41 results found
Hoyles L, Mayneris-Perxachs J, Cardellini M, et al., 2021, Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome, Microbiome, Vol: 9, Pages: 1-18, ISSN: 2049-2618
Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The
Brezovjakova H, Tomlinson C, Mohd Naim N, et al., 2019, Junction Mapper is a novel computer vision tool to decipher cell-cell contact phenotypes., eLife, Vol: 8, Pages: 1-48, ISSN: 2050-084X
Stable cell-cell contacts underpin tissue architecture and organization. Quantification of junctions of mammalian epithelia requires laborious manual measurements that are a major roadblock for mechanistic studies. We designed Junction Mapper as an open access, semi-automated software that defines the status of adhesiveness via the simultaneous measurement of pre-defined parameters at cell-cell contacts. It identifies contacting interfaces and corners with minimal user input and quantifies length, area and intensity of junction markers. Its ability to measure fragmented junctions is unique. Importantly, junctions that considerably deviate from the contiguous staining and straight contact phenotype seen in epithelia are also successfully quantified (i.e. cardiomyocytes or endothelia). Distinct phenotypes of junction disruption can be clearly differentiated among various oncogenes, depletion of actin regulators or stimulation with other agents. Junction Mapper is thus a powerful, unbiased and highly applicable software for profiling cell-cell adhesion phenotypes and facilitate studies on junction dynamics in health and disease.
White N, Oostendorp LJM, Tomlinson C, et al., 2019, Online training improves medical students' ability to recognise when a person is dying: The ORaClES randomised controlled trial, Palliative Medicine, Vol: 34, Pages: 134-144, ISSN: 0269-2163
Background:Recognising dying is a key clinical skill for doctors, yet there is little training.Aim:To assess the effectiveness of an online training resource designed to enhance medical students’ ability to recognise dying.Design:Online multicentre double-blind randomised controlled trial (NCT03360812). The training resource for the intervention group was developed from a group of expert palliative care doctors’ weightings of various signs/symptoms to recognise dying. The control group received no training.Setting/participants:Participants were senior UK medical students. They reviewed 92 patient summaries and provided a probability of death within 72 hours (0% certain survival – 100% certain death) pre, post, and 2 weeks after the training. Primary outcome: (1) Mean Absolute Difference (MAD) score between participants’ and the experts’ scores, immediately post intervention. Secondary outcomes: (2) weight attributed to each factor, (3) learning effect and (4) level of expertise (Cochran–Weiss–Shanteau (CWS)).Results:Out of 168 participants, 135 completed the trial (80%); 66 received the intervention (49%). After using the training resource, the intervention group had better agreement with the experts in their survival estimates (δMAD = −3.43, 95% CI −0.11 to −0.34, p = <0.001) and weighting of clinical factors. There was no learning effect of the MAD scores at the 2-week time point (δMAD = 1.50, 95% CI −0.87 to 3.86, p = 0.21). At the 2-week time point, the intervention group was statistically more expert in their decision-making versus controls (intervention CWS = 146.04 (SD 140.21), control CWS = 110.75 (SD 104.05); p = 0.01).Conclusion:The online training resource proved effective in altering the decision-making of medical students to agree more with expert decision-making.
