Showing papers by "Mayo Clinic published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.
4,804 citations
Yale University1, Netherlands Cancer Institute2, Seoul National University Hospital3, Hebron University4, University of Navarra5, Mayo Clinic6, Samsung Medical Center7, Rush University Medical Center8, University of São Paulo9, Pontifical Catholic University of Chile10, Merck & Co.11, University of California, Los Angeles12
TL;DR: In this article, the authors evaluated the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
4,693 citations
TL;DR: Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography and the European Association of Cardiovascular Imaging are presented.
Abstract: Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography : An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging
4,020 citations
Columbia University1, Scott & White Hospital2, Cedars-Sinai Medical Center3, Cleveland Clinic4, Emory University5, Stanford University6, University of Pennsylvania7, MedStar Washington Hospital Center8, Hospital Corporation of America9, New York University10, Advocate Lutheran General Hospital11, Mayo Clinic12, Primary Children's Hospital13, Laval University14, University of British Columbia15
TL;DR: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke; surgery resulted in fewer major vascular complications and less paravalvular aorta regurgitation.
Abstract: BackgroundPrevious trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. MethodsWe randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. ResultsThe rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event...
3,744 citations
Memorial Sloan Kettering Cancer Center1, Thomas Jefferson University2, Queen Mary University of London3, Netherlands Cancer Institute4, New York University5, University of Milan6, MedStar Georgetown University Hospital7, University of Chicago8, University of Paris-Sud9, Stanford University10, Technische Universität München11, Cleveland Clinic12, Mayo Clinic13, Icahn School of Medicine at Mount Sinai14, Yale University15, University of Navarra16, Sarah Cannon Research Institute17, Ottawa Hospital Research Institute18, Harvard University19, Genentech20, Foundation Medicine21, University of Virginia22
TL;DR: Treatment with atezolizumab resulted in a significantly improved RECIST v1.1 response rate, compared with a historical control overall response rate of 10%, and Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolediazepine.
2,934 citations
Imperial College London1, University of Barcelona2, Keio University3, University of Duisburg-Essen4, Queen's University5, Peter MacCallum Cancer Centre6, University of Michigan7, University of São Paulo8, Yale University9, Northern General Hospital10, University of Caen Lower Normandy11, Fred Hutchinson Cancer Research Center12, University of Oxford13, Memorial Sloan Kettering Cancer Center14, University of Sydney15, Sungkyunkwan University16, Seoul National University17, Kyorin University18, University of Copenhagen19, Nippon Medical School20, Katholieke Universiteit Leuven21, University of Texas MD Anderson Cancer Center22, University of Antwerp23, Hyogo College of Medicine24, University of Western Australia25, Glenfield Hospital26, Cleveland Clinic27, Icahn School of Medicine at Mount Sinai28, University of Turin29, Université libre de Bruxelles30, Juntendo University31, National Cancer Research Institute32, Mayo Clinic33, University of Toronto34, Sinai Grace Hospital35, Netherlands Cancer Institute36, Hiroshima University37, City of Hope National Medical Center38, University of Chicago39, New York University40, Georgetown University41, University of Tokushima42, University of Pisa43, Osaka University44, University of Valencia45, Good Samaritan Hospital46, Military Medical Academy47, Fundación Favaloro48, Autonomous University of Barcelona49, Complutense University of Madrid50, University of Oviedo51, National and Kapodistrian University of Athens52, Rovira i Virgili University53, Autonomous University of Madrid54, Ghent University55
TL;DR: The methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition of the TNM Classification for lung cancer due to be published late 2016 are described.
2,826 citations
TL;DR: The primary goal of this update is to simplify the approach and thus increase the utility of the guidelines in daily clinical practice.
Abstract: Echocardiographic assessment of left ventricular (LV) diastolic function is an integral part of the routine evaluation of patients presenting with symptoms of dyspnea or heart failure. The 2009 American Society of Echocardiography (ASE) and European Association of Echocardiography (now European Association of Cardiovascular Imaging [EACVI]) guidelines for diastolic function assessment were comprehensive, including several two-dimensional (2D) and Doppler parameters to grade diastolic dysfunction and to estimate LV filling pressures.1 Notwithstanding, the inclusion of many parameters in the guidelines was perceived to render diastolic function assessment too complex, because several readers have interpreted the guidelines as mandating all the listed parameters in the document to fall within specified values before assigning a specific grade. The primary goal of this update is to simplify the approach and thus increase the utility of the guidelines in daily clinical practice.
