Showing papers by "University of Kansas published in 2020"
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TL;DR: The outcomes of a cohort of patients with cancer and COVID-19 are characterised and potential prognostic factors for mortality and severe illness are identified and race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.
1,344 citations
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TL;DR: It is recommended that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that the authors could not make a determination whether the benefits outweigh harms for most treatments.
Abstract: Background There are many pharmacologic therapies that are being used or considered for treatment of COVID-19. There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature. Objective Develop evidence-based rapid guidelines intended to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19. Methods IDSA formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. Process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and grey literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Results The IDSA guideline panel agreed on 7 treatment recommendations and provided narrative summaries of other treatments undergoing evaluations. Conclusions The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.
897 citations
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Memorial Sloan Kettering Cancer Center1, Cornell University2, University of Michigan3, Institut Gustave Roussy4, University of Verona5, University of Kansas6, Baylor University Medical Center7, Mayo Clinic8, Memorial Hospital of South Bend9, Johns Hopkins University School of Medicine10, Seoul National University Hospital11, Fox Chase Cancer Center12, University of Chicago13, Katholieke Universiteit Leuven14, Incyte15, Hannover Medical School16
TL;DR: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Abstract: Summary Background Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. Methods In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov , NCT02924376 , and enrolment is completed. Findings Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. Interpretation These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Funding Incyte Corporation.
756 citations
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McMaster University1, Lanzhou University2, Cochrane Collaboration3, Chosun University4, Chongqing Medical University5, University of Toronto6, University of Oslo7, Norwegian Institute of Public Health8, Toronto General Hospital9, University of Western Ontario10, Hull York Medical School11, University of British Columbia12, University of Kansas13, Pontifical Catholic University of Chile14, Mayo Clinic15, Monash University16, University Health Network17, Utrecht University18
TL;DR: Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care and the effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.
Abstract: Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. 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 is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
602 citations
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TL;DR: Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with programmed death ligand-1 combined positive score (CPS) ≥ 10, with fewer treatment-related adverse events.
Abstract: PURPOSEPatients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy.PATIENTS AND METHODSIn this open-label, phase III study, we randoml...
511 citations
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TL;DR: Key ADE mechanisms are described and mitigation strategies for SARS-CoV-2 vaccines and therapies in development are discussed and recently published data is outlined to evaluate the risks and opportunities for antibody-based protection against Sars-Cov-2.
Abstract: Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.
503 citations
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University of Milan1, University of Washington2, University of South Florida3, Georgetown University4, University of Minnesota5, Mayo Clinic6, University of Kansas7, University of Liège8, University of Chicago9, Vanderbilt University10, Stanford University11, Université libre de Bruxelles12, Washington University in St. Louis13, Tel Aviv University14, University of Pennsylvania15, City of Hope National Medical Center16, Duke University17, Heidelberg University18
TL;DR: Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment, and guidance regarding prevention, screening, monitoring and treatment of CV toxicity is provided.
484 citations
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Emory University1, University of Texas MD Anderson Cancer Center2, University of Maryland, Baltimore3, Princess Margaret Cancer Centre4, Icahn School of Medicine at Mount Sinai5, University of Kansas6, University of Wisconsin-Madison7, Memorial Sloan Kettering Cancer Center8, Huntsman Cancer Institute9, Indiana University10, University of Lyon11, University of Washington12, University of Navarra13, Medical College of Wisconsin14, St. Vincent's Health System15, GlaxoSmithKline16, Research Triangle Park17, University College London Hospitals NHS Foundation Trust18, UCL Institute of Ophthalmology19, Harvard University20
TL;DR: Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
Abstract: Summary Background Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. Methods DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov , NCT03525678 , and is ongoing. Findings Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). Interpretation Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. Funding GlaxoSmithKline.
458 citations
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University of California, Irvine1, Alfred Wegener Institute for Polar and Marine Research2, University of Texas at Austin3, University of Tübingen4, University of Bremen5, British Antarctic Survey6, National Space Institute7, Northumbria University8, Polar Research Institute of China9, Ohio State University10, Norwegian Polar Institute11, University of Kansas12, Université libre de Bruxelles13, University of Tasmania14, Institute for Geosciences and Natural Resources15, California Institute of Technology16, Utrecht University17
TL;DR: In this paper, a high-resolution and physically based description of Antarctica bed topography using mass conservation is presented, revealing previously unknown basal features with major implications for glacier response to climate change.
