Showing papers by "University of Massachusetts Medical School published in 2021"
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 Carlson3 +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
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
TL;DR: In this paper, the authors summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis.
Abstract: Cell death is a fundamental physiological process in all living organisms Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death These studies have highlighted the complex mechanisms tipping the balance between different cell fates Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole
376 citations
University of Michigan1, Cornell University2, University of Pennsylvania3, University of Massachusetts Medical School4, University of Naples Federico II5, Baylor College of Medicine6, Spanish National Research Council7, Complutense University of Madrid8, New York University9, Boston Children's Hospital10, University of Rome Tor Vergata11, NewYork–Presbyterian Hospital12, University of Pittsburgh13, University of Paris14, French Institute of Health and Medical Research15, National University of Cuyo16, Albert Einstein College of Medicine17, University of New Mexico18, Goethe University Frankfurt19, Weizmann Institute of Science20, University of Turku21, Sapienza University of Rome22, Virginia Commonwealth University23, St. Jude Children's Research Hospital24, Discovery Institute25, University of Copenhagen26, University of Tromsø27, Eötvös Loránd University28, Merck & Co.29, University of Freiburg30, Babraham Institute31, University of South Australia32, University of Adelaide33, University of Oviedo34, University of Chicago35, University of Graz36, National Institutes of Health37, Queens College38, City University of New York39, University of Tokyo40, University of Zurich41, University of British Columbia42, Austrian Academy of Sciences43, University of California, San Francisco44, Russian Academy of Sciences45, University Medical Center Groningen46, University of Cambridge47, University of Glasgow48, Rutgers University49, University of Padua50, Kazan Federal University51, University of Bern52, University of Oxford53, Oslo University Hospital54, University of Oslo55, University of Crete56, Foundation for Research & Technology – Hellas57, Francis Crick Institute58, Osaka University59, Harvard University60, Chinese Academy of Sciences61, Icahn School of Medicine at Mount Sinai62, Shanghai Jiao Tong University63, Karolinska Institutet64
TL;DR: In this paper, preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Abstract: Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
365 citations
TL;DR: Viral vector-based gene therapy has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes as discussed by the authors, such as vector based cancer therapies, to treating monogenic diseases with life-altering outcomes.
Abstract: Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.
302 citations
TL;DR: In this article, the authors review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers and discuss new insights into some common underlying mechanisms through which some cancers inactivate the major histocompatibility class I (MHC I) pathway and consider some possible strategies to overcome this limitation.
Abstract: Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.
262 citations
TL;DR: Investigating the introduction and spread of severe acute respiratory syndrome coronavirus 2 in the Boston area across the first wave of the pandemic provides powerful evidence of the importance of superspreading events in shaping the course of this pandemic and illustrates how some introductions, when amplified under unfortunate circumstances, can have an outsized effect with devastating consequences that extend far beyond the initial events themselves.
Abstract: Analysis of 772 complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from early in the Boston-area epidemic revealed numerous introductions of the virus, a small number of which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, whereas other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread. The two events also differed substantially in the genetic variation they generated, suggesting varying transmission dynamics in superspreading events. Our results show how genomic epidemiology can help to understand the link between individual clusters and wider community spread.
238 citations
TL;DR: In this paper, the authors analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months.
192 citations
TL;DR: In this article, the authors used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation and uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge.
Abstract: Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.
TL;DR: In this article, some attempts have been devoted to investigating the dynamic features of discrete fractional calculus (DFC) systems with complex dynamics, such as DFCs with complex dynamics.
Abstract: In this paper, some attempts have been devoted to investigating the dynamic features of discrete fractional calculus (DFC). To date, discrete fractional systems with complex dynamics have attracted...
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 North Carolina at Chapel Hill7, Mayo Clinic8, Virginia Tech9, George Mason University10, New York University11, University of Massachusetts Medical School12, Boston University13, Northwestern University14, University of Hawaii15, Tufts University16
TL;DR: The United States Preventable cause of disease, disability, and death in the US is attributed to cigarette smoking, including second-hand smoke exposure and complications in the offspring (such as sudden infant death syndrome and impaired lung function in childhood).
