@Oxford Publications 2015

Li HK, Scarborough M, Zambellas R, Cooper C, Rombach I, Walker AS, Lipsky BA, Briggs A, Seaton A, Atkins B et al. 2015. Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial. Trials, 16 (1), pp. 583. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy. METHODS: The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). DISCUSSION: If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. TRIAL REGISTRATION: ISRCTN91566927 - 14/02/2013.

Longley RJ, Reyes-Sandoval A, Montoya-Díaz E, Dunachie S, Kumpitak C, Nguitragool W, Mueller I, Sattabongkot J. 2015. Acquisition and Longevity of Antibodies to Plasmodium vivax Preerythrocytic Antigens in Western Thailand. Clin Vaccine Immunol, 23 (2), pp. 117-124. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

Plasmodium vivax is now the dominant Plasmodium species causing malaria in Thailand, yet little is known about naturally acquired immune responses to this parasite in this low-transmission region. The preerythrocytic stage of the P. vivax life cycle is considered an excellent target for a malaria vaccine, and in this study, we assessed the stability of the seropositivity and the magnitude of IgG responses to three different preerythrocytic P. vivax proteins in two groups of adults from a region of western Thailand where malaria is endemic. These individuals were enrolled in a yearlong cohort study, which comprised one group that remained P. vivax free (by quantitative PCR [qPCR] detection, n = 31) and another that experienced two or more blood-stage P. vivax infections during the year of follow up (n = 31). Despite overall low levels of seropositivity, IgG positivity and magnitude were long-lived over the 1-year period in the absence of qPCR-detectable blood-stage P. vivax infections. In contrast, in the adults with two or more P. vivax infections during the year, IgG positivity was maintained, but the magnitude of the response to P. vivax circumsporozoite protein 210 (CSP210) decreased over time. These findings demonstrate that long-term humoral immunity can develop in low-transmission regions.

Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, Al-Hameed FM, Taha Y, Shindo N, Whitehead J et al. 2015. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus, 4 (1), pp. 709. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

As of September 30, 2015, a total of 1589 laboratory-confirmed cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization (WHO). At present there is no effective specific therapy against MERS-CoV. The use of convalescent plasma (CP) has been suggested as a potential therapy based on existing evidence from other viral infections. We aim to study the feasibility of CP therapy as well as its safety and clinical and laboratory effects in critically ill patients with MERS-CoV infection. We will also examine the pharmacokinetics of the MERS-CoV antibody response and viral load over the course of MERS-CoV infection. This study will inform a future randomized controlled trial that will examine the efficacy of CP therapy for MERS-CoV infection. In the CP collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (ELISA) and the indirect fluorescent antibody (IFA) techniques for the presence of anti-MERS-CoV antibodies. Subjects with anti-MERS-CoV IFA titer of ≥1:160 and no clinical or laboratory evidence of MERS-CoV infection will be screened for eligibility for plasma donation according to standard donation criteria. In the CP therapy phase, 20 consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed MERS-CoV infection will be enrolled and each will receive 2 units of CP. Post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-MERS-CoV antibodies and viral load. This protocol was developed collaboratively by King Abdullah International Medical Research Center (KAIMRC), Gulf Cooperation Council (GCC) Infection Control Center Group and the World Health Organization-International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) MERS-CoV Working Group. It was approved in June 2014 by the Ministry of the National Guard Health Affairs Institutional Review Board (IRB). A data safety monitoring board (DSMB) was formulated. The study is registered at http://www.clinicaltrials.gov (NCT02190799).

Darton T, Jones C, Waddington C, Blohmke C, Peters A, Haworth K, Green C, Jeppesen C, Moore M, Thompson B et al. 2015. LIVE ATTENUATED ORAL VACCINE, AGE AND ANTI-VI ANTIBODY STATUS AT BASELINE SIGNIFICANTLY AFFECT ATTACK RATE IN A HUMAN SALMONELLA TYPHI CHALLENGE MODEL JOURNAL OF INFECTION, 71 (6), pp. 689-689. | Read more

Preston EC, Ariana P, Penny ME, Frost M, Plugge E. 2015. Prevalence of childhood overweight and obesity and associated factors in Peru. Rev Panam Salud Publica, 38 (6), pp. 472-478. | Citations: 3 (Scopus) | Show Abstract

OBJECTIVE: To determine the prevalence of and factors associated with childhood overweight and obesity among a cohort of children 7-8 years of age in Peru. METHODS: This was a cross-sectional secondary analysis of data from the Young Lives longitudinal study of childhood poverty. The sample was a cohort of 1 737 children 7-8 years of age in 2009. Prevalence of overweight and obesity was assessed using body mass index-forage Z-scores. Logistic regression was used to determine associations with a number of individual, household, and community factors. RESULTS: Prevalences of overweight and obesity were 19.2% and 8.6%, respectively. A prevalence of 32.0% and 23.5% overweight and obesity was found among males and females, respectively. High socioeconomic status, living in Lima, having a mother who was overweight or obese, being male, and being an only child or having only one sibling were associated with being overweight and obese at this age. CONCLUSIONS: This study shows a high prevalence of childhood and maternal overweight and obesity in Peru. In contrast to findings in many high-income countries, the findings in Peru indicate that children from wealthier households were more likely to be overweight or obese than those from poorer households. In addition, there is something particularly obesogenic about the Lima environment that merits further investigation, and several key issues to consider when targeting future interventions and research.

Hodgson S, Juma E, Hoffman S, Ogutu B, Marsh K. 2015. CONTROLLED HUMAN MALARIA INFECTION IN KENYAN ADULTS: A SAFE MODEL THAT COULD ACCELERATE ASSESSMENT OF NOVEL DRUGS AND VACCINES IN MALARIA ENDEMIC POPULATIONS JOURNAL OF INFECTION, 71 (6), pp. 683-683. | Read more

Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A, Lievens M, Abdulla S, Adjei S, Agbenyega T et al. 2015. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med, 373 (21), pp. 2025-2037. | Citations: 65 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Furtado T, Jule A, Boggs L, van Loggerenberg F, Ewing V, Lang T. 2015. Developing a global core competency framework for clinical research TRIALS, 16 (S2), | Read more

Erber A, Lopez-Carvajal L, Arana B, Lang T, Olliaro P. 2015. Using a consensus technique for improving the methodology of clinical trials assessing treatments for Cutaneous Leishmaniasis TRIALS, 16 (S2), | Read more

Lubell Y, Blacksell SD, Dunachie S, Tanganuchitcharnchai A, Althaus T, Watthanaworawit W, Paris DH, Mayxay M, Peto TJ, Dondorp AM et al. 2015. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial and malarial causes of fever in Southeast Asia. BMC Infect Dis, 15 (1), pp. 511. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Poor targeting of antimicrobial drugs contributes to the millions of deaths each year from malaria, pneumonia, and other tropical infectious diseases. While malaria rapid diagnostic tests have improved use of antimalarial drugs, there are no similar tests to guide the use of antibiotics in undifferentiated fevers. In this study we estimate the diagnostic accuracy of two well established biomarkers of bacterial infection, procalcitonin and C-reactive protein (CRP) in discriminating between common viral and bacterial infections in malaria endemic settings of Southeast Asia. METHODS: Serum procalcitonin and CRP levels were measured in stored serum samples from febrile patients enrolled in three prospective studies conducted in Cambodia, Laos and, Thailand. Of the 1372 patients with a microbiologically confirmed diagnosis, 1105 had a single viral, bacterial or malarial infection. Procalcitonin and CRP levels were compared amongst these aetiological groups and their sensitivity and specificity in distinguishing bacterial infections and bacteraemias from viral infections were estimated using standard thresholds. RESULTS: Serum concentrations of both biomarkers were significantly higher in bacterial infections and malaria than in viral infections. The AUROC for CRP in discriminating between bacterial and viral infections was 0.83 (0.81-0.86) compared with 0.74 (0.71-0.77) for procalcitonin (p < 0.0001). This relative advantage was evident in all sites and when stratifying patients by age and admission status. For CRP at a threshold of 10 mg/L, the sensitivity of detecting bacterial infections was 95% with a specificity of 49%. At a threshold of 20 mg/L sensitivity was 86% with a specificity of 67%. For procalcitonin at a low threshold of 0.1 ng/mL the sensitivity was 90% with a specificity of 39%. At a higher threshold of 0.5 ng/ul sensitivity was 60% with a specificity of 76%. CONCLUSION: In samples from febrile patients with mono-infections from rural settings in Southeast Asia, CRP was a highly sensitive and moderately specific biomarker for discriminating between viral and bacterial infections. Use of a CRP rapid test in peripheral health settings could potentially be a simple and affordable measure to better identify patients in need of antibacterial treatment and part of a global strategy to combat the emergence of antibiotic resistance.

Jenjaroen K, Chumseng S, Sumonwiriya M, Ariyaprasert P, Chantratita N, Sunyakumthorn P, Hongsuwan M, Wuthiekanun V, Fletcher HA, Teparrukkul P et al. 2015. T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients. PLoS Negl Trop Dis, 9 (10), pp. e0004152. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Melioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei. Risk factors include diabetes, alcoholism and renal disease, and a vaccine targeting at-risk populations is urgently required. A better understanding of the protective immune response in naturally infected patients is essential for vaccine design. METHODS: We conducted a longitudinal clinical and immunological study of 200 patients with melioidosis on admission, 12 weeks (n = 113) and 52 weeks (n = 65) later. Responses to whole killed B. pseudomallei were measured in peripheral blood mononuclear cells (PBMC) by interferon-gamma (IFN-γ) ELIspot assay and flow cytometry and compared to those of control subjects in the region with diabetes (n = 45) and without diabetes (n = 43). RESULTS: We demonstrated strong CD4+ and CD8+ responses to B. pseudomallei during acute disease, 12 weeks and 52 weeks later. 28-day mortality was 26% for melioidosis patients, and B. pseudomallei-specific cellular responses in fatal cases (mean 98 IFN-γ cells per million PBMC) were significantly lower than those in the survivors (mean 142 IFN-γ cells per million PBMC) in a multivariable logistic regression model (P = 0.01). A J-shaped curve association between circulating neutrophil count and mortality was seen with an optimal count of 4000 to 8000 neutrophils/μl. Melioidosis patients with known diabetes had poor diabetic control (median glycated haemoglobin HbA1c 10.2%, interquartile range 9.2-13.1) and showed a stunted B. pseudomallei-specific cellular response during acute illness compared to those without diabetes. CONCLUSIONS: The results demonstrate the role of both CD4+ and CD8+ T-cells in protection against melioidosis, and an interaction between diabetes and cellular responses. This supports development of vaccine strategies that induce strong T-cell responses for the control of intracellular pathogens such as B. pseudomallei.

