Showing papers by "Oregon Health & Science University published in 2020"
University of Coimbra1, University of Southern Queensland2, National Institute for Health and Welfare3, Arizona State University4, Ghent University5, Institute of Technology, Tralee6, University of Ottawa7, Glasgow Caledonian University8, Oregon Health & Science University9, Cambridge University Hospitals NHS Foundation Trust10, George Washington University11, Norwegian School of Sport Sciences12, Norwegian Institute of Public Health13, University of Sydney14, Alberta Health Services15, Queen's University Belfast16, University of Bristol17, Pennington Biomedical Research Center18, University of Cape Town19, University of Regensburg20, University of East Anglia21, University of Granada22, University of Colombo23, National Institutes of Health24, World Health Organization25
TL;DR: New WHO 2020 guidelines on physical activity and sedentary behaviour reaffirm messages that some physical activity is better than none, that more physical Activity is better for optimal health outcomes and provide a new recommendation on reducing sedentary behaviours.
Abstract: Objectives To describe new WHO 2020 guidelines on physical activity and sedentary behaviour. Methods The guidelines were developed in accordance with WHO protocols. An expert Guideline Development Group reviewed evidence to assess associations between physical activity and sedentary behaviour for an agreed set of health outcomes and population groups. The assessment used and systematically updated recent relevant systematic reviews; new primary reviews addressed additional health outcomes or subpopulations. Results The new guidelines address children, adolescents, adults, older adults and include new specific recommendations for pregnant and postpartum women and people living with chronic conditions or disability. All adults should undertake 150-300 min of moderate-intensity, or 75-150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity, per week. Among children and adolescents, an average of 60 min/day of moderate-to-vigorous intensity aerobic physical activity across the week provides health benefits. The guidelines recommend regular muscle-strengthening activity for all age groups. Additionally, reducing sedentary behaviours is recommended across all age groups and abilities, although evidence was insufficient to quantify a sedentary behaviour threshold. Conclusion These 2020 WHO guidelines update previous WHO recommendations released in 2010. They reaffirm messages that some physical activity is better than none, that more physical activity is better for optimal health outcomes and provide a new recommendation on reducing sedentary behaviours. These guidelines highlight the importance of regularly undertaking both aerobic and muscle strengthening activities and for the first time, there are specific recommendations for specific populations including for pregnant and postpartum women and people living with chronic conditions or disability. These guidelines should be used to inform national health policies aligned with the WHO Global Action Plan on Physical Activity 2018-2030 and to strengthen surveillance systems that track progress towards national and global targets.
3,218 citations
Francis Crick Institute1, Fox Chase Cancer Center2, Washington University in St. Louis3, Cold Spring Harbor Laboratory4, Howard Hughes Medical Institute5, Salk Institute for Biological Studies6, Cornell University7, Goethe University Frankfurt8, Fred Hutchinson Cancer Research Center9, Massachusetts Institute of Technology10, Harvard University11, University of Manchester12, New York University13, University of Texas Health Science Center at Houston14, University of Pennsylvania15, Stony Brook University16, Hofstra University17, Weizmann Institute of Science18, Oregon Health & Science University19, University of California, San Francisco20, King's College London21, Johns Hopkins University22
TL;DR: This Consensus Statement issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance the understanding of this important cell type in the tumour microenvironment.
Abstract: Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
1,616 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
United States Department of Energy1, Vanderbilt University2, Harvard University3, Wake Forest University4, Hennepin County Medical Center5, Tufts University6, Yeshiva University7, Ohio State University8, University of Washington9, Stanford University10, Oregon Health & Science University11, University of California, Los Angeles12, Primary Children's Hospital13, Johns Hopkins University14, University of Colorado Denver15
TL;DR: It is indicated that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults, and effective public health messaging targeting these groups is warranted.
