of these, where CAB/G members often advise researchers on behalf of the communities they represent. In this paper we describe a network of community members ('KEMRI Community Representatives', or 'KCRs') linked to a large multi-disciplinary research programme on the Kenyan Coast. Unlike many CAB/Gs, the intention with the KCR network has evolved to be for members to represent the geographical areas in which a diverse range of health studies are conducted through being typical of those communities. We draw on routine reports, self-administered questionnaires and interviews to: 1) document how typical KCR members are of the local communities in terms of basic characteristics, and 2) explore KCR's perceptions of their roles, and of the benefits and challenges of undertaking these roles. We conclude that this evolving network is a potentially valuable way of strengthening interactions between a research institution and a local geographic community, through contributing to meeting intrinsic ethical values such as showing respect, and instrumental values such as improving consent processes. However, there are numerous challenges involved. Other ways of interacting with members of local communities, including community leaders, and the most vulnerable groups least likely to be vocal in representative groups, have always been, and remain, essential.

Bjerk SM, Baker JV, Emery S, Neuhaus J, Angus B, Gordin FM, Pett SL, Stephan C, Kunisaki KM, INSIGHT SMART Study Group. 2013. Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study. PLoS One, 8 (2), pp. e56249. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Lundblom K, Murungi L, Nyaga V, Olsson D, Rono J, Osier F, Ogada E, Montgomery S, Scott JAG, Marsh K, Färnert A. 2013. Plasmodium falciparum infection patterns since birth and risk of severe malaria: a nested case-control study in children on the coast of Kenya. PLoS One, 8 (2), pp. e56032. | Citations: 7 (Scopus) | Show Abstract | Read more

Children in malaria endemic areas acquire immunity to severe malaria faster than to mild malaria. Only a minority of children suffers from severe malaria and it is not known what determines this. The aim of this study was to establish how P. falciparum infections during the first years of life affect the risk of severe malaria. A matched case-control study was nested within a large birth cohort set up to study the immunoepidemiology of pneumococci on the Kenyan coast. Infection patterns in three-monthly blood samples in cohort children admitted to hospital with severe malaria were compared to controls matched on age, residential location and time of sampling. P. falciparum detected at least once from birth conferred an increased risk of severe malaria and particularly if multiclonal infections, as characterized by genotyping of a polymorphic antigen gene, were ever detected. The results show for the first time that children with severe malaria have more infections early in life compared to community controls. These findings provide important insights on the immunity to severe disease, knowledge essential for the development of a vaccine against severe malaria.

Davey RT, Lynfield R, Dwyer DE, Losso MH, Cozzi-Lepri A, Wentworth D, Lane HC, Dewar R, Rupert A, Metcalf JA et al. 2013. The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies. PLoS One, 8 (2), pp. e57121. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies. METHODS: Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified. RESULTS: In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1)pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3(rd) versus 1(st) tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-α, D-dimer, and sVCAM-1), all with ORs for the 3(rd) versus 1(st) tertile greater than 3.2, were significantly (p≤.002) associated with disease progression among hospitalized patients only. CONCLUSIONS: In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome.

Nzinga J, Mbaabu L, English M. 2013. Service delivery in Kenyan district hospitals - what can we learn from literature on mid-level managers? Hum Resour Health, 11 (1), pp. 10. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: There is a growing emphasis on the need to tackle inadequate human resources for health (HRH) as an essential part of strengthening health systems; but the focus is mostly on macro-level issues, such as training, recruitment, skill mix and distribution. Few attempts have been made to understand the capability of health workers, their motivation and other structural and organizational aspects of systems that influence workforce performance. We have examined literature on the roles of mid-level managers to help us understand how they might influence service delivery quality in Kenyan hospitals. In the Kenyan hospital settings, these are roles that head of departments who are also clinical or nursing service providers might play. METHODS: A computerized search strategy was run in Pub Med, Cochrane Library, Directory of Open Access Journals Social Science Research Network, Eldis, Google Scholar and Human Resources for Health web site databases using both free-text and MeSH terms from 1980 to 2011. In addition, citation searching from excluded and included articles was used and relevant unpublished literature systematically identified. RESULTS AND DISCUSSION: A total of 23 articles were finally included in the review from over 7000 titles and abstracts initially identified. The most widely documented roles of mid-level managers were decision-making or problem-solving, strategist or negotiator and communicator. Others included being a therapist or motivator, goal setting or articulation and mentoring or coaching. In addition to these roles, we identified important personal attributes of a good manager, which included interpersonal skills, delegation and accountability, and honesty. The majority of studies included in the review concerned the roles that mid-level managers are expected to play in times of organizational change. CONCLUSION: This review highlights the possible significance of mid-level managers in achieving delivery of high-quality services in Kenyan public hospitals and strongly suggests that approaches to strengthen this level of management will be valuable. The findings from this review should also help inform empirical studies of the roles of mid-level managers in these settings.

