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Showing papers by "University of Iowa published in 2019"


Journal ArticleDOI
TL;DR: fMRIPrep is a robust and easy-to-use pipeline for preprocessing of diverse fMRI data that dispenses of manual intervention, thereby ensuring the reproducibility of the results.
Abstract: Preprocessing of functional magnetic resonance imaging (fMRI) involves numerous steps to clean and standardize the data before statistical analysis. Generally, researchers create ad hoc preprocessing workflows for each dataset, building upon a large inventory of available tools. The complexity of these workflows has snowballed with rapid advances in acquisition and processing. We introduce fMRIPrep, an analysis-agnostic tool that addresses the challenge of robust and reproducible preprocessing for fMRI data. fMRIPrep automatically adapts a best-in-breed workflow to the idiosyncrasies of virtually any dataset, ensuring high-quality preprocessing without manual intervention. By introducing visual assessment checkpoints into an iterative integration framework for software testing, we show that fMRIPrep robustly produces high-quality results on a diverse fMRI data collection. Additionally, fMRIPrep introduces less uncontrolled spatial smoothness than observed with commonly used preprocessing tools. fMRIPrep equips neuroscientists with an easy-to-use and transparent preprocessing workflow, which can help ensure the validity of inference and the interpretability of results.

1,465 citations


Journal ArticleDOI
TL;DR: Long-term activity and safety outcomes of the ZUMA-1 study suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable relapsed or refractory disease or relapsed after autologous stem-cell transplantation.
Abstract: Summary Background Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov , number NCT02348216 . Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

1,285 citations


Journal ArticleDOI
TL;DR: In this article, a convolution neural network (CNN)-based regularization prior is proposed for inverse problems with the arbitrary structure, where the forward model is explicitly accounted for and a smaller network with fewer parameters is sufficient to capture the image information compared to direct inversion.
Abstract: We introduce a model-based image reconstruction framework with a convolution neural network (CNN)-based regularization prior. The proposed formulation provides a systematic approach for deriving deep architectures for inverse problems with the arbitrary structure. Since the forward model is explicitly accounted for, a smaller network with fewer parameters is sufficient to capture the image information compared to direct inversion approaches. Thus, reducing the demand for training data and training time. Since we rely on end-to-end training with weight sharing across iterations, the CNN weights are customized to the forward model, thus offering improved performance over approaches that rely on pre-trained denoisers. Our experiments show that the decoupling of the number of iterations from the network complexity offered by this approach provides benefits, including lower demand for training data, reduced risk of overfitting, and implementations with significantly reduced memory footprint. We propose to enforce data-consistency by using numerical optimization blocks, such as conjugate gradients algorithm within the network. This approach offers faster convergence per iteration, compared to methods that rely on proximal gradients steps to enforce data consistency. Our experiments show that the faster convergence translates to improved performance, primarily when the available GPU memory restricts the number of iterations.

815 citations


Journal ArticleDOI
TL;DR: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations.
Abstract: Background Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions...

782 citations


Journal ArticleDOI
TL;DR: It is determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response and providing a potential target for treatment of SARS-CoV or other virus-mediated lung injury.
Abstract: Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV-induced MCP1 and IL-8 production by human monocyte-derived wound-healing macrophages, whereas blockade of FcγR reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury.

751 citations


Journal ArticleDOI
29 Apr 2019-eLife
TL;DR: The goal is to facilitate a more accurate use of the stop-signal task and provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
Abstract: Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.

617 citations


Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1491 moreInstitutions (239)
TL;DR: In this article, the authors present the second volume of the Future Circular Collider Conceptual Design Report, devoted to the electron-positron collider FCC-ee, and present the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan.
Abstract: In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics.