White N, Reid F, Vickerstaff V, et al., 2019, Imminent death: Clinician certainty and accuracy of prognostic predictions, BMJ Supportive & Palliative Care, ISSN: 2045-435X
Objectives To determine the accuracy of predictions of dying at different cut-off thresholds and to acknowledge the extent of clinical uncertainty.Design Secondary analysis of data from a prospective cohort study.Setting An online prognostic test, accessible by eligible participants across the UK.Participants Eligible participants were members of the Association of Palliative Medicine. 99/166 completed the test (60%), resulting in 1980 estimates (99 participants × 20 summaries).Main outcome measures The probability of death occurring within 72 hours (0% certain survival−100% certain death) for 20 patient summaries. The estimates were analysed using five different thresholds: 50/50%, 40/60%, 30/70%, 20/80% and 10/90%, with percentage values between these extremes being regarded as ‘indeterminate’. The positive predictive value (PPV), negative predictive value (NPV) and the number of indeterminate cases were calculated for each cut-off.Results Using a <50% versus >50% threshold produced a PPV of 62%, an NPV of 74% and 5% indeterminate cases. When the threshold was changed to ≤10% vs ≥90%, the PPV and NPV increased to 75% and 88%, respectively, at the expense of an increase of indeterminate cases up to 62%.Conclusion When doctors assign a very high (≥90%) or very low (≤10%) probability of imminent death, their prognostic accuracy is improved; however, this increases the number of ‘indeterminate’ cases. This suggests that clinical predictions may continue to have a role for routine prognostication but that other approaches (such as the use of prognostic scores) may be required for those cases where doctors’ estimates are indeterminate.
White N, Oostendorp L, Vickerstaff V, et al., 2019, An online international comparison of thresholds for triggering a negative response to the “Surprise Question”: a study protocol, BMC Palliative Care, Vol: 18, ISSN: 1472-684X
BackgroundThe Surprise Question (SQ) “would I be surprised if this patient were to die in the next 12 months?” has been suggested to help clinicians, and especially General Practitioners (GPs), identify people who might benefit from palliative care. The prognostic accuracy of this approach is unclear and little is known about how GPs use this tool in practice. Are GPs consistent, individually and as a group? Are there international differences in the use of the tool? Does including the alternative Surprise Question (“Would I be surprised if the patient were still alive after 12 months?”) alter the response? What is the impact on the treatment plan in response to the SQ? This study aims to address these questions.MethodsAn online study will be completed by 600 (100 per country) registered GPs. They will be asked to review 20 hypothetical patient vignettes. For each vignette they will be asked to provide a response to the following four questions: (1) the SQ [Yes/No]; (2) the alternative SQ [Yes/No]; (3) the percentage probability of dying [0% no chance – 100% certain death]; and (4) the proposed treatment plan [multiple choice]. A “surprise threshold” for each participant will be calculated by comparing the responses to the SQ with the probability estimates of death. We will use linear regression to explore any differences in thresholds between countries and other clinician-related factors, such as years of experience. We will describe the actions taken by the clinicians and explore the differences between groups. We will also investigate the relationship between the alternative SQ and the other responses. Participants will receive a certificate of completion and the option to receive feedback on their performance.DiscussionThis study explores the extent to which the SQ is consistently used at an individual, group, and national level. The findings of this study will help to understand the clinical value of using the SQ in rou
Oostendorp L, White N, Harries P, et al., 2019, Protocol for the ORaClES study: an online randomised controlled trial to improve clinical estimates of survival using a training resource for medical students, BMJ Open, Vol: 9, ISSN: 2044-6055
