Showing papers by "University of Cologne published in 2020"
Katholieke Universiteit Leuven1, Public Health Research Institute2, Leiden University3, John Radcliffe Hospital4, University of Oxford5, Keele University6, Medical University of Vienna7, University Medical Center Utrecht8, University College Cork9, University of Pennsylvania10, University of Cologne11, Manchester Academic Health Science Centre12, University of Aberdeen13, RMIT University14, University of Manchester15, University of Amsterdam16, Imperial College London17, University of Ioannina18, Maastricht University Medical Centre19, Humboldt University of Berlin20
TL;DR: Proposed models for covid-19 are poorly reported, at high risk of bias, and their reported performance is probably optimistic, according to a review of published and preprint reports.
Abstract: Objective To review and appraise the validity and usefulness of published and preprint reports of prediction models for diagnosing coronavirus disease 2019 (covid-19) in patients with suspected infection, for prognosis of patients with covid-19, and for detecting people in the general population at increased risk of covid-19 infection or being admitted to hospital with the disease. Design Living systematic review and critical appraisal by the COVID-PRECISE (Precise Risk Estimation to optimise covid-19 Care for Infected or Suspected patients in diverse sEttings) group. Data sources PubMed and Embase through Ovid, up to 1 July 2020, supplemented with arXiv, medRxiv, and bioRxiv up to 5 May 2020. Study selection Studies that developed or validated a multivariable covid-19 related prediction model. Data extraction At least two authors independently extracted data using the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist; risk of bias was assessed using PROBAST (prediction model risk of bias assessment tool). Results 37 421 titles were screened, and 169 studies describing 232 prediction models were included. The review identified seven models for identifying people at risk in the general population; 118 diagnostic models for detecting covid-19 (75 were based on medical imaging, 10 to diagnose disease severity); and 107 prognostic models for predicting mortality risk, progression to severe disease, intensive care unit admission, ventilation, intubation, or length of hospital stay. The most frequent types of predictors included in the covid-19 prediction models are vital signs, age, comorbidities, and image features. Flu-like symptoms are frequently predictive in diagnostic models, while sex, C reactive protein, and lymphocyte counts are frequent prognostic factors. Reported C index estimates from the strongest form of validation available per model ranged from 0.71 to 0.99 in prediction models for the general population, from 0.65 to more than 0.99 in diagnostic models, and from 0.54 to 0.99 in prognostic models. All models were rated at high or unclear risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, high risk of model overfitting, and unclear reporting. Many models did not include a description of the target population (n=27, 12%) or care setting (n=75, 32%), and only 11 (5%) were externally validated by a calibration plot. The Jehi diagnostic model and the 4C mortality score were identified as promising models. Conclusion Prediction models for covid-19 are quickly entering the academic literature to support medical decision making at a time when they are urgently needed. This review indicates that almost all pubished prediction models are poorly reported, and at high risk of bias such that their reported predictive performance is probably optimistic. However, we have identified two (one diagnostic and one prognostic) promising models that should soon be validated in multiple cohorts, preferably through collaborative efforts and data sharing to also allow an investigation of the stability and heterogeneity in their performance across populations and settings. Details on all reviewed models are publicly available at https://www.covprecise.org/. Methodological guidance as provided in this paper should be followed because unreliable predictions could cause more harm than benefit in guiding clinical decisions. Finally, prediction model authors should adhere to the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) reporting guideline. Systematic review registration Protocol https://osf.io/ehc47/, registration https://osf.io/wy245. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.
2,183 citations
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
Paris 12 Val de Marne University1, University Medical Center Groningen2, Eindhoven University of Technology3, University Hospital of Lausanne4, French Institute of Health and Medical Research5, Università Campus Bio-Medico6, University of Belgrade7, University of Cologne8, Ludwig Maximilian University of Munich9, École Polytechnique Fédérale de Lausanne10, Turku University Hospital11, University of Regensburg12, Università telematica San Raffaele13, Paris Descartes University14, Paracelsus Private Medical University of Salzburg15, University of Bern16, Universidade Nova de Lisboa17, Medical Park18, University of Göttingen19, University of Messina20, Central European Institute of Technology21, University of Siena22, University of Turku23, University of Tübingen24
TL;DR: These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018, and are based on the differences reached in therapeutic efficacy of real vs. sham rT MS protocols.
