Showing papers by "John Radcliffe Hospital published in 2017"
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Howard Hughes Medical Institute1, Broad Institute2, Massachusetts Institute of Technology3, University of Cambridge4, European Bioinformatics Institute5, Wellcome Trust Sanger Institute6, Harvard University7, Weizmann Institute of Science8, University of Zurich9, Laboratory of Molecular Biology10, Utrecht University11, École Polytechnique Fédérale de Lausanne12, University of Pennsylvania13, Heidelberg University14, German Cancer Research Center15, Ludwig Maximilian University of Munich16, John Radcliffe Hospital17, Newcastle University18, Stanford University19, University of Oxford20, University of California, San Francisco21, Allen Institute for Brain Science22, Karolinska Institutet23, Royal Institute of Technology24, Icahn School of Medicine at Mount Sinai25, University of Cape Town26, University Medical Center Groningen27, Radboud University Nijmegen28, Kettering University29, University of Edinburgh30, Babraham Institute31, New York University32, Netherlands Cancer Institute33, Ragon Institute of MGH, MIT and Harvard34, University of Texas Health Science Center at Houston35, Technische Universität München36, Technical University of Denmark37, University of California, Berkeley38, King's College London39, California Institute of Technology40
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
1,391 citations
TL;DR: A historical perspective of their discovery is provided and their established functions in sensing and responding to genotoxic stress are discussed, as well as emerging non-canonical roles and how knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.
1,175 citations
TL;DR: The R/Bioconductor package scater is developed to facilitate rigorous pre‐processing, quality control, normalization and visualization of scRNA‐seq data and provides a convenient, flexible workflow to process raw sequencing reads into a high‐quality expression dataset ready for downstream analysis.
Abstract: Single-cell RNA sequencing (scRNA-seq) is increasingly used to study gene expression at the level of individual cells. However, preparing raw sequence data for further analysis is not a straightforward process. Biases, artifacts and other sources of unwanted variation are present in the data, requiring substantial time and effort to be spent on pre-processing, quality control (QC) and normalization.We have developed the R/Bioconductor package scater to facilitate rigorous pre-processing, quality control, normalization and visualization of scRNA-seq data. The package provides a convenient, flexible workflow to process raw sequencing reads into a high-quality expression dataset ready for downstream analysis. scater provides a rich suite of plotting tools for single-cell data and a flexible data structure that is compatible with existing tools and can be used as infrastructure for future software development.The open-source code, along with installation instructions, vignettes and case studies, is available through Bioconductor at http://bioconductor.org/packages/scater .davis@ebi.ac.uk.Supplementary data are available at Bioinformatics online.
1,093 citations
Wellcome Trust Sanger Institute1, Newcastle University2, Broad Institute3, Brigham and Women's Hospital4, University of Exeter5, Canterbury Christ Church University6, Wellcome Trust Centre for Human Genetics7, University of Edinburgh8, Torbay Hospital9, Royal Hospital for Sick Children10, Ninewells Hospital11, Guy's and St Thomas' NHS Foundation Trust12, John Radcliffe Hospital13, University of Oxford14, Norfolk and Norwich University Hospital15, University of the Witwatersrand16, King's College London17, University of Manchester18, Manchester Academic Health Science Centre19, University of Nottingham20
TL;DR: This work identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease and identified 3 associated variants that are correlated with expression changes in response to immune stimulus at two of these genes.
Abstract: Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
813 citations
Guy's and St Thomas' NHS Foundation Trust1, John Radcliffe Hospital2, University of Nottingham3, Brigham and Women's Hospital4, ISMETT5, Banaras Hindu University6, Newton Wellesley Hospital7, Madras Institute of Orthopaedics and Traumatology8, University of the West Indies9, University of Michigan10, Sahlgrenska University Hospital11, Queen Mary University of London12, Aga Khan University13, University of Manchester14, Virginia Commonwealth University15, University of Padua16, Changi General Hospital17, King's College London18, Southampton General Hospital19, Texas Tech University Health Sciences Center20, McMaster University21, University Hospital Waterford22, Turku University Hospital23, University of Mainz24, Bezmialem Foundation University25, Colchester Hospital University NHS Foundation Trust26, Kent State University27, Guy's Hospital28, Cairo University29, Children's of Alabama30
TL;DR: The development of the STROCSS guideline (Strengthening the Reporting of Cohort Studies in Surgery), consisting of a 17-item checklist, is described and it is hoped its use will increase the transparency and reporting quality of such studies.
