Showing papers by "Utrecht University published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 citations
Tufts Medical Center1, Northeastern University2, McGill University3, Johns Hopkins University4, Utrecht University5, Vanderbilt University Medical Center6, Brigham and Women's Hospital7, New York University8, McMaster University9, Ohio State University10, Radboud University Nijmegen11, University of Western Ontario12, London Health Sciences Centre13, University of Montpellier14, RMIT University15, University of Poitiers16, Maine Medical Center17, University of Washington18, University of Chicago19, Intermountain Healthcare20, Deakin University21, Johns Hopkins University School of Medicine22, Yale University23, University of Grenoble24, University of California, San Francisco25, Monash University26, Case Western Reserve University27, New York Medical College28, University of Toronto29, Stanford University30
TL;DR: Substantial agreement was found among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults.
Abstract: Objective:To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.Design:Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups g
1,935 citations
TL;DR: This work presents a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and shows that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
1,620 citations
Ottawa Hospital Research Institute1, Jewish General Hospital2, McGill University3, University of Ottawa4, University of Amsterdam5, Canadian Agency for Drugs and Technologies in Health6, Paris Descartes University7, University of Birmingham8, Brown University9, Utrecht University10, University of Exeter11, University of Sydney12, Public Health Agency of Canada13, University of Bern14, University of Split15, University of Calgary16, University of Bristol17
TL;DR: A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline.
Abstract: Importance Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. Objective To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. Design Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. Findings The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. Conclusions and Relevance The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.
1,616 citations
University of Southern California1, Duke University2, Stockholm School of Economics3, University of Virginia4, Center for Open Science5, University of Amsterdam6, University of Pennsylvania7, University of North Carolina at Chapel Hill8, University of Regensburg9, California Institute of Technology10, Research Institute of Industrial Economics11, New York University12, Cardiff University13, Northwestern University14, Mathematica Policy Research15, Ohio State University16, University of Sussex17, Texas A&M University18, Royal Holloway, University of London19, University of Zurich20, University of Melbourne21, University of Wisconsin-Madison22, University of Michigan23, Stanford University24, Rutgers University25, Columbia University26, University of Washington27, University of Edinburgh28, National University of Singapore29, Utrecht University30, Arizona State University31, Princeton University32, University of California, Los Angeles33, Imperial College London34, University of Innsbruck35, Harvard University36, University of Chicago37, University of Pittsburgh38, University of Notre Dame39, University of California, Berkeley40, Johns Hopkins University41, University of Bristol42, University of New South Wales43, Dartmouth College44, Whitman College45, University of Puerto Rico46, University of Milan47, University of California, Irvine48, Paris Dauphine University49, University of British Columbia50, Ludwig Maximilian University of Munich51, Purdue University52, Washington University in St. Louis53, University of California, Davis54, Microsoft55
TL;DR: The default P-value threshold for statistical significance is proposed to be changed from 0.05 to 0.005 for claims of new discoveries in order to reduce uncertainty in the number of discoveries.
Abstract: We propose to change the default P-value threshold for statistical significance from 0.05 to 0.005 for claims of new discoveries.
1,586 citations
University of East Anglia1, University of Exeter2, Alfred Wegener Institute for Polar and Marine Research3, Ludwig Maximilian University of Munich4, Max Planck Society5, Commonwealth Scientific and Industrial Research Organisation6, Karlsruhe Institute of Technology7, Cooperative Institute for Marine and Atmospheric Studies8, Atlantic Oceanographic and Meteorological Laboratory9, École Normale Supérieure10, Centre national de la recherche scientifique11, University of Maryland, College Park12, University of Virginia13, Flanders Marine Institute14, Oak Ridge National Laboratory15, Woods Hole Research Center16, University of Illinois at Urbana–Champaign17, Geophysical Institute, University of Bergen18, Met Office19, University of California, San Diego20, Utrecht University21, Netherlands Environmental Assessment Agency22, University of Paris23, Oeschger Centre for Climate Change Research24, Tsinghua University25, National Center for Atmospheric Research26, Institute of Arctic and Alpine Research27, National Institute for Environmental Studies28, Hobart Corporation29, Cooperative Research Centre30, Japan Agency for Marine-Earth Science and Technology31, University of Groningen32, Wageningen University and Research Centre33, Bjerknes Centre for Climate Research34, Goddard Space Flight Center35, Leibniz Institute for Baltic Sea Research36, Princeton University37, Leibniz Institute of Marine Sciences38, National Oceanic and Atmospheric Administration39, Auburn University40, Food and Agriculture Organization41, VU University Amsterdam42
TL;DR: In this article, the authors describe data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties, including emissions from land use and land-use change data and bookkeeping models.
