46 results found
Knackstedt S, Georgiadou A, Apel F, et al., 2019, Neutrophil extracellular traps drive inflammatory pathogenesis in malaria, Science Immunology, Vol: 4, Pages: 1-17, ISSN: 2470-9468
Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs). This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via GCSF production, and induction of the endothelial cytoadhesion receptor ICAM-1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.
Levin M, Cunnington AJ, Hoggart CJ, 2019, Secondary re-analysis of the FEAST trial - Authors' reply, The Lancet Respiratory Medicine, Vol: 7, Pages: e31-e31, ISSN: 2213-2600
Charani E, Cunnington AJ, Yousif AHA, et al., 2019, In transition: current health challenges and priorities in Sudan, BMJ Global Health, Vol: 4, ISSN: 2059-7908
A recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal, and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency, and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the UN sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.
Evans C, Fitzgerald F, Cunnington A, 2019, Review of UK malaria treatment guidelines 2016 (Public Health England Advisory Committee on Malaria Prevention), ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION, Vol: 104, Pages: 218-220, ISSN: 1743-0585
Levin M, Cunnington A, Hoggart C, Adverse effects of saline or albumin fluid bolus in resuscitation: response to Maitland et al. and Quartagno et al., Lancet Respiratory Medicine, ISSN: 2213-2600
Levin M, Cunnington AJ, Wilson C, et al., 2019, Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial, Lancet Respiratory Medicine, Vol: 7, Pages: 581-593, ISSN: 2213-2600
BACKGROUND: Fluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry. METHODS: We developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593. FINDINGS: Increasing respiratory (odds ratio 1·09, 95% CI 1·07-1·11), neurological (1·26, 1·21-1·31), and cardiovascular scores (1·09, 1·05-1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20-0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76-2·06; p=0·0002) in mean base excess and increase o
Georgiadou A, Lee HJ, Walther M, et al., Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions, Nature Microbiology, ISSN: 2058-5276
During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in severe malaria cases, with severe anemia being more insidious than cerebral malaria. We predicted that parasite growth-inhibition was associated with platelet consumption, lower expression of CXCL10 and type-1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. Parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.
Georgiadou A, Cunnington AJ, 2019, Shedding of the vascular endothelial glycocalyx - a common pathway to severe malaria?, Clinical Infectious Diseases, ISSN: 1058-4838
Thompson H, Hogan A, Walker P, et al., 2018, MODELLING THE RELATIVE ROLES OF ANTIBODY TITRE AND AVIDITY IN PROTECTION FROM <it>PLASMODIUM FALCIPARUM</it> INFECTION FOLLOWING RTS,S VACCINATION IN A HUMAN CHALLENGE STUDY, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 468-468, ISSN: 0002-9637
van Beek A, Pouw R, Sarr I, et al., 2018, Complement factor H levels associate with severity of Plasmodium falciparum malaria, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 234-234, ISSN: 0161-5890
van Beek AE, Sarr I, Correa S, et al., 2018, Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity., Open Forum Infect Dis, Vol: 5, ISSN: 2328-8957
Background: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity. Methods: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity. Results: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load. Conclusions: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.
Lee HJ, Georgiadou A, Walther M, et al., 2018, Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria, Science Translational Medicine, Vol: 10, ISSN: 1946-6234
The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.
Lee HJ, Georgiadou A, Otto T, et al., 2018, Transcriptomic studies in malaria – a paradigm for investigation of systemic host-pathogen interactions, Microbiology and Molecular Biology Reviews, Vol: 82, ISSN: 1092-2172
Transcriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analysis of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions. This exciting prospect is not without challenges, especially as focus moves from interactions in vitro under tightly controlled conditions to tissue-and systemic-level interactions in animal models and natural and experimental infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria, a parasitic disease which has exerted a major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria as a paradigm for transcriptomic assessment of systemic host-pathogen interaction in humans, because much of the direct host-pathogen interaction occurs within the blood–a readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria, and how these may guide studies of host-pathogen interaction in other infectious diseases. We propose that the potential of transcriptomic studies to improve understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence of technological constraints. Further advances will require integration of transcriptomic data with analytical approaches from other scientific disciplines including epidemiology and mathematical modelling.