Kamuya DM, Marsh V, Kombe FK, Geissler PW, Molyneux SC. 2013. Engaging Communities to Strengthen Research Ethics in Low-Income Settings: Selection and Perceptions of Members of a Network of Representatives in Coastal Kenya Developing World Bioethics, 13 (1), pp. 10-20. | Citations: 27 (Scopus) | Show Abstract | Read more

There is wide agreement that community engagement is important for many research types and settings, often including interaction with 'representatives' of communities. There is relatively little published experience of community engagement in international research settings, with available information focusing on Community Advisory Boards or Groups (CAB/CAGs), or variants of these, where CAB/G members often advise researchers on behalf of the communities they represent. In this paper we describe a network of community members ('KEMRI Community Representatives', or 'KCRs') linked to a large multi-disciplinary research programme on the Kenyan Coast. Unlike many CAB/Gs, the intention with the KCR network has evolved to be for members to represent the geographical areas in which a diverse range of health studies are conducted through being typical of those communities. We draw on routine reports, self-administered questionnaires and interviews to: 1) document how typical KCR members are of the local communities in terms of basic characteristics, and 2) explore KCR's perceptions of their roles, and of the benefits and challenges of undertaking these roles. We conclude that this evolving network is a potentially valuable way of strengthening interactions between a research institution and a local geographic community, through contributing to meeting intrinsic ethical values such as showing respect, and instrumental values such as improving consent processes. However, there are numerous challenges involved. Other ways of interacting with members of local communities, including community leaders, and the most vulnerable groups least likely to be vocal in representative groups, have always been, and remain, essential. © 2013 Blackwell Publishing Ltd.

Gikonyo C, Kamuya D, Mbete B, Njuguna P, Olotu A, Bejon P, Marsh V, Molyneux S. 2013. Feedback of Research Findings for Vaccine Trials: Experiences from Two Malaria Vaccine Trials Involving Healthy Children on the Kenyan Coast Developing World Bioethics, 13 (1), pp. 48-56. | Citations: 10 (Scopus) | Show Abstract | Read more

Internationally, calls for feedback of findings to be made an 'ethical imperative' or mandatory have been met with both strong support and opposition. Challenges include differences in issues by type of study and context, disentangling between aggregate and individual study results, and inadequate empirical evidence on which to draw. In this paper we present data from observations and interviews with key stakeholders involved in feeding back aggregate study findings for two Phase II malaria vaccine trials among children under the age of 5 years old on the Kenyan Coast. In our setting, feeding back of aggregate findings was an appreciated set of activities. The inclusion of individual results was important from the point of view of both participants and researchers, to reassure participants of trial safety, and to ensure that positive results were not over-interpreted and that individual level issues around blinding and control were clarified. Feedback sessions also offered an opportunity to re-evaluate and re-negotiate trial relationships and benefits, with potentially important implications for perceptions of and involvement in follow-up work for the trials and in future research. We found that feedback of findings is a complex but key step in a continuing set of social interactions between community members and research staff (particularly field staff who work at the interface with communities), and among community members themselves; a step which needs careful planning from the outset. We agree with others that individual and aggregate results need to be considered separately, and that for individual results, both the nature and value of the information, and the context, including social relationships, need to be taken into account. Copyright © 2013 Blackwell Publishing Ltd.

Dieu Ngan TT, Thomas S, Larsson M, Horby P, Diep NN, Dat VQ, Trung NV, Ha NH, Rogier van Doorn H, Van Kinh N, Wertheim HFL. 2013. First report of human psittacosis in Vietnam Journal of Infection, 66 (5), pp. 461-464. | Citations: 4 (Scopus) | Read more

De Beaudrap P, Turyakira E, White LJ, Nabasumba C, Tumwebaze B, Muehlenbachs A, Guérin PJ, Boum Y, McGready R, Piola P. 2013. Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospective cohort with intensive malaria screening and prompt treatment. Malar J, 12 (1), pp. 139. | Citations: 32 (Scopus) | Show Abstract | Read more