Abstract: . Accurate assessment of anthropogenic carbon dioxide
( CO2 ) emissions and their redistribution among the atmosphere,
ocean, and terrestrial biosphere – the “global carbon budget” – is
important to better understand the global carbon cycle, support the
development of climate policies, and project future climate change. Here we
describe data sets and methodology to quantify the five major components of
the global carbon budget and their uncertainties. Fossil CO2
emissions ( EFF ) are based on energy statistics and cement
production data, while emissions from land use and land-use change ( ELUC ),
mainly deforestation, are based on land use and land-use change data and
bookkeeping models. Atmospheric CO2 concentration is measured
directly and its growth rate ( GATM ) is computed from the annual
changes in concentration. The ocean CO2 sink ( SOCEAN )
and terrestrial CO2 sink ( SLAND ) are estimated with
global process models constrained by observations. The resulting carbon
budget imbalance ( BIM ), the difference between the estimated
total emissions and the estimated changes in the atmosphere, ocean, and
terrestrial biosphere, is a measure of imperfect data and understanding of
the contemporary carbon cycle. All uncertainties are reported as ±1σ . For the last decade available (2008–2017), EFF was
9.4±0.5 GtC yr −1 , ELUC 1.5±0.7 GtC yr −1 , GATM 4.7±0.02 GtC yr −1 ,
SOCEAN 2.4±0.5 GtC yr −1 , and SLAND 3.2±0.8 GtC yr −1 , with a budget imbalance BIM of
0.5 GtC yr −1 indicating overestimated emissions and/or underestimated
sinks. For the year 2017 alone, the growth in EFF was about 1.6 %
and emissions increased to 9.9±0.5 GtC yr −1 . Also for 2017,
ELUC was 1.4±0.7 GtC yr −1 , GATM was 4.6±0.2 GtC yr −1 , SOCEAN was 2.5±0.5 GtC yr −1 , and SLAND was 3.8±0.8 GtC yr −1 ,
with a BIM of 0.3 GtC. The global atmospheric
CO2 concentration reached 405.0±0.1 ppm averaged over 2017.
For 2018, preliminary data for the first 6–9 months indicate a renewed
growth in EFF of + 2.7 % (range of 1.8 % to 3.7 %) based
on national emission projections for China, the US, the EU, and India and
projections of gross domestic product corrected for recent changes in the
carbon intensity of the economy for the rest of the world. The analysis
presented here shows that the mean and trend in the five components of the
global carbon budget are consistently estimated over the period of 1959–2017,
but discrepancies of up to 1 GtC yr −1 persist for the representation
of semi-decadal variability in CO2 fluxes. A detailed comparison
among individual estimates and the introduction of a broad range of
observations show (1) no consensus in the mean and trend in land-use change
emissions, (2) a persistent low agreement among the different methods on
the magnitude of the land CO2 flux in the northern extra-tropics,
and (3) an apparent underestimation of the CO2 variability by ocean
models, originating outside the tropics. This living data update documents
changes in the methods and data sets used in this new global carbon budget
and the progress in understanding the global carbon cycle compared with
previous publications of this data set (Le Quere et al., 2018, 2016,
2015a, b, 2014, 2013). All results presented here can be downloaded from
https://doi.org/10.18160/GCP-2018 .
1,458 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
Health Canada1, United States Environmental Protection Agency2, Brigham Young University3, University of Texas at Austin4, University of British Columbia5, Health Effects Institute6, McGill University7, University of Minnesota8, Harvard University9, Utrecht University10, University of Washington11, Fudan University12, New York University13, University of California, Los Angeles14, University of Ottawa15, American Cancer Society16, University of California, Davis17, Cancer Prevention Institute of California18, University of New Brunswick19, Dalhousie University20, Carleton University21, Statistics Canada22, University of Toronto23, Chinese Center for Disease Control and Prevention24, St George's, University of London25, University of Hong Kong26, University of Ulm27, SERC Reliability Corporation28
TL;DR: PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.
Abstract: Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.
1,283 citations
TL;DR: A definition of keystone taxa in microbial ecology is proposed and over 200 microbial keystoneTaxa that have been identified in soil, plant and marine ecosystems, as well as in the human microbiome are summarized.
