@Oxford Publications 2017
INTRODUCTION: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). METHODS: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. RESULTS: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos inex vivoElispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. CONCLUSIONS: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. CLINICAL TRIALS REGISTRATION: NCT01024842.
BACKGROUND: Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. METHODS: Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). RESULTS: Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. CONCLUSION: Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed.
The ongoing Zika virus (ZIKV) outbreak in Latin America, the Caribbean, and the Pacific Islands has underlined the need for a coordinated research network across the whole region that can respond rapidly to address the current knowledge gaps in Zika and enhance research preparedness beyond Zika. The European Union under its Horizon 2020 Research and Innovation Programme awarded three research consortia to respond to this need. Here we present the ZikaPLAN (Zika Preparedness Latin American Network) consortium. ZikaPLAN combines the strengths of 25 partners in Latin America, North America, Africa, Asia, and various centers in Europe. We will conduct clinical studies to estimate the risk and further define the full spectrum and risk factors of congenital Zika virus syndrome (including neurodevelopmental milestones in the first 3 years of life), delineate neurological complications associated with ZIKV due to direct neuroinvasion and immune-mediated responses in older children and adults, and strengthen surveillance for birth defects and Guillain-Barré Syndrome. Laboratory-based research to unravel neurotropism and investigate the role of sexual transmission, determinants of severe disease, and viral fitness will underpin the clinical studies. Social messaging and engagement with affected communities, as well as development of wearable repellent technologies against Aedes mosquitoes will enhance the impact. Burden of disease studies, data-driven vector control, and vaccine modeling as well as risk assessments on geographic spread of ZIKV will form the foundation for evidence-informed policies. While addressing the research gaps around ZIKV, we will engage in capacity building in laboratory and clinical research, collaborate with existing and new networks to share knowledge, and work with international organizations to tackle regulatory and other bottlenecks and refine research priorities. In this way, we can leverage the ZIKV response toward building a long-term emerging infectious diseases response capacity in the region to address future challenges.
BACKGROUND: There is no agreed standard method to assess the efficacy of anti-malarials for uncomplicated falciparum in pregnancy despite an increased risk of adverse outcomes for the mother and the fetus. The aim of this review is to present the currently available evidence from both observational and interventional cohort studies on anti-malarial efficacy in pregnancy and summarize the variability of assessment and reporting found in the review process. METHODS: Efficacy methodology and assessment of artemisinin-based treatments (ABT) and quinine-based treatments (QBT) were reviewed systematically using seven databases and two clinical trial registries (protocol registration-PROSPERO: CRD42017054808). Pregnant women in all trimesters with parasitologically confirmed uncomplicated falciparum malaria were included irrespective of symptoms. This review attempted to re-calculate proportions of treatment success applying the same definition as the standard WHO methodology for non-pregnant populations. Aggregated data meta-analyses using data from randomized control trials (RCTs) comparing different treatments were performed by random effects model. RESULTS: A total of 48 eligible efficacy studies were identified including 7279 treated Plasmodium falciparum episodes. While polymerase chain reaction (PCR) was used in 24 studies for differentiating recurrence, the assessment and reporting of treatment efficacy was heterogeneous. When the same definition could be applied, PCR-corrected treatment failure of ≥ 10% at any time points was observed in 3/30 ABT and 3/7 QBT arms. Ten RCTs compared different combinations of ABT but there was a maximum of two published RCTs with PCR-corrected outcomes for each comparison. Five RCTs compared ABT and QBT. Overall, the risk of treatment failure was significantly lower in ABT than in QBT (risk ratio 0.22, 95% confidence interval 0.07-0.63), although the actual drug combinations and outcome endpoints were different. First trimester women were included in 12 studies none of which were RCTs of ABT. CONCLUSIONS: Efficacy studies in pregnancy are not only limited in number but use varied methodological assessments. In five RCTs with comparable methodology, ABT resulted in higher efficacy than QBT in the second and third trimester of pregnancy. Individual patient data meta-analysis can include data from observational cohort studies and could overcome some of the limitations of the current assessment given the paucity of data in this vulnerable group.
BACKGROUND: Treatment intensity scores can predict mortality and estimate resource use. They may therefore be of interest for essential neonatal care in low resource settings where neonatal mortality remains high. We sought to systematically review neonatal treatment intensity scores to (1) assess the level of evidence on predictive performance in predicting clinical outcomes and estimating resource utilisation and (2) assess the applicability of the identified models to decision making for neonatal care in low resource settings. METHODS: We conducted a systematic search of PubMed, EMBASE (OVID), CINAHL, Global Health Library (Global index, WHO) and Google Scholar to identify studies published up until 21 December 2016. Included were all articles that used treatments as predictors in neonatal models. Individual studies were appraised using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS). In addition, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used as a guiding framework to assess certainty in the evidence for predicting outcomes across studies. RESULTS: Three thousand two hundred forty-nine articles were screened, of which ten articles were included in the review. All of the studies were conducted in neonatal intensive care units with sample sizes ranging from 22 to 9978, with a median of 163. Two articles reported model development, while eight reported external application of existing models to new populations. Meta-analysis was not possible due heterogeneity in the conduct and reporting of the identified studies. Discrimination as assessed by area under receiver operating characteristic curve was reported for in-hospital mortality, median 0.84 (range 0.75-0.96, three studies), early adverse outcome and late adverse outcome (0.78 and 0.59, respectively, one study). CONCLUSION: Existing neonatal treatment intensity models show promise in predicting mortality and morbidity. There is however low certainty in the evidence on their performance in essential neonatal care in low resource settings as all studies had methodological limitations and were conducted in intensive care. The approach may however be developed further for low resource settings like Kenya because treatment data may be easier to obtain compared to measures of physiological status. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016034205.
It is widely accepted that healthcare-seeking behaviour is neither limited to nor terminated by access to one single healthcare provider. Yet the sequential conceptualisation of healthcare-seeking processes has not diffused into quantitative research, which continues to analyse healthcare access as a "one-off" event. The ensuing lack of understanding healthcare behaviour is problematic in light of the immense burden of premature death especially in low- and middle-income countries. This paper presents an alternative approach. Based on a novel survey instrument, we analyse original survey data from rural India and China that contain 119 unique healthcare pathways among 637 respondents. We offer three applications of how such sequential data can be analysed to enhance our understanding of people's health behaviour. First, descriptive analysis of sequential data enables more a comprehensive representation of people's health behaviours, for example the time spent in various healthcare activities, common healthcare pathways across different groups, or shifts in healthcare provider access during a typical illness. Second, by analysing the effect of mobile technology on healthcare-seeking process characteristics, we demonstrate that conventional, sequence-insensitive indicators are potentially inconsistent and misleading approximations when compared to a more precise, sequence-sensitive measure. Third, we describe how sequential data enable transparent and flexible evaluations of people's healthcare behaviour. The example of a sequence-insensitive evaluation suggests that household wealth has no statistical link to an illustrative "ideal" form of public healthcare utilisation. In contrast, sequence-sensitive evaluations demonstrate that household wealth is associated with an increased likelihood of bypassing referral processes and approaching unregulated and costly informal and private practitioners before accessing a public clinic. Sequential data therefore do not only reveal otherwise neglected locational idiosyncrasies, but they also yield deeper insights into the drivers of people's health behaviours compared to a conventional approach to "access to healthcare."
We explain social and organisational processes influencing health professionals in a Kenyan clinical network to implement a form of quality improvement (QI) into clinical practice, using the concept of 'pastoral practices'. Our qualitative empirical case study, conducted in 2015-16, shows the way practices constructing and linking local evidence-based guidelines and data collection processes provided a foundation for QI. Participation in these constructive practices gave network leaders pastoral status to then inscribe use of evidence and data into routine care, through championing, demonstrating, supporting and mentoring, with the support of a constellation of local champions. By arranging network meetings, in which the professional community discussed evidence, data, QI and professionalism, network leaders also facilitated the reconstruction of network members' collective professional identity. This consequently strengthened top-down and lateral accountability and inspection practices, disciplining evidence and audit-based QI in local hospitals. By explaining pastoral practices in this way and setting, we contribute to theory about governmentality in health care and extend Foucauldian analysis of QI, clinical networks and governance into low and middle income health care contexts.
The first Phase II and III clinical trials for treatments for Ebola Virus Disease were conducted during the west Africa (2013-16) outbreak. We report the operational practicalities of conducting a phase II clinical trial of TKM-130803 to international standards during this outbreak.
OBJECTIVES: Kenyan guidelines for antibiotic treatment of pneumonia recommended treatment of pneumonia characterised by indrawing with injectable penicillin alone in inpatient settings until early 2016. At this point, they were revised becoming consistent with WHO guidance after results of a Kenyan trial provided further evidence of equivalence of oral amoxicillin and injectable penicillin. This change also made possible use of oral amoxicillin for outpatient treatment in this patient group. However, given non-trivial mortality in Kenyan children with indrawing pneumonia, it remained possible they would benefit from a broader spectrum antibiotic regimen. Therefore, we compared the effectiveness of injectable penicillin monotherapy with a regimen combining penicillin with gentamicin. SETTING: We used a large routine observational dataset that captures data on all admissions to 13 Kenyan county hospitals. PARTICIPANTS AND MEASURES: The analyses included children aged 2-59 months. Selection of study population was based on inclusion criteria typical of a prospective trial, primary analysis (experiment 1, n=4002), but we also explored more pragmatic inclusion criteria (experiment 2, n=6420) as part of a secondary analysis. To overcome the challenges associated with the non-random allocation of treatments and missing data, we used propensity score (PS) methods and multiple imputation to minimise bias. Further, we estimated mortality risk ratios using log binomial regression and conducted sensitivity analyses using an instrumental variable and PS trimming. RESULTS: The estimated risk of dying, in experiment 1, in those receiving penicillin plus gentamicin was 1.46 (0.85 to 2.43) compared with the penicillin monotherapy group. In experiment 2, the estimated risk was 1.04(0.76 to 1.40). CONCLUSION: There is no statistical difference in the treatment of indrawing pneumonia with either penicillin or penicillin plus gentamicin. By extension, it is unlikely that treatment with penicillin plus gentamicin would offer an advantage to treatment with oral amoxicillin.
