Showing papers by "University of Alabama at Birmingham published in 2021"
TL;DR: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death, in an international, randomized, double-blind, placebo-controlled, phase 3 trial.
Abstract: Background The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-...
1,760 citations
University of Nebraska Medical Center1, University of Texas Health Science Center at San Antonio2, Emory University3, National Institutes of Health4, Duke University5, University of California, Irvine6, University of Minnesota7, Cedars-Sinai Medical Center8, University of Florida9, Parkland Health & Hospital System10, University of California, San Diego11, Baylor College of Medicine12, University of Rochester13, Tan Tock Seng Hospital14, Scott & White Hospital15, University of California, San Francisco16, University of California, Davis17, University of Massachusetts Medical School18, University of Virginia19, Northwestern University20, Pennsylvania State University21, Providence Sacred Heart Medical Center and Children's Hospital22, University of Alabama at Birmingham23, Stanford University24, Denver Health Medical Center25, Seoul National University26, Changi General Hospital27, Kaiser Permanente28, Uniformed Services University of the Health Sciences29, Eli Lilly and Company30
TL;DR: Baricitinib plus remdesivir was superior to remdes Vivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation.
Abstract: Background Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. Methods We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. Results A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). Conclusions Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).
1,301 citations
Daniel J. Klionsky1, Amal Kamal Abdel-Aziz2, Sara Abdelfatah3, Mahmoud Abdellatif4 +2980 more•Institutions (777)
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
1,129 citations
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson1 +202 more•Institutions (61)
TL;DR: The Trans-Omics for Precision Medicine (TOPMed) project as discussed by the authors aims to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases.
Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history
801 citations
Université Paris-Saclay1, Autonomous University of Barcelona2, University of Cambridge3, National Institute for Occupational Safety and Health4, University of Bonn5, German Center for Neurodegenerative Diseases6, Harvard University7, University of Lausanne8, National Research Council9, University of Padua10, Heidelberg University11, Salk Institute for Biological Studies12, University of Minnesota13, Pasteur Institute14, Tel Aviv University15, Johns Hopkins University16, University of Portsmouth17, Katholieke Universiteit Leuven18, PSL Research University19, Trinity College, Dublin20, Baylor College of Medicine21, University College London22, University of Edinburgh23, Oregon Health & Science University24, National Institutes of Health25, Columbia University26, University of Copenhagen27, University of Rochester28, Ludwig Maximilian University of Munich29, University of Málaga30, Tufts University31, University of Freiburg32, Utrecht University33, Nihon University34, Max Delbrück Center for Molecular Medicine35, University of California, Los Angeles36, University of Yamanashi37, New York University38, University of British Columbia39, King Abdullah University of Science and Technology40, University of Wisconsin-Madison41, University of California, San Francisco42, McGill University43, University of Kentucky44, Kyushu University45, University of Bordeaux46, Polytechnic Institute of Cávado and Ave47, University of Minho48, University of Alabama at Birmingham49, University of Gothenburg50, University of Poitiers51, Cajal Institute52, King's College London53, University of Strasbourg54, Virginia Tech55, University of Düsseldorf56, Russian Academy of Sciences57, I.M. Sechenov First Moscow State Medical University58, University of Seville59, Georgia Institute of Technology60, University of Texas Health Science Center at Houston61, University of California, San Diego62, Universidade Federal do Rio Grande do Sul63, University of Ljubljana64, University of Manchester65, Ikerbasque66
TL;DR: In this article, the authors point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic vs-neuroprotective or A1-vs.A2.
Abstract: Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
797 citations
Virginia Commonwealth University1, The Feinstein Institute for Medical Research2, University of California, Los Angeles3, Harvard University4, University of California, San Francisco5, Oregon Health & Science University6, University of Pittsburgh7, University of North Carolina at Chapel Hill8, Mayo Clinic9, George Mason University10, University of Alabama at Birmingham11, University of Virginia12, New York University13, Stanford University14, University of Massachusetts Medical School15, Boston University16, University of Missouri17, University of Hawaii18, Tufts University19
TL;DR: The US Preventive Services Task Force (USPSTF) concluded with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking as mentioned in this paper.