Abstract: Microorganisms have a pivotal role in the functioning of ecosystems. Recent studies have shown that microbial communities harbour keystone taxa, which drive community composition and function irrespective of their abundance. In this Opinion article, we propose a definition of keystone taxa in microbial ecology and summarize over 200 microbial keystone taxa that have been identified in soil, plant and marine ecosystems, as well as in the human microbiome. We explore the importance of keystone taxa and keystone guilds for microbiome structure and functioning and discuss the factors that determine their distribution and activities.
1,188 citations
TL;DR: It is shown that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle.
Abstract: Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradati...
Monash University1, National Health and Medical Research Council2, University of New South Wales3, University of Pennsylvania4, Erasmus University Rotterdam5, Oulu University Hospital6, University of Adelaide7, Odense University Hospital8, State University of New York System9, Australian Catholic University10, University Medical Center Utrecht11, Sanjay Gandhi Post Graduate Institute of Medical Sciences12, University of Chile13, university of lille14, Utrecht University15, Imperial College London16, University of Western Australia17, Karolinska Institutet18, University of Rochester19, Pennsylvania State University20, Peking University21, Cornell University22, Royal College of Surgeons in Ireland23, University of Hong Kong24, Columbia University Medical Center25, Pennington Biomedical Research Center26, Agostino Gemelli University Polyclinic27, Deakin University28, Universidade Federal do Rio Grande do Sul29, Victoria University, Australia30, University of Helsinki31, Queen Mary University of London32, Taipei Medical University Hospital33, University of Cape Town34, Norwegian University of Science and Technology35, Children's Hospital of Philadelphia36, University of Colombo37, University of Pittsburgh38, Boston Children's Hospital39, Hacettepe University40
TL;DR: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.
Abstract: Study Question What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary Answer International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What Is Known Already Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study Design, Size, Duration International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/Materials, Setting, Methods Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main Results and the Role of Chance The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; ii) reducing unnecessary testing; iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, Reasons for Caution Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider Implications of the Findings The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. Study Funding/Competing Interest(S) The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREEII criteria and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.
TL;DR: This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.
University of Lyon1, University of Burgundy2, Université de Sherbrooke3, The Chinese University of Hong Kong4, Pompeu Fabra University5, Stanford University6, Queen Mary University of London7, University of Crete8, Indian Institute of Technology Madras9, French Institute for Research in Computer Science and Automation10, German Cancer Research Center11, Mannheim University of Applied Sciences12, ETH Zurich13, Utrecht University14, Yonsei University15, University of Nice Sophia Antipolis16
TL;DR: How far state-of-the-art deep learning methods can go at assessing CMRI, i.e., segmenting the myocardium and the two ventricles as well as classifying pathologies is measured, to open the door to highly accurate and fully automatic analysis of cardiac CMRI.
Abstract: Delineation of the left ventricular cavity, myocardium, and right ventricle from cardiac magnetic resonance images (multi-slice 2-D cine MRI) is a common clinical task to establish diagnosis. The automation of the corresponding tasks has thus been the subject of intense research over the past decades. In this paper, we introduce the “Automatic Cardiac Diagnosis Challenge” dataset (ACDC), the largest publicly available and fully annotated dataset for the purpose of cardiac MRI (CMR) assessment. The dataset contains data from 150 multi-equipments CMRI recordings with reference measurements and classification from two medical experts. The overarching objective of this paper is to measure how far state-of-the-art deep learning methods can go at assessing CMRI, i.e., segmenting the myocardium and the two ventricles as well as classifying pathologies. In the wake of the 2017 MICCAI-ACDC challenge, we report results from deep learning methods provided by nine research groups for the segmentation task and four groups for the classification task. Results show that the best methods faithfully reproduce the expert analysis, leading to a mean value of 0.97 correlation score for the automatic extraction of clinical indices and an accuracy of 0.96 for automatic diagnosis. These results clearly open the door to highly accurate and fully automatic analysis of cardiac CMRI. We also identify scenarios for which deep learning methods are still failing. Both the dataset and detailed results are publicly available online, while the platform will remain open for new submissions.
TL;DR: Among patients with stage III epithelial ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in longer recurrence‐free survival and overall survival than surgery alone and did not result in higher rates of side effects.
Abstract: Background Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Methods In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measu...
TL;DR: Key studies in which systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting, and how these approaches can be employed to enhance patient responses are summarized.
TL;DR: To avoid a global collapse in the ability to control fungal infections and to avoid critical failures in medicine and food security, the authors must improve the stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.
Abstract: The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals. To avoid a global collapse in our ability to control fungal infections and to avoid critical failures in medicine and food security, we must improve our stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.