822 citations
TL;DR: The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe, and is detailed in this paper.
Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.
681 citations
TL;DR: In this article, a survey of early career teachers conducted in May and June 2020 was conducted to investigate the extent to which they maintained social contact with students and mastered core teaching challenges.
Abstract: As in many countries worldwide, as part of the consequences of the COVID-19 pandemic lockdown schools in Germany closed in March 2020 and only partially re-opened in May. Teachers were confronted with the need to adapt to online teaching. This paper presents the results of a survey of early career teachers conducted in May and June 2020. First, we analysed the extent to which they maintained social contact with students and mastered core teaching challenges. Second, we analysed potential factors (school computer technology, teacher competence such as their technological pedagogical knowledge, and teacher education learning opportunities pertaining to digital teaching and learning). Findings from regression analyses show that information and communication technologies (ICT) tools, particularly digital teacher competence and teacher education opportunities to learn digital competence, are instrumental in adapting to online teaching during COVID-19 school closures. Implications are discussed for the field of teacher education and the adoption of ICT by teachers.
651 citations
European Bioinformatics Institute1, Wellcome Trust Sanger Institute2, Francis Crick Institute3, Broad Institute4, University of Oxford5, University of Cambridge6, University of Toronto7, Oregon Health & Science University8, University of Texas MD Anderson Cancer Center9, German Cancer Research Center10, Heidelberg University11, University of Ljubljana12, NorthShore University HealthSystem13, Vancouver Prostate Centre14, Simon Fraser University15, University of Melbourne16, Walter and Eliza Hall Institute of Medical Research17, Katholieke Universiteit Leuven18, Cornell University19, University of California, Santa Cruz20, Ontario Institute for Cancer Research21, University of California, Los Angeles22, Peter MacCallum Cancer Centre23, Harvard University24, Indiana University25, University of Chicago26, University of Cologne27, University of Helsinki28, University of Glasgow29
TL;DR: Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.
Abstract: Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
565 citations
TL;DR: Improved methods are summarized and the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster is presented, reducing the effort needed to answer circuit questions and providing procedures linking the neurons defined by the analysis with genetic reagents.
Abstract: Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons – compared to some 86 billion in humans – the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map – or connectome – the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.
546 citations
German Center for Neurodegenerative Diseases1, University of Cologne2, Brigham and Women's Hospital3, University of Melbourne4, Harvard University5, VU University Amsterdam6, University of Barcelona7, Yeshiva University8, City University of New York9, Indiana University10, University of Victoria11, University Hospital Bonn12
TL;DR: The majority of individuals with SCD will not show progressive cognitive decline, and an individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual withSCD who actively seeks medical help.
Abstract: A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.
518 citations
TL;DR: This study evaluates coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany to evaluate patients with acute respiratory distress syndrome due to viral infection.
Abstract: Objectives Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. Methods A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. Results COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. Conclusion Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.
497 citations
Cornell University1, Harvard University2, The Chinese University of Hong Kong3, Sarah Cannon Research Institute4, University of California, San Francisco5, University of Bern6, Institut Gustave Roussy7, Yonsei University8, Ben-Gurion University of the Negev9, University of North Carolina at Chapel Hill10, Seoul National University11, Japanese Foundation for Cancer Research12, Sungkyunkwan University13, University of Chicago14, Tottori University15, Ohio State University16, University of California, San Diego17, New York University18, Okayama University19, University of Milan20, City of Hope National Medical Center21, Roswell Park Cancer Institute22, University of Cologne23, Peter MacCallum Cancer Centre24, University of Texas MD Anderson Cancer Center25
TL;DR: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated.
Abstract: Background RET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibi...