LV diastolic dysfunction is usually the result of impaired LV relaxation with or without …
2,541 citations
University of Queensland1, University of Glasgow2, QIMR Berghofer Medical Research Institute3, Garvan Institute of Medical Research4, Baylor College of Medicine5, University of Utah6, South Australia Pathology7, University of Adelaide8, Harvard University9, Campbelltown Hospital10, St. Vincent's Health System11, University of New South Wales12, University of Newcastle13, Royal North Shore Hospital14, University of Sydney15, Royal Prince Alfred Hospital16, Fiona Stanley Hospital17, Royal Adelaide Hospital18, Princess Alexandra Hospital19, University of Western Australia20, Beatson West of Scotland Cancer Centre21, Southern General Hospital22, Dresden University of Technology23, University of Texas MD Anderson Cancer Center24, Memorial Sloan Kettering Cancer Center25, Johns Hopkins University School of Medicine26, University of Verona27, Mayo Clinic28, University of Melbourne29
TL;DR: Detailed genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing.
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
2,443 citations
Katholieke Universiteit Leuven1, University of Valencia2, Radboud University Nijmegen3, Sheba Medical Center4, University of Turin5, Hospital Clínico San Carlos6, Université Paris-Saclay7, University of Pisa8, Mayo Clinic9, University of São Paulo10, The Chinese University of Hong Kong11, University of Oxford12, Helsinki University Central Hospital13, University of Helsinki14, Institute of Cancer Research15, Bank of Cyprus16, University of Ioannina17, Odense University Hospital18, University of Amsterdam19, Otto-von-Guericke University Magdeburg20, Geneva College21, Medical University of Vienna22, Martin Luther University of Halle-Wittenberg23, Hebron University24, Imperial College Healthcare25
TL;DR: These ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
2,382 citations
TL;DR: This paper considered four distinct medical imaging applications in three specialties involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner.
Abstract: Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data.
University of Alabama at Birmingham1, American University of Beirut2, Tufts Medical Center3, Beth Israel Deaconess Medical Center4, University of California, Los Angeles5, Washington University in St. Louis6, University of California, San Diego7, University of Nebraska Medical Center8, Mayo Clinic9, University of Minnesota10, NorthShore University HealthSystem11, Duke University12, American College of Rheumatology13
TL;DR: To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA), a large number of patients with RA are referred to a single clinic for treatment with these medications.
Abstract: Objective
To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA).
Methods
We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.
Results
The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.
Conclusion
This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
TL;DR: It is shown that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds and the clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects.
Abstract: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
TL;DR: This guideline recommends that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma and advises that an experienced radiologist should establish/exclude unilateral primary aldehydes using bilateral adrenal venous sampling.
Abstract: Objective: To develop clinical practice guidelines for the management of patients with primary aldosteronism. Participants: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration. Evidence: We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommenda...
Mayo Clinic1, University of Navarra2, Harvard University3, Cedars-Sinai Medical Center4, Memorial Sloan Kettering Cancer Center5, Emory University6, National and Kapodistrian University of Athens7, University of Turin8, Mount Sinai Hospital9, University of Texas MD Anderson Cancer Center10, Heidelberg University11, Alfred Hospital12, University Health System13, Carolinas Healthcare System14, University of Bologna15, Aalborg University16, Dalhousie University17, Erasmus University Rotterdam18, Roswell Park Cancer Institute19, Columbia University20, University of Toulouse21
TL;DR: Several aspects of disease response assessment are clarified, along with endpoints for clinical trials, and future directions for disease response assessments are highlighted, to allow uniform reporting within and outside clinical trials.
Abstract: Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.
TL;DR: Aasld Guidelines for Treatment of Chronic Hepatitis B Norah Terrault;Natalie Bzowej;Kyong-Mi Chang;Jessica Hwang;Maureen Jonas;Hassan Murad; Hepatology
TL;DR: Venous thromboembolism is a complex disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thromBosis, and, in women, pregnancy and puerperium.