BACKGROUND: Malaria in pregnancy (MiP) is a major public health problem in endemic areas of sub-Saharan Africa and has important consequences on birth outcome. Because MiP is a complex phenomenon and malaria epidemiology is rapidly changing, additional evidence is still required to understand how best to control malaria. This study followed a prospective cohort of pregnant women who had access to intensive malaria screening and prompt treatment to identify factors associated with increased risk of MiP and to analyse how various characteristics of MiP affect delivery outcomes. METHODS: Between October 2006 and May 2009, 1,218 pregnant women were enrolled in a prospective cohort. After an initial assessment, they were screened weekly for malaria. At delivery, blood smears were obtained from the mother, placenta, cord and newborn. Multivariate analyses were performed to analyse the association between mothers' characteristics and malaria risk, as well as between MiP and birth outcome, length and weight at birth. This study is a secondary analysis of a trial registered with ClinicalTrials.gov, number NCT00495508. RESULTS: Overall, 288/1,069 (27%) mothers had 345 peripheral malaria infections. The risk of peripheral malaria was higher in mothers who were younger, infected with HIV, had less education, lived in rural areas or reported no bed net use, whereas the risk of placental infection was associated with more frequent malaria infections and with infection during late pregnancy. The risk of pre-term delivery and of miscarriage was increased in mothers infected with HIV, living in rural areas and with MiP occurring within two weeks of delivery.In adjusted analysis, birth weight but not length was reduced in babies of mothers exposed to MiP (-60 g, 95%CI: -120 to 0 for at least one infection and -150 g, 95%CI: -280 to -20 for >1 infections). CONCLUSIONS: In this study, the timing, parasitaemia level and number of peripherally-detected malaria infections, but not the presence of fever, were associated with adverse birth outcomes. Hence, prompt malaria detection and treatment should be offered to pregnant women regardless of symptoms or other preventive measures used during pregnancy, and with increased focus on mothers living in remote areas.

Nacher M, Guérin PJ, Demar-Pierre M, Djossou F, Nosten F, Carme B. 2013. Made in Europe: will artemisinin resistance emerge in French Guiana? Malar J, 12 (1), pp. 152. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

Resistance to artemisinin casts a shadow on the fight against malaria. The importance of illegal gold miners and of malaria in isolated regions of French Guiana constitutes a threat that endangers the fight against malaria in the Amazon. The hurdles of French laws and the remoteness of the territory from France make it impossible for the system to adapt to the problem of total inaccessibility of an important part of the malaria problem. Transmission is high in these areas and gold miners self-medicate with erratic regimens of artemisinin combinations, thus creating perfect conditions for the emergence of resistance. What needs to be done is being done, but within the limits of national law, with some results. However, facing the same difficult problem, Suriname shows more flexibility and is doing much better than French Guiana despite having lower resources. Local authorities in French Guiana cannot overrule the laws that block appropriate malaria care from reaching a third of malaria-exposed persons. Thus the health authorities in France should take immediate calibrated legislative and financial measures to avoid a predictable disaster.

Page A-L, de Rekeneire N, Sayadi S, Aberrane S, Janssens A-C, Rieux C, Djibo A, Manuguerra J-C, Ducou-le-Pointe H, Grais RF et al. 2013. Infections in children admitted with complicated severe acute malnutrition in Niger. PLoS One, 8 (7), pp. e68699. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Although malnutrition affects thousands of children throughout the Sahel each year and predisposes them to infections, there is little data on the etiology of infections in these populations. We present a clinical and biological characterization of infections in hospitalized children with complicated severe acute malnutrition (SAM) in Maradi, Niger. METHODS: Children with complicated SAM hospitalized in the intensive care unit of a therapeutic feeding center, with no antibiotics in the previous 7 days, were included. A clinical examination, blood, urine and stool cultures, and chest radiography were performed systematically on admission. RESULTS: Among the 311 children included in the study, gastroenteritis was the most frequent clinical diagnosis on admission, followed by respiratory tract infections and malaria. Blood or urine culture was positive in 17% and 16% of cases, respectively, and 36% had abnormal chest radiography. Enterobacteria were sensitive to most antibiotics, except amoxicillin and cotrimoxazole. Twenty-nine (9%) children died, most frequently from sepsis. Clinical signs were poor indicators of infection and initial diagnoses correlated poorly with biologically or radiography-confirmed diagnoses. CONCLUSIONS: These data confirm the high level of infections and poor correlation with clinical signs in children with complicated SAM, and provide antibiotic resistance profiles from an area with limited microbiological data. These results contribute unique data to the ongoing debate on the use and choice of broad-spectrum antibiotics as first-line treatment in children with complicated SAM and reinforce the call for an update of international guidelines on management of complicated SAM based on more recent data.

Warimwe GM, Recker M, Kiragu EW, Buckee CO, Wambua J, Musyoki JN, Marsh K, Bull PC. 2013. Plasmodium falciparum var gene expression homogeneity as a marker of the host-parasite relationship under different levels of naturally acquired immunity to malaria. PLoS One, 8 (7), pp. e70467. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season.