Abstract: Importance Lung cancer is the second most common cancer and the leading cause of cancer death in the US. In 2020, an estimated 228 820 persons were diagnosed with lung cancer, and 135 720 persons died of the disease. The most important risk factor for lung cancer is smoking. Increasing age is also a risk factor for lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year survival rate of 20.5%. However, early-stage lung cancer has a better prognosis and is more amenable to treatment. Objective To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models. Population This recommendation statement applies to adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Evidence Assessment The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking. Recommendation The USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.
600 citations
Northwestern University1, University of California, San Francisco2, University of Michigan3, City of Hope National Medical Center4, Vanderbilt University5, Seattle Cancer Care Alliance6, Fox Chase Cancer Center7, University of Wisconsin-Madison8, University of Texas Southwestern Medical Center9, University of Utah10, University of Nebraska Medical Center11, University of Alabama at Birmingham12, University of California, Los Angeles13, University of South Florida14, Mayo Clinic15, Washington University in St. Louis16, Yale Cancer Center17, Stanford University18, Case Western Reserve University19, University of Colorado Boulder20, Brigham and Women's Hospital21, Ohio State University22, Roswell Park Cancer Institute23, University of Texas MD Anderson Cancer Center24, Harvard University25, University of California, San Diego26, Memorial Sloan Kettering Cancer Center27, University of Pennsylvania28, University of Tennessee29, Johns Hopkins University30, Duke University31, National Comprehensive Cancer Network32
TL;DR: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section as discussed by the authors.
Abstract: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
589 citations
United States Public Health Service1, Centers for Disease Control and Prevention2, Harvard University3, New York University4, University of Colorado Denver5, University of Texas at Dallas6, Nationwide Children's Hospital7, Johns Hopkins University8, Yale University9, Westchester Medical Center10, Rutgers University11, University of Alabama at Birmingham12, Children's Mercy Hospital13, University of Miami14, University of North Carolina at Chapel Hill15, Baylor College of Medicine16, University of Mississippi17, Vanderbilt University18, SUNY Downstate Medical Center19, California State University, Long Beach20, University of Minnesota21, Saint Barnabas Medical Center22, University of Arkansas for Medical Sciences23, Children's Hospital Oakland Research Institute24, Boston Children's Hospital25, University of Washington26, Central Michigan University27, Icahn School of Medicine at Mount Sinai28, University of Iowa29, Indiana University30, Emory University31, Medical University of South Carolina32, University of Pennsylvania33, Northwestern University34
TL;DR: In this article, the authors compared clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19) at 66 US hospitals in 31 states.
Abstract: Importance Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase–polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure SARS-CoV-2. Main Outcomes and Measures Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7,P Conclusions and Relevance This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.
493 citations
Fox Chase Cancer Center1, Vanderbilt University2, University of Tennessee Health Science Center3, University of Utah4, Washington University in St. Louis5, University of Pennsylvania6, University of Alabama at Birmingham7, Johns Hopkins University8, Roswell Park Cancer Institute9, University of California, Los Angeles10, Northwestern University11, University of Colorado Boulder12, Stanford University13, University of South Florida14, University of Texas MD Anderson Cancer Center15, University of California, San Francisco16, Duke University17, University of Michigan18, Seattle Cancer Care Alliance19, Memorial Sloan Kettering Cancer Center20, Case Western Reserve University21, University of Nebraska Medical Center22, Ohio State University23, Harvard University24, University of California, San Diego25, City of Hope National Medical Center26, Mayo Clinic27, University of Wisconsin-Madison28, Brigham and Women's Hospital29, National Comprehensive Cancer Network30
TL;DR: The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies as mentioned in this paper.
Abstract: The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
455 citations
University of California, San Francisco1, University of South Florida2, University of Michigan3, University of Tennessee Health Science Center4, Northwestern University5, Vanderbilt University6, Seattle Cancer Care Alliance7, City of Hope National Medical Center8, Duke University9, University of Colorado Boulder10, Ohio State University11, University of California, Los Angeles12, Fox Chase Cancer Center13, Harvard University14, Roswell Park Cancer Institute15, Case Western Reserve University16, Washington University in St. Louis17, University of Nebraska Medical Center18, Yale Cancer Center19, University of Wisconsin-Madison20, University of California, San Diego21, Pancreatic Cancer Action Network22, Johns Hopkins University23, University of Texas Southwestern Medical Center24, University of Alabama at Birmingham25, Memorial Sloan Kettering Cancer Center26, University of Utah27, Stanford University28, University of Pennsylvania29, University of Texas MD Anderson Cancer Center30, Brigham and Women's Hospital31, National Comprehensive Cancer Network32
Abstract: Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.
