Showing papers by "University of Southern California published in 2020"
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01 Jan 2020TL;DR: In this article, the authors present a comprehensive introduction to the theory and practice of artificial intelligence for modern applications, including game playing, planning and acting, and reinforcement learning with neural networks.
Abstract: The long-anticipated revision of this #1 selling book offers the most comprehensive, state of the art introduction to the theory and practice of artificial intelligence for modern applications. Intelligent Agents. Solving Problems by Searching. Informed Search Methods. Game Playing. Agents that Reason Logically. First-order Logic. Building a Knowledge Base. Inference in First-Order Logic. Logical Reasoning Systems. Practical Planning. Planning and Acting. Uncertainty. Probabilistic Reasoning Systems. Making Simple Decisions. Making Complex Decisions. Learning from Observations. Learning with Neural Networks. Reinforcement Learning. Knowledge in Learning. Agents that Communicate. Practical Communication in English. Perception. Robotics. For computer professionals, linguists, and cognitive scientists interested in artificial intelligence.
16,983 citations
Camden and Islington NHS Foundation Trust1, University College London2, Royal Melbourne Hospital3, University of Exeter4, University of Plymouth5, University of Cambridge6, University of Manchester7, Tel Aviv University8, Goa Medical College9, Johns Hopkins University10, University of California, Davis11, Kaiser Permanente12, University College Hospital, Ibadan13, University of Montpellier14, Dalhousie University15, University of Southern California16, Oslo University Hospital17, University of Washington18
TL;DR: Author(s): Livingston, Gill; Huntley, Jonathan; Sommerlad, Andrew ; Sommer Glad, Andrew; Ames, David; Ballard, Clive; Banerjee, Sube; Brayne, Carol; Burns, Alistair; Cohen-Mansfield, Jiska; Cooper, Claudia; Costafreda, Sergi G; Dias, Amit; Fox, Nick; Gitlin, Laura N; Howard, Robert; Kales, Helen C;
3,559 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
TL;DR: A systematic review of current literature on COVID-19 provides insight into the initial and follow-up CT characteristics of the disease.
Abstract: OBJECTIVE. Available information on CT features of the 2019 novel coronavirus disease (COVID-19) is scattered in different publications, and a cohesive literature review has yet to be compiled. MAT...
1,216 citations
University of Massachusetts Medical School1, Broad Institute2, Stanford University3, Cold Spring Harbor Laboratory4, University of Washington5, University of California, San Diego6, Massachusetts Institute of Technology7, Ludwig Institute for Cancer Research8, University of California, San Francisco9, Salk Institute for Biological Studies10, California Institute of Technology11, University of California, Irvine12, Pennsylvania State University13, Lawrence Berkeley National Laboratory14, University of Connecticut Health Center15, Université de Montréal16, McGill University17, Florida State University18, University of Minnesota19, Yale University20, University of Alabama in Huntsville21, University of Chicago22, University of California, Merced23, University of Colorado Boulder24, Icahn School of Medicine at Mount Sinai25, Pompeu Fabra University26, University of Southern California27, University of California, Berkeley28, Harvard University29, Boston University30, Tongji University31
TL;DR: The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development.
Abstract: The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
999 citations
University of North Carolina at Chapel Hill1, Cleveland Clinic2, University of Washington3, American Society of Clinical Oncology4, BC Cancer Agency5, University of Granada6, Dartmouth–Hitchcock Medical Center7, Penn State Cancer Institute8, Emory University9, University of Rochester10, University College London11, McMaster University12, University of Southern California13, University of California, San Francisco14, Fred Hutchinson Cancer Research Center15, University of Milan16
TL;DR: An Expert Panel convened an Expert Panel to review the evidence and revise previous recommendations as needed to provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer.
Abstract: PURPOSETo provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer.METHODSPubMed and the Cochrane Library were searched for randomized...
900 citations
University of Colorado Boulder1, Memorial Sloan Kettering Cancer Center2, Cornell University3, Complutense University of Madrid4, University of Milan5, Harvard University6, University of California, San Francisco7, Yonsei University8, Institut Gustave Roussy9, University of California, San Diego10, University of Michigan11, Northwestern University12, Huntsman Cancer Institute13, Georgetown University14, City of Hope National Medical Center15, University of Texas MD Anderson Cancer Center16, The Chinese University of Hong Kong17, University of Alcalá18, University of Southern California19, Emory University20, University of Göttingen21, Children's Hospital of Philadelphia22, Genentech23
TL;DR: Results show that entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile.
Abstract: Summary Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Interpretation Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Funding Ignyta/F Hoffmann-La Roche.