Abstract: Importance Tobacco use is the leading preventable cause of disease, disability, and death in the US In 2014, it was estimated that 480 000 deaths annually are attributed to cigarette smoking, including second hand smoke exposure Smoking during pregnancy can increase the risk of numerous adverse pregnancy outcomes (eg, miscarriage and congenital anomalies) and complications in the offspring (including sudden infant death syndrome and impaired lung function in childhood) In 2019, an estimated 506 million US adults (208% of the adult population) used tobacco; 140% of the US adult population currently smoked cigarettes and 45% of the adult population used electronic cigarettes (e-cigarettes) Among pregnant US women who gave birth in 2016, 72% reported smoking cigarettes while pregnant Objective To update its 2015 recommendation, the USPSTF commissioned a review to evaluate the benefits and harms of primary care interventions on tobacco use cessation in adults, including pregnant persons Population This recommendation statement applies to adults 18 years or older, including pregnant persons Evidence assessment The USPSTF concludes with high certainty that the net benefit of behavioral interventions and US Food and Drug Associated (FDA)-approved pharmacotherapy for tobacco smoking cessation, alone or combined, in nonpregnant adults who smoke is substantial The USPSTF concludes with high certainty that the net benefit of behavioral interventions for tobacco smoking cessation on perinatal outcomes and smoking cessation in pregnant persons is substantial The USPSTF concludes that the evidence on pharmacotherapy interventions for tobacco smoking cessation in pregnant persons is insufficient because few studies are available, and the balance of benefits and harms cannot be determined The USPSTF concludes that the evidence on the use of e-cigarettes for tobacco smoking cessation in adults, including pregnant persons, is insufficient, and the balance of benefits and harms cannot be determined The USPSTF has identified the lack of well-designed, randomized clinical trials on e-cigarettes that report smoking abstinence or adverse events as a critical gap in the evidence Recommendations The USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and FDA-approved pharmacotherapy for cessation to nonpregnant adults who use tobacco (A recommendation) The USPSTF recommends that clinicians ask all pregnant persons about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant persons who use tobacco (A recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant persons (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of e-cigarettes for tobacco cessation in adults, including pregnant persons The USPSTF recommends that clinicians direct patients who use tobacco to other tobacco cessation interventions with proven effectiveness and established safety (I statement)
TL;DR: In this review, there appears to be favorable outcomes related to myocarditis treated with steroid therapy treated with glucocorticoids and other agents including IL-6 inhibitors, IVIG and colchicine in COVID-19myocarditis is debatable.
Centers for Disease Control and Prevention1, University of Iowa2, Tufts University3, Harvard University4, University of Miami5, Louisiana State University6, Thomas Jefferson University7, Truman Medical Center8, University of Chicago9, University of Massachusetts Medical School10, University of Mississippi11, University of Alabama at Birmingham12, University of California, San Francisco13, University of Washington14, Colorado Department of Public Health and Environment15, Yale University16, Emory University17, University of New Mexico18, University of Rochester19, Oregon Health Authority20, Vanderbilt University21, Duke University22, Johns Hopkins University23, Rush University Medical Center24, University of Utah25, United States Department of Veterans Affairs26, University of Wisconsin-Madison27, Alaska Native Tribal Health Consortium28
TL;DR: In this article, a test-negative case-control study is underway to evaluate mRNA COVID-19 vaccine effectiveness (VE) against symptomatic illness among health care personnel at 33 U.S. sites across 25 states, and the results indicated that the VE of a single dose (measured 14 days after the first dose through 6 days after a second dose) was 82% (95% confidence interval [CI] = 74%-87), adjusted for age, race/ethnicity, and underlying medical conditions.
Abstract: Throughout the COVID-19 pandemic, health care personnel (HCP) have been at high risk for exposure to SARS-CoV-2, the virus that causes COVID-19, through patient interactions and community exposure (1). The Advisory Committee on Immunization Practices recommended prioritization of HCP for COVID-19 vaccination to maintain provision of critical services and reduce spread of infection in health care settings (2). Early distribution of two mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to HCP allowed assessment of the effectiveness of these vaccines in a real-world setting. A test-negative case-control study is underway to evaluate mRNA COVID-19 vaccine effectiveness (VE) against symptomatic illness among HCP at 33 U.S. sites across 25 U.S. states. Interim analyses indicated that the VE of a single dose (measured 14 days after the first dose through 6 days after the second dose) was 82% (95% confidence interval [CI] = 74%-87%), adjusted for age, race/ethnicity, and underlying medical conditions. The adjusted VE of 2 doses (measured ≥7 days after the second dose) was 94% (95% CI = 87%-97%). VE of partial (1-dose) and complete (2-dose) vaccination in this population is comparable to that reported from clinical trials and recent observational studies, supporting the effectiveness of mRNA COVID-19 vaccines against symptomatic disease in adults, with strong 2-dose protection.