Murray DD, Suzuki K, Law M, Trebicka J, Neuhaus J, Wentworth D, Johnson M, Vjecha MJ, Kelleher AD, Emery S, INSIGHT ESPRIT and SMART Study Groups. 2015. Circulating microRNAs in Sera Correlate with Soluble Biomarkers of Immune Activation but Do Not Predict Mortality in ART Treated Individuals with HIV-1 Infection: A Case Control Study. PLoS One, 10 (10), pp. e0139981. | Citations: 4 (Scopus) | Show Abstract | Read more

INTRODUCTION: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. MATERIALS AND METHODS: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. RESULTS: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count. DISCUSSION: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.

Malaria Genomic Epidemiology Network, Band G, Rockett KA, Spencer CCA, Kwiatkowski DP. 2015. A novel locus of resistance to severe malaria in a region of ancient balancing selection. Nature, 526 (7572), pp. 253-257. | Citations: 32 (Scopus) | Show Abstract | Read more

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60-0.76, P value = 9.5 × 10(-11)) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection.

Angus BJ, Dobinson H, Thomaides-Brears H, Jones C, Campbell D, Voysey M, Kerridge S, Martin LB, Leroy O, Dalessio F, Pollard AJ. 2015. A NOVEL HUMAN MODEL OF SALMONELLA ENTERICA SEROVAR PARATYPHI A CHALLENGE IN HEALTHY ADULT VOLUNTEERS AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 93 (4), pp. 365-366.

WWARN Parasite Clearance Study Group, Abdulla S, Ashley EA, Bassat Q, Bethell D, Björkman A, Borrmann S, D'Alessandro U, Dahal P, Day NP et al. 2015. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis. Malar J, 14 (1), pp. 359. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. METHODS: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. RESULTS: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. CONCLUSIONS: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

Le Viet T, Choisy M, Bryant JE, Vu Trong D, Pham Quang T, Horby P, Nguyen Tran H, Tran Thi Kieu H, Nguyen Vu T, Nguyen Van K et al. 2015. A dengue outbreak on a floating village at Cat Ba Island in Vietnam. BMC Public Health, 15 (1), pp. 940. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: A dengue outbreak in an ecotourism destination spot in Vietnam, from September to November 2013, impacted a floating village of fishermen on the coastal island of Cat Ba. The outbreak raises questions about how tourism may impact disease spread in rural areas. METHODS: Epidemiological data were obtained from the Hai Phong Preventive Medical Center (PMC), including case histories and residential location from all notified dengue cases from this outbreak. All household addresses were geo-located. Knox test, a spatio-temporal analysis that enables inference dengue clustering constrained by space and time, was performed on the geocoded locations. From the plasma available from two patients, positive for Dengue serotype 3 virus (DENV3), the Envelope (E) gene was sequenced, and their genetic relationships compared to other E sequences in the region. RESULTS: Of 192 dengue cases, the odds ratio of contracting dengue infections for people living in the floating villages compared to those living on the island was 4.9 (95 % CI: 3.6-6.7). The space-time analyses on 111 geocoded dengue residences found the risk of dengue infection to be the highest within 4 days and a radius of 20 m of a given case. Of the total of ten detected clusters with an excess risk greater than 2, the cluster with the highest number of cases was in the floating village area (24 patients for a total duration of 31 days). Phylogenetic analysis revealed a high homology of the two DENV3 strains (genotype III) from Cat Ba with DENV3 viruses circulating in Hanoi in the same year (99.1 %). CONCLUSIONS: Our study showed that dengue transmission is unlikely to be sustained on Cat Ba Island and that the 2013 epidemic likely originated through introduction of viruses from the mainland, potentially Hanoi. These findings suggest that prevention efforts should be focused on mainland rather than on the island.

Ashley EA, Aweeka F, Barnes KI, Bassat Q, Borrmann S, Dahal P, Davis TME, Deloron P, Denis MB, Djimde AA et al. 2015. Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data BMC Medicine, 13 (1), | Citations: 14 (Scopus) | Show Abstract | Read more

© 2015 WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group. Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children ( < 3 years), among whom underweight-for-age children had 23 % (95 % CI -1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with > 98 % cure rates (if parasitemia < 135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Dahal P, d'Alessandro U, Dorsey G, Guerin PJ, Nsanzabana C, Price RN, Sibley CH, Stepniewska K, Talisuna AO. 2015. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data. BMC Med, 13 (1), pp. 212. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Jule A, Garba A, Guerin P, Lang T, Olliaro P. 2015. Building a data-sharing platform for schistosomiasis treatment data: opportunities and challenges TROPICAL MEDICINE & INTERNATIONAL HEALTH, 20 pp. 228-229.

Hopkins H, Thomas NV, Crump JA, Gonzalez IJ, Guerin PJ, Newton PN, Schellenberg D, Bell D, Reyburn H. 2015. Mapping fever aetiologies in malaria-endemic areas: an interactive, open-access, on-line map TROPICAL MEDICINE & INTERNATIONAL HEALTH, 20 pp. 179-179.

Green CA, Scarselli E, Sande CJ, Thompson AJ, de Lara CM, Taylor KS, Haworth K, Del Sorbo M, Angus B, Siani L et al. 2015. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med, 7 (300), pp. 300ra126. | Citations: 31 (Web of Science Lite) | Show Abstract | Read more

Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.

Lang T. 2015. Ebola: Embed research in outbreak response. Nature, 524 (7563), pp. 29-31. | Citations: 8 (Scopus) | Read more

Dunachie S, Hill AVS, Fletcher HA. 2015. Profiling the host response to malaria vaccination and malaria challenge. Vaccine, 33 (40), pp. 5316-5320. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research.

Dunachie S, Berthoud T, Hill AVS, Fletcher HA. 2015. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model. Vaccine, 33 (40), pp. 5321-5331. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. METHODS: We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. RESULTS: Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. CONCLUSIONS: These results represent novel insights into the immune repertoires involved in malaria vaccination.

Lang T. 2015. Embed research in outbreak response NATURE, 524 (7563), pp. 29-31. | Citations: 9 (Web of Science Lite) | Read more

Ndungu FM, Marsh K, Fegan G, Wambua J, Nyangweso G, Ogada E, Mwangi T, Nyundo C, Macharia A, Uyoga S et al. 2015. Identifying children with excess malaria episodes after adjusting for variation in exposure: identification from a longitudinal study using statistical count models. BMC Med, 13 (1), pp. 183. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The distribution of Plasmodium falciparum clinical malaria episodes is over-dispersed among children in endemic areas, with more children experiencing multiple clinical episodes than would be expected based on a Poisson distribution. There is consistent evidence for micro-epidemiological variation in exposure to P. falciparum. The aim of the current study was to identify children with excess malaria episodes after controlling for malaria exposure. METHODS: We selected the model that best fit the data out of the models examined and included the following covariates: age, a weighted local prevalence of infection as an index of exposure, and calendar time to predict episodes of malaria on active surveillance malaria data from 2,463 children of under 15 years of age followed for between 5 and 15 years each. Using parameters from the zero-inflated negative binomial model which best fitted our data, we ran 100 simulations of the model based on our population to determine the variation that might be seen due to chance. RESULTS: We identified 212 out of 2,463 children who had a number of clinical episodes above the 95(th) percentile of the simulations run from the model, hereafter referred to as "excess malaria (EM)". We then identified exposure-matched controls with "average numbers of malaria" episodes, and found that the EM group had higher parasite densities when asymptomatically infected or during clinical malaria, and were less likely to be of haemoglobin AS genotype. CONCLUSIONS: Of the models tested, the negative zero-inflated negative binomial distribution with exposure, calendar year, and age acting as independent predictors, fitted the distribution of clinical malaria the best. Despite accounting for these factors, a group of children suffer excess malaria episodes beyond those predicted by the model. An epidemiological framework for identifying these children will allow us to study factors that may explain excess malaria episodes.

Tanner M, Greenwood B, Whitty CJM, Ansah EK, Price RN, Dondorp AM, von Seidlein L, Baird JK, Beeson JG, Fowkes FJI et al. 2015. Malaria eradication and elimination: views on how to translate a vision into reality. BMC Med, 13 (1), pp. 167. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths. In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated. Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.

Guyant P, Corbel V, Guérin PJ, Lautissier A, Nosten F, Boyer S, Coosemans M, Dondorp AM, Sinou V, Yeung S, White N. 2015. Past and new challenges for malaria control and elimination: the role of operational research for innovation in designing interventions Malaria Journal, 14 (1), | Citations: 15 (Scopus) | Show Abstract | Read more

© 2015 Guyant et al. This meeting report presents the outcomes of a workshop held in Bangkok on December 1st 2014, where the following challenges were discussed: the threat of resistance to artemisinin and artemisinin-based combination therapy in the Greater Mekong Sub-region (GMS) and in Africa; access to treatment for most at risk and hard to reach population; insecticide resistance, residual and outdoors transmission. The role of operational research and the interactions between research institutions, National Malaria Control Programmes, Civil Society Organizations, and of financial and technical partners to address those challenges and to accelerate translation of research into policies and programmes were debated. The threat and the emergency of the artemisinin resistance spread and independent emergence in the GMS was intensely debated as it is now close to the border of India. The need for key messages, based on scientific evidence and information available and disseminated without delay , was highlighted as crucial for an effective and urgent response.

RTS,S Clinical Trials Partnership. 2015. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet, 386 (9988), pp. 31-45. | Citations: 125 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. METHODS: From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. FINDINGS: 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. INTERPRETATION: RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.

Parry CM, Thieu NTV, Dolecek C, Karkey A, Gupta R, Turner P, Dance D, Maude RR, Ha V, Tran CN et al. 2015. Erratum for Parry et al., Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A. Antimicrob Agents Chemother, 59 (7), pp. 4364. | Citations: 2 (Scopus) | Read more

Bull S, Cheah PY, Denny S, Jao I, Marsh V, Merson L, Shah More N, Nhan LNT, Osrin D, Tangseefa D et al. 2015. Best Practices for Ethical Sharing of Individual-Level Health Research Data From Low- and Middle-Income Settings. J Empir Res Hum Res Ethics, 10 (3), pp. 302-313. | Citations: 15 (Scopus) | Show Abstract | Read more

Sharing individual-level data from clinical and public health research is increasingly being seen as a core requirement for effective and efficient biomedical research. This article discusses the results of a systematic review and multisite qualitative study of key stakeholders' perspectives on best practices in ethical data sharing in low- and middle-income settings. Our research suggests that for data sharing to be effective and sustainable, multiple social and ethical requirements need to be met. An effective model of data sharing will be one in which considered judgments will need to be made about how best to achieve scientific progress, minimize risks of harm, promote fairness and reciprocity, and build and sustain trust.