Fox A, Hung TM, Wertheim H, Hoa LNM, Vincent A, Lang B, Waters P, Ha NH, Trung NV, Farrar J et al. 2013. Acute measles encephalitis in partially vaccinated adults. PLoS One, 8 (8), pp. e71671. | Citations: 6 (Scopus) | Show Abstract | Read more

BACKGROUND: The pathogenesis of acute measles encephalitis (AME) is poorly understood. Treatment with immune-modulators is based on theories that post-infectious autoimmune responses cause demyelination. The clinical course and immunological parameters of AME were examined during an outbreak in Vietnam. METHODS AND FINDINGS: Fifteen measles IgM-positive patients with confusion or Glasgow Coma Scale (GCS) score below 13, and thirteen with uncomplicated measles were enrolled from 2008-2010. Standardized clinical exams were performed and blood collected for lymphocyte and measles- and auto-antibody analysis. The median age of AME patients was 21 years, similar to controls. Eleven reported receiving measles vaccination when aged one year. Confusion developed a median of 4 days after rash. Six patients had GCS <8 and four required mechanical ventilation. CSF showed pleocytosis (64%) and proteinorrhachia (71%) but measles virus RNA was not detected. MRI revealed bilateral lesions in the cerebellum and brain stem in some patients. Most received dexamethasone +/- IVIG within 4 days of admission but symptoms persisted for ≥3 weeks in five. The concentration of voltage gated calcium channel-complex-reactive antibodies was 900 pM in one patient, and declined to 609 pM ∼ 3 months later. Measles-reactive IgG antibody avidity was high in AME patients born after vaccine coverage exceeded 50% (∼ 25 years earlier). AME patients had low CD4 (218/µl, p = 0.029) and CD8 (200/µl, p = 0.012) T-cell counts compared to controls. CONCLUSION: Young adults presenting with AME in Vietnam reported a history of one prior measles immunization, and those aged <25 years had high measles-reactive IgG avidity indicative of prior vaccination. This suggests that one-dose measles immunization is not sufficient to prevent AME in young adults and reinforces the importance of maintaining high coverage with a two-dose measles immunization schedule. Treatment with corticosteroids and IVIG is common practice, and should be assessed in randomized clinical trials.

Karkey A, Thompson CN, Tran Vu Thieu N, Dongol S, Le Thi Phuong T, Voong Vinh P, Arjyal A, Martin LB, Rondini S, Farrar JJ et al. 2013. Differential epidemiology of Salmonella Typhi and Paratyphi A in Kathmandu, Nepal: a matched case control investigation in a highly endemic enteric fever setting. PLoS Negl Trop Dis, 7 (8), pp. e2391. | Citations: 26 (Scopus) | Show Abstract | Read more

BACKGROUND: Enteric fever, a systemic infection caused by the bacteria Salmonella Typhi and Salmonella Paratyphi A, is endemic in Kathmandu, Nepal. Previous work identified proximity to poor quality water sources as a community-level risk for infection. Here, we sought to examine individual-level risk factors related to hygiene and sanitation to improve our understanding of the epidemiology of enteric fever in this setting. METHODOLOGY AND PRINCIPAL FINDINGS: A matched case-control analysis was performed through enrollment of 103 blood culture positive enteric fever patients and 294 afebrile community-based age and gender-matched controls. A detailed questionnaire was administered to both cases and controls and the association between enteric fever infection and potential exposures were examined through conditional logistic regression. Several behavioral practices were identified as protective against infection with enteric fever, including water storage and hygienic habits. Additionally, we found that exposures related to poor water and socioeconomic status are more influential in the risk of infection with S. Typhi, whereas food consumption habits and migration play more of a role in risk of S. Paratyphi A infection. CONCLUSIONS AND SIGNIFICANCE: Our work suggests that S. Typhi and S. Paratyphi A follow different routes of infection in this highly endemic setting and that sustained exposure to both serovars probably leads to the development of passive immunity. In the absence of a polyvalent vaccine against S. Typhi and S. Paratyphi A, we advocate better systems for water treatment and storage, improvements in the quality of street food, and vaccination with currently available S. Typhi vaccines.

Horby P, Nguyen NY, Dunstan SJ, Baillie JK. 2013. An updated systematic review of the role of host genetics in susceptibility to influenza. Influenza Other Respir Viruses, 7 Suppl 2 (SUPPL.2), pp. 37-41. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted in June 2011 to summarise the evidence on the role of host genetics in susceptibility to influenza, and this report updates that previously published review. Animal studies suggest that genetic control of susceptibility to severe influenza in mice is complex and not controlled by a single locus, but there is encouraging evidence that some of the host genetic determinants of susceptibility to severe disease may be common across influenza subtypes. Although a number of studies on genetic susceptibility to influenza in humans have been published recently, all are underpowered and unreplicated, so do not provide robust statistical evidence of an association between the identified genetic loci and susceptibility. One study does however present convincing functional evidence for an important role for IFITM3 in susceptibility to severe influenza in mice, and some evidence that this may also be important in human A/H1N1/pdm2009 infection.