The Feinstein Institute for Medical Research1, Harvard University2, University of California, Los Angeles3, Albert Einstein College of Medicine4, Oregon Health & Science University5, University of Pittsburgh6, University of North Carolina at Chapel Hill7, Mayo Clinic8, Virginia Commonwealth University9, George Mason University10, University of Virginia11, New York University12, Stanford University13, University of Massachusetts Medical School14, Boston University15, University of Missouri16, University of Hawaii17, Tufts University18
TL;DR: In this article, the authors present a systematic review to evaluate screening for prediabetes and type 2 diabetes in asymptomatic, non-pregnant adults and preventive interventions for those with pre-diabetes.
Abstract: Importance An estimated 13% of all US adults (18 years or older) have diabetes, and 34.5% meet criteria for prediabetes. The prevalences of prediabetes and diabetes are higher in older adults. Estimates of the risk of progression from prediabetes to diabetes vary widely, perhaps because of differences in the definition of prediabetes or the heterogeneity of prediabetes. Diabetes is the leading cause of kidney failure and new cases of blindness among adults in the US. It is also associated with increased risks of cardiovascular disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis and was estimated to be the seventh leading cause of death in the US in 2017. Screening asymptomatic adults for prediabetes and type 2 diabetes may allow earlier detection, diagnosis, and treatment, with the ultimate goal of improving health outcomes. Objective To update its 2015 recommendation, the USPSTF commissioned a systematic review to evaluate screening for prediabetes and type 2 diabetes in asymptomatic, nonpregnant adults and preventive interventions for those with prediabetes. Population Nonpregnant adults aged 35 to 70 years seen in primary care settings who have overweight or obesity (defined as a body mass index ≥25 and ≥30, respectively) and no symptoms of diabetes. Evidence Assessment The USPSTF concludes with moderate certainty that screening for prediabetes and type 2 diabetes and offering or referring patients with prediabetes to effective preventive interventions has a moderate net benefit. Conclusions and Recommendation The USPSTF recommends screening for prediabetes and type 2 diabetes in adults aged 35 to 70 years who have overweight or obesity. Clinicians should offer or refer patients with prediabetes to effective preventive interventions. (B recommendation)
TL;DR: In a survey of 714 practicing US physicians nationwide, 82.4% reported that people with significant disability have worse quality of life than nondisabled people, and only 40.7% of physicians were very confident about their ability to provide the same quality of care to patients with disability.
Abstract: More than sixty-one million Americans have disabilities, and increasing evidence documents that they experience health care disparities. Although many factors likely contribute to these disparities, one little-studied but potential cause involves physicians' perceptions of people with disability. In our survey of 714 practicing US physicians nationwide, 82.4 percent reported that people with significant disability have worse quality of life than nondisabled people. Only 40.7 percent of physicians were very confident about their ability to provide the same quality of care to patients with disability, just 56.5 percent strongly agreed that they welcomed patients with disability into their practices, and 18.1 percent strongly agreed that the health care system often treats these patients unfairly. More than thirty years after the Americans with Disabilities Act of 1990 was enacted, these findings about physicians' perceptions of this population raise questions about ensuring equitable care to people with disability. Potentially biased views among physicians could contribute to persistent health care disparities affecting people with disability.
TL;DR: In this paper, an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines using this genome modification system, they could also seed tumor formation through somatic cell editing in the adult mouse.
Abstract: Prime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor DNA as a template PEs facilitate nucleotide substitutions or local insertions or deletions within the genome based on the template sequence encoded within the prime editing guide RNA (pegRNA) However, the efficacy of prime editing in adult mice has not been established Here we report an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines Using this genome modification system, we could also seed tumor formation through somatic cell editing in the adult mouse Finally, we successfully utilize dual adeno-associated virus (AAVs) for the delivery of a split-intein prime editor and demonstrate that this system enables the correction of a pathogenic mutation in the mouse liver Our findings further establish the broad potential of this genome editing technology for the directed installation of sequence modifications in vivo, with important implications for disease modeling and correction
TL;DR: In this article, an annotation-efficient deep learning approach was proposed for mammogram classification, which achieved state-of-the-art performance on 2D and 3D mammograms.