TL;DR: In this article, the authors present the first large-N-study on circular economy barriers in the EU (208 survey respondents, 47 expert interviews) and find that cultural barriers, particularly a lack of consumer interest and awareness as well as a hesitant company culture, are considered the main barriers by businesses and policy-makers.
ETH Zurich1, International Institute for Applied Systems Analysis2, Potsdam Institute for Climate Impact Research3, Joint Global Change Research Institute4, Eni5, Netherlands Environmental Assessment Agency6, Utrecht University7, National Institute for Environmental Studies8, Polytechnic University of Milan9
TL;DR: In this paper, the authors describe scenarios that limit end-of-century radiative forcing to 1.9 Wm−2, and consequently restrict median warming in the year 2100 to below 1.5 W m−2.
Abstract: The 2015 Paris Agreement calls for countries to pursue efforts to limit global-mean temperature rise to 1.5 °C. The transition pathways that can meet such a target have not, however, been extensively explored. Here we describe scenarios that limit end-of-century radiative forcing to 1.9 W m−2, and consequently restrict median warming in the year 2100 to below 1.5 °C. We use six integrated assessment models and a simple climate model, under different socio-economic, technological and resource assumptions from five Shared Socio-economic Pathways (SSPs). Some, but not all, SSPs are amenable to pathways to 1.5 °C. Successful 1.9 W m−2 scenarios are characterized by a rapid shift away from traditional fossil-fuel use towards large-scale low-carbon energy supplies, reduced energy use, and carbon-dioxide removal. However, 1.9 W m−2 scenarios could not be achieved in several models under SSPs with strong inequalities, high baseline fossil-fuel use, or scattered short-term climate policy. Further research can help policy-makers to understand the real-world implications of these scenarios.
TL;DR: The results reveal a mechanism by which plants determine the composition of rhizosphere microbiota, plant performance and plant-herbivore interactions of the next generation by modifying root-associated microbiota.
Abstract: By changing soil properties, plants can modify their growth environment. Although the soil microbiota is known to play a key role in the resulting plant-soil feedbacks, the proximal mechanisms underlying this phenomenon remain unknown. We found that benzoxazinoids, a class of defensive secondary metabolites that are released by roots of cereals such as wheat and maize, alter root-associated fungal and bacterial communities, decrease plant growth, increase jasmonate signaling and plant defenses, and suppress herbivore performance in the next plant generation. Complementation experiments demonstrate that the benzoxazinoid breakdown product 6-methoxy-benzoxazolin-2-one (MBOA), which accumulates in the soil during the conditioning phase, is both sufficient and necessary to trigger the observed phenotypic changes. Sterilization, fungal and bacterial profiling and complementation experiments reveal that MBOA acts indirectly by altering root-associated microbiota. Our results reveal a mechanism by which plants determine the composition of rhizosphere microbiota, plant performance and plant-herbivore interactions of the next generation.
University of Cambridge1, Australian National University2, Norwegian Institute of Public Health3, Utrecht University4, University of Tromsø5, The George Institute for Global Health6, Johns Hopkins University7, University of Oxford8, National Institutes of Health9, Copenhagen University Hospital10, University of Copenhagen11, University of Western Australia12, Harry Perkins Institute of Medical Research13, Fiona Stanley Hospital14, University of London15, Lund University16, University of Pittsburgh17, French Institute of Health and Medical Research18, University College London19, University of Ulm20, Technische Universität München21, University of Padua22, University of Southampton23, German Cancer Research Center24, Erasmus University Medical Center25, Umeå University26, Cardiff University27, Greifswald University Hospital28, Aarhus University29, Portland State University30, University of New South Wales31, National and Kapodistrian University of Athens32, Harvard University33, University of Hawaii34, Columbia University35, University of Iowa36, Duke University37, Yamagata University38, Tuskegee University39, University of Helsinki40, University of Oulu41, Medical University of South Carolina42, Kaiser Permanente43, University of Washington44, University of Groningen45, University of Granada46, Yale University47, Prevention Institute48, University of Edinburgh49, Uppsala University50, Basque Government51, Royal Prince Alfred Hospital52, Kyushu University53, Harokopio University54, University of California, San Diego55, VU University Medical Center56, Aalborg University57, University of Eastern Finland58, Laval University59, University of Vermont60, Wake Forest Baptist Medical Center61, Wake Forest University62, Kanazawa Medical University63, Baker IDI Heart and Diabetes Institute64, Heidelberg University65, Istituto Superiore di Sanità66, Pasteur Institute67, City College of New York68, Howard University69, University of Glasgow70, International Agency for Research on Cancer71, University of Bristol72, University of Auckland73
TL;DR: Current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week, and data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
Catholic University of the Sacred Heart1, Memorial Sloan Kettering Cancer Center2, International Agency for Research on Cancer3, University Health Network4, University of Lausanne5, Centre Hospitalier Universitaire de Grenoble6, Utrecht University7, Charité8, University of Texas MD Anderson Cancer Center9, Technische Universität München10, Belfast Health and Social Care Trust11, University of Zurich12, University of Nottingham13, Beatson West of Scotland Cancer Centre14, Tohoku University15, University of Verona16, Institut Gustave Roussy17, University of Bologna18, Radboud University Nijmegen19
TL;DR: This work believes this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.
