Showing papers by "Newcastle University published in 2019"
Deakin University1, University of Auckland2, Virginia Tech3, Commonwealth Scientific and Industrial Research Organisation4, Catholic University of Leuven5, Public Health Foundation of India6, Imperial College London7, Australian National University8, Washington University in St. Louis9, Brookings Institution10, University of Stirling11, University of London12, Harvard University13, University of Hertfordshire14, McGill University15, Drexel University16, Tehran University of Medical Sciences17, George Washington University18, Newcastle University19, Wellington Management Company20, Huazhong University of Science and Technology21, World Bank22, University of Cape Town23, University of Amsterdam24, University of Newcastle25
TL;DR: This work aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about concrete mechanical properties such as E-modulus and compressive strength.
1,480 citations
TL;DR: The current range of approaches to electric-vehicle lithium-ion battery recycling and re-use are outlined, areas for future progress are highlighted, and processes for dismantling and recycling lithium-ions from scrap electric vehicles are outlined.
Abstract: Rapid growth in the market for electric vehicles is imperative, to meet global targets for reducing greenhouse gas emissions, to improve air quality in urban centres and to meet the needs of consumers, with whom electric vehicles are increasingly popular. However, growing numbers of electric vehicles present a serious waste-management challenge for recyclers at end-of-life. Nevertheless, spent batteries may also present an opportunity as manufacturers require access to strategic elements and critical materials for key components in electric-vehicle manufacture: recycled lithium-ion batteries from electric vehicles could provide a valuable secondary source of materials. Here we outline and evaluate the current range of approaches to electric-vehicle lithium-ion battery recycling and re-use, and highlight areas for future progress. Processes for dismantling and recycling lithium-ion battery packs from scrap electric vehicles are outlined.
1,333 citations
University of Glasgow1, University of Lugano2, St George's, University of London3, Pasteur Institute4, Queen Mary University of London5, Buck Institute for Research on Aging6, National and Kapodistrian University of Athens7, Université de Montréal8, Imperial College London9, Osaka University10, Weizmann Institute of Science11, Mayo Clinic12, University of Melbourne13, University of Cambridge14, University of Minnesota15, Max Delbrück Center for Molecular Medicine16, Brown University17, Academy of Athens18, Newcastle University19, University of Florida20, Catalan Institution for Research and Advanced Studies21, University of Groningen22
TL;DR: A consensus from the International Cell Senescence Association (ICSA) is presented, defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers.
1,220 citations
Newcastle upon Tyne Hospitals NHS Foundation Trust1, Newcastle University2, University of Exeter3, University of Cambridge4, Chelsea and Westminster Hospital NHS Foundation Trust5, Imperial College London6, Royal Liverpool and Broadgreen University Hospital NHS Trust7, Pennine Acute Hospitals NHS Trust8, University of Manchester9, King's College London10, Guy's and St Thomas' NHS Foundation Trust11, Queen Mary University of London12, Barts Health NHS Trust13, University of Leeds14, Leeds Teaching Hospitals NHS Trust15, Royal College of Surgeons in Ireland16, Western General Hospital17, University of Edinburgh18, University Hospitals Bristol NHS Foundation Trust19, Glasgow Royal Infirmary20, University of Glasgow21, University of Birmingham22, Queen Elizabeth Hospital Birmingham23, University College London24, University College London Hospitals NHS Foundation Trust25, Brighton and Sussex University Hospitals NHS Trust26, Brighton and Sussex Medical School27, University of Wolverhampton28, University Hospital of Wales29
TL;DR: Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care.
Abstract: Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.
1,140 citations
TL;DR: This Review discusses NAFLD-associated HCC, including its epidemiology, key features that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities, and the challenges and future directions of research.
Abstract: Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.
761 citations
University of Kentucky1, Mayo Clinic2, University of Pennsylvania3, Rush University Medical Center4, Illinois Institute of Technology5, Uppsala University6, Newcastle University7, University of Cambridge8, University of Southern California9, University of Minnesota10, University of Sydney11, University of California, Irvine12, University of Washington13, Medical University of Vienna14, Emory University15, Stanford University16, University of California, San Diego17, University of California, San Francisco18, Harvard University19, University of Texas Southwestern Medical Center20
TL;DR: A recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE).