Introduction Clinicians often struggle to recognise when palliative care patients are imminently dying (last 72 hours of life). A previous study identified the factors that expert palliative care doctors (with demonstrated prognostic skills) had used, to form a judgement about which patients were imminently dying. This protocol describes a study to evaluate whether an online training resource showing how experts weighted the importance of various symptoms and signs can teach medical students to formulate survival estimates for palliative care patients that are more similar to the experts’ estimates.Methods and analysis This online double-blind randomised controlled trial will recruit at least 128 students in the penultimate or final year of medical school in the UK. Participants are asked to review three series of vignettes describing patients referred to palliative care and provide an estimate about the probability (0%–100%) that each patient will die within 72 hours. After the first series, students randomised to the intervention arm are given access to an online training resource. All participants are asked to complete a second series of vignettes. After 2 weeks, all participants are asked to complete a third series. The primary outcome will be the probability of death estimates (0%–100%) provided by students in the intervention and control arms for the second series of vignettes. Secondary outcomes include the maintenance effect at 2-week follow-up, weighting of individual symptoms and signs, and level of expertise (discrimination and consistency).Ethics and dissemination Approval has been obtained from the UCL Research Ethics Committee (8675/002) and local approvals will be obtained as appropriate. Results will be published in peer-reviewed journals using an open access format and presented at academic conferences. We will also publicise our findings on the Marie Curie website
White N, Harries P, Harris AJL, et al., 2018, How do palliative care doctors recognise imminently dying patients? A judgement analysis, BMJ Open, Vol: 8, ISSN: 2044-6055
Objectives To identify a group of palliative care doctors who perform well on a prognostic test and to understand how they make their survival predictions.Design Prospective observational study and two cross-sectional online studies.Setting Phase I: an online prognostic test, developed from a prospective observational study of patients referred to palliative care. Phase II: an online judgement task consisting of 50 hypothetical vignettes.Participants All members of the Association of Palliative Medicine (APM) were eligible (n=~1100). 99 doctors completed the prognostic test and were included in the phase I analysis. The top 20% were invited to participate in phase II; 14/19 doctors completed the judgement task and were included in the phase II analysis.Measures Phase I: participants were asked to give a probability of death within 72 hours (0%–100%) for all 20 cases. Accuracy on the prognostic test was measured with the Brier score which was used to identify the ‘expert’ group (scale range: 0 (expert)–1 (non-expert)). Phase II: participants gave a probability of death within 72 hours (0%–100%). A mixed model regression analysis was completed using the percentage estimate as the outcome and the patient information included in the vignettes as the predictors.Results The mean Brier score of all participants was 0.237 (95% CI 0.235 to 0.239). The mean Brier score of the ‘experts’ was 0.184 (95% CI 0.176 to 0.192). Six of the seven prognostic variables included in the hypothetical vignettes were significantly associated with clinician predictions of death. The Palliative Performance Score was identified as being the most influential in the doctors’ prognostic decision making (β=0.48, p<0.001).Conclusions This study identified six clinical signs and symptoms which influenced the judgement policies of palliative care doctors. These results may be used to teach novice doctors how to improve their prognost
Harries P, Gokalp H, Davies M, et al., 2018, Enhanced referral prioritisation for acute adult dietetic services: A randomised control trial to test a web-based decision training tool, CLINICAL NUTRITION, Vol: 37, Pages: 1456-1461, ISSN: 0261-5614
Hoyles L, Fernandez-Real J-M, Federici M, et al., 2018, Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1628-1628, ISSN: 1078-8956
In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.
White N, Harries P, Harris AJL, et al., 2018, 44 An evidenced-based heuristics model (or rule of thumb) to improve doctors’ intuition about when patients are imminently dying, BMJ Supportive & Palliative Care, Vol: 8, Pages: 376.2-376, ISSN: 2045-435X
