James A Berkley

University of Oxford, Oxford, England, United Kingdom

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Publications (112)1135.01 Total impact

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    ABSTRACT: HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag-specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class-switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV-infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age-dependent accumulation of resting memory B cells. Copyright © 2015 The Authors.
    The Journal of Immunology 06/2015; DOI:10.4049/jimmunol.1500491 · 5.36 Impact Factor
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    ABSTRACT: Ready-to-use therapeutic foods (RUTFs) are a key component of a life-saving treatment for young children who present with uncomplicated severe acute malnutrition in resource limited settings. Increasing recognition of the role of balanced dietary omega-6 and omega-3 polyunsaturated fatty acids (PUFA) in neurocognitive and immune development led two independent groups to evaluate RUTFs. Jones et al. (BMC Med 13:93, 2015), in a study in BMC Medicine, and Hsieh et al. (J Pediatr Gastroenterol Nutr 2015), in a study in the Journal of Pediatric Gastroenterology and Nutrition, reformulated RUTFs with altered PUFA content and looked at the effects on circulating omega-3 docosahexaenoic acid (DHA) status as a measure of overall omega-3 status. Supplemental oral administration of omega-3 DHA or reduction of RUTF omega-6 linoleic acid using high oleic peanuts improved DHA status, whereas increasing omega-3 alpha-linolenic acid in RUTF did not. The results of these two small studies are consistent with well-established effects in animal studies and highlight the need for basic and operational research to improve fat composition in support of omega-3-specific development in young children as RUTF use expands. Please see related article: http://www.biomedcentral.com/1741-7015/13/93
    BMC Medicine 05/2015; 13(1). DOI:10.1186/s12916-015-0352-1 · 7.28 Impact Factor
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    ABSTRACT: Scale up of antiretroviral therapy (ART) has led to substantial declines in HIV related morbidity and mortality. However, attrition from ART care remains a major public health concern and has been identified as one of the key reportable indicators in assessing the success of ART programs. To describe the incidence and predictors of attrition among adults initiating ART in a rural HIV clinic in Coastal Kenya. A retrospective cohort study design was used. Adults (≥15 years) initiated ART between January 2008 and December 2010 were followed up for two years. Attrition was defined as individuals who were either reported dead or lost to follow up (LFU, ≥ 180 days late since the last clinic visit). Kaplan Meier survival probabilities and Weibull baseline hazard regression analyses were used to model the incidence and predictors of time to attrition. Of the 928 eligible participants, 308 (33.2% [95% CI, 30.2 - 36.3]) underwent attrition at an incident rate of 23.1 (95% CI, 20.6 - 25.8)/100 pyo. Attrition at 6 and 12 months was 18.4% (95% CI, 16.0 - 21.1) and 23.2% (95% CI, 19.9 - 25.3) respectively. Gender (male vs. female, adjusted hazard ratio [95% CI], p-value: 1.5 [1.1 - 2.0], p = 0.014), age (15 - 24 vs. ≥ 45 years, 2.2 [1.3 - 3.7], p = 0.034) and baseline CD4 T-cell count (100 - 350 cells/uL vs. <100 cells/uL, 0.5 [0.3 - 0.7], p = 0.002) were independent predictors of time to attrition. A third of individuals initiating ART were either reported dead or LFU during two years of care, with more than a half of these occurring within six months of treatment initiation. Practical and sustainable biomedical interventions and psychosocial support systems are warranted to improve ART retention in this setting.
    BMC Public Health 05/2015; 15(1):478. DOI:10.1186/s12889-015-1814-2 · 2.32 Impact Factor
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    ABSTRACT: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrolment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. Clinicaltrials.gov NCT01593969 . Registered 4 May 2012.
    BMC Medicine 04/2015; 13(1):93. DOI:10.1186/s12916-015-0315-6 · 7.28 Impact Factor
  • Anna C Seale, Christina W Obiero, James A Berkley
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    ABSTRACT: This review discusses the rational development of guidelines for the management of neonatal sepsis in developing countries. Diagnosis of neonatal sepsis with high specificity remains challenging in developing countries. Aetiology data, particularly from rural, community-based studies, are very limited, but molecular tests to improve diagnostics are being tested in a community-based study in South Asia. Antibiotic susceptibility data are limited, but suggest reducing susceptibility to first-and second-line antibiotics in both hospital and community-acquired neonatal sepsis. Results of clinical trials in South Asia and sub-Saharan Africa assessing feasibility of simplified antibiotic regimens are awaited. Effective management of neonatal sepsis in developing countries is essential to reduce neonatal mortality and morbidity. Simplified antibiotic regimens are currently being examined in clinical trials, but reduced antimicrobial susceptibility threatens current empiric treatment strategies. Improved clinical and microbiological surveillance is essential, to inform current practice, treatment guidelines, and monitor implementation of policy changes.