400 citations
TL;DR: An approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation is developed.
TL;DR: Imaging neurons of organoids reveal that SARS‐CoV‐2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death, and these studies provide initial insights into the potential neurotoxic effect of Sars‐Cov‐2.
Abstract: COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Dusseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS-CoV-2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS-CoV-2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS-CoV-2 and emphasize that brain organoids could model CNS pathologies of COVID-19.
Oslo University Hospital1, Cardiff University2, University of Helsinki3, Leiden University Medical Center4, Royal Melbourne Hospital5, Leipzig University6, University of Bonn7, University of Melbourne8, Aarhus University Hospital9, Aarhus University10, Aalborg University11, University of Barcelona12, Imperial College London13, University of Manchester14, Central Manchester University Hospitals NHS Foundation Trust15, Newcastle University16, University of Vermont17, University Medical Center Groningen18, European Institute of Oncology19, Vita-Salute San Raffaele University20, Karolinska Institutet21, Tel Aviv University22, Sheba Medical Center23, University Hospital of Basel24, Hospital Italiano de Buenos Aires25, University of Cologne26, Dresden University of Technology27, Ludwig Maximilian University of Munich28, University Hospital Bonn29, German Cancer Research Center30, University Hospital Heidelberg31, University of Düsseldorf32, Ruhr University Bochum33, Helsinki University Central Hospital34, Stanford University35, Mayo Clinic36, Lunenfeld-Tanenbaum Research Institute37, University of Hawaii38, Fred Hutchinson Cancer Research Center39, Cedars-Sinai Medical Center40, Copenhagen University Hospital41, Leiden University42, Karolinska University Hospital43, University of Jyväskylä44, University of Oslo45
TL;DR: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
University of Reading1, Leipzig University2, Imperial College London3, Max Planck Society4, University of Oxford5, University of Paris6, University of Leeds7, University of Bordeaux8, École Normale Supérieure9, National Oceanic and Atmospheric Administration10, University of Cologne11, National Center for Atmospheric Research12, University of Exeter13, Met Office14, ETH Zurich15, Stockholm University16, University of Oslo17, Carnegie Institution for Science18, Goethe University Frankfurt19, Hokkaido University20, Nagoya University21, Norwegian Meteorological Institute22, Brookhaven National Laboratory23, Lille University of Science and Technology24, University of Tartu25, Langley Research Center26
TL;DR: A new range of aerosol radiative forcing over the industrial era is provided based on multiple, traceable, and arguable lines of evidence, including modeling approaches, theoretical considerations, and observations, to constrain the forcing from aerosol‐radiation interactions.
Abstract: Aerosols interact with radiation and clouds. Substantial progress made over the past 40 years in observing, understanding, and modeling these processes helped quantify the imbalance in the Earth’s radiation budget caused by anthropogenic aerosols, called aerosol radiative forcing, but uncertainties remain large. This review provides a new range of aerosol radiative forcing over the industrial era based on multiple, traceable and arguable lines of evidence, including modelling approaches, theoretical considerations, and observations. Improved understanding of aerosol absorption and the causes of trends in surface radiative fluxes constrain the forcing from aerosol-radiation interactions. A robust theoretical foundation and convincing evidence constrain the forcing caused by aerosol-driven increases in liquid cloud droplet number concentration. However, the influence of anthropogenic aerosols on cloud liquid water content and cloud fraction is less clear, and the influence on mixed-phase and ice clouds remains poorly constrained. Observed changes in surface temperature and radiative fluxes provide additional constraints. These multiple lines of evidence lead to a 68% confidence interval for the total aerosol effective radiative forcing of −1.60 to −0.65 W m−2, or −2.0 to −0.4 W m−2 with a 90% likelihood. Those intervals are of similar width to the last Intergovernmental Panel on Climate Change assessment but shifted towards more negative values. The uncertainty will narrow in the future by continuing to critically combine multiple lines of evidence, especially those addressing industrial-era changes in aerosol sources and aerosol effects on liquid cloud amount and on ice clouds.