871 citations
TL;DR: Ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines and recapitulates aspects of human disease.
786 citations
TL;DR: Therapeutic advancements for moderate to severe plaque psoriasis include biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor.
Abstract: Importance Approximately 125 million people worldwide have psoriasis. Patients with psoriasis experience substantial morbidity and increased rates of inflammatory arthritis, cardiometabolic diseases, and mental health disorders. Observations Plaque psoriasis is the most common variant of psoriasis. The most rapid advancements addressing plaque psoriasis have been in its pathogenesis, genetics, comorbidities, and biologic treatments. Plaque psoriasis is associated with a number of comorbidities including psoriatic arthritis, cardiometabolic diseases, and depression. For patients with mild psoriasis, topical agents remain the mainstay of treatment, and they include topical corticosteroids, vitamin D analogues, calcineurin inhibitors, and keratolytics. The American Academy of Dermatology-National Psoriasis Foundation guidelines recommend biologics as an option for first-line treatment of moderate to severe plaque psoriasis because of their efficacy in treating it and acceptable safety profiles. Specifically, inhibitors to tumor necrosis factor α (TNF-α) include etanercept, adalimumab, certolizumab, and infliximab. Other biologics inhibit cytokines such as the p40 subunit of the cytokines IL-12 and IL-13 (ustekinumab), IL-17 (secukinumab, ixekizumab, bimekizumab, and brodalumab), and the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab, and mirikizumab). Biologics that inhibit TNF-α, p40IL-12/23, and IL-17 are also approved for the treatment of psoriatic arthritis. Oral treatments include traditional agents such as methotrexate, acitretin, cyclosporine, and the advanced small molecule apremilast, which is a phosphodiesterase 4 inhibitor. The most commonly prescribed light therapy used to treat plaque psoriasis is narrowband UV-B phototherapy. Conclusions and Relevance Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients’ quality of life. Topical therapies remain the cornerstone for treating mild psoriasis. Therapeutic advancements for moderate to severe plaque psoriasis include biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor.
693 citations
Eugene Applebaum College of Pharmacy and Health Sciences1, University of Montana2, Albany College of Pharmacy and Health Sciences3, Wayne State University4, University of California, San Diego5, Fred Hutchinson Cancer Research Center6, University of Michigan7, University of Southern California8, University of Minnesota9, University of Illinois at Urbana–Champaign10, Arkansas Children's Hospital11, Albany Medical College12
TL;DR: The primary recommendations consisted of eliminating routine monitoring of serum peak concentrations, emphasizing a ratio of area under the curve over 24 hours to minimum inhibitory concentration (AUC/ MIC) of ≥400 as the primary PK/ PD predictor of vancomycin activity, and promoting serum trough concentrations of 15 to 20 mg/L as a surrogate marker for the optimal vancomYcin AUC/MIC if the MIC was ≤1mg/L in patients with normal renal function.
Abstract: Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.
622 citations
TL;DR: The authors identify nine themes, organized by predicted imminence (i.e., the immediate, near, and far futures), that they believe will meaningfully shape the future of social media through three lenses: consumer, industry, and public policy.
Abstract: Social media allows people to freely interact with others and offers multiple ways for marketers to reach and engage with consumers. Considering the numerous ways social media affects individuals and businesses alike, in this article, the authors focus on where they believe the future of social media lies when considering marketing-related topics and issues. Drawing on academic research, discussions with industry leaders, and popular discourse, the authors identify nine themes, organized by predicted imminence (i.e., the immediate, near, and far futures), that they believe will meaningfully shape the future of social media through three lenses: consumer, industry, and public policy. Within each theme, the authors describe the digital landscape, present and discuss their predictions, and identify relevant future research directions for academics and practitioners.
TL;DR: The findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target inAPOE4 carriers.
Abstract: Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the e3/e4 or e4/e4 alleles) are distinguished from those without APOE4 (e3/e3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
TL;DR: Regulation of autophagy can be used as effective interventional strategies for cancer therapy and contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis.
Abstract: Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.
University of Hong Kong1, Asan Medical Center2, Seoul National University3, University of Southern California4, Humanitas University5, University of Navarra6, Kindai University7, Memorial Hospital of South Bend8, Hospital General Universitario Gregorio Marañón9, University of Bologna10, Princess Margaret Cancer Centre11, Georgetown University Medical Center12, Emory University13, Samsung Medical Center14, Bristol-Myers Squibb15, National Taiwan University16
TL;DR: The manageable safety profile and promising response rates observed in this study support further investigation of nivolumab plus ipilimumab as a treatment option for this patient population.