Universal access to quality newborn health services will be essential to meeting specific Sustainable Development Goals to reduce neonatal and overall child mortality. Data for decision making are crucial for planning services and monitoring progress in these endeavours. However, gaps in local population-level and facility-based data hinder estimation of health service requirements for effective planning in many low-income and middle-income settings. We worked with local policy makers and experts in Nairobi City County, an area with a population of four million and the highest neonatal mortality rate amongst counties in Kenya, to address this gap, and developed a systematic approach to use available data to support policy and planning. We developed a framework to identify major neonatal conditions likely to require inpatient neonatal care and identified estimates of incidence through literature review and expert consultation, to give an overall estimate for the year 2017 of the need for inpatient neonatal care, taking account of potential comorbidities. Our estimates suggest that almost 1 in 5 newborns (183/1000 live births) in Nairobi City County may need inpatient care, resulting in an estimated 24 161 newborns expected to require care in 2017. Our approach has been well received by local experts, who showed a willingness to work together and engage in the use of evidence in healthcare planning. The process highlighted the need for co-ordinated thinking on admission policy and referral care especially in a pluralistic provider environment helping build further appetite for data-informed decision making.
BACKGROUND: Childhood pneumonia is the leading infectious cause of mortality in children younger than 5 years old. Recent updates to World Health Organization pneumonia guidelines recommend outpatient care for a population of children previously classified as high risk. This revision has been challenged by policymakers in Africa, where mortality related to pneumonia is higher than in other regions and often complicated by comorbidities. This study aimed to identify factors that best discriminate inpatient mortality risk in non-severe pneumonia and explore whether these factors offer any added benefit over the current criteria used to identify children with pneumonia requiring inpatient care. METHODS: We undertook a retrospective cohort study of children aged 2-59 months admitted with a clinical diagnosis of pneumonia at 14 public hospitals in Kenya between February 2014 and February 2016. Using machine learning techniques, we analysed whether clinical characteristics and common comorbidities increased the risk of inpatient mortality for non-severe pneumonia. The topmost risk factors were subjected to decision curve analysis to explore if using them as admission criteria had any net benefit above the current criteria. RESULTS: Out of 16,162 children admitted with pneumonia during the study period, 10,687 were eligible for subsequent analysis. Inpatient mortality within this non-severe group was 252/10,687 (2.36%). Models demonstrated moderately good performance; the partial least squares discriminant analysis model had higher sensitivity for predicting mortality in comparison to logistic regression. Elevated respiratory rate (≥70 bpm), age 2-11 months and weight-for-age Z-score (WAZ) < -3SD were highly discriminative of mortality. These factors ranked consistently across the different models. For a risk threshold probability of 7-14%, there is a net benefit to admitting the patient sub-populations with these features as additional criteria alongside those currently used to classify severe pneumonia. Of the population studied, 70.54% met at least one of these criteria. Sensitivity analyses indicated that the overall results were not significantly affected by variations in pneumonia severity classification criteria. CONCLUSIONS: Children with non-severe pneumonia aged 2-11 months or with respiratory rate ≥ 70 bpm or very low WAZ experience risks of inpatient mortality comparable to severe pneumonia. Inpatient care is warranted in these high-risk groups of children.
© 2017, Centers for Disease Control and Prevention (CDC). All rights reserved. Zika virus RNA is frequently detected in the semen of men after Zika virus infection. To learn more about persistence of viruses in genital fluids, we searched PubMed for relevant articles. We found evidence that 27 viruses, across a broad range of virus families, can be found in human semen.
BACKGROUND: Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period. METHODS: We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms. RESULTS: Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates. CONCLUSIONS: Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy.
BACKGROUND: Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)'s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance. METHODOLOGY: We performed a systematic literature review to identify studies concluding after 2000 that collected IPD suitable for estimating drug efficacy against STH. We included studies that administered a variety of anthelmintics with follow ups less than 60 days after treatment. We estimated the number of IPD and extracted cohort- and study-level meta-data. PRINCIPAL FINDINGS: We estimate that there exist individual data on approximately 35,000 participants from 129 studies conducted in 39 countries, including 34 out of 103 countries where PCT is recommended. We find significant heterogeneity in diagnostic methods, times of outcome assessment, and the reported measure of efficacy. We also quantify cohorts comprising pre-school age children, pregnant women, and co-infected participants, including with HIV. CONCLUSIONS: We argue that establishing a global IPD repository would improve the capacity to monitor and evaluate the efficacy of anthelmintic drugs, respond to changes and safeguard the ongoing effectiveness of PCT. Establishing a fair, transparent data governance policy will be key for the engagement of the global STH community.
OBJECTIVE: We compared characteristics and outcomes of children enrolled in a randomized controlled trial (RCT) comparing oral amoxicillin and benzyl penicillin for the treatment of chest indrawing pneumonia versus children who received routine care to determine the external validity of the trial results. STUDY DESIGN AND SETTING: We undertook a retrospective cohort study of children aged 2 - 59 months admitted in six Kenyan hospitals. Data for non-trial participants were extracted from inpatient records upon conclusion of the RCT. Mortality among trial versus non-trial participants was compared in multivariate models. RESULTS: 1709 children were included, of whom 527 were enrolled in the RCT and 1182 received routine care. History of a wheeze was more common among trial participants (35.4% versus 11.2%; p<0.01), while dehydration was more common among non-trial participants (8.6% versus 5.9%; p=0.05). Other patient characteristics were balanced between the two groups. Among those with available outcome data, 14/1140 (1.2%) non-trial participants died compared to 4/527 (0.8%) enrolled in the trial (adjusted odds ratio 0.7; 95% confidence interval 0.2 to 2.1). CONCLUSION: Patient characteristics were similar and mortality was low among trial and non-trial participants. These findings support the revised World Health Organization treatment recommendations for chest indrawing pneumonia.
AIM: There are 2.7 million neonatal deaths annually, 75% of which occur in sub-Saharan Africa and South Asia. Effective treatment of hypoxaemia through tailored oxygen therapy could reduce neonatal mortality and prevent oxygen toxicity. METHODS: We undertook a two-part prospective study of neonates admitted to a neonatal unit in Nairobi, Kenya, between January and December 2015. We determined the prevalence of hypoxaemia and explored associations of clinical risk factors and signs of respiratory distress with hypoxaemia and mortality. After staff training on oxygen saturation (SpO2 ) target ranges, we enrolled a consecutive sample of neonates admitted for oxygen and measured SpO2 at 0, 6, 12, 18 and 24 h post-admission. We estimated the proportion of neonates outside the target range (≥34 weeks: ≥92%; <34 weeks: 89-93%) with 95% confidence intervals (CIs). RESULTS: A total of 477 neonates were enrolled. Prevalence of hypoxaemia was 29.2%. Retractions (odds ratio (OR) 2.83, 95% CI 1.47-5.47), nasal flaring (OR 2.68, 95% CI 1.51-4.75), and grunting (OR 2.47, 95% CI 1.27-4.80) were significantly associated with hypoxaemia. Nasal flaring (OR 2.85, 95% CI 1.25-6.54), and hypoxaemia (OR 3.06, 95% CI 1.54-6.07) were significantly associated with mortality; 64% of neonates receiving oxygen were out of range at ≥2 time points and 43% at ≥3 time points. CONCLUSION: There is a high prevalence of hypoxaemia at admission and a strong association between hypoxaemia and mortality in this Kenyan neonatal unit. Many neonates had out of range SpO2 values while receiving oxygen. Further research is needed to test strategies aimed at improving the accuracy of oxygen provision in low-resource settings.
A detailed understanding of the human infectious reservoir is essential for improving malaria transmission-reducing interventions. Here we report a multi-regional assessment of population-wide malaria transmission potential based on 1209 mosquito feeding assays in endemic areas of Burkina Faso and Kenya. Across both sites, we identified 39 infectious individuals. In high endemicity settings, infectious individuals were identifiable by research-grade microscopy (92.6%; 25/27), whilst one of three infectious individuals in the lowest endemicity setting was detected by molecular techniques alone. The percentages of infected mosquitoes in the different surveys ranged from 0.05 (4/7716) to 1.6% (121/7749), and correlate positively with transmission intensity. We also estimated exposure to malaria vectors through genetic matching of blood from 1094 wild-caught bloodfed mosquitoes with that of humans resident in the same houses. Although adults transmitted fewer parasites to mosquitoes than children, they received more mosquito bites, thus balancing their contribution to the infectious reservoir.
The Kaplan-Meier (K-M) method is currently the preferred approach to derive an efficacy estimate from anti-malarial trial data. In this approach event times are assumed to be continuous and estimates are generated on the assumption that there is only one cause of failure. In reality, failures are captured at pre-scheduled time points and patients can fail treatment due to a variety of causes other than the primary endpoint, commonly termed competing risk events. Ignoring these underlying assumptions can potentially distort the derived efficacy estimates and result in misleading conclusions. This review details the evolution of statistical methods used to derive anti-malarial efficacy for uncomplicated Plasmodium falciparum malaria and assesses the limitations of the current practices. Alternative approaches are explored and their implementation is discussed using example data from a large multi-site study.
Strongyloidiasis is a neglected tropical disease caused by the roundworm Strongyloides stercoralis affecting 30-100 million people worldwide. Many Southeast-Asian countries report a high prevalence of S. stercoralis infection, but there are little data from Vietnam. Here, we evaluated the seroprevalence of S. stercoralis related to geography, sex and age in Vietnam through serological testing of anonymized sera. Sera (n = 1710, 1340 adults and 270 children) from an anonymized age-stratified serum bank from four regions in Vietnam between 2012 and 2013 were tested using a commercial Strongyloides ratti immunoglobulin G ELISA. Seroreactivity was found in 29·1% (390/1340) of adults and 5·5% (15/270) of children. Male adults were more frequently seroreactive than females (33·3% vs. 24·9%, P = 0·001). The rural central highlands had the highest seroprevalence (42·4% of adults). Seroreactivity in the other regions was 29·9% (Hue) and 26·0% and 18·2% in the large urban centres of Hanoi and Ho Chi Minh City, respectively. We conclude that seroprevalence of S. stercoralis was high in the Vietnamese adult population, especially in rural areas.