402 citations
Yale University1, NewYork–Presbyterian Hospital2, University of Nebraska Medical Center3, Duke University4, Cornell University5, University of California, San Diego6, University of Colorado Boulder7, Stanford University8, Howard University9, Albany Medical College10, University of California, San Francisco11, Hospital for Special Surgery12, University of Alabama at Birmingham13, Florida State University14, Brigham and Women's Hospital15, American University of Beirut16, University of Pennsylvania17, Centers for Disease Control and Prevention18, Oregon Health & Science University19, Johns Hopkins University20, Toronto Western Hospital21, University of Toronto22, University of Washington23, American College of Rheumatology24
TL;DR: In this article, the authors developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions to develop updated guidelines for the pharmacologic management of rheumatoid arthritis.
Abstract: Objective To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. Methods We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. Results The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). Conclusion This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.
Georgetown University1, Tufts Medical Center2, Anschutz Medical Campus3, Indiana University4, Columbia University5, Emory University6, West Virginia University7, Society of Thoracic Surgeons8, University of Florida9, University of Alabama at Birmingham10, University of Michigan11, Henry Ford Hospital12
TL;DR: The Society of Thoracic Surgeons (STS)-Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) 2020 Annual Report reviews outcomes on 25,551 patients undergoing primary isolated continuous-flow left ventricular assist device (LVAD) implantation between 2010 and 2019 as discussed by the authors.
Northwestern University1, Memorial Sloan Kettering Cancer Center2, University of Wisconsin-Madison3, University of South Florida4, Johns Hopkins University5, University of Nebraska Medical Center6, Mayo Clinic7, Vanderbilt University8, University of California, San Diego9, Case Western Reserve University10, Stanford University11, Ohio State University12, University of Tennessee Health Science Center13, Harvard University14, Washington University in St. Louis15, Roswell Park Cancer Institute16, University of Alabama at Birmingham17, University of California, San Francisco18, University of Utah19, University of Pennsylvania20, Duke University21, Seattle Cancer Care Alliance22, University of California, Los Angeles23, Fox Chase Cancer Center24, University of Michigan25, University of Colorado Boulder26, City of Hope National Medical Center27, Yale University28, University of Texas MD Anderson Cancer Center29, University of Texas Southwestern Medical Center30, National Comprehensive Cancer Network31
TL;DR: The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts as discussed by the authors.
Abstract: The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.
Boston Children's Hospital1, University of Pittsburgh2, Morgan Stanley Children's Hospital3, Hackensack University Medical Center4, Children's Hospital of Philadelphia5, Columbia University6, Cincinnati Children's Hospital Medical Center7, Johns Hopkins University School of Medicine8, University of California, San Diego9, University of Toronto10, University of Alabama at Birmingham11, American College of Rheumatology12, University of Texas Southwestern Medical Center13
TL;DR: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) infection.
Abstract: OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection. The Task Force also provided recommendations for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and discussion through webinars. A 9-point scale was used to determine the appropriateness of each statement (1-3, inappropriate; 4-6, uncertain; 7-9, appropriate), and consensus was rated as low (L), moderate (M), or high (H) based on dispersion of the votes along the numeric scale. Approved guidance statements had to be classified as appropriate with moderate or high levels of consensus, which were pre-specified prior to voting. RESULTS: The first version of the guidance was approved by the Task Force in June 2020 and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion but is meant to be modified as additional data become available.
TL;DR: In this article, the effects of operating parameters on the photocatalytic degradation of textile dyes using various photatalysts have been examined, and the results of the study will help determine the most effective and economical options for removal of dyes in industrial wastewater.