Abstract: Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.
TL;DR: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
Abstract: Background Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
TL;DR: The literature indicates that both individual-focused and structural or organisational strategies can result in clinically meaningful reductions in burnout among physicians, and further research is needed to establish which interventions are most effective in specific populations.
Stanford University1, Icahn School of Medicine at Mount Sinai2, Indiana University3, Memorial Sloan Kettering Cancer Center4, Mayo Clinic5, National Institutes of Health6, University of Utah7, Fred Hutchinson Cancer Research Center8, Johns Hopkins University9, NorthShore University HealthSystem10, University of Michigan11, University of North Carolina at Chapel Hill12, University of Turku13, Translational Genomics Research Institute14, Wayne State University15, University of Paris16, University of Melbourne17, Cancer Council Victoria18, University of Ulm19, University of Southern California20, Karolinska Institutet21, Northwestern University22, McGill University23, LSU Health Sciences Center New Orleans24
TL;DR: This work developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, LRT, GERP, SiPhy, phyloP, and phastCons.
Abstract: The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p −12 ) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies
Pierre-and-Marie-Curie University1, AXA2, University of British Columbia3, VU University Medical Center4, University of Southern California5, University of Toulouse6, ICM Partners7, French Institute of Health and Medical Research8, University of Lübeck9, Imperial College London10, Sahlgrenska University Hospital11, Federal Institute for Drugs and Medical Devices12, UCL Institute of Neurology13, University of Bordeaux14, University of Geneva15, McGill University16, University of Paris17, University of Washington18, Karolinska University Hospital19, University of Eastern Finland20, University of North Texas Health Science Center21, University of California, San Francisco22, University of Melbourne23, Brown University24, Harvard University25, Brigham and Women's Hospital26, Alzheimer's Association27, Lou Ruvo Brain Institute28, Mayo Clinic29
TL;DR: An updated review of the literature and evidence on the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage of Alzheimer's disease are provided.
Abstract: During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.
TL;DR: Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma, and endoscopic surveillance intervals are attenuated, based on recent level 1 evidence.
TL;DR: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy, and proposes noninvasive diagnostic criteria that are applicable to the majority of patients with this disease.
Abstract: Background—Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed...
University of Turin1, Mayo Clinic2, University of Tübingen3, Emory University4, Semmelweis University5, Ankara University6, Charles University in Prague7, University of Mainz8, Cornell University9, Johnson & Johnson Pharmaceutical Research and Development10, Janssen Pharmaceutica11, Monash University12, Erasmus University Rotterdam13
TL;DR: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than borteonib and DexamethAsone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia.
Abstract: BackgroundDaratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. ResultsA prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period ...
TL;DR: This work proposes the “A/T/N” system, a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use and suited to population studies of cognitive aging.
Abstract: Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.
TL;DR: Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months, and in the absence of a difference in overall survival, these findings suggest that.
Abstract: Importance Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. Objective To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. Design, Setting, and Participants At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. Interventions The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. Main Outcomes and Measures The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. Results There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, −28.2%; 90% CI, −41.9% to −14.4%; P P = .002). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, −48.7%; 95% CI, −87.6% to −9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, −34.4%; 95% CI, −74.4% to 5.5%; P = .04). Conclusions and Relevance Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy. Trial Registration clinicaltrials.gov Identifier:NCT00377156
TL;DR: This guideline provides guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy, and offers recommendations for the follow-up of patients with adrenal incidentalomas.
Abstract: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.
TL;DR: A low diagnostic threshold in acutely ill patients, as well as in patients with predisposing factors, is suggested for pregnant women with unexplained persistent nausea, fatigue, and hypotension and a short corticotropin test is recommended as the "gold standard" diagnostic tool to establish the diagnosis.
Abstract: Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. Consensus Process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was ...
NewYork–Presbyterian Hospital1, Columbia University Medical Center2, European Organisation for Research and Treatment of Cancer3, University Medical Center Groningen4, East Surrey Hospital5, Mayo Clinic6, National Institutes of Health7, Queen's University8, Bristol-Myers Squibb9, Harvard University10, VU University Medical Center11, Memorial Sloan Kettering Cancer Center12
TL;DR: The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication of Response Evaluation Criteria in Solid Tumours.
TL;DR: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life.