Abstract: Prolonged symptom duration and disability are common in adults hospitalized with severe coronavirus disease 2019 (COVID-19). Characterizing return to baseline health among outpatients with milder COVID-19 illness is important for understanding the full spectrum of COVID-19-associated illness and tailoring public health messaging, interventions, and policy. During April 15-June 25, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had a first positive reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, the virus that causes COVID-19, at an outpatient visit at one of 14 U.S. academic health care systems in 13 states. Interviews were conducted 14-21 days after the test date. Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Among 292 respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18-34 years, 32% among those aged 35-49 years, and 47% among those aged ≥50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults. Effective public health messaging targeting these groups is warranted. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.
945 citations
TL;DR: Data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates, and these findings have key implications for public health and economic initiatives if validated in human studies.
Abstract: An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.
787 citations
Sahlgrenska University Hospital1, National Institutes of Health2, University of Paris3, Children's Hospital Oakland Research Institute4, University of Glasgow5, Centro Nacional de Investigaciones Cardiovasculares6, Aarhus University7, Medical University of Vienna8, University of Amsterdam9, University of California, Los Angeles10, University of Western Ontario11, Monash University12, University of Copenhagen13, University of Western Australia14, Royal Perth Hospital15, French Institute of Health and Medical Research16, Oregon Health & Science University17, University of Cambridge18, University of Bristol19, Trinity College, Dublin20, University of Texas Southwestern Medical Center21, Charité22, Utrecht University23, University of the Witwatersrand24, Imperial College London25, Technische Universität München26, University of Helsinki27, University of Groningen28, Hacettepe University29, University of Milan30, Columbia University31
TL;DR: In this paper, the authors proposed a method to solve the problem of the problem: this paper ] of "uniformity" of the distribution of data points in the data set.
Abstract: Abstract
655 citations
National Institutes of Health1, Wellcome Trust Sanger Institute2, Rockefeller University3, University of California, Davis4, European Bioinformatics Institute5, Seoul National University6, Max Planck Society7, Durham University8, University of Massachusetts Amherst9, University of Adelaide10, University of Missouri11, East Carolina University12, University of Queensland13, Queen Mary University of London14, Wellington Management Company15, University of Arizona16, Natural History Museum17, Bangor University18, University of Konstanz19, Northeastern University20, Naturalis21, University of Graz22, Florida Museum of Natural History23, University of California, Santa Cruz24, Pacific Biosciences25, University of Maryland, College Park26, Harbin Institute of Technology27, University of Chicago28, Oregon Health & Science University29, Monash University Malaysia Campus30, University of Milan31, University of Copenhagen32, Pennsylvania State University33, University of Los Andes34, Agency for Science, Technology and Research35, Royal Ontario Museum36, Smithsonian Conservation Biology Institute37, University of East Anglia38, Pompeu Fabra University39, University College Dublin40, University of Illinois at Urbana–Champaign41, La Trobe University42, University of California, San Diego43, UPRRP College of Natural Sciences44, Dresden University of Technology45
TL;DR: The Vertebrate Genomes Project is embarked on, an effort to generate high-quality, complete reference genomes for all ~70,000 extant vertebrate species and help enable a new era of discovery across the life sciences.
Abstract: High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are only available for a few non-microbial species. To address this issue, the international Genome 10K (G10K) consortium has worked over a five-year period to evaluate and develop cost-effective methods for assembling the most accurate and complete reference genomes to date. Here we summarize these developments, introduce a set of quality standards, and present lessons learned from sequencing and assembling 16 species representing major vertebrate lineages (mammals, birds, reptiles, amphibians, teleost fishes and cartilaginous fishes). We confirm that long-read sequencing technologies are essential for maximizing genome quality and that unresolved complex repeats and haplotype heterozygosity are major sources of error in assemblies. Our new assemblies identify and correct substantial errors in some of the best historical reference genomes. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an effort to generate high-quality, complete reference genomes for all ~70,000 extant vertebrate species and help enable a new era of discovery across the life sciences.