Jao I, Kombe F, Mwalukore S, Bull S, Parker M, Kamuya D, Molyneux S, Marsh V. 2015. Involving Research Stakeholders in Developing Policy on Sharing Public Health Research Data in Kenya: Views on Fair Process for Informed Consent, Access Oversight, and Community Engagement. J Empir Res Hum Res Ethics, 10 (3), pp. 264-277. | Citations: 13 (Scopus) | Show Abstract | Read more

Increased global sharing of public health research data has potential to advance scientific progress but may present challenges to the interests of research stakeholders, particularly in low-to-middle income countries. Policies for data sharing should be responsive to public views, but there is little evidence of the systematic study of these from low-income countries. This qualitative study explored views on fair data-sharing processes among 60 stakeholders in Kenya with varying research experience, using a deliberative approach. Stakeholders' attitudes were informed by perceptions of benefit and concerns for research data sharing, including risks of stigmatization, loss of privacy, and undermining scientific careers and validity, reported in detail elsewhere. In this article, we discuss institutional trust-building processes seen as central to perceptions of fairness in sharing research data in this setting, including forms of community involvement, individual prior awareness and agreement to data sharing, independence and accountability of governance mechanisms, and operating under a national framework.

Parry CM, Thieu NTV, Dolecek C, Karkey A, Gupta R, Turner P, Dance D, Maude RR, Ha V, Tran CN et al. 2015. Clinically and Microbiologically Derived Azithromycin Susceptibility Breakpoints for Salmonella enterica Serovars Typhi and Paratyphi A (vol 59, pg 2756, 2015) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59 (7), pp. 4364-4364. | Citations: 2 (Web of Science Lite) | Read more

Atkinson SH, Uyoga SM, Armitage AE, Khandwala S, Mugyenyi CK, Bejon P, Marsh K, Beeson JG, Prentice AM, Drakesmith H, Williams TN. 2015. Malaria and Age Variably but Critically Control Hepcidin Throughout Childhood in Kenya. EBioMedicine, 2 (10), pp. 1478-1486. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Both iron deficiency (ID) and malaria are common among African children. Studies show that the iron-regulatory hormone hepcidin is induced by malaria, but few studies have investigated this relationship longitudinally. We measured hepcidin concentrations, markers of iron status, and antibodies to malaria antigens during two cross-sectional surveys within a cohort of 324 Kenyan children ≤ 8 years old who were under intensive surveillance for malaria and other febrile illnesses. Hepcidin concentrations were the highest in the youngest, and female infants, declined rapidly in infancy and more gradually thereafter. Asymptomatic malaria and malaria antibody titres were positively associated with hepcidin concentrations. Recent episodes of febrile malaria were associated with high hepcidin concentrations that fell over time. Hepcidin concentrations were not associated with the subsequent risk of either malaria or other febrile illnesses. Given that iron absorption is impaired by hepcidin, our data suggest that asymptomatic and febrile malaria contribute to the high burden of ID seen in African children. Further, the effectiveness of iron supplementation may be sub-optimal in the presence of asymptomatic malaria. Thus, strategies to prevent and eliminate malaria may have the added benefit of addressing an important cause of ID for African children.

Treweek S, Altman DG, Bower P, Campbell M, Chalmers I, Cotton S, Craig P, Crosby D, Davidson P, Devane D et al. 2015. Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform. Trials, 16 (1), pp. 261. | Citations: 18 (Scopus) | Show Abstract | Read more

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge ( www.trialforge.org ) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.

Hodgson SH, Juma E, Salim A, Magiri C, Njenga D, Molyneux S, Njuguna P, Awuondo K, Lowe B, Billingsley PF et al. 2015. Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya. Malar J, 14 (1), pp. 182. | Citations: 7 (Scopus) | Show Abstract | Read more

BACKGROUND: Controlled human malaria infection (CHMI) studies, in which healthy volunteers are infected with Plasmodium falciparum to assess the efficacy of novel malaria vaccines and drugs, have become a vital tool to accelerate vaccine and drug development. CHMI studies provide a cost-effective and expeditious way to circumvent the use of large-scale field efficacy studies to deselect intervention candidates. However, to date few modern CHMI studies have been performed in malaria-endemic countries. METHODS: An open-label, randomized pilot CHMI study was conducted using aseptic, purified, cryopreserved, infectious P. falciparum sporozoites (SPZ) (Sanaria® PfSPZ Challenge) administered intramuscularly (IM) to healthy Kenyan adults (n = 28) with varying degrees of prior exposure to P. falciparum. The purpose of the study was to establish the PfSPZ Challenge CHMI model in a Kenyan setting with the aim of increasing the international capacity for efficacy testing of malaria vaccines and drugs, and allowing earlier assessment of efficacy in a population for which interventions are being developed. This was part of the EDCTP-funded capacity development of the CHMI platform in Africa. DISCUSSION: This paper discusses in detail lessons learnt from conducting the first CHMI study in Kenya. Issues pertinent to the African setting, including community sensitization, consent and recruitment are considered. Detailed reasoning regarding the study design (for example, dose and route of administration of PfSPZ Challenge, criteria for grouping volunteers according to prior exposure to malaria and duration of follow-up post CHMI) are given and changes other centres may want to consider for future studies are suggested. CONCLUSIONS: Performing CHMI studies in an African setting presents unique but surmountable challenges and offers great opportunity for acceleration of malaria vaccine and drug development. The reflections in this paper aim to aid other centres and partners intending to use the CHMI model in Africa.

Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. 2015. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis, 15 (6), pp. 692-702. | Citations: 32 (Scopus) | Show Abstract | Read more

BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation.

Limmathurotsakul D, Funnell SGP, Torres AG, Morici LA, Brett PJ, Dunachie S, Atkins T, Altmann DM, Bancroft G, Peacock SJ, Steering Group on Melioidosis Vaccine Development. 2015. Consensus on the development of vaccines against naturally acquired melioidosis. Emerg Infect Dis, 21 (6), pp. e1-e7. | Citations: 17 (Scopus) | Show Abstract | Read more

Several candidates for a vaccine against Burkholderia pseudomallei, the causal bacterium of melioidosis, have been developed, and a rational approach is now needed to select and advance candidates for testing in relevant nonhuman primate models and in human clinical trials. Development of such a vaccine was the topic of a meeting in the United Kingdom in March 2014 attended by international candidate vaccine developers, researchers, and government health officials. The focus of the meeting was advancement of vaccines for prevention of natural infection, rather than for protection from the organism's known potential for use as a biological weapon. A direct comparison of candidate vaccines in well-characterized mouse models was proposed. Knowledge gaps requiring further research were identified. Recommendations were made to accelerate the development of an effective vaccine against melioidosis.

Toapanta FR, Bernal PJ, Fresnay S, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 9 (6), pp. e0003837. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi.

Rono J, Färnert A, Murungi L, Ojal J, Kamuyu G, Guleid F, Nyangweso G, Wambua J, Kitsao B, Olotu A et al. 2015. Multiple clinical episodes of Plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity. BMC Med, 13 (1), pp. 114. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Epidemiological studies indicate that some children experience many more episodes of clinical malaria than their age mates in a given location. Whether this is as a result of the micro-heterogeneity of malaria transmission with some children effectively getting more exposure to infectious mosquitoes than others, or reflects a failure in the acquisition of immunity needs to be elucidated. Here, we investigated the determinants of increased susceptibility to clinical malaria by comparing the intensity of exposure to Plasmodium falciparum and the acquisition of immunity in children at the extreme ends of the over-dispersed distribution of the incidence of clinical malaria. METHODS: The study was nested within a larger cohort in an area where the intensity of malaria transmission was low. We identified children who over a five-year period experienced 5 to 16 clinical malaria episodes (children at the tail-end of the over-dispersed distribution, n = 35), remained malaria-free (n = 12) or had a single episode (n = 26). We quantified antibodies against seven Plasmodium falciparum merozoite antigens in plasma obtained at six cross-sectional surveys spanning these five years. We analyzed the antibody responses to identify temporal dynamics that associate with disease susceptibility. RESULTS: Children experiencing multiple episodes of malaria were more likely to be parasite positive by microscopy at cross-sectional surveys (X (2) test for trend 14.72 P = 0.001) and had a significantly higher malaria exposure index, than those in the malaria-free or single episode groups (Kruskal-Wallis test P = 0.009). In contrast, the five-year temporal dynamics of anti-merozoite antibodies were similar in the three groups. Importantly in all groups, antibody levels were below the threshold concentrations previously observed to be correlated with protective immunity. CONCLUSIONS: We conclude that in the context of a low malaria transmission setting, susceptibility to clinical malaria is not accounted for by anti-merozoite antibodies but appears to be a consequence of increased parasite exposure. We hypothesize that intensive exposure is a prerequisite for protective antibody concentrations, while little to modest exposure may manifest as multiple clinical infections with low levels of antibodies. These findings have implications for interventions that effectively lower malaria transmission intensity.

Ogwang C, Kimani D, Edwards NJ, Roberts R, Mwacharo J, Bowyer G, Bliss C, Hodgson SH, Njuguna P, Viebig NK et al. 2015. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci Transl Med, 7 (286), pp. 286re5. | Citations: 35 (Scopus) | Show Abstract | Read more

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).

Qin Y, Horby PW, Tsang TK, Chen E, Gao L, Ou J, Nguyen TH, Duong TN, Gasimov V, Feng L et al. 2015. Differences in the Epidemiology of Human Cases of Avian Influenza A(H7N9) and A(H5N1) Viruses Infection. Clin Infect Dis, 61 (4), pp. 563-571. | Citations: 30 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The pandemic potential of avian influenza viruses A(H5N1) and A(H7N9) remains an unresolved but critically important question. METHODS: We compared the characteristics of sporadic and clustered cases of human H5N1 and H7N9 infection, estimated the relative risk of infection in blood-related contacts, and the reproduction number (R). RESULTS: We assembled and analyzed data on 720 H5N1 cases and 460 H7N9 cases up to 2 November 2014. The severity and average age of sporadic/index cases of H7N9 was greater than secondary cases (71% requiring intensive care unit admission vs 33%, P = .007; median age 59 years vs 31, P < .001). We observed no significant differences in the age and severity between sporadic/index and secondary H5N1 cases. The upper limit of the 95% confidence interval (CI) for R was 0.12 for H5N1 and 0.27 for H7N9. A higher proportion of H5N1 infections occurred in clusters (20%) compared to H7N9 (8%). The relative risk of infection in blood-related contacts of cases compared to unrelated contacts was 8.96 for H5N1 (95% CI, 1.30, 61.86) and 0.80 for H7N9 (95% CI, .32, 1.97). CONCLUSIONS: The results are consistent with an ascertainment bias towards severe and older cases for sporadic H7N9 but not for H5N1. The lack of evidence for ascertainment bias in sporadic H5N1 cases, the more pronounced clustering of cases, and the higher risk of infection in blood-related contacts, support the hypothesis that susceptibility to H5N1 may be limited and familial. This analysis suggests the potential pandemic risk may be greater for H7N9 than H5N1.