Mcardle A, Turkova A, Cunnington A, 2018, When do co-infections matter?, Current Opinion in Infectious Diseases, Vol: 31, Pages: 209-215, ISSN: 0951-7375
Purpose of review: Advances in diagnostic methods mean that co-infections are increasingly being detected in clinical practice, yet their significance is not always obvious. In parallel, basic science studies are increasingly investigating interactions between pathogens to try to explain real-life observations and elucidate biological mechanisms. Recent findings: Co-infections may be insignificant, detrimental or even beneficial, and these outcomes can occur through multiple levels of interactions which include modulation of the host response, altering the performance of diagnostic tests and drug-drug interactions during treatment. The harmful effects of chronic co-infections such as tuberculosis or Hepatitis B and C in association with HIV are well established, and recent studies have focussed on strategies to mitigate these effects. However consequences of many acute co-infections are much less certain, and recent conflicting findings simply highlight many of the challenges of studying naturally acquired infections in humans. Summary: Tackling these challenges, using animal models or careful prospective studies in humans may prove to be worthwhile. There are already tantalising examples where identification and treatment of relevant co-infections seems to hold promise for improved health outcomes.
Evans C, Fitzgerald F, Cunnington A, Review of UK malaria treatment guidelines 2016, Archives of Disease in Childhood.education and Practice Edition, ISSN: 1743-0585
Georgiadou A, Bretscher M, Lee H, et al., 2018, COMBINING RNA-SEQUENCING AND MATHEMATICAL MODELLING TO IDENTIFY MECHANISTIC CORRELATES OF PROTECTION IN MALARIA, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 27-27, ISSN: 0002-9637
Ikeda AK, Rowley C, Yang Y, et al., 2017, PLASMA HAPTOGLOBIN AS A MARKER OF CLINICAL SEVERITY IN GAMBIAN AND MALAWIAN CHILDREN INFECTED WITH PLASMODIUM FALCIPARUM, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 464-464, ISSN: 0002-9637
Lee HJ, Walther M, Georgiadou A, et al., 2017, Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>The pathogenesis of severe <jats:italic>Plasmodium falciparum</jats:italic> malaria is incompletely understood. Since the pathogenic stage of the parasite is restricted to blood, dual RNA-sequencing of host and parasite transcripts in blood can reveal their interactions at a systemic scale. Here we identify human and parasite gene expression associated with severe disease features in Gambian children. Differences in parasite load explained up to 99% of differential expression of human genes but only a third of the differential expression of parasite genes. Co-expression analyses showed a remarkable co-regulation of host and parasite genes controlling translation, and host granulopoiesis genes uniquely co-regulated and differentially expressed in severe malaria. Our results indicate that high parasite load is the proximal stimulus for severe <jats:italic>P. falciparum</jats:italic> malaria, that there is an unappreciated role for many parasite genes in determining virulence, and hint at a molecular arms-race between host and parasite to synthesise protein products.</jats:p>
Soothill G, Darboe S, Bah G, et al., 2017, Invasive bacterial infections in gambian patients with Sickle Cell Anemia in an era of widespread pneumococcal and haemophilus influenza type B vaccination, 22nd Congress of the European-Hematology-Association, Publisher: Ferrata Storti Foundation, Pages: 606-606, ISSN: 0390-6078
Cheung R, Cunnington A, Drysdale S, et al., 2017, 100 Cases in Paediatrics, Second Edition, Publisher: CRC Press, ISBN: 9781315351599
The new edition of this best-selling title from the popular 100 cases series explores common paediatric scenarios that will be encountered by the medical student and junior doctor during practical training on the ward, in the emergency ...
Soothill G, Darboe S, Bah G, et al., 2016, Invasive bacterial infections in Gambians with sickle cell anaemia in an era of widespread Pneumococcal and Haemophilus influenzae type B vaccination, Medicine, Vol: 95, ISSN: 0025-7974
Background: There is relatively little data on the aetiology of bacterial infections in patients with sickle cell anaemia (SCA) in West Africa, and no data from countries that have implemented conjugate vaccines against both Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Methods: We conducted a retrospective analysis of SCA patients admitted to the Medical Research Council Unit, The Gambia during a five-year period when there was high coverage of Hib and Pneumococcal conjugate vaccination. We evaluated 161 admissions of 126 patients between April 2010 and April 2015. Results: Pathogenic bacteria were identified in blood cultures from 11 of the 131 admissions that had cultures taken (8.4%, 95% CI 4.5-14.1%). The most frequent isolate was Salmonella Typhimurium (6/11; 54.5%), followed by Staphylococcus aureus (2/11; 18.2%) and other enteric Gram-negative pathogens (2/11; 18.2%) and there was one case of H. influenzae non-type b bacteraemia (1/11; 9.1%). There were no episodes of bacteraemia caused by S. pneumoniae or Hib. Conclusions: The low prevalence of S. pneumoniae and Hib, and the predominance of non-typhoidal Salmonella as a cause of bacteraemia suggest the need to reconsider optimal antimicrobial prophylaxis and the empirical treatment regimens for patients with SCA.