<jats:sec><jats:title>Introduction</jats:title><jats:p>Evidence suggests that the majority of doctors are not very good at identifying when a patient is dying<jats:sup>1</jats:sup> however there is little training available to improve this skill. Even experts are unable to articulate how they recognise when a patient is dying other than by saying that ‘I just knew’.<jats:sup>2</jats:sup></jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To understand how expert palliative care doctors recognise a dying person.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Rather than relying on ‘years of experience’ as a surrogate measure of expertise we developed a test to identify which doctors really are the prognostic ‘experts’. The prognostic test consisted of 20 real patient case summaries. Participants (palliative care doctors) were asked to predict whether or not they expected the patient to die within the next 3 days. Those who were the most accurate at this task were deemed to be the ‘prognostic experts’ and were invited to complete an additional online judgement task. In this task it was possible to identify which factors were most influential in their prognostic decision-making.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>19/99 doctors who completed the prognostic test were deemed to be ‘experts’. Of those 14 also completed the additional judgement task. The following factors influenced the experts’ decisions: Cheyne Stokes breathing palliative performance score (PPS) a decline in condition in the previous 24 hours respiratory secretions cyanosis and level of agitation or sedation.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p
Hoyles L, Fernández-Real JM, Federici M, et al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1-17, ISSN: 1078-8956
Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
Harries P, Unsworth C, Gokalp H, et al., 2018, A randomised controlled trial to test the effectiveness of decision training on assessors’ ability to determine optimal fitness-to-drive recommendations for older or disabled drivers, BMC Medical Education, Vol: 18, ISSN: 1472-6920
BackgroundDriving licensing jurisdictions require detailed assessments of fitness-to-drive from occupational therapy driver assessors (OTDAs). We developed decision training based on the recommendations of expert OTDAs, to enhance novices’ capacity to make optimal fitness-to-drive decisions. The aim of this research was to determine effectiveness of training on novice occupational therapists’ ability to make fitness-to-drive decisions.MethodsA double blind, parallel, randomised controlled trial was conducted to test the effectiveness of decision training on novices’ fitness-to-drive recommendations. Both groups made recommendations on a series of 64 case scenarios with the intervention group receiving training after reviewing two thirds of the cases; the control group, at this same point, just received a message of encouragement to continue. Participants were occupational therapy students on UK and Australian pre-registration programmes who individually took part online, following the website instructions. The main outcome of training was the reduction in mean difference between novice and expert recommendations on the cases.ResultsTwo hundred eighty-nine novices were randomised into intervention; 166 completed the trial (70 in intervention; 96 in control). No statistical differences in scores were found pre-training. Post training, the control group showed no significant change in recommendations compared to the experts (t(96) = −.69; p = .5), whereas the intervention group exhibited a significant change (t(69) = 6.89; p < 0.001). For the intervention group, the mean difference compared with the experts’ recommendations reduced with 95% CI from −.13 to .09. Effect size calculated at the post-training demonstrated a moderate effect (d = .69, r = .32).ConclusionsNovices who received the decision training were able to change their recommendations
Hoyles L, Fernández-Real JM, Federici M, et al., 2017, Integrated systems biology to study the contribution of the gut microbiome to steatosis in obese women, Exploring Human Host-Microbiome Interactions in Health and Disease
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, increasing in worldwide prevalence as a result of the obesity epidemic. It manifests in hepatic cells as steatosis with or without lobular inflammation and/or ballooning. Animal and human studies have suggested the gut microbiome contributes to steatosis/NAFLD. The aim of this study was to use an integrated approach with various -omics and clinical data to evaluate the contribution of the gut microbiome to the molecular phenome (hepatic transcriptome, metabonome) of steatosis. Metagenomic (faecal microbiome), transcriptomic (liver biopsy), metabonomic (plasma and urine, 1H-NMR) and clinical data were collected for 56 morbidly obese (BMI >35) women from Italy (n = 31) and Spain (n = 25) who elected for bariatric surgery. Confounder analyses of clinical data were done using linear modelling. Histological examination of liver biopsies was used to grade steatosis. Faecal metagenomes were generated and analysed using the SCalable Automated Metagenomics Pipeline (SCAMP). Differentially expressed genes were identified in hepatic transcriptomes, and analysed using a range of different bioinformatics tools. 