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Proceedings Article
12 Feb 2016
TL;DR: The authors extend the hierarchical recurrent encoder-decoder neural network to the dialogue domain, and demonstrate that this model is competitive with state-of-the-art neural language models and backoff n-gram models.
Abstract: We investigate the task of building open domain, conversational dialogue systems based on large dialogue corpora using generative models. Generative models produce system responses that are autonomously generated word-by-word, opening up the possibility for realistic, flexible interactions. In support of this goal, we extend the recently proposed hierarchical recurrent encoder-decoder neural network to the dialogue domain, and demonstrate that this model is competitive with state-of-the-art neural language models and backoff n-gram models. We investigate the limitations of this and similar approaches, and show how its performance can be improved by bootstrapping the learning from a larger question-answer pair corpus and from pretrained word embeddings.

1,533 citations


Journal ArticleDOI
TL;DR: In this paper, leave-one-out cross-validation (LOO) and the widely applicable information criterion (WAIC) are used to estimate pointwise out-of-sample prediction accuracy from a fitted Bayesian model using the log-likelihood evaluated at the posterior simulations of the parameter values.
Abstract: Leave-one-out cross-validation (LOO) and the widely applicable information criterion (WAIC) are methods for estimating pointwise out-of-sample prediction accuracy from a fitted Bayesian model using the log-likelihood evaluated at the posterior simulations of the parameter values. LOO and WAIC have various advantages over simpler estimates of predictive error such as AIC and DIC but are less used in practice because they involve additional computational steps. Here we lay out fast and stable computations for LOO and WAIC that can be performed using existing simulation draws. We introduce an efficient computation of LOO using Pareto-smoothed importance sampling (PSIS), a new procedure for regularizing importance weights. Although WAIC is asymptotically equal to LOO, we demonstrate that PSIS-LOO is more robust in the finite case with weak priors or influential observations. As a byproduct of our calculations, we also obtain approximate standard errors for estimated predictive errors and for comparison of predictive errors between two models. We implement the computations in an R package called loo and demonstrate using models fit with the Bayesian inference package Stan.

1,533 citations


Journal ArticleDOI
TL;DR: A clinically oriented review and evidence-based recommendations regarding physical activity and exercise in people with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and prediabetes are provided.
Abstract: The adoption and maintenance of physical activity are critical foci for blood glucose management and overall health in individuals with diabetes and prediabetes. Recommendations and precautions vary depending on individual characteristics and health status. In this Position Statement, we provide a clinically oriented review and evidence-based recommendations regarding physical activity and exercise in people with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and prediabetes. Physical activity includes all movement that increases energy use, whereas exercise is planned, structured physical activity. Exercise improves blood glucose control in type 2 diabetes, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being (1,2). Regular exercise may prevent or delay type 2 diabetes development (3). Regular exercise also has considerable health benefits for people with type 1 diabetes (e.g., improved cardiovascular fitness, muscle strength, insulin sensitivity, etc.) (4). The challenges related to blood glucose management vary with diabetes type, activity type, and presence of diabetes-related complications (5,6). Physical activity and exercise recommendations, therefore, should be tailored to meet the specific needs of each individual. Physical activity recommendations and precautions may vary by diabetes type. The primary types of diabetes are type 1 and type 2. Type 1 diabetes (5%–10% of cases) results from cellular-mediated autoimmune destruction of the pancreatic β-cells, producing insulin deficiency (7). Although it can occur at any age, β-cell destruction rates vary, typically occurring more rapidly in youth than in adults. Type 2 diabetes (90%–95% of cases) results from a progressive loss of insulin secretion, usually also with insulin resistance. Gestational diabetes mellitus occurs during pregnancy, with screening typically occurring at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. Prediabetes is diagnosed when blood glucose levels are above the normal range but not high enough to be classified as …

1,532 citations


Proceedings Article
19 Jun 2016
TL;DR: In this article, an end-to-end deep learning approach was used to recognize either English or Mandarin Chinese speech-two vastly different languages-using HPC techniques, enabling experiments that previously took weeks to now run in days.
Abstract: We show that an end-to-end deep learning approach can be used to recognize either English or Mandarin Chinese speech-two vastly different languages. Because it replaces entire pipelines of hand-engineered components with neural networks, end-to-end learning allows us to handle a diverse variety of speech including noisy environments, accents and different languages. Key to our approach is our application of HPC techniques, enabling experiments that previously took weeks to now run in days. This allows us to iterate more quickly to identify superior architectures and algorithms. As a result, in several cases, our system is competitive with the transcription of human workers when benchmarked on standard datasets. Finally, using a technique called Batch Dispatch with GPUs in the data center, we show that our system can be inexpensively deployed in an online setting, delivering low latency when serving users at scale.