University of Utah1, University of Colorado Denver2, Oregon Health & Science University3, Harvard University4, University of California, San Diego5, University of Texas Health Science Center at Houston6, Medical College of Wisconsin7, Medical University of South Carolina8, Northwestern University9, Emory University10, University of Pennsylvania11, University of São Paulo12, Karolinska Institutet13, Ghent University14, Sun Yat-sen University15, University of Chicago16, Rush University Medical Center17, University of Barcelona18, University of California, Los Angeles19, Vanderbilt University20, University of Arizona21, University of Kansas22, Université de Montréal23, University of Auckland24, Rutgers University25, University of Amsterdam26, Columbia University27, Eastern Virginia Medical School28, University of New South Wales29, Katholieke Universiteit Leuven30, Guy's Hospital31, Stanford University32, University of British Columbia33, Mayo Clinic34, Johns Hopkins University35, Korea University36, Uniformed Services University of the Health Sciences37, Jikei University School of Medicine38, University of Washington39, University of Siena40, University of East Anglia41, University of Adelaide42, Pusan National University43, University of Calgary44, University of Cincinnati45, University of North Carolina at Chapel Hill46, Cleveland Clinic47, University of Winnipeg48, Chulalongkorn University49, Cornell University50, National University of Singapore51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in the understanding and treatment of rhinologic disease.
Abstract: I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.
Oregon Health & Science University1, Oregon State University2, Johns Hopkins University3, University of Colorado Denver4, University of Iowa5, Sage Bionetworks6, Duke University7, Washington University in St. Louis8, University of North Carolina at Chapel Hill9, Stony Brook University10, University of Texas Medical Branch11, University of Washington12, Tufts Medical Center13, Scripps Research Institute14, Janssen Pharmaceutica15, University of Alabama at Birmingham16, Johns Hopkins University School of Medicine17, National Institutes of Health18, Columbia University19, Harvard University20, Durham University21, Tufts University22, University of Pittsburgh23, Palantir Technologies24
TL;DR: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics.
TL;DR: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks.
Abstract: Importance Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches. Objective To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity. Design, setting, and participants Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30). Interventions Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks. Main outcomes and measures The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight. Results Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P Conclusions and relevance Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings. Trial registration ClinicalTrials.gov Identifier: NCT03611582.
University of Düsseldorf1, University of Washington2, European Bioinformatics Institute3, German Cancer Research Center4, University of Michigan5, Harvard University6, Broad Institute7, Yale University8, Xi'an Jiaotong University9, University of Alabama at Birmingham10, University of Southern California11, University of Santiago de Compostela12, University of Maryland, Baltimore13, Temple University14, Pacific Biosciences15, Max Planck Society16, Saarland University17, Washington University in St. Louis18, University of Chicago19, Ewha Womans University20
TL;DR: In this article, the authors present 64 assembled haplotypes from 32 diverse human genomes, which integrate all forms of genetic variation, even across complex loci, and identify 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing.
Abstract: Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.
University of Groningen1, Erasmus University Rotterdam2, Katholieke Universiteit Leuven3, Chinese Academy of Sciences4, University of Surrey5, King's College London6, University of Toronto7, Avera Health8, Karolinska Institutet9, University of Copenhagen10, University of Greifswald11, University of Kiel12, Yeshiva University13, Sungkyunkwan University14, University of Tartu15, Weizmann Institute of Science16, Copenhagen University Hospital17, University of Texas Health Science Center at Houston18, University of Alabama at Birmingham19, Stockholm University20, University of Michigan21, VU University Amsterdam22, University of Oxford23, University of Bristol24, University of Amsterdam25, Maastricht University26, University of California, San Diego27, University of Eastern Finland28, National Institutes of Health29, University of California, Los Angeles30, Linköping University31, Harvard University32, Radboud University Nijmegen33, University of North Carolina at Chapel Hill34, Ewha Womans University35, Fred Hutchinson Cancer Research Center36, National Research Council37
TL;DR: In this article, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts) and found high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples.