Tran ST, Renschler JP, Le HT, Dang HTT, Dao TM, Pham AN, Nguyen LT, Van Nguyen H, Thi Thu Nguyen T, Ngoc Le S et al. 2013. Diagnostic accuracy of microscopic Observation Drug Susceptibility (MODS) assay for pediatric tuberculosis in Hanoi, Vietnam. PLoS One, 8 (9), pp. e72100. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Microscopic [corrected] Observation Drug Susceptibility (MODS) has been shown to be an effective and rapid technique for early diagnosis of tuberculosis (TB). Thus far only a limited number of studies evaluating MODS have been performed in children and in extra-pulmonary tuberculosis. This study aims to assess relative accuracy and time to positive culture of MODS for TB diagnosis in children admitted to a general pediatric hospital in Vietnam. METHODS/PRINCIPAL FINDINGS: Specimens from children with suspected TB were tested by smear, MODS and Lowenstein-Jensen agar (LJ). 1129 samples from 705 children were analyzed, including sputum (n=59), gastric aspirate (n=775), CSF (n=148), pleural fluid (n=33), BAL (n=41), tracheal fluid (n=45), other (n=28). 113 TB cases were defined based on the "clinical diagnosis" (confirmed and probable groups) as the reference standard, in which 26% (n=30) were diagnosed as extra-pulmonary TB. Analysis by patient shows that the overall sensitivity and specificity of smear, LJ and MODS against "clinical diagnosis" was 8.8% and 100%, 38.9% and 100%, 46% and 99.5% respectively with MODS significantly more sensitive than LJ culture (P=0.02). When analyzed by sample type, the sensitivity of MODS was significantly higher than LJ for gastric aspirates (P=0.004). The time to detection was also significantly shorter for MODS than LJ (7 days versus 32 days, P<0.001). CONCLUSION: MODS [corrected] is a sensitive and rapid culture technique for detecting TB in children. As MODS culture can be performed at a BSL2 facility and is inexpensive, it can therefore be recommended as a routine test for children with symptoms suggestive of TB in resource-limited settings.

Murhekar M, Arima Y, Horby P, Vandemaele KAH, Vong S, Zijian F, Lee C-K, Li A, World Health Organization Regional Office for the Western Pacific Event Management Team. 2013. Avian influenza A(H7N9) and the closure of live bird markets. Western Pac Surveill Response J, 4 (2), pp. 4-7. | Citations: 24 (Scopus) | Read more

Tran ST, Renschler JP, Le HT, Dang HT, Dao TM, Pham AN, Nguyen LT, Van Nguyen H, Thi Thu Nguyen T, Ngoc Le S et al. 2013. Correction: Diagnostic Accuracy of Microscopic Observation Drug Susceptibility (MODS) Assay for Pediatric Tuberculosis in Hanoi, Vietnam. PLoS One, 8 (9), | Show Abstract | Read more

[This corrects the article on p. e72100 in vol. 8.].

Paton C, Househ M, Malik M. 2013. The challenges of publishing on health informatics in developing countries. Appl Clin Inform, 4 (3), pp. 428-433. | Citations: 15 (Scopus) | Show Abstract | Read more

The Journal of Health Informatics in Developing Countries was established to meet a perceived need for Health Informaticians in developing countries to be able to share the results of their research in an affordable and easy-to-access online publication. The journal was developed using the open source platform "Open Journal System," and has now published 67 articles across 13 issues. A collaborative editorial approach has been established to address the problems of limited research budgets, difficulties with translating to English and other problems specific to authors from developing countries. The journal faces many challenges including ensuring future financial sustainability and inclusion in journal indexing systems. However, the continuing support of an international body of Associate Editors and Editorial Board Members has enabled a wide range of useful and informative health informatics research to be disseminated across the developing world.

Tetteh KKA, Osier FHA, Salanti A, Kamuyu G, Drought L, Failly M, Martin C, Marsh K, Conway DJ. 2013. Analysis of antibodies to newly described Plasmodium falciparum merozoite antigens supports MSPDBL2 as a predicted target of naturally acquired immunity. Infect Immun, 81 (10), pp. 3835-3842. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in Plasmodium falciparum schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n = 497] and Ngerenya [n = 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.