    Current Opinion in Infectious Diseases 04/2015; 28(3). DOI:10.1097/QCO.0000000000000163 · 5.03 Impact Factor
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    ABSTRACT: Background
    PLoS ONE 04/2015; 10(4). DOI:10.1371/journal.pone.0122606 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Neonatal Tetanus (NT) is a preventable cause of mortality and neurological sequelae that occurs at higher incidence in resource-poor countries, presumably because of low maternal immunisation rates and unhygienic cord care practices. We aimed to determine changes in the incidence of NT, characterize and investigate the associated risk factors and mortality in a prospective cohort study including all admissions over a 15-year period at a County hospital on the Kenyan coast, a region with relatively high historical NT rates within Kenya. METHODS: We assessed all neonatal admissions to Kilifi County Hospital in Kenya (1999-2013) and identified cases of NT (standard clinical case definition) admitted during this time. Poisson regression was used to examine change in incidence of NT using accurate denominator data from an area of active demographic surveillance. Logistic regression was used to investigate the risk factors for NT and factors associated with mortality in NT amongst neonatal admissions. A subset of sera from mothers (n = 61) and neonates (n = 47) were tested for anti-tetanus antibodies. RESULTS: There were 191 NT admissions, of whom 187 (98%) were home deliveries. Incidence of NT declined significantly (Incidence Rate Ratio: 0.85 (95% Confidence interval 0.81-0.89), P<0.001) but the case fatality (62%) did not change over the study period (P = 0.536). Younger infant age at admission (P = 0.001) was the only independent predictor of mortality. Compared to neonatal hospital admittee controls, the proportion of home births was higher among the cases. Sera tested for antitetanus antibodies showed most mothers (50/61, 82%) had undetectable levels of antitetanus antibodies, and most (8/9, 89%) mothers with detectable antibodies had a neonate without protective levels. CONCLUSIONS: Incidence of NT in Kilifi County has significantly reduced, with reductions following immunisation campaigns. Our results suggest immunisation efforts are effective if sustained and efforts should continue to expand coverage.
    PLoS ONE 04/2015; · 3.53 Impact Factor
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    ABSTRACT: By engaging expert opinion, Marko Kerac and colleagues set research priorities for the management of acute malnutrition in infants.
    PLoS Medicine 04/2015; 12(4):e1001812. DOI:10.1371/journal.pmed.1001812 · 14.00 Impact Factor
  • Christina W Obiero, Anna C Seale, James A Berkley
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    ABSTRACT: Infections are among the leading causes of neonatal mortality, and about 75% of the burden occurs in developing countries. Diagnosis of neonatal sepsis in these countries is dependent on the recognition of a set of non-specific clinical signs that maximise sensitivity since staff making initial assessments may not have specialist paediatric training. Accurate diagnosis is usually limited by the unavailability of reliable microbiological investigation. The World Health Organization recommends ampicillin (or penicillin; cloxacilllin if staphylococcal infection is suspected) plus gentamicin for empiric treatment of neonates with suspected clinical sepsis or meningitis. However, there is a lack of comprehensive data on the causes of infection and antimicrobial susceptibility in developing countries to support these recommendations, especially in rural settings. Bacterial pathogens (predominantly Gram negative) with reduced susceptibility to empiric medication have been reported, with variations both between and within regions. Nosocomial infections with resistant organisms and high case fatality challenges the first-line use of cephalosporins. Improving local surveillance data using standardised antimicrobial susceptibility testing methods and validation of diagnostic algorithms against microbial findings are essential. Standardised reporting of treatment outcomes is required to evaluate practice, provide guidance on second-line regimes, and for studies of new approaches such as simplified community-based regimens and to determine the appropriate duration of empiric treatment for apparently low-risk neonates with early resolution of clinical signs, or where available, negative blood cultures. Thus, a multifaceted approach, with attention to microbiological quality-assurance, is needed to better guide antimicrobial use, and reduce mortality and long term impairments.
    The Pediatric Infectious Disease Journal 03/2015; 34(6). DOI:10.1097/INF.0000000000000692 · 3.14 Impact Factor