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
University of California, Los Angeles1, Fred Hutchinson Cancer Research Center2, LSU Health Sciences Center New Orleans3, University of São Paulo4, Asociación Civil Impacta Salud y Educación5, Chiang Mai University6, Centers for Disease Control and Prevention7, University of Pennsylvania8, St. Jude Children's Research Hospital9, University of North Carolina at Chapel Hill10, University of Cape Town11, University of Alabama at Birmingham12, Rutgers University13, Cornell University14, Johns Hopkins University15, Anschutz Medical Campus16, Harvard University17, University of Miami18, National Institutes of Health19
TL;DR: In this paper, safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
Abstract: Background Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
Harvard University1, Johns Hopkins University2, University of Texas at Dallas3, University of North Carolina at Chapel Hill4, Westchester Medical Center5, New York University6, University of Mississippi7, University of Miami8, University of Colorado Denver9, Boston Children's Hospital10, Indiana University – Purdue University Indianapolis11, University of Washington12, University of Pennsylvania13, Saint Barnabas Medical Center14, University of Texas Health Science Center at Houston15, University of Arkansas for Medical Sciences16, Mayo Clinic17, University of Cincinnati18, Centers for Disease Control and Prevention19, Vanderbilt University20, Yale University21, Nationwide Children's Hospital22, University of Alabama at Birmingham23, Children's Mercy Hospital24, SUNY Downstate Medical Center25, Baylor College of Medicine26, Emory University27, California State University, Long Beach28, Rutgers University29, University of California, San Francisco30, Washington University in St. Louis31, University of Minnesota32, University of Iowa33, Medical University of South Carolina34, Northwestern University35, University of Michigan36
TL;DR: In this article, the authors investigated the range and severity of neurologic involvement among children and adolescents associated with COVID-19 and found that patients with involvement were more likely to have underlying neurologic disorders (81 of 365 [22] compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]).
Abstract: Importance Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants Case series of patients (age Exposures Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barre syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.
TL;DR: In this paper, the effects of metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes.
Abstract: Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.
Auckland University of Technology1, Institute for Health Metrics and Evaluation2, University of Washington3, Mayo Clinic4, University of the Philippines Manila5, Johns Hopkins University6, Heidelberg University7, Harvard University8, Mario Negri Institute for Pharmacological Research9, New York University10, University at Buffalo11, University of California, San Diego12, Veterans Health Administration13, University of Peradeniya14, University of Rochester15, Tufts Medical Center16, Rowan University17, Kaiser Permanente18, Istituto Superiore di Sanità19, Tehran University of Medical Sciences20, University of Texas at Austin21, Sheffield Hallam University22, Florida State University College of Arts and Sciences23, Ball State University24, Northeastern University25, Duke University26, University of Michigan27, Nationwide Children's Hospital28, Ohio State University29, University of Bari30, University of Cape Town31, National Institutes of Health32, Curtin University33, Pacific Institute34, University of Mississippi35, Mizan–Tepi University36, Iran University of Medical Sciences37, Emory University38, Lund University39, University of Central Florida40, Charité41, University of Edinburgh42, Yonsei University43, United States Department of Veterans Affairs44, University of Alabama at Birmingham45, Imperial College London46, Norwegian University of Science and Technology47, University of Maryland, Baltimore48, George Washington University49, University of California, Berkeley50
TL;DR: A large and increasing number of people have various neurological disorders in the US, with significant variation in the burden of and trends in neurological disorders across the US states, and the reasons for these geographic variations need to be explored further.
Abstract: IMPORTANCE Accurate and up-to-date estimates on incidence, prevalence, mortality, and
disability-adjusted life-years (burden) of neurological disorders are the backbone of
evidence-based health care planning and resource allocation for these disorders. It appears
that no such estimates have been reported at the state level for the US.
OBJECTIVE To present burden estimates of major neurological disorders in the US states by
age and sex from 1990 to 2017.
DESIGN, SETTING, AND PARTICIPANTS This is a systematic analysis of the Global Burden of
Disease (GBD) 2017 study. Data on incidence, prevalence, mortality, and disability-adjusted
life-years (DALYs) of major neurological disorders were derived from the GBD 2017 study of
the 48 contiguous US states, Alaska, and Hawaii. Fourteen major neurological disorders were
analyzed: stroke, Alzheimer disease and other dementias, Parkinson disease, epilepsy,
multiple sclerosis, motor neuron disease, migraine, tension-type headache, traumatic brain
injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis,
and tetanus.
EXPOSURES Any of the 14 listed neurological diseases.
MAIN OUTCOME AND MEASURE Absolute numbers in detail by age and sex and
age-standardized rates (with 95% uncertainty intervals) were calculated.