McArthur MA, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model. PLoS Pathog, 11 (5), pp. e1004914. | Citations: 17 (Scopus) | Show Abstract | Read more

Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.

Li HK, Agweyu A, English M, Bejon P. 2015. An unsupported preference for intravenous antibiotics. PLoS Med, 12 (5), pp. e1001825. | Citations: 5 (Web of Science Lite) | Read more

Taylor WR, Fox A, Pham KT, Le HNM, Tran NTH, Tran GV, Nguyen BT, Nguyen MV, Nguyen LT, Yacoub S et al. 2015. Dengue in adults admitted to a referral hospital in Hanoi, Vietnam. Am J Trop Med Hyg, 92 (6), pp. 1141-1149. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Knowledge of adult dengue virus (DENV) infection from Hanoi, Vietnam, is limited. In 2008, we prospectively studied 143 (77 male) confirmed (nonstructural 1 antigen enzyme-linked immunosorbent assay [ELISA], DENV polymerase chain reaction, paired serology) adult dengue patients of median age 23.5 (range 16-72) years. They were admitted to the National Hospital for Tropical Diseases, Hanoi, on median illness day (D) 5 (range 1-8). By D8, 141 (98.6%) were afebrile. Platelet counts and hematocrit (median, interquartile range [IQR]) nadired and peaked on D5 and D4, respectively: 40,000/μL (10,000-109,000/μL), 43.4% (34.9-49.7%). Four (2.8%) patients had severe dengue: 1) D10 shock (N = 1) and 2) aspartate aminotransferase (AST) ≥ 1,000 IU/L (N = 3, D5 and D7). Of 143 patients, 118 (82.5%) had ≥ 1 warning sign (World Health Organization [WHO] 2009 criteria): mucosal bleeding 66/143 (46.1%), soft tissue edema 54/143 (37.7%), and ultrasound detected plasma leakage (pleural effusions/ascites) 30/129 (23.25%). 138 (96.5%) patients received intravenous (IV) fluids: 3 L (IQR: 0.5-8.5 L). Most patients had non-severe dengue with warning signs. High rates of edema and plasma leakage may be explained partly by liberal use of IV fluids. Studies are needed on optimizing fluid management in non-severe adult dengue.

Reynolds C, Goudet A, Jenjaroen K, Sumonwiriya M, Rinchai D, Musson J, Overbeek S, Makinde J, Quigley K, Manji J et al. 2015. T Cell Immunity to the Alkyl Hydroperoxide Reductase of Burkholderia pseudomallei: A Correlate of Disease Outcome in Acute Melioidosis. J Immunol, 194 (10), pp. 4814-4824. | Citations: 11 (Scopus) | Show Abstract | Read more

There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of 'humanized' HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.

Aluvaala J, Okello D, Murithi G, Wafula L, Wanjala L, Isika N, Wasunna A, Were F, Nyamai R, English M. 2015. Delivery outcomes and patterns of morbidity and mortality for neonatal admissions in five Kenyan hospitals. J Trop Pediatr, 61 (4), pp. 255-259. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

A cross-sectional survey was conducted in neonatal and maternity units of five Kenyan district public hospitals. Data for 1 year were obtained: 3999 maternal and 1836 neonatal records plus tallies of maternal deaths, deliveries and stillbirths. There were 40 maternal deaths [maternal mortality ratio: 276 per 100 000 live births, 95% confidence interval (CI): 197-376]. Fresh stillbirths ranged from 11 to 43 per 1000 births. A fifth (19%, 263 of 1384, 95% CI: 11-30%) of the admitted neonates died. Compared with normal birth weight, odds of death were significantly higher in all of the low birth weight (LBW, <2500 g) categories, with the highest odds for the extremely LBW (<1000 g) category (odds ratio: 59, 95% CI: 21-158, p < 0.01). The observed maternal mortality, stillbirths and neonatal mortality call for implementation of the continuum of care approach to intervention delivery with particular emphasis on LBW babies.

Cooper BS, Boni MF, Pan-ngum W, Day NPJ, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med, 12 (4), pp. e1001815. | Citations: 35 (Scopus) | Show Abstract | Read more

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Inverarity DJ, Forrester VM, Cumming JGR, Paterson PJ, Campbell RJ, Brooks TJG, Carson GL, Ruddy JP. 2015. Injectional anthrax at a Scottish district general hospital. Epidemiol Infect, 143 (6), pp. 1311-1321. | Show Abstract | Read more

This retrospective, descriptive case-series reviews the clinical presentations and significant laboratory findings of patients diagnosed with and treated for injectional anthrax (IA) since December 2009 at Monklands Hospital in Central Scotland and represents the largest series of IA cases to be described from a single location. Twenty-one patients who fulfilled National Anthrax Control Team standardized case definitions of confirmed, probable or possible IA are reported. All cases survived and none required limb amputation in contrast to an overall mortality of 28% being experienced for this condition in Scotland. We document the spectrum of presentations of soft tissue infection ranging from mild cases which were managed predominantly with oral antibiotics to severe cases with significant oedema, organ failure and coagulopathy. We describe the surgical management, intensive care management and antibiotic management including the first description of daptomycin being used to treat human anthrax. It is noted that some people who had injected heroin infected with Bacillus anthracis did not develop evidence of IA. Also highlighted are biochemical and haematological parameters which proved useful in identifying deteriorating patients who required greater levels of support and surgical debridement.

WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group, Adjuik MA, Allan R, Anvikar AR, Ashley EA, Ba MS, Barennes H, Barnes KI, Bassat Q, Baudin E et al. 2015. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Med, 13 (1), pp. 66. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Boyle MJ, Reiling L, Feng G, Langer C, Osier FH, Aspeling-Jones H, Cheng YS, Stubbs J, Tetteh KKA, Conway DJ et al. 2015. Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity, 42 (3), pp. 580-590. | Citations: 67 (Web of Science Lite) | Show Abstract | Read more

Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.

Abdulla S, Binka F, Graves P, Greenwood B, Leke R, Malik E, Marsh K, Meek S, Mendis K, Schapira A et al. 2015. Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of sixth biannual meeting (September 2014) MALARIA JOURNAL, 14 (1), | Read more

Parry CM, Thieu NTV, Dolecek C, Karkey A, Gupta R, Turner P, Dance D, Maude RR, Ha V, Tran CN et al. 2015. Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A. Antimicrob Agents Chemother, 59 (5), pp. 2756-2764. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 μg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 μg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-μg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 μg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 μg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 μg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.

Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA et al. 2015. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis, 15 (4), pp. 415-421. | Citations: 170 (Scopus) | Show Abstract | Read more

BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

Thompson CN, Blacksell SD, Paris DH, Arjyal A, Karkey A, Dongol S, Giri A, Dolecek C, Day N, Baker S et al. 2015. Undifferentiated febrile illness in Kathmandu, Nepal. Am J Trop Med Hyg, 92 (4), pp. 875-878. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

Undifferentiated febrile illnesses (UFIs) are common in low- and middle-income countries. We prospectively investigated the causes of UFIs in 627 patients presenting to a tertiary referral hospital in Kathmandu, Nepal. Patients with microbiologically confirmed enteric fever (218 of 627; 34.8%) randomized to gatifloxacin or ofloxacin treatment were previously reported. We randomly selected 125 of 627 (20%) of these UFI patients, consisting of 96 of 409 (23%) cases with sterile blood cultures and 29 of 218 (13%) cases with enteric fever, for additional diagnostic investigations. We found serological evidence of acute murine typhus in 21 of 125 (17%) patients, with 12 of 21 (57%) patients polymerase chain reaction (PCR)-positive for Rickettsia typhi. Three UFI cases were quantitative PCR-positive for Rickettsia spp., two UFI cases were seropositive for Hantavirus, and one UFI case was seropositive for Q fever. Fever clearance time (FCT) for rickettsial infection was 44.5 hours (interquartile range = 26-66 hours), and there was no difference in FCT between ofloxacin or gatifloxacin. Murine typhus represents an important cause of predominantly urban UFIs in Nepal, and fluoroquinolones seem to be an effective empirical treatment.

Mwinga S, Kulohoma C, Mwaniki P, Idowu R, Masasabi J, English M, SIRCLE Collaboration. 2015. Quality of surgical care in hospitals providing internship training in Kenya: a cross sectional survey. Trop Med Int Health, 20 (2), pp. 240-249. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To evaluate services in hospitals providing internship training to graduate doctors in Kenya. METHODS: A survey of 22 internship training hospitals was conducted. Availability of key resources spanning infrastructure, personnel, equipment and drugs was assessed by observation. Outcomes and process of care for pre-specified priority conditions (head injury, chest injury, fractures, burns and acute abdomen) were evaluated by auditing case records. RESULTS: Each hospital had at least one consultant surgeon. Scheduled surgical outpatient clinics, major ward rounds and elective (half day) theatre lists were provided once per week in 91%, 55% and 9%, respectively. In all other hospitals, these were conducted twice weekly. Basic drugs were not always available (e.g. gentamicin, morphine and pethidine in 50%, injectable antistaphylococcal penicillins in 5% hospitals). Fewer than half of hospitals had all resources needed to provide oxygen. One hundred and forty-five of 956 cases evaluated underwent operations under general or spinal anaesthesia. We found operation notes for 99% and anaesthetic records for 72%. Pre-operatively measured vital signs were recorded in 80% of cases, and evidence of consent to operation was found in 78%. Blood loss was documented in only one case and sponge and instrument counts in 7%. CONCLUSIONS: Evaluation of surgical services would be improved by development and dissemination of clear standards of care. This survey suggests that internship hospitals may be poorly equipped and documented care suggests inadequacies in quality and training.

English M, English R, English A. 2015. Millennium Development Goals progress: a perspective from sub-Saharan Africa. Arch Dis Child, 100 Suppl 1 (Suppl 1), pp. S57-S58. | Citations: 8 (Scopus) | Show Abstract | Read more

Sub-Saharan Africa is a highly diverse geo-political region. Any brief discussion of the progress made over the last 15 years towards the Millennium Development Goals (MDGs) will therefore not do justice to the true complexity of context and events. Our focus will be MDG4-to reduce child mortality by 66% from 1990 levels. We will touch briefly on MDG1, to eradicate extreme poverty and hunger, MDG2, to achieve universal primary education, and MDG5, to improve maternal health, which are inextricably linked with child well-being. We will also draw on an eclectic mix of additional global indicators. Acknowledging the limitations of this approach, we first offer a summary of expected progress and then point to debates on future goals.