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    ABSTRACT: Globally, some 4.7 million infants aged under 6 months are moderately wasted and 3.8 million are severely wasted. Traditionally, they have been over-looked by clinicians, nutritionists, and policy makers. To present evidence and arguments for why treating acute malnutrition in infants under 6 months of age is important and outline some of the key debates and research questions needed to advance their care. Narrative review. Treating malnourished infants under 6 months of age is important to avoid malnutrition-associated mortality in the short-term and adverse health and development outcomes in the long-term. Physiological and pathological differences demand a different approach from that in older children; key among these is a focus on exclusive breastfeeding wherever possible. New World Health Organization guidelines for the management of severe acute malnutrition (SAM) include this age group for the first time and are also applicable to management of moderate acute malnutrition (MAM). Community-based breastfeeding support is the core, but not the sole, treatment. The mother-infant dyad is at the heart of approaches, but wider family and community relationships are also important. An urgent priority is to develop better case definitions; criteria based on mid-upper-arm circumference (MUAC) are promising but need further research. To effectively move forward, clinical trials of assessment and treatment are needed to bolster the currently sparse evidence base. In the meantime, nutrition surveys and screening at health facilities should routinely include infants under 6 months of age in order to better define the burden and outcomes of acute malnutrition in this age group.
    Food and nutrition bulletin 03/2015; 36(1):S30. · 1.50 Impact Factor
  • Rosie J Crane, Kelsey D J Jones, James A Berkley
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    ABSTRACT: Environmental enteric dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries. Understanding of EED and its possible consequences for health is currently limited. A narrative review of the current understanding of EED: epidemiology, pathogenesis, therapies, and relevance to child health. Searches for key papers and ongoing trials were conducted using PUBMED 1966-June 2014; ClinicalTrials.gov; the WHO Clinical Trials Registry; the Cochrane Library; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. EED is established during infancy and is associated with poor sanitation, certain gut infections, and micronutrient deficiencies. Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), abnormal gut microbiota, undernutrition, and toxins may all play a role. EED is usually asymptomatic, but it is important due to its association with stunting. Diagnosis is frequently by the dual sugar absorption test, although other biomarkers are emerging. EED may partly explain the reduced efficacy of oral vaccines in low- and middle-income countries and the increased risk of serious infection seen in children with undernutrition. Despite its potentially significant impacts, it is currently unclear exactly what causes EED and how it can be treated or prevented. Ongoing trials involve nutritional supplements, water and sanitation interventions, and immunomodulators. Further research is needed to better understand this condition, which is of likely crucial importance for child health and development in low- and middle-income settings.
    Food and nutrition bulletin 03/2015; 36(1 Suppl):S76-87. · 1.50 Impact Factor
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    Kelsey D J Jones, James A Berkley
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    ABSTRACT: Severe acute malnutrition (SAM) is associated with increased severity of common infectious diseases, and death amongst children with SAM is almost always as a result of infection. The diagnosis and management of infection are often different in malnourished versus well-nourished children. The objectives of this brief are to outline the evidence underpinning important practical questions relating to the management of infectious diseases in children with SAM and to highlight research gaps. Overall, the evidence base for many aspects covered in this brief is very poor. The brief addresses antimicrobials; antipyretics; tuberculosis; HIV; malaria; pneumonia; diarrhoea; sepsis; measles; urinary tract infection; nosocomial Infections; soil transmitted helminths; skin infections and pharmacology in the context of SAM. The brief is structured into sets of clinical questions, which we hope will maximise the relevance to contemporary practice.
    Annals of Tropical Paediatrics International Child Health 12/2014; 34 Suppl 1:S1-S29. DOI:10.1179/2046904714Z.000000000218 · 1.17 Impact Factor
  • Shiraz Badurdeen, Musa Mulongo, James A Berkley