736 citations
Charité1, Oregon Health & Science University2, French Institute of Health and Medical Research3, University of Western Australia4, King Edward Memorial Hospital5, Sanford Health6, Children's Hospital of Eastern Ontario7, University of Toronto8, University of Cambridge9, University College London10, Cold Spring Harbor Laboratory11, Queen Mary University of London12, Radboud University Nijmegen13, Wellcome Trust Sanger Institute14, Katholieke Universiteit Leuven15, Johns Hopkins University School of Medicine16, University of Kiel17, University of Pennsylvania18, University of Luxembourg19, Medical College of Wisconsin20, Newcastle University21, Tohoku University22, Manchester Royal Eye Hospital23, John Radcliffe Hospital24, University of Sydney25, University of Miami26, Garvan Institute of Medical Research27, Lawrence Berkeley National Laboratory28, University of Connecticut29
TL;DR: The progress of the HPO project is reviewed, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
Abstract: Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
638 citations
TL;DR: MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset, and permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.
Abstract: See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article. A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.
469 citations
Broad Institute1, Harvard University2, University of Liège3, University of Oxford4, Wellcome Trust Sanger Institute5, Montreal Heart Institute6, University of Southern Denmark7, Katholieke Universiteit Leuven8, Wellcome Trust Centre for Human Genetics9, John Radcliffe Hospital10, Karolinska Institutet11, Ikerbasque12, Illumina13, University of Kiel14, Örebro University15, Cedars-Sinai Medical Center16, Lancaster University17, University of Western Australia18, Western General Hospital19, Norwegian University of Life Sciences20, Wellcome Trust21, University Medical Center Groningen22, University of Groningen23, University of Pittsburgh24, University of the Witwatersrand25, King's College London26, Université de Montréal27, Yale University28
TL;DR: The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Abstract: Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
447 citations
TL;DR: This poster presents a state-of-the-art virtual reality simulation system that allows for real-time monitoring of the response of the immune system to treatments such as chemotherapy.
Abstract: The demand for platelets in England was stable at around 220,000 adult therapeutic doses (ATD) per year until 2007/8 at which point demand has increased year on year to 275,000 ATD in 2014/15, an increase of 25%. Similar rises in demand have been seen in Australia and the United States. A recent review which considered causes for this dramatic rise identified that an ageing population and an increase in the incidence of haematological malignancies (with increased treatment intensity, duration and survival) accounted for most of this change (Estcourt 2014). This guideline aims to provide practical advice on platelet transfusions to help clinicians to decide when support is expected to be beneficial and to reduce inappropriate use.
418 citations
TL;DR: The roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction are considered, by providing an evaluation of the known and emerging inflammatory pathways.
Abstract: Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure 'inflammation' are insufficiently precise and do not provide information about disease site and activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction, by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including their current limitations and challenges that are the focus of ongoing study.
348 citations
Public Health England1, Technical University of Denmark2, Karolinska University Hospital3, University of Freiburg4, Statens Serum Institut5, University of St Andrews6, University of Sydney7, University of Cambridge8, North Bristol NHS Trust9, Utrecht University10, Wageningen University and Research Centre11, National Microbiology Laboratory12, John Radcliffe Hospital13, Aix-Marseille University14, University Hospital of North Norway15
TL;DR: The European Committee on Antimicrobial Susceptibility Testing established a subcommittee to review the current development status of Whole Genome Sequencing (WGS) for bacterial antimicrobial susceptibility testing (AST) as discussed by the authors.