OBJECTIVES: In 2013, the WHO stated that unless low-income and middle-income countries (LMICs) become producers of research, health goals would be hard to achieve. Among the capacities required to build a local evidence base, ability to conduct clinical trials is important. There is no evidence-based guidance for the best ways to develop locally led trial capacity. This research aims to identify the barriers and enablers to locally led clinical trial conduct in LMICs and determine strategies for their sustainable development. DESIGN: Prospective, multiple case study design consisting of interviews (n=34), focus group discussions (n=13) and process mapping exercises (n=10). SETTING: Case studies took place in Ethiopia (2011), Cameroon (2012) and Sri Lanka (2013). PARTICIPANTS: Local health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were purposively selected through registration searches and snowball sampling (n=100). PRIMARY AND SECONDARY OUTCOME MEASURES: Discussion notes and transcripts were analysed using thematic coding analysis. Key themes and mechanisms were identified. RESULTS: Institutions and individuals were variably successful at conducting trials, but there were strong commonalities in the barriers and enablers across all levels and functions of the research systems. Transferable mechanisms were summarised into the necessary conditions for trial undertaking, which included: awareness of research, motivation, knowledge and technical skills, leadership capabilities, forming collaborations, inclusive trial operations, policy relevance and uptake and macro and institutional strengthening. CONCLUSIONS: Barriers and enablers to locally led trial undertaking exist at all levels and functions of LMIC research systems. Establishing the necessary conditions to facilitate this research will require multiple, coordinated interventions that seek to resolve them in a systemic manner. The strategies presented in the discussion provide an evidence-based framework for a self-sustaining capacity development approach. This represents an important contribution to the literature that will be relevant for research funders, users and producers.
BACKGROUND: Predicting when and where pathogens will emerge is difficult, yet, as shown by the recent Ebola and Zika epidemics, effective and timely responses are key. It is therefore crucial to transition from reactive to proactive responses for these pathogens. To better identify priorities for outbreak mitigation and prevention, we developed a cohesive framework combining disparate methods and data sources, and assessed subnational pandemic potential for four viral haemorrhagic fevers in Africa, Crimean-Congo haemorrhagic fever, Ebola virus disease, Lassa fever, and Marburg virus disease. METHODS: In this multistage analysis, we quantified three stages underlying the potential of widespread viral haemorrhagic fever epidemics. Environmental suitability maps were used to define stage 1, index-case potential, which assesses populations at risk of infection due to spillover from zoonotic hosts or vectors, identifying where index cases could present. Stage 2, outbreak potential, iterates upon an existing framework, the Index for Risk Management, to measure potential for secondary spread in people within specific communities. For stage 3, epidemic potential, we combined local and international scale connectivity assessments with stage 2 to evaluate possible spread of local outbreaks nationally, regionally, and internationally. FINDINGS: We found epidemic potential to vary within Africa, with regions where viral haemorrhagic fever outbreaks have previously occurred (eg, western Africa) and areas currently considered non-endemic (eg, Cameroon and Ethiopia) both ranking highly. Tracking transitions between stages showed how an index case can escalate into a widespread epidemic in the absence of intervention (eg, Nigeria and Guinea). Our analysis showed Chad, Somalia, and South Sudan to be highly susceptible to any outbreak at subnational levels. INTERPRETATION: Our analysis provides a unified assessment of potential epidemic trajectories, with the aim of allowing national and international agencies to pre-emptively evaluate needs and target resources. Within each country, our framework identifies at-risk subnational locations in which to improve surveillance, diagnostic capabilities, and health systems in parallel with the design of policies for optimal responses at each stage. In conjunction with pandemic preparedness activities, assessments such as ours can identify regions where needs and provisions do not align, and thus should be targeted for future strengthening and support. FUNDING: Paul G Allen Family Foundation, Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development.
AIM: Even though systematic reviews have examined how aspects of propensity score methods are used, none has reviewed how the challenge of missing data is addressed with these methods. This review therefore describes how missing data are addressed with propensity score methods in observational comparative effectiveness studies. METHODS: Published articles on observational comparative effectiveness studies were extracted from MEDLINE and EMBASE databases. RESULTS: Our search yielded 167 eligible articles. Majority of these studies (114; 68%) conducted complete case analysis with only 53 of them stating this in the methods. Only 16 articles reported use of multiple imputation. CONCLUSION: Few researchers use correct methods for handling missing data or reported missing data methodology which may lead to reporting biased findings.
PLoS Negl Trop Dis, 11 (10), pp. e0005842. | Read more2017. Hepatitis B virus infection as a neglected tropical disease.
TROPICAL MEDICINE & INTERNATIONAL HEALTH, 22 pp. 167-168.2017. A training curriculum for conducting clinical research during outbreaks
BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).
Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.
INTRODUCTION: WHO treatment guidelines are widely recommended for guiding treatment for millions of children with pneumonia every year across multiple low-income and middle-income countries. Guidelines are based on synthesis of available evidence that provides moderate certainty in evidence of effects for forms of pneumonia that can result in hospitalisation. However, trials have included fewer children from Africa than other settings, and it is suggested that African children with pneumonia have higher mortality. Thus, despite improving access to recommended treatments and deployment with high coverage of childhood vaccines, pneumonia remains one of the top causes of mortality for children in Kenya. Establishing whether there are benefits of alternative treatment regimens to help reduce mortality would require pragmatic clinical trials. However, these remain relatively expensive and time consuming. This protocol describes an approach to using secondary analysis of a new, large observational dataset as a potentially cheaper and quicker way to examine the comparative effectiveness of penicillin versus penicillin plus gentamicin in treatment of indrawing pneumonia. Addressing this question is important, as although it is now recommended that this form of pneumonia is treated with oral medication as an outpatient, it remains associated with non-trivial mortality that may be higher outside trial populations. METHODS AND ANALYSIS: We will use a large observational dataset that captures data on all admissions to 13 Kenyan county hospitals. These data represent the findings of clinicians in practice and, because the system was developed for large observational research, pose challenges of non-random treatment allocation and missing data. To overcome these challenges, this analysis will use a rigorous approach to study design, propensity score methods and multiple imputation to minimise bias. ETHICS AND DISSEMINATION: The primary data are held by hospitals participating in the Kenyan Clinical Information Network project with de-identifed data shared with the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme for agreed analyses. The use of data for the analysis described received ethical clearance from the KEMRI scientific and ethical review committee. The findings of this analysis will be published.
Scrub typhus is a febrile infection caused by the obligate intracellular bacterium Orientia tsutsugamushi, which causes significant morbidity and mortality across the Asia-Pacific region. The control of this vector-borne disease is challenging due to humans being dead-end hosts, vertical maintenance of the pathogen in the vector itself, and a potentially large rodent reservoir of unclear significance, coupled with a lack of accurate diagnostic tests. Development of an effective vaccine is highly desirable. This however requires better characterization of the natural immune response of this neglected but important disease. Here we implement a novel IFN-γ ELISpot assay as a tool for studying O. tsutsugamushi induced cellular immune responses in an experimental scrub typhus rhesus macaque model and human populations. Whole cell antigen for O. tsutsugamushi (OT-WCA) was prepared by heat inactivation of Karp-strain bacteria. Rhesus macaques were infected intradermally with O. tsutsugamushi. Freshly isolated peripheral blood mononuclear cells (PBMC) from infected (n = 10) and uninfected animals (n = 5) were stimulated with OT-WCA, and IFN-γ secreting cells quantitated by ELISpot assay at five time points over 28 days. PBMC were then assayed from people in a scrub typhus-endemic region of Thailand (n = 105) and responses compared to those from a partially exposed population in a non-endemic region (n = 14), and to a naïve population in UK (n = 12). Mean results at Day 0 prior to O. tsutsugamushi infection were 12 (95% CI 0-25) and 15 (2-27) spot-forming cells (SFC)/106 PBMC for infected and control macaques respectively. Strong O. tsutsugamushi-specific IFN-γ responses were seen post infection, with ELISpot responses 20-fold higher than baseline at Day 7 (mean 235, 95% CI 200-270 SFC/106 PBMC), 105-fold higher at Day 14 (mean 1261, 95% CI 1,097-1,425 SFC/106 PBMC), 125-fold higher at Day 21 (mean 1,498, 95% CI 1,496-1,500 SFC/106 PBMC) and 118-fold higher at Day 28 (mean 1,416, 95% CI 1,306-1,527 SFC/106 PBMC). No significant change was found in the control group at any time point compared to baseline. Humans from a scrub typhus endemic region of Thailand had mean responses of 189 (95% CI 88-290) SFC/106 PBMC compared to mean responses of 40 (95% CI 9-71) SFC/106 PBMC in people from a non-endemic region and 3 (95% CI 0-7) SFC/106 PBMC in naïve controls. In summary, this highly sensitive assay will enable field immunogenicity studies and further characterization of the host response to O. tsutsugamushi, and provides a link between human and animal models to accelerate vaccine development.
BACKGROUND: The national pneumonia treatment guidelines in Kenya changed in February 2016 but such guideline changes are often characterized by prolonged delays in affecting practice. We designed an enhanced feedback intervention, delivered within an ongoing clinical network that provides a general form of feedback, aimed at improving and sustaining uptake of the revised pneumonia treatment policy. The objective was to determine whether an enhanced feedback intervention will improve correctness of classification and treatment of childhood pneumonia, compared to an existing approach to feedback, after nationwide treatment policy change and within an existing hospital network. METHODS/DESIGN: A pragmatic, cluster randomized trial conducted within a clinical network of 12 Kenyan county referral hospitals providing inpatient pediatric care to children (aged 2-59 months) with acute medical conditions between March and November 2016. The intervention comprised enhanced feedback (monthly written feedback incorporating goal setting, and action planning delivered by a senior clinical coordinator for selected pneumonia indicators) and this was compared to standard feedback (2-monthly written feedback on multiple quality of pediatric care indicators) both delivered within a clinical network promoting clinical leadership linked to mentorship and peer-to-peer support, and improved use of health information on service delivery. The 12 hospitals were randomized to receive either enhanced feedback (n = 6) or standard feedback (n = 6) delivered over a 9-month period following nationwide pneumonia treatment policy change. The primary outcome is the proportion of all admitted patients with pneumonia (fulfilling criteria for treatment with orally administered amoxicillin) who are correctly classified and treated in the first 24 h. The secondary outcome will be measured over the course of the admission as any change in treatment for pneumonia after the first 24 h. DISCUSSION: This trial protocol employs a pragmatic trial design during a period of nationwide change in treatment guidelines to address two high-priority areas within implementation research: promoting adoption of health policies and optimizing effectiveness of feedback. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02817971 . Registered retrospectively on 27 June 2016.