1H-NMR data were generated for plasma and urinary metabonomes. Clinical, metagenomic, transcriptomic and metabonomic data were integrated in the context of steatosis using partial Spearman's correlation, taking confounders (age, body mass index and cohort) into account. Steatosis was anti-correlated with microbial gene richness, and correlated with abundance of Proteobacteria. KEGG analyses of metagenomic data suggested increased microbial processing of dietary lipids and amino acids, as well as endotoxin-related processes related to Proteobacteria. Steatosis-associated hepatic transcriptomes were associated with branched-chain amino acid (BCAA) metabolism, endoplasmic reticulum/phagosome, and immune responses associated with non-specific microbial infections. Metabonom
Hoyles L, Fernández-Real JM, Federici M, et al., 2017, Integrated systems biology to study non-alcoholic fatty liver disease in obese women, International Scientific Association for Probiotics and Prebiotics
Metagenomic (faecal microbiome), transcriptomic (liver biopsy), metabonomic (plasma and urine, 1H-NMR) and clinical (28 variables) data were collected for 56 morbidly obese (BMI >35) women from Italy (n = 31) and Spain (n = 25) who elected for bariatric surgery. Data were integrated to evaluate the contribution of the gut microbiome to the molecular phenome (hepatic transcriptome, plasma and urine metabonome) of NAFLD independent of clinical confounders (age, BMI, cohort) using partial Spearman’s correlation. NAFLD activity score (NAS) was anti-correlated with microbial gene richness, and correlated with abundance of Proteobacteria. KEGG analyses of metagenomic data suggested increased microbial processing of dietary lipids and amino acids, as well as endotoxin-related processes related to Proteobacteria. Metabonomic profiles highlighted imbalances in choline metabolism, branched-chain amino acid (BCAA) metabolism and gut-derived microbial metabolites resulting from metabolism of amino acids. NAFLD-associated hepatic transcriptomes were associated with BCAA metabolism, endoplasmic reticulum/phagosome, and immune responses associated with non-specific microbial infections. Molecular phenomic signatures were stable and predictive regardless of sample size, and consistent with the microbiome making a significant contribution to the NAFLD phenome. There is disruption of the gut– liver axis in NAFLD, which can be seen in the gut microbiome, hepatic transcriptome and urinary and plasma metabonomes. Consistency of phenome signatures strongly supports a relationship between microbial amino acid metabolism and microbial gene richness, hepatic gene expression and biofluid metabonomes, and ultimately NAS.
Hoyles L, Fernandez-Real JM, Federici M, et al., 2017, Integrated systems biology to study non-alcoholic fatty liver disease in obese women, Tranlsational Bioinformatics
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition and one of the most common causes of chronic liver disease, with increasing worldwide prevalence. Microbiome-associated lipopolysaccharides (LPS) are associated with NAFLD in rodent models, but their relevance in human liver disease is not understood. In addition, microbiome-driven degradation of dietary choline – and its subsequent removal from host-associated metabolic processes – is thought to contribute to development of NAFLD. The FLORINASH study set out to determine the contribution of the gut microbiome to the NAFLD-associated molecular phenome (transcriptome, metabonome) independent of clinical confounders.Morbidly obese women [body mass index (BMI) >35] from Italy (n = 31) and Spain (n = 25) who elected for bariatric surgery were recruited to the study. Clinical data (28 variables) were recorded. Faecal samples, liver biopsies, blood and urine samples were collected. Faecal metagenomes were analysed using an in-house metagenomics pipeline (SCaleble Automated Metagenomics Pipeline). NAFLD activity score (NAS; 0, 1, 2, 3) was determined by histological examination of liver biopsies. Differentially expressed genes in hepatic transcriptomes were identified, and analysed using several complementary tools. 1H-NMR data were generated for plasma and urinary metabonomes. Clinical, metagenomic, transcriptomic and metabonomic data were integrated using partial Spearman’s correlation, taking identified confounders (age, BMI and cohort) into account.NAS was anti-correlated with microbial gene richness, and correlated with abundance of Gram-negative Proteobacteria. KEGG analyses of metagenomic data suggested increased microbial processing of dietary lipids and amino acids, as well as LPS-related processes associated with Proteobacteria in NAFLD. Activation of immune responses associated with Gram-negative (LPS-associated) microbial infections was correlated with NAS in hepatic tr