1,531 citations


Journal ArticleDOI
TL;DR: The computer program LOBSTER (Local Orbital Basis Suite Towards Electronic‐Structure Reconstruction) enables chemical‐bonding analysis based on periodic plane‐wave density‐functional theory output and is applicable to a wide range of first‐principles simulations in solid‐state and materials chemistry.
Abstract: The computer program LOBSTER (Local Orbital Basis Suite Towards Electronic-Structure Reconstruction) enables chemical-bonding analysis based on periodic plane-wave (PAW) density-functional theory (DFT) output and is applicable to a wide range of first-principles simulations in solid-state and materials chemistry. LOBSTER incorporates analytic projection routines described previously in this very journal [J. Comput. Chem. 2013, 34, 2557] and offers improved functionality. It calculates, among others, atom-projected densities of states (pDOS), projected crystal orbital Hamilton population (pCOHP) curves, and the recently introduced bond-weighted distribution function (BWDF). The software is offered free-of-charge for non-commercial research. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

1,531 citations


Journal ArticleDOI
23 Feb 2016-JAMA
TL;DR: A consensus process using results from a systematic review, surveys, and cohort studies found that adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.
Abstract: Importance Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition. Objective To develop a new definition and clinical criteria for identifying septic shock in adults. Design, Setting, and Participants The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28 150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1 309 025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1 847 165) electronic health record (EHR) data sets. Main Outcomes and Measures Evidence for and agreement on septic shock definitions and criteria. Results The systematic review identified 44 studies reporting septic shock outcomes (total of 166 479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock–associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity ( I 2 = 99.5%; τ 2 = 182.5; P Conclusions and Relevance Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

1,531 citations


Journal ArticleDOI
TL;DR: The current contents of the GO knowledgebase are summarized, several new features and improvements that have been made to the ontology, the annotations and the tools are presented, and extensions to the resource are extended, increasing support for descriptions of causal models of biological systems and network biology.
Abstract: The Gene Ontology (GO) is a comprehensive resource of computable knowledge regarding the functions of genes and gene products. As such, it is extensively used by the biomedical research community for the analysis of -omics and related data. Our continued focus is on improving the quality and utility of the GO resources, and we welcome and encourage input from researchers in all areas of biology. In this update, we summarize the current contents of the GO knowledgebase, and present several new features and improvements that have been made to the ontology, the annotations and the tools. Among the highlights are 1) developments that facilitate access to, and application of, the GO knowledgebase, and 2) extensions to the resource as well as increasing support for descriptions of causal models of biological systems and network biology. To learn more, visit http://geneontology.org/.

1,531 citations


Journal ArticleDOI
TL;DR: In this paper, the current status of the intrinsic mechanical properties of the graphene-family of materials along with the preparation and properties of bulk graphene-based nanocomposites is thoroughly examined.

1,531 citations


Journal ArticleDOI
12 Mar 2015-Cell
TL;DR: It is shown that hundreds of circRNAs are regulated during human epithelial-mesenchymal transition (EMT) and that the production of over one-third of abundant circ RNAs is dynamically regulated by the alternative splicing factor, Quaking (QKI), which itself is regulated during EMT.

1,531 citations


Journal ArticleDOI
TL;DR: The MetaboAnalyst 5.0 as mentioned in this paper is the latest version of the web-based platform for comprehensive metabolomics data analysis and interpretation, aiming to narrow the gap from raw data to functional insights for global metabolomics based on HRMS.
Abstract: Since its first release over a decade ago, the MetaboAnalyst web-based platform has become widely used for comprehensive metabolomics data analysis and interpretation. Here we introduce MetaboAnalyst version 5.0, aiming to narrow the gap from raw data to functional insights for global metabolomics based on high-resolution mass spectrometry (HRMS). Three modules have been developed to help achieve this goal, including: (i) a LC-MS Spectra Processing module which offers an easy-to-use pipeline that can perform automated parameter optimization and resumable analysis to significantly lower the barriers to LC-MS1 spectra processing; (ii) a Functional Analysis module which expands the previous MS Peaks to Pathways module to allow users to intuitively select any peak groups of interest and evaluate their enrichment of potential functions as defined by metabolic pathways and metabolite sets; (iii) a Functional Meta-Analysis module to combine multiple global metabolomics datasets obtained under complementary conditions or from similar studies to arrive at comprehensive functional insights. There are many other new functions including weighted joint-pathway analysis, data-driven network analysis, batch effect correction, merging technical replicates, improved compound name matching, etc. The web interface, graphics and underlying codebase have also been refactored to improve performance and user experience. At the end of an analysis session, users can now easily switch to other compatible modules for a more streamlined data analysis. MetaboAnalyst 5.0 is freely available at https://www.metaboanalyst.ca.

1,530 citations



Proceedings ArticleDOI
10 Jan 2017
TL;DR: The authors describe an open-source toolkit for neural machine translation (NMT) that prioritizes efficiency, modularity, and extensibility with the goal of supporting NMT research into model architectures, feature representations, and source modalities.
Abstract: We describe an open-source toolkit for neural machine translation (NMT). The toolkit prioritizes efficiency, modularity, and extensibility with the goal of supporting NMT research into model architectures, feature representations, and source modalities, while maintaining competitive performance and reasonable training requirements. The toolkit consists of modeling and translation support, as well as detailed pedagogical documentation about the underlying techniques.

Journal ArticleDOI
David Ellinghaus1, Frauke Degenhardt1, Luis Bujanda1, Maria Buti1, Agustín Albillos1, Pietro Invernizzi1, J. Fernández1, Daniele Prati1, Guido Baselli1, Rosanna Asselta1, Marit Mæhle Grimsrud1, Chiara Milani1, Fatima Aziz1, Jan Christian Kässens1, Sandra May1, Mareike Wendorff1, Lars Wienbrandt1, Florian Uellendahl-Werth1, Tenghao Zheng1, Xiaoli Yi1, Raúl de Pablo1, Adolfo Garrido Chercoles1, Adriana Palom1, Alba Estela Garcia-Fernandez1, Francisco Rodriguez-Frias1, Alberto Zanella1, Alessandra Bandera1, Alessandro Protti1, Alessio Aghemo1, Ana Lleo1, Andrea Biondi1, Andrea Caballero-Garralda1, Andrea Gori1, Anja Tanck1, Anna Carreras Nolla1, Anna Latiano1, Anna Ludovica Fracanzani1, Anna Peschuck1, Antonio Julià1, Antonio Pesenti1, Antonio Voza1, David Jiménez1, Beatriz Mateos1, Beatriz Nafria Jimenez1, Carmen Quereda1, Cinzia Paccapelo1, Christoph Gassner1, Claudio Angelini1, Cristina Cea1, Aurora Solier1, David Pestana1, Eduardo Muñiz-Diaz1, Elena Sandoval1, Elvezia Maria Paraboschi1, Enrique Navas1, Félix García Sánchez1, Ferruccio Ceriotti1, F. Martinelli-Boneschi1, Flora Peyvandi1, Francesco Blasi1, Luis Téllez1, Albert Blanco-Grau1, Georg Hemmrich-Stanisak1, Giacomo Grasselli1, Giorgio Costantino1, Giulia Cardamone1, Giuseppe Foti1, Serena Aneli1, Hayato Kurihara1, Hesham ElAbd1, Ilaria My1, Iván Galván-Femenía1, Javier Martin1, Jeanette Erdmann1, José Ferrusquía-Acosta1, Koldo Garcia-Etxebarria1, Laura Izquierdo-Sanchez1, Laura Rachele Bettini1, Lauro Sumoy1, Leonardo Terranova1, Leticia Moreira1, Luigi Santoro1, Luigia Scudeller1, Francisco Mesonero1, Luisa Roade1, Malte C. Rühlemann1, Marco Schaefer1, Maria Carrabba1, Mar Riveiro-Barciela1, Maria Eloina Figuera Basso1, Maria Grazia Valsecchi1, María Hernández-Tejero1, Marialbert Acosta-Herrera1, Mariella D'Angiò1, Marina Baldini1, Marina Cazzaniga1, Martin Schulzky1, Maurizio Cecconi1, Michael Wittig1, Michele Ciccarelli1, Miguel Rodríguez-Gandía1, Monica Bocciolone1, Monica Miozzo1, Nicola Montano1, Nicole Braun1, Nicoletta Sacchi1, Nilda Martinez1, Onur Özer1, Orazio Palmieri1, Paola Faverio1, Paoletta Preatoni1, Paolo Bonfanti1, Paolo Omodei1, Paolo Tentorio1, Pedro Castro1, Pedro M. Rodrigues1, Aaron Blandino Ortiz1, Rafael de Cid1, Ricard Ferrer1, Roberta Gualtierotti1, Rosa Nieto1, Siegfried Goerg1, Salvatore Badalamenti1, Sara Marsal1, Giuseppe Matullo1, Serena Pelusi1, Simonas Juzenas1, Stefano Aliberti1, Valter Monzani1, Victor Moreno1, Tanja Wesse1, Tobias L. Lenz1, Tomás Pumarola1, Valeria Rimoldi1, Silvano Bosari1, Wolfgang Albrecht1, Wolfgang Peter1, Manuel Romero-Gómez1, Mauro D'Amato1, Stefano Duga1, Jesus M. Banales1, Johannes R. Hov1, Trine Folseraas1, Luca Valenti1, Andre Franke1, Tom H. Karlsen1 
TL;DR: A 3p21.31 gene cluster is identified as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and a potential involvement of the ABO blood-group system is confirmed.
Abstract: Background There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19) Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19 Methods We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels Results We detected cross-replicating associations with rs11385942 at locus 3p2131 and with rs657152 at locus 9q342, which were significant at the genomewide level (P Conclusions We identified a 3p2131 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system (Funded by Stein Erik Hagen and others)

Journal ArticleDOI
TL;DR: The HAM10000 dataset as mentioned in this paper contains 10015 dermatoscopic images from different populations acquired and stored by different modalities and applied different acquisition and cleaning methods and developed semi-automatic workflows utilizing specifically trained neural networks.
Abstract: Training of neural networks for automated diagnosis of pigmented skin lesions is hampered by the small size and lack of diversity of available datasets of dermatoscopic images. We tackle this problem by releasing the HAM10000 ("Human Against Machine with 10000 training images") dataset. We collected dermatoscopic images from different populations acquired and stored by different modalities. Given this diversity we had to apply different acquisition and cleaning methods and developed semi-automatic workflows utilizing specifically trained neural networks. The final dataset consists of 10015 dermatoscopic images which are released as a training set for academic machine learning purposes and are publicly available through the ISIC archive. This benchmark dataset can be used for machine learning and for comparisons with human experts. Cases include a representative collection of all important diagnostic categories in the realm of pigmented lesions. More than 50% of lesions have been confirmed by pathology, while the ground truth for the rest of the cases was either follow-up, expert consensus, or confirmation by in-vivo confocal microscopy.

Journal ArticleDOI
03 Oct 2016-PLOS ONE
TL;DR: The objective is to understand the current research topics, challenges and future directions regarding Blockchain technology from the technical perspective, and recommendations on future research directions are provided for researchers.
Abstract: Blockchain is a decentralized transaction and data management technology developed first for Bitcoin cryptocurrency. The interest in Blockchain technology has been increasing since the idea was coined in 2008. The reason for the interest in Blockchain is its central attributes that provide security, anonymity and data integrity without any third party organization in control of the transactions, and therefore it creates interesting research areas, especially from the perspective of technical challenges and limitations. In this research, we have conducted a systematic mapping study with the goal of collecting all relevant research on Blockchain technology. Our objective is to understand the current research topics, challenges and future directions regarding Blockchain technology from the technical perspective. We have extracted 41 primary papers from scientific databases. The results show that focus in over 80% of the papers is on Bitcoin system and less than 20% deals with other Blockchain applications including e.g. smart contracts and licensing. The majority of research is focusing on revealing and improving limitations of Blockchain from privacy and security perspectives, but many of the proposed solutions lack concrete evaluation on their effectiveness. Many other Blockchain scalability related challenges including throughput and latency have been left unstudied. On the basis of this study, recommendations on future research directions are provided for researchers.

Journal ArticleDOI
TL;DR: It is found that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation, highlighting stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.
Abstract: Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.

Proceedings ArticleDOI
01 Jun 2019
TL;DR: In this paper, a generalized IoU (GIoU) metric is proposed for non-overlapping bounding boxes, which can be directly used as a regression loss.
Abstract: Intersection over Union (IoU) is the most popular evaluation metric used in the object detection benchmarks. However, there is a gap between optimizing the commonly used distance losses for regressing the parameters of a bounding box and maximizing this metric value. The optimal objective for a metric is the metric itself. In the case of axis-aligned 2D bounding boxes, it can be shown that IoU can be directly used as a regression loss. However, IoU has a plateau making it infeasible to optimize in the case of non-overlapping bounding boxes. In this paper, we address the this weakness by introducing a generalized version of IoU as both a new loss and a new metric. By incorporating this generalized IoU ( GIoU) as a loss into the state-of-the art object detection frameworks, we show a consistent improvement on their performance using both the standard, IoU based, and new, GIoU based, performance measures on popular object detection benchmarks such as PASCAL VOC and MS COCO.

Proceedings ArticleDOI
21 Jul 2017
TL;DR: This paper introduces a novel convolutional neural network dubbed SCA-CNN that incorporates Spatial and Channel-wise Attentions in a CNN that significantly outperforms state-of-the-art visual attention-based image captioning methods.
Abstract: Visual attention has been successfully applied in structural prediction tasks such as visual captioning and question answering. Existing visual attention models are generally spatial, i.e., the attention is modeled as spatial probabilities that re-weight the last conv-layer feature map of a CNN encoding an input image. However, we argue that such spatial attention does not necessarily conform to the attention mechanism — a dynamic feature extractor that combines contextual fixations over time, as CNN features are naturally spatial, channel-wise and multi-layer. In this paper, we introduce a novel convolutional neural network dubbed SCA-CNN that incorporates Spatial and Channel-wise Attentions in a CNN. In the task of image captioning, SCA-CNN dynamically modulates the sentence generation context in multi-layer feature maps, encoding where (i.e., attentive spatial locations at multiple layers) and what (i.e., attentive channels) the visual attention is. We evaluate the proposed SCA-CNN architecture on three benchmark image captioning datasets: Flickr8K, Flickr30K, and MSCOCO. It is consistently observed that SCA-CNN significantly outperforms state-of-the-art visual attention-based image captioning methods.

Journal ArticleDOI
TL;DR: Investigation on patients in a local hospital who were infected with a novel coronavirus found the presence of 2019-nCoV in anal swabs and blood, and more anal swab positives than oral swabs positives in a later stage of infection, suggesting shedding and thereby transmitted through oral–fecal route.
Abstract: In December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral-fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral-fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.

Journal ArticleDOI
TL;DR: This primer will equip both scientists and practitioners to understand the ontology and methodology of scale development and validation, thereby facilitating the advancement of the understanding of a range of health, social, and behavioral outcomes.
Abstract: Scale development and validation are critical to much of the work in the health, social, and behavioral sciences. However, the constellation of techniques required for scale development and evaluation can be onerous, jargon-filled, unfamiliar, and resource-intensive. Further, it is often not a part of graduate training. Therefore, our goal was to concisely review the process of scale development in as straightforward a manner as possible, both to facilitate the development of new, valid, and reliable scales, and to help improve existing ones. To do this, we have created a primer for best practices for scale development in measuring complex phenomena. This is not a systematic review, but rather the amalgamation of technical literature and lessons learned from our experiences spent creating or adapting a number of scales over the past several decades. We identified three phases that span nine steps. In the first phase, items are generated and the validity of their content is assessed. In the second phase, the scale is constructed. Steps in scale construction include pre-testing the questions, administering the survey, reducing the number of items, and understanding how many factors the scale captures. In the third phase, scale evaluation, the number of dimensions is tested, reliability is tested, and validity is assessed. We have also added examples of best practices to each step. In sum, this primer will equip both scientists and practitioners to understand the ontology and methodology of scale development and validation, thereby facilitating the advancement of our understanding of a range of health, social, and behavioral outcomes.

Journal ArticleDOI
TL;DR: The importance of management of inhibition problems is envisaged to increase as issues that become increasingly relevant will include the possibility to use recalcitrant feedstocks, obtaining high product yields and high productivity, minimizing the charges of enzymes and microorganisms, and using high solids loadings to obtain high product titers.

Journal ArticleDOI
TL;DR: Overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer was compared.
Abstract: Summary Background We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. Methods In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0–1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m 2 paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m 2 cetuximab was given on day 1 followed by weekly doses of 250 mg/m 2 , and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. Findings Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22·9 months (IQR 27·5–33·3). Median overall survival was 28·7 months (95% CI 24·1–36·9) for patients who received standard-dose radiotherapy and 20·3 months (17·7–25·0) for those who received high-dose radiotherapy (hazard ratio [HR] 1·38, 95% CI 1·09–1·76; p=0·004). Median follow-up for the cetuximab comparison was 21·3 months (IQR 23·5–29·8). Median overall survival in patients who received cetuximab was 25·0 months (95% CI 20·2–30·5) compared with 24·0 months (19·8–28·6) in those who did not (HR 1·07, 95% CI 0·84–1·35; p=0·29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p Interpretation 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. Funding National Cancer Institute and Bristol-Myers Squibb.

Proceedings ArticleDOI
22 May 2016
TL;DR: In this article, the authors present Hawk, a decentralized smart contract system that does not store financial transactions in the clear on the blockchain, thus retaining transactional privacy from the public's view.
Abstract: Emerging smart contract systems over decentralized cryptocurrencies allow mutually distrustful parties to transact safely without trusted third parties. In the event of contractual breaches or aborts, the decentralized blockchain ensures that honest parties obtain commensurate compensation. Existing systems, however, lack transactional privacy. All transactions, including flow of money between pseudonyms and amount transacted, are exposed on the blockchain. We present Hawk, a decentralized smart contract system that does not store financial transactions in the clear on the blockchain, thus retaining transactional privacy from the public's view. A Hawk programmer can write a private smart contract in an intuitive manner without having to implement cryptography, and our compiler automatically generates an efficient cryptographic protocol where contractual parties interact with the blockchain, using cryptographic primitives such as zero-knowledge proofs. To formally define and reason about the security of our protocols, we are the first to formalize the blockchain model of cryptography. The formal modeling is of independent interest. We advocate the community to adopt such a formal model when designing applications atop decentralized blockchains.

Journal ArticleDOI
TL;DR: Using MODIS data from 2003 to 2012, it is shown that the UHI effect decayed exponentially toward rural areas for majority of the 32 Chinese cities, and an obvious urban/rural temperature “cliff” is found.
Abstract: Urban heat island (UHI) is one major anthropogenic modification to the Earth system that transcends its physical boundary. Using MODIS data from 2003 to 2012, we showed that the UHI effect decayed exponentially toward rural areas for majority of the 32 Chinese cities. We found an obvious urban/rural temperature “cliff”, and estimated that the footprint of UHI effect (FP, including urban area) was 2.3 and 3.9 times of urban size for the day and night, respectively, with large spatiotemporal heterogeneities. We further revealed that ignoring the FP may underestimate the UHI intensity in most cases and even alter the direction of UHI estimates for few cities. Our results provide new insights to the characteristics of UHI effect and emphasize the necessity of considering city- and time-specific FP when assessing the urbanization effects on local climate.

Journal ArticleDOI
TL;DR: This guide offers practical guidance for those who wish to apply the Theoretical Domains Framework to assess implementation problems and support intervention design, and provides a brief rationale for using a theoretical approach to investigate and address implementation problems.
Abstract: Implementing new practices requires changes in the behaviour of relevant actors, and this is facilitated by understanding of the determinants of current and desired behaviours. The Theoretical Domains Framework (TDF) was developed by a collaboration of behavioural scientists and implementation researchers who identified theories relevant to implementation and grouped constructs from these theories into domains. The collaboration aimed to provide a comprehensive, theory-informed approach to identify determinants of behaviour. The first version was published in 2005, and a subsequent version following a validation exercise was published in 2012. This guide offers practical guidance for those who wish to apply the TDF to assess implementation problems and support intervention design. It presents a brief rationale for using a theoretical approach to investigate and address implementation problems, summarises the TDF and its development, and describes how to apply the TDF to achieve implementation objectives. Examples from the implementation research literature are presented to illustrate relevant methods and practical considerations. Researchers from Canada, the UK and Australia attended a 3-day meeting in December 2012 to build an international collaboration among researchers and decision-makers interested in the advancing use of the TDF. The participants were experienced in using the TDF to assess implementation problems, design interventions, and/or understand change processes. This guide is an output of the meeting and also draws on the authors’ collective experience. Examples from the implementation research literature judged by authors to be representative of specific applications of the TDF are included in this guide. We explain and illustrate methods, with a focus on qualitative approaches, for selecting and specifying target behaviours key to implementation, selecting the study design, deciding the sampling strategy, developing study materials, collecting and analysing data, and reporting findings of TDF-based studies. Areas for development include methods for triangulating data, e.g. from interviews, questionnaires and observation and methods for designing interventions based on TDF-based problem analysis. We offer this guide to the implementation community to assist in the application of the TDF to achieve implementation objectives. Benefits of using the TDF include the provision of a theoretical basis for implementation studies, good coverage of potential reasons for slow diffusion of evidence into practice and a method for progressing from theory-based investigation to intervention.