Abstract: Importance Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. Objective To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. Design, Setting, and Participants CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). Interventions Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). Main Outcomes and Measures Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). Results Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). Conclusions and Relevance In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. Trial Registration ClinicalTrials.gov Identifier:NCT01658878
TL;DR: Short-term changes in PA and SB in reaction to COVID-19 may become permanently entrenched, leading to increased risk of obesity, diabetes, and cardiovascular disease in children, and programmatic and policy strategies should be geared towards promoting PA and reducing SB.
Abstract: COVID-19 restrictions such as the closure of schools and parks, and the cancellation of youth sports and activity classes around the United States may prevent children from achieving recommended levels of physical activity (PA). This study examined the effects of the COVID-19 pandemic on PA and sedentary behavior (SB) in U.S. children. Parents and legal guardians of U.S. children (ages 5–13) were recruited through convenience sampling and completed an online survey between April 25–May 16, 2020. Measures included an assessment of their child’s previous day PA and SB by indicating time spent in 11 common types of PA and 12 common types of SB for children. Parents also reported perceived changes in levels of PA and SB between the pre-COVID-19 (February 2020) and early-COVID-19 (April–May 2020) periods. Additionally, parents reported locations (e.g., home/garage, parks/trails, gyms/fitness centers) where their children had performed PA and their children’s use of remote/streaming services for PA. From parent reports, children (N = 211) (53% female, 13% Hispanic, Mage = 8.73 [SD = 2.58] years) represented 35 states and the District of Columbia. The most common physical activities during the early-COVID-19 period were free play/unstructured activity (e.g., running around, tag) (90% of children) and going for a walk (55% of children). Children engaged in about 90 min of school-related sitting and over 8 h of leisure-related sitting a day. Parents of older children (ages 9–13) vs. younger children (ages 5–8) perceived greater decreases in PA and greater increases in SB from the pre- to early-COVID-19 periods. Children were more likely to perform PA at home indoors or on neighborhood streets during the early- vs. pre-COVID-19 periods. About a third of children used remote/streaming services for activity classes and lessons during the early-COVID-19 period. Short-term changes in PA and SB in reaction to COVID-19 may become permanently entrenched, leading to increased risk of obesity, diabetes, and cardiovascular disease in children. Programmatic and policy strategies should be geared towards promoting PA and reducing SB over the next 12 months.
Tokyo Institute of Technology1, Cornell University2, Yonsei University3, Uppsala University4, Linköping University5, National Institutes of Health6, Memorial Sloan Kettering Cancer Center7, University of Porto8, Rockefeller University9, École Polytechnique Fédérale de Lausanne10, Carlos III Health Institute11, University of Tokyo12, Ohio State University13, Princeton University14, University of Oviedo15, Icahn School of Medicine at Mount Sinai16, Weizmann Institute of Science17, Lucile Packard Children's Hospital18, New York University19, Champalimaud Foundation20, University of Nebraska Medical Center21, Fred Hutchinson Cancer Research Center22, University of Pennsylvania23, University of California, San Diego24, University of Vermont25, University of Southern California26, City of Hope National Medical Center27, Lawrence Berkeley National Laboratory28
TL;DR: EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type, and a panel of tumor-type-specific EVP proteins in TEs and plasma are defined, which can classify tumors of unknown primary origin.
TL;DR: The R package WRS2 is introduced that implements various robust statistical methods by introducing robust location, dispersion, and correlation measures, and robust ANCOVA as well as robust mediation models are introduced.
Abstract: This paper introduces the R package WRS2 that implements various robust statistical methods. It elaborates on the basics of robust statistics by introducing robust location, dispersion, and correlation measures. The location and dispersion measures are then used in robust variants of independent and dependent samples t tests and ANOVA, including between-within subject designs and quantile ANOVA. Further, robust ANCOVA as well as robust mediation models are introduced. The paper targets applied researchers; it is therefore kept rather non-technical and written in a tutorial style. Special emphasis is placed on applications in the social and behavioral sciences and illustrations of how to perform corresponding robust analyses in R. The R code for reproducing the results in the paper is given in the Supplementary Materials.
TL;DR: The population prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that the infection is much more widespread than indicated by the number of confirmed cases.
Abstract: Background
Addressing COVID-19 is a pressing health and social concern. To date, many epidemic projections and policies addressing COVID-19 have been designed without seroprevalence data to inform epidemic parameters. We measured the seroprevalence of antibodies to SARS-CoV-2 in Santa Clara County.