567 citations
Wellcome Trust Sanger Institute1, European Bioinformatics Institute2, Francis Crick Institute3, Broad Institute4, University of Oxford5, University of Cambridge6, University of Toronto7, Oregon Health & Science University8, University of Texas MD Anderson Cancer Center9, Heidelberg University10, German Cancer Research Center11, University of Ljubljana12, NorthShore University HealthSystem13, Vancouver Prostate Centre14, Simon Fraser University15, University of Melbourne16, Walter and Eliza Hall Institute of Medical Research17, Katholieke Universiteit Leuven18, Cornell University19, University of California, Santa Cruz20, University of California, Los Angeles21, Ontario Institute for Cancer Research22, Peter MacCallum Cancer Centre23, Harvard University24, Indiana University25, University of Chicago26, University of Cologne27, University of Helsinki28, University of Glasgow29
TL;DR: Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.
Abstract: Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
565 citations
TL;DR: The symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health are characterized, to report prolonged multisystem involvement and significant disability.
Abstract: Objective To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. Design International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020. Setting Survey distribution via online COVID-19 support groups and social media Participants 3,762 respondents from 56 countries completed the survey. 1166 (33.7%) were 40-49 years old, 937 (27.1%) were 50-59 years old, and 905 (26.1%) were 30-39 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 8.4% reported being hospitalized. 27% reported receiving a laboratory-confirmed diagnosis of COVID-19. 96% reported symptoms beyond 90 days. Results Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions. Conclusions Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden.
542 citations
TL;DR: The strongest evidence on risk factors was on PPE use and decreased infection risk and the association was most consistent for masks but was also observed for gloves, gowns, eye protection, and handwashing; evidence suggested a dose-response relationship.
Abstract: This rapid and living review examines the epidemiology and risk factors for coronavirus infection in health care workers.
489 citations
TL;DR: ECMO preparedness for the COVID-19 pandemic is important in view of the high transmission rate of the virus and respiratory-related mortality and ensuring that systems enable safe and coordinated movement of critically ill patients, staff, and equipment is important to improve ECMO access.
New York University1, Yeshiva University2, University of Michigan3, Oregon Health & Science University4, Singapore General Hospital5, Harvard University6, Indiana University – Purdue University Indianapolis7, Louisiana State University in Shreveport8, Stanford University9, Royal College of Surgeons in Ireland10, University of Cincinnati11, Memorial Sloan Kettering Cancer Center12, United States Department of Veterans Affairs13
TL;DR: In this paper, a set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic.
Abstract: Importance The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists–head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.
TL;DR: Genetic variability across the three major histocompatibility complex (MHC) class I genes may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronav virus disease 2019 (COVID-19), and the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses.
Abstract: Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
TL;DR: DSP may be used to profile not only proteins and RNAs in biobanked samples but also immune markers in patient samples, with potential prognostic and predictive potential for clinical decision-making.
Abstract: Digital Spatial Profiling (DSP) is a method for highly multiplex spatial profiling of proteins or RNAs suitable for use on formalin-fixed, paraffin-embedded (FFPE) samples. The approach relies on (1) multiplexed readout of proteins or RNAs using oligonucleotide tags; (2) oligonucleotide tags attached to affinity reagents (antibodies or RNA probes) through a photocleavable (PC) linker; and (3) photocleaving light projected onto the tissue sample to release PC oligonucleotides in any spatial pattern across a region of interest (ROI) covering 1 to ~5,000 cells. DSP is capable of single-cell sensitivity within an ROI using the antibody readout, with RNA detection feasible down to ~600 individual mRNA transcripts. We show spatial profiling of up to 44 proteins and 96 genes (928 RNA probes) in lymphoid, colorectal tumor and autoimmune tissues by using the nCounter system and 1,412 genes (4,998 RNA probes) by using next-generation sequencing (NGS). DSP may be used to profile not only proteins and RNAs in biobanked samples but also immune markers in patient samples, with potential prognostic and predictive potential for clinical decision-making. A turnkey system allows for spatial profiling of proteins and RNA in fixed tissues, providing a window on cellular heterogeneity.
Harvard University1, Memorial Sloan Kettering Cancer Center2, Royal North Shore Hospital3, Peter MacCallum Cancer Centre4, University of California, San Francisco5, University of Michigan6, University of Pennsylvania7, University of Chicago8, Aix-Marseille University9, Mayo Clinic10, Emory University11, University of Bern12, University of North Carolina at Chapel Hill13, University of Wisconsin-Madison14, University of British Columbia15, Oregon Health & Science University16, University of Würzburg17, University of California, Los Angeles18, Sarah Cannon Research Institute19, Johns Hopkins University20, University of California, Irvine21, Autonomous University of Madrid22, University of Texas MD Anderson Cancer Center23, Ohio State University24
TL;DR: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment.
Abstract: Background RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and sa...
University of Chicago1, Mayo Clinic2, University of California, San Francisco3, University of California, San Diego4, Yale University5, University of Alabama at Birmingham6, University of Pennsylvania7, Loyola University Chicago8, University of Colorado Boulder9, Georgetown University10, Oregon Health & Science University11, University of Texas MD Anderson Cancer Center12, University of Minnesota13
TL;DR: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ER BB2- negative breast cancer is highly likely to succeed in a phase 3 trial.
Abstract: Importance Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients withERBB2(formerlyHER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in theERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years’ median follow-up). Conclusions and Relevance When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk,ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. Trial Registration ClinicalTrials.gov Identifier:NCT01042379
Emory University1, Harvard University2, Huntsman Cancer Institute3, University of North Carolina at Chapel Hill4, Wake Forest University5, Icahn School of Medicine at Mount Sinai6, Oregon Health & Science University7, University of Alabama at Birmingham8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, University of California, San Francisco11, Ohio State University12, University of Nebraska Medical Center13, University of California, San Diego14, University of Chicago15, Washington University in St. Louis16, University of Texas MD Anderson Cancer Center17, University of South Florida18, University of Washington19, Janssen Pharmaceutica20
TL;DR: Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns.
University of Florence1, University of California, Los Angeles2, Oregon Health & Science University3, Universidad Francisco de Vitoria4, Autonomous University of Madrid5, University of Michigan6, Harvard University7, Stanford University8, University of Pennsylvania9, University of Silesia in Katowice10, Aarhus University11, Primary Children's Hospital12, United States Department of Veterans Affairs13, Mayo Clinic14, Duke University15, Yale University16, Aarhus University Hospital17, University of California, San Francisco18, Brigham and Women's Hospital19
TL;DR: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy and highlights the benefits of disease-specific treatment for this condition.
Children's Hospital of Eastern Ontario1, University of Ottawa2, World Health Organization3, Oregon Health & Science University4, Norwegian Institute of Public Health5, Norwegian School of Sport Sciences6, University of Sydney7, University of Manchester8, University Hospitals Bristol NHS Foundation Trust9, University of Bristol10, University of Granada11, Pennington Biomedical Research Center12
TL;DR: There was sufficient evidence to support recommendations on limiting sedentary behaviours, which was not addressed in the 2010 WHO guidelines, but there is still insufficient evidence available to fully describe the dose-response relationships between physical activity or sedentary behaviour and health outcomes.
Abstract: The World Health Organization (WHO) released in 2020 updated global guidelines on physical activity and sedentary behaviour for children, adolescents, adults, older adults and sub-populations such as pregnant and postpartum women and those living with chronic conditions or disabilities. To summarize the evidence on the associations between physical activity, sedentary behaviour, and health-related outcomes used to inform the 2020 WHO guidelines on physical activity and sedentary behaviour for children and adolescents aged 5–17 years. The update of the WHO guideline recommendations for children and adolescents utilized and systematically updated the evidence syntheses on physical activity and sedentary behaviour conducted for the 2016 Canadian 24-Hour Movement Guidelines for Children and Youth, the 2019 Australian 24-Hour Movement Guidelines for Children and Young People (5–17 years), and the 2018 Physical Activity Guidelines for Americans, Second Edition. Systematic reviews published from 2017 up to July 2019 that addressed the key questions were identified, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to rate the certainty of the evidence for the entire body of evidence. The updated literature search yielded 21 relevant systematic reviews. The evidence base reviewed (i.e., existing and new systematic reviews) provided evidence that greater amounts and higher intensities of physical activity as well as different types of physical activity (i.e., aerobic and muscle and bone strengthening activities) are associated with improved health outcomes (primarily intermediate outcomes). There was sufficient evidence to support recommendations on limiting sedentary behaviours, which was not addressed in the 2010 WHO guidelines. However, there is still insufficient evidence available to fully describe the dose-response relationships between physical activity or sedentary behaviour and health outcomes, and whether the associations vary by type or domain of physical activity or sedentary behaviour. Addressing the identified research gaps will better inform guideline recommendations in children and adolescents, and future work should aim to prioritize these areas of research. In the meantime, investment and leadership is needed to scale up known effective policies and programs aimed at increasing activity in children and adolescents.
Duke University1, University of California, Los Angeles2, Tufts University3, Queen's University Belfast4, University of Miami5, University of Bonn6, University of Paris7, Vita-Salute San Raffaele University8, Tokyo Medical and Dental University9, University of Wisconsin-Madison10, Peking University11, University of Pennsylvania12, Case Western Reserve University13, University College London14, Emory University15, Oregon Health & Science University16, University of Melbourne17, National Institutes of Health18, Massachusetts Institute of Technology19
TL;DR: The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.
TL;DR: Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status.
Abstract: PURPOSEPatients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiv...
University of Colorado Denver1, Boston University2, Paris Diderot University3, University of Texas System4, University of Zurich5, McMaster University6, University of Texas Health Science Center at San Antonio7, Pierre-and-Marie-Curie University8, University Health Network9, Bellvitge University Hospital10, Duke University11, Radboud University Nijmegen12, University of Freiburg13, Oregon Health & Science University14
TL;DR: This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, MycOBacterium kansasii, and Myc Cobacterium xenopi among the slowly growing NTM and MyCobacterius abscessus among the rapidly growing N TM.
Abstract: Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
Vanderbilt University1, Primary Children's Hospital2, University of Utah3, University of Pittsburgh4, Johns Hopkins University5, University of California, Los Angeles6, Duke University7, Harvard University8, Wake Forest University9, University of Colorado Denver10, Yeshiva University11, Oregon Health & Science University12, University of Washington13, University of California, San Francisco14, University of Michigan15, University of Massachusetts Medical School16
TL;DR: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14, and these findings do not support the use of hydroxy chloroquine for treatment of CO VID-19 among hospitalized adults.
Abstract: Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991
TL;DR: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon.
Abstract: Background Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration–approved medical therapy is available...
University of Colorado Denver1, Boston University2, Paris Diderot University3, University of Texas System4, University of Zurich5, McMaster University6, University of Texas Health Science Center at San Antonio7, Pierre-and-Marie-Curie University8, University Health Network9, Bellvitge University Hospital10, Duke University11, Radboud University Nijmegen12, University of Freiburg13, Oregon Health & Science University14
TL;DR: This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, MycOBacterium kansasii, and Myc Cobacterium xenopi among the slowly growing NTM and MyCobacteria abscessus among the rapidly growing N TM.
Abstract: Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
TL;DR: In this paper, the authors present unique opportunities and challenges as a result of the disruption of COVID-19, and the pandemic represents a unique opportunity to study the crisis itself, social...