TL;DR: It is demonstrated that SARS-CoV-2-neutralizing antibodies are readily generated from a diverse pool of precursors, fostering hope for rapid induction of a protective immune response upon vaccination.
TL;DR: The existence of brain-first and body-first subtypes of Parkinson's disease is supported by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups using multimodal imaging.
Abstract: Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner However, it remains uncertain where the initial α-synuclein aggregates originate We have hypothesized that Parkinson's disease comprises two subtypes A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity Colon volume and transit times were assessed with CT scans and radiopaque markers Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA) When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0008, ANOVA) The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 007, t-test) In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0001, ANOVA) and delayed colonic transit times (P = 001, Kruskal-Wallis) The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal These findings support the existence of brain-first and body-first subtypes of Parkinson's disease
TL;DR: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19, a first living update of this review is published.
Abstract: Background Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. Search methods We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020. Selection criteria We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. Data collection and analysis We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. MAIN RESULTS: This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19 We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome. Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event. Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events (14 studies, 5201 participants) Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events. Authors' conclusions We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19. While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms. There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.
Memorial Sloan Kettering Cancer Center1, University of North Carolina at Chapel Hill2, National Institutes of Health3, University of Cambridge4, Harvard University5, Washington University in St. Louis6, University of Texas MD Anderson Cancer Center7, University of Cologne8, Cornell University9, AstraZeneca10, Johns Hopkins University11
TL;DR: It is found mutations are selected differentially based on exposures, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2).
Abstract: Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.
TL;DR: An ordinal tool is proposed to measure the full spectrum of functional outcomes following COVID-19 and can be used for tracking functional status over time as well as for research purposes.
Abstract: We propose an ordinal tool to measure the full spectrum of functional outcomes following COVID-19. This “Post-COVID-19 Functional Status (PCFS) Scale” can be used for tracking functional status over time as well as for research purposes.
California Institute of Technology1, Cornell University2, ETH Zurich3, University of British Columbia4, Planetary Science Institute5, Institut de Physique du Globe de Paris6, Institut Universitaire de France7, University of Paris8, German Aerospace Center9, Universities Space Research Association10, University of California, Los Angeles11, University of Oxford12, Colorado School of Mines13, Max Planck Society14, Imperial College London15, Royal Observatory of Belgium16, Université catholique de Louvain17, University of California, Berkeley18, Institut supérieur de l'aéronautique et de l'espace19, Goddard Space Flight Center20, Smithsonian Institution21, Princeton University22, Austrian Academy of Sciences23, Virginia Tech24, University of Cologne25, Space Science Institute26, Johns Hopkins University Applied Physics Laboratory27, Paul Sabatier University28, Stony Brook University29, École normale supérieure de Lyon30, University of Nantes31, Texas Tech University32, University of California, Santa Cruz33, Spanish National Research Council34, University of Maryland, College Park35, Southern Methodist University36, Johns Hopkins University37, University of Bristol38, State University of New York at Geneseo39, Marshall Space Flight Center40
TL;DR: For example, the first ten months of the InSight lander on Mars revealed a planet that is seismically active and provided information about the interior, surface and atmospheric workings of Mars as mentioned in this paper.
Abstract: NASA’s InSight (Interior exploration using Seismic Investigations, Geodesy and Heat Transport) mission landed in Elysium Planitia on Mars on 26 November 2018. It aims to determine the interior structure, composition and thermal state of Mars, as well as constrain present-day seismicity and impact cratering rates. Such information is key to understanding the differentiation and subsequent thermal evolution of Mars, and thus the forces that shape the planet’s surface geology and volatile processes. Here we report an overview of the first ten months of geophysical observations by InSight. As of 30 September 2019, 174 seismic events have been recorded by the lander’s seismometer, including over 20 events of moment magnitude Mw = 3–4. The detections thus far are consistent with tectonic origins, with no impact-induced seismicity yet observed, and indicate a seismically active planet. An assessment of these detections suggests that the frequency of global seismic events below approximately Mw = 3 is similar to that of terrestrial intraplate seismic activity, but there are fewer larger quakes; no quakes exceeding Mw = 4 have been observed. The lander’s other instruments—two cameras, atmospheric pressure, temperature and wind sensors, a magnetometer and a radiometer—have yielded much more than the intended supporting data for seismometer noise characterization: magnetic field measurements indicate a local magnetic field that is ten-times stronger than orbital estimates and meteorological measurements reveal a more dynamic atmosphere than expected, hosting baroclinic and gravity waves and convective vortices. With the mission due to last for an entire Martian year or longer, these results will be built on by further measurements by the InSight lander. Geophysical and meteorological measurements by NASA’s InSight lander on Mars reveal a planet that is seismically active and provide information about the interior, surface and atmospheric workings of Mars.