Hoyles L, Fernández-Real JM, Federici M, et al., 2017, Integrated systems biology to study non-alcoholic fatty liver disease in obese women, Gut Microbiota for Health World Summit 2017
Objectives: To integrate metagenomic (faecal microbiome), transcriptomic, metabonomic and clinical data to evaluate the contribution of the gut microbiome to the molecular phenome (hepatic transcriptome, plasma and urine metabonome) of non-alcoholic fatty liver disease (NAFLD) independent of clinical confounders in morbidly obese women recruited to the FLORINASH study.Methods: Faecal, liver biopsy, blood and urine samples and data for 28 clinical variables were collected for 56 obese [body mass index (BMI) >35] women from Italy (n = 31) and Spain (n = 25) who elected for bariatric surgery. Confounder analyses of clinical data were done using linear modeling. Histological examination of liver biopsies was used to grade NAFLD (NAFLD activity score: 0, 1, 2, 3). Faecal metagenomes were generated and analysed using the Imperial Metagenomics Pipeline. Differentially expressed genes were identified in hepatic transcriptomes, and analysed using Enrichr, network analyses and Signaling Pathway Impact Analysis. 1H-NMR data were generated for plasma and urinary metabonomes. Clinical, metagenomic, transcriptomic and metabonomic data were integrated using partial Spearman’s correlation, taking confounders (age, body mass index and cohort) into account.Results: NAFLD activity score was anti-correlated with microbial gene richness, and correlated with abundance of Proteobacteria. KEGG analyses of metagenomic data suggested increased microbial processing of dietary lipids and amino acids, as well as endotoxin-related processes related to Proteobacteria. Metabonomic profiles highlighted imbalances in choline metabolism, branched-chain amino acid metabolism and gut-derived microbial metabolites resulting from metabolism of amino acids. NAFLD-associated hepatic transcriptomes were associated with branched-chain amino acid metabolism, endoplasmic reticulum/phagosome, and immune responses associated with microbial infections. Molecular phenomic signatures were stable and predic
Grundmann H, Glasner C, Albiger B, et al., 2017, Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study., Lancet Infect Dis, Vol: 17, Pages: 153-163
BACKGROUND: Gaps in the diagnostic capacity and heterogeneity of national surveillance and reporting standards in Europe make it difficult to contain carbapenemase-producing Enterobacteriaceae. We report the development of a consistent sampling framework and the results of the first structured survey on the occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in European hospitals. METHODS: National expert laboratories recruited hospitals with diagnostic capacities, who collected the first ten carbapenem non-susceptible clinical isolates of K pneumoniae or E coli and ten susceptible same-species comparator isolates and pertinent patient and hospital information. Isolates and data were relayed back to national expert laboratories, which made laboratory-substantiated information available for central analysis. FINDINGS: Between Nov 1, 2013, and April 30, 2014, 455 sentinel hospitals in 36 countries submitted 2703 clinical isolates (2301 [85%] K pneumoniae and 402 (15%) E coli). 850 (37%) of 2301 K pneumoniae samples and 77 (19%) of 402 E coli samples were carbapenemase (KPC, NDM, OXA-48-like, or VIM) producers. The ratio of K pneumoniae to E coli was 11:1. 1·3 patients per 10 000 hospital admissions had positive clinical specimens. Prevalence differed greatly, with the highest rates in Mediterranean and Balkan countries. Carbapenemase-producing K pneumoniae isolates showed high resistance to last-line antibiotics. INTERPRETATION: This initiative shows an encouraging commitment by all participants, and suggests that challenges in the establishment of a continent-wide enhanced sentinel surveillance for carbapenemase-producing Enterobacteriaeceae can be overcome. Strengthening infection control efforts in hospitals is crucial for controlling spread through local and national health care networks. FUNDING: European Centre for Disease Prevention and Control.
Hoyles L, Fernández-Real JM, Federici M, et al., 2017, Integrated systems biology to study non-alcoholic fatty liver disease in obese women, MRC-PHE Centre for Environment & Health - Centre Training Programme Annual Meeting
Braga VMM, 2016, Defining functional interactions during biogenesis of epithelial junctions, Nature Communications, Vol: 7, Pages: 1-17, ISSN: 2041-1723
In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.