Abstract: Breast cancer remains a global challenge, causing over 600,000 deaths in 2018 (ref. 1). To achieve earlier cancer detection, health organizations worldwide recommend screening mammography, which is estimated to decrease breast cancer mortality by 20–40% (refs. 2,3). Despite the clear value of screening mammography, significant false positive and false negative rates along with non-uniformities in expert reader availability leave opportunities for improving quality and access4,5. To address these limitations, there has been much recent interest in applying deep learning to mammography6–18, and these efforts have highlighted two key difficulties: obtaining large amounts of annotated training data and ensuring generalization across populations, acquisition equipment and modalities. Here we present an annotation-efficient deep learning approach that (1) achieves state-of-the-art performance in mammogram classification, (2) successfully extends to digital breast tomosynthesis (DBT; ‘3D mammography’), (3) detects cancers in clinically negative prior mammograms of patients with cancer, (4) generalizes well to a population with low screening rates and (5) outperforms five out of five full-time breast-imaging specialists with an average increase in sensitivity of 14%. By creating new ‘maximum suspicion projection’ (MSP) images from DBT data, our progressively trained, multiple-instance learning approach effectively trains on DBT exams using only breast-level labels while maintaining localization-based interpretability. Altogether, our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide. A generalizable and interpretable artificial-intelligence system achieves clinical accuracy for screening and early breast-cancer detection on 2D and 3D mammograms.
TL;DR: The role of fragile X mental retardation protein (FMRP) in the development of the neurodevelopmental disorder fragile X syndrome (FXS) has been investigated in this paper.
Abstract: Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that - when epigenetically inactivated by a triplet nucleotide repeat expansion - causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.
TL;DR: The significant increase in complicated appendicitis and simultaneous significant decrease in uncomplicated appendix during the COVID-19 pandemic indicate that patients are not seeking appropriate, timely surgical care.
Abstract: Background The novel coronavirus (COVID-19) strain has resulted in restrictions potentially impacting patients presenting with acute appendicitis and their disease burden. Methods All acute appendicitis admissions (281 patients) between 1/1/2018-4/30/2020 were reviewed. Two groups were created: 6 weeks before (Group A) and 6 weeks after (Group B) the date elective surgeries were postponed in Massachusetts for COVID-19. Acute appendicitis incidence and disease characteristics were compared between the groups. Similar time periods from 2018 to 2019 were also compared. Results Fifty-four appendicitis patients were categorized in Group A and thirty-seven in Group B. Those who underwent surgery were compared and revealed a 45.5% decrease (CI: 64.2,-26.7) in uncomplicated appendicitis, a 21.1% increase (CI:3.9,38.3) in perforated appendicitis and a 29% increase (CI:11.5,46.5) in gangrenous appendicitis. Significant differences in the incidence of uncomplicated and complicated appendicitis were also noted when comparing 2020 to previous years. Conclusions The significant increase in complicated appendicitis and simultaneous significant decrease in uncomplicated appendicitis during the COVID-19 pandemic indicate that patients are not seeking appropriate, timely surgical care.
Wouter van Rheenen1, Rick A.A. van der Spek1, Mark K Bakker1, Joke J.F.A. van Vugt1 +209 more•Institutions (82)
TL;DR: All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
TL;DR: A systematic review of 25 studies synthesizes research examining possible risk and protective factors that might explain the established link between child sexual abuse and future victimizations and highlights the need for standardized definitions of both CSA and revictimization.
Abstract: Child sexual abuse (CSA) is a widespread public health problem in the United States. It has been associated with multiple long-term deleterious outcomes including revictimization in adulthood. This systematic review of 25 studies synthesizes research examining possible risk and protective factors that might explain the established link between CSA and future victimizations. Specific risk factors identified included co-occurring maltreatment in the home, risky sexual behavior (particularly in adolescence), post-traumatic stress disorder, emotion dysregulation, and other maladaptive coping strategies. Only one protective factor was identified: perceived parental care. The review also revealed considerable variability in definitions and measurement of both CSA and adult victimization, particularly in terms of how researchers conceptualized age. Many of the studies were limited in generalizability by including only college-age women. These findings have clinical and research implications. Public health interventions working to prevent revictimization among CSA survivors can utilize these findings when designing programs. For researchers, the results highlight the need for standardized definitions of both CSA and revictimization, for well-validated and consistent measurement, and for inclusion of additional population groups in future research.
Green Templeton College1, University of Waterloo2, Hospital Authority3, Harvard University4, University of Vermont5, National Institutes of Health6, Aga Khan University Hospital7, University of Pennsylvania8, University of Toronto9, University of Hong Kong10, University of Liberia11, University of Barcelona12, University of Cape Town13, Cayetano Heredia University14, University of Massachusetts Medical School15, McGill University16, Johns Hopkins University17, University of Malaya18, Centers for Disease Control and Prevention19, University of Michigan20, King's College London21, Singapore General Hospital22, Indian Council of Medical Research23
TL;DR: This article established a whitepaper workgroup to delineate the current status of the field and outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD.
Abstract: Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.
TL;DR: In this paper, the authors studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance, and found that microglias exposed to αsyn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-Syn from overloaded microglions to neighboring naive microglians where the α-sync cargo got rapidly and effectively degraded.