European Southern Observatory1, University of Lisbon2, Max Planck Society3, University of Grenoble4, CERN5, University of Paris6, Leiden University7, University of Colorado Boulder8, University of Cologne9, University of Porto10, University of California, Berkeley11, University of Cambridge12, Weizmann Institute of Science13
TL;DR: In this article, the first detection of the GR Schwarzschild precession (SP) in S2's orbit was reported, which is a kink between the pre-and post-pericentre directions of motion ≈±1 year around pericentre passage.
Abstract: The star S2 orbiting the compact radio source Sgr A* is a precision probe of the gravitational field around the closest massive black hole (candidate). Over the last 2.7 decades we have monitored the star’s radial velocity and motion on the sky, mainly with the SINFONI and NACO adaptive optics (AO) instruments on the ESO VLT, and since 2017, with the four-telescope interferometric beam combiner instrument GRAVITY. In this Letter we report the first detection of the General Relativity (GR) Schwarzschild Precession (SP) in S2’s orbit. Owing to its highly elliptical orbit (e = 0.88), S2’s SP is mainly a kink between the pre-and post-pericentre directions of motion ≈±1 year around pericentre passage, relative to the corresponding Kepler orbit. The superb 2017−2019 astrometry of GRAVITY defines the pericentre passage and outgoing direction. The incoming direction is anchored by 118 NACO-AO measurements of S2’s position in the infrared reference frame, with an additional 75 direct measurements of the S2-Sgr A* separation during bright states (“flares”) of Sgr A*. Our 14-parameter model fits for the distance, central mass, the position and motion of the reference frame of the AO astrometry relative to the mass, the six parameters of the orbit, as well as a dimensionless parameter f SP for the SP (f SP = 0 for Newton and 1 for GR). From data up to the end of 2019 we robustly detect the SP of S2, δ ϕ ≈ 12′ per orbital period. From posterior fitting and MCMC Bayesian analysis with different weighting schemes and bootstrapping we find f SP = 1.10 ± 0.19. The S2 data are fully consistent with GR. Any extended mass inside S2’s orbit cannot exceed ≈0.1% of the central mass. Any compact third mass inside the central arcsecond must be less than about 1000 M ⊙ .
TL;DR: It is shown that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin.
TL;DR: The treatment of CAPA is complicated by drug–drug interactions associated with broad spectrum azoles, renal tropism and damage caused by SARS-CoV-2, which may challenge the use of liposomal amphotericin B, as well as the emergence of azole-resistance.
Abstract: Like severe influenza, coronavirus disease-19 (COVID-19) resulting in acute respiratory distress syndrome (ARDS) has emerged as an important disease that predisposes patients to secondary pulmonary aspergillosis, with 35 cases of COVID-19 associated pulmonary aspergillosis (CAPA) published until June 2020. The release of danger-associated molecular patterns during severe COVID-19 results in both pulmonary epithelial damage and inflammatory disease, which are predisposing risk factors for pulmonary aspergillosis. Moreover, collateral effects of host recognition pathways required for the activation of antiviral immunity may, paradoxically, contribute to a highly permissive inflammatory environment that favors fungal pathogenesis. Diagnosis of CAPA remains challenging, mainly because bronchoalveolar lavage fluid galactomannan testing and culture, which represent the most sensitive diagnostic tests for aspergillosis in the ICU, are hindered by the fact that bronchoscopies are rarely performed in COVID-19 patients due to the risk of disease transmission. Similarly, autopsies are rarely performed, which may result in an underestimation of the prevalence of CAPA. Finally, the treatment of CAPA is complicated by drug–drug interactions associated with broad spectrum azoles, renal tropism and damage caused by SARS-CoV-2, which may challenge the use of liposomal amphotericin B, as well as the emergence of azole-resistance. This clinical reality creates an urgency for new antifungal drugs currently in advanced clinical development with more promising pharmacokinetic and pharmacodynamic profiles.