Hodgson SH, Douglas AD, Edwards NJ, Kimani D, Elias SC, Chang M, Daza G, Seilie AM, Magiri C, Muia A et al. 2015. Increased sample volume and use of quantitative reverse-transcription PCR can improve prediction of liver-to-blood inoculum size in controlled human malaria infection studies. Malar J, 14 (1), pp. 33. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Controlled human malaria infection (CHMI) studies increasingly rely on nucleic acid test (NAT) methods to detect and quantify parasites in the blood of infected participants. The lower limits of detection and quantification vary amongst the assays used throughout the world, which may affect the ability of mathematical models to accurately estimate the liver-to-blood inoculum (LBI) values that are used to judge the efficacy of pre-erythrocytic vaccine and drug candidates. METHODS: Samples were collected around the time of onset of pre-patent parasitaemia from subjects who enrolled in two different CHMI clinical trials. Blood samples were tested for Plasmodium falciparum 18S rRNA and/or rDNA targets by different NAT methods and results were compared. Methods included an ultrasensitive, large volume modification of an established quantitative reverse transcription PCR (qRT-PCR) assay that achieves detection of as little as one parasite/mL of whole blood. RESULTS: Large volume qRT-PCR at the University of Washington was the most sensitive test and generated quantifiable data more often than any other NAT methodology. Standard quantitative PCR (qPCR) performed at the University of Oxford and standard volume qRT-PCR performed at the University of Washington were less sensitive than the large volume qRT-PCR, especially at 6.5 days after CHMI. In these trials, the proportion of participants for whom LBI could be accurately quantified using parasite density value greater than or equal to the lower limit of quantification was increased. A greater improvement would be expected in trials in which numerous subjects receive a lower LBI or low dose challenge. CONCLUSIONS: Standard qPCR and qRT-PCR methods with analytical sensitivities of ~20 parasites/mL probably suffice for most CHMI purposes, but the newly developed large volume qRT-PCR may be able to answer specific questions when more analytical sensitivity is required.

Aluvaala J, Nyamai R, Were F, Wasunna A, Kosgei R, Karumbi J, Gathara D, English M, Kamau K, Kimani F et al. 2015. Assessment of neonatal care in clinical training facilities in Kenya Archives of Disease in Childhood, 100 (1), pp. 42-47. | Citations: 16 (Scopus) | Show Abstract | Read more

Objective An audit of neonatal care services provided by clinical training centres was undertaken to identify areas requiring improvement as part of wider efforts to improve newborn survival in Kenya. Design Cross-sectional study using indicators based on prior work in Kenya. Statistical analyses were descriptive with adjustment for clustering of data. Setting Neonatal units of 22 public hospitals. Patients Neonates aged < 7 days. Main outcome measures Quality of care was assessed in terms of availability of basic resources (principally equipment and drugs) and audit of case records for documentation of patient assessment and treatment at admission. Results All hospitals had oxygen, 19/22 had resuscitation and phototherapy equipment, but some key resources were missing-for example kangaroo care was available in 14/22. Out of 1249 records, 56.9% (95% CI 36.2% to 77.6%) had a standard neonatal admission form. A median score of 0 out of 3 for symptoms of severe illness (IQR 0-3) and a median score of 6 out of 8 for signs of severe illness (IQR 4-7) were documented. Maternal HIV status was documented in 674/1249 (54%, 95% CI 41.9% to 66.1%) cases. Drug doses exceeded recommendations by > 20% in prescriptions for penicillin (11.6%, 95% CI 3.4% to 32.8%) and gentamicin (18.5%, 95% CI 13.4% to 25%), respectively. Conclusions Basic resources are generally available, but there are deficiencies in key areas. Poor documentation limits the use of routine data for quality improvement. Significant opportunities exist for improvement in service delivery and adherence to guidelines in hospitals providing professional training.

Newton PN, Schellenberg D, Ashley EA, Ravinetto R, Green MD, ter Kuile FO, Tabernero P, White NJ, Guerin PJ. 2015. Quality assurance of drugs used in clinical trials: proposal for adapting guidelines. BMJ, 350 (feb25 10), pp. h602. | Citations: 9 (Scopus) | Read more

Das D, Guerin PJ, Leroy S, Sayeed AA, Faiz MA. 2015. The Largest Ebola Outbreak– What Have We Learned So Far Journal of Medicine, 16 (1), pp. 1-4. | Citations: 1 (Scopus) | Read more

Gathara D, Nyamai R, Were F, Mogoa W, Karumbi J, Kihuba E, Mwinga S, Aluvaala J, Mulaku M, Kosgei R et al. 2015. Moving towards routine evaluation of quality of inpatient pediatric care in Kenya. PLoS One, 10 (3), pp. e0117048. | Citations: 12 (Scopus) | Show Abstract | Read more

BACKGROUND: Regular assessment of quality of care allows monitoring of progress towards system goals and identifies gaps that need to be addressed to promote better outcomes. We report efforts to initiate routine assessments in a low-income country in partnership with government. METHODS: A cross-sectional survey undertaken in 22 'internship training' hospitals across Kenya that examined availability of essential resources and process of care based on review of 60 case-records per site focusing on the common childhood illnesses (pneumonia, malaria, diarrhea/dehydration, malnutrition and meningitis). RESULTS: Availability of essential resources was 75% (45/61 items) or more in 8/22 hospitals. A total of 1298 (range 54-61) case records were reviewed. HIV testing remained suboptimal at 12% (95% CI 7-19). A routinely introduced structured pediatric admission record form improved documentation of core admission symptoms and signs (median score for signs 22/22 and 8/22 when form used and not used respectively). Correctness of penicillin and gentamicin dosing was above 85% but correctness of prescribed intravenous fluid or oral feed volumes for severe dehydration and malnutrition were 54% and 25% respectively. Introduction of Zinc for diarrhea has been relatively successful (66% cases) but use of artesunate for malaria remained rare. Exploratory analysis suggests considerable variability of the quality of care across hospitals. CONCLUSION: Quality of pediatric care in Kenya has improved but can improve further. The approach to monitoring described in this survey seems feasible and provides an opportunity for routine assessments across a large number of hospitals as part of national efforts to sustain improvement. Understanding variability across hospitals may help target improvement efforts.

Gathara D, English M, van Hensbroek MB, Todd J, Allen E. 2015. Exploring sources of variability in adherence to guidelines across hospitals in low-income settings: a multi-level analysis of a cross-sectional survey of 22 hospitals. Implement Sci, 10 (1), pp. 60. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Variability in processes of care and outcomes has been reported widely in high-income settings (at geographic, hospital, physician group and individual physician levels); however, such variability and the factors driving it are rarely examined in low-income settings. METHODS: Using data from a cross-sectional survey undertaken in 22 hospitals (60 case records from each hospital) across Kenya that aimed at evaluating the quality of routine hospital services, we sought to explore variability in four binary inpatient paediatric process indicators. These included three prescribing tasks and use of one diagnostic. To examine for sources of variability, we examined intra-class correlation coefficients (ICC) and their changes using multi-level mixed models with random intercepts for hospital and clinician levels and adjusting for patient and clinician level covariates. RESULTS: Levels of performance varied substantially across indicators and hospitals. The absolute values for ICCs also varied markedly ranging from a maximum of 0.48 to a minimum of 0.09 across the models for HIV testing and prescription of zinc, respectively. More variation was attributable at the hospital level than clinician level after allowing for nesting of clinicians within hospitals for prescription of quinine loading dose for malaria (ICC = 0.30), prescription of zinc for diarrhoea patients (ICC = 0.11) and HIV testing for all children (ICC = 0.43). However, for prescription of correct dose of crystalline penicillin, more of the variability was explained by the clinician level (ICC = 0.21). Adjusting for clinician and patient level covariates only altered, marginally, the ICCs observed in models for the zinc prescription indicator. CONCLUSIONS: Performance varied greatly across place and indicator. The variability that could be explained suggests interventions to improve performance might be best targeted at hospital level factors for three indicators and clinician factors for one. Our data suggest that better understanding of performance and sources of variation might help tailor improvement interventions although further data across a larger set of indicators and sites would help substantiate these findings.

Kamuya DM, Theobald SJ, Marsh V, Parker M, Geissler WP, Molyneux SC. 2015. "The one who chases you away does not tell you go": silent refusals and complex power relations in research consent processes in Coastal Kenya. PLoS One, 10 (5), pp. e0126671. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Consent processes have attracted significant research attention over the last decade, including in the global south. Although relevant studies suggest consent is a complex negotiated process involving multiple actors, most guidelines assume consent is a one-off encounter with a clear 'yes' or 'no' decision. In this paper we explore the concept of 'silent refusals', a situation where it is not clear whether potential participants want to join studies or those in studies want to withdraw from research, as they were not actively saying no. We draw on participant observation, in-depth interviews and group discussions conducted with a range of stakeholders in two large community based studies conducted by the KEMRI Wellcome Trust programme in coastal Kenya. We identified three broad inter-related rationales for silent refusals: 1) a strategy to avoid conflicts and safeguard relations within households, - for young women in particular-to appear to conform to the wishes of elders; 2) an approach to maintain friendly, appreciative and reciprocal relationships with fieldworkers, and the broader research programme; and 3) an effort to retain study benefits, either for individuals, whole households or wider communities. That refusals and underlying rationales were silent posed multiple dilemmas for fieldworkers, who are increasingly recognised to play a key interface role between researchers and communities in many settings. Silent refusals reflect and reinforce complex power relations embedded in decisions about research participation, with important implications for consent processes and broader research ethics practice. Fieldworkers need support to reflect upon and respond to the ethically charged environment they work in.

Muinga N, Sen B, Ayieko P, Todd J, English M. 2015. Access to and value of information to support good practice for staff in Kenyan hospitals. Glob Health Action, 8 (1), pp. 26559. | Show Abstract | Read more

BACKGROUND: Studies have sought to define information needs of health workers within very specific settings or projects. Lacking in the literature is how hospitals in low-income settings are able to meet the information needs of their staff and the use of information communication technologies (ICT) in day-to-day information searching. OBJECTIVE: The study aimed to explore where professionals in Kenyan hospitals turn to for work-related information in their day-to-day work. Additionally, it examined what existing solutions are provided by hospitals with regard to provision of best practice care. Lastly, the study explored the use of ICT in information searching. DESIGN: Data for this study were collected in July 2012. Self-administered questionnaires (SAQs) were distributed across 22 study hospitals with an aim to get a response from 34 health workers per hospital. RESULTS: SAQs were collected from 657 health workers. The most popular sources of information to guide work were fellow health workers and printed guidelines while the least popular were scientific journals. Of value to health workers were: national treatment policies, new research findings, regular reports from surveillance data, information on costs of services and information on their performance of routine clinical tasks; however, hospitals only partially met these needs. Barriers to accessing information sources included: 'not available/difficult to get' and 'difficult to understand'. ICT use for information seeking was reported and with demographic specific differences noted from the multivariate logistic regression model; nurses compared to medical doctors and older workers were less likely to use ICT for health information searching. Barriers to accessing Internet were identified as: high costs and the lack of the service at home or at work. CONCLUSIONS: Hospitals need to provide appropriate information by improving information dissemination efforts and providing an enabling environment that allows health workers find the information they need for best practice.

Heymann DL, Chen L, Takemi K, Fidler DP, Tappero JW, Thomas MJ, Kenyon TA, Frieden TR, Yach D, Nishtar S et al. 2015. Global health security: the wider lessons from the west African Ebola virus disease epidemic. Lancet, 385 (9980), pp. 1884-1901. | Citations: 88 (Scopus) | Show Abstract | Read more

The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security--its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.

Njue M, Molyneux S, Kombe F, Mwalukore S, Kamuya D, Marsh V. 2015. Benefits in cash or in kind? A community consultation on types of benefits in health research on the Kenyan Coast. PLoS One, 10 (5), pp. e0127842. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Providing benefits and payments to participants in health research, either in cash or in kind, is a common but ethically controversial practice. While much literature has concentrated on appropriate levels of benefits or payments, this paper focuses on less well explored ethical issues around the nature of study benefits, drawing on views of community members living close to an international health research centre in Kenya. METHODS: The consultation, including 90 residents purposively chosen to reflect diversity, used a two-stage deliberative process. Five half-day workshops were each followed by between two and four small group discussions, within a two week period (total 16 groups). During workshops and small groups, facilitators used participatory methods to share information, and promote reflection and debate on ethical issues around types of benefits, including cash, goods, medical and community benefits. Data from workshop and field notes, and voice recordings of small group discussions, were managed using Nvivo 10 and analysed using a Framework Analysis approach. FINDINGS AND CONCLUSIONS: The methods generated in-depth discussion with high levels of engagement. Particularly for the most-poor, under-compensation of time in research carries risks of serious harm. Cash payments may best support compensation of costs experienced; while highly valued, goods and medical benefits may be more appropriate as an 'appreciation' or incentive for participation. Community benefits were seen as important in supporting but not replacing individual-level benefits, and in building trust in researcher-community relations. Cash payments were seen to have higher risks of undue inducement, commercialising relationships and generating family conflicts than other benefits, particularly where payments are high. Researchers should consider and account for burdens families may experience when children are involved in research. Careful context-specific research planning and skilled and consistent communication about study benefits and payments are important, including in mitigating potential negative effects.

Wong VK, Baker S, Pickard DJ, Parkhill J, Page AJ, Feasey NA, Kingsley RA, Thomson NR, Keane JA, Weill F-X et al. 2015. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat Genet, 47 (6), pp. 632-639. | Citations: 79 (Scopus) | Show Abstract | Read more

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

McCullagh D, Dobinson HC, Darton T, Campbell D, Jones C, Snape M, Stevens Z, Plested E, Voysey M, Kerridge S et al. 2015. Understanding paratyphoid infection: study protocol for the development of a human model of Salmonella enterica serovar Paratyphi A challenge in healthy adult volunteers. BMJ Open, 5 (6), pp. e007481. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: This study will develop the first human challenge model of paratyphoid infection which may then be taken forward to evaluate paratyphoid vaccine candidates. Salmonella Paratyphi A is believed to cause a quarter of the estimated 20 million cases of enteric fever annually. Epidemiological evidence also suggests that an increasing proportion of the enteric fever burden is attributable to S. Paratyphi infection meriting further attention and interest in vaccine development. Assessment of paratyphoid vaccine efficacy in preclinical studies is complicated by the lack of a small animal model and the human-restricted nature of the infection. The use of experimental human infection in healthy volunteers provides an opportunity to address these problems in a cost-effective manner. METHODS AND ANALYSIS: Volunteers will ingest virulent S. Paratyphi A bacteria (NVGH308 strain) with a bicarbonate buffer solution to establish the infectious dose resulting in an 'attack rate' of 60-75%. Using an a priori decision-making algorithm, the challenge dose will be escalated or de-escalated to achieve the target attack rate, with the aim of reaching the study end point while exposing as few individuals as possible to infection. The attack rate will be determined by the proportion of paratyphoid infection in groups of 20 healthy adult volunteers, with infection being defined by one or more positive blood cultures (microbiological end point) and/or fever, defined as an oral temperature exceeding 38 °C sustained for at least 12 h (clinical end point); 20-80 participants will be required. Challenge participants will start a 2-week course of an oral antibiotic on diagnosis of infection, or after 14 days follow-up. ETHICS AND DISSEMINATION: The strict eligibility criterion aims to minimise risk to participants and their close contacts. Ethical approval has been obtained. The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02100397.

Guyant P, Corbel V, Guérin PJ, Lautissier A, Nosten F, Boyer S, Coosemans M, Dondorp AM, Sinou V, Yeung S, White N. 2015. Past and new challenges for malaria control and elimination: the role of operational research for innovation in designing interventions. Malar J, 14 pp. 279. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

This meeting report presents the outcomes of a workshop held in Bangkok on December 1st 2014, where the following challenges were discussed: the threat of resistance to artemisinin and artemisinin-based combination therapy in the Greater Mekong Sub-region (GMS) and in Africa; access to treatment for most at risk and hard to reach population; insecticide resistance, residual and outdoors transmission. The role of operational research and the interactions between research institutions, National Malaria Control Programmes, Civil Society Organizations, and of financial and technical partners to address those challenges and to accelerate translation of research into policies and programmes were debated. The threat and the emergency of the artemisinin resistance spread and independent emergence in the GMS was intensely debated as it is now close to the border of India. The need for key messages, based on scientific evidence and information available and disseminated without delay, was highlighted as crucial for an effective and urgent response.

Negussie H, Kassahun MM, Fegan G, Njuguna P, Enquselassie F, McKay A, Newport M, Lang T, Davey G. 2015. Podoconiosis treatment in northern Ethiopia (GoLBet): study protocol for a randomised controlled trial. Trials, 16 (1), pp. 307. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Podoconiosis is one of the forgotten types of leg swelling (elephantiasis) in the tropics. Unlike the other, better-known types of leg swelling, podoconiosis is not caused by any parasite, virus or bacterium, but by an abnormal reaction to minerals found in the clay soils of some tropical highland areas. Non-governmental Organizations (NGOs) have been responsible for the development of simple treatment methods without systematic evaluation of its effectiveness. It is essential that a large scale, fully controlled, pragmatic trial of the intervention is conducted. We aim to test the hypothesis that community-based treatment of podoconiosis lymphoedema reduces the frequency of acute dermatolymphangioadenitis episodes ('acute attacks') and improves other clinical, social and economic outcomes. METHODS/DESIGN: This is a pragmatic, individually randomised controlled trial. We plan to randomly allocate 680 podoconiosis patients from the East Gojjam Zone in northern Ethiopia to one of two groups: 'Standard Treatment' or 'Delayed Treatment'. Those randomised to standard treatment will receive the hygiene and foot-care intervention from May 2015 for one year, whereas those in the control arm will be followed through 2015 and be offered the intervention in 2016. The trial will be preceded by an economic context survey and a Rapid Ethical Assessment to identify optimal methods of conveying information about the trial and the approaches to obtaining informed consent preferred by the community. The primary outcome will be measured by recording patient recall and using a simple, patient-held diary that will be developed to record episodes of acute attacks. Adherence to treatment, clinical stage of disease, quality of life, disability and stigma will be considered secondary outcome measures. Other outcomes will include adverse events and economic productivity. Assessments will be made at baseline and at 3, 6, 9 and 12 months thereafter. DISCUSSION: The evidence is highly likely to inform implementation of the new master plan for integrated control of Neglected Tropical Diseases (NTDs), in which podoconiosis is identified as one of eight NTDs prioritised for control. Potentially, an estimated 3 million patients in Ethiopia will therefore benefit from the results of this trial. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number. REGISTRATION NUMBER: ISRCTN67805210. Date of registration: 24 January 2013.

Shelton JMG, Corran P, Risley P, Silva N, Hubbart C, Jeffreys A, Rowlands K, Craik R, Cornelius V, Hensmann M et al. 2015. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study. Malar J, 14 (1), pp. 333. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. METHODS: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. RESULTS: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. CONCLUSION: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

Jao I, Kombe F, Mwalukore S, Bull S, Parker M, Kamuya D, Molyneux S, Marsh V. 2015. Research Stakeholders' Views on Benefits and Challenges for Public Health Research Data Sharing in Kenya: The Importance of Trust and Social Relations. PLoS One, 10 (9), pp. e0135545. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: There is increasing recognition of the importance of sharing research data within the international scientific community, but also of the ethical and social challenges this presents, particularly in the context of structural inequities and varied capacity in international research. Public involvement is essential to building locally responsive research policies, including on data sharing, but little research has involved stakeholders from low-to-middle income countries. METHODS: Between January and June 2014, a qualitative study was conducted in Kenya involving sixty stakeholders with varying experiences of research in a deliberative process to explore views on benefits and challenges in research data sharing. In-depth interviews and extended small group discussions based on information sharing and facilitated debate were used to collect data. Data were analysed using Framework Analysis, and charting flow and dynamics in debates. FINDINGS: The findings highlight both the opportunities and challenges of communicating about this complex and relatively novel topic for many stakeholders. For more and less research-experienced stakeholders, ethical research data sharing is likely to rest on the development and implementation of appropriate trust-building processes, linked to local perceptions of benefits and challenges. The central nature of trust is underpinned by uncertainties around who might request what data, for what purpose and when. Key benefits perceived in this consultation were concerned with the promotion of public health through science, with legitimate beneficiaries defined differently by different groups. Important challenges were risks to the interests of study participants, communities and originating researchers through stigmatisation, loss of privacy, impacting autonomy and unfair competition, including through forms of intentional and unintentional 'misuse' of data. Risks were also seen for science. DISCUSSION: Given background structural inequities in much international research, building trust in this low-to-middle income setting includes ensuring that the interests of study participants, primary communities and originating researchers will be promoted as far as possible, as well as protected. Important ways of building trust in data sharing include involving the public in policy development and implementation, promoting scientific collaborations around data sharing and building close partnerships between researchers and government health authorities to provide checks and balances on data sharing, and promote near and long-term translational benefits.