Giotis ES, Robey RC, Skinner NG, et al., 2016, Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-α), Veterinary Research, Vol: 47, ISSN: 1297-9716
Viruses that infect birds pose major threats—to the global supply of chicken, the major, universally-acceptable meat, and as zoonotic agents (e.g. avian influenza viruses H5N1 and H7N9). Controlling these viruses in birds as well as understanding their emergence into, and transmission amongst, humans will require considerable ingenuity and understanding of how different species defend themselves. The type I interferon-coordinated response constitutes the major antiviral innate defence. Although interferon was discovered in chicken cells, details of the response, particularly the identity of hundreds of stimulated genes, are far better described in mammals. Viruses induce interferon-stimulated genes but they also regulate the expression of many hundreds of cellular metabolic and structural genes to facilitate their replication. This study focusses on the potentially anti-viral genes by identifying those induced just by interferon in primary chick embryo fibroblasts. Three transcriptomic technologies were exploited: RNA-seq, a classical 3′-biased chicken microarray and a high density, “sense target”, whole transcriptome chicken microarray, with each recognising 120–150 regulated genes (curated for duplication and incorrect assignment of some microarray probesets). Overall, the results are considered robust because 128 of the compiled, curated list of 193 regulated genes were detected by two, or more, of the technologies.
Stanford NJ, Tomlinson CD, et al, 2015, The evolution of standards and data management practices in systems biology, Molecular Systems Biology, Vol: 11, ISSN: 1744-4292
McArdle I, Fare C, Bearpark M, et al., 2015, Research Data Management 'Green Shoots' Pilot Programme, Final Reports, Research Data Management 'Green Shoots' Pilot Programme, Final Reports
This document contains the final reports of six Research Data Management "Green Shoots" projects run at Imperial College in 2014.
Shand B, Thomas GA, Blaveri E, et al., 2014, BiobankLink: automating data exchange between the cancer registry and human biosample collections, Cancer Outcomes Conference 2014
Harries P, Davies M, Gilhooley K, et al., 2014, Educating novice practitioners to detect elder financial abuse: a randomised controlled trial, BMC Medical Education, Vol: 14
Tomlinson CD, Barton GR, Woodbridge M, et al., 2013, XperimentR: painless annotation of a biological experiment for the laboratory scientist, Bmc Bioinformatics
Harries P, Tomlinson CD, 2012, Teaching young dogs new tricks: improving occupational therapists' referral prioritization capacity with a web-based decision-training aid, Scandinavian Journal of Occupational Therapy
Thomas G, Unger K, Krznaric M, et al., 2012, The Chernobyl Tissue Bank - A Repository for Biomaterial and Data Used in Integrative and Systems Biology Modeling the Human Response to Radiation, Genes, Vol: 3, Pages: 278-290, ISSN: 2073-4425
The only unequivocal radiological effect of the Chernobyl accident on human health is the increase in thyroid cancer in those exposed in childhood or early adolescence. In response to the scientific interest in studying the molecular biology of thyroid cancer post Chernobyl, the Chernobyl Tissue Bank (CTB: www.chernobyltissuebank.com) was established in 1998. Thus far it is has collected biological samples from 3,861 individuals, and provided 27 research projects with 11,254 samples. The CTB was designed from its outset as a resource to promote the integration of research and clinical data to facilitate a systems biology approach to radiation related thyroid cancer. The project has therefore developed as a multidisciplinary collaboration between clinicians, dosimetrists, molecular biologists and bioinformaticians and serves as a paradigm for tissue banking in the omics era.
Woodbridge M, Tomlinson CD, Butcher S, 2012, ADAM: Automated Data Management for research datasets, Bioinformatics
Harries P, Tomlinson CD, Notley E, et al., 2012, Effectiveness of a decision-training aid on referral prioritization capacity: a randomized controlled trial, Journal of Medical Decision Making
Harries P, Tomlinson CD, Notley E, 2011, Randomized controlled trial to test the effectiveness of a referral prioritization decision training tool for student occupational therapists, Higher Education Academy conference
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