Gharbi M, Flegg JA, Pradines B, Berenger A, Ndiaye M, Djimdé AA, Roper C, Hubert V, Kendjo E, Venkatesan M et al. 2013. Surveillance of travellers: an additional tool for tracking antimalarial drug resistance in endemic countries. PLoS One, 8 (10), pp. e77775. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: There are growing concerns about the emergence of resistance to artemisinin-based combination therapies (ACTs). Since the widespread adoption of ACTs, there has been a decrease in the systematic surveillance of antimalarial drug resistance in many malaria-endemic countries. The aim of this work was to test whether data on travellers returning from Africa with malaria could serve as an additional surveillance system of local information sources for the emergence of drug resistance in endemic-countries. METHODOLOGY: Data were collected from travellers with symptomatic Plasmodium falciparum malaria returning from Senegal (n = 1,993), Mali (n = 2,372), Cote d'Ivoire (n = 4,778) or Cameroon (n = 3,272) and recorded in the French Malaria Reference Centre during the period 1996-2011. Temporal trends of the proportion of parasite isolates that carried the mutant genotype, pfcrt 76T, a marker of resistance to chloroquine (CQ) and pfdhfr 108N, a marker of resistance to pyrimethamine, were compared for travellers and within-country surveys that were identified through a literature review in PubMed. The in vitro response to CQ was also compared between these two groups for parasites from Senegal. RESULTS: The trends in the proportion of parasites that carried pfcrt 76T, and pfdhfr 108N, were compared for parasites from travellers and patients within-country using the slopes of the curves over time; no significant differences in the trends were found for any of the 4 countries. These results were supported by in vitro analysis of parasites from the field in Senegal and travellers returning to France, where the trends were also not significantly different. CONCLUSION: The results have not shown different trends in resistance between parasites derived from travellers or from parasites within-country. This work highlights the value of an international database of drug responses in travellers as an additional tool to assess the emergence of drug resistance in endemic areas where information is limited.

Kloprogge F, Piola P, Dhorda M, Muwanga S, Turyakira E, Apinan S, Lindegårdh N, Nosten F, Day NPJ, White NJ et al. 2013. Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda. CPT Pharmacometrics Syst Pharmacol, 2 (11), pp. e83. | Citations: 14 (Scopus) | Show Abstract | Read more

Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e83; doi:10.1038/psp.2013.59; advance online publication 13 November 2013.

Franzen SRP, Chandler C, Enquselassie F, Siribaddana S, Atashili J, Angus B, Lang T. 2013. Understanding the investigators: a qualitative study investigating the barriers and enablers to the implementation of local investigator-initiated clinical trials in Ethiopia. BMJ Open, 3 (11), pp. e003616. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: Clinical trials provide 'gold standard' evidence for policy, but insufficient locally relevant trials are conducted in low-income and middle-income countries. Local investigator-initiated trials could generate highly relevant data for national governments, but information is lacking on how to facilitate them. We aimed to identify barriers and enablers to investigator-initiated trials in Ethiopia to inform and direct capacity strengthening initiatives. DESIGN: Exploratory, qualitative study comprising of in-depth interviews (n=7) and focus group discussions (n=3). SETTING: Fieldwork took place in Ethiopia during March 2011. PARTICIPANTS: Local health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were recruited through snowball sampling (n=20). OUTCOME MEASURES: Detailed discussion notes were analysed using thematic coding analysis and key themes were identified. RESULTS: All participants perceived investigator-initiated trials as important for generating local evidence. System and organisational barriers included: limited funding allocation, weak regulatory and administrative systems, few learning opportunities, limited human and material capacity and poor incentives for conducting research. Operational hurdles were symptomatic of these barriers. Lack of awareness, confidence and motivation to undertake trials were important individual barriers. Training, knowledge sharing and experience exchange were key enablers to trial conduct and collaboration was unanimously regarded as important for improving capacity. CONCLUSIONS: Barriers to trial conduct were found at individual, operational, organisational and system levels. These findings indicate that to increase locally led trial conduct in Ethiopia, system wide changes are needed to create a more receptive and enabling research environment. Crucially, the creation of research networks between potential trial groups could provide much needed practical collaborative support through sharing of financial and project management burdens, knowledge and resources. These findings could have important implications for capacity-strengthening initiatives but further research is needed before the results can be generalised more widely.