The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research.
There are few examples of sustained nationally organised, evidence-informed clinical guidelines development processes in Sub-Saharan Africa. We describe the evolution of efforts from 2005 to 2015 to support evidence-informed decision making to guide admission hospital care practices in Kenya. The approach to conduct reviews, present evidence, and structure and promote transparency of consensus-based procedures for making recommendations improved over four distinct rounds of policy making. Efforts to engage important voices extended from government and academia initially to include multiple professional associations, regulators and practitioners. More than 100 people have been engaged in the decision-making process; an increasing number outside the research team has contributed to the conduct of systematic reviews, and 31 clinical policy recommendations has been developed. Recommendations were incorporated into clinical guideline booklets that have been widely disseminated with a popular knowledge and skills training course. Both helped translate evidence into practice. We contend that these efforts have helped improve the use of evidence to inform policy. The systematic reviews, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approaches and evidence to decision-making process are well understood by clinicians, and the process has helped create a broad community engaged in evidence translation together with a social or professional norm to use evidence in paediatric care in Kenya. Specific sustained efforts should be made to support capacity and evidence-based decision making in other African settings and clinical disciplines.
BACKGROUND: The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells. Previous studies have suggested that parasites expressing PfEMP1 subclasses group A and DC8, associated with severe malaria, may have a growth advantage in immunologically naïve individuals. However, this idea has not been tested in longitudinal studies. METHODS: Here we assessed expression of the var genes encoding PfEMP1, in parasites sampled from volunteers with varying prior exposure to malaria, following experimental infection by sporozoites (PfSPZ). Using qPCR, we tested for associations between the expression of various var subgroups in surviving parasite populations from each volunteer and 1) the levels of participants' antibodies to infected erythrocytes before challenge infection and 2) the apparent in vivo parasite multiplication rate. RESULTS: We show that 1) expression of var genes encoding for group A and DC8-like PfEMP1 were associated with low levels of antibodies to infected erythrocytes (αIE) before challenge, and 2) expression of a DC8-like CIDRα1.1 domain was associated with higher apparent parasite multiplication rate in a manner that was independent of levels of prior antibodies to infected erythrocytes. CONCLUSIONS: This study provides insight into the role of antibodies to infected erythrocytes surface antigens in the development of naturally acquired immunity and may help explain why specific PfEMP1 variants may be associated with severe malaria. TRIAL REGISTRATION: Pan African Clinical Trial Registry: PACTR201211000433272 . Date of registration: 10th October 2012.
Background: We investigated the poorly understood impact of declining malaria transmission on maintenance of antibodies to Plasmodium falciparum merozoite antigens and infected erythrocytes (IEs), including functional immunity. Methods: In a 3-year longitudinal cohort of 300 Kenyan children, antibodies to different AMA1 and MSP2 alleles of merozoites, IE surface antigens, and antibody functional activities were quantified. Results: Over a period in which malaria transmission declined markedly, AMA1 and MSP2 antibodies decreased substantially; estimated half-lives of antibody duration were 0.8 year and 1-3 years, respectively. However, 69%-74% of children maintained their seropositivity to AMA1 alleles and 42%-52% to MSP2 alleles. Levels and prevalence of antimerozoite antibodies were consistently associated with increasing age and concurrent parasitemia. Antibodies promoting opsonic phagocytosis of merozoites declined rapidly (half-life, 0.15 years). In contrast, complement-fixing antibodies to merozoites did not decline and antibodies to IE surface antigens expressing virulent phenotypes were much better maintained (half-life, 4-10 years). Conclusions: A decline in malaria transmission is associated with reduction in naturally acquired immunity. However, loss of immunity is not universal; some key functional responses and antibodies to IEs were better maintained and these may continue to provide some protection. Findings have implications for malaria surveillance and control measures and informing vaccine development.
INTRODUCTION: Recurrent P. vivax infections are associated with significant morbidity and mortality. Although radical cure can reduce recurrent infection, it is confounded by antimalarial resistance and the lack of safe and effective hypnozoitocidal treatment. This study documents the available literature of published clinical trials of P. vivax, providing an up to date, online, open access tool to view and download available information. METHODS: A systematic review was conducted according to PRISMA guidelines to identify prospective P. vivax therapeutic clinical trials with at least 28 days follow-up published between 1st January 1960 and 12th October 2016. Treatment arms and evidence of chloroquine resistance were mapped to trial sites. RESULTS: Since 1960, a total of 1152 antimalarial clinical trials with a minimum 28 days follow-up have been published, of which 230 (20.0%) enrolled patients with P. vivax and were included. Trials were conducted in 38 countries: 168 (73.0%) in the Asia-Pacific, 13 (5.7%) in Africa and 43 (18.7%) in the Americas. The proportion of antimalarial trials assessing P. vivax rose from 10.7% (12/112) in 1991-1995, to 24.9% (56/225) in 2011-2015. Overall, 188 (81.7%) P. vivax trials included a chloroquine treatment arm, either alone or in combination with primaquine, and 107 (46.5%) trials included a chloroquine treatment arm with early primaquine to assess radical cure. There has been a recent increase in treatment arms with artemisinin derivatives. Of the 131 sites in which chloroquine resistance could be quantified, resistance was present in 59 (45.0%) sites in 15 endemic countries. CONCLUSIONS: Over the last 20 years there has been a substantial increase in clinical research on the treatment of P. vivax, which has generated a greater awareness of the global extent of chloroquine resistance. The WWARN open access, online interactive map provides up to date information of areas where drug resistant P. vivax is emerging.
Objective: To give an overview of the role of Free/Libre and Open Source Software (FLOSS) in the context of secondary use of patient data to enable Learning Health Systems (LHSs). Methods: We conducted an environmental scan of the academic and grey literature utilising the MedFLOSS database of open source systems in healthcare to inform a discussion of the role of open source in developing LHSs that reuse patient data for research and quality improvement. Results: A wide range of FLOSS is identified that contributes to the information technology (IT) infrastructure of LHSs including operating systems, databases, frameworks, interoperability software, and mobile and web apps. The recent literature around the development and use of key clinical data management tools is also reviewed. Conclusions: FLOSS already plays a critical role in modern health IT infrastructure for the collection, storage, and analysis of patient data. The nature of FLOSS systems to be collaborative, modular, and modifiable may make open source approaches appropriate for building the digital infrastructure for a LHS.
INTRODUCTION: Invasive infections caused bySalmonella entericaserovar Typhi and Paratyphi A are estimated to account for 12-27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidalSalmonellaeinfections is hindered by lack of population-based studies and adequate laboratory diagnostics.The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidalSalmonellaeinfections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history ofSalmonellatransmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies. METHODS/DESIGN: Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidalSalmonellae(seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers. ETHICS AND DISSEMINATION: This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN 12131979. ETHICS REFERENCES: Oxford (Oxford Tropical Research Ethics Committee 39-15).Bangladesh (icddr,b Institutional Review Board PR-15119).Malawi (National Health Sciences Research Committee 15/5/1599).Nepal (Nepal Health Research Council 306/2015).
Background: We examined associations between single-nucleotide polymorphisms (SNPs) of IFITM3, TLR3, and CD55 genes and influenza clinical outcomes in Chinese. Methods: A multicenter study was conducted on 275 adult cases of avian (H7N9) and pandemic (H1N1pdm09) influenza. Host DNA was extracted from diagnostic respiratory samples; IFITM3 rs12252, TLR3 rs5743313, CD55 rs2564978, and TLR4 rs4986790/4986791 were targeted for genotyping (Sanger sequencing). The primary outcome analyzed was death. Results: IFITM3 and TLR3 SNPs were in Hardy-Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of homozygous IFITM3 CC (54.5% vs 33.2%; P = .02) and TLR3 CC (93.3% vs 76.9%; P = .04) genotypes among fatal cases. Recessive genetic models showed their significant independent associations with higher death risks (adjusted hazard ratio [aHR] 2.78, 95% confidence interval [CI] 1.29-6.02, and aHR 4.85, 95% CI 1.11-21.06, respectively). Cumulative effects were found (aHR 3.53, 95% CI 1.64-7.59 per risk genotype; aHR 9.99, 95% CI 1.27-78.59 with both). Results were consistent for each influenza subtype and other severity indicators. The CD55 TT genotype was linked to severity. TLR4 was nonpolymorphic. Conclusions: Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings have important implications on disease burden and patient care in at-risk populations.
© 2017 Elsevier B.V. This paper explains a novel approach for knowledge discovery from data generated by Point of Care (POC) devices. A very important element of this type of knowledge extraction is that the POC generated data would never be identifiable, thereby protecting the rights and the anonymity of the individual, whilst still allowing for vital population-level evidence to be obtained. This paper also reveals a real-world implementation of the novel approach in a big data analytics system. Using Internet of Things (IoT) enabled POC devices and the big data analytics system, the data can be collected, stored, and analyzed in batch and real-time modes to provide a detailed picture of a healthcare system as well to identify high-risk populations and their locations. In addition, the system offers benefits to national health authorities in forms of optimized resource allocation (from allocating consumables to finding the best location for new labs) thus supports efficient and timely decision-making processes.