Abstract: The Antarctic ice sheet has been losing mass over past decades through the accelerated flow of its glaciers, conditioned by ocean temperature and bed topography. Glaciers retreating along retrograde slopes (that is, the bed elevation drops in the inland direction) are potentially unstable, while subglacial ridges slow down the glacial retreat. Despite major advances in the mapping of subglacial bed topography, significant sectors of Antarctica remain poorly resolved and critical spatial details are missing. Here we present a novel, high-resolution and physically based description of Antarctic bed topography using mass conservation. Our results reveal previously unknown basal features with major implications for glacier response to climate change. For example, glaciers flowing across the Transantarctic Mountains are protected by broad, stabilizing ridges. Conversely, in the marine basin of Wilkes Land, East Antarctica, we find retrograde slopes along Ninnis and Denman glaciers, with stabilizing slopes beneath Moscow University, Totten and Lambert glacier system, despite corrections in bed elevation of up to 1 km for the latter. This transformative description of bed topography redefines the high- and lower-risk sectors for rapid sea level rise from Antarctica; it will also significantly impact model projections of sea level rise from Antarctica in the coming centuries.
433 citations
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New York University1, Johns Hopkins University2, University of Washington3, Duke University4, University of North Carolina at Chapel Hill5, Scripps Research Institute6, Hebrew University of Jerusalem7, Ohio State University8, University of California, San Francisco9, École Polytechnique Fédérale de Lausanne10, Baylor College of Medicine11, Vanderbilt University12, Rutgers University13, Swiss Institute of Bioinformatics14, Fred Hutchinson Cancer Research Center15, Rensselaer Polytechnic Institute16, Northeastern University17, Stanford University18, DSM19, Fox Chase Cancer Center20, University of Maryland, College Park21, University of Warsaw22, University of Denver23, Australian National University24, University of Kansas25, University of Zurich26, University of Massachusetts Dartmouth27, University of Tokyo28, Franklin & Marshall College29, Weizmann Institute of Science30, Lund University31, University of California, Santa Cruz32, University of California, Davis33
TL;DR: This Perspective reviews tools developed over the past five years in the Rosetta software, including over 80 methods, and discusses improvements to the score function, user interfaces and usability.
Abstract: The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.
430 citations
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Stony Brook University1, University of Minnesota2, University Health Network3, University of Strasbourg4, Duke University5, University of Kansas6, Scott & White Hospital7, Brigham and Women's Hospital8, University of California, San Francisco9, Case Western Reserve University10, University of Miami11, University of Virginia Health System12, University of Colorado Hospital13, University of Texas MD Anderson Cancer Center14, Yale University15, Harvard University16
TL;DR: This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations based on a comprehensive search and review of literature up to September 2019.
Abstract: This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations. The guidelines are established by an international panel of experts under the auspices of the American Society of Enhanced Recovery and Society for Ambulatory Anesthesia based on a comprehensive search and review of literature up to September 2019. The guidelines provide recommendation on identifying high-risk patients, managing baseline PONV risks, choices for prophylaxis, and rescue treatment of PONV as well as recommendations for the institutional implementation of a PONV protocol. In addition, the current guidelines focus on the evidence for newer drugs (eg, second-generation 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, neurokinin 1 (NK1) receptor antagonists, and dopamine antagonists), discussion regarding the use of general multimodal PONV prophylaxis, and PONV management as part of enhanced recovery pathways. This set of guidelines have been endorsed by 23 professional societies and organizations from different disciplines (Appendix 1).Guidelines currently available include the 3 iterations of the consensus guideline we previously published, which was last updated 6 years ago; a guideline published by American Society of Health System Pharmacists in 1999; a brief discussion on PONV management as part of a comprehensive postoperative care guidelines; focused guidelines published by the Society of Obstetricians and Gynecologists of Canada, the Association of Paediatric Anaesthetists of Great Britain & Ireland and the Association of Perianesthesia Nursing; and several guidelines published in other languages.The current guideline was developed to provide perioperative practitioners with a comprehensive and up-to-date, evidence-based guidance on the risk stratification, prevention, and treatment of PONV in both adults and children. The guideline also provides guidance on the management of PONV within enhanced recovery pathways.The previous consensus guideline was published 6 years ago with a literature search updated to October 2011. Several guidelines, which have been published since, are either limited to a specific populations or do not address all aspects of PONV management. The current guideline was developed based on a systematic review of the literature published up through September 2019. This includes recent studies of newer pharmacological agents such as the second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, a dopamine antagonist, neurokinin 1 (NK1) receptor antagonists as well as several novel combination therapies. In addition, it also contains an evidence-based discussion on the management of PONV in enhanced recovery pathways. We have also discussed the implementation of a general multimodal PONV prophylaxis in all at-risk surgical patients based on the consensus of the expert panel.