526 citations


Posted Content
TL;DR: In this paper, a self-supervised pre-training strategy is proposed to pre-train an expressive GNN at the level of individual nodes as well as entire graphs so that the GNN can learn useful local and global representations simultaneously.
Abstract: Many applications of machine learning require a model to make accurate pre-dictions on test examples that are distributionally different from training ones, while task-specific labels are scarce during training. An effective approach to this challenge is to pre-train a model on related tasks where data is abundant, and then fine-tune it on a downstream task of interest. While pre-training has been effective in many language and vision domains, it remains an open question how to effectively use pre-training on graph datasets. In this paper, we develop a new strategy and self-supervised methods for pre-training Graph Neural Networks (GNNs). The key to the success of our strategy is to pre-train an expressive GNN at the level of individual nodes as well as entire graphs so that the GNN can learn useful local and global representations simultaneously. We systematically study pre-training on multiple graph classification datasets. We find that naive strategies, which pre-train GNNs at the level of either entire graphs or individual nodes, give limited improvement and can even lead to negative transfer on many downstream tasks. In contrast, our strategy avoids negative transfer and improves generalization significantly across downstream tasks, leading up to 9.4% absolute improvements in ROC-AUC over non-pre-trained models and achieving state-of-the-art performance for molecular property prediction and protein function prediction.

477 citations


Journal ArticleDOI
Albert M. Sirunyan, Armen Tumasyan, Wolfgang Adam1, Federico Ambrogi1  +2265 moreInstitutions (153)
TL;DR: Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented and constraints are placed on various two Higgs doublet models.
Abstract: Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented. The analysis uses the LHC proton–proton collision data set recorded with the CMS detector in 2016 at $\sqrt{s}=13\,\text {Te}\text {V} $ , corresponding to an integrated luminosity of 35.9 ${\,\text {fb}^{-1}} $ . The combination is based on analyses targeting the five main Higgs boson production mechanisms (gluon fusion, vector boson fusion, and associated production with a $\mathrm {W}$ or $\mathrm {Z}$ boson, or a top quark-antiquark pair) and the following decay modes: $\mathrm {H} \rightarrow \gamma \gamma $ , $\mathrm {Z}\mathrm {Z}$ , $\mathrm {W}\mathrm {W}$ , $\mathrm {\tau }\mathrm {\tau }$ , $\mathrm {b} \mathrm {b} $ , and $\mathrm {\mu }\mathrm {\mu }$ . Searches for invisible Higgs boson decays are also considered. The best-fit ratio of the signal yield to the standard model expectation is measured to be $\mu =1.17\pm 0.10$ , assuming a Higgs boson mass of $125.09\,\text {Ge}\text {V} $ . Additional results are given for various assumptions on the scaling behavior of the production and decay modes, including generic parametrizations based on ratios of cross sections and branching fractions or couplings. The results are compatible with the standard model predictions in all parametrizations considered. In addition, constraints are placed on various two Higgs doublet models.

451 citations


Journal ArticleDOI
TL;DR: It is suggested that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice, and IFn-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.
Abstract: Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

448 citations


Journal ArticleDOI
TL;DR: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants and among the participants who were Hla-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody- negative, fewer participants in the teplizuab group than in the placebo group had diabetes diagnosed.
Abstract: Background Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions ha...