Radboud University Nijmegen1, Erasmus University Rotterdam2, University of Genoa3, Ghent University4, University of Queensland5, University of Lausanne6, University of Virginia7, University of Pittsburgh8, University of Cologne9, Centers for Disease Control and Prevention10, Ghent University Hospital11, Katholieke Universiteit Leuven12, Innsbruck Medical University13, University of Bologna14, Fu Jen Catholic University15, Necker-Enfants Malades Hospital16, Pasteur Institute17, University of Barcelona18, University of Texas Health Science Center at San Antonio19, Trinity College, Dublin20
TL;DR: The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.
Abstract: PURPOSE: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU) Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies METHODS: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus RESULTS: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung CONCLUSION: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA
University College London1, Oregon Health & Science University2, Harvard University3, Lund University4, Vita-Salute San Raffaele University5, University of Manchester6, University of British Columbia7, Monash University8, The Royal Marsden NHS Foundation Trust9, Columbia University10, University of Texas MD Anderson Cancer Center11, University of California, Davis12, University of Bologna13, University of California, San Francisco14, Institut Gustave Roussy15, Duke University16, University of Cologne17, Medical University of Vienna18, University of Oslo19, Fred Hutchinson Cancer Research Center20, University of Washington21, University of Melbourne22, Peter MacCallum Cancer Centre23, Northwestern University24, Cornell University25, Memorial Sloan Kettering Cancer Center26, American University of Beirut27, Tel Aviv University28, National and Kapodistrian University of Athens29, Tata Memorial Hospital30, Icahn School of Medicine at Mount Sinai31, Ghent University32, Belfast City Hospital33, Queen's University Belfast34, The Chinese University of Hong Kong35, University of California, Los Angeles36, University of Bern37, University of Minnesota38, Université de Montréal39, Tulane University40, Prostate Cancer Foundation41, University of Hamburg42, Toho University43, Université catholique de Louvain44, Radboud University Nijmegen45, University of St. Gallen46
TL;DR: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse and provide a practical guide to help clinicians discuss therapeutic options with patients.
Technische Universität München1, Centre national de la recherche scientifique2, Ludwig Maximilian University of Munich3, University of Mainz4, Karlsruhe Institute of Technology5, Max Planck Society6, Dalhousie University7, University of Groningen8, University of Tokyo9, Global Alliance in Management Education10, University of Cologne11, Harvard University12, University of Hamburg13, University of New Hampshire14
TL;DR: The notion of non-trivial topological winding in condensed matter systems represents a major area of present-day theoretical and experimental research as discussed by the authors, and the potential for major breakthroughs ranging from fundamental questions to applications as driven by an interdisciplinary exchange of ideas between areas in magnetism which traditionally have been pursued rather independently.
Abstract: The notion of non-trivial topological winding in condensed matter systems represents a major area of present-day theoretical and experimental research. Magnetic materials offer a versatile platform that is particularly amenable for the exploration of topological spin solitons in real space such as skyrmions. First identified in non-centrosymmetric bulk materials, the rapidly growing zoology of materials systems hosting skyrmions and related topological spin solitons includes bulk compounds, surfaces, thin films, heterostructures, nano-wires and nano-dots. This underscores an exceptional potential for major breakthroughs ranging from fundamental questions to applications as driven by an interdisciplinary exchange of ideas between areas in magnetism which traditionally have been pursued rather independently. The skyrmionics roadmap provides a review of the present state of the art and the wide range of research directions and strategies currently under way. These are, for instance, motivated by the identification of the fundamental structural properties of skyrmions and related textures, processes of nucleation and annihilation in the presence of non-trivial topological winding, an exceptionally efficient coupling to spin currents generating spin transfer torques at tiny current densities, as well as the capability to purpose-design broad-band spin dynamic and logic devices.
