@Oxford Publications 2018

Rosala-Hallas A, Bhangu A, Blazeby J, Bowman L, Clarke M, Lang T, Nasser M, Siegfried N, Soares-Weiser K, Sydes MR et al. 2018. Global health trials methodological research agenda: results from a priority setting exercise. Trials, 19 (1), pp. 48. | Show Abstract | Read more

BACKGROUND: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. METHODS: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. FINDINGS: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. CONCLUSION: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Salam AP, Horby P. 2018. Isolation of viable Zika virus from spermatozoa. Lancet Infect Dis, 18 (2), pp. 144. | Read more

Zaka N, Alexander EC, Manikam L, Norman ICF, Akhbari M, Moxon S, Ram PK, Murphy G, English M, Niermeyer S, Pearson L. 2018. Quality improvement initiatives for hospitalised small and sick newborns in low- and middle-income countries: a systematic review. Implement Sci, 13 (1), pp. 20. | Show Abstract | Read more

BACKGROUND: An estimated 2.6 million newborns died in 2016; over 98.5% of deaths occurred in low- and middle-income countries (LMICs). Neonates born preterm and small for gestational age are particularly at risk given the high incidence of infectious complications, cardiopulmonary, and neurodevelopmental disorders in this group. Quality improvement (QI) initiatives can reduce the burden of mortality and morbidity for hospitalised newborns in these settings. We undertook a systematic review to synthesise evidence from LMICs on QI approaches used, outcome measures employed to estimate effects, and the nature of implementation challenges. METHODS: We searched Medline, EMBASE, WHO Global Health Library, Cochrane Library, WHO ICTRP, and ClinicalTrials.gov and scanned the references of identified studies and systematic reviews. Searches covered January 2000 until April 2017. Search terms were "quality improvement", "newborns", "hospitalised", and their derivatives. Studies were excluded if they took place in high-income countries, did not include QI interventions, or did not include small and sick hospitalised newborns. Cochrane Risk of Bias tools were used to quality appraise the studies. RESULTS: From 8110 results, 28 studies were included, covering 23 LMICs and 65,642 participants. Most interventions were meso level (district and clinic level); fewer were micro (patient-provider level) or macro (above district level). In-service training was the most common intervention subtype; service organisation and distribution of referencing materials were also frequently identified. The most commonly assessed outcome was mortality, followed by length of admission, sepsis rates, and infection rates. Key barriers to implementation of quality improvement initiatives included overburdened staff and lack of sufficient equipment. CONCLUSIONS: The frequency of meso level, single centre, and educational interventions suggests that these interventions may be easier for programme planners to implement. The success of some interventions in reducing morbidity and mortality rates suggests that QI approaches have a high potential for benefit to newborns. Going forward, there are opportunities to strengthen the focus of QI initiatives and to develop improved, larger-scale, collaborative research into implementation of quality improvement initiatives for this high-risk group. TRIAL REGISTRATION: PROSPERO CRD42017055459 .

Harvala H, Broberg E, Benschop K, Berginc N, Ladhani S, Susi P, Christiansen C, McKenna J, Allen D, Makiello P et al. 2018. Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. J Clin Virol, 101 pp. 11-17. | Show Abstract | Read more

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden.

Agweyu A, Lilford RJ, English M, Clinical Information Network Author Group. 2018. Appropriateness of clinical severity classification of new WHO childhood pneumonia guidance: a multi-hospital, retrospective, cohort study. Lancet Glob Health, 6 (1), pp. e74-e83. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Management of pneumonia in many low-income and middle-income countries is based on WHO guidelines that classify children according to clinical signs that define thresholds of risk. We aimed to establish whether some children categorised as eligible for outpatient treatment might have a risk of death warranting their treatment in hospital. METHODS: We did a retrospective cohort study of children aged 2-59 months admitted to one of 14 hospitals in Kenya with pneumonia between March 1, 2014, and Feb 29, 2016, before revised WHO pneumonia guidelines were adopted in the country. We modelled associations with inpatient mortality using logistic regression and calculated absolute risks of mortality for presenting clinical features among children who would, as part of revised WHO pneumonia guidelines, be eligible for outpatient treatment (non-severe pneumonia). FINDINGS: We assessed 16 162 children who were admitted to hospital in this period. 832 (5%) of 16 031 children died. Among groups defined according to new WHO guidelines, 321 (3%) of 11 788 patients with non-severe pneumonia died compared with 488 (14%) of 3434 patients with severe pneumonia. Three characteristics were strongly associated with death of children retrospectively classified as having non-severe pneumonia: severe pallor (adjusted risk ratio 5·9, 95% CI 5·1-6·8), mild to moderate pallor (3·4, 3·0-3·8), and weight-for-age Z score (WAZ) less than -3 SD (3·8, 3·4-4·3). Additional factors that were independently associated with death were: WAZ less than -2 to -3 SD, age younger than 12 months, lower chest wall indrawing, respiratory rate of 70 breaths per min or more, female sex, admission to hospital in a malaria endemic region, moderate dehydration, and an axillary temperature of 39°C or more. INTERPRETATION: In settings of high mortality, WAZ less than -3 SD or any degree of pallor among children with non-severe pneumonia was associated with a clinically important risk of death. Our data suggest that admission to hospital should not be denied to children with these signs and we urge clinicians to consider these risk factors in addition to WHO criteria in their decision making. FUNDING: Wellcome Trust.