Hannover Medical School1, University of Bonn2, National Institute for Health Research3, Karolinska University Hospital4, University of North Dakota5, Mayo Clinic6, Oslo University Hospital7, University Hospital Heidelberg8, University of Helsinki9, University of Gothenburg10, Royal Free Hospital11, University Medical Center Groningen12, Katholieke Universiteit Leuven13, Charité14, Pierre-and-Marie-Curie University15, University of Hamburg16, Linköping University17, University College London18, University of Miami19, University of Alberta20, University of Oslo21, University of California, Davis22, University of Padua23, Medical University of Vienna24, California Pacific Medical Center25, Pomeranian Medical University26, Medical University of Warsaw27, Royal Adelaide Hospital28, University of Barcelona29, University of Zurich30, University of Thessaly31, University of Calgary32, University of Milan33, University of Tübingen34, Goethe University Frankfurt35, Saarland University36, Marche Polytechnic University37, John Radcliffe Hospital38, University of Oxford39, Arizona State University40, Toronto General Hospital41, University of Toronto42, Erasmus University Medical Center43
TL;DR: In an analysis of data from individual patients with PSC worldwide, significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes is found.
Imperial College London1, University of Amsterdam2, Medical University of Vienna3, Gloucestershire Hospitals NHS Foundation Trust4, University of Hamburg5, Karolinska University Hospital6, Erasmus University Rotterdam7, University of Oslo8, John Radcliffe Hospital9, Coventry University10, Katholieke Universiteit Leuven11, University of Porto12
TL;DR: Endoscopy services across Europe are recommended to adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level.
Abstract: The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for lower gastrointestinal endoscopy. We recommend that endoscopy services across Europe adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level: 1 rate of adequate bowel preparation (minimum standard 90%); 2 cecal intubation rate (minimum standard 90%); 3 adenoma detection rate (minimum standard 25%); 4 appropriate polypectomy technique (minimum standard 80%); 5 complication rate (minimum standard not set); 6 patient experience (minimum standard not set); 7 appropriate post-polypectomy surveillance recommendations (minimum standard not set). Other identified performance measures have been listed as less relevant based on an assessment of their importance, scientific acceptability, feasibility, usability, and comparison to competing measures.
TL;DR: This work investigates the dual regression approach that is frequently applied with group ICA to assess group differences in resting state functional connectivity of brain networks and shows how ignoring amplitude effects and how excessive motion corrupts connectivity maps and results in spurious connectivity differences.
Abstract: Independent Component Analysis (ICA) is one of the most popular techniques for the analysis of resting state FMRI data because it has several advantageous properties when compared with other techniques. Most notably, in contrast to a conventional seed-based correlation analysis, it is model-free and multivariate, thus switching the focus from evaluating the functional connectivity of single brain regions identified a priori to evaluating brain connectivity in terms of all brain resting state networks (RSNs) that simultaneously engage in oscillatory activity. Furthermore, typical seed-based analysis characterizes RSNs in terms of spatially distributed patterns of correlation (typically by means of simple Pearson's coefficients) and thereby confounds together amplitude information of oscillatory activity and noise. ICA and other regression techniques, on the other hand, retain magnitude information and therefore can be sensitive to both changes in the spatially distributed nature of correlations (differences in the spatial pattern or "shape") as well as the amplitude of the network activity. Furthermore, motion can mimic amplitude effects so it is crucial to use a technique that retains such information to ensure that connectivity differences are accurately localized. In this work, we investigate the dual regression approach that is frequently applied with group ICA to assess group differences in resting state functional connectivity of brain networks. We show how ignoring amplitude effects and how excessive motion corrupts connectivity maps and results in spurious connectivity differences. We also show how to implement the dual regression to retain amplitude information and how to use dual regression outputs to identify potential motion effects. Two key findings are that using a technique that retains magnitude information, e.g., dual regression, and using strict motion criteria are crucial for controlling both network amplitude and motion-related amplitude effects, respectively, in resting state connectivity analyses. We illustrate these concepts using realistic simulated resting state FMRI data and in vivo data acquired in healthy subjects and patients with bipolar disorder and schizophrenia.