BACKGROUND: Arthropod-borne virus (Arbovirus) infections are considered an emerging threat for Europe, with an increase in cases in recent decades. The increase in global travel and trade has contributed to the introduction of vectors and viruses into new geographical areas. Tropical arboviruses such as dengue and chikungunya have re-emerged causing local, sporadic outbreaks ignited by travel-imported cases. The recent Zika virus outbreak in the Americas highlighted a need to strengthen preparedness for (re-)emerging arbovirus infections globally. AIMS: To strengthen preparedness for the early identification of (re-)emerging arbovirus outbreaks in Europe and highlight areas for research. SOURCES: An evidence review of published and grey literature together with consultations with European arbovirus experts. CONTENT: This paper presents an overview of endemic and travel-imported arboviruses of clinical significance in Europe. The overview includes syndromic presentation, risk factors for infection and risk of transmission as well as an update on treatments and vaccinations and surveillance notifications and reporting. The paper also presents predictive modelled risks of further geographical expansion of vectors and viruses. IMPLICATIONS: There are a range of arboviruses of clinical significance to Europe. There has been an increase in notifications of endemic and travel-imported arbovirus cases in recent years and an increased geographical range of vectors and viruses. The heterogeneity in surveillance reporting indicates a risk for the early identification of (re-)emerging outbreaks. The data presented show a need to strengthen preparedness for (re-)emerging arbovirus infections and a need for research into neglected arboviruses, risks of non-vector transmission and effective therapeutics and vaccinations.
SCIENCE, 356 (6343), | Citations: 2 (Web of Science Lite) | Read more2017. Resistance to malaria through structural variation of red blood cell invasion receptors
BACKGROUND: The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016-17 prompted concerns that the epidemiology of the virus might have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016-17 epidemic compared with previous epidemics. METHODS: In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques. FINDINGS: Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013-14, 219 in 2014-15, 114 in 2015-16, and 447 in 2016-17. The 2016-17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016-17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015-16 and 2016-17 epidemics (63% [72 of 114] and 61% [274 of 447], respectively) were higher than those in the first three epidemics (39% [52 of 134], 55% [169 of 306], and 56% [122 of 219], respectively). The clinical severity of individuals admitted to hospital in the 2016-17 epidemic was similar to that in the previous epidemics. INTERPRETATION: Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus. FUNDING: The National Science Fund for Distinguished Young Scholars.
© 2017 The Authors After three decades of mobile phone diffusion, thousands of mobile-phone-based health projects worldwide (“mHealth”), and hundreds of thousands of smartphone health applications, fundamental questions about the effect of phone diffusion on people's healthcare behavior continue to remain unanswered. This study investigated whether, in the absence of specific mHealth interventions, people make different healthcare decisions if they use mobile phones during an illness. Following mainstream narratives, we hypothesized that phone use during an illness (a) increases and (b) accelerates healthcare access. Our study was based on original survey data from 800 respondents in rural Rajasthan (India) and Gansu (China), sampled from the general adult population in 2014 in a three-stage stratified cluster random sampling design. We analyzed single- and multi-level logistic, Poisson, and negative binomial regression models with cluster-robust standard errors. Contrary to other research at the intersection of mobile phones and healthcare, we captured actual health-related mobile phone use during people's illnesses irrespective of whether they own a phone. Our analysis produced the first quantitative micro-evidence that patients’ personal mobile phone use is correlated with their healthcare decisions. Despite a positive association between phone use and healthcare access, health-related phone use was also linked to delayed access to public doctors and nurses. We considered theoretical explanations for the observed patterns by augmenting transaction cost and information deficit arguments with the prevailing health system configuration and with notions of heuristic decision-making during the healthcare-seeking process. Our study was a first step toward understanding the implications of mobile technology diffusion on health behavior in low- and middle-income countries in the absence of specific mHealth interventions. Future research will have to explore the causal relationships underlying these statistical associations. Such a link could potentially mean that development interventions aimed at improving access to healthcare continue to require conventional solutions to sustain healthcare equity.
Background.: Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. Methods.: Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. Results.: Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. Conclusion.: The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.
The malaria parasitePlasmodium falciparuminvades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genesGYPAandGYPBWe find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss ofGYPBand gain of twoGYPB-Ahybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.
Immunoepidemiological studies typically reveal slow, age-dependent acquisition of immune responses againstPlasmodium falciparumsporozoites. Naturally acquired immunity against preerythrocytic stages is considered inadequate to confer protection against clinical malaria. To explore previously unrecognized antisporozoite responses, we measured serum levels of naturally acquired antibodies to wholePlasmodium falciparumsporozoites (Pfspz) and the immunodominant (NANP)5repeats of the major sporozoite surface protein, circumsporozoite protein, in a well-characterized Kenyan cohort. Sera were sampled at the start of the malaria transmission season, and all subjects were prospectively monitored for uncomplicated clinical malaria in the ensuing 6 months. We used Kaplan-Meier analysis and multivariable regression to investigate the association of antisporozoite immunity with incidence of clinical malaria. Although naturally acquired humoral responses againstPfspz and (NANP)5were strongly correlated (p < 0.0001), 37% ofPfspz responders did not recognize (NANP)5. The prevalence and magnitude of antisporozoite responses increased with age, although some highPfspz responders were identified among children. Survival analysis revealed a reduced risk of and increased time to first or only episode of clinical malaria amongPfspz or (NANP)5responders carrying microscopically detectablePlasmodium falciparum(Pf) parasitemia at the start of the transmission season (p < 0.03). Our Cox regression interaction models indicated a potentially protective interaction between high anti-Pfspz (p = 0.002) or anti-(NANP)5(p = 0.001) antibody levels and microscopically detectablePfparasitemia on the risk of subsequent clinical malaria. Our findings indicate that robust antisporozoite immune responses can be naturally acquired already at an early age. A potentially protective role of high levels of anti-Pfspz antibodies against clinical episodes of uncomplicated malaria was detected, suggesting that antibody-mediated preerythrocytic immunity might indeed contribute to protection in nature.
Zika virus (ZIKV) infection in pregnancy is associated with adverse fetal outcomes, such as microcephaly and other congenital malformations. No therapeutic options are available to pregnant women with ZIKV infection to prevent these effects. Drug trials in pregnancy raise several scientific, ethical, and logistic challenges, which are compounded further in ZIKV because of limited knowledge of the disease pathophysiology and a product development pipeline in its infancy. We evaluate the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations. These challenges must be characterized and planned for now so that clinical trials can progress expediently and effectively in the future.
© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Increasing scholarly attention has focussed on how to integrate technology within the Capability Approach (CA), yet without a consistent solution. Some describe technology as a special kind of capability input, but others consider the concept of technology to be fundamentally different from that of an ordinary input. We aim to contribute to the theoretical development of the CA by offering a consistent justification for the explicit inclusion of technology in this framework. We propose that technical objects have a ‘generative’ and a ‘transformative’ dimension through which they enable capabilities directly and affect other inputs in the attainment of valued capabilities. The objects acquire the transformative dimension from the broader technological context, which we propose as a new class of conversion factors. Using the example of mobile phones and their role in healthcare access, we demonstrate that our proposal helps to frame the analysis of the development impact of technology.
BACKGROUND: Audit and feedback is a common intervention for supporting clinical behaviour change. Increasingly, health data are available in electronic format. Yet, little is known regarding if and how electronic audit and feedback (e-A&F) improves quality of care in practice. OBJECTIVE: The study aimed to assess the effectiveness of e-A&F interventions in a primary care and hospital context and to identify theoretical mechanisms of behaviour change underlying these interventions. METHODS: In August 2016, we searched five electronic databases, including MEDLINE and EMBASE via Ovid, and the Cochrane Central Register of Controlled Trials for published randomised controlled trials. We included studies that evaluated e-A&F interventions, defined as a summary of clinical performance delivered through an interactive computer interface to healthcare providers. Data on feedback characteristics, underlying theoretical domains, effect size and risk of bias were extracted by two independent review authors, who determined the domains within the Theoretical Domains Framework (TDF). We performed a meta-analysis of e-A&F effectiveness, and a narrative analysis of the nature and patterns of TDF domains and potential links with the intervention effect. RESULTS: We included seven studies comprising of 81,700 patients being cared for by 329 healthcare professionals/primary care facilities. Given the extremely high heterogeneity of the e-A&F interventions and five studies having a medium or high risk of bias, the average effect was deemed unreliable. Only two studies explicitly used theory to guide intervention design. The most frequent theoretical domains targeted by the e-A&F interventions included 'knowledge', 'social influences', 'goals' and 'behaviour regulation', with each intervention targeting a combination of at least three. None of the interventions addressed the domains 'social/professional role and identity' or 'emotion'. Analyses identified the number of different domains coded in control arm to have the biggest role in heterogeneity in e-A&F effect size. CONCLUSIONS: Given the high heterogeneity of identified studies, the effects of e-A&F were found to be highly variable. Additionally, e-A&F interventions tend to implicitly target only a fraction of known theoretical domains, even after omitting domains presumed not to be linked to e-A&F. Also, little evaluation of comparative effectiveness across trial arms was conducted. Future research should seek to further unpack the theoretical domains essential for effective e-A&F in order to better support strategic individual and team goals.
BMJ, 357 pp. j1447. | Read more2017. Emerging and re-emerging infectious disease threats in South Asia: status, vulnerability, preparedness, and outlook.
Although, after an epidemic of over 28 000 cases, there are still no licensed treatments for Ebola virus disease (EVD), significant progress was made during the West Africa outbreak. The pace of pre-clinical development was exceptional and a number of therapeutic clinical trials were conducted in the face of considerable challenges. Given the on-going risk of emerging infectious disease outbreaks in an era of unprecedented population density, international travel and human impact on the environment it is pertinent to focus on improving the research and development landscape for treatments of emerging and epidemic-prone infections. This is especially the case since there are no licensed therapeutics for some of the diseases considered by the World Health Organization as most likely to cause severe outbreaks-including Middle East respiratory syndrome coronavirus, Marburg virus, Crimean Congo haemorrhagic fever and Nipah virus. EVD, therefore, provides a timely exemplar to discuss the barriers, enablers and incentives needed to find effective treatments in advance of health emergencies caused by emerging infectious diseases.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.
Precision global health is an approach similar to precision medicine, which facilitates, through innovation and technology, better targeting of public health interventions on a global scale, for the purpose of maximising their effectiveness and relevance. Illustrative examples include: the use of remote sensing data to fight vector-borne diseases; large databases of genomic sequences of foodborne pathogens helping to identify origins of outbreaks; social networks and internet search engines for tracking communicable diseases; cell phone data in humanitarian actions; drones to deliver healthcare services in remote and secluded areas. Open science and data sharing platforms are proposed for fostering international research programmes under fair, ethical and respectful conditions. Innovative education, such as massive open online courses or serious games, can promote wider access to training in public health and improving health literacy. The world is moving towards learning healthcare systems. Professionals are equipped with data collection and decision support devices. They share information, which are complemented by external sources, and analysed in real time using machine learning techniques. They allow for the early detection of anomalies, and eventually guide appropriate public health interventions. This article shows how information-driven approaches, enabled by digital technologies, can help improving global health with greater equity.
Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8+ MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8+ MAIT cell immune response to S. Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type S. Typhi. We define the kinetics of CD8+ MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8+ MAIT cells after S. Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case S. Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection.
BACKGROUND: Hospital mortality data can inform planning for health interventions and may help optimize resource allocation if they are reliable and appropriately interpreted. However such data are often not available in low income countries including Kenya. METHODS: Data from the Clinical Information Network covering 12 county hospitals' paediatric admissions aged 2-59 months for the periods September 2013 to March 2015 were used to describe mortality across differing contexts and to explore whether simple clinical characteristics used to classify severity of illness in common treatment guidelines are consistently associated with inpatient mortality. Regression models accounting for hospital identity and malaria prevalence (low or high) were used. Multiple imputation for missing data was based on a missing at random assumption with sensitivity analyses based on pattern mixture missing not at random assumptions. RESULTS: The overall cluster adjusted crude mortality rate across hospitals was 6 · 2% with an almost 5 fold variation across sites (95% CI 4 · 9 to 7 · 8; range 2 · 1% - 11 · 0%). Hospital identity was significantly associated with mortality. Clinical features included in guidelines for common diseases to assess severity of illness were consistently associated with mortality in multivariable analyses (AROC =0 · 86). CONCLUSION: All-cause mortality is highly variable across hospitals and associated with clinical risk factors identified in disease specific guidelines. A panel of these clinical features may provide a basic common data framework as part of improved health information systems to support evaluations of quality and outcomes of care at scale and inform health system strengthening efforts.
The spread of artemisinin-resistantPlasmodium falciparumcompromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT forP. falciparuminfection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060P. falciparumisolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA)in vitroand prolonged parasite clearancein vivoAn analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.
Bull World Health Organ, 95 (4), pp. 243. | Read more2017. Progress in promoting data sharing in public health emergencies.
BACKGROUND: Melioidosis is a severe disease caused by Burkholderia pseudomallei. Clinical manifestations are diverse and acute infections require immediate treatment with effective antibiotics. While culture is the current diagnostic standard, it is time-consuming and has low sensitivity. In endemic areas, inaccessibility to biosafety level 3 facilities and a lack of good serodiagnostic tools can impede diagnosis and disease surveillance. Recent studies have suggested that O-polysaccharide (OPS) and hemolysin co-regulated protein 1 (Hcp1) are promising target antigens for serodiagnosis of melioidosis. METHODOLOGY/PRINCIPLE FINDINGS: We evaluated rapid ELISAs using crude antigens, purified OPS and Hcp1 to measure antibody levels in three sets of sera: (i) 419 serum samples from melioidosis patients, Thai and U.S. healthy donors, (ii) 120 serum samples from patients with other bacterial infections, and (iii) 423 serum samples from 200 melioidosis patients obtained upon admission and at 12 and 52 weeks post-recovery. We observed significantly higher antibody levels using the crude antigen prepared from wild type B. pseudomallei K96243 compared to that of an OPS-mutant. The areas under receiver operator characteristics (AUROCCs) for diagnosis were compared for individual Hcp1-ELISA or OPS-ELISA or combined Hcp1/OPS-ELISA. For Thai donors, AUROCCs were highest and comparable between the Hcp1-ELISA and the combined Hcp1/OPS-ELISA (0.95 versus 0.94). For U.S. donors, the AUROCC was highest for the combined Hcp1/OPS-ELISA (0.96). Significantly higher seropositivity was observed in diabetic patients compared to those without diabetes for both the Hcp1-ELISA (87.3% versus 69.7%) and OPS-ELISA (88.1% versus 60.6%). Although antibody levels for Hcp1 were highest upon admission, the titers declined by week 52 post-recovery. CONCLUSIONS/SIGNIFICANCE: Hcp1 and OPS are promising candidates for serodiagnosis of melioidosis in different groups of patients. The Hcp1-ELISA performed better than the OPS-ELISA in endemic areas, thus, Hcp1 represents a promising target antigen for the development of POC tests for acute melioidosis.
Capacity development for clinical research is held back by a lack of recognition for the skills acquired through involvement in clinical trials and in other varied types of global health research studies. Although some competency frameworks and associated recognised career pathways exist for different clinical research roles, they mostly apply to a single role or study setting. Our experience supports the need for an integrated approach, looking at the many roles in parallel and at all types of clinical research beyond trials. Here, we propose a single, flexible framework which is applicable to the full global health research team, and can be used for recognising staff by highlighting acquired skills and possible progression between various roles. It can also illuminate where capacity needs strengthening and contribute to raising research engagement. Through systematic analysis of existing competency frameworks and current job descriptions covering 11 distinct, broad clinical research roles, we identified and defined 50 key competencies required by the team as a whole and throughout the study life cycle. The competencies are relevant and adaptable to studies that differ in design, geographical location or disease, and fall in five main areas-(1) Ethics, Quality and Risk Management; (2) Study and Site Management; (3) Research Operations; (4) Scientific Thinking; and (5) Professional Skills. A pilot framework and implementation tools are now available online and in paper format. They have the potential to be a new mechanism for enabling research skills development and career progression for all staff engaged in clinical research globally.
BACKGROUND: Conducting clinical trials to assess experimental treatments for potentially pandemic infectious diseases is challenging. Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. Outbreaks are sudden and unpredictable and so it is essential that as much planning as possible takes place in advance. Statistical aspects of such trial designs should be evaluated and discussed in readiness for implementation. METHODOLOGY/PRINCIPAL FINDINGS: This paper proposes a generic ordinal sequential trial design (GOST) for a randomised clinical trial comparing an experimental treatment for an emerging infectious disease with standard care. The design is intended as an off-the-shelf, ready-to-use robust and flexible option. The primary endpoint is a categorisation of patient outcome according to an ordinal scale. A sequential approach is adopted, stopping as soon as it is clear that the experimental treatment has an advantage or that sufficient advantage is unlikely to be detected. The properties of the design are evaluated using large-sample theory and verified for moderate sized samples using simulation. The trial is powered to detect a generic clinically relevant difference: namely an odds ratio of 2 for better rather than worse outcomes. Total sample sizes (across both treatments) of between 150 and 300 patients prove to be adequate in many cases, but the precise value depends on both the magnitude of the treatment advantage and the nature of the ordinal scale. An advantage of the approach is that any erroneous assumptions made at the design stage about the proportion of patients falling into each outcome category have little effect on the error probabilities of the study, although they can lead to inaccurate forecasts of sample size. CONCLUSIONS/SIGNIFICANCE: It is important and feasible to pre-determine many of the statistical aspects of an efficient trial design in advance of a disease outbreak. The design can then be tailored to the specific disease under study once its nature is better understood.
BACKGROUND: Vibrio cholerae, a Gram-negative, non-spore forming curved rod is found in diverse aquatic ecosystems around the planet. It is classified according to its major surface antigen into around 206 serogroups, of which O1 and O139 cause epidemic cholera. A recent spatial modelling technique estimated that around 2.86 million cholera cases occur globally every year, and of them approximately 95,000 die. About 1.3 billion people are currently at risk of infection from cholera. Meta-analysis and mathematical modelling have demonstrated that due to global warming the burden of vector-borne diseases like malaria, leishmaniasis, meningococcal meningitis, viral encephalitis, dengue and chikungunya will increase in the coming years in the tropics and beyond. CHOLERA AND CLIMATE: This review offers an overview of the interplay between global warming and the pathogenicity and epidemiology of V. cholerae. Several distinctive features of cholera survival (optimal thriving at 15% salinity, 30 °C water temperature, and pH 8.5) indicate a possible role of climate change in triggering the epidemic process. Genetic exchange (ctxAB, zot, ace, cep, and orfU) between strains and transduction process allows potential emergence of new toxigenic clones. These processes are probably controlled by precise environmental signals such as optimum temperature, sunlight and osmotic conditions. Environmental influences on phytoplankton growth and chitin remineralization will be discussed alongside the interplay of poor sanitary conditions, overcrowding, improper sewage disposal and global warming in promoting the growth and transmission of this deadly disease. CONCLUSION: The development of an effective early warning system based on climate data could help to prevent and control future outbreaks. It may become possible to integrate real-time monitoring of oceanic regions, climate variability and epidemiological and demographic population dynamics to predict cholera outbreaks and support the design of cost-effective public health strategies.
BACKGROUND: Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped TLR5 c.1174C>T in 194 acute melioidosis patients in Thailand. Twenty-six (13%) were genotype CT or TT. In univariable analysis, carriage of the c.1174C>T variant was associated with lower 28-day mortality (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05-0.94, P = 0.04) and with lower 90-day mortality (OR 0.25, 95% CI 0.07-086, P = 0.03). In multivariable analysis adjusting for age, sex, diabetes and renal disease, the adjusted OR for 28-day mortality in carriers of the variant was 0.24 (95% CI 0.05-1.08, P = 0.06); and the adjusted OR for 90-day mortality was 0.27 (95% CI 0.08-0.97, P = 0.04). c.1174C>T was associated with a lower rate of bacteremia (P = 0.04) and reduced plasma levels of IL-10 (P = 0.049) and TNF-α (P < 0.0001). We did not find an association between c.1174C>T and IFN-γ ELISPOT (T-cell) responses (P = 0.49), indirect haemagglutination titers or IgG antibodies to bacterial flagellin during acute melioidosis (P = 0.30 and 0.1, respectively). CONCLUSIONS/SIGNIFICANCE: This study independently confirms the association of TLR5 c.1174C>T with protection against death in melioidosis, identifies lower bacteremia, IL-10 and TNF-α production in carriers of the variant with melioidosis, but does not demonstrate an association of the variant with acute T-cell IFN-γ response, indirect haemagglutination antibody titer, or anti-flagellin IgG antibodies.
Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~104 CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S. Typhi-responsive CD8+ T effector memory cells at baseline. Early decreases of these cells in circulation following challenge were observed in both S. Typhi-responsive integrin α4β7- and integrin α4β7+ CD8+ T effector memory (TEM) cells, suggesting their potential to home to both mucosal and extra-intestinal sites. Participants with higher baseline levels of S. Typhi-responsive CD8+ T memory cells had a higher risk of acquiring disease, but among those who acquired disease, those with a higher baseline responses took longer to develop disease. In contrast, protection against disease was associated with low or absent S. Typhi-responsive T cells at baseline and no changes in circulation following challenge. These data highlight the importance of pre-existing S. Typhi-responsive immunity in predicting clinical outcome following infection with wild-type S. Typhi and provide novel insights into the complex mechanisms involved in protective immunity to natural infection in a stringent human model with a high challenge dose. They also contribute important information on the immunological responses to be assessed in the appraisal and selection of new generation typhoid vaccines.
Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results: The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration: NCT02100397.
There are minimal data to define normal oxygen saturation (SpO2) levels for infants within the first 24 hours of life and even fewer data generalisable to the 7% of the global population that resides at an altitude of >1500 m. The aim of this study was to establish the reference range for SpO2 in healthy term and preterm neonates within 24 hours in Nairobi, Kenya, located at 1800 m. A random sample of clinically well infants had SpO2 measured once in the first 24 hours. A total of 555 infants were enrolled. The 5th-95th percentile range for preductal and postductal SpO2 was 89%-97% for the term and normal birthweight groups, and 90%-98% for the preterm and low birthweight (LBW) groups. This may suggest that 89% and 97% are reasonable SpO2 bounds for well term, preterm and LBW infants within 24 hours at an altitude of 1800 m.
BACKGROUND: The creation of a clinical network was proposed as a means to promote implementation of a set of recommended clinical practices targeting inpatient paediatric care in Kenya. The rationale for selecting a network as a strategy has been previously described. Here, we aim to describe network activities actually conducted over its first 2.5 years, deconstruct its implementation into specific components and provide our 'insider' interpretation of how the network is functioning as an intervention. METHODS: We articulate key activities that together have constituted network processes over 2.5 years and then utilise a recently published typology of implementation components to give greater granularity to this description from the perspective of those delivering the intervention. Using the Behaviour Change Wheel we then suggest how the network may operate to achieve change and offer examples of change before making an effort to synthesise our understanding in the form of a realist context-mechanism-outcome configuration. RESULTS: We suggest our network is likely to comprise 22 from a total of 73 identifiable intervention components, of which 12 and 10 we consider major and minor components, respectively. At the policy level, we employed clinical guidelines, marketing and communication strategies with intervention characteristics operating through incentivisation, persuasion, education, enablement, modelling and environmental restructuring. These might influence behaviours by enhancing psychological capability, creating social opportunity and increasing motivation largely through a reflective pathway. CONCLUSIONS: We previously proposed a clinical network as a solution to challenges implementing recommended practices in Kenyan hospitals based on our understanding of theory and context. Here, we report how we have enacted what was proposed and use a recent typology to deconstruct the intervention into its elements and articulate how we think the network may produce change. We offer a more generalised statement of our theory of change in a context-mechanism-outcome configuration. We hope this will complement a planned independent evaluation of 'how things work', will help others interpret results of change reported more formally in the future and encourage others to consider further examination of networks as means to scale up improvement practices in health in lower income countries.
Young infants are less susceptible to severe episodes of malaria but the targets and mechanisms of protection are not clear. Cord blood antibodies may play an important role in mediating protection but many studies have examined their association with the outcome of infection or non-severe malaria. Here, we investigated whether cord blood IgG to Plasmodium falciparum merozoite antigens and antibody-mediated effector functions were associated with reduced odds of developing severe malaria at different time points during the first year of life. We conducted a case-control study of well-defined severe falciparum malaria nested within a longitudinal birth cohort of Kenyan children. We measured cord blood total IgG levels against five recombinant merozoite antigens and antibody function in the growth inhibition activity and neutrophil antibody-dependent respiratory burst assays. We also assessed the decay of maternal antibodies during the first 6months of life. The mean antibody half-life range was 2.51months (95% confidence interval (CI): 2.19-2.92) to 4.91months (95% CI: 4.47-6.07). The rate of decline of maternal antibodies was inversely proportional to the starting concentration. The functional assay of antibody-dependent respiratory burst activity predicted significantly reduced odds of developing severe malaria during the first 6months of life (Odds ratio (OR) 0.07, 95% CI: 0.007-0.74, P=0.007). Identification of the targets of antibodies mediating antibody-dependent respiratory burst activity could contribute to the development of malaria vaccines that protect against severe episodes of malaria in early infancy.
This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.
BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine. METHODS AND FINDINGS: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. CONCLUSIONS: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015).
OBJECTIVES: Locally led health research in low and middle income countries (LMICs) is critical for overcoming global health challenges. Yet, despite over 25 years of international efforts, health research capacity in LMICs remains insufficient and development attempts continue to be fragmented. The aim of this systematic review is to identify and critically examine the main approaches and trends in health research capacity development and consolidate key thinking to identify a more coherent approach. METHODS: This review includes academic and grey literature published between January 2000 and July 2013. Using a predetermined search strategy, we systematically searched PubMed, hand-searched Google Scholar and checked reference lists. This process yielded 1668 papers. 240 papers were selected based on a priori criteria. A modified version of meta-narrative synthesis was used to analyse the papers. RESULTS: 3 key narratives were identified: the effect of power relations on capacity development; demand for stronger links between research, policy and practice and the importance of a systems approach. Capacity development was delivered through 4 main modalities: vertical research projects, centres of excellence, North-South partnerships and networks; all were controversial, and each had their strengths and weaknesses. A plurality of development strategies was employed to address specific barriers to health research. However, lack of empirical research and monitoring and evaluation meant that their effectiveness was unclear and learning was weak. CONCLUSIONS: There has been steady progress in LMIC health research capacity, but major barriers to research persist and more empirical evidence on development strategies is required. Despite an evolution in development thinking, international actors continue to use outdated development models that are recognised as ineffective. To realise newer development thinking, research capacity outcomes need to be equally valued as research outputs. While some development actors are now adopting this dedicated capacity development approach, they are in the minority.
BACKGROUND: Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in pfmdr1, which encodes the Plasmodium falciparum multidrug resistance transporter. In Africa the N86Y and D1246Y polymorphisms have been shown to be selected by treatment, with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) selecting for wild-type and mutant alleles, respectively. However, there has been little study of pfmdr1 haplotypes, in part because haplotype analyses are complicated by multiclonal infections. METHODS: We fit a haplotype frequency estimation model, which accounts for multiclonal infections, to the polymorphic pfmdr1 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated P falciparum malaria in Tororo, Uganda from 2007 to 2012. We regressed estimates onto covariates of trial arm and selective drug pressure. RESULTS: Yearly trends showed increasing frequency estimates for haplotypes with wild type pfmdr1 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant pfmdr1 86Y allele. Considering days since prior therapy, we saw evidence suggestive of selection by AL for haplotypes with N86 combined with 184F, D1246, or both, and against all haplotypes with 86Y, and evidence suggestive of selection by DP for 86Y only when combined with Y184 and 1246Y (haplotype YYY) and against haplotypes NFD and NYY. CONCLUSIONS: Based on our model, AL selected several haplotypes containing N86, whereas DP selection was haplotype specific, demonstrating the importance of haplotype analyses. Inverse selective pressure of AL and DP on the complementary haplotypes NFD and YYY suggests that rotating artemisinin-based antimalarial combination regimens may be the best treatment option to prevent resistance selection.
ASM Science Journal, 2017 (Specialissue1), pp. 87-89.2017. Absolute humidity drives the epidemiology of influenza-like illness in Vietnam
Background: Audit and feedback (A&F) is widely used in healthcare but there are few examples of how to deploy it at scale in low-income countries. Establishing the Clinical Information Network (CIN) in Kenya provided an opportunity to examine the effect of A&F delivered as part of a wider set of activities to promote paediatric guideline adherence. Methods: We analysed data collected from medical records on discharge for children aged 2-59 months from 14 Kenyan hospitals in the CIN. Hospitals joined CIN in phases and for each we analysed their initial 25 months of participation that occurred between December 2013 and March 2016. A total of 34 indicators of adherence to recommendations were selected for evaluation each classified by form of feedback (passive, active and none) and type of task (simple or difficult documentation and those requiring cognitive work). Performance change was explored graphically and using generalised linear mixed models with attention given to the effects of time and use of a standardised paediatric admission record (PAR) form. Results: Data from 60 214 admissions were eligible for analysis. Adherence to recommendations across hospitals significantly improved for 24/34 indicators. Improvements were not obviously related to nature of feedback, may be related to task type and were related to PAR use in the case of documentation indicators. There was, however, marked variability in adoption and adherence to recommended practices across sites and indicators. Hospital-specific factors, low baseline performance and specific contextual changes appeared to influence the magnitude of change in specific cases. Conclusion: Our observational data suggest some change in multiple indicators of adherence to recommendations (aspects of quality of care) can be achieved in low-resource hospitals using A&F and simple job aides in the context of a wider network approach.