Abstract: We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
753 citations
TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
698 citations
University of Birmingham1, Newcastle University2, Weston Park Hospital3, University of Warwick4, Castle Hill Hospital5, Aberdeen Royal Infirmary6, Royal Surrey County Hospital7, Mount Sinai St. Luke's and Mount Sinai Roosevelt8, Cheltenham General Hospital9, Nottingham University Hospitals NHS Trust10, James Cook University Hospital11, Abertawe Bro Morgannwg University Health Board12, United Hospitals13, University Hospital Coventry14, Western General Hospital15, Beatson West of Scotland Cancer Centre16, VU University Amsterdam17, The Royal Marsden NHS Foundation Trust18, University of Oxford19
TL;DR: Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin, and cetuximab showed significant detriment in terms of tumour control.
661 citations
TL;DR: In a prospective analysis of patients with NAFLD, FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) found to be effective in assessing liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89.
640 citations
TL;DR: In this article, a combination of water-quality observations and simulated nitrogen discharge from agricultural and other sources was used to estimate spatial patterns of nitrogen discharge into water bodies across China from 1955 to 2014.
Abstract: The nitrogen cycle has been radically changed by human activities1. China consumes nearly one third of the world’s nitrogen fertilizers. The excessive application of fertilizers2,3 and increased nitrogen discharge from livestock, domestic and industrial sources have resulted in pervasive water pollution. Quantifying a nitrogen ‘boundary’4 in heterogeneous environments is important for the effective management of local water quality. Here we use a combination of water-quality observations and simulated nitrogen discharge from agricultural and other sources to estimate spatial patterns of nitrogen discharge into water bodies across China from 1955 to 2014. We find that the critical surface-water quality standard (1.0 milligrams of nitrogen per litre) was being exceeded in most provinces by the mid-1980s, and that current rates of anthropogenic nitrogen discharge (14.5 ± 3.1 megatonnes of nitrogen per year) to fresh water are about 2.7 times the estimated ‘safe’ nitrogen discharge threshold (5.2 ± 0.7 megatonnes of nitrogen per year). Current efforts to reduce pollution through wastewater treatment and by improving cropland nitrogen management can partially remedy this situation. Domestic wastewater treatment has helped to reduce net discharge by 0.7 ± 0.1 megatonnes in 2014, but at high monetary and energy costs. Improved cropland nitrogen management could remove another 2.3 ± 0.3 megatonnes of nitrogen per year—about 25 per cent of the excess discharge to fresh water. Successfully restoring a clean water environment in China will further require transformational changes to boost the national nutrient recycling rate from its current average of 36 per cent to about 87 per cent, which is a level typical of traditional Chinese agriculture. Although ambitious, such a high level of nitrogen recycling is technologically achievable at an estimated capital cost of approximately 100 billion US dollars and operating costs of 18–29 billion US dollars per year, and could provide co-benefits such as recycled wastewater for crop irrigation and improved environmental quality and ecosystem services. Estimates of spatial patterns of nitrogen discharge into water bodies across China between 1955 and 2014 show that current discharge rates are almost three times the acceptable threshold, and ways to restore a clean water environment are suggested.
537 citations
Humboldt University of Berlin1, Oregon Health & Science University2, Queen Mary University of London3, Lawrence Berkeley National Laboratory4, European Bioinformatics Institute5, Oregon State University6, University of North Carolina at Chapel Hill7, Curtin University8, Government of Western Australia9, Chestnut Hill College10, Vrije Universiteit Brussel11, Garvan Institute of Medical Research12, University of Toronto13, National Institutes of Health14, Medical College of Wisconsin15, Pompeu Fabra University16, Manchester Royal Eye Hospital17, French Institute of Health and Medical Research18, Sanford Health19, Stanford University20, Utrecht University21, Newcastle University22, Icahn School of Medicine at Mount Sinai23, University College London24, University of Strasbourg25, Children's Hospital of Philadelphia26, University of Connecticut27
TL;DR: The HPO’s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data and plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data.
Abstract: The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.
TL;DR: Sustained remission was linked to the extent of sustained weight loss, and the DiRECT programme sustained remissions at 24 months for more than a third of people with type 2 diabetes.