Koirala S, Basnyat B, Arjyal A, Shilpakar O, Shrestha K, Shrestha R, Shrestha UM, Agrawal K, Koirala KD, Thapa SD et al. 2013. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled trial. PLoS Negl Trop Dis, 7 (10), pp. e2523. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: Fluoroquinolones are the most commonly used group of antimicrobials for the treatment of enteric fever, but no direct comparison between two fluoroquinolones has been performed in a large randomised trial. An open-label randomized trial was conducted to investigate whether gatifloxacin is more effective than ofloxacin in the treatment of uncomplicated enteric fever caused by nalidixic acid-resistant Salmonella enterica serovars Typhi and Paratyphi A. METHODOLOGY AND PRINCIPAL FINDINGS: Adults and children clinically diagnosed with uncomplicated enteric fever were enrolled in the study to receive gatifloxacin (10 mg/kg/day) in a single dose or ofloxacin (20 mg/kg/day) in two divided doses for 7 days. Patients were followed for six months. The primary outcome was treatment failure in patients infected with nalidixic acid resistant isolates. 627 patients with a median age of 17 (IQR 9-23) years were randomised. Of the 218 patients with culture confirmed enteric fever, 170 patients were infected with nalidixic acid-resistant isolates. In the ofloxacin group, 6 out of 83 patients had treatment failure compared to 5 out of 87 in the gatifloxacin group (hazard ratio [HR] of time to failure 0.81, 95% CI 0.25 to 2.65, p = 0.73). The median time to fever clearance was 4.70 days (IQR 2.98-5.90) in the ofloxacin group versus 3.31 days (IQR 2.29-4.75) in the gatifloxacin group (HR = 1.59, 95% CI 1.16 to 2.18, p = 0.004). The results in all blood culture-confirmed patients and all randomized patients were comparable. CONCLUSION: Gatifloxacin was not superior to ofloxacin in preventing failure, but use of gatifloxacin did result in more prompt fever clearance time compared to ofloxacin. TRIAL REGISTRATION: ISRCTN 63006567 (www.controlled-trials.com).

Borrmann S, Straimer J, Mwai L, Abdi A, Rippert A, Okombo J, Muriithi S, Sasi P, Kortok MM, Lowe B et al. 2013. Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. Sci Rep, 3 (1), pp. 3318. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.

Ramachandran S, Singhal M, McKenzie KG, Osborn JL, Arjyal A, Dongol S, Baker SG, Basnyat B, Farrar J, Dolecek C et al. 2013. A Rapid, Multiplexed, High-Throughput Flow-Through Membrane Immunoassay: A Convenient Alternative to ELISA. Diagnostics (Basel), 3 (2), pp. 244-260. | Show Abstract | Read more

This paper describes a rapid, high-throughput flow-through membrane immunoassay (FMIA) platform. A nitrocellulose membrane was spotted in an array format with multiple capture and control reagents for each sample detection area, and assay steps were carried out by sequential aspiration of sample and reagents through each detection area using a 96-well vacuum manifold. The FMIA provides an alternate assay format with several advantages over ELISA. The high surface area of the membrane permits high label concentration using gold labels, and the small pores and vacuum control provide rapid diffusion to reduce total assay time to ~30 min. All reagents used in the FMIA are compatible with dry storage without refrigeration. The results appear as colored spots on the membrane that can be quantified using a flatbed scanner. We demonstrate the platform for detection of IgM specific to lipopolysaccharides (LPS) derived from Salmonella Typhi. The FMIA format provides analytical results comparable to ELISA in less time, provides integrated assay controls, and allows compensation for specimen-to-specimen variability in background, which is a particular challenge for IgM assays.

Thompson K-A, Pappachan JV, Bennett AM, Mittal H, Macken S, Dove BK, Nguyen-Van-Tam JS, Copley VR, O'Brien S, Hoffman P et al. 2013. Influenza aerosols in UK hospitals during the H1N1 (2009) pandemic--the risk of aerosol generation during medical procedures. PLoS One, 8 (2), pp. e56278. | Show Abstract | Read more

BACKGROUND: Nosocomial infection of health-care workers (HCWs) during outbreaks of respiratory infections (e.g. Influenza A H1N1 (2009)) is a significant concern for public health policy makers. World Health Organization (WHO)-defined 'aerosol generating procedures' (AGPs) are thought to increase the risk of aerosol transmission to HCWs, but there are presently insufficient data to quantify risk accurately or establish a hierarchy of risk-prone procedures. METHODOLOGY/PRINCIPAL FINDINGS: This study measured the amount of H1N1 (2009) RNA in aerosols in the vicinity of H1N1 positive patients undergoing AGPs to help quantify the potential risk of transmission to HCWs. There were 99 sampling occasions (windows) producing a total of 198 May stages for analysis in the size ranges 0.86-7.3 µm. Considering stages 2 (4-7.3 µm) and 3 (0.86-4 µm) as comprising one sample, viral RNA was detected in 14 (14.1%) air samples from 10 (25.6%) patients. Twenty three air samples were collected while potential AGPs were being performed of which 6 (26.1%) contained viral RNA; in contrast, 76 May samples were collected when no WHO 2009 defined AGP was being performed of which 8 (10.5%) contained viral RNA (unadjusted OR = 2.84 (95% CI 1.11-7.24) adjusted OR = 4.31 (0.83-22.5)). CONCLUSIONS/SIGNIFICANCE: With our small sample size we found that AGPs do not significantly increase the probability of sampling an H1N1 (2009) positive aerosol (OR (95% CI) = 4.31 (0.83-22.5). Although the probability of detecting positive H1N1 (2009) positive aerosols when performing various AGPs on intensive care patients above the baseline rate (i.e. in the absence of AGPs) did not reach significance, there was a trend towards hierarchy of AGPs, placing bronchoscopy and respiratory and airway suctioning above baseline (background) values. Further, larger studies are required but these preliminary findings may be of benefit to infection control teams.