31 May 2018
TL;DR: The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes as discussed by the authors.
Abstract: Since the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has emerged, disseminated globally and become a leading cause of bacterial infections in both health-care and community settings. However, there is marked geographical variation in MRSA burden owing to several factors, including differences in local infection control practices and pathogen-specific characteristics of the circulating clones. Different MRSA clones have resulted from the independent acquisition of staphylococcal cassette chromosome mec (SCCmec), which contains genes encoding proteins that render the bacterium resistant to most β-lactam antibiotics (such as methicillin), by several S. aureus clones. The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes. Clinical manifestations of MRSA range from asymptomatic colonization of the nasal mucosa to mild skin and soft tissue infections to fulminant invasive disease with high mortality. Although treatment options for MRSA are limited, several new antimicrobials are under development. An understanding of colonization dynamics, routes of transmission, risk factors for progression to infection and conditions that promote the emergence of resistance will enable optimization of strategies to effectively control MRSA. Vaccine candidates are also under development and could become an effective prevention measure.
Cold Spring Harbor Laboratory1, Johns Hopkins University2, Ontario Institute for Cancer Research3, École Polytechnique Fédérale de Lausanne4, Stony Brook University5, Memorial Sloan Kettering Cancer Center6, University of California, Davis7, Thomas Jefferson University8, SUNY Downstate Medical Center9, Utrecht University10, Broad Institute11, Hofstra University12, University of Pennsylvania13, University of Nebraska Medical Center14, Eppley Institute for Research in Cancer and Allied Diseases15, Princess Margaret Cancer Centre16, Cornell University17, University Health Network18, University of Toronto19
TL;DR: A pancreatic cancer patient-derived organoid (PDO) library is generated that recapitulates the mutational spectrum and transcriptional subtypes of primary Pancreatic cancer and proposes that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.
Abstract: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemo-sensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemo-sensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemo-refractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.
TL;DR: A platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner is established and co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer.
TL;DR: The evolving insights from studies on risk factors, brain imaging and neuropathology are reviewed, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction.
Abstract: Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
Princess Margaret Cancer Centre1, University of Cambridge2, Wellcome Trust Sanger Institute3, University of Toronto4, Weizmann Institute of Science5, Ontario Institute for Cancer Research6, International Agency for Research on Cancer7, European Bioinformatics Institute8, University Health Network9, Norwich University10, University of East Anglia11, National and Kapodistrian University of Athens12, University of Milan13, University of Granada14, Cancer Epidemiology Unit15, Prevention Institute16, University of Naples Federico II17, German Cancer Research Center18, Imperial College London19, Utrecht University20, Memorial Sloan Kettering Cancer Center21
TL;DR: Deep sequencing is used to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH, providing proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation.
Abstract: The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4–8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
TL;DR: Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated, representing a meaningful therapeutic advance for this orphan disease.
Abstract: Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.
TL;DR: The authors will explain the technical principles of photon-counting CT in nonmathematical terms for radiologists and clinicians to create opportunities for quantitative imaging relative to current CT technology.
Abstract: Photon-counting CT is an emerging technology with the potential to dramatically change clinical CT Photon-counting CT uses new energy-resolving x-ray detectors, with mechanisms that differ substantially from those of conventional energy-integrating detectors Photon-counting CT detectors count the number of incoming photons and measure photon energy This technique results in higher contrast-to-noise ratio, improved spatial resolution, and optimized spectral imaging Photon-counting CT can reduce radiation exposure, reconstruct images at a higher resolution, correct beam-hardening artifacts, optimize the use of contrast agents, and create opportunities for quantitative imaging relative to current CT technology In this review, the authors will explain the technical principles of photon-counting CT in nonmathematical terms for radiologists and clinicians Following a general overview of the current status of photon-counting CT, they will explain potential clinical applications of this technology