Tsinghua University1, Southwest University2, University of Oklahoma3, Newcastle University4, Northeastern University (China)5, Washington University in St. Louis6, University of Vienna7, Northwestern University8, Chinese Academy of Sciences9, Shandong University10, University of Hong Kong11, Sun Yat-sen University12, University of Queensland13, Aalborg University14, Rice University15, Stanford University16, Michigan State University17, University of Tennessee18, University of Washington19, Lawrence Berkeley National Laboratory20, Arizona State University21
TL;DR: Global sampling of microbial communities associated with wastewater treatment plants and application of ecological theory revealed a small, core bacterial community associated with performance and provides insights into the community dynamics in this environment.
Abstract: Microorganisms in wastewater treatment plants (WWTPs) are essential for water purification to protect public and environmental health. However, the diversity of microorganisms and the factors that control it are poorly understood. Using a systematic global-sampling effort, we analysed the 16S ribosomal RNA gene sequences from ~1,200 activated sludge samples taken from 269 WWTPs in 23 countries on 6 continents. Our analyses revealed that the global activated sludge bacterial communities contain ~1 billion bacterial phylotypes with a Poisson lognormal diversity distribution. Despite this high diversity, activated sludge has a small, global core bacterial community (n = 28 operational taxonomic units) that is strongly linked to activated sludge performance. Meta-analyses with global datasets associate the activated sludge microbiomes most closely to freshwater populations. In contrast to macroorganism diversity, activated sludge bacterial communities show no latitudinal gradient. Furthermore, their spatial turnover is scale-dependent and appears to be largely driven by stochastic processes (dispersal and drift), although deterministic factors (temperature and organic input) are also important. Our findings enhance our mechanistic understanding of the global diversity and biogeography of activated sludge bacterial communities within a theoretical ecology framework and have important implications for microbial ecology and wastewater treatment processes.
University of Southern California1, Huntington Medical Research Institutes2, University of Edinburgh3, University of Toronto4, Yale University5, Ludwig Maximilian University of Munich6, Cornell University7, University of Bristol8, University of Nottingham9, Nottingham City Hospital10, University of Cambridge11, University of Manchester12, University of Glasgow13, Newcastle University14, UCL Institute of Neurology15, University of Southampton16, British Heart Foundation17, King's College London18, Harvard University19, Mayo Clinic20, University of Illinois at Chicago21, University of Arizona22, University of British Columbia23, University of California, San Diego24, University of Washington25, Wake Forest University26, National University of Singapore27, University of New South Wales28, University of Gothenburg29, SUNY Downstate Medical Center30, Utrecht University31, University of Calgary32, The Chinese University of Hong Kong33, Queen's University Belfast34, University College London35, VU University Amsterdam36, VU University Medical Center37, German Center for Neurodegenerative Diseases38, University of Bonn39, Houston Methodist Hospital40, McGill University41, Boston University42, National Institutes of Health43, Johns Hopkins University44, Leiden University45, Rush University Medical Center46, University of Minnesota47, University of Western Ontario48
TL;DR: Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize and should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
Abstract: Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
University of Lausanne1, Heidelberg University2, Chinese Academy of Sciences3, National Research University – Higher School of Economics4, Skolkovo Institute of Science and Technology5, Cardiff University6, École Polytechnique Fédérale de Lausanne7, Children's Mercy Hospital8, University of Kansas9, University of Porto10, Francis Crick Institute11, The University of Texas Rio Grande Valley12, Linköping University13, German Primate Center14, Newcastle University15, CAS-MPG Partner Institute for Computational Biology16, Stanford University17
TL;DR: It is found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase during development.
Abstract: The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.
TL;DR: A systematic review of the smart home literature and survey the current state of play from the users' perspective, which presents a comprehensive view of smart home definitions and characteristics.
TL;DR: A shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs is demonstrated, which is validated to produce an integrated map of fetal liver haematopoiesis.
Abstract: Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Using single cell transcriptome profiling of ~140,000 liver and ~74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the impact of tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, NK and ILC precursors in the yolk sac. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for harnessing the therapeutic potential of HSC/MPPs.
TL;DR: It is shown that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction and that emerging senolytics agents hold promise for treating obesity‐related metabolic dysfunction and its complications.
Abstract: Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.
26 Feb 2019
TL;DR: High quality evidence to recommend MT plus best medical management (BMM, including intravenous thrombolysis whenever indicated) to improve functional outcome in patients with LVO-related acute ischaemic stroke within 6 hours after symptom onset is found.