TL;DR: Tinkhauser et al. show that adaptive DBS regulates pathological beta synchronisation in the subthalamic nucleus by selectively limiting long duration beta bursts, which are related to clinical impairment.
Abstract: Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could be more efficacious than conventional continuous deep brain stimulation in the treatment of Parkinson's disease, and helps inform how adaptive deep brain stimulation might best be delivered.
TL;DR: This multiancestry study recommends investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G 6PD deficiency is common, and investigates the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance.
Abstract: Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identif ...
TL;DR: A low-cost method of DNA extraction directly from patient samples for M. tuberculosis WGS is demonstrated, providing a potential solution to the problem of variable amounts of M.culosis DNA in direct samples.
Abstract: Routine full characterization of Mycobacterium tuberculosis is culture based, taking many weeks. Whole-genome sequencing (WGS) can generate antibiotic susceptibility profiles to inform treatment, augmented with strain information for global surveillance; such data could be transformative if provided at or near the point of care. We demonstrate a low-cost method of DNA extraction directly from patient samples for M. tuberculosis WGS. We initially evaluated the method by using the Illumina MiSeq sequencer (40 smear-positive respiratory samples obtained after routine clinical testing and 27 matched liquid cultures). M. tuberculosis was identified in all 39 samples from which DNA was successfully extracted. Sufficient data for antibiotic susceptibility prediction were obtained from 24 (62%) samples; all results were concordant with reference laboratory phenotypes. Phylogenetic placement was concordant between direct and cultured samples. With Illumina MiSeq/MiniSeq, the workflow from patient sample to results can be completed in 44/16 h at a reagent cost of £96/£198 per sample. We then employed a nonspecific PCR-based library preparation method for sequencing on an Oxford Nanopore Technologies MinION sequencer. We applied this to cultured Mycobacterium bovis strain BCG DNA and to combined culture-negative sputum DNA and BCG DNA. For flow cell version R9.4, the estimated turnaround time from patient to identification of BCG, detection of pyrazinamide resistance, and phylogenetic placement was 7.5 h, with full susceptibility results 5 h later. Antibiotic susceptibility predictions were fully concordant. A critical advantage of MinION is the ability to continue sequencing until sufficient coverage is obtained, providing a potential solution to the problem of variable amounts of M. tuberculosis DNA in direct samples.
TL;DR: It is concluded that CRISPR–Cas9-mediated genome editing is a powerful method for investigating gene function in the context of human development.
Abstract: Despite their fundamental biological and clinical importance, the molecular mechanisms that regulate the first cell fate decisions in the human embryo are not well understood. Here we use CRISPR-Cas9-mediated genome editing to investigate the function of the pluripotency transcription factor OCT4 during human embryogenesis. We identified an efficient OCT4-targeting guide RNA using an inducible human embryonic stem cell-based system and microinjection of mouse zygotes. Using these refined methods, we efficiently and specifically targeted the gene encoding OCT4 (POU5F1) in diploid human zygotes and found that blastocyst development was compromised. Transcriptomics analysis revealed that, in POU5F1-null cells, gene expression was downregulated not only for extra-embryonic trophectoderm genes, such as CDX2, but also for regulators of the pluripotent epiblast, including NANOG. By contrast, Pou5f1-null mouse embryos maintained the expression of orthologous genes, and blastocyst development was established, but maintenance was compromised. We conclude that CRISPR-Cas9-mediated genome editing is a powerful method for investigating gene function in the context of human development.
TL;DR: In patients receiving aspirin-based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper gastrointestinal bleeding.
University of Gondar1, Simon Fraser University2, Centers for Disease Control and Prevention3, McMaster University4, Critical Path Institute5, National Institutes of Health6, World Health Organization7, Foundation for Innovative New Diagnostics8, Chinese Academy of Sciences9, Stellenbosch University10, Public Health England11, John Radcliffe Hospital12, Swiss Tropical and Public Health Institute13, University of Basel14, Karolinska Institutet15, Public Health Agency of Sweden16, Spanish National Research Council17, Translational Genomics Research Institute18, Harvard University19, Rutgers University20, Institute of Tropical Medicine Antwerp21, University of Cape Town22, Aga Khan University23, Indian Council of Medical Research24, University of Cambridge25, University of California, San Diego26
TL;DR: This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug- resistant phenotypes and has implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
Abstract: A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
TL;DR: This review focuses on the emerging concept of white matter plasticity, which is growing evidence, both from animal studies and from human neuroimaging, that activity-dependent regulation of myelin may play a role in learning.