RESULTS The 3 most burdensome neurological disorders in the US in terms of absolute
number of DALYs were stroke (3.58 [95% uncertainty interval [UI], 3.25-3.92] million DALYs),
Alzheimer disease and other dementias (2.55 [95% UI, 2.43-2.68] million DALYs), and
migraine (2.40 [95% UI, 1.53-3.44] million DALYs). The burden of almost all neurological
disorders (in terms of absolute number of incident, prevalent, and fatal cases, as well as
DALYs) increased from 1990 to 2017, largely because of the aging of the population.
Exceptions for this trend included traumatic brain injury incidence (−29.1% [95% UI, −32.4%
to −25.8%]); spinal cord injury prevalence (−38.5% [95% UI, −43.1% to −34.0%]); meningitis
prevalence (−44.8% [95% UI, −47.3% to −42.3%]), deaths (−64.4% [95% UI, −67.7% to
−50.3%]), and DALYs (−66.9% [95% UI, −70.1% to −55.9%]); and encephalitis DALYs
(−25.8% [95% UI, −30.7% to −5.8%]). The different metrics of age-standardized rates varied
between the US states from a 1.2-fold difference for tension-type headache to 7.5-fold for
tetanus; southeastern states and Arkansas had a relatively higher burden for stroke, while
northern states had a relatively higher burden of multiple sclerosis and eastern states had
higher rates of Parkinson disease, idiopathic epilepsy, migraine and tension-type headache,
and meningitis, encephalitis, and tetanus.
CONCLUSIONS AND RELEVANCE There is a large and increasing burden of noncommunicable
neurological disorders in the US, with up to a 5-fold variation in the burden of and trends in
particular neurological disorders across the US states. The information reported in this article
can be used by health care professionals and policy makers at the national and state levels to
advance their health care planning and resource allocation to prevent and reduce the burden
of neurological disorders.
Boston Children's Hospital1, Centers for Disease Control and Prevention2, Johns Hopkins University3, Baylor College of Medicine4, Children's Medical Center of Dallas5, New York Medical College6, Central Michigan University7, University of Pennsylvania8, University of Alabama at Birmingham9, Yale University10, University of Minnesota11, University of Mississippi Medical Center12, Children's Mercy Hospital13, Rutgers University14, Nationwide Children's Hospital15, University of Washington16, University of North Carolina at Chapel Hill17, Arkansas Children's Hospital18, Louisiana State University19, University of Colorado Denver20
TL;DR: In this article, the assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy, and the authors analyzed surve...
Abstract: Background The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods We analyzed surve...
TL;DR: In this paper, the authors examined outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS and concomitant SARS-CoV-2 infections.
Abstract: Importance Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.
Ohio State University1, University of Nebraska Medical Center2, Northwestern University3, University of California, San Francisco4, Harvard University5, Brigham and Women's Hospital6, Vanderbilt University7, University of Tennessee Health Science Center8, University of California, San Diego9, University of Michigan10, Mayo Clinic11, University of Texas MD Anderson Cancer Center12, Johns Hopkins University13, University of California, Los Angeles14, University of Alabama at Birmingham15, City of Hope National Medical Center16, Case Western Reserve University17, Yale Cancer Center18, Roswell Park Cancer Institute19, University of Colorado Boulder20, Seattle Cancer Care Alliance21, Memorial Sloan Kettering Cancer Center22, University of Texas Southwestern Medical Center23, Stanford University24, University of Utah25, University of Pennsylvania26, University of South Florida27, Washington University in St. Louis28, University of Wisconsin-Madison29, Fox Chase Cancer Center30, Duke University31, National Comprehensive Cancer Network32
TL;DR: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia as mentioned in this paper.
Abstract: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.
TL;DR: Test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain, and demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions.
Abstract: No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced α-syn inclusions. Mice exposed to α-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD-associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition.
University of Utah1, Stanford University2, University of Tennessee Health Science Center3, University of Pennsylvania4, Children's Hospital of Philadelphia5, Southern Medical University6, Veterans Health Administration7, University of California, San Diego8, Ottawa Hospital Research Institute9, University of Alabama at Birmingham10, Pontifícia Universidade Católica do Paraná11, Tufts Medical Center12, Northern Ontario School of Medicine13, University of Toronto14, Freeman Hospital15, McMaster University16, Cochrane Collaboration17, Flinders University18, University of Sydney19, University of Calgary20, University of Erlangen-Nuremberg21
TL;DR: A systolic blood pressure target of less than 120 mm Hg is proposed using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients.