Showing papers by "University of Southern California published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
University of Pennsylvania1, University of Texas Southwestern Medical Center2, University of Oslo3, Boston Children's Hospital4, University of Utah5, Université de Montréal6, Goethe University Frankfurt7, University of Minnesota8, Children's Mercy Hospital9, Emory University10, Ghent University11, Kyoto University12, Stanford University13, Duke University14, Oregon Health & Science University15, University of Michigan16, Medical University of Vienna17, University of Paris18, Royal Children's Hospital19, University of Milan20, University of Toronto21, Novartis22, University of Southern California23
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f
3,237 citations
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 citations
University of Southern California1, Stanford University2, University of Iowa3, Brown University4, Ohio State University5, University of Cincinnati6, Medical University of South Carolina7, New York University8, Harvard University9, University of Texas Health Science Center at Houston10, University of Pennsylvania11, Northwestern University12, University of Calgary13
TL;DR: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical Therapy alone among patients with proximal middle‐cerebral‐artery or internal‐carotid‐arterY occlusion and a region of tissue that was ischeMIC but not yet infarcted.
Abstract: Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. Methods We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Results The trial was conducted at 38 U.S. centers and termina...
2,292 citations
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
1,898 citations
University of Texas Southwestern Medical Center1, Stanford University2, University of Southern California3, University of California, Los Angeles4, West Virginia University5, Harvard University6, University of Colorado Boulder7, Vanderbilt University8, Case Western Reserve University9, Cincinnati Children's Hospital Medical Center10, Cleveland Clinic11, Fox Chase Cancer Center12, University of Pennsylvania13, University of Washington14, Seattle Children's15, University of Texas MD Anderson Cancer Center16, Nemours Foundation17, Oregon Health & Science University18, International University, Cambodia19
TL;DR: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.
Abstract: Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. Results A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence ...
1,773 citations
University of Minnesota1, University of Colorado Boulder2, VU University Amsterdam3, Harvard University4, University of Southern California5, University of Queensland6, University of Tartu7, Erasmus University Rotterdam8, Hospital for Special Surgery9, University of Copenhagen10, Statens Serum Institut11, Broad Institute12, University of Essex13, University of Edinburgh14, University of Cambridge15, University Hospital of Lausanne16, Geisinger Health System17, Wenzhou Medical College18, Stanford University19, University of North Carolina at Chapel Hill20, University of Wisconsin-Madison21, Hofstra University22, The Feinstein Institute for Medical Research23, University of Dundee24, University of Toronto25, Princeton University26, Queen's University27, New York University Shanghai28, National Bureau of Economic Research29, Karolinska Institutet30, Uppsala University31, University of Lausanne32, New York University33, Stockholm School of Economics34
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
1,658 citations
University of Southern California1, Duke University2, Stockholm School of Economics3, University of Virginia4, Center for Open Science5, University of Amsterdam6, University of Pennsylvania7, University of North Carolina at Chapel Hill8, University of Regensburg9, California Institute of Technology10, Research Institute of Industrial Economics11, New York University12, Cardiff University13, Mathematica Policy Research14, Northwestern University15, Ohio State University16, University of Sussex17, Texas A&M University18, Royal Holloway, University of London19, University of Zurich20, University of Melbourne21, University of Wisconsin-Madison22, University of Michigan23, Stanford University24, Rutgers University25, Columbia University26, University of Washington27, University of Edinburgh28, National University of Singapore29, Utrecht University30, Arizona State University31, Princeton University32, University of California, Los Angeles33, Imperial College London34, University of Innsbruck35, Harvard University36, University of Chicago37, University of Pittsburgh38, University of Notre Dame39, University of California, Berkeley40, Johns Hopkins University41, University of Bristol42, University of New South Wales43, Dartmouth College44, Whitman College45, University of Puerto Rico46, University of Milan47, University of California, Irvine48, Paris Dauphine University49, University of British Columbia50, Ludwig Maximilian University of Munich51, Purdue University52, Washington University in St. Louis53, University of California, Davis54, Microsoft55
TL;DR: The default P-value threshold for statistical significance is proposed to be changed from 0.05 to 0.005 for claims of new discoveries in order to reduce uncertainty in the number of discoveries.
Abstract: We propose to change the default P-value threshold for statistical significance from 0.05 to 0.005 for claims of new discoveries.
1,586 citations
TL;DR: A comprehensive and structured analysis of various graph embedding techniques proposed in the literature, and the open-source Python library, named GEM (Graph Embedding Methods, available at https://github.com/palash1992/GEM ), which provides all presented algorithms within a unified interface to foster and facilitate research on the topic.
Abstract: Graphs, such as social networks, word co-occurrence networks, and communication networks, occur naturally in various real-world applications. Analyzing them yields insight into the structure of society, language, and different patterns of communication. Many approaches have been proposed to perform the analysis. Recently, methods which use the representation of graph nodes in vector space have gained traction from the research community. In this survey, we provide a comprehensive and structured analysis of various graph embedding techniques proposed in the literature. We first introduce the embedding task and its challenges such as scalability, choice of dimensionality, and features to be preserved, and their possible solutions. We then present three categories of approaches based on factorization methods, random walks, and deep learning, with examples of representative algorithms in each category and analysis of their performance on various tasks. We evaluate these state-of-the-art methods on a few common datasets and compare their performance against one another. Our analysis concludes by suggesting some potential applications and future directions. We finally present the open-source Python library we developed, named GEM (Graph Embedding Methods, available at https://github.com/palash1992/GEM ), which provides all presented algorithms within a unified interface to foster and facilitate research on the topic.
1,553 citations
TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Abstract: The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented
1,507 citations
Memorial Sloan Kettering Cancer Center1, University College London2, National Taiwan University3, University of Southern California4, University of Ulsan5, Trakya University6, University of Bordeaux7, University of Bologna8, University of Amsterdam9, The Chinese University of Hong Kong10, University of California, San Francisco11
TL;DR: Treatment with cabozantinib resulted in longer overall survival and progression‐free survival than placebo among patients with previously treated advanced hepatocellular carcinoma, and the rate of high‐grade adverse events in the cabozaninib group was approximately twice that observed in the placebo group.
Abstract: Background Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellul...
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
University of Texas MD Anderson Cancer Center1, University of Sydney2, University of Southern California3, University of Modena and Reggio Emilia4, University of Turin5, Katholieke Universiteit Leuven6, University College Dublin7, University of Alberta8, Université libre de Bruxelles9, Vrije Universiteit Brussel10, Bristol-Myers Squibb11
TL;DR: Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile.
Abstract: PurposeNivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported.Patients and MethodsPatients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR.ResultsOf 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reac...
25 Apr 2018
TL;DR: An overview of core ideas in GSP and their connection to conventional digital signal processing are provided, along with a brief historical perspective to highlight how concepts recently developed build on top of prior research in other areas.
Abstract: Research in graph signal processing (GSP) aims to develop tools for processing data defined on irregular graph domains. In this paper, we first provide an overview of core ideas in GSP and their connection to conventional digital signal processing, along with a brief historical perspective to highlight how concepts recently developed in GSP build on top of prior research in other areas. We then summarize recent advances in developing basic GSP tools, including methods for sampling, filtering, or graph learning. Next, we review progress in several application areas using GSP, including processing and analysis of sensor network data, biological data, and applications to image processing and machine learning.
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Joint Genome Institute1, Bigelow Laboratory For Ocean Sciences2, United States Department of Agriculture3, University of California, Merced4, Broad Institute5, Oak Ridge National Laboratory6, Michigan State University7, California State University, San Bernardino8, J. Craig Venter Institute9, Max Planck Society10, Argonne National Laboratory11, Pacific Northwest National Laboratory12, University of British Columbia13, University of Southern California14, Science for Life Laboratory15, University of Vermont16, Georgia Institute of Technology17, University of Illinois at Urbana–Champaign18, University of Texas at Austin19, University of Vienna20, University of California, Davis21, University of Nevada, Las Vegas22, University of Wisconsin-Madison23, Cooperative Institute for Research in Environmental Sciences24, University of California, San Diego25, European Bioinformatics Institute26, National Institutes of Health27, University of Queensland28, Saint Petersburg State University29, University of California, Berkeley30
TL;DR: Two standards developed by the Genomic Standards Consortium (GSC) for reporting bacterial and archaeal genome sequences are presented, including the Minimum Information about a Single Amplified Genome (MISAG) and the Minimum information about a Metagenome-Assembled Genomes (MIMAG), including estimates of genome completeness and contamination.
Abstract: We present two standards developed by the Genomic Standards Consortium (GSC) for reporting bacterial and archaeal genome sequences. Both are extensions of the Minimum Information about Any (x) Sequence (MIxS). The standards are the Minimum Information about a Single Amplified Genome (MISAG) and the Minimum Information about a Metagenome-Assembled Genome (MIMAG), including, but not limited to, assembly quality, and estimates of genome completeness and contamination. These standards can be used in combination with other GSC checklists, including the Minimum Information about a Genome Sequence (MIGS), Minimum Information about a Metagenomic Sequence (MIMS), and Minimum Information about a Marker Gene Sequence (MIMARKS). Community-wide adoption of MISAG and MIMAG will facilitate more robust comparative genomic analyses of bacterial and archaeal diversity.
Johns Hopkins University1, University of Utah2, Stanford University3, American Society of Clinical Oncology4, Ontario Institute for Cancer Research5, University of Sydney6, University of Nottingham7, St. Jude Medical Center8, University of Toronto9, Mayo Clinic10, University of Southern California11, Indiana University12, National Institutes of Health13, The Royal Marsden NHS Foundation Trust14
TL;DR: The HER2 testing algorithm for breast cancer is updated and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays.
Abstract: Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .
TL;DR: In this article, a deep learning model based on Gated Recurrent Unit (GRU) is proposed to exploit the missing values and their missing patterns for effective imputation and improving prediction performance.
Abstract: Multivariate time series data in practical applications, such as health care, geoscience, and biology, are characterized by a variety of missing values. In time series prediction and other related tasks, it has been noted that missing values and their missing patterns are often correlated with the target labels, a.k.a., informative missingness. There is very limited work on exploiting the missing patterns for effective imputation and improving prediction performance. In this paper, we develop novel deep learning models, namely GRU-D, as one of the early attempts. GRU-D is based on Gated Recurrent Unit (GRU), a state-of-the-art recurrent neural network. It takes two representations of missing patterns, i.e., masking and time interval, and effectively incorporates them into a deep model architecture so that it not only captures the long-term temporal dependencies in time series, but also utilizes the missing patterns to achieve better prediction results. Experiments of time series classification tasks on real-world clinical datasets (MIMIC-III, PhysioNet) and synthetic datasets demonstrate that our models achieve state-of-the-art performance and provide useful insights for better understanding and utilization of missing values in time series analysis.
TL;DR: Insight is given into the origins and evolution of peptidase families, including an expansion in the number of proteasome components in Asgard archaeotes and as organisms increase in complexity.
Abstract: The MEROPS database (http://www.ebi.ac.uk/merops/) is an integrated source of information about peptidases, their substrates and inhibitors. The hierarchical classification is: protein-species, family, clan, with an identifier at each level. The MEROPS website moved to the EMBL-EBI in 2017, requiring refactoring of the code-base and services provided. The interface to sequence searching has changed and the MEROPS protein sequence libraries can be searched at the EMBL-EBI with HMMER, FastA and BLASTP. Cross-references have been established between MEROPS and the PANTHER database at both the family and protein-species level, which will help to improve curation and coverage between the resources. Because of the increasing size of the MEROPS sequence collection, in future only sequences of characterized proteins, and from completely sequenced genomes of organisms of evolutionary, medical or commercial significance will be added. As an example, peptidase homologues in four proteomes from the Asgard superphylum of Archaea have been identified and compared to other archaean, bacterial and eukaryote proteomes. This has given insights into the origins and evolution of peptidase families, including an expansion in the number of proteasome components in Asgard archaeotes and as organisms increase in complexity. Novel structures for proteasome complexes in archaea are postulated.
TL;DR: It is suggested that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost.
Abstract: Objective To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus process One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.
TL;DR: Randomized Controlled Trials (RCTs) are increasingly popular in the social sciences, not only in medicine as discussed by the authors, and they can play a role in building scientific knowledge and useful predictions but they can only do so as part of a cumulative program, combining with other methods, including conceptual and theoretical development, to discover not 'what works', but 'why things work'.
Proceedings Article•
15 Feb 2018TL;DR: In this paper, the authors propose to model the traffic flow as a diffusion process on a directed graph and introduce Diffusion Convolutional Recurrent Neural Network (DCRNN), a deep learning framework for traffic forecasting that incorporates both spatial and temporal dependency in the traffic flows.
Abstract: Spatiotemporal forecasting has various applications in neuroscience, climate and transportation domain. Traffic forecasting is one canonical example of such learning task. The task is challenging due to (1) complex spatial dependency on road networks, (2) non-linear temporal dynamics with changing road conditions and (3) inherent difficulty of long-term forecasting. To address these challenges, we propose to model the traffic flow as a diffusion process on a directed graph and introduce Diffusion Convolutional Recurrent Neural Network (DCRNN), a deep learning framework for traffic forecasting that incorporates both spatial and temporal dependency in the traffic flow. Specifically, DCRNN captures the spatial dependency using bidirectional random walks on the graph, and the temporal dependency using the encoder-decoder architecture with scheduled sampling. We evaluate the framework on two real-world large scale road network traffic datasets and observe consistent improvement of 12% - 15% over state-of-the-art baselines.
TL;DR: In this paper, the equivalence of the adiabatic and circuit models of quantum computation has been proved, and the placement of quantum computations in the more general classification of computational complexity theory is discussed.
Abstract: The simple act of slowly varying the parameters of a quantum system so that it remains always in its ground state is extremely rich from an information processing point of view. For an ideal, closed system, this adiabatic evolution is equivalent to full quantum computation, and it is convenient for establishing quantum algorithms for optimization. This review presents adiabatic quantum algorithms, proves the closed-system equivalence of the adiabatic and circuit models of quantum computation, reviews the placement of adiabatic quantum computation in the more general classification of computational complexity theory, and discusses the case of ``stoquastic'' quantum evolutions.
VU University Amsterdam1, Erasmus University Rotterdam2, Karolinska Institutet3, Charité4, Virginia Commonwealth University5, South London and Maudsley NHS Foundation Trust6, QIMR Berghofer Medical Research Institute7, King's College London8, University of Southern Denmark9, University of California, Riverside10, University of Southern California11, University of Minnesota12, University of Queensland13, University College London14, Johns Hopkins University15, University of California, Los Angeles16, University of Crete17, Harvard University18, Icahn School of Medicine at Mount Sinai19, Veterans Health Administration20, Yale University21, Haukeland University Hospital22, Trinity College, Dublin23, University of Edinburgh24, Hofstra University25, North Shore-LIJ Health System26, National Institutes of Health27, University of Bergen28, Oslo University Hospital29, National University of Ireland, Galway30, University of Helsinki31, University of Oslo32, Martin Luther University of Halle-Wittenberg33, Duke University34, National and Kapodistrian University of Athens35, Mental Health Research Institute36, University of Colorado Boulder37, Imperial College London38, University of Manchester39, Wellcome Trust40, Manchester Academic Health Science Centre41, Stanford University42, University of Oregon43, University of Toronto44, University of Michigan45, Erasmus University Medical Center46, Broad Institute47, University of North Carolina at Chapel Hill48
TL;DR: A large-scale genetic association study of intelligence identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure, a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Proceedings Article•
03 Dec 2018
TL;DR: DiffPool as discussed by the authors learns a differentiable soft cluster assignment for nodes at each layer of a deep GNN, mapping nodes to a set of clusters, which then form the coarsened input for the next GNN layer.
Abstract: Recently, graph neural networks (GNNs) have revolutionized the field of graph representation learning through effectively learned node embeddings, and achieved state-of-the-art results in tasks such as node classification and link prediction. However, current GNN methods are inherently flat and do not learn hierarchical representations of graphs---a limitation that is especially problematic for the task of graph classification, where the goal is to predict the label associated with an entire graph. Here we propose DiffPool, a differentiable graph pooling module that can generate hierarchical representations of graphs and can be combined with various graph neural network architectures in an end-to-end fashion. DiffPool learns a differentiable soft cluster assignment for nodes at each layer of a deep GNN, mapping nodes to a set of clusters, which then form the coarsened input for the next GNN layer. Our experimental results show that combining existing GNN methods with DiffPool yields an average improvement of 5-10% accuracy on graph classification benchmarks, compared to all existing pooling approaches, achieving a new state-of-the-art on four out of five benchmark datasets.
TL;DR: What is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration are discussed, are discussed.
Abstract: Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist—including insulin and lifestyle interventions—there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.
TL;DR: This article critically interrogates the ideal of transparency, traces some of its roots in scientific and sociotechnical epistemological cultures, and sketches an alternative typology of algorithmic accountability grounded in constructive engagements with the limitations of transparency ideals.
Abstract: Models for understanding and holding systems accountable have long rested upon ideals and logics of transparency. Being able to see a system is sometimes equated with being able to know how it work...
TL;DR: The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis), but there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis).
Johns Hopkins University1, University of Utah2, Stanford University3, American Society of Clinical Oncology4, Ontario Institute for Cancer Research5, University of Sydney6, University of Nottingham7, St. Jude Medical Center8, University of Toronto9, Mayo Clinic10, University of Southern California11, Indiana University12, National Institutes of Health13, The Royal Marsden NHS Foundation Trust14
TL;DR: The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISh and IHC assays.
Abstract: Purpose.— To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast ...
Stony Brook University1, Yale University2, University of North Carolina at Chapel Hill3, University of California, Los Angeles4, University of Southern California5, Sage Bionetworks6, University of Massachusetts Medical School7, University of Chicago8, Icahn School of Medicine at Mount Sinai9, Duke University10, Johns Hopkins University11, SUNY Downstate Medical Center12
TL;DR: The resource and integrative analyses have uncovered genomic elements and networks in the brain, which in turn have provided insight into the molecular mechanisms underlying psychiatric disorders.
Abstract: Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.