Journal ArticleDOI
05 Aug 2016-Science
TL;DR: LshC2c2 is a RNA-guided RNase which requires the activity of its two HEPN domains, suggesting previously unidentified mechanisms of RNA targeting and degradation by CRISPR systems.
Abstract: The clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated genes (Cas) adaptive immune system defends microbes against foreign genetic elements via DNA or RNA-DNA interference. We characterize the class 2 type VI CRISPR-Cas effector C2c2 and demonstrate its RNA-guided ribonuclease function. C2c2 from the bacterium Leptotrichia shahii provides interference against RNA phage. In vitro biochemical analysis shows that C2c2 is guided by a single CRISPR RNA and can be programmed to cleave single-stranded RNA targets carrying complementary protospacers. In bacteria, C2c2 can be programmed to knock down specific mRNAs. Cleavage is mediated by catalytic residues in the two conserved Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) domains, mutations of which generate catalytically inactive RNA-binding proteins. These results broaden our understanding of CRISPR-Cas systems and suggest that C2c2 can be used to develop new RNA-targeting tools.

Proceedings ArticleDOI
24 Mar 2017
TL;DR: A new method for setting the learning rate, named cyclical learning rates, is described, which practically eliminates the need to experimentally find the best values and schedule for the global learning rates.
Abstract: It is known that the learning rate is the most important hyper-parameter to tune for training deep neural networks. This paper describes a new method for setting the learning rate, named cyclical learning rates, which practically eliminates the need to experimentally find the best values and schedule for the global learning rates. Instead of monotonically decreasing the learning rate, this method lets the learning rate cyclically vary between reasonable boundary values. Training with cyclical learning rates instead of fixed values achieves improved classification accuracy without a need to tune and often in fewer iterations. This paper also describes a simple way to estimate "reasonable bounds" – linearly increasing the learning rate of the network for a few epochs. In addition, cyclical learning rates are demonstrated on the CIFAR-10 and CIFAR-100 datasets with ResNets, Stochastic Depth networks, and DenseNets, and the ImageNet dataset with the AlexNet and GoogLeNet architectures. These are practical tools for everyone who trains neural networks.

Journal ArticleDOI
05 Feb 2020-Nature
TL;DR: The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet- base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.
Abstract: Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3–15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer. The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Journal ArticleDOI
TL;DR: Parton distribution functions (PDFs) are crucial ingredients for the calculation of the relevant cross sections for various scattering processes at the Large Hadron Collider (LHC). as mentioned in this paper found new PDFs, which will be important for the data analysis at the LHC Run-2.
Abstract: Parton distribution functions (PDFs) are crucial ingredients for the calculation of the relevant cross sections for various scattering processes at the Large Hadron Collider (LHC). Including data from several previous experiments, the authors find new PDFs, which will be important for the data analysis at the LHC Run-2.

01 Jan 2016
TL;DR: In this paper, a forward algorithm for a solution to the following dynamic version of the economic lot size model is given: allowing the possibility of demands for a single item,,inventory holding charges, anid setup costs to vary over N periods, we desire a minimum total cost inventory management scheme which satisfies known demand in every period.
Abstract: A forward algorithm for a solution to the following dynamic version of the economic lot size model is given: allowing the possibility of demands for a single item,,inventory holding charges, anid setup costs to vary over N periods, we desire a minimum total cost inventory management scheme which satisfies known demand in every period. Disjoint planning horizons are shown to be possible which eliminate the necessity of having data for the full N periods.