Rono MK, Nyonda MA, Simam JJ, Ngoi JM, Mok S, Kortok MM, Abdullah AS, Elfaki MM, Waitumbi JN, El-Hassan IM et al. 2018. Adaptation of Plasmodium falciparum to its transmission environment. Nat Ecol Evol, 2 (2), pp. 377-387. | Show Abstract | Read more

Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control.

Huong VTL, Long HB, Kinh NV, Ngan TTD, Dung VTV, Nadjm B, van Doorn HR, Hoa NT, Horby P, Wertheim HFL. 2018. Long-term outcomes of patients with Streptococcus suis infection in Viet Nam: A case-control study. J Infect, 76 (2), pp. 159-167. | Show Abstract | Read more

OBJECTIVES: Streptococcus suis is a zoonotic cause of severe meningitis and sepsis in humans. We aimed to assess the long-term outcomes in patients who survived S. suis infection, in particular the progress and impact of vestibulocochlear sequelae. METHODS: This case-control study evaluated outcomes of S. suis infection at discharge and 3 and 9 months post-discharge for 47 prospectively enrolled cases and at 11-34 months for 31 retrospectively enrolled cases. Outcomes in patients were compared to 270 controls matched for age, sex and residency. RESULTS: The prevalence ratio (PR) of moderate-to-complete hearing loss was 5.0(95%CI 3.6-7.1) in cases at discharge, 3.7(2.5-5.4) at 3 months, 3.2(2.2-4.7) at 9 months, and 3.1(2.1-4.4) in retrospective cases compared to controls. Hearing improvement occurred mostly within the first 3 months with a change in hearing level of 11.1%(95%CI 7.0-15.1%) compared to discharge. The PR of vestibular dysfunction was 2.4(95%CI 1.7-3.3) at discharge, 2.2(1.4-3.1) at 3 months, 1.8(1.1-2.5) at 9 months, and 1.8(1.1-2.6) for retrospective cases compared to controls. Cases also indicated more problems with mobility, self-care and usual activities. CONCLUSIONS: Both hearing and vestibular impairment were common and persist in cases. Appropriate patient management strategies are needed to reduce the incidence and impact of these sequelae.

Ssewanyana D, Mwangala PN, Marsh V, Jao I, van Baar A, Newton CR, Abubakar A. 2018. Young people's and stakeholders' perspectives of adolescent sexual risk behavior in Kilifi County, Kenya: A qualitative study. J Health Psychol, 23 (2), pp. 188-205. | Show Abstract | Read more

A lack of research exists around the most common forms of sexual risk behaviors among adolescents, including their underlying factors, in Sub-Saharan Africa. Using an Ecological Model of Adolescent Behavior, we explore the perceptions of 85 young people and 10 stakeholders on sexual risk behavior of adolescents in Kilifi County on the coast of Kenya. Our findings show that transactional sex, early sexual debut, coerced sex, and multiple sexual partnerships are prevalent. An urgent need exists to develop measures to counter sexual risk behaviors. The results contribute to understanding the range of risks and protective factors in differing contexts, tackling underlying issues at individual, family, local institutional, wider socio-economic, and political levels.

Akech S, Rotich B, Chepkirui M, Ayieko P, Irimu G, English M. 2018. The Prevalence and Management of Dehydration amongst Neonatal Admissions to General Paediatric Wards in Kenya-A Clinical Audit. J Trop Pediatr, | Show Abstract | Read more

An audit of randomly selected case records of 810 patients admitted to 13 hospitals between December 2015 and November 2016 was done. Prevalence of dehydration was 19.7% (2293 of 11 636) [95% CI: 17.1-22.6%], range across hospitals was 9.4% to 27.0%. Most cases with dehydration were clinically diagnosed (82 of 153; 53.6%), followed by excessive weight loss (54 of 153; 35.3%) and abnormal urea/electrolytes/creatinine (23 of 153; 15.0%). Documentation of fluids prescribed was poor but, where data were available, Ringers lactate (30 of 153; 19.6%) and 10% dextrose (18 of 153; 11.8%) were mostly used. Only 17 of 153 (11.1%) children had bolus fluid prescription, and Ringer's lactate was most commonly used for bolus at a median volume per kilogram body weight of 20 ml/kg (interquartile range, 12-30 ml/kg). Neonatal dehydration is common, but current documentation may underestimate the burden. Heterogeneity in practice likely reflects the absence of guidelines that in turn reflects a lack of research informing practical treatment guidelines.