McArdle AJ, Webbe J, Sim K, et al., 2016, Determinants of Carboxyhemoglobin Levels and Relationship with Sepsis in a Retrospective Cohort of Preterm Neonates, PLOS One, Vol: 11, ISSN: 1932-6203
Carboxyhemoglobin levels in blood reflect endogenous carbon monoxide production and are often measured during routine blood gas analysis. Endogenous carbon monoxide production has been reported to be increased during sepsis, but carboxyhemoglobin levels have not been thoroughly evaluated as a biomarker of sepsis. We sought to determine whether carboxyhemoglobin levels were elevated during sepsis in a high risk population of premature neonates. We conducted a retrospective cohort study of 30 infants in two neonatal intensive care units using electronic medical and laboratory records. The majority of infants were extremely premature and extremely low birth weight, and 25 had at least one episode of sepsis. We collected all carboxyhemoglobin measurements during their in-patient stay and examined the relationship between carboxyhemoglobin and a variety of clinical and laboratory parameters, in addition to the presence or absence of sepsis, using linear mixed-effect models. We found that postnatal age had the most significant effect on carboxyhemoglobin levels, and other significant associations were identified with gestational age, hemoglobin concentration, oxyhemoglobin saturation, and blood pH. Accounting for these covariates, there was no significant relationship between the onset of sepsis and carboxyhemoglobin levels. Our results show that carboxyhemoglobin is unlikely to be a clinically useful biomarker of sepsis in premature infants, and raise a note of caution about factors which may confound the use of carbon monoxide as a clinical biomarker for other disease processes such as hemolysis.
Cunnington AJ, 2016, Author's reply to Banda and Lokugamage, British Medical Journal, Vol: 352, ISSN: 1468-5833
Cunnington A, Sim K, Deierl A, et al., 2016, “Vaginal seeding” of infants born by Caesarean section.How should health professionals engage with this increasingly popular but unproven practice?, BMJ, Vol: 352, ISSN: 0959-8138
Chertow JH, Alkaitis MS, Nardone G, et al., 2015, Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis., PLOS Pathogens, Vol: 11, ISSN: 1553-7366
Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.
Evans C, Orf K, Horvath E, et al., 2015, Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1, Haematologica - the Hematology Journal, Vol: 100, Pages: 1508-1516, ISSN: 0390-6078
Sickle cell disease is a risk factor for invasive bacterial infections, and splenic dysfunction is believed to be the main underlying cause. We have previously shown that the liberation of heme in acute hemolysis can induce heme oxygenase-1 during granulopoiesis, impairing the ability of developing neutrophils to mount a bactericidal oxidative burst, and increasing susceptibility to bacterial infection. We hypothesised that this may also occur with the chronic hemolysis of sickle cell disease, potentially contributing to susceptibility to infections. We found that neutrophil oxidative burst activity was significantly lower in treatment-naive children with sickle cell disease compared to age-, gender- and ethnicity-matched controls, whilst degranulation was similar. The defect in neutrophil oxidative burst was quantitatively related to both systemic heme oxygenase-1 activity (assessed by carboxyhemoglobin concentration) and neutrophil mobilization. A distinct population of heme oxygenase-1-expressing cells was present in the bone marrow of children with sickle cell disease, but not in healthy children, with a surface marker profile consistent with neutrophil progenitors (CD49dHi CD24Lo CD15Int CD16Int CD11b+/-). Incubation of promyelocytic HL-60 cells with the heme oxygenase-1 substrate and inducer, hemin, demonstrated that heme oxygenase-1 induction during neutrophilic differentiation could reduce oxidative burst capacity. These findings indicate that impairment of neutrophil oxidative burst activity in sickle cell disease is associated with hemolysis and heme oxygenase-1 expression. Neutrophil dysfunction might contribute to risk of infection in sickle cell disease, and measurement of neutrophil oxidative burst might be used to identify patients at greatest risk of infection, who might benefit from enhanced prophylaxis.
Cunnington A, Orf K, 2015, Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection, Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X
Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterised by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defence mechanisms, including macrophage dysfunction, neutrophil dysfunction and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.
Cunnington AJ, 2015, The Importance of Pathogen Load, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
Takem EN, Roca A, Cunnington A, 2014, The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review, MALARIA JOURNAL, Vol: 13, ISSN: 1475-2875
Cunnington AJ, Riley EM, Walther M, 2013, Stuck in a rut? Reconsidering the role of parasite sequestration in severe malaria syndromes, TRENDS IN PARASITOLOGY, Vol: 29, Pages: 585-592, ISSN: 1471-4922
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.