TL;DR: The mechanism of pathogen effector recognition by plant innate immune receptors and the formation of a signaling-active complex are elucidated and a deeper understanding of the principles that govern nonself recognition by NLRs and their activation of innate immune responses is explained.
Abstract: Direct or indirect recognition of pathogen-derived effectors by plant nucleotide-binding leucine-rich repeat (LRR) receptors (NLRs) initiates innate immune responses. The Hyaloperonospora arabidopsidis effector ATR1 activates the N-terminal Toll-interleukin-1 receptor (TIR) domain of Arabidopsis NLR RPP1. We report a cryo-electron microscopy structure of RPP1 bound by ATR1. The structure reveals a C-terminal jelly roll/Ig-like domain (C-JID) for specific ATR1 recognition. Biochemical and functional analyses show that ATR1 binds to the C-JID and the LRRs to induce an RPP1 tetrameric assembly required for nicotinamide adenine dinucleotide hydrolase (NADase) activity. RPP1 tetramerization creates two potential active sites, each formed by an asymmetric TIR homodimer. Our data define the mechanism of direct effector recognition by a plant NLR leading to formation of a signaling-active holoenzyme.
TL;DR: The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond classical immune cells and may serve as an entry point to develop biomarkers and targeted treatments of patients with COVID-19.
TL;DR: The history of this research area is presented, important older reports are highlighted, and the evolution and further development of the concept of 1,3‐dipolar cycloadditions are described.
Abstract: The concept of 1,3-dipolar cycloadditions was presented by Rolf Huisgen 60 years ago. Previously unknown reactive intermediates, for example azomethine ylides, were introduced to organic chemistry and the (3+2) cycloadditions of 1,3-dipoles to multiple-bond systems (Huisgen reaction) developed into one of the most versatile synthetic methods in heterocyclic chemistry. In this Review, we present the history of this research area, highlight important older reports, and describe the evolution and further development of the concept. The most important mechanistic and synthetic results are discussed. Quantum-mechanical calculations support the concerted mechanism always favored by R. Huisgen; however, in extreme cases intermediates may be involved. The impact of 1,3-dipolar cycloadditions on the click chemistry concept of K. B. Sharpless will also be discussed.
Humboldt University of Berlin1, McMaster University2, National Institutes of Health3, Ghent University Hospital4, University of Amsterdam5, University of Marburg6, Nova Southeastern University7, Transylvania University8, Charité9, Woolcock Institute of Medical Research10, Laval University11, Humanitas University12, University of Cartagena13, University of South Florida14, University of Porto15, Federal University of Bahia16, University of Naples Federico II17, Université Paris-Saclay18, Saint Louis University19, Istanbul University20, Erasmus University Rotterdam21, University of Helsinki22, Odense University Hospital23, University of Crete24, Chiba University25, Wrocław Medical University26, Ukrainian Medical Stomatological Academy27, Hacettepe University28, Medical University of Łódź29, Vilnius University30, National Research Council31, University of Tennessee32, Oslo University Hospital33, University of Beira Interior34, Karolinska Institutet35, University of Cologne36, University of Barcelona37, Russian National Research Medical University38, Monash University39, Ajou University40, Charles University in Prague41, University of Genoa42, Pasteur Institute43, University of Southampton44, University of Edinburgh45, Medical University of Warsaw46, University College London47, Imperial College London48, University of Coimbra49, University of Turku50, University of Bari51, Celal Bayar University52
TL;DR: Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines forThe disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.
Abstract: The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.