Methods
On 4/3-4/4, 2020, we tested county residents for antibodies to SARS-CoV-2 using a lateral flow immunoassay. Participants were recruited using Facebook ads targeting a representative sample of the county by demographic and geographic characteristics. We report the prevalence of antibodies to SARS-CoV-2 in a sample of 3,330 people, adjusting for zip code, sex, and race/ethnicity. We also adjust for test performance characteristics using 3 different estimates: (i) the test manufacturer9s data, (ii) a sample of 37 positive and 30 negative controls tested at Stanford, and (iii) a combination of both.
Results
The unadjusted prevalence of antibodies to SARS-CoV-2 in Santa Clara County was 1.5% (exact binomial 95CI 1.11-1.97%), and the population-weighted prevalence was 2.81% (95CI 2.24-3.37%). Under the three scenarios for test performance characteristics, the population prevalence of COVID-19 in Santa Clara ranged from 2.49% (95CI 1.80-3.17%) to 4.16% (2.58-5.70%). These prevalence estimates represent a range between 48,000 and 81,000 people infected in Santa Clara County by early April, 50-85-fold more than the number of confirmed cases.
Conclusions
The population prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that the infection is much more widespread than indicated by the number of confirmed cases. Population prevalence estimates can now be used to calibrate epidemic and mortality projections.
University of Texas MD Anderson Cancer Center1, Harvard University2, Stanford University3, University of Washington4, University of Copenhagen5, German Cancer Research Center6, Heidelberg University7, Nemours Foundation8, Vanderbilt University Medical Center9, University of California, Los Angeles10, University of Southern California11, Université Paris-Saclay12, University Hospitals of Cleveland13, St. Jude Children's Research Hospital14, Paris Descartes University15, University of Chicago16, Thomas Jefferson University17, Memorial Sloan Kettering Cancer Center18, Seattle Children's19, Bayer HealthCare Pharmaceuticals20, University of Texas Southwestern Medical Center21, Cornell University22
TL;DR: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active and indicate that long-term administration of larot rectinib are feasible.
Abstract: Summary Background The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. Methods Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov , NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). Findings Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72–85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [ Interpretation These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. Funding Bayer and Loxo Oncology.
TL;DR: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of broluczumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48 and Anatomic retinal fluid outcomes favored Brolucizuab over afl fibercept.
Cornell University1, Memorial Sloan Kettering Cancer Center2, Hebron University3, University of Texas MD Anderson Cancer Center4, University of California, San Francisco5, University of Wisconsin-Madison6, Harvard University7, University of Chicago8, Mayo Clinic9, University of Washington10, Johns Hopkins University11, Seoul National University Hospital12, Trinity College, Dublin13, University of Arizona14, University of Southern California15, Agios Pharmaceuticals16, University of Manchester17, Fudan University18
TL;DR: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivOSidenib was well tolerated, and this study shows the clinical benefit of targeting IDH1 mutations in advanced,IDH1-mutant cholangiocarcinoma.
Abstract: Summary Background Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov , NCT02989857 . Findings Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p Interpretation Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Funding Agios Pharmaceuticals.
14 Jun 2020
TL;DR: In this paper, a multi-level architecture is proposed to estimate high-resolution human shape from low-resolution images, where a coarse level observes the whole image at lower resolution and focuses on holistic reasoning, and a fine level estimates highly detailed geometry by observing higher resolution images.
Abstract: Recent advances in image-based 3D human shape estimation have been driven by the significant improvement in representation power afforded by deep neural networks. Although current approaches have demonstrated the potential in real world settings, they still fail to produce reconstructions with the level of detail often present in the input images. We argue that this limitation stems primarily form two conflicting requirements; accurate predictions require large context, but precise predictions require high resolution. Due to memory limitations in current hardware, previous approaches tend to take low resolution images as input to cover large spatial context, and produce less precise (or low resolution) 3D estimates as a result. We address this limitation by formulating a multi-level architecture that is end-to-end trainable. A coarse level observes the whole image at lower resolution and focuses on holistic reasoning. This provides context to an fine level which estimates highly detailed geometry by observing higher-resolution images. We demonstrate that our approach significantly outperforms existing state-of-the-art techniques on single image human shape reconstruction by fully leveraging 1k-resolution input images.
TL;DR: The COVID-19-TweetIDs GitHub repository as mentioned in this paper provides a multilingual COVID19 Twitter data set that is made available to the research community via a GitHub repository, with over 60% of the tweets in English.
Abstract: Background: At the time of this writing, the coronavirus disease (COVID-19) pandemic outbreak has already put tremendous strain on many countries' citizens, resources, and economies around the world. Social distancing measures, travel bans, self-quarantines, and business closures are changing the very fabric of societies worldwide. With people forced out of public spaces, much of the conversation about these phenomena now occurs online on social media platforms like Twitter.