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    ABSTRACT: Preterm newborns are highly susceptible to bacterial infections. This susceptibility is regarded as being due to immaturity of multiple pathways of the immune system. However, it is unclear whether a mechanism that unifies these different, suppressed pathways exists. Here we argue that the immune vulnerability of the preterm neonate is critically related to arginine depletion. Arginine, a 'conditionally essential' amino acid, is depleted in acute catabolic states, including sepsis. Its metabolism is highly compartmentalised and regulated, including by arginase-mediated hydrolysis. Recent data suggest that arginase II-mediated arginine depletion is essential for the innate immune suppression that occurs in newborn models of bacterial challenge impairing pathways critical for the immune response. Evidence that arginine depletion mediates protection from immune activation during first gut colonisation suggests a regulatory role in controlling gut-derived pathogens. Clinical studies show that plasma arginine is depleted during sepsis. In keeping with animal studies, small clinical trials of L-arginine supplementation have shown benefit in reducing necrotising enterocolitis in premature neonates. We propose a novel, broader hypothesis that arginine depletion during bacterial challenge is a key factor limiting the neonate's ability to mount an adequate immune response, contributing to the increased susceptibility to infections, particularly with respect to gut-derived sepsis.Pediatric Research (2014); doi:10.1038/pr.2014.177.
    Pediatric Research 10/2014; 77(2). DOI:10.1038/pr.2014.177 · 2.84 Impact Factor
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    ABSTRACT: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy.
    BMC Medicine 08/2014; 12(1):133. DOI:10.1186/s12916-014-0133-2 · 7.28 Impact Factor
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    ABSTRACT: Background Bacterial infections are a leading cause of the 2.9 million annual neonatal deaths. Treatment is usually based on clinical diagnosis of possible severe bacterial infection (pSBI). To guide programme planning, we have undertaken the first estimates of neonatal pSBI, by sex and by region, for sub-Saharan Africa, south Asia, and Latin America. Methods We induded data for pSBI incidence in neonates of 32 weeks' gestation or more (or birthweight >= 1500 g) with livebirth denominator data, undertaking a systematic review and forming an investigator group to obtain unpublished data. We calculated pooled risk estimates for neonatal pSBI and case fatality risk, by sex and by region. We then applied these risk estimates to estimates of livebirths in sub-Saharan Africa, south Asia, and Latin America to estimate cases and associated deaths in 2012. Findings We induded data from 22 studies, for 259 944 neonates and 20 196 pSBI cases, with most of the data (18 of the 22 studies) coming from the investigator group. The pooled estimate of pSBI incidence risk was 7.6% (95% CI 6.1-9.2%) and the case-fatality risk associated with pSBI was 9.8% (7.4-12.2). We estimated that in 2012 there were 6.9 million cases (uncertainty range 5.5 million-8.3 million) of pSBI in neonates needing treatment: 3.5 million (2.8 million-4.2 million) in south Asia, 2.6 million (2.1 million-3.1 million) in sub-Saharan Africa, and 0.8 million (0.7 million-1.0 million) in Latin America. The risk of pSBI was greater in boys (risk ratio 1.12, 95% CI 1.06-1.18) than girls. We estimated that there were 0.68 million (0.46 million-0.92 million) neonatal deaths associated with pSBI in 2012. Interpretation The need-to-treat population for pSBI in these three regions is high, with ten cases of pSBI diagnosed for each associated neonatal death. Deaths and disability can be reduced through improved prevention, detection, and case management.
    The Lancet Infectious Diseases 08/2014; DOI:10.1016/S1473-3099(14)70804-7 · 19.45 Impact Factor
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    ABSTRACT: The Sackler Institute for Nutrition Science and the World Health Organization (WHO) have worked together to formulate a research agenda for nutrition science. Undernutrition of children has profound effects on health, development, and achievement of full human capacity. Undernutrition is not simply caused by a lack of food, but results from a complex interplay of intra- and intergenerational factors. Representative preclinical models and comprehensive well-controlled longitudinal clinical studies are needed to further understand the contributions and the interrelationships among these factors and to develop interventions that are effective and durable. This paper summarizes work on mechanisms underlying the varied manifestations of childhood undernutrition and discusses current gaps in knowledge and challenges to our understanding of undernutrition and infection/immunity throughout the human life cycle, focusing on early childhood growth. It proposes a series of basic and clinical studies to address this global health challenge.
    Annals of the New York Academy of Sciences 08/2014; DOI:10.1111/nyas.12487 · 4.31 Impact Factor
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    ABSTRACT: Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure.
    Food and nutrition bulletin 06/2014; 35(2 Suppl):S64-70. · 1.50 Impact Factor

Publication Stats

3k Citations
1,135.01 Total Impact Points

Institutions

  • 1999–2015
    • University of Oxford
      • • Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)
      • • Nuffield Department of Clinical Medicine
      • • Department of Paediatrics
      Oxford, England, United Kingdom
  • 2002–2014
    • KEMRI-Wellcome Trust Research Programme
      Kilifi, Kilifi, Kenya
  • 2013
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2002–2012
    • Kenya Medical Research Institute
      • Centre for Clinical Research
      Nairoba, Nairobi Area, Kenya
  • 2006–2011
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Medicine
      Oxford, England, United Kingdom