TL;DR: This Review discusses the possible neuroimmunological mechanisms underlying the nervous system and skeletal muscle involvement, and viral triggered neuroIMmunological conditions associated with SARS-CoV-2, as well as therapeutic approaches that have been considered for these specific complications worldwide.
20 Jan 2021
TL;DR: In this paper, the strengths and weaknesses of current state-of-the-art viral and non-viral miRNA delivery systems and how these tools can be exploited to improve the outcomes of miRNA-based therapeutics.
Abstract: MicroRNAs (miRNAs) represent a family of short non-coding regulatory RNA molecules that are produced in a tissue and time-specific manner to orchestrate gene expression post-transcription. MiRNAs hybridize to target mRNA(s) to induce translation repression or mRNA degradation. Functional studies have demonstrated that miRNAs are engaged in virtually every physiological process and, consequently, miRNA dysregulations have been linked to multiple human pathologies. Thus, miRNA mimics and anti-miRNAs that restore miRNA expression or downregulate aberrantly expressed miRNAs, respectively, are highly sought-after therapeutic strategies for effective manipulation of miRNA levels. In this regard, carrier vehicles that facilitate proficient and safe delivery of miRNA-based therapeutics are fundamental to the clinical success of these pharmaceuticals. Here, we highlight the strengths and weaknesses of current state-of-the-art viral and non-viral miRNA delivery systems and provide perspective on how these tools can be exploited to improve the outcomes of miRNA-based therapeutics.
TL;DR: In a longitudinal study of 43 adults newly infected with SARS-CoV-2, all provided daily saliva and nasal swabs for quantitative reverse transcription polymerase chain reaction (RT-qPCR), Quidel SARS Sofia antigen fluorescent immunoassay (FIA), and live virus culture as mentioned in this paper.
Abstract: BACKGROUND Serial screening is critical for restricting spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by facilitating timely identification of infected individuals to interrupt transmission. Variation in sensitivity of different diagnostic tests at different stages of infection has not been well documented. METHODS In a longitudinal study of 43 adults newly infected with SARS-CoV-2, all provided daily saliva and nasal swabs for quantitative reverse transcription polymerase chain reaction (RT-qPCR), Quidel SARS Sofia antigen fluorescent immunoassay (FIA), and live virus culture. RESULTS Both RT-qPCR and Quidel SARS Sofia antigen FIA peaked in sensitivity during the period in which live virus was detected in nasal swabs, but sensitivity of RT-qPCR tests rose more rapidly prior to this period. We also found that serial testing multiple times per week increases the sensitivity of antigen tests. CONCLUSIONS RT-qPCR tests are more effective than antigen tests at identifying infected individuals prior to or early during the infectious period and thus for minimizing forward transmission (given timely results reporting). All tests showed >98% sensitivity for identifying infected individuals if used at least every 3 days. Daily screening using antigen tests can achieve approximately 90% sensitivity for identifying infected individuals while they are viral culture positive.
The Feinstein Institute for Medical Research1, Harvard University2, University of California, Los Angeles3, Albert Einstein College of Medicine4, Oregon Health & Science University5, University of Pittsburgh6, University of North Carolina at Chapel Hill7, Mayo Clinic8, George Mason University9, University of Virginia10, New York University11, University of Massachusetts Medical School12, Boston University13, Northwestern University14, University of Missouri15, University of Hawaii16, Tufts University17
TL;DR: The USPSTF concluded with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, small for gestational age/intrauterine growth restriction, and perinatal mortality as discussed by the authors.
Abstract: Importance Preeclampsia is one of the most serious health problems that affect pregnant persons. It is a complication in approximately 4% of pregnancies in the US and contributes to both maternal and infant morbidity and mortality. Preeclampsia also accounts for 6% of preterm births and 19% of medically indicated preterm births in the US. There are racial and ethnic disparities in the prevalence of and mortality from preeclampsia. Non-Hispanic Black women are at greater risk for developing preeclampsia than other women and experience higher rates of maternal and infant morbidity and perinatal mortality. Objective To update its 2014 recommendation, the USPSTF commissioned a systematic review to evaluate the effectiveness of low-dose aspirin use to prevent preeclampsia. Population Pregnant persons at high risk for preeclampsia who have no prior adverse effects with or contraindications to low-dose aspirin. Evidence assessment The USPSTF concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, small for gestational age/intrauterine growth restriction, and perinatal mortality in pregnant persons at high risk for preeclampsia. Recommendation The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication for preeclampsia after 12 weeks of gestation in persons who are at high risk for preeclampsia. (B recommendation).