@Oxford Publications 2016

Murphy GAV, Gathara D, Aluvaala J, Mwachiro J, Abuya N, Ouma P, Snow RW, English M. 2016. Nairobi Newborn Study: a protocol for an observational study to estimate the gaps in provision and quality of inpatient newborn care in Nairobi City County, Kenya. BMJ Open, 6 (12), pp. e012448. | Show Abstract | Read more

INTRODUCTION: Progress has been made in Kenya towards reducing child mortality as part of efforts aligned with the fourth Millennium Development Goal. However, little advancement has been made in reducing mortality among newborns, which now accounts for 45% of all child deaths. The frequently unanticipated nature of neonatal illness, its severity and the high dependency of sick newborns on skilled care make the provision of inpatient hospital services one key component of strategies to improve newborn survival. METHODS AND ANALYSES: This project aims to assess the availability and quality of inpatient newborn care in hospitals in Nairobi City County across the public, private and not-for-profit sectors and align this to the estimated need for such services, providing a description of the quantity and quality gaps between capacity and demand. The population level burden of disease will be estimated using morbidity incidence estimates from a literature review applied to subcounty estimates of population-adjusted births, providing a spatially disaggregated estimate of need within the county. This will be followed by a survey of neonatal services across all health facilities providing 24/7 inpatient newborn care in the county. The survey will include: a retrospective audit of admission registers to estimate the usage of facilities and case-mix of patients; a structural assessment of facilities to gain insight into capacity; a questionnaire to nursing staff focusing on the process of delivering key obstetric and neonatal interventions; and a retrospective case audit to assess adherence to guidelines by clinicians. ETHICS AND DISSEMINATION: This study has been approved by the Kenya Medical Research Institute Scientific and Ethics Review Unit (SSC protocol No.2999). Results will be disseminated: to participating facilities through individualised reports and a joint workshop; to local and national stakeholders through meetings and a summary report; and to the international community through peer-review publication and international meetings.

Rojek AM, Horby PW. 2016. Modernising epidemic science: enabling patient-centred research during epidemics. BMC Med, 14 (1), pp. 212. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Emerging and epidemic infectious disease outbreaks are a significant public health problem and global health security threat. As an outbreak begins, epidemiological investigations and traditional public health responses are generally mounted very quickly. However, patient-centred research is usually not prioritised when planning and enacting the response. Instead, the clinical research response occurs subsequent to and separate from the public health response, and is inadequate for evidence-based decision-making at the bedside or in the offices of public health policymakers. DISCUSSION: The deficiencies of the clinical research response to severe acute respiratory syndrome, pandemic influenza, Middle East respiratory syndrome coronavirus and Ebola virus demonstrate that current research models do not adequately inform and improve the quality of clinical care or public health response. Three suggestions for improvements are made. First, integrate the data and sample collection needs for clinical and public health decision-making within a unified framework, combined with a risk-based, rather than a discipline-based, approach to ethical review and consent. Second, develop clinical study methods and tools that are specifically designed to meet the epidemiological and contextual challenges of emerging and epidemic infectious diseases. Third, invest in investigator-led clinical research networks that are primed and incentivised to respond to outbreak infections, and which can call on the support and resources of a central centre of excellence. CONCLUSIONS: It is crucial that the field of epidemic science matures to place patients at the heart of the response. This can only be achieved when patient-centred research is integrated in the outbreak response from day one and practical steps are taken to reduce the barriers to the generation of reliable and useful evidence.

Brown A, Halliday JS, Swadling L, Madden RG, Bendall R, Hunter JG, Maggs J, Simmonds P, Smith DB, Vine L et al. 2016. Characterization of the Specificity, Functionality, and Durability of Host T-Cell Responses Against the Full-Length Hepatitis E Virus. Hepatology, 64 (6), pp. 1934-1950. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

The interplay between host antiviral immunity and immunopathology during hepatitis E virus (HEV) infection determines important clinical outcomes. We characterized the specificity, functionality, and durability of host T-cell responses against the full-length HEV virus and assessed a novel "Quantiferon" assay for the rapid diagnosis of HEV infection. Eighty-nine volunteers were recruited from Oxford, Truro (UK), and Toulouse (France), including 44 immune-competent patients with acute HEV infection, 18 HEV-exposed immunosuppressed organ-transplant recipients (8 with chronic HEV), and 27 healthy volunteers. A genotype 3a peptide library (616 overlapping peptides spanning open reading frames [ORFs] 1-3) was used in interferon-gamma (IFN-γ) T-cell ELISpot assays. CD4+/CD8+T-cell subsets and polyfunctionality were defined using ICCS and SPICE analysis. Quantification of IFN-γ used whole-blood stimulation with recombinant HEV-capsid protein in the QuantiFERON kit. HEV-specific T-cell responses were detected in 41/44 immune-competent HEV exposed volunteers (median magnitude: 397 spot-forming units/106peripheral blood mononuclear cells), most frequently targeting ORF2. High-magnitude, polyfunctional CD4 and CD8+T cells were detected during acute disease and maintained to 12 years, but these declined over time, with CD8+responses becoming more monofunctional. Low-level responses were detectable in immunosuppressed patients. Twenty-three novel HEV CD4+and CD8+T-cell targets were mapped predominantly to conserved genomic regions. QuantiFERON testing demonstrated an inverse correlation between IFN-γ production and the time from clinical presentation, providing 100% specificity, and 71% sensitivity (area under the receiver operator characteristic curve of 0.86) for HEV exposure at 0.3 IU/mL. CONCLUSION: Robust HEV-specific T-cell responses generated during acute disease predominantly target ORF2, but decline in magnitude and polyfunctionality over time. Defining HEV T-cell targets will be important for the investigation of HEV-associated autoimmune disease. (Hepatology 2016;64:1934-1950).

Hendrickx S, Guerin PJ, Caljon G, Croft SL, Maes L. 2016. Evaluating drug resistance in visceral leishmaniasis: the challenges. Parasitology, pp. 1-11. | Show Abstract | Read more

For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as first-line therapy in the endemic VL region in the Indian subcontinent. The application of other drugs has been limited due to adverse effects, perceived high cost, need for parenteral administration and increasing rate of treatment failures. Liposomal amphotericin B (AmB) and miltefosine (MIL) have been positioned as the effective first-line treatments; however, the number of monotherapy MIL-failures has increased after a decade of use. Since no validated molecular resistance markers are yet available, monitoring and surveillance of changes in drug sensitivity and resistance still depends on standard phenotypic in vitro promastigote or amastigote susceptibility assays. Clinical isolates displaying defined MIL- or AmB-resistance are still fairly scarce and fundamental and applied research on resistance mechanisms and dynamics remains largely dependent on laboratory-generated drug resistant strains. This review addresses the various challenges associated with drug susceptibility and -resistance monitoring in VL, with particular emphasis on the choice of strains, susceptibility model selection and standardization of procedures with specific read-out parameters and well-defined threshold criteria. The latter are essential to support surveillance systems and safeguard the limited number of currently available antileishmanial drugs.

Mbevi G, Ayieko P, Irimu G, Akech S, English M, Clinical Information Network authors. 2016. Prevalence, aetiology, treatment and outcomes of shock in children admitted to Kenyan hospitals. BMC Med, 14 (1), pp. 184. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Shock may complicate several acute childhood illnesses in hospitals within low-income countries and has a high case fatality. Hypovolemic shock secondary to diarrhoea/dehydration and septic shock are thought to be common, but there are few reliable data on prevalence or treatment that differ for the two major forms of shock. Examining prevalence and treatment practices has become important since reports suggest high risks from liberal use of fluid boluses in African children. The present study aims to estimate the prevalence, fluid management practices and outcomes of shock among hospitalised children. METHODS: We analysed paediatric in-patient data collected using discharge case record review between October 2013 and February 2016 from 14 hospitals in Kenya which are part of a network (referred to as the Clinical Information Network) using similar tools for standardised clinical records with care directed by the local clinical team leaders. Data are from a period after dissemination of national guidance seeking to limit use of bolus fluids. RESULTS: A total of 74,402 children were admitted between October 2013 and February 2016. Children aged < 30 days or > 5 years, with severe acute malnutrition, surgical/burns, or cases with pre-defined minimum data sets were excluded from analysis. This resulted in 42,937 patients meeting the inclusion criteria. Prevalence of clinically diagnosed shock was 1.5 % (n = 622) and overall bolus use was 0.9 % (n = 366); 41 % (256/622) of children with clinically diagnosed shock did not receive a fluid bolus (but had a fluid plan for management of dehydration). Identified cases appeared mostly to be hypovolaemic shock secondary to dehydration/diarrhoea (94 %, 582/622), with a high case fatality (34 %, 211/622). Overall mortality for all admitted children was 5 % (2115/42,937) and was 7.9 % (798/10,096) in children with dehydration/diarrhoea. The diagnosis of hypovolaemic shock was nearly always accompanied by additional clinical diagnosis (99 %), most often pneumonia or malaria. Where bolus fluids were used, they were prescribed in accordance with guidelines (isotonic fluid at correct volume) in 92 % of cases. Inappropriate use of bolus fluids to treat milder forms of impaired circulation appeared very rarely. CONCLUSION: A diagnosis of shock is uncommon at admission and use of fluid bolus is rare in admissions to Kenyan hospitals. A fluid bolus, when prescribed, is mostly used in children with hypovolemic shock secondary to dehydration and case fatality in these cases is high. We found little evidence of liberal use of fluid bolus that might cause harm in a period following dissemination of national guidelines suggesting very strict criteria for fluid bolus use.

Van Kerkhove MD, Reveiz L, Souza JP, Jaenisch T, Carson G, Broutet N, Working Group on ZIKV Harmonized Research. 2016. Harmonisation of Zika virus research protocols to address key public health concerns. Lancet Glob Health, 4 (12), pp. e911-e912. | Citations: 1 (Web of Science Lite) | Read more

Grist EPM, Flegg JA, Humphreys G, Mas IS, Anderson TJC, Ashley EA, Day NPJ, Dhorda M, Dondorp AM, Faiz MA et al. 2016. Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia. Int J Health Geogr, 15 (1), pp. 37. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. METHODS: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. RESULTS: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. CONCLUSION: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas.

Denoeud-Ndam L, Dicko A, Baudin E, Guindo O, Grandesso F, Diawara H, Sissoko S, Sanogo K, Traoré S, Keita S et al. 2016. Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger. BMC Med, 14 (1), pp. 167. | Show Abstract | Read more

BACKGROUND: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without. METHODS: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF - Plumpy'Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. RESULTS: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8-100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4-99.7 %) at day 28 and 98.3 % (95.6-99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04-4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049). CONCLUSIONS: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013.

Cowman AF, Healer J, Marapana D, Marsh K. 2016. Malaria: Biology and Disease. Cell, 167 (3), pp. 610-624. | Citations: 32 (Scopus) | Show Abstract | Read more

Malaria has been a major global health problem of humans through history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility. Achievement of this goal requires the development of new tools including novel antimalarial drugs and more efficacious vaccines as well as an increased understanding of the disease and biology of the parasite. This has catalyzed a major effort resulting in development and regulatory approval of the first vaccine against malaria (RTS,S/AS01) as well as identification of novel drug targets and antimalarial compounds, some of which are in human clinical trials.

Amboko BI, Ayieko P, Ogero M, Julius T, Irimu G, English M, Clinical Information Network authors. 2016. Malaria investigation and treatment of children admitted to county hospitals in western Kenya. Malar J, 15 (1), pp. 506. | Show Abstract | Read more

BACKGROUND: Up to 90 % of the global burden of malaria morbidity and mortality occurs in sub-Saharan Africa and children under-five bear a disproportionately high malaria burden. Effective inpatient case management can reduce severe malaria mortality and morbidity, but there are few reports of how successfully international and national recommendations are adopted in management of inpatient childhood malaria. METHODS: A descriptive cross-sectional study of inpatient malaria case management practices was conducted using data collected over 24 months in five hospitals from high malaria risk areas participating in the Clinical Information Network (CIN) in Kenya. This study describes documented clinical features, laboratory investigations and treatment of malaria in children (2-59 months) and adherence to national guidelines. RESULTS: A total of 13,014 children had a malaria diagnosis on admission to the five hospitals between March, 2014 and February, 2016. Their median age was 24 months (IQR 12-36 months). The proportion with a diagnostic test for malaria requested was 11,981 (92.1 %). Of 10,388 patients with malaria test results documented, 8050 (77.5 %) were positive and anti-malarials were prescribed in 6745 (83.8 %). Malaria treatment was prescribed in 1613/2338 (69.0 %) children with a negative malaria result out of which only 52 (3.2 %) had a repeat malaria test done as recommended in national guidelines. Documentation of clinical features was good across all hospitals, but quinine remained the most prescribed malaria drug (47.2 % of positive cases) although a transition to artesunate (46.1 %) was observed. Although documented clinical features suggested approximately half of positive malaria patients were not severe cases artemether-lumefantrine was prescribed on admission in only 3.7 % cases. CONCLUSIONS: Despite improvements in inpatient malaria care, high rates of presumptive treatment for test negative children and likely over-use of injectable anti-malarial drugs were observed. Three years after national policy change, there is a gradual transition to artesunate. Continued efforts to support improved routine inpatient malaria care through dissemination and implementation of guidelines, and access to recommended drugs are needed together with improved capacity of hospitals to investigate other causes of severe illness in children. Efforts to improve clinical information could help track progress.

Hodgson SH, Llewellyn D, Silk SE, Milne KH, Elias SC, Miura K, Kamuyu G, Juma EA, Magiri C, Muia A et al. 2016. Changes in Serological Immunology Measures in UK and Kenyan Adults Post-controlled Human Malaria Infection. Front Microbiol, 7 (OCT), pp. 1604. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049) (ClinicalTrials.gov NCT01465048) using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens [merozoite surface protein 1 (MSP1), apical membrane protein 1 (AMA1), and reticulocyte-binding protein homolog 5 (RH5)] and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA) assay and the antibody-dependent respiratory burst activity (ADRB) assay. Results:Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR) post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan volunteers. Quinine and atovaquone/proguanil, previously assumed to be removed by IgG purification, were identified as likely giving rise to aberrantly high in vitro GIA results. Conclusions: The ADRB activity assay is a promising functional assay that warrants further investigation as a measure of prior exposure to malaria and predictor of control of parasite growth. The CHMI model can be used to evaluate potential measures of naturally-acquired immunity to malaria.

Pisani E, Aaby P, Breugelmans JG, Carr D, Groves T, Helinski M, Kamuya D, Kern S, Littler K, Marsh V et al. 2016. Beyond open data: realising the health benefits of sharing data. BMJ, 355 pp. i5295. | Citations: 3 (Scopus) | Read more

Wong VK, Baker S, Connor TR, Pickard D, Page AJ, Dave J, Murphy N, Holliman R, Sefton A, Millar M et al. 2016. An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid. Nat Commun, 7 pp. 12827. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

The population of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, exhibits limited DNA sequence variation, which complicates efforts to rationally discriminate individual isolates. Here we utilize data from whole-genome sequences (WGS) of nearly 2,000 isolates sourced from over 60 countries to generate a robust genotyping scheme that is phylogenetically informative and compatible with a range of assays. These data show that, with the exception of the rapidly disseminating H58 subclade (now designated genotype 4.3.1), the global S. Typhi population is highly structured and includes dozens of subclades that display geographical restriction. The genotyping approach presented here can be used to interrogate local S. Typhi populations and help identify recent introductions of S. Typhi into new or previously endemic locations, providing information on their likely geographical source. This approach can be used to classify clinical isolates and provides a universal framework for further experimental investigations.

Kumar P, Paton C, Kirigia D. 2016. I've got 99 problems but a phone ain't one: Electronic and mobile health in low and middle income countries. Arch Dis Child, 101 (10), pp. 974-979. | Show Abstract | Read more

Mobile technology is very prevalent in Kenya-mobile phone penetration is at 88% and mobile data subscriptions form 99% of all internet subscriptions. While there is great potential for such ubiquitous technology to revolutionise access and quality of healthcare in low-resource settings, there have been few successes at scale. Implementations of electronic health (e-Health) and mobile health (m-Health) technologies in countries like Kenya are yet to tackle human resource constraints or the political, ethical and financial considerations of such technologies. We outline recent innovations that could improve access and quality while considering the costs of healthcare. One is an attempt to create a scalable clinical decision support system by engaging a global network of specialist doctors and reversing some of the damaging effects of medical brain drain. The other efficiently extracts digital information from paper-based records using low-cost and locally produced tools such as rubber stamps to improve adherence to clinical practice guidelines. By bringing down the costs of remote consultations and clinical audit, respectively, these projects offer the potential for clinics in resource-limited settings to deliver high-quality care. This paper makes a case for continued and increased investment in social enterprises that bridge academia, public and private sectors to deliver sustainable and scalable e-Health and m-Health solutions.

Koh WM, Bogich T, Siegel K, Jin J, Chong EY, Tan CY, Chen MI, Horby P, Cook AR. 2016. The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis. Pediatr Infect Dis J, 35 (10), pp. e285-e300. | Citations: 17 (Scopus) | Show Abstract | Read more

CONTEXT: Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). OBJECTIVE: This study reports a systematic review of the epidemiology of HFMD in Asia. DATA SOURCES: PubMed, Web of Science and Google Scholar were searched up to December 2014. STUDY SELECTION: Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. DATA EXTRACTION: Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. RESULTS: HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. LIMITATIONS: Diversity of study designs complicates attempts to identify features of HFMD epidemiology. CONCLUSIONS: Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps.

Barasa EW, Cleary S, English M, Molyneux S. 2016. The influence of power and actor relations on priority setting and resource allocation practices at the hospital level in Kenya: a case study. BMC Health Serv Res, 16 (1), pp. 536. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Priority setting and resource allocation in healthcare organizations often involves the balancing of competing interests and values in the context of hierarchical and politically complex settings with multiple interacting actor relationships. Despite this, few studies have examined the influence of actor and power dynamics on priority setting practices in healthcare organizations. This paper examines the influence of power relations among different actors on the implementation of priority setting and resource allocation processes in public hospitals in Kenya. METHODS: We used a qualitative case study approach to examine priority setting and resource allocation practices in two public hospitals in coastal Kenya. We collected data by a combination of in-depth interviews of national level policy makers, hospital managers, and frontline practitioners in the case study hospitals (n = 72), review of documents such as hospital plans and budgets, minutes of meetings and accounting records, and non-participant observations in case study hospitals over a period of 7 months. We applied a combination of two frameworks, Norman Long's actor interface analysis and VeneKlasen and Miller's expressions of power framework to examine and interpret our findings RESULTS: The interactions of actors in the case study hospitals resulted in socially constructed interfaces between: 1) senior managers and middle level managers 2) non-clinical managers and clinicians, and 3) hospital managers and the community. Power imbalances resulted in the exclusion of middle level managers (in one of the hospitals) and clinicians and the community (in both hospitals) from decision making processes. This resulted in, amongst others, perceptions of unfairness, and reduced motivation in hospital staff. It also puts to question the legitimacy of priority setting processes in these hospitals. CONCLUSIONS: Designing hospital decision making structures to strengthen participation and inclusion of relevant stakeholders could improve priority setting practices. This should however, be accompanied by measures to empower stakeholders to contribute to decision making. Strengthening soft leadership skills of hospital managers could also contribute to managing the power dynamics among actors in hospital priority setting processes.

Barasa EW, Cleary S, English M, Molyneux S. 2016. The influence of power and actor relations on priority setting and resource allocation practices at the hospital level in Kenya: a case study BMC health services research, 16 (1), pp. 536. | Show Abstract

BACKGROUND: Priority setting and resource allocation in healthcare organizations often involves the balancing of competing interests and values in the context of hierarchical and politically complex settings with multiple interacting actor relationships. Despite this, few studies have examined the influence of actor and power dynamics on priority setting practices in healthcare organizations. This paper examines the influence of power relations among different actors on the implementation of priority setting and resource allocation processes in public hospitals in Kenya. METHODS: We used a qualitative case study approach to examine priority setting and resource allocation practices in two public hospitals in coastal Kenya. We collected data by a combination of in-depth interviews of national level policy makers, hospital managers, and frontline practitioners in the case study hospitals (n = 72), review of documents such as hospital plans and budgets, minutes of meetings and accounting records, and non-participant observations in case study hospitals over a period of 7 months. We applied a combination of two frameworks, Norman Long's actor interface analysis and VeneKlasen and Miller's expressions of power framework to examine and interpret our findings RESULTS: The interactions of actors in the case study hospitals resulted in socially constructed interfaces between: 1) senior managers and middle level managers 2) non-clinical managers and clinicians, and 3) hospital managers and the community. Power imbalances resulted in the exclusion of middle level managers (in one of the hospitals) and clinicians and the community (in both hospitals) from decision making processes. This resulted in, amongst others, perceptions of unfairness, and reduced motivation in hospital staff. It also puts to question the legitimacy of priority setting processes in these hospitals. CONCLUSIONS: Designing hospital decision making structures to strengthen participation and inclusion of relevant stakeholders could improve priority setting practices. This should however, be accompanied by measures to empower stakeholders to contribute to decision making. Strengthening soft leadership skills of hospital managers could also contribute to managing the power dynamics among actors in hospital priority setting processes.

Edgcombe H, Paton C, English M. 2016. Enhancing emergency care in low-income countries using mobile technology-based training tools. Arch Dis Child, 101 (12), pp. 1149-1152. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

In this paper, we discuss the role of mobile technology in developing training tools for health workers, with particular reference to low-income countries (LICs). The global and technological context is outlined, followed by a summary of approaches to using and evaluating mobile technology for learning in healthcare. Finally, recommendations are made for those developing and using such tools, based on current literature and the authors' involvement in the field.

International Typhoid Consortium, Wong VK, Holt KE, Okoro C, Baker S, Pickard DJ, Marks F, Page AJ, Olanipekun G, Munir H et al. 2016. Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa. PLoS Negl Trop Dis, 10 (9), pp. e0004781. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. METHODS: A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. RESULTS: Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. CONCLUSIONS: These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid.

Bediako Y, Ngoi JM, Nyangweso G, Wambua J, Opiyo M, Nduati EW, Bejon P, Marsh K, Ndungu FM. 2016. The effect of declining exposure on T cell-mediated immunity to Plasmodium falciparum - an epidemiological "natural experiment". BMC Med, 14 (1), pp. 143. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Naturally acquired immunity to malaria may be lost with lack of exposure. Recent heterogeneous reductions in transmission in parts of Africa mean that large populations of previously protected people may lose their immunity while remaining at risk of infection. METHODS: Using two ethnically similar long-term cohorts of children with historically similar levels of exposure to Plasmodium falciparum who now experience very different levels of exposure, we assessed the effect of decreased parasite exposure on antimalarial immunity. Peripheral blood mononuclear cells (PBMCs) from children in each cohort were stimulated with P. falciparum and their P. falciparum-specific proliferative and cytokine responses were compared. RESULTS: We demonstrate that, while P. falciparum-specific CD4+T cells are maintained in the absence of exposure, the proliferative capacity of these cells is altered considerably. P. falciparum-specific CD4+T cells isolated from children previously exposed, but now living in an area of minimal exposure ("historically exposed") proliferate significantly more upon stimulation than cells isolated from children continually exposed to the parasite. Similarly, PBMCs from historically exposed children expressed higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines after stimulation with P. falciparum. Notably, we found a significant positive association between duration since last febrile episode and P. falciparum-specific CD4+T cell proliferation, with more recent febrile episodes associated with lower proliferation. CONCLUSION: Considered in the context of existing knowledge, these data suggest a model explaining how immunity is lost in absence of continuing exposure to P. falciparum.

Otienoburu SD, Maïga-Ascofaré O, Schramm B, Jullien V, Jones JJ, Zolia YM, Houzé P, Ashley EA, Kiechel J-R, Guérin PJ et al. 2016. Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate-amodiaquine fixed dose combination or artemether-lumefantrine in Liberia. Malar J, 15 (1), pp. 452. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance. METHODS: The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing. RESULTS: High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine. CONCLUSIONS: Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments. The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.

Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-Omari A, Al-Hameed F et al. 2016. Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia. Emerg Infect Dis, 22 (9), pp. 1554-1561. | Citations: 12 (Scopus) | Show Abstract | Read more

We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.

Darton TC, Jones C, Blohmke CJ, Waddington CS, Zhou L, Peters A, Haworth K, Sie R, Green CA, Jeppesen CA et al. 2016. Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis, 10 (8), pp. e0004926. | Citations: 11 (Scopus) | Show Abstract | Read more

BACKGROUND: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. METHODS AND FINDINGS: We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. CONCLUSIONS: Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

Mijovic H, McKnight J, English M. 2016. What does the literature tell us about health workers' experiences of task-shifting projects in sub-Saharan Africa? A systematic, qualitative review. J Clin Nurs, 25 (15-16), pp. 2083-2100. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

AIMS AND OBJECTIVES: To review systematically, qualitative literature covering the implementation of task shifting in sub-Saharan Africa to address the growing interest in interventions of this kind. This review aims to distil the key practical findings to both guide a specific project aiming to improve the quality of neonatal care in Kenya and to contribute to the broader literature. BACKGROUND: Task-shifting programmes aim to improve access to healthcare by delegating specific tasks from higher to lower skilled health workers. Evidence suggests that task-shifting programmes in sub-Saharan Africa may improve patient outcomes, but they have also been criticised for providing fragmented, unsustainable services. This systematic review of qualitative literature summarises factors affecting implementation of task shifting and how such interventions in sub-Saharan Africa may have affected health workers' feelings about their own positions and their ability to provide care. DESIGN: Following literature search, a modified Critical Appraisal Skills Program (CASP) framework was used to assess quality. Thereafter, analysis adopted a thematic synthesis approach. METHODS: A systematic literature search identified qualitative studies examining task -shifting interventions in sub-Saharan Africa. Thematic synthesis was used to identify overarching themes arising from across the studies and infer how task-shifting interventions may impact on the health workers from whom tasks are being shifted. RESULTS: From the 230 studies screened, 13 met the inclusion criteria. Overarching themes identified showed that task shifting has been associated with jurisdictional debates linked to new cadres working beyond their scope of practice, and tension around compensation and career development for those taking on tasks that were being delegated. CONCLUSIONS: Based on the qualitative data available, it appears that task shifting may negatively impact the sense of agency and the ability to perform of health workers' from whom tasks are shifted. The potential implications of task shifting on all health workers should be considered prior to implementing task-shifting solutions.

Churchill D, Waters L, Ahmed N, Angus B, Boffito M, Bower M, Dunn D, Edwards S, Emerson C, Fidler S et al. 2016. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. HIV Med, 17 Suppl 4 pp. s2-s104. | Citations: 19 (Scopus) | Read more

Nguyen DNT, Mai LQ, Bryant JE, Hang NLK, Hoa LNM, Nadjm B, Thai PQ, Duong TN, Anh DD, Horby P et al. 2016. Epidemiology and etiology of influenza-like-illness in households in Vietnam; it's not all about the kids! J Clin Virol, 82 pp. 126-132. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: Household studies provide opportunities to understand influenza-like-illness (ILI) transmission, but data from (sub)tropical developing countries are scarce. OBJECTIVE: To determine the viral etiology and epidemiology of ILI in households. STUDY DESIGN: ILI was detected by active case finding amongst a cohort of 263 northern Vietnam households between 2008 and 2013. Health workers collected nose and throat swabs for virus detection by multiplex real-time RT-PCR. RESULTS: ILI was detected at least once in 219 (23.7%) of 945 household members. 271 (62.3%) of 435 nose/throat swabs were positive for at least one of the 15 viruses tested. Six viruses predominated amongst positive swabs: Rhinovirus (28%), Influenza virus (17%), Coronavirus (8%), Enterovirus (5%), Respiratory syncytial virus (3%), Metapneumovirus virus (2.5%) and Parainfluenza virus 3 (1.8%). There was no clear seasonality, but 78% of episodes occurred in Winter/Spring for Influenza compared to 32% for Rhinovirus. Participants, on average, suffered 0.49 ILI, and 0.29 virus-positive ILI episodes, with no significant effects of gender, age, or household size. In contrast to US and Australian community studies, the frequency of ILI decreased as the number of household members aged below 5 years increased (p=0.006). CONCLUSION: The findings indicate the need for tailored ILI control strategies, and for better understanding of how local childcare practices and seasonality may influence transmission and the role of children.

Kohler C, Dunachie SJ, Müller E, Kohler A, Jenjaroen K, Teparrukkul P, Baier V, Ehricht R, Steinmetz I. 2016. Rapid and Sensitive Multiplex Detection of Burkholderia pseudomallei-Specific Antibodies in Melioidosis Patients Based on a Protein Microarray Approach. PLoS Negl Trop Dis, 10 (7), pp. e0004847. | Show Abstract | Read more

BACKGROUND: The environmental bacterium Burkholderia pseudomallei causes the infectious disease melioidosis with a high case-fatality rate in tropical and subtropical regions. Direct pathogen detection can be difficult, and therefore an indirect serological test which might aid early diagnosis is desirable. However, current tests for antibodies against B. pseudomallei, including the reference indirect haemagglutination assay (IHA), lack sensitivity, specificity and standardization. Consequently, serological tests currently do not play a role in the diagnosis of melioidosis in endemic areas. Recently, a number of promising diagnostic antigens have been identified, but a standardized, easy-to-perform clinical laboratory test for sensitive multiplex detection of antibodies against B. pseudomallei is still lacking. METHODS AND PRINCIPAL FINDINGS: In this study, we developed and validated a protein microarray which can be used in a standard 96-well format. Our array contains 20 recombinant and purified B. pseudomallei proteins, previously identified as serodiagnostic candidates in melioidosis. In total, we analyzed 196 sera and plasmas from melioidosis patients from northeast Thailand and 210 negative controls from melioidosis-endemic and non-endemic regions. Our protein array clearly discriminated between sera from melioidosis patients and controls with a specificity of 97%. Importantly, the array showed a higher sensitivity than did the IHA in melioidosis patients upon admission (cut-off IHA titer ≥1:160: IHA 57.3%, protein array: 86.7%; p = 0.0001). Testing of sera from single patients at 0, 12 and 52 weeks post-admission revealed that protein antigens induce either a short- or long-term antibody response. CONCLUSIONS: Our protein array provides a standardized, rapid, easy-to-perform test for the detection of B. pseudomallei-specific antibody patterns. Thus, this system has the potential to improve the serodiagnosis of melioidosis in clinical settings. Moreover, our high-throughput assay might be useful for the detection of anti-B. pseudomallei antibodies in epidemiological studies. Further studies are needed to elucidate the clinical and diagnostic significance of the different antibody kinetics observed during melioidosis.

Arabi YM, Al-Enezi F, Longuere K-S, Balkhy HH, Al-Sultan M, Al-Omari A, Al-Hameed FM, Carson G, Shindo N, Fowler R. 2016. Feasibility of a randomized controlled trial to assess treatment of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Saudi Arabia: a survey of physicians. BMC Anesthesiol, 16 (1), pp. 36. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging respiratory pathogen with a high mortality rate and no specific treatments available to date. The purpose of this study was to determine the feasibility of conducting a randomized controlled trial (RCT) of convalescent plasma therapy for MERS-CoV-infected patients by using MERS-CoV-specific convalescent plasma obtained from previously recovered patients. METHODS: A survey was adapted from validated questionnaire originally aimed to measure network capacities and capabilities within the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC). The questionnaire was modified for this study to include 26 items that were divided into three main domains of interest: (1) the ability to care for critically ill MERS-CoV patients; (2) laboratory capacity to diagnose MERS-CoV and blood bank ability to prepare convalescent plasma; and (3), research capacity to conduct randomized controlled trials. The questionnaire was emailed to physicians. RESULTS: Of 582 physicians who were invited to the survey, 327 responded (56.2 %). The professional focus of the majority of respondents was critical care (106/249 (43 %)), pediatrics (59/249, (24 %)) or internal medicine (52/249 (21 %)) but none was blood banking. Nearly all respondents (251/263 (95 %)) reported to have access to ICU facilities within their institutions. Most respondents (219/270 (81 %)) reported that intensivists were the most physician group responsible for treatment decisions about critically ill SARI patients. While 125/165 respondents (76 %) reported that they conduct research in ICUs, and 80/161 (49.7 %) had been involved in the conduct of RCTs, including using a placebo comparison (60/161 (37 %)), only 49/226 (21 %) of respondents regularly participated in research networks. CONCLUSIONS: Our survey indicated that in the Kingdom of Saudi Arabia (KSA), ICUs are the most likely clinical locations for conducting a clinical trial of convalescent plasma therapy for MERS-CoV, and that most ICUs have experience with such research designs.

Opondo C, Allen E, Todd J, English M. 2016. The Paediatric Admission Quality of Care (PAQC) score: designing a tool to measure the quality of early inpatient paediatric care in a low-income setting. Trop Med Int Health, 21 (10), pp. 1334-1345. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Evaluating clinician compliance with recommended steps in clinical guidelines provides one measure of quality of process of care but can result in a multiplicity of indicators across illnesses, making it problematic to produce any summative picture of process quality, information that may be most useful to policy-makers and managers. OBJECTIVE: We set out to develop a clinically logical summative measure of the quality of care provided to children admitted to hospital in Kenya spanning the three diagnoses present in 60% or more of admissions that would provide a patient-level measure of quality of care in the face of comorbidity. METHODS: We developed a conceptual model of care based on three domains: assessment, diagnosis and treatment of illnesses. Individual items within domains correspond to recommended processes of care within national clinical practice guidelines. Summative scores were created to reduce redundancy and enable aggregation across illnesses while maintaining a clear link to clinical domains and our conceptual model. The potential application of the score was explored using data from more than 12 000 children from eight hospitals included in a prior intervention study in Kenya. RESULTS: Summative scores obtained from items representing discrete clinical decision points reduced redundancy, aided balance of score contribution across domains and enabled direct comparison of disease-specific scores and the calculation of scores for children with comorbidity. CONCLUSION: This work describes the development of a summative Paediatric Admission Quality of Care score measured at the patient level that spans three common diseases. The score may be an efficient tool for assessing quality with an ability to adjust for case mix or other patient-level factors if needed. The score principles may have applicability to multiple illnesses and settings. Future analysis will be needed to validate the score.

Hoa LNM, Mai LQ, Bryant JE, Thai PQ, Hang NLK, Yen NTT, Duong TN, Thoang DD, Horby P, Werheim HFL, Fox A. 2016. Association between Hemagglutinin Stem-Reactive Antibodies and Influenza A/H1N1 Virus Infection during the 2009 Pandemic. J Virol, 90 (14), pp. 6549-6556. | Citations: 2 (Scopus) | Show Abstract | Read more

UNLABELLED: The discovery of influenza virus broadly neutralizing (BrN) antibodies prompted efforts to develop universal vaccines. Influenza virus stem-reactive (SR) broadly neutralizing antibodies have been detected by screening antibody phage display libraries. However, studies of SR BrN antibodies in human serum, and their association with natural infection, are limited. To address this, pre- and postpandemic sera from a prospective community cohort study in Vietnam were assessed for antibodies that inhibit SR BrN monoclonal antibody (MAb) (C179) binding to H1N1 pandemic 2009 virus (H1N1pdm09). Of 270 households, 33 with at least one confirmed H1N1pdm09 illness or at least two seroconverters were included. The included households comprised 71 infected and 41 noninfected participants. Sera were tested as 2-fold dilutions between 1:5 and 1:40. Fifty percent C179 inhibition (IC50) titers did not exceed 10, although both IC50 titers and percent C179 inhibition by sera diluted 1:5 or 1:10 correlated with hemagglutination inhibition (HI) and microneutralization (MN) titers (all P < 0.001). Thirteen (12%) participants had detectable prepandemic IC50 titers, but only one reached a titer of 10. This proportion increased to 44% after the pandemic, when 39 participants had a titer of 10, and 67% of infected compared to 44% of noninfected had detectable IC50 titers (P < 0.001). The low levels of SR antibodies in prepandemic sera were not associated with subsequent H1N1pdm09 infection (P = 0.241), and the higher levels induced by H1N1pdm09 infection returned to prepandemic levels within 2 years. The findings indicate that natural infection induces only low titers of SR antibodies that are not sustained. IMPORTANCE: Universal influenza vaccines could have substantial health and economic benefits. The focus of universal vaccine research has been to induce antibodies that prevent infection by diverse influenza virus strains. These so-called broadly neutralizing antibodies are readily detected in mice and ferrets after infection with a series of distinct influenza virus strains. The 2009 H1N1 pandemic provided an opportunity to investigate whether infection with a novel strain induced broadly neutralizing antibodies in humans. We found that broadly neutralizing antibodies were induced, but levels were low and poorly maintained. This could represent an obstacle for universal vaccine development and warrants further investigation.

Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, Kaslow DC, Njuguna P, Marsh K, Bejon P. 2016. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med, 374 (26), pp. 2519-2529. | Citations: 37 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. METHODS: We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. RESULTS: Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]). CONCLUSIONS: A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).

Mogeni P, Williams TN, Fegan G, Nyundo C, Bauni E, Mwai K, Omedo I, Njuguna P, Newton CR, Osier F et al. 2016. Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study. PLoS Med, 13 (6), pp. e1002047. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children due to lower acquired immunity, and this has implications for ongoing control strategies. METHODS AND FINDINGS: We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child's age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval [CI] 0.54-0.58) in 1998 to 0.07 (95% CI 0.06-0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22-0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030-0.040] among young children compared to 0.22 [95% CI 0.21-0.23] in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child's residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis, we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. CONCLUSION: Following a period of reduced transmission, a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate the increasing burden among older children, and universal ITN coverage is a promising strategy to achieve this goal.

Pearson RD, Amato R, Auburn S, Miotto O, Almagro-Garcia J, Amaratunga C, Suon S, Mao S, Noviyanti R, Trimarsanto H et al. 2016. Genomic analysis of local variation and recent evolution in Plasmodium vivax. Nat Genet, 48 (8), pp. 959-964. | Citations: 33 (Scopus) | Show Abstract | Read more

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region and analyzed data on >300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax.

Julé AM, Vaillant M, Lang TA, Guérin PJ, Olliaro PL. 2016. The Schistosomiasis Clinical Trials Landscape: A Systematic Review of Antischistosomal Treatment Efficacy Studies and a Case for Sharing Individual Participant-Level Data (IPD). PLoS Negl Trop Dis, 10 (6), pp. e0004784. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Schistosomiasis control mainly relies on preventive chemotherapy with praziquantel (PZQ) distributed through mass drug administration. With a target of 260 million treatments yearly, reliably assessing and monitoring efficacy is all-important. Recommendations for treatment and control of schistosomiasis are supported by systematic reviews and meta-analyses of aggregated data, which however also point to limitations due to heterogeneity in trial design, analyses and reporting. Some such limitations could be corrected through access to individual participant-level data (IPD), which facilitates standardised analyses. METHODOLOGY: A systematic literature review was conducted to identify antischistosomal drug efficacy studies performed since 2000; including electronic searches of the Cochrane Infectious Diseases Group specialised register and the Cochrane Library, PubMed, CENTRAL and Embase; complemented with a manual search for articles listed in past reviews. Antischistosomal treatment studies with assessment of outcome within 60 days post-treatment were eligible. Meta-data, i.e. study-level characteristics (Schistosoma species, number of patients, drug administered, country, etc.) and efficacy parameters were extracted from published documents to evaluate the scope of an individual-level data sharing platform. PRINCIPAL FINDINGS: Out of 914 documents screened, 90 studies from 26 countries were included, enrolling 20,517 participants infected with Schistosoma spp. and treated with different PZQ regimens or other drugs. Methodologies varied in terms of diagnostic approaches (number of samples and test repeats), time of outcome assessment, and outcome measure (cure rate or egg reduction rate, as an arithmetic or geometric mean), making direct comparison of published data difficult. CONCLUSIONS: This review describes the landscape of schistosomiasis clinical research. The volume of data and the methodological and reporting heterogeneity identified all indicate that there is scope for an individual participant-level database, to allow for standardised analyses.

Arias A, Watson SJ, Asogun D, Tobin EA, Lu J, Phan MVT, Jah U, Wadoum REG, Meredith L, Thorne L et al. 2016. Rapid outbreak sequencing of Ebola virus in Sierra Leone identifies transmission chains linked to sporadic cases. Virus Evol, 2 (1), pp. vew016. | Show Abstract | Read more

To end the largest known outbreak of Ebola virus disease (EVD) in West Africa and to prevent new transmissions, rapid epidemiological tracing of cases and contacts was required. The ability to quickly identify unknown sources and chains of transmission is key to ending the EVD epidemic and of even greater importance in the context of recent reports of Ebola virus (EBOV) persistence in survivors. Phylogenetic analysis of complete EBOV genomes can provide important information on the source of any new infection. A local deep sequencing facility was established at the Mateneh Ebola Treatment Centre in central Sierra Leone. The facility included all wetlab and computational resources to rapidly process EBOV diagnostic samples into full genome sequences. We produced 554 EBOV genomes from EVD cases across Sierra Leone. These genomes provided a detailed description of EBOV evolution and facilitated phylogenetic tracking of new EVD cases. Importantly, we show that linked genomic and epidemiological data can not only support contact tracing but also identify unconventional transmission chains involving body fluids, including semen. Rapid EBOV genome sequencing, when linked to epidemiological information and a comprehensive database of virus sequences across the outbreak, provided a powerful tool for public health epidemic control efforts.

Toapanta FR, Bernal PJ, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2016. Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 10 (6), pp. e0004766. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

A novel human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently established by the Oxford Vaccine Group. In this model, 104 CFU of Salmonella resulted in 65% of participants developing typhoid fever (referred here as typhoid diagnosis -TD-) 6-9 days post-challenge. TD was diagnosed in participants meeting clinical (oral temperature ≥38°C for ≥12h) and/or microbiological (S. Typhi bacteremia) endpoints. Changes in B cell subpopulations following S. Typhi challenge remain undefined. To address this issue, a subset of volunteers (6 TD and 4 who did not develop TD -NoTD-) was evaluated. Notable changes included reduction in the frequency of B cells (cells/ml) of TD volunteers during disease days and increase in plasmablasts (PB) during the recovery phase (>day 14). Additionally, a portion of PB of TD volunteers showed a significant increase in activation (CD40, CD21) and gut homing (integrin α4β7) molecules. Furthermore, all BM subsets of TD volunteers showed changes induced by S. Typhi infections such as a decrease in CD21 in switched memory (Sm) CD27+ and Sm CD27- cells as well as upregulation of CD40 in unswitched memory (Um) and Naïve cells. Furthermore, changes in the signaling profile of some BM subsets were identified after S. Typhi-LPS stimulation around time of disease. Notably, naïve cells of TD (compared to NoTD) volunteers showed a higher percentage of cells phosphorylating Akt suggesting enhanced survival of these cells. Interestingly, most these changes were temporally associated with disease onset. This is the first study to describe differences in B cell subsets directly related to clinical outcome following oral challenge with wild-type S. Typhi in humans.

Tabernero P, Parker M, Ravinetto R, Phanouvong S, Yeung S, Kitutu FE, Cheah PY, Mayxay M, Guerin PJ, Newton PN. 2016. Ethical challenges in designing and conducting medicine quality surveys. Trop Med Int Health, 21 (6), pp. 799-806. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: In this paper we discuss the main ethical challenges related to the conduct of medicine quality surveys and make suggestions on how to address them. METHOD: Most evidence-based information regarding medicine quality derives from surveys. However, existing research ethical guidelines do not provide specific guidance for medicine quality surveys. Hence, those conducting surveys are often left wondering how to judge what counts as best practice. A list of the main ethical challenges in the design and conduct of surveys is presented. RESULTS AND CONCLUSIONS: It is vital that the design and conduct of medicine quality surveys uphold moral and ethical obligations and analyse the ethical implications and consequences of such work. These aspects include the impact on the local availability of and access to medicines; the confidentiality and privacy of the surveyors and the surveyed; questions as to whether outlet staff personnel should be told they are part of a survey; the need of ethical and regulatory approvals; and how the findings should be disseminated. Medicine quality surveys should ideally be conducted in partnership with the relevant national Medicine Regulatory Authorities. An international, but contextually sensitive, model of good ethical practice for such surveys is needed.

Yoshida S, Martines J, Lawn JE, Wall S, Souza JP, Rudan I, Cousens S, neonatal health research priority setting group, Aaby P, Adam I et al. 2016. Setting research priorities to improve global newborn health and prevent stillbirths by 2025. J Glob Health, 6 (1), pp. 010508. | Citations: 19 (Scopus) | Show Abstract | Read more

BACKGROUND: In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013-2025. METHODS: We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts. RESULTS: Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour. CONCLUSION: These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed.

Bassat Q, Tanner M, Guerin PJ, Stricker K, Hamed K. 2016. Combating poor-quality anti-malarial medicines: a call to action. Malar J, 15 (1), pp. 302. | Citations: 9 (Scopus) | Show Abstract | Read more

The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial-key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development and malaria elimination programmes.

Radin E, Ariana P, Broekel T, Tran TK. 2016. Analyzing demand-side efficiency in global health: an application to maternal care in Vietnam. Health Policy Plan, 31 (9), pp. 1281-1290. | Show Abstract | Read more

This article investigates demand-side efficiency in global health-or the efficiency with which health system users convert public health resources into health outcomes. We introduce and explain the concept of demand-side efficiency as well as quantitative methods to empirically estimate it. Using a robust nonparametric form of technical efficiency analysis, we estimate demand side efficiency and its social determinants. We pilot these methods looking at how efficiently pregnant women in Northern Vietnam convert public health resources into appropriate maternal care as defined by national policy. We find that women who live in non-mountainous geographies, who are formally employed, who are pregnant with a boy and who are ethnic minorities are all more likely to be efficient at achieving appropriate care. We find no significant association between wealth or education and efficiency. Our results suggest that, in the Vietnamese context, women who are the most likely to achieve appropriate maternal care, are not necessarily the most likely to do so efficiently. Women who live in non-mountainous geographies and who are formally employed are both more likely to achieve appropriate care and to do so efficiently. Yet ethnic minority women, who do not systematically achieve better care, are more likely to be efficient or to achieve better care when compared with those with the same endowment of public health resources. On the methodological level, the pilot highlights that this approach can provide useful information for policy by identifying which groups of people are more and less likely to be efficient. By understanding which groups are more likely to be efficient-and in turn how and why-it may be possible to devise policies to promote the drivers of, or conversely address the constraints to, optimizing demand-side efficiency.

Molyneux S, Sariola S, Allman D, Dijkstra M, Gichuru E, Graham S, Kamuya D, Gakii G, Kayemba B, Kombo B et al. 2016. Public/community engagement in health research with men who have sex with men in sub-Saharan Africa: challenges and opportunities. Health Res Policy Syst, 14 (1), pp. 40. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Community engagement, incorporating elements of the broader concepts of public and stakeholder engagement, is increasingly promoted globally, including for health research conducted in developing countries. In sub-Saharan Africa, community engagement needs and challenges are arguably intensified for studies involving gay, bisexual and other men who have sex with men, where male same-sex sexual interactions are often highly stigmatised and even illegal. This paper contextualises, describes and interprets the discussions and outcomes of an international meeting held at the Kenya Medical Research Institute-Wellcome Trust in Kilifi, Kenya, in November 2013, to critically examine the experiences with community engagement for studies involving men who have sex with men. DISCUSSION: We discuss the ethically charged nature of the language used for men who have sex with men, and of working with 'representatives' of these communities, as well as the complementarity and tensions between a broadly public health approach to community engagement, and a more rights based approach. We highlight the importance of researchers carefully considering which communities to engage with, and the goals, activities, and indicators of success and potential challenges for each. We suggest that, given the unintended harms that can emerge from community engagement (including through labelling, breaches in confidentiality, increased visibility and stigma, and threats to safety), representatives of same-sex populations should be consulted from the earliest possible stage, and that engagement activities should be continuously revised in response to unfolding realities. Engagement should also include less vocal and visible men who have sex with men, and members of other communities with influence on the research, and on research participants and their families and friends. Broader ethics support, advice and research into studies involving men who have sex with men is needed to ensure that ethical challenges - including but not limited to those related to community engagement - are identified and addressed. Underlying challenges and dilemmas linked to stigma and discrimination of men who have sex with men in Africa raise special responsibilities for researchers. Community engagement is an important way of identifying responses to these challenges and responsibilities but itself presents important ethical challenges.

WWARN Gametocyte Study Group. 2016. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med, 14 (1), pp. 79. | Citations: 18 (Scopus) | Show Abstract | Read more

BACKGROUND: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). METHODS: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. RESULTS: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. CONCLUSIONS: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

Blohmke CJ, Darton TC, Jones C, Suarez NM, Waddington CS, Angus B, Zhou L, Hill J, Clare S, Kane L et al. 2016. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med, 213 (6), pp. 1061-1077. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.

Chan J-A, Howell KB, Langer C, Maier AG, Hasang W, Rogerson SJ, Petter M, Chesson J, Stanisic DI, Duffy MF et al. 2016. A single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies. Cell Mol Life Sci, 73 (21), pp. 4141-4158. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Antibodies to blood-stage antigens of Plasmodium falciparum play a pivotal role in human immunity to malaria. During parasite development, multiple proteins are trafficked from the intracellular parasite to the surface of P. falciparum-infected erythrocytes (IEs). However, the relative importance of different proteins as targets of acquired antibodies, and key pathways involved in trafficking major antigens remain to be clearly defined. We quantified antibodies to surface antigens among children, adults, and pregnant women from different malaria-exposed regions. We quantified the importance of antigens as antibody targets using genetically engineered P. falciparum with modified surface antigen expression. Genetic deletion of the trafficking protein skeleton-binding protein-1 (SBP1), which is involved in trafficking the surface antigen PfEMP1, led to a dramatic reduction in antibody recognition of IEs and the ability of human antibodies to promote opsonic phagocytosis of IEs, a key mechanism of parasite clearance. The great majority of antibody epitopes on the IE surface were SBP1-dependent. This was demonstrated using parasite isolates with different genetic or phenotypic backgrounds, and among antibodies from children, adults, and pregnant women in different populations. Comparisons of antibody reactivity to parasite isolates with SBP1 deletion or inhibited PfEMP1 expression suggest that PfEMP1 is the dominant target of acquired human antibodies, and that other P. falciparum IE surface proteins are minor targets. These results establish SBP1 as part of a critical pathway for the trafficking of major surface antigens targeted by human immunity, and have key implications for vaccine development, and quantifying immunity in populations.

Newton PN, Caillet C, Guerin PJ. 2016. A link between poor quality antimalarials and malaria drug resistance? Expert Rev Anti Infect Ther, 14 (6), pp. 531-533. | Citations: 4 (Scopus) | Read more

Lai S, Qin Y, Cowling BJ, Ren X, Wardrop NA, Gilbert M, Tsang TK, Wu P, Feng L, Jiang H et al. 2016. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data. Lancet Infect Dis, 16 (7), pp. e108-e118. | Citations: 29 (Scopus) | Show Abstract | Read more

Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67·2%) occurred from December to March, and the overall case-fatality risk was 483 (53·5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases.

Merson L, Gaye O, Guerin PJ. 2016. Avoiding Data Dumpsters--Toward Equitable and Useful Data Sharing. N Engl J Med, 374 (25), pp. 2414-2415. | Citations: 28 (Scopus) | Read more

Ochola-Oyier LI, Okombo J, Wagatua N, Ochieng J, Tetteh KK, Fegan G, Bejon P, Marsh K. 2016. Comparison of allele frequencies of Plasmodium falciparum merozoite antigens in malaria infections sampled in different years in a Kenyan population. Malar J, 15 (1), pp. 261. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum merozoite antigens elicit antibody responses in malaria-endemic populations, some of which are clinically protective, which is one of the reasons why merozoite antigens are the focus of malaria vaccine development efforts. Polymorphisms in several merozoite antigen-encoding genes are thought to arise as a result of selection by the human immune system. METHODS: The allele frequency distribution of 15 merozoite antigens over a two-year period, 2007 and 2008, was examined in parasites obtained from children with uncomplicated malaria. In the same population, allele frequency changes pre- and post-anti-malarial treatment were also examined. Any gene which showed a significant shift in allele frequencies was also assessed longitudinally in asymptomatic and complicated malaria infections. RESULTS: Fluctuating allele frequencies were identified in codons 147 and 148 of reticulocyte-binding homologue (Rh) 5, with a shift from HD to YH haplotypes over the two-year period in uncomplicated malaria infections. However, in both the asymptomatic and complicated malaria infections YH was the dominant and stable haplotype over the two-year and ten-year periods, respectively. A logistic regression analysis of all three malaria infection populations between 2007 and 2009 revealed, that the chance of being infected with the HD haplotype decreased with time from 2007 to 2009 and increased in the uncomplicated and asymptomatic infections. CONCLUSION: Rh5 codons 147 and 148 showed heterogeneity at both an individual and population level and may be under some degree of immune selection.

Tuti T, Bitok M, Malla L, Paton C, Muinga N, Gathara D, Gachau S, Mbevi G, Nyachiro W, Ogero M et al. 2016. Improving documentation of clinical care within a clinical information network: an essential initial step in efforts to understand and improve care in Kenyan hospitals. BMJ Glob Health, 1 (1), pp. e000028. | Show Abstract | Read more

In many low income countries health information systems are poorly equipped to provide detailed information on hospital care and outcomes. Information is thus rarely used to support practice improvement. We describe efforts to tackle this challenge and to foster learning concerning collection and use of information. This could improve hospital services in Kenya. We are developing a Clinical Information Network, a collaboration spanning 14 hospitals, policy makers and researchers with the goal of improving information available on the quality of inpatient paediatric care across common childhood illnesses in Kenya. Standardised data from hospitals' paediatric wards are collected using non-commercial and open source tools. We have implemented procedures for promoting data quality which are performed prior to a process of semi-automated analysis and routine report generation for hospitals in the network. In the first phase of the Clinical Information Network, we collected data on over 65 000 admission episodes. Despite clinicians' initial unfamiliarity with routine performance reporting, we found that, as an initial focus, both engaging with each hospital and providing them information helped improve the quality of data and therefore reports. The process has involved mutual learning and building of trust in the data and should provide the basis for collaborative efforts to improve care, to understand patient outcome, and to evaluate interventions through shared learning. We have found that hospitals are willing to support the development of a clinically focused but geographically dispersed Clinical Information Network in a low-income setting. Such networks show considerable promise as platforms for collaborative efforts to improve care, to provide better information for decision making, and to enable locally relevant research.

Marsh K. 2016. Africa in transition: the case of malaria. Int Health, 8 (3), pp. 155-156. | Citations: 3 (Web of Science Lite) | Read more

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK et al. 2016. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial. PLoS Med, 13 (4), pp. e1001997. | Citations: 41 (Scopus) | Show Abstract | Read more

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Milligan ID, Gibani MM, Sewell R, Clutterbuck EA, Campbell D, Plested E, Nuthall E, Voysey M, Silva-Reyes L, McElrath MJ et al. 2016. Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA, 315 (15), pp. 1610-1623. | Citations: 38 (Scopus) | Show Abstract | Read more

IMPORTANCE: Developing effective vaccines against Ebola virus is a global priority. OBJECTIVE: To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo). DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015. INTERVENTIONS: Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10(10) viral particles) or MVA-BN-Filo (1 × 10(8) median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. MAIN OUTCOMES AND MEASURES: The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations. RESULTS: Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses. CONCLUSIONS AND RELEVANCE: In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02313077.

Kangoye DT, Noor A, Midega J, Mwongeli J, Mkabili D, Mogeni P, Kerubo C, Akoo P, Mwangangi J, Drakeley C et al. 2016. Malaria hotspots defined by clinical malaria, asymptomatic carriage, PCR and vector numbers in a low transmission area on the Kenyan Coast. Malar J, 15 (1), pp. 213. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Targeted malaria control interventions are expected to be cost-effective. Clinical, parasitological and serological markers of malaria transmission have been used to detect malaria transmission hotspots, but few studies have examined the relationship between the different potential markers in low transmission areas. The present study reports on the relationships between clinical, parasitological, serological and entomological markers of malaria transmission in an area of low transmission intensity in Coastal Kenya. METHODS: Longitudinal data collected from 831 children aged 5-17 months, cross-sectional survey data from 800 older children and adults, and entomological survey data collected in Ganze on the Kenyan Coast were used in the present study. The spatial scan statistic test used to detect malaria transmission hotspots was based on incidence of clinical malaria episodes, prevalence of asymptomatic asexual parasites carriage detected by microscopy and polymerase chain reaction (PCR), seroprevalence of antibodies to two Plasmodium falciparum merozoite antigens (AMA1 and MSP1-19) and densities of Anopheles mosquitoes in CDC light-trap catches. RESULTS: There was considerable overlapping of hotspots by these different markers, but only weak to moderate correlation between parasitological and serological markers. PCR prevalence and seroprevalence of antibodies to AMA1 or MSP1-19 appeared to be more sensitive markers of hotspots at very low transmission intensity. CONCLUSION: These findings may support the choice of either serology or PCR as markers in the detection of malaria transmission hotspots for targeted interventions.

Lybbert J, Gullingsrud J, Chesnokov O, Turyakira E, Dhorda M, Guerin PJ, Piola P, Muehlenbachs A, Oleinikov AV. 2016. Abundance of megalin and Dab2 is reduced in syncytiotrophoblast during placental malaria, which may contribute to low birth weight. Sci Rep, 6 (1), pp. 24508. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Placental malaria caused by Plasmodium falciparum contributes to ~200,000 child deaths annually, mainly due to low birth weight (LBW). Parasitized erythrocyte sequestration and consequent inflammation in the placenta are common attributes of placental malaria. The precise molecular details of placental changes leading to LBW are still poorly understood. We hypothesized that placental malaria may disturb maternofetal exchange of vitamins, lipids, and hormones mediated by the multi-ligand (n ~ 50) scavenging/signaling receptor megalin, which is abundantly expressed in placenta but was not previously analyzed in pregnancy outcomes. We studied abundance of megalin and its intracellular adaptor protein Dab2 by immunofluorescence microscopy in placental biopsies from Ugandan women with (n = 8) and without (n = 20) active placental malaria. We found that: (a) abundances of both megalin (p = 0.01) and Dab2 (p = 0.006) were significantly reduced in brush border of syncytiotrophoblast of infected placentas; (b) amounts of megalin and Dab2 were strongly correlated (Spearman's r = 0.53, p = 0.003); (c) abundances of megalin and Dab2 (p = 0.046) were reduced in infected placentas from women with LBW deliveries. This study provides first evidence that placental malaria infection is associated with reduced abundance of megalin transport/signaling system and indicate that these changes may contribute to the pathology of LBW.

Thuan PD, Ca NTN, Van Toi P, Nhien NTT, Thanh NV, Anh ND, Phu NH, Thai CQ, Thai LH, Hoa NT et al. 2016. A Randomized Comparison of Chloroquine Versus Dihydroartemisinin-Piperaquine for the Treatment of Plasmodium vivax Infection in Vietnam. Am J Trop Med Hyg, 94 (4), pp. 879-885. | Citations: 1 (Scopus) | Show Abstract | Read more

A total of 128 Vietnamese patients with symptomatic Plasmodium vivax mono-infections were enrolled in a prospective, open-label, randomized trial to receive either chloroquine or dihydroartemisinin-piperaquine (DHA-PPQ). The proportions of patients with adequate clinical and parasitological responses were 47% in the chloroquine arm (31 of 65 patients) and 66% in the DHA-PPQ arm (42 of 63 patients) in the Kaplan-Meier intention-to-treat analysis (absolute difference 19%, 95% confidence interval = 0-37%), thus establishing non-inferiority of DHA-PPQ. Fever clearance time (median 24 versus 12 hours,P= 0.02), parasite clearance time (median 36 versus 18 hours,P< 0.001), and parasite clearance half-life (mean 3.98 versus 1.80 hours,P< 0.001) were all significantly shorter in the DHA-PPQ arm. All cases of recurrent parasitemia in the chloroquine arm occurred from day 33 onward, with corresponding whole blood chloroquine concentration lower than 100 ng/mL in all patients. Chloroquine thus remains efficacious for the treatment of P. vivax malaria in southern Vietnam, but DHA-PPQ provides more rapid symptomatic and parasitological recovery.

English M, Irimu G, Agweyu A, Gathara D, Oliwa J, Ayieko P, Were F, Paton C, Tunis S, Forrest CB. 2016. Building Learning Health Systems to Accelerate Research and Improve Outcomes of Clinical Care in Low- and Middle-Income Countries. PLoS Med, 13 (4), pp. e1001991. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

Mike English and colleagues argue that as efforts are made towards achieving universal health coverage it is also important to build capacity to develop regionally relevant evidence to improve healthcare.

Thuan PD, Ca NTN, Toi PV, Nhien NTT, Thanh NV, Anh ND, Phu NH, Thai CQ, Thai LH, Hoa NT et al. 2016. A Randomized Comparison of Chloroquine versus Dihydroartemisinin-Piperaquine for the Treatment of Plasmodium vivax Infection in Vietnam AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 94 (4), pp. 879-885. | Citations: 1 (Web of Science Lite) | Read more

Warimwe GM, Abdi AI, Muthui M, Fegan G, Musyoki JN, Marsh K, Bull PC. 2016. Serological Conservation of Parasite-Infected Erythrocytes Predicts Plasmodium falciparum Erythrocyte Membrane Protein 1 Gene Expression but Not Severity of Childhood Malaria. Infect Immun, 84 (5), pp. 1331-1335. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on P. falciparum-infected erythrocytes, is a major family of clonally variant targets of naturally acquired immunity to malaria. Previous studies have demonstrated that in areas where malaria is endemic, antibodies to infected erythrocytes from children with severe malaria tend to be more seroprevalent than antibodies to infected erythrocytes from children with nonsevere malaria. These data have led to a working hypothesis that PfEMP1 variants associated with parasite virulence are relatively conserved in structure. However, the longevity of such serologically conserved variants in the parasite population is unknown. Here, using infected erythrocytes from recently sampled clinical P. falciparum samples, we measured serological conservation using pools of antibodies in sera that had been sampled 10 to 12 years earlier. The serological conservation of infected erythrocytes strongly correlated with the expression of specific PfEMP1 subsets previously found to be associated with severe malaria. However, we found no association between serological conservation per se and disease severity within these data. This contrasts with the simple hypothesis that P. falciparum isolates with a serologically conserved group of PfEMP1 variants cause severe malaria. The data are instead consistent with periodic turnover of the immunodominant epitopes of PfEMP1 associated with severe malaria.

Arjyal A, Basnyat B, Nhan HT, Koirala S, Giri A, Joshi N, Shakya M, Pathak KR, Mahat SP, Prajapati SP et al. 2016. Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial. Lancet Infect Dis, 16 (5), pp. 535-545. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever. METHODS: We did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2-13 years) and adult (aged 14-45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2-13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed. FINDINGS: Between Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55-1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08-0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71-32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported. INTERPRETATION: Our results suggest that fluoroquinolones should no longer be used for treatment of enteric fever in Nepal. Additionally, under our study conditions, ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever. Since antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever, the assessment of novel diagnostics, new treatment options, and use of existing vaccines and development of next-generation vaccines are now a high priority. FUNDING: Wellcome Trust and Li Ka Shing Foundation.

Murungi LM, Sondén K, Llewellyn D, Rono J, Guleid F, Williams AR, Ogada E, Thairu A, Färnert A, Marsh K et al. 2016. Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children. Infect Immun, 84 (4), pp. 950-963. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Severe malaria (SM) is a life-threatening complication of infection with Plasmodium falciparum Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and have rarely been undertaken. We investigated the merozoite targets and antibody-mediated mechanisms associated with protection against SM in Kenyan children aged 0 to 2 years. We designed a unique prospective matched case-control study of well-characterized SM clinical phenotypes nested within a longitudinal birth cohort of children (n= 5,949) monitored over the first 2 years of life. We quantified immunological parameters in sera collected before the SM event in cases and their individually matched controls to evaluate the prospective odds of developing SM in the first 2 years of life. Anti-AMA1 antibodies were associated with a significant reduction in the odds of developing SM (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.15 to 0.90; P= 0.029) after adjustment for responses to all other merozoite antigens tested, while those against MSP-2, MSP-3, Plasmodium falciparum Rh2 [PfRh2], MSP-119, and the infected red blood cell surface antigens were not. The combined ability of total IgG to inhibit parasite growth and mediate the release of reactive oxygen species from neutrophils was associated with a marked reduction in the odds of developing SM (OR = 0.07; 95% CI = 0.006 to 0.82;P= 0.03). Assays of these two functional mechanisms were poorly correlated (Spearman rank correlation coefficient [rs] = 0.12;P= 0.07). Our data provide epidemiological evidence that multiple antibody-dependent mechanisms contribute to protective immunity via distinct targets whose identification could accelerate the development of vaccines to protect against SM.

Whitehead J, Olliaro P, Lang T, Horby P. 2016. Trial design for evaluating novel treatments during an outbreak of an infectious disease. Clin Trials, 13 (1), pp. 31-38. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Tragically, the outbreak of Ebola that started in West Africa in 2014 has been far more extensive and damaging than any previous outbreaks. The duration of the outbreak has, for the first time, allowed the clinical evaluation of Ebola treatments. This article discusses the designs used for two such clinical trials which have recruited patients in Liberia and Sierra Leone. General principles are outlined for trial designs intended to be deployed quickly, adapt flexibly and provide results soon enough to influence the course of the current epidemic rather than just providing evidence for use should Ebola break out again. Lessons are drawn for the conduct of clinical research in future outbreaks of infectious diseases, where the sequence of events may or may not be similar to the West African Ebola epidemic.

Tan J, Pieper K, Piccoli L, Abdi A, Perez MF, Geiger R, Tully CM, Jarrossay D, Maina Ndungu F, Wambua J et al. 2016. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature, 529 (7584), pp. 105-109. | Citations: 26 (Scopus) | Show Abstract | Read more

Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide the pathogen with a powerful means of escape from host antibodies. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 98 amino acid collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B-cell clone and carry distinct somatic mutations in the LAIR1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine.

van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, Antierens A et al. 2016. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med, 374 (1), pp. 33-42. | Citations: 77 (Scopus) | Show Abstract | Read more

BACKGROUND: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Kangoye DT, Mensah VA, Murungi LM, Nkumama I, Nebie I, Marsh K, Cisse B, Bejon P, Osier FHA, Sirima SB, MVVC Infant Immunology Study Group. 2016. Dynamics and role of antibodies to Plasmodium falciparum merozoite antigens in children living in two settings with differing malaria transmission intensity. Vaccine, 34 (1), pp. 160-166. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Young infants have reduced susceptibility to febrile malaria compared with older children, but the mechanism for this remains unclear. There are conflicting data on the role of passively acquired antibodies. Here, we examine antibody titres to merozoite surface antigens in the protection of children in their first two years of life in two settings with differing malaria transmission intensity and compare these titres to previously established protective thresholds. METHODS: Two cohorts of children aged four to six weeks were recruited in Banfora, Burkina and Keur Soce, Senegal and followed up for two years. Malaria infections were detected by light microscopic examination of blood smears collected at active and passive case detection visits. The titres of antibodies to the Plasmodium falciparum recombinant merozoite proteins (AMA1-3D7, MSP1-19, MSP2-Dd2, and MSP3-3D7) were measured by enzyme-linked immunosorbent assay at 1-6, 9, 12, 15 and 18 months of age and compared with the protective thresholds established in Kenyan children. RESULTS: Antibody titres were below the protective thresholds throughout the study period and we did not find any association with protection against febrile malaria. Antibodies to AMA1 and MSP1-19 appeared to be markers of exposure in the univariate analysis (and so associated with increasing risk) and adjusting for exposure reduced the strength and significance of this association. CONCLUSION: The antibody levels we measured are unlikely to be responsible for the apparent protection against febrile malaria seen in young infants. Further work to identify protective antibody responses might include functional assays and a wider range of antigens.

Hodkinson P, Argent A, Wallis L, Reid S, Perera R, Harrison S, Thompson M, English M, Maconochie I, Ward A. 2016. Pathways to Care for Critically Ill or Injured Children: A Cohort Study from First Presentation to Healthcare Services through to Admission to Intensive Care or Death. PLoS One, 11 (1), pp. e0145473. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

PURPOSE: Critically ill or injured children require prompt identification, rapid referral and quality emergency management. We undertook a study to evaluate the care pathway of critically ill or injured children to identify preventable failures in the care provided. METHODS: A year-long cohort study of critically ill and injured children was performed in Cape Town, South Africa, from first presentation to healthcare services until paediatric intensive care unit (PICU) admission or emergency department death, using expert panel review of medical records and caregiver interview. Main outcomes were expert assessment of overall quality of care; avoidability of severity of illness and PICU admission or death and the identification of modifiable factors. RESULTS: The study enrolled 282 children, 252 emergency PICU admissions, and 30 deaths. Global quality of care was graded good in 10% of cases, with half having at least one major impact modifiable factor. Key modifiable factors related to access to care and identification of the critically ill, assessment of severity, inadequate resuscitation, and delays in decision making and referral. Children were transferred with median time from first presentation to PICU admission of 12.3 hours. There was potentially avoidable severity of illness in 185 (74%) of children, and death prior to PICU admission was avoidable in 17/30 (56.7%) of children. CONCLUSIONS: The study presents a novel methodology, examining quality of care across an entire system, and highlighting the complexity of the pathway and the modifiable events amenable to interventions, that could reduce mortality and morbidity, and optimize utilization of scarce critical care resources; as well as demonstrating the importance of continuity and quality of care.

English M, Karumbi J, Maina M, Aluvaala J, Gupta A, Zwarenstein M, Opiyo N. 2016. The need for pragmatic clinical trials in low and middle income settings - taking essential neonatal interventions delivered as part of inpatient care as an illustrative example. BMC Med, 14 (1), pp. 5. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Pragmatic randomized trials aim to examine the effects of interventions in the full spectrum of patients seen by clinicians who receive routine care. Such trials should be employed in parallel with efforts to implement many interventions which appear promising but where evidence of effectiveness is limited. We illustrate this need taking the case of essential interventions to reduce inpatient neonatal mortality in low and middle income countries (LMIC) but suggest the arguments are applicable in most clinical areas. DISCUSSION: A set of basic interventions have been defined, based on available evidence, that could substantially reduce early neonatal deaths if successfully implemented at scale within district and sub-district hospitals in LMIC. However, we illustrate that there remain many gaps in the evidence available to guide delivery of many inpatient neonatal interventions, that existing evidence is often from high income settings and that it frequently indicates uncertainty in the magnitude or even direction of estimates of effect. Furthermore generalizing results to LMIC where conditions include very high patient staff ratios, absence of even basic technologies, and a reliance on largely empiric management is problematic. Where there is such uncertainty over the effectiveness of interventions in different contexts or in the broad populations who might receive the intervention in routine care settings pragmatic trials that preserve internal validity while promoting external validity should be increasingly employed. Many interventions are introduced without adequate evidence of their effectiveness in the routine settings to which they are introduced. Global efforts are needed to support pragmatic research to establish the effectiveness in routine care of many interventions intended to reduce mortality or morbidity in LMIC. Such research should be seen as complementary to efforts to optimize implementation.

Fresnay S, McArthur MA, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM, Pollard AJ, Sztein MB. 2016. Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. J Transl Med, 14 (1), pp. 62. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.

Hodgson SH, Angus BJ. 2016. Malaria: fluid therapy in severe disease. BMJ Clin Evid, 2016 | Show Abstract

INTRODUCTION: Severe malaria mainly affects children aged under 5 years, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and may lead to neurological sequelae in survivors. Severe malarial anaemia may have a mortality rate of over 13%. The role of fluid resuscitation in severe malaria is complex and controversial. Volume expansion could help to improve impaired organ perfusion and correct metabolic acidosis. However, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What is the optimal method of fluid resuscitation in patients with severe malaria? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 187 studies. After deduplication and removal of conference abstracts, 93 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 82 studies and the further review of 11 full publications. Of the 11 full articles evaluated, two systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for seven PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of human albumin, intravenous fluids, and whole blood or plasma.

MalariaGEN Plasmodium falciparum Community Project. 2016. Genomic epidemiology of artemisinin resistant malaria. Elife, 5 (MARCH2016), | Citations: 21 (Scopus) | Show Abstract | Read more

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.

Pham Thanh D, Karkey A, Dongol S, Ho Thi N, Thompson CN, Rabaa MA, Arjyal A, Holt KE, Wong V, Tran Vu Thieu N et al. 2016. A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure. Elife, 5 (MARCH2016), pp. e14003. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure.

Kihuba E, Gheorghe A, Bozzani F, English M, Griffiths UK. 2016. Opportunities and challenges for implementing cost accounting systems in the Kenyan health system. Glob Health Action, 9 pp. 30621. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Low- and middle-income countries need to sustain efficiency and equity in health financing on their way to universal health care coverage. However, systems meant to generate quality economic information are often deficient in such settings. We assessed the feasibility of streamlining cost accounting systems within the Kenyan health sector to illustrate the pragmatic challenges and opportunities. DESIGN: We reviewed policy documents, and conducted field observations and semi-structured interviews with key informants in the health sector. We used an adapted Human, Organization and Technology fit (HOT-fit) framework to analyze the components and standards of a cost accounting system. RESULTS: Among the opportunities for a viable cost accounting system, we identified a supportive broad policy environment, political will, presence of a national data reporting architecture, good implementation experience with electronic medical records systems, and the availability of patient clinical and resource use data. However, several practical issues need to be considered in the design of the system, including the lack of a framework to guide the costing process, the lack of long-term investment, the lack of appropriate incentives for ground-level staff, and a risk of overburdening the current health management information system. CONCLUSION: To facilitate the implementation of cost accounting into the health sector, the design of any proposed system needs to remain simple and attuned to the local context.

Peto TJ, Tripura R, Lee SJ, Althaus T, Dunachie S, Nguon C, Dhorda M, Promnarate C, Chalk J, Imwong M et al. 2016. Association between Subclinical Malaria Infection and Inflammatory Host Response in a Pre-Elimination Setting. PLoS One, 11 (7), pp. e0158656. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Subclinical infections in endemic areas of Southeast Asia sustain malaria transmission. These asymptomatic infections might sustain immunity against clinical malaria and have been considered benign for the host, but if they are associated with chronic low-grade inflammation this could be harmful. We conducted a case-control study to explore the association between subclinical malaria and C-reactive protein (CRP), an established biomarker of inflammation. METHODS: Blood samples from asymptomatic villagers in Pailin, Western Cambodia were tested for malaria by high-volume ultra-sensitive polymerase chain reaction (uPCR) to determine the Plasmodium species. Plasma CRP concentration was measured in 328 individuals with parasitaemia (cases) and compared with: i) the same individual's value at the first time point when they had no detectable parasites (n = 282); and ii) age- sex- and village-matched controls (n = 328) free of Plasmodium infection. Plasma CRP concentrations were compared against thresholds of 3mg/L and 10mg/L. Subgroup analysis was carried out for cases with P vivax and P falciparum mono-infections. RESULTS: Median plasma CRP level for all samples was 0.59mg/L (interquartile range: 0.24-1.64mg/L). CRP concentrations were higher in parasitaemic individuals compared with same-person-controls (p = 0.050); and matched-controls (p = 0.025). 4.9% of samples had CRP concentrations above 10mg/L and 14.6% were above 3mg/L. Cases were more likely to have plasma CRP concentrations above these thresholds than age/sex matched controls, odds ratio 3.5 (95%CI 1.5-9.8) and 1.8 (95%CI 1.1-2.9), respectively. Amongst cases, parasite density and CRP were positively correlated (p<0.001), an association that remained significant when controlling for age and fever. Individuals with P.vivax mono-infections had the highest plasma CRP concentrations with the greatest association with parasitaemia. DISCUSSION: In this setting persistent malaria infections in asymptomatic individuals were associated with moderately elevated plasma CRP concentrations; chiefly evident in cases with P.vivax mono-infections. As well as interrupting malaria transmission within the community, treatment of asymptomatic malaria infections, in particular radical cure of vivax malaria, may benefit the health of infected individuals.