Opondo C, Allen E, Todd J, English M. 2018. Association of the Paediatric Admission Quality of Care score with mortality in Kenyan hospitals: a validation study. Lancet Glob Health, 6 (2), pp. e203-e210. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Measuring the quality of hospital admission care is essential to ensure that standards of practice are met and continuously improved to reduce morbidity and mortality associated with the illnesses most responsible for inpatient deaths. The Paediatric Admission Quality of Care (PAQC) score is a tool for measuring adherence to guidelines for children admitted with acute illnesses in a low-income setting. We aimed to explore the external and criterion-related validity of the PAQC score by investigating its association with mortality using data drawn from a diverse sample of Kenyan hospitals. METHODS: We identified children admitted to Kenyan hospitals for treatment of malaria, pneumonia, diarrhoea, or dehydration from datasets from three sources: an observational study, a clinical trial, and a national cross-sectional survey. We extracted variables describing the process of care provided to patients at admission and their eventual outcomes from these data. We applied the PAQC scoring algorithm to the data to obtain a quality-of-care score for each child. We assessed external validity of the PAQC score by its systematic replication in datasets that had not been previously used to investigate properties of the PAQC score. We assessed criterion-related validity by using hierarchical logistic regression to estimate the association between PAQC score and the outcome of mortality, adjusting for other factors thought to be predictive of the outcome or responsible for heterogeneity in quality of care. FINDINGS: We found 19 065 eligible admissions in the three validation datasets that covered 27 hospitals, of which 12 969 (68%) were complete cases. Greater guideline adherence, corresponding to higher PAQC scores, was associated with a reduction in odds of death across the three datasets, ranging between 9% (odds ratio 0·91, 95% CI 0·84-0·99; p=0·031) and 30% (0·70, 0·63-0·78; p<0·0001) adjusted reduction per unit increase in the PAQC score, with a pooled estimate of 17% (0·83, 0·78-0·89; p<0·0001). These findings were consistent with a multiple imputation analysis that used information from all observations in the combined dataset. INTERPRETATION: The PAQC score, designed as an index of the technical quality of care for the three commonest causes of admission in children, is also associated with mortality. This finding suggests that it could be a meaningful summary measure of the quality of care for common inpatient conditions and supports a link between process quality and outcome. It might have potential for application in low-income countries with similar disease profiles and in which paediatric practice recommendations are based on WHO guidelines. FUNDING: The Wellcome Trust.

Ouma PO, Maina J, Thuranira PN, Macharia PM, Alegana VA, English M, Okiro EA, Snow RW. 2018. Access to emergency hospital care provided by the public sector in sub-Saharan Africa in 2015: a geocoded inventory and spatial analysis. Lancet Glob Health, | Show Abstract | Read more

BACKGROUND: Timely access to emergency care can substantially reduce mortality. International benchmarks for access to emergency hospital care have been established to guide ambitions for universal health care by 2030. However, no Pan-African database of where hospitals are located exists; therefore, we aimed to complete a geocoded inventory of hospital services in Africa in relation to how populations might access these services in 2015, with focus on women of child bearing age. METHODS: We assembled a geocoded inventory of public hospitals across 48 countries and islands of sub-Saharan Africa, including Zanzibar, using data from various sources. We only included public hospitals with emergency services that were managed by governments at national or local levels and faith-based or non-governmental organisations. For hospital listings without geographical coordinates, we geocoded each facility using Microsoft Encarta (version 2009), Google Earth (version 7.3), Geonames, Fallingrain, OpenStreetMap, and other national digital gazetteers. We obtained estimates for total population and women of child bearing age (15-49 years) at a 1 km2 spatial resolution from the WorldPop database for 2015. Additionally, we assembled road network data from Google Map Maker Project and OpenStreetMap using ArcMap (version 10.5). We then combined the road network and the population locations to form a travel impedance surface. Subsequently, we formulated a cost distance algorithm based on the location of public hospitals and the travel impedance surface in AccessMod (version 5) to compute the proportion of populations living within a combined walking and motorised travel time of 2 h to emergency hospital services. FINDINGS: We consulted 100 databases from 48 sub-Saharan countries and islands, including Zanzibar, and identified 4908 public hospitals. 2701 hospitals had either full or partial information about their geographical coordinates. We estimated that 287 282 013 (29·0%) people and 64 495 526 (28·2%) women of child bearing age are located more than 2-h travel time from the nearest hospital. Marked differences were observed within and between countries, ranging from less than 25% of the population within 2-h travel time of a public hospital in South Sudan to more than 90% in Nigeria, Kenya, Cape Verde, Swaziland, South Africa, Burundi, Comoros, São Tomé and Príncipe, and Zanzibar. Only 16 countries reached the international benchmark of more than 80% of their populations living within a 2-h travel time of the nearest hospital. INTERPRETATION: Physical access to emergency hospital care provided by the public sector in Africa remains poor and varies substantially within and between countries. Innovative targeting of emergency care services is necessary to reduce these inequities. This study provides the first spatial census of public hospital services in Africa. FUNDING: Wellcome Trust and the UK Department for International Development.

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