Objective: In this paper, we describe a multilingual COVID-19 Twitter data set that we are making available to the research community via our COVID-19-TweetIDs GitHub repository.
Methods: We started this ongoing data collection on January 28, 2020, leveraging Twitter’s streaming application programming interface (API) and Tweepy to follow certain keywords and accounts that were trending at the time data collection began. We used Twitter’s search API to query for past tweets, resulting in the earliest tweets in our collection dating back to January 21, 2020.
Results: Since the inception of our collection, we have actively maintained and updated our GitHub repository on a weekly basis. We have published over 123 million tweets, with over 60% of the tweets in English. This paper also presents basic statistics that show that Twitter activity responds and reacts to COVID-19-related events.
Conclusions: It is our hope that our contribution will enable the study of online conversation dynamics in the context of a planetary-scale epidemic outbreak of unprecedented proportions and implications. This data set could also help track COVID-19-related misinformation and unverified rumors or enable the understanding of fear and panic—and undoubtedly more.
University of Queensland1, Westmead Hospital2, University of Sydney3, University of Genoa4, National and Kapodistrian University of Athens5, St. Vincent's Health System6, University of Southern California7, Children's Hospital Los Angeles8, Misericordia University9, Paris Diderot University10, Claude Bernard University Lyon 111, Monash University12, University of Hamburg13, Medical University of Vienna14, Ghent University Hospital15
TL;DR: Routine TDM is recommended to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.
Abstract: This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes. TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients. Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.
Katrina L. Grasby1, Neda Jahanshad2, Jodie N. Painter1, Lucía Colodro-Conde3 +356 more•Institutions (115)
TL;DR: Results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness and find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
University of Southern California1, University of Surrey2, Royal Surrey County Hospital3, University of California, San Diego4, Emory University5, University of California, San Francisco6, University of Münster7, University of Dundee8, University of Florida9, Ghent University Hospital10, Baystate Medical Center11, Cincinnati Children's Hospital Medical Center12, Brigham and Women's Hospital13, Innsbruck Medical University14, Mayo Clinic15, University of Chicago16, King Chulalongkorn Memorial Hospital17, Columbia University18, University of Alberta19, Wuhan University20, Queen Mary University of London21, Royal Society22, University of Alabama at Birmingham23, Washington University in St. Louis24, Health Science University25, Peking University26, University of Padua27, University of Pittsburgh28
TL;DR: This Consensus Statement from the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI and for areas of future research, with the aim of improving understanding of the underlying processes and outcomes for patients with CO VID- 19 AKI.
Abstract: Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.
TL;DR: The results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
Max Planck Society1, Columbia University2, Broad Institute3, University of Chicago4, Polytechnic University of Catalonia5, Massachusetts Eye and Ear Infirmary6, King's College London7, University of California, Los Angeles8, University of Southern California9, University of Michigan10, Pfizer11, University of Geneva12, University of Dundee13, Harvard University14, Swiss Institute of Bioinformatics15, Pompeu Fabra University16, Northwestern University17
TL;DR: A growing number of in silico cell type deconvolution methods and associated reference panels with cell type–specific marker genes enable the robust estimation of the enrichment of specific cell types from bulk tissue gene expression data.
Abstract: The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.
TL;DR: This population epidemiology study investigates the prevalence of IgG and IgM antibodies to SARS-CoV-2 in Los Angeles County, California, as a marker of both active and past infections.
Abstract: This population epidemiology study investigates the prevalence of IgG and IgM antibodies to SARS-CoV-2 in Los Angeles County, California, as a marker of both active and past infections.
TL;DR: The purpose of the present review is to briefly discuss the known epidemiology and the imaging findings of coronavirus syndromes, with a focus on the reported Imaging findings of novel COVID-19–infected pneumonia.
Abstract: In December 2019, a novel coronavirus (COVID-19) pneumonia emerged in Wuhan, China. Since then, this highly contagious COVID-19 has been spreading worldwide, with a rapid rise in the number of deaths. Novel COVID-19-infected pneumonia (NCIP) is characterized by fever, fatigue, dry cough, and dyspnea. A variety of chest imaging features have been reported, similar to those found in other types of coronavirus syndromes. The purpose of the present review is to briefly discuss the known epidemiology and the imaging findings of coronavirus syndromes, with a focus on the reported imaging findings of NCIP. Moreover, the authors review precautions and safety measures for radiology department personnel to manage patients with known or suspected NCIP. Implementation of a robust plan in the radiology department is required to prevent further transmission of the virus to patients and department staff members.