Abstract: BackgroundMechanical thrombectomy (MT) has become the cornerstone of acute ischaemic stroke management in patients with large vessel occlusion (LVO). The aim of this guideline document is to assist...
TL;DR: High quality evidence is found to recommend Mechanical thrombectomy plus best medical management (BMM) to improve functional outcome in patients with LVO related acute ischemic stroke within 6 hours after symptom onset.
Abstract: Background Mechanical thrombectomy (MT) has become the cornerstone of acute ischemic stroke management in patients with large vessel occlusion (LVO). Objective To assist physicians in their clinical decisions with regard toMT. Methods These guidelines were developed based on the standard operating procedure of the European Stroke Organisation and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. An interdisciplinary working group identified 15 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert opinion was provided if not enough evidence was available to provide recommendations based on the GRADE approach. Results We found high-quality evidence to recommend MT plus best medical management (BMM, including intravenous thrombolysis whenever indicated) to improve functional outcome in patients with LVO-related acute ischemic stroke within 6 hours after symptom onset. We found moderate quality of evidence to recommend MT plus BMM in the 6–24h time window in patients meeting the eligibility criteria of published randomized trials. These guidelinesdetails aspects of prehospital management, patient selection based on clinical and imaging characteristics, and treatment modalities. Conclusions MT is the standard of care in patients with LVO-related acute stroke. Appropriate patient selection and timely reperfusion are crucial. Further randomized trials are needed to inform clinical decision-making with regard tothe mothership and drip-and-ship approaches, anesthaesia modalities during MT, and to determine whether MT is beneficial in patients with low stroke severity or large infarct volume.
TL;DR: The Faculty of Intensive Care Medicine and Intensive care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS).
Abstract: The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal.
TL;DR: It is called for the development of participatory research skills among the autism research community and the facilitation of greater autistic leadership of, and partnership in, research to lead to better translation into practice and improved outcomes for autistic people and those who support them.
Abstract: Participatory research methods connect researchers with relevant communities to achieve shared goals. These methods can deliver results that are relevant to people’s lives and thus likely to have a positive impact. In the context of a large and growing body of autism research, with continued poor implementation, and some evidence of community dissatisfaction, there is a powerful case for participatory autism research. In order to develop a framework for such collaborative working, a UK seminar series was organised and co-produced by autistic and non-autistic people with academic, practitioner and lived expertise. This article reports on the outcomes from the series, identifying five topics relevant to building a community of practice in participatory research: Respect, Authenticity, Assumptions, Infrastructure and Empathy. Each topic is connected to a specific example from within and beyond research, to inspire new practices in the field. We call for the development of participatory research skills among the autism research community and the facilitation of greater autistic leadership of, and partnership in, research. Such work, if delivered to a high standard, is likely to lead to better translation into practice and improved outcomes for autistic people and those who support them.
TL;DR: It is shown that Treg cells segregate into subpopulations along a continuum of tissue adaptation and present conserved expression programs between homeostasis and disease and mouse and human.
TL;DR: It is found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs, and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
University of Arkansas for Medical Sciences1, Celgene2, Washington University in St. Louis3, Harvard University4, Multiple Myeloma Research Foundation5, Translational Genomics Research Institute6, University of Milan7, University of Nantes8, Cedars-Sinai Medical Center9, Mayo Clinic10, German Cancer Research Center11, Erasmus University Rotterdam12, University of Navarra13, Emory University14, Newcastle University15, French Institute of Health and Medical Research16
TL;DR: In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, DNA drivers of aggressive clinical behavior are defined and Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
Abstract: Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
TL;DR: A mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues is described.
Abstract: Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.
Bruce C.V. Campbell1, Charles B. L. M. Majoie2, Gregory W. Albers3, Bijoy K Menon4 +1293 more•Institutions (26)
TL;DR: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome.
Abstract: BACKGROUND: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. METHODS: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. FINDINGS: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. INTERPRETATION: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. FUNDING: Medtronic.
TL;DR: This study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
Abstract: Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
TL;DR: It is proposed that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescence-associated cells during ageing.
Abstract: Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.
TL;DR: This study reports the deepest record of microplastic ingestion, indicating that anthropogenic debris is bioavailable to organisms at some of the deepest locations in the Earth's oceans.
Abstract: While there is now an established recognition of microplastic pollution in the oceans, and the detrimental effects this may have on marine animals, the ocean depth at which such contamination is in...