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University of Texas MD Anderson Cancer Center1, University of South Florida2, Stanford University3, Washington University in St. Louis4, Mayo Clinic5, University of Maryland, Baltimore6, University of Nebraska Medical Center7, University of Miami8, University of Rochester9, Vanderbilt University10, University of Kansas11, Wayne State University12, University of Pittsburgh13, Cleveland Clinic14, University of California, San Francisco15
TL;DR: The safety and efficacy of axi-cel in the standard-of-care (SOC) setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
Abstract: PURPOSEAxicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of ...
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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.
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Université de Sherbrooke1, Mayo Clinic2, University of Oslo3, University of Düsseldorf4, Kent State University5, Monash University, Clayton campus6, Cornell University7, University of Arizona8, Rhode Island Hospital9, University of Basel10, University of Dundee11, Heidelberg University12, French Institute of Health and Medical Research13, University of Coimbra14, MRC Mitochondrial Biology Unit15, Columbia University Medical Center16, University of Bordeaux17, University of Grenoble18, Johns Hopkins University School of Medicine19, University of Kansas20
TL;DR: The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
Abstract: The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes. Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics.
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TL;DR: Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes.
Abstract: Rationale: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among patients with asthma may identify subgroups at risk for COVID-19 morbidity.Objectives: To determine the relationship between demographic features and sputum ACE2 and TMPRSS2 gene expression in asthma.Methods: We analyzed gene expression for ACE2 and TMPRSS2, and for ICAM-1 (intercellular adhesion molecule 1) (rhinovirus receptor as a comparator) in sputum cells from 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects.Measurements and Main Results: Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes were similar in asthma and health. Among patients with asthma, male sex, African American race, and history of diabetes mellitus were associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to sex, race, and use of ICS.Conclusions: Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.
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01 Jun 2020
TL;DR: It is suggested that patients with SARS-CoV-2 infection can present with gastrointestinal symptoms with possible fecal-oral route of transmission due to the presence of viral RNA in stool.
Abstract: Importance Coronavirus disease 2019 (COVID-19) is a global pandemic and can involve the gastrointestinal (GI) tract, including symptoms like diarrhea and shedding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in feces. Objective To provide a pooled estimate of GI symptoms, liver enzyme levels outside reference ranges, and fecal tests positive for SARS-CoV-2 among patients with COVID-19. Data Sources An electronic literature search was performed for published (using MEDLINE/PubMed and Embase) and preprint (using bioRxiv and medRxiv) studies of interest conducted from November 1, 2019, to March 30, 2020. Search terms included “COVID-19,” “SARS-Cov-2,” and/or “novel coronavirus.” Study Selection Eligible studies were those including patients with SARS-CoV-2 infection who reported GI symptoms. Data Extraction and Synthesis Data on patients with GI symptoms (ie, diarrhea, nausea, or vomiting), liver enzyme level changes, and fecal shedding of virus were extracted. Quality of studies was examined using methodological index for nonrandomized studies. Pooled estimates (%) were reported with 95% CIs with level of heterogeneity (I2). Main Outcomes and Measures Study and patient characteristics with pooled detection rates for diarrhea, nausea or vomiting, liver enzyme levels outside reference ranges, and SARS-CoV-2 positivity in feces tests were analyzed. Results Of 1484 records reviewed, 23 published and 6 preprint studies were included in the analysis, with a total of 4805 patients (mean [SD] age, 52.2 [14.8] years; 1598 [33.2%] women) with COVID-19. The pooled rates were 7.4% (95% CI, 4.3%-12.2%) of patients reporting diarrhea and 4.6% (95% CI, 2.6%-8.0%) of patients reporting nausea or vomiting. The pooled rate for aspartate aminotransferase levels outside reference ranges was 20% (95% CI, 15.3%-25.6%) of patients, and the pooled rate for alanine aminotransferase levels outside reference ranges was 14.6% (95% CI, 12.8%-16.6%) of patients. Fecal tests that were positive for SARS-CoV-2 were reported in 8 studies, and viral RNA shedding was detected in feces in 40.5% (95% CI, 27.4%-55.1%) of patients. There was high level of heterogeneity (I2 = 94%), but no statistically significant publication bias noted. Conclusions and Relevance These findings suggest that that 12% of patients with COVID-19 will manifest GI symptoms; however, SAR-CoV-2 shedding was observed in 40.5% of patients with confirmed SARS-CoV-2 infection. This highlights the need to better understand what measures are needed to prevent further spread of this highly contagious pathogen.