Dunning J, Kennedy SB, Antierens A, Whitehead J, Ciglenecki I, Carson G, Kanapathipillai R, Castle L, Howell-Jones R, Pardinaz-Solis R et al. 2016. Experimental Treatment of Ebola Virus Disease with Brincidofovir. PLoS One, 11 (9), pp. e0162199. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. METHODS AND FINDINGS: In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. CONCLUSIONS: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000939962.

Sigfrid L, Reusken C, Carson G, Koopmans M. 2016. Zika: structuring the European research response. ERJ Open Res, 2 (1), pp. 00025-2016-00025-2016. | Show Abstract | Read more

Studies are needed to assess #Zika virus risks and to develop diagnostic tests http://ow.ly/ZaOZw.

Kihuba E, Gheorghe A, Bozzani F, English M, Griffiths UK. 2016. Opportunities and challenges for implementing cost accounting systems in the Kenyan health system. Glob Health Action, 9 (1), pp. 30621. | Show Abstract | Read more

Background Low- and middle-income countries need to sustain efficiency and equity in health financing on their way to universal health care coverage. However, systems meant to generate quality economic information are often deficient in such settings. We assessed the feasibility of streamlining cost accounting systems within the Kenyan health sector to illustrate the pragmatic challenges and opportunities. Design We reviewed policy documents, and conducted field observations and semi-structured interviews with key informants in the health sector. We used an adapted Human, Organization and Technology fit (HOT-fit) framework to analyze the components and standards of a cost accounting system. Results Among the opportunities for a viable cost accounting system, we identified a supportive broad policy environment, political will, presence of a national data reporting architecture, good implementation experience with electronic medical records systems, and the availability of patient clinical and resource use data. However, several practical issues need to be considered in the design of the system, including the lack of a framework to guide the costing process, the lack of long-term investment, the lack of appropriate incentives for ground-level staff, and a risk of overburdening the current health management information system. Conclusion To facilitate the implementation of cost accounting into the health sector, the design of any proposed system needs to remain simple and attuned to the local context.

Enoch AJ, English M, Shepperd S. 2016. Does pulse oximeter use impact health outcomes? A systematic review. Arch Dis Child, 101 (8), pp. 694-700. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: Do newborns, children and adolescents up to 19 years have lower mortality rates, lower morbidity and shorter length of stay in health facilities where pulse oximeters are used to inform diagnosis and treatment (excluding surgical care) compared with health facilities where pulse oximeters are not used? DESIGN: Studies were obtained for this systematic literature review by systematically searching the Database of Abstracts of Reviews of Effects, Cochrane, Medion, PubMed, Web of Science, Embase, Global Health, CINAHL, WHO Global Health Library, international health organisation and NGO websites, and study references. PATIENTS: Children 0-19 years presenting for the first time to hospitals, emergency departments or primary care facilities. INTERVENTIONS: Included studies compared outcomes where pulse oximeters were used for diagnosis and/or management, with outcomes where pulse oximeters were not used. MAIN OUTCOME MEASURES: mortality, morbidity, length of stay, and treatment and management changes. RESULTS: The evidence is low quality and hypoxaemia definitions varied across studies, but the evidence suggests pulse oximeter use with children can reduce mortality rates (when combined with improved oxygen administration) and length of emergency department stay, increase admission of children with previously unrecognised hypoxaemia, and change physicians' decisions on illness severity, diagnosis and treatment. Pulse oximeter use generally increased resource utilisation. CONCLUSIONS: As international organisations are investing in programmes to increase pulse oximeter use in low-income settings, more research is needed on the optimal use of pulse oximeters (eg, appropriate oxygen saturation thresholds), and how pulse oximeter use affects referral and admission rates, length of stay, resource utilisation and health outcomes.

Ayieko P, Ogero M, Makone B, Julius T, Mbevi G, Nyachiro W, Nyamai R, Were F, Githanga D, Irimu G et al. 2016. Characteristics of admissions and variations in the use of basic investigations, treatments and outcomes in Kenyan hospitals within a new Clinical Information Network. Arch Dis Child, 101 (3), pp. 223-229. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Lack of detailed information about hospital activities, processes and outcomes hampers planning, performance monitoring and improvement in low-income countries (LIC). Clinical networks offer one means to advance methods for data collection and use, informing wider health system development in time, but are rare in LIC. We report baseline data from a new Clinical Information Network (CIN) in Kenya seeking to promote data-informed improvement and learning. METHODS: Data from 13 hospitals engaged in the Kenyan CIN between April 2014 and March 2015 were captured from medical and laboratory records. We use these data to characterise clinical care and outcomes of hospital admission. RESULTS: Data were available for a total of 30 042 children aged between 2 months and 15 years. Malaria (in five hospitals), pneumonia and diarrhoea/dehydration (all hospitals) accounted for the majority of diagnoses and comorbidity was found in 17 710 (59%) patients. Overall, 1808 deaths (6%) occurred (range per hospital 2.5%-11.1%) with 1037 deaths (57.4%) occurring by day 2 of admission (range 41%-67.8%). While malaria investigations are commonly done, clinical health workers rarely investigate for other possible causes of fever, test for blood glucose in severe illness or ascertain HIV status of admissions. Adherence to clinical guideline-recommended treatment for malaria, pneumonia, meningitis and acute severe malnutrition varied widely across hospitals. CONCLUSION: Developing clinical networks is feasible with appropriate support. Early data demonstrate that hospital mortality remains high in Kenya, that resources to investigate severe illness are limited, that care provided and outcomes vary widely and that adoption of effective interventions remains slow. Findings suggest considerable scope for improving care within and across sites.

Holmes AH, Moore LSP, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, Guerin PJ, Piddock LJV. 2016. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 387 (10014), pp. 176-187. | Citations: 128 (Web of Science Lite) | Show Abstract | Read more

To combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in microorganisms is a natural phenomenon, yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fitness cost, an effect not always apparent. Minimising resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the health-care, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials.

Kulsantiwong P, Pudla M, Boondit J, Wikraiphat C, Dunachie SJ, Chantratita N, Utaisincharoen P. 2016. Burkholderia pseudomallei induces IL-23 production in primary human monocytes. Med Microbiol Immunol, 205 (3), pp. 255-260. | Citations: 3 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei, a gram-negative intracellular bacterium, is a causative agent of melioidosis. The bacterium has been shown to induce the innate immune response, particularly pro-inflammatory cytokine production in several of both mouse and human cell types. In the present study, we investigate host immune response in B. pseudomallei-infected primary human monocytes. We discover that wild-type B. pseudomallei is able to survive and multiply inside the primary human monocytes. In contrast, B. pseudomallei LPS mutant, a less virulent strain, is susceptible to host killing during bacterial infection. Moreover, microarray result showed that wild-type B. pseudomallei but not B. pseudomallei LPS mutant is able to activate gene expression of IL-23 as demonstrated by the up-regulation of p19 and p40 subunit expression. Consistent with gene expression analysis, the secretion of IL-23 analyzed by ELISA also showed that wild-type B. pseudomallei induces a significantly higher level of IL-23 secretion than that of B. pseudomallei LPS mutant. These results implied that IL-23 may be an important cytokine for the innate immune response during B. pseudomallei infection. The regulation of IL-23 production may drive the different host innate immune responses between patients and may relate to the severity of melioidosis.

Tuti T, Bitok M, Paton C, Makone B, Malla L, Muinga N, Gathara D, English M. 2016. Innovating to enhance clinical data management using non-commercial and open source solutions across a multi-center network supporting inpatient pediatric care and research in Kenya. J Am Med Inform Assoc, 23 (1), pp. 184-192. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To share approaches and innovations adopted to deliver a relatively inexpensive clinical data management (CDM) framework within a low-income setting that aims to deliver quality pediatric data useful for supporting research, strengthening the information culture and informing improvement efforts in local clinical practice. MATERIALS AND METHODS: The authors implemented a CDM framework to support a Clinical Information Network (CIN) using Research Electronic Data Capture (REDCap), a noncommercial software solution designed for rapid development and deployment of electronic data capture tools. It was used for collection of standardized data from case records of multiple hospitals' pediatric wards. R, an open-source statistical language, was used for data quality enhancement, analysis, and report generation for the hospitals. RESULTS: In the first year of CIN, the authors have developed innovative solutions to support the implementation of a secure, rapid pediatric data collection system spanning 14 hospital sites with stringent data quality checks. Data have been collated on over 37 000 admission episodes, with considerable improvement in clinical documentation of admissions observed. Using meta-programming techniques in R, coupled with branching logic, randomization, data lookup, and Application Programming Interface (API) features offered by REDCap, CDM tasks were configured and automated to ensure quality data was delivered for clinical improvement and research use. CONCLUSION: A low-cost clinically focused but geographically dispersed quality CDM (Clinical Data Management) in a long-term, multi-site, and real world context can be achieved and sustained and challenges can be overcome through thoughtful design and implementation of open-source tools for handling data and supporting research.

Huong VTL, Thanh LV, Phu VD, Trinh DT, Inui K, Tung N, Oanh NTK, Trung NV, Hoa NT, Bryant JE et al. 2016. Temporal and spatial association of Streptococcus suis infection in humans and porcine reproductive and respiratory syndrome outbreaks in pigs in northern Vietnam. Epidemiol Infect, 144 (1), pp. 35-44. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Porcine reproductive and respiratory syndrome (PRRS) outbreaks in pigs are associated with increased susceptibility of pigs to secondary bacterial infections, including Streptococcus suis - an important zoonotic pathogen causing bacterial meningitis in humans. This case-control study examined the association between human S. suis infection and PRRS outbreaks in pigs in northern Vietnam. We included 90 S. suis case-patients and 183 non-S. suis sepsis controls from a referral hospital in Hanoi in 2010, a period of major PRRS epizootics in Vietnam. PRRS exposure was determined using data from the National Centre of Veterinary Diagnosis. By univariate analysis, significantly more S. suis patients were reported residing in or adjacent to a PRRS district compared to controls [odds ratio (OR) 2·82, 95% confidence interval (CI) 1·35-5·89 and OR 3·15, 95% CI 1·62-6·15, respectively]. Only residency in adjacent districts remained significantly associated with risk of S. suis infection after adjusting for sex, occupation, and eating practices. SaTScan analysis showed a possible cluster of S. suis infection in humans around PRRS confirmed locations during the March-August period. The findings indicate an epidemiological association between PRRS in pigs and S. suis infections in humans. Effective strategies to strengthen control of PRRS in pigs may help reduce transmission of S. suis infection to humans.

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