Illingworth J, Butler NS, Roetynck S, Mwacharo J, Pierce SK, Bejon P, Crompton PD, Marsh K, Ndungu FM. 2013. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol, 190 (3), pp. 1038-1047. | Citations: 94 (Scopus) | Show Abstract | Read more

Naturally acquired immunity to malaria develops slowly, requiring several years of repeated exposure to be effective. The cellular and molecular factors underlying this observation are only partially understood. Recent studies suggest that chronic Plasmodium falciparum exposure may induce functional exhaustion of lymphocytes, potentially impeding optimal control of infection. However, it remains unclear whether the "atypical" memory B cells (MBCs) and "exhausted" CD4 T cells described in humans exposed to endemic malaria are driven by P. falciparum per se or by other factors commonly associated with malaria, such as coinfections and malnutrition. To address this critical question we took advantage of a "natural" experiment near Kilifi, Kenya, and compared profiles of B and T cells of children living in a rural community where P. falciparum transmission is ongoing to the profiles of age-matched children living under similar conditions in a nearby community where P. falciparum transmission ceased 5 y prior to this study. We found that continuous exposure to P. falciparum drives the expansion of atypical MBCs. Persistent P. falciparum exposure was associated with an increased frequency of CD4 T cells expressing phenotypic markers of exhaustion, both programmed cell death-1 (PD-1) alone and PD-1 in combination with lymphocyte-activation gene-3 (LAG-3). This expansion of PD-1-expressing and PD-1/LAG-3-coexpressing CD4 T cells was largely confined to CD45RA(+) CD4 T cells. The percentage of CD45RA(+)CD27(+) CD4 T cells coexpressing PD-1 and LAG-3 was inversely correlated with frequencies of activated and classical MBCs. Taken together, these results suggest that P. falciparum infection per se drives the expansion of atypical MBCs and phenotypically exhausted CD4 T cells, which has been reported in other endemic areas.

Dieu Ngan TT, Thomas S, Larsson M, Horby P, Diep NN, Dat VQ, Trung NV, Ha NH, Rogier van Doorn H, Van Kinh N, Wertheim HFL. 2013. First report of human psittacosis in Vietnam. J Infect, 66 (5), pp. 461-464. | Citations: 3 (Web of Science Lite) | Read more

Karumbi J, Mulaku M, Aluvaala J, English M, Opiyo N. 2013. Topical umbilical cord care for prevention of infection and neonatal mortality. Pediatr Infect Dis J, 32 (1), pp. 78-83. | Citations: 25 (Web of Science Lite) | Show Abstract | Read more

Umbilical cord care varies often reflecting community or health-worker beliefs. We undertook a review of current evidence on topical umbilical cord care. Study quality was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system, and a meta-analysis was conducted for comparable trials. Available moderate-quality to high-quality evidence indicate that cord cleansing with 4% chlorhexidine may reduce the risk of neonatal mortality and sepsis (omphalitis) in low-resource settings.

Barnett I, Ariana P, Petrou S, Penny ME, Duc LT, Galab S, Woldehanna T, Escobal JA, Plugge E, Boyden J. 2013. Cohort profile: the Young Lives study. Int J Epidemiol, 42 (3), pp. 701-708. | Citations: 37 (Scopus) | Show Abstract | Read more

Young Lives is an international longitudinal study investigating the changing nature of childhood poverty in four low-income countries [Ethiopia, India (Andhra Pradesh), Peru and Vietnam] over a 15-year period. In each country, the cohort is comprised of ≈ 2000 children aged between 6 and 18 months and up to 1000 children aged between 7 and 8 years, recruited in 2002 and sampled from 20 sentinel sites. The first survey data collection from primary caregivers and older children took place in 2002, the second in 2006-07 and the third in 2009-10. Data on the community contexts were collected to complement the household surveys. To elaborate and extend the quantitative data, longitudinal qualitative research with a subgroup of the children was carried out in 2007, 2008 and 2010-11. Topic areas covered included nutrition, health and well-being, cognitive and physical development, health behaviours and education, as well as the social, demographic and economic status of the household. Survey data from the study are archived in the International Section of the UK Public Data Archive.

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