Triantafyllidis A, Velardo C, Chantler T, Shah SA, Paton C, Khorshidi R, Tarassenko L, Rahimi K, Cleland J, MacMahon S et al. 2015. A personalised mobile-based home monitoring system for heart failure: The SUPPORT-HF Study International Journal of Medical Informatics, 84 (10), pp. 743-753. | Citations: 7 (Scopus) | Show Abstract | Read more

© 2015 Elsevier Ireland Ltd. Background: Despite their potential for improving health outcomes, mobile-based home monitoring systems for heart failure have not yet been taken up widely by the patients and providers. Objectives: To design and iteratively move towards a personalised mobile health monitoring system for patients living with heart failure, according to their health care and usability needs. Methods: We present an iterative approach to refining a remote health monitoring system that is based on interactions between different actors (patients, clinicians, social scientists and engineers) and supports the collection of quantitative and qualitative information about user experience and engagement. Patients were provided with tablet computers and commercially available sensing devices (a blood pressure monitor, a set of weighing scales, and a pulse oximeter) in order to complete physiological measurements at home, answer symptom-specific questionnaires, review their personal readings, view educational material on heart failure self-management, and communicate with their health professionals. The system supported unobtrusive remote software upgrades via an application distribution channel and the activation or deactivation of functional components by health professionals during run-time operation. We report early findings from the application of this approach in a cohort of 26 heart failure patients (mean age 72. ±. 15 years), their caregivers and healthcare professionals who participated in the SUPPORT-HF (Seamless User-centred Proactive Provision Of Risk-stratified Treatment for Heart Failure) study over a one-year study period (mean patient follow-up duration. = 270. ±. 62 days). Results: The approach employed in this study led to several system upgrades dealing in particular with patient requirements for better communication with the development team and personalised self-monitoring interfaces. Engagement with the system was constantly high throughout the study and during the last week of the evaluation, 23 patients (88%) used the system at least once and 16 patients (62%) at least three times. Conclusions: Designers of future mobile-based home monitoring systems for heart failure and other chronic conditions could leverage the described approach as a means of meeting patients' needs during system use within the home environment and facilitating successful uptake.

Thai PQ, Choisy M, Duong TN, Thiem VD, Yen NT, Hien NT, Weiss DJ, Boni MF, Horby P. 2015. Seasonality of absolute humidity explains seasonality of influenza-like illness in Vietnam. Epidemics, 13 pp. 65-73. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Experimental and ecological studies have shown the role of climatic factors in driving the epidemiology of influenza. In particular, low absolute humidity (AH) has been shown to increase influenza virus transmissibility and has been identified to explain the onset of epidemics in temperate regions. Here, we aim to study the potential climatic drivers of influenza-like illness (ILI) epidemiology in Vietnam, a tropical country characterized by a high diversity of climates. We specifically focus on quantifying and explaining the seasonality of ILI. METHODS: We used 18 years (1993-2010) of monthly ILI notifications aggregated by province (52) and monthly climatic variables (minimum, mean, maximum temperatures, absolute and relative humidities, rainfall and hours of sunshine) from 67 weather stations across Vietnam. Seasonalities were quantified from global wavelet spectra, using the value of the power at the period of 1 year as a measure of the intensity of seasonality. The 7 climatic time series were characterized by 534 summary statistics which were entered into a regression tree to identify factors associated with the seasonality of AH. Results were extrapolated to the global scale using simulated climatic times series from the NCEP/NCAR project. RESULTS: The intensity of ILI seasonality in Vietnam is best explained by the intensity of AH seasonality. We find that ILI seasonality is weak in provinces experiencing weak seasonal fluctuations in AH (annual power <17.6), whereas ILI seasonality is strongest in provinces with pronounced AH seasonality (power >17.6). In Vietnam, AH and ILI are positively correlated. CONCLUSIONS: Our results identify a role for AH in driving the epidemiology of ILI in a tropical setting. However, in contrast to temperate regions, high rather than low AH is associated with increased ILI activity. Fluctuation in AH may be the climate factor that underlies and unifies the seasonality of ILI in both temperate and tropical regions. Alternatively, the mechanism of action of AH on disease transmission may be different in cold-dry versus hot-humid settings.

Hoa LNM, Bryant JE, Choisy M, Nguyet LA, Bao NT, Trang NH, Chuc NTK, Toan TK, Saito T, Takemae N et al. 2015. Population susceptibility to a variant swine-origin influenza virus A(H3N2) in Vietnam, 2011-2012. Epidemiol Infect, 143 (14), pp. 2959-2964. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

A reassortant swine-origin A(H3N2) virus (A/swine/BinhDuong/03-9/2010) was detected through swine surveillance programmes in southern Vietnam in 2010. This virus contains haemagglutinin and neuraminidase genes from a human A(H3N2) virus circulating around 2004-2006, and the internal genes from triple-reassortant swine influenza A viruses (IAVs). To assess population susceptibility to this virus we measured haemagglutination inhibiting (HI) titres to A/swine/BinhDuong/03-9/2010 and to seasonal A/Perth/16/2009 for 947 sera collected from urban and rural Vietnamese people during 2011-2012. Seroprevalence (HI ⩾ 40) was high and similar for both viruses, with 62·6% [95% confidence interval (CI) 59·4-65·7] against A/Perth/16/2009 and 54·6% (95% CI 51·4-57·8%) against A/swine/BinhDuong/03-9/2010, and no significant differences between urban and rural participants. Children aged <5 years lacked antibodies to the swine origin H3 virus despite high seroprevalence for A/Perth/16/2009. These results reveal vulnerability to infection to this contemporary swine IAV in children aged <5 years; however, cross-reactive immunity in adults would likely limit epidemic emergence potential.

Horby PW, Endzt H, Muyembe-Tamfum J-J, van Griensven J, Gevao S, Goossens H, Malvy D, Haba NY, Yazdanpanah Y, Olliaro P et al. 2015. Ebola: Europe-Africa research collaborations. Lancet Infect Dis, 15 (11), pp. 1258-1259. | Citations: 6 (Web of Science Lite) | Read more

Yazdanpanah Y, Horby P, van Griensven J, Mentre F, Nguyen V-K, Malvy JMD, Dunning J, Sissoko D, Delfraissy J-F, Levy Y. 2015. Drug assessment in the Ebola virus disease epidemic in west Africa. Lancet Infect Dis, 15 (11), pp. 1258. | Citations: 5 (Scopus) | Read more

Barasa EW, Molyneux S, English M, Cleary S. 2015. Setting Healthcare Priorities at the Macro and Meso Levels: A Framework for Evaluation. Int J Health Policy Manag, 4 (11), pp. 719-732. | Citations: 6 (Scopus) | Show Abstract | Read more

BACKGROUND: Priority setting in healthcare is a key determinant of health system performance. However, there is no widely accepted priority setting evaluation framework. We reviewed literature with the aim of developing and proposing a framework for the evaluation of macro and meso level healthcare priority setting practices. METHODS: We systematically searched Econlit, PubMed, CINAHL, and EBSCOhost databases and supplemented this with searches in Google Scholar, relevant websites and reference lists of relevant papers. A total of 31 papers on evaluation of priority setting were identified. These were supplemented by broader theoretical literature related to evaluation of priority setting. A conceptual review of selected papers was undertaken. RESULTS: Based on a synthesis of the selected literature, we propose an evaluative framework that requires that priority setting practices at the macro and meso levels of the health system meet the following conditions: (1) Priority setting decisions should incorporate both efficiency and equity considerations as well as the following outcomes; (a) Stakeholder satisfaction, (b) Stakeholder understanding, (c) Shifted priorities (reallocation of resources), and (d) Implementation of decisions. (2) Priority setting processes should also meet the procedural conditions of (a) Stakeholder engagement, (b) Stakeholder empowerment, (c) Transparency, (d) Use of evidence, (e) Revisions, (f) Enforcement, and (g) Being grounded on community values. CONCLUSION: Available frameworks for the evaluation of priority setting are mostly grounded on procedural requirements, while few have included outcome requirements. There is, however, increasing recognition of the need to incorporate both consequential and procedural considerations in priority setting practices. In this review, we adapt an integrative approach to develop and propose a framework for the evaluation of priority setting practices at the macro and meso levels that draws from these complementary schools of thought.

Duru V, Khim N, Leang R, Kim S, Domergue A, Kloeung N, Ke S, Chy S, Eam R, Khean C et al. 2015. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations. BMC Med, 13 (1), pp. 305. | Citations: 27 (Scopus) | Show Abstract | Read more

BACKGROUND: The declining efficacy of dihydroartemisinin-piperaquine against Plasmodium falciparum in Cambodia, along with increasing numbers of recrudescent cases, suggests resistance to both artemisinin and piperaquine. Available in vitro piperaquine susceptibility assays do not correlate with treatment outcome. A novel assay using a pharmacologically relevant piperaquine dose/time exposure was designed and its relevance explored in retrospective and prospective studies. METHODS: The piperaquine survival assay (PSA) exposed parasites to 200 nM piperaquine for 48 hours and monitored survival 24 hours later. The retrospective study tested 32 culture-adapted, C580Y-K13 mutant parasites collected at enrolment from patients treated with a 3-day course of dihydroartemisinin-piperaquine and having presented or not with a recrudescence at day 42 (registered ACTRN12615000793516). The prospective study assessed ex vivo PSA survival rate alongside K13 polymorphism of isolates collected from patients enrolled in an open-label study with dihydroartemisinin-piperaquine for uncomplicated P. falciparum malaria in Cambodia (registered ACTRN12615000696594). RESULTS: All parasites from recrudescent cases had in vitro or ex vivo PSA survival rates ≥10%, a relevant cut-off value for piperaquine-resistance. Ex vivo PSA survival rates were higher for recrudescent than non-recrudescent cases (39.2% vs. 0.17%, P <1 × 10(-7)). Artemisinin-resistant K13 mutants with ex vivo PSA survival rates ≥10% were associated with 32-fold higher risk of recrudescence (95% CI, 4.5-224; P = 0.0005). CONCLUSION: PSA adequately captures the piperaquine resistance/recrudescence phenotype, a mainstay to identify molecular marker(s) and evaluate efficacy of alternative drugs. Combined ex vivo PSA and K13 genotyping provides a convenient monitor for both artemisinin and piperaquine resistance where dihydroartemisinin-piperaquine is used.

White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D et al. 2015. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect Dis, 15 (12), pp. 1450-1458. | Citations: 43 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. METHODS: Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. FINDINGS: RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. INTERPRETATION: Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. FUNDING: UK Medical Research Council.

Muinga N, Sen B, Ayieko P, Todd J, English M. 2015. Access to and value of information to support good practice for staff in Kenyan hospitals. Glob Health Action, 8 (1), pp. 26559. | Show Abstract | Read more

Background Studies have sought to define information needs of health workers within very specific settings or projects. Lacking in the literature is how hospitals in low-income settings are able to meet the information needs of their staff and the use of information communication technologies (ICT) in day-to-day information searching. Objective The study aimed to explore where professionals in Kenyan hospitals turn to for work-related information in their day-to-day work. Additionally, it examined what existing solutions are provided by hospitals with regard to provision of best practice care. Lastly, the study explored the use of ICT in information searching. Design Data for this study were collected in July 2012. Self-administered questionnaires (SAQs) were distributed across 22 study hospitals with an aim to get a response from 34 health workers per hospital. Results SAQs were collected from 657 health workers. The most popular sources of information to guide work were fellow health workers and printed guidelines while the least popular were scientific journals. Of value to health workers were: national treatment policies, new research findings, regular reports from surveillance data, information on costs of services and information on their performance of routine clinical tasks; however, hospitals only partially met these needs. Barriers to accessing information sources included: 'not available/difficult to get' and 'difficult to understand'. ICT use for information seeking was reported and with demographic specific differences noted from the multivariate logistic regression model; nurses compared to medical doctors and older workers were less likely to use ICT for health information searching. Barriers to accessing Internet were identified as: high costs and the lack of the service at home or at work. Conclusions Hospitals need to provide appropriate information by improving information dissemination efforts and providing an enabling environment that allows health workers find the information they need for best practice.

Agweyu A, Gathara D, Oliwa J, Muinga N, Edwards T, Allen E, Maleche-Obimbo E, English M, Severe Pneumonia Study Group. 2015. Oral amoxicillin versus benzyl penicillin for severe pneumonia among kenyan children: a pragmatic randomized controlled noninferiority trial. Clin Infect Dis, 60 (8), pp. 1216-1224. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: There are concerns that the evidence from studies showing noninferiority of oral amoxicillin to benzyl penicillin for severe pneumonia may not be generalizable to high-mortality settings. METHODS: An open-label, multicenter, randomized controlled noninferiority trial was conducted at 6 Kenyan hospitals. Eligible children aged 2-59 months were randomized to receive amoxicillin or benzyl penicillin and followed up for the primary outcome of treatment failure at 48 hours. A noninferiority margin of risk difference between amoxicillin and benzyl penicillin groups was prespecified at 7%. RESULTS: We recruited 527 children, including 302 (57.3%) with comorbidity. Treatment failure was observed in 20 of 260 (7.7%) and 21 of 261 (8.0%) of patients in the amoxicillin and benzyl penicillin arms, respectively (risk difference, -0.3% [95% confidence interval, -5.0% to 4.3%]) in per-protocol analyses. These findings were supported by the results of intention-to-treat analyses. Treatment failure by day 5 postenrollment was 11.4% and 11.0% and rising to 13.5% and 16.8% by day 14 in the amoxicillin vs benzyl penicillin groups, respectively. The most frequent cause of cumulative treatment failure at day 14 was clinical deterioration within 48 hours of enrollment (33/59 [55.9%]). Four patients died (overall mortality 0.8%) during the study, 3 of whom were allocated to the benzyl penicillin group. The presence of wheeze was independently associated with less frequent treatment failure. CONCLUSIONS: Our findings confirm noninferiority of amoxicillin to benzyl penicillin, provide estimates of risk of treatment failure in Kenya, and offer important additional evidence for policy making in sub-Saharan Africa. CLINICAL TRIAL REGISTRATION: NCT01399723.

Ochola-Oyier LI, Okombo J, Mwai L, Kiara SM, Pole L, Tetteh KKA, Nzila A, Marsh K. 2015. The MSPDBL2 codon 591 polymorphism is associated with lumefantrine in vitro drug responses in Plasmodium falciparum isolates from Kilifi, Kenya. Antimicrob Agents Chemother, 59 (3), pp. 1770-1775. | Citations: 1 (Scopus) | Show Abstract | Read more

The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04). The high frequency of Pfmspdbl2 codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem).

Triantafyllidis A, Velardo C, Chantler T, Shah SA, Paton C, Khorshidi R, Tarassenko L, Rahimi K, SUPPORT-HF Investigators. 2015. A personalised mobile-based home monitoring system for heart failure: The SUPPORT-HF Study. Int J Med Inform, 84 (10), pp. 743-753. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Despite their potential for improving health outcomes, mobile-based home monitoring systems for heart failure have not yet been taken up widely by the patients and providers. OBJECTIVES: To design and iteratively move towards a personalised mobile health monitoring system for patients living with heart failure, according to their health care and usability needs. METHODS: We present an iterative approach to refining a remote health monitoring system that is based on interactions between different actors (patients, clinicians, social scientists and engineers) and supports the collection of quantitative and qualitative information about user experience and engagement. Patients were provided with tablet computers and commercially available sensing devices (a blood pressure monitor, a set of weighing scales, and a pulse oximeter) in order to complete physiological measurements at home, answer symptom-specific questionnaires, review their personal readings, view educational material on heart failure self-management, and communicate with their health professionals. The system supported unobtrusive remote software upgrades via an application distribution channel and the activation or deactivation of functional components by health professionals during run-time operation. We report early findings from the application of this approach in a cohort of 26 heart failure patients (mean age 72±15 years), their caregivers and healthcare professionals who participated in the SUPPORT-HF (Seamless User-centred Proactive Provision Of Risk-stratified Treatment for Heart Failure) study over a one-year study period (mean patient follow-up duration=270±62 days). RESULTS: The approach employed in this study led to several system upgrades dealing in particular with patient requirements for better communication with the development team and personalised self-monitoring interfaces. Engagement with the system was constantly high throughout the study and during the last week of the evaluation, 23 patients (88%) used the system at least once and 16 patients (62%) at least three times. CONCLUSIONS: Designers of future mobile-based home monitoring systems for heart failure and other chronic conditions could leverage the described approach as a means of meeting patients' needs during system use within the home environment and facilitating successful uptake.

Fox A, Mai LQ, Thanh LT, Wolbers M, Le Khanh Hang N, Thai PQ, Thi Thu Yen N, Minh Hoa LN, Bryant JE, Duong TN et al. 2015. Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection. J Infect, 70 (2), pp. 187-196. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: Hemagglutination inhibiting (HI) antibodies correlate with influenza vaccine protection but their association with protection induced by natural infection has received less attention and was studied here. METHODS: 940 people from 270 unvaccinated households participated in active ILI surveillance spanning 3 influenza seasons. At least 494 provided paired blood samples spanning each season. Influenza infection was confirmed by RT-PCR on nose/throat swabs or serum HI assay conversion. RESULTS: Pre-season homologous HI titer was associated with a significantly reduced risk of infection for H3N2 (OR 0.61, 95%CI 0.44-0.84) and B (0.65, 95%CI 0.54-0.80) strains, but not H1N1 strains, whether re-circulated (OR 0.90, 95%CI 0.71-1.15), new seasonal (OR 0.86, 95%CI 0.54-1.36) or pandemic H1N1-2009 (OR 0.77, 95%CI 0.40-1.49). The risk of seasonal and pandemic H1N1 decreased with increasing age (both p < 0.0001), and the risk of pandemic H1N1 decreased with prior seasonal H1N1 (OR 0.23, 95%CI 0.08-0.62) without inducing measurable A/California/04/2009-like titers. CONCLUSIONS: While H1N1 immunity was apparent with increasing age and prior infection, the effect of pre-season HI titer was at best small, and weak for H1N1 compared to H3N2 and B. Antibodies targeting non-HI epitopes may have been more important mediators of infection-neutralizing immunity for H1N1 compared to other subtypes in this setting.

Aluvaala J, Nyamai R, Were F, Wasunna A, Kosgei R, Karumbi J, Gathara D, English M, SIRCLE/Ministry of Health Hospital Survey Group. 2015. Assessment of neonatal care in clinical training facilities in Kenya. Arch Dis Child, 100 (1), pp. 42-47. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: An audit of neonatal care services provided by clinical training centres was undertaken to identify areas requiring improvement as part of wider efforts to improve newborn survival in Kenya. DESIGN: Cross-sectional study using indicators based on prior work in Kenya. Statistical analyses were descriptive with adjustment for clustering of data. SETTING: Neonatal units of 22 public hospitals. PATIENTS: Neonates aged <7 days. MAIN OUTCOME MEASURES: Quality of care was assessed in terms of availability of basic resources (principally equipment and drugs) and audit of case records for documentation of patient assessment and treatment at admission. RESULTS: All hospitals had oxygen, 19/22 had resuscitation and phototherapy equipment, but some key resources were missing—for example kangaroo care was available in 14/22. Out of 1249 records, 56.9% (95% CI 36.2% to 77.6%) had a standard neonatal admission form. A median score of 0 out of 3 for symptoms of severe illness (IQR 0-3) and a median score of 6 out of 8 for signs of severe illness (IQR 4-7) were documented. Maternal HIV status was documented in 674/1249 (54%, 95% CI 41.9% to 66.1%) cases. Drug doses exceeded recommendations by >20% in prescriptions for penicillin (11.6%, 95% CI 3.4% to 32.8%) and gentamicin (18.5%, 95% CI 13.4% to 25%), respectively. CONCLUSIONS: Basic resources are generally available, but there are deficiencies in key areas. Poor documentation limits the use of routine data for quality improvement. Significant opportunities exist for improvement in service delivery and adherence to guidelines in hospitals providing professional training.

Barasa EW, Molyneux S, English M, Cleary S. 2015. Setting healthcare priorities in hospitals: a review of empirical studies. Health Policy Plan, 30 (3), pp. 386-396. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

Priority setting research has focused on the macro (national) and micro (bedside) level, leaving the meso (institutional, hospital) level relatively neglected. This is surprising given the key role that hospitals play in the delivery of healthcare services and the large proportion of health systems resources that they absorb. To explore the factors that impact upon priority setting at the hospital level, we conducted a thematic review of empirical studies. A systematic search of PubMed, EBSCOHOST, Econlit databases and Google scholar was supplemented by a search of key websites and a manual search of relevant papers' reference lists. A total of 24 papers were identified from developed and developing countries. We applied a policy analysis framework to examine and synthesize the findings of the selected papers. Findings suggest that priority setting practice in hospitals was influenced by (1) contextual factors such as decision space, resource availability, financing arrangements, availability and use of information, organizational culture and leadership, (2) priority setting processes that depend on the type of priority setting activity, (3) content factors such as priority setting criteria and (4) actors, their interests and power relations. We observe that there is need for studies to examine these issues and the interplay between them in greater depth and propose a conceptual framework that might be useful in examining priority setting practices in hospitals.

Folayan MO, Peterson K, Haire B, Brown B, Audu K, Makanjuola O, Pelemo B, Marsh V. 2015. Debating Ethics in HIV Research: Gaps between Policy and Practice in Nigeria. Dev World Bioeth, 15 (3), pp. 214-225. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

HIV prevention is a critical health issue in Nigeria; a country that has one of the worst HIV epidemic profiles in the world. With 270,000 new infections in 2012, Nigeria is a prime site for HIV prevention research. One effect of the HIV epidemic has been to revolutionalise ethical norms for the conduct of research: it is now considered unethical to design and implement HIV related studies without community engagement. Unfortunately, there is very little commensurate effort in building the capacity of local persons to engage actively with researchers, and there is no existing platform to facilitate dialogue between researchers and communities engaged in research in Nigeria. In an effort to address this gap, we undertook a series of three community dialogues (Phase One) and two community-researcher interface meetings (Phase Two) in Nigeria. This paper aims to give an empirical account of the dialogue from these community engagement processes and provide a resulting critique of the implementation of research ethics practices in Nigeria. It is anticipated that the outputs will: (i) support researchers in designing community-based research protocols; (ii) inform ethics committees of key considerations during research protocol reviews from a community perspective; and (iii) inform policy makers and research sponsors about issues of primary concern to communities with respect to HIV research.

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