Abstract: Qualitative researchers face unique opportunities and challenges as a result of the disruption of COVID-19. Although the pandemic represents a unique opportunity to study the crisis itself, social ...
University of Washington1, University of Florida2, University of Düsseldorf3, University of Iowa4, Oregon Health & Science University5, University of California, Irvine6, Alfred I. duPont Hospital for Children7, Thomas Jefferson University8, University of Texas Southwestern Medical Center9, St Thomas' Hospital10, Columbia University11, Maastricht University12, University of Regensburg13, Emory University14
TL;DR: These guidelines are not meant to replace sound clinical judgment or specialist consultation but rather to strengthen provision and clinical management of ECMO specifically, in the context of the COVID-19 pandemic.
Abstract: Disclaimer: The Extracorporeal Life Support Organization (ELSO) Coronavirus Disease 2019 (COVID-19) Guidelines have been developed to assist existing extracorporeal membrane oxygenation (ECMO) centers to prepare and plan provision of ECMO during the ongoing pandemic. The recommendations have been put together by a team of interdisciplinary ECMO providers from around the world. Recommendations are based on available evidence, existing best practice guidelines, ethical principles, and expert opinion. This is a living document and will be regularly updated when new information becomes available. ELSO is not liable for the accuracy or completeness of the information in this document. These guidelines are not meant to replace sound clinical judgment or specialist consultation but rather to strengthen provision and clinical management of ECMO specifically, in the context of the COVID-19 pandemic.
New York University1, Yeshiva University2, University of Michigan3, Oregon Health & Science University4, Singapore General Hospital5, Harvard University6, Indiana University – Purdue University Indianapolis7, Louisiana State University in Shreveport8, Stanford University9, Royal College of Surgeons in Ireland10, University of Cincinnati11, Memorial Sloan Kettering Cancer Center12, United States Department of Veterans Affairs13
TL;DR: A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic, which could be used as broad guidance for all health care workers who are involved in the care of patients with CO VID-19.
Abstract: Importance The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists–head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.
University of Michigan1, University of Alabama at Birmingham2, University of Washington3, Indiana University4, University of Hawaii5, Lahey Hospital & Medical Center6, University of Houston7, Central Michigan University8, University of Grenoble9, Erasmus University Rotterdam10, Stony Brook University11, University of North Carolina at Chapel Hill12, Uniformed Services University of the Health Sciences13, Duke University14, Paris Descartes University15, Medical University of Silesia16, University of Otago17, Mayo Clinic18, University of California, Los Angeles19, Oregon Health & Science University20, Rutgers University21
TL;DR: The CEAP Task Force has adopted the revised Delphi process and made several changes, including adding Corona phlebectatica as the C4c clinical subclass, introducing the modifier "r" for recurrent varicose veins and recurrent venous ulcers, and replacing numeric descriptions of the venous segments by their common abbreviations.
Abstract: The CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification is an internationally accepted standard for describing patients with chronic venous disorders and it has been used for reporting clinical research findings in scientific journals. Developed in 1993, updated in 1996, and revised in 2004, CEAP is a classification system based on clinical manifestations of chronic venous disorders, on current understanding of the etiology, the involved anatomy, and the underlying venous pathology. As the evidence related to these aspects of venous disorders, and specifically of chronic venous diseases (CVD, C2-C6) continue to develop, the CEAP classification needs periodic analysis and revisions. In May of 2017, the American Venous Forum created a CEAP Task Force and charged it to critically analyze the current classification system and recommend revisions, where needed. Guided by four basic principles (preservation of the reproducibility of CEAP, compatibility with prior versions, evidence-based, and practical for clinical use), the Task Force has adopted the revised Delphi process and made several changes. These changes include adding Corona phlebectatica as the C4c clinical subclass, introducing the modifier "r" for recurrent varicose veins and recurrent venous ulcers, and replacing numeric descriptions of the venous segments by their common abbreviations. This report describes all these revisions and the rationale for making these changes.