TL;DR: It is demonstrated that long duration beta bursts are associated with an increase in local and interhemispheric synchronization, which may compromise information coding capacity and thereby motor processing.
Abstract: Exaggerated basal ganglia beta activity (13-35 Hz) is commonly found in patients with Parkinson's disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson's disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state. Local field potentials were recorded from the subthalamic nucleus of eight Parkinson's disease patients during temporary lead externalization during surgery for deep brain stimulation. The recordings took place with the patient quietly seated following overnight withdrawal of levodopa and after administration of levodopa. Beta bursts were defined by applying a common amplitude threshold and burst characteristics were compared between the two drug conditions. The amplitude of beta bursts, indicative of the degree of local neural synchronization, progressively increased with burst duration. Treatment with levodopa limited this evolution leading to a relative increase of shorter, lower amplitude bursts. Synchronization, however, was not limited to local neural populations during bursts, but also, when such bursts were cotemporaneous across the hemispheres, was evidenced by bilateral phase synchronization. The probability of beta bursts and the proportion of cotemporaneous bursts were reduced by levodopa. The percentage number of longer beta bursts in a given interval was positively related to motor impairment, while the opposite was true for the percentage number of short duration beta bursts. Importantly, the decrease in burst duration was also correlated with the motor improvement. In conclusion, we demonstrate that long duration beta bursts are associated with an increase in local and interhemispheric synchronization. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits this uncontrolled beta synchronization by terminating long duration beta bursts, with positive consequences on network state and motor symptoms.
TL;DR: The protocol for the development of the STROCSS Guideline for surgical cohort studies is provided and dissemination to interested parties and journals will be encouraged to endorse the reporting guideline.
TL;DR: It is suggested that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions that appear associated with a higher risk of future neoplasia or colorectal cancer should be offered a one-off colonoscopic surveillance examination at 3 years.
Abstract: Serrated polyps have been recognised in the last decade
as important premalignant lesions accounting for
between 15% and 30% of colorectal cancers. There is
therefore a clinical need for guidance on how to manage
these lesions; however, the evidence base is limited. A
working group was commission by the British Society of
Gastroenterology (BSG) Endoscopy section to review the
available evidence and develop a position statement to
provide clinical guidance until the evidence becomes
available to support a formal guideline. The scope of the
position statement was wide-ranging and included:
evidence that serrated lesions have premalignant
potential; detection and resection of serrated lesions;
surveillance strategies after detection of serrated lesions;
special situations—serrated polyposis syndrome
(including surgery) and serrated lesions in colitis;
education, audit and benchmarks and research
questions. Statements on these issues were proposed
where the evidence was deemed sufficient, and reevaluated
modified via a Delphi process until >80%
agreement was reached. The Grading of
Recommendations, Assessment, Development and
Evaluations (GRADE) tool was used to assess the
strength of evidence and strength of recommendation
for finalised statements. Key recommendation: we
suggest that until further evidence on the efficacy or
otherwise of surveillance are published, patients with
sessile serrated lesions (SSLs) that appear associated
with a higher risk of future neoplasia or colorectal
cancer (SSLs ≥10 mm or serrated lesions harbouring
dysplasia including traditional serrated adenomas)
should be offered a one-off colonoscopic surveillance
examination at 3 years (weak recommendation, low
quality evidence, 90% agreement).
TL;DR: It is argued that motivated behaviour requires a willingness to work, to keep working, and to learn what is worth working for, and that deficits in any one or more of these processes can lead to the clinical syndrome of apathy.