Background: Nutritional rickets is a public health concern in developing countries despite tropical climates and a re-emerging issue in developed countries. In this study, we reviewed pediatric admission data from the Clinical Information Network (CIN) to help determine hospital and region based prevalence of rickets in three regions of Kenya (Central Kenya, Western Kenya and Nairobi County). We also examine the association of rickets with other diagnosis, such as malnutrition and pneumonia, and study the effect of rickets on regional hospital stays. Methods: We analyzed discharge records for children aged 1 month to 5 years from county (formerly district) hospitals in the CIN, with admissions from February 1 st 2014 to February 28 th 2015. The strength of the association between rickets and key demographic factors, as well as with malnutrition and pneumonia, was assessed using odds ratios. The Fisher exact test was used to test the significance of the estimated odd ratios. Kaplan-Meier curves were used to analyze length of hospital stays. Results: There was a marked difference in prevalence across the three regions, with Nairobi having the highest number of cases of rickets at a proportion of 4.01%, followed by Central Region at 0.92%. Out of 9756 admissions in the Western Region, there was only one diagnosis of rickets. Malnutrition was associated with rickets; this association varied regionally. Pneumonia was found to be associated with rickets in Central Kenya. Children diagnosed with rickets had longer hospital stays, even when cases of malnutrition and pneumonia were excluded in the analysis. Conclusion: There was marked regional variation in hospital based prevalence of rickets, but in some regions it is a common clinical diagnosis suggesting the need for targeted public health interventions. Factors such as maternal and child nutrition, urbanization and cultural practices might explain these differences.
© 2017 Acute respiratory infections are one of the top five causes of mortality worldwide and contribute to > 4 million deaths per year. Consequently, emerging respiratory viruses are a continuing threat to global health security and have the potential to affect our economies. Since the millennium, there have been around a dozen different outbreaks, several capturing international interest. The outbreak of severe acute respiratory syndrome coronavirus saw the beginning of an extensive global collaboration and has influenced many outbreak preparedness protocols now in place. Avian influenza is a particular threat, with cases of A(H5N1) and A(H7N9) reported most recently. Middle East respiratory syndrome coronavirus is causing continuing concerns with outbreaks in the Arabian Peninsula. Healthcare facilities worldwide play a crucial role in identifying threats and must be vigilant. Particularly important is identifying and managing emerging respiratory viruses when they are infrequently encountered. Surveillance, continuing research, vaccine and treatment developments are key to guiding the efforts and actions of healthcare workers, international health organizations, governments and other stakeholders. Each individual has a part to play in protecting our global health.
Background: Small and sick newborns need high quality specialised care within health facilities to address persistently high neonatal mortality in low-income settings, including Kenya. Methods: We examined neonatal admissions in 12 public-sector County (formerly District) hospitals in Kenya between November 2014 and November 2016. Using data abstracted from newborn unit (NBU) admission registers and paediatric ward (PW) medical records, we explore the magnitude and distribution of admissions. In addition, interviews with senior staff were conducted to understand admission policies for newborns in these facilities. Results: Of the total 80,666 paediatric admissions, 28,884 (35.8%) were aged ≤28 days old. 24,212 (83.8%) of newborns were admitted to organisationally distinct NBU and 4,672 (16.2%) to general PW, though the proportion admitted to NBUs varied substantially (range 59.9-99.0%) across hospitals, reflecting widely varying infrastructure and policies. Neonatal mortality was high in NBU (12%) and PW (11%), though varied widely across facilities, with documentation of outcomes poor for the NBU. Conclusion: Improving quality of care on NBUs would affect almost a third of paediatric admissions in Kenya. However, comprehensive policies and strategies are needed to ensure sick newborns on general PWs also receive appropriate care.
There is a dearth of literature on priority setting and resource allocation (PSRA) practices in hospitals, particularly in low and middle income countries (LMICs). Using a case study approach, we examined PSRA practices in 2 public hospitals in coastal Kenya. We collected data through 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 of PSRA practices in case study hospitals over a period of 7 months. In this paper, we apply complex adaptive system (CAS) theory to examine the factors that influence PSRA practices. We found that PSRA practices in the case hospitals were influenced by, 1) inadequate financing level and poorly designed financing arrangements, 2) limited hospital autonomy and decision space, and 3) inadequate management and leadership capacity in the hospital. The case study hospitals exhibited properties of complex adaptive systems (CASs) that exist in a dynamic state with multiple interacting agents. Weaknesses in system 'hardware' (resource scarcity) and 'software' (including PSRA guidelines that reduced hospitals decision space, and poor leadership skills) led to the emergence of undesired properties. The capacity of hospitals to set priorities should be improved across these interacting aspects of the hospital organizational system. Interventions should however recognize that hospitals are CAS. Rather than rectifying isolated aspects of the system, they should endeavor to create conditions for productive emergence.
OBJECTIVE: To examine trends in prescription of cough medicines over the period 2002-2015 in children aged 1 month to 12 years admitted to Kenyan hospitals with cough, difficulty breathing or diagnosed with a respiratory tract infection. METHODS: We reviewed hospitalisation records of children included in four studies providing cross-sectional prevalence estimates from government hospitals for six time periods between 2002 and 2015. Children with an atopic illness were excluded. Amongst eligible children, we determined the proportion prescribed any adjuvant medication for cough. Active ingredients in these medicines were often multiple and were classified into five categories: antihistamines, antitussives, mucolytics/expectorants, decongestants and bronchodilators. From late 2006, guidelines discouraging cough medicine use have been widely disseminated and in 2009 national directives to decrease cough medicine use were issued. RESULTS: Across the studies, 17 963 children were eligible. Their median age and length of hospital stay were comparable. The proportion of children who received cough medicines shrank across the surveys: approximately 6% [95% CI: 5.4, 6.6] of children had a prescription in 2015 vs. 40% [95% CI: 35.5, 45.6] in 2002. The most common active ingredients were antihistamines and bronchodilators. The relative proportion that included antihistamines has increased over time. CONCLUSIONS: There has been an overall decline in the use of cough medicines among hospitalised children over time. This decline has been associated with educational, policy and mass media interventions.
Severe anemia is a leading indication for blood transfusion and a major cause of hospital admission and mortality in African children. Failure to initiate blood transfusion rapidly enough contributes to anemia deaths in sub-Saharan Africa. This article examines delays in accessing blood and outcomes in transfused children in Kenyan hospitals. Children admitted with nonsurgical conditions in 10 Kenyan county hospitals participating in the Clinical Information Network who had blood transfusion ordered from September 2013 to March 2016 were studied. The delay in blood transfusion was calculated from the date when blood transfusion was prescribed to date of actual transfusion. Five percent (2,875/53,174) of admissions had blood transfusion ordered. Approximately half (45%, 1,295/2,875) of children who had blood transfusion ordered at admission had a documented hemoglobin < 5 g/dl and 36% (2,232/6,198) of all children admitted with a diagnosis of anemia were reported to have hemoglobin < 5 g/dL. Of all the ordered transfusions, 82% were administered and documented in clinical records, and three-quarters of these (75%, 1,760/2,352) were given on the same day as ordered but these proportions varied from 71% to 100% across the 10 hospitals. Children who had a transfusion ordered but did not receive the prescribed transfusion had a mortality of 20%, compared with 12% among those transfused. Malaria-associated anemia remains the leading indication for blood transfusion in acute childhood illness admissions. Delays in transfusion are common and associated with poor outcomes. Variance in delay across hospitals may be a useful indicator of health system performance.
Antibodies play a key role in acquired human immunity toPlasmodium falciparum(Pf) malaria and target merozoites to reduce or prevent blood-stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen-specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen-specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance.
This paper describes and evaluates the budgeting and planning processes in public hospitals in Kenya. We used a qualitative case study approach to examine these processes in two hospitals in Kenya. We collected data by in-depth interviews of national level policy makers, hospital managers, and frontline practitioners in the case study hospitals (n = 72), a review of documents, and non-participant observations within the hospitals over a 7 month period. We applied an evaluative framework that considers both consequentialist and proceduralist conditions as important to the quality of priority-setting processes. The budgeting and planning process in the case study hospitals was characterized by lack of alignment, inadequate role clarity and the use of informal priority-setting criteria. With regard to consequentialist conditions, the hospitals incorporated economic criteria by considering the affordability of alternatives, but rarely considered the equity of allocative decisions. In the first hospital, stakeholders were aware of - and somewhat satisfied with - the budgeting and planning process, while in the second hospital they were not. Decision making in both hospitals did not result in reallocation of resources. With regard to proceduralist conditions, the budgeting and planning process in the first hospital was more inclusive and transparent, with the stakeholders more empowered compared to the second hospital. In both hospitals, decisions were not based on evidence, implementation of decisions was poor and the community was not included. There were no mechanisms for appeals or to ensure that the proceduralist conditions were met in both hospitals. Public hospitals in Kenya could improve their budgeting and planning processes by harmonizing these processes, improving role clarity, using explicit priority-setting criteria, and by incorporating both consequentialist (efficiency, equity, stakeholder satisfaction and understanding, shifted priorities, implementation of decisions), and proceduralist (stakeholder engagement and empowerment, transparency, use of evidence, revisions, enforcement, and incorporating community values) conditions.
BACKGROUND: Population-based serologic studies are a vital tool for understanding the epidemiology of influenza and other respiratory viruses, including the early assessment of the transmissibility and severity of the 2009 influenza pandemic, and Middle East respiratory syndrome coronavirus. However, interpretation of the results of serologic studies has been hampered by the diversity of approaches and the lack of standardized methods and reporting. OBJECTIVE: The objective of the CONSISE ROSES-I statement was to improve the quality and transparency of reporting of influenza seroepidemiologic studies and facilitate the assessment of the validity and generalizability of published results. METHODS: The ROSES-I statement was developed as an expert consensus of the CONSISE epidemiology and laboratory working groups. The recommendations are presented in the familiar format of a reporting guideline. Because seroepidemiologic studies are a specific type of observational epidemiology study, the ROSES-I statement is built upon the STROBE guidelines. As such, the ROSES-I statement should be seen as an extension of the STROBE guidelines. RESULTS: The ROSES-I statement presents 42 items that can be used as a checklist of the information that should be included in the results of published seroepidemiologic studies, and which can also serve as a guide to the items that need to be considered during study design and implementation. CONCLUSIONS: We hope that the ROSES-I statement will contribute to improving the quality of reporting of seroepidemiologic studies.
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