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Humboldt University of Berlin1, University of California2, University of St Andrews3, University of Freiburg4, University of Arizona5, Harvard University6, University of Kansas7, California Academy of Sciences8, Agro ParisTech9, University of Savoy10, University of Salford11, École Polytechnique Fédérale de Lausanne12, University of Connecticut13
TL;DR: This work proposes a standard protocol for reporting SDMs, and introduces a structured format for documenting and communicating the models, ensuring transparency and reproducibility, facilitating peer review and expert evaluation of model quality, as well as meta-analyses.
Abstract: Species distribution models (SDMs) constitute the most common class of models
across ecology, evolution and conservation. The advent of ready-to-use software pack
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ages and increasing availability of digital geoinformation have considerably assisted
the application of SDMs in the past decade, greatly enabling their broader use for
informing conservation and management, and for quantifying impacts from global
change. However, models must be fit for purpose, with all important aspects of their
development and applications properly considered. Despite the widespread use of
SDMs, standardisation and documentation of modelling protocols remain limited,
which makes it hard to assess whether development steps are appropriate for end use.
To address these issues, we propose a standard protocol for reporting SDMs, with an
emphasis on describing how a study’s objective is achieved through a series of model
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ing decisions. We call this the ODMAP (Overview, Data, Model, Assessment and
Prediction) protocol, as its components reflect the main steps involved in building
SDMs and other empirically-based biodiversity models. The ODMAP protocol serves
two main purposes. First, it provides a checklist for authors, detailing key steps for model building and analyses, and thus represents a quick guide and generic workflow for modern SDMs. Second, it introduces
a structured format for documenting and communicating the models, ensuring transparency and reproducibility, facilitating
peer review and expert evaluation of model quality, as well as meta-analyses. We detail all elements of ODMAP, and explain
how it can be used for different model objectives and applications, and how it complements efforts to store associated metadata
and define modelling standards. We illustrate its utility by revisiting nine previously published case studies, and provide an
interactive web-based application to facilitate its use. We plan to advance ODMAP by encouraging its further refinement and
adoption by the scientific community.
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TL;DR: For the first time, predictions from pythia8 obtained with tunes based on NLO or NNLO PDFs are shown to reliably describe minimum-bias and underlying-event data with a similar level of agreement to predictions from tunes using LO PDF sets.
Abstract: New sets of CMS underlying-event parameters (“tunes”) are presented for the pythia8 event generator. These tunes use the NNPDF3.1 parton distribution functions (PDFs) at leading (LO), next-to-leading (NLO), or next-to-next-to-leading (NNLO) orders in perturbative quantum chromodynamics, and the strong coupling evolution at LO or NLO. Measurements of charged-particle multiplicity and transverse momentum densities at various hadron collision energies are fit simultaneously to determine the parameters of the tunes. Comparisons of the predictions of the new tunes are provided for observables sensitive to the event shapes at LEP, global underlying event, soft multiparton interactions, and double-parton scattering contributions. In addition, comparisons are made for observables measured in various specific processes, such as multijet, Drell–Yan, and top quark-antiquark pair production including jet substructure observables. The simulation of the underlying event provided by the new tunes is interfaced to a higher-order matrix-element calculation. For the first time, predictions from pythia8 obtained with tunes based on NLO or NNLO PDFs are shown to reliably describe minimum-bias and underlying-event data with a similar level of agreement to predictions from tunes using LO PDF sets.
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University of Alabama at Birmingham1, State University of New York System2, Flinders University3, Brigham and Women's Hospital4, Ljubljana University Medical Centre5, University of Alberta6, Oslo University Hospital7, Stanford University8, Leiden University Medical Center9, University of Kansas10, Regeneron11, Duke University12, Katholieke Universiteit Leuven13, University of California, San Diego14, University of Colorado Denver15, Auckland City Hospital16, Ben-Gurion University of the Negev17, Goethe University Frankfurt18, National Institutes of Health19, Anschutz Medical Campus20
TL;DR: Baseline lipoprotein(a) levels and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS, which suggests that lipoproteins should be an independent treatment target after ACS.
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TL;DR: The results, all based on searches for a cumulative neutrino signal integrated over the 10 years of available data, motivate further study of these and similar sources, including time-dependent analyses, multimessenger correlations, and the possibility of stronger evidence with coming upgrades to the detector.
Abstract: This Letter presents the results from pointlike neutrino source searches using ten years of IceCube data collected between April 6, 2008 and July 10, 2018. We evaluate the significance of an astrophysical signal from a pointlike source looking for an excess of clustered neutrino events with energies typically above ∼1 TeV among the background of atmospheric muons and neutrinos. We perform a full-sky scan, a search within a selected source catalog, a catalog population study, and three stacked Galactic catalog searches. The most significant point in the northern hemisphere from scanning the sky is coincident with the Seyfert II galaxy NGC 1068, which was included in the source catalog search. The excess at the coordinates of NGC 1068 is inconsistent with background expectations at the level of 2.9σ after accounting for statistical trials from the entire catalog. The combination of this result along with excesses observed at the coordinates of three other sources, including TXS 0506+056, suggests that, collectively, correlations with sources in the northern catalog are inconsistent with background at 3.3σ significance. The southern catalog is consistent with background. These results, all based on searches for a cumulative neutrino signal integrated over the 10 years of available data, motivate further study of these and similar sources, including time-dependent analyses, multimessenger correlations, and the possibility of stronger evidence with coming upgrades to the detector.
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TL;DR: Given the potential for long-term physical distancing, concerted efforts are required to provide necessary resources and support for LGBTQ youth during the COVID-19 pandemic.
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TL;DR: Over a 35-year period, women physicians in academic medical centers were less likely than men to be promoted to the rank of associate or full professor or to be appointed to department chair, and there was no apparent narrowing in the gap over time.
Abstract: Background In 2000, a landmark study showed that women who graduated from U.S. medical schools from 1979 through 1997 were less likely than their male counterparts to be promoted to upper ...
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TL;DR: Universal access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention and the public response to the COVID-19 pandemic.
Abstract: Background Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19) Direct detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids in respiratory tract specimens informs patient, healthcare institution and public health level decision-making The numbers of available SARS-CoV-2 nucleic acid detection tests are rapidly increasing, as is the COVID-19 diagnostic literature Thus, the Infectious Diseases Society of America (IDSA) recognized a significant need for frequently updated systematic reviews of the literature to inform evidence-based best practice guidance Objective The IDSA's goal was to develop an evidence-based diagnostic guideline to assists clinicians, clinical laboratorians, patients and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss the nuance of test result interpretation in a variety of practice settings, and highlight important unmet research needs in the COVID-19 diagnostic testing space Methods IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations Results The panel agreed on 15 diagnostic recommendations Conclusions Universal access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention and the public response to the COVID-19 pandemic Information on the clinical performance of available tests is rapidly emerging, but the quality of evidence of the current literature is considered low to very low Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19 In addition, testing is recommended for asymptomatic individuals with known or suspected contact with a COVID-19 case Testing asymptomatic individuals without known exposure is suggested when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions, dictate eligibility for surgery, or inform administration of immunosuppressive therapy Ultimately, prioritization of testing will depend on institutional-specific resources and the needs of different patient populations
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California Institute of Technology1, United States Department of Agriculture2, King Abdullah University of Science and Technology3, McMaster University4, University of California, Berkeley5, University of Montpellier6, University of Illinois at Urbana–Champaign7, Dresden University of Technology8, Lawrence Berkeley National Laboratory9, Ohio State University10, University of Kansas11, University of Alberta12, United States Environmental Protection Agency13, University of Wisconsin-Madison14, University of Liège15, Academy of Sciences of the Czech Republic16, University of California, Irvine17, University of Minnesota18, University of British Columbia19, Washington State University20, Texas A&M University21, Harvard University22, International Trademark Association23, Northern Arizona University24, Forschungszentrum Jülich25, Weizmann Institute of Science26, Georgia Institute of Technology27, Marshall Space Flight Center28, Princeton University29
TL;DR: In 2018, the ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station (ECOSTRESS) was launched to the International Space Station by the National Aeronautics and Space Administration (NASA).
Abstract: The ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station (ECOSTRESS) was launched to the International Space Station on 29 June 2018 by the National Aeronautics and Space Administration (NASA). The primary science focus of ECOSTRESS is centered on evapotranspiration (ET), which is produced as Level-3 (L3) latent heat flux (LE) data products. These data are generated from the Level-2 land surface temperature and emissivity product (L2_LSTE), in conjunction with ancillary surface and atmospheric data. Here, we provide the first validation (Stage 1, preliminary) of the global ECOSTRESS clear-sky ET product (L3_ET_PT-JPL, Version 6.0) against LE measurements at 82 eddy covariance sites around the world. Overall, the ECOSTRESS ET product performs well against the site measurements (clear-sky instantaneous/time of overpass: r(2) = 0.88; overall bias = 8%; normalized root-mean-square error, RMSE = 6%). ET uncertainty was generally consistent across climate zones, biome types, and times of day (ECOSTRESS samples the diurnal cycle), though temperate sites are overrepresented. The 70-m-high spatial resolution of ECOSTRESS improved correlations by 85%, and RMSE by 62%, relative to 1-km pixels. This paper serves as a reference for the ECOSTRESS L3 ET accuracy and Stage 1 validation status for subsequent science that follows using these data.
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TL;DR: A genome-wide association study including 133,384 breast cancer cases and 113,789 controls plus 18,908 BRCA1 mutation carriers of European ancestry provides an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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TL;DR: Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% OrR in low/intermediate grade disease.
Abstract: Purpose: Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (non-pancreatic) neuroendocrine neoplasm cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). Experimental Design: We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (non-pancreatic) neuroendocrine cohort reported here. Response assessment by grade was not pre-specified. The primary endpoint was overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial response (PR)); secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity. Results: Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N= 15) and lung (19%; N= 6). The overall ORR was 25% (95% confidence interval (CI) 13-64%; CR, 3%, N= 1; PR, 22%, N= 7). Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients) (p=0.004). The 6-month PFS was 31% (95% CI 19-52%); median OS was 11 months (95% CI 6- ). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%); with alanine aminotransferase (ALT) elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events. Conclusions: Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with non-pancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.
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TL;DR: This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T- cell therapy.
Abstract: The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells.
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TL;DR: This analysis provides the most detailed characterization of the neutrino flux at energies below ∼100 TeV compared to previous IceCube results, and suggests the existence of astrophysical neutrinos sources characterized by dense environments which are opaque to gamma rays.
Abstract: We report on the first measurement of the astrophysical neutrino flux using particle showers (cascades) in IceCube data from 2010-2015. Assuming standard oscillations, the astrophysical neutrinos in this dedicated cascade sample are dominated (∼90%) by electron and tau flavors. The flux, observed in the sensitive energy range from 16 TeV to 2.6 PeV, is consistent with a single power-law model as expected from Fermi-type acceleration of high energy particles at astrophysical sources. We find the flux spectral index to be γ=2.53±0.07 and a flux normalization for each neutrino flavor of ϕ_{astro}=1.66_{-0.27}^{+0.25} at E_{0}=100 TeV, in agreement with IceCube's complementary muon neutrino results and with all-neutrino flavor fit results. In the measured energy range we reject spectral indices γ≤2.28 at ≥3σ significance level. Because of high neutrino energy resolution and low atmospheric neutrino backgrounds, this analysis provides the most detailed characterization of the neutrino flux at energies below ∼100 TeV compared to previous IceCube results. Results from fits assuming more complex neutrino flux models suggest a flux softening at high energies and a flux hardening at low energies (p value ≥0.06). The sizable and smooth flux measured below ∼100 TeV remains a puzzle. In order to not violate the isotropic diffuse gamma-ray background as measured by the Fermi Large Area Telescope, it suggests the existence of astrophysical neutrino sources characterized by dense environments which are opaque to gamma rays.
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TL;DR: Clinicians and patients are informed of the trustworthiness of the estimates from systematic reviews of studies addressing such individual prognostic factors to determine certainty in estimates of future events in broad categories of patients.