Complutense University of Madrid1, John Radcliffe Hospital2, Belfast Health and Social Care Trust3, Imperial College London4, Hospital Universitario La Paz5, Papworth Hospital6, Newcastle University7, Manchester Royal Infirmary8, Erasmus University Rotterdam9, Brighton and Sussex University Hospitals NHS Trust10, Jagiellonian University11
TL;DR: At one year, clinical outcomes with the SYNTAX-II strategy were associated with improved clinical results compared to the PCI performed in comparable patients from the original SYN TAX-I trial, and a randomized clinical trial with contemporary CABG is warranted.
Abstract: Aims: To investigate if recent technical and procedural developments in percutaneous coronary intervention (PCI) significantly influence outcomes in appropriately selected patients with three-vessel (3VD) coronary artery disease. Methods and results: The SYNTAX II study is a multicenter, all-comers, open-label, single arm study that investigated the impact of a contemporary PCI strategy on clinical outcomes in patients with 3VD in 22 centres from four European countries. The SYNTAX-II strategy includes: heart team decision-making utilizing the SYNTAX Score II (a clinical tool combining anatomical and clinical factors), coronary physiology guided revascularisation, implantation of thin strut bio-resorbable-polymer drug-eluting stents, intravascular ultrasound (IVUS) guided stent implantation, contemporary chronic total occlusion revascularisation techniques and guideline-directed medical therapy. The rate of major adverse cardiac and cerebrovascular events (MACCE [composite of all-cause death, cerebrovascular event, any myocardial infarction and any revascularisation]) at one year was compared to a predefined PCI cohort from the original SYNTAX-I trial selected on the basis of equipoise 4-year mortality between CABG and PCI. As an exploratory endpoint, comparisons were made with the historical CABG cohort of the original SYNTAX-I trial. Overall 708 patients were screened and discussed within the heart team; 454 patients were deemed appropriate to undergo PCI. At one year, the SYNTAX-II strategy was superior to the equipoise-derived SYNTAX-I PCI cohort (MACCE SYNTAX-II 10.6% vs. SYNTAX-I 17.4%; HR 0.58, 95% CI 0.39-0.85, P= 0.006). This difference was driven by a significant reduction in the incidence of MI (HR 0.27, 95% CI 0.11-0.70, P= 0.007) and revascularisation (HR 0.57, 95% CI 0.37-0.9, P = 0.015). Rates of all-cause death (HR 0.69, 95% CI 0.27-1.73, P = 0.43) and stroke (HR 0.69, 95% CI 0.10-4.89, P = 0.71) were similar. The rate of definite stent thrombosis was significantly lower in SYNTAX-II (HR 0.26, 95% CI 0.07-0.97, P = 0.045). Conclusion: At one year, clinical outcomes with the SYNTAX-II strategy were associated with improved clinical results compared to the PCI performed in comparable patients from the original SYNTAX-I trial. Longer term follow-up is awaited and a randomized clinical trial with contemporary CABG is warranted.
TL;DR: Analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota.
St. Jude Children's Research Hospital1, QIMR Berghofer Medical Research Institute2, deCODE genetics3, Wellcome Trust Centre for Human Genetics4, University of Liverpool5, Katholieke Universiteit Leuven6, Brigham and Women's Hospital7, Harvard University8, University of Queensland9, Vanderbilt University Medical Center10, University of California, San Diego11, Copenhagen University Hospital12, John Radcliffe Hospital13, Niigata University14, University of Tokyo15, RMIT University16, Aarhus University17, Lundbeck18, Merck KGaA19, Queensland University of Technology20
TL;DR: A meta-analysis of genome-wide association case-control data sets for endometriosis highlights novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offers unique opportunities for more targeted functional research efforts.
Abstract: Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB) Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 519% of variance in endometriosis These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts
TL;DR: The potential-and limitations-of new ways of undertaking specific tasks in living systematic reviews are described, identifying areas where these human/machine "technologies" are already in use, and where further research and development is needed.
TL;DR: The early studies leading to the prediction of the existence of Keap1, followed by the discovery ofKeap1 as the main negative regulator of Nrf2 are summarized and the available structural information on Keap 1, its assembly with Cullin3, and its interaction with Nrf 2 are described.