Journal ArticleDOI
TL;DR: Control of Confounding and Reporting of Results in Causal Inference Studies Guidance for Authors from Editors of Respiratory, Sleep, and Critical Care Journals is published.
Abstract: Control of Confounding and Reporting of Results in Causal Inference Studies Guidance for Authors fromEditors of Respiratory, Sleep, andCritical Care Journals David J. Lederer*, Scott C. Bell*, Richard D. Branson*, James D. Chalmers*, Rachel Marshall*, David M. Maslove*, David E. Ost*, Naresh M. Punjabi*, Michael Schatz*, Alan R. Smyth*, Paul W. Stewart*, Samy Suissa*, Alex A. Adjei, Cezmi A. Akdis, Élie Azoulay, Jan Bakker, Zuhair K. Ballas, Philip G. Bardin, Esther Barreiro, Rinaldo Bellomo, Jonathan A. Bernstein, Vito Brusasco, Timothy G. Buchman, Sudhansu Chokroverty, Nancy A. Collop, James D. Crapo, Dominic A. Fitzgerald, Lauren Hale, Nicholas Hart, Felix J. Herth, Theodore J. Iwashyna, Gisli Jenkins, Martin Kolb, Guy B. Marks, Peter Mazzone, J. Randall Moorman, ThomasM.Murphy, Terry L. Noah, Paul Reynolds, Dieter Riemann, Richard E. Russell, Aziz Sheikh, Giovanni Sotgiu, Erik R. Swenson, Rhonda Szczesniak, Ronald Szymusiak, Jean-Louis Teboul, and Jean-Louis Vincent Department of Medicine and Department of Epidemiology, Columbia University Irving Medical Center, New York, New York; Editor-inChief, Annals of the American Thoracic Society; Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland, Australia; Editor-in-Chief, Journal of Cystic Fibrosis; Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Editor-in-Chief, Respiratory Care; University of Dundee, Dundee, Scotland; Deputy Chief Editor, European Respiratory Journal; London, England; Deputy Editor, The Lancet Respiratory Medicine; Department of Medicine, Queen’s University, Kingston, Ontario, Canada; Associate Editor for Data Science, Critical Care Medicine; Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas; Editor-in-Chief, Journal of Bronchology and Interventional Pulmonology; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; Deputy Editor-in-Chief, SLEEP; Department of Allergy, Kaiser Permanente Medical Center, San Diego, California; Editor-in-Chief, The Journal of Allergy & Clinical Immunology: In Practice; Division of Child Health, Obstetrics, and Gynecology, University of Nottingham, Nottingham, England; Joint Editor-in-Chief, Thorax; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina; Associate Editor, Pediatric Pulmonology; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Advisor, COPD: Journal of Chronic Obstructive Pulmonary Disease; Department of Oncology, Mayo Clinic, Rochester, Minnesota; Editor-in-Chief, Journal of Thoracic Oncology; Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland; Editor-in-Chief, Allergy; St. Louis Hospital, University of Paris, Paris, France; Editor-in-Chief, Intensive Care Medicine; Department of Medicine, Columbia University Irving Medical Center, and Division of Pulmonary, Critical Care, and Sleep, NYU Langone Health, New York, New York; Department of Intensive Care Adults, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Intensive Care, Pontificia Universidad Católica de Chile, Santiago, Chile; Editor-in-Chief, Journal of Critical Care; Department of Internal Medicine, University of Iowa and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa; Editor-in-Chief, The Journal of Allergy and Clinical Immunology; Monash Lung and Sleep, Monash Hospital and University, Melbourne, Victoria, Australia; Co-Editor-in-Chief, Respirology; Pulmonology Department, Muscle and Lung Cancer Research Group, Research Institute of Hospital del Mar and Centro de Investigación Biomédica en Red Enfermedades Respiratorias Instituto de Salud Carlos III, Barcelona, Spain; Editor-in-Chief, Archivos de Bronconeumologia; Department of Intensive Care Medicine, Austin Hospital and University of Melbourne, Melbourne, Victoria, Australia; Editor-in-Chief, Critical Care & Resuscitation; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Editor-in-Chief, Journal of Asthma; Department of Internal Medicine, University of Genoa, Genoa, Italy; Editor-in-Chief, COPD: Journal of Chronic Obstructive Pulmonary Disease; Department of Surgery, Department of Anesthesiology, and Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia; Editor-in-Chief,Critical CareMedicine; JFKNewJersey Neuroscience Institute, HackensackMeridian Health–JFKMedical Center, Edison, New Jersey; Editor-in-Chief, Sleep Medicine; Department of Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia; Editor-in-Chief, Journal of Clinical Sleep Medicine; Department of Medicine, National Jewish Hospital, Denver, Colorado; Editor-in-Chief, Journal of the COPD Foundation; The Children’s Hospital at Westmead, Sydney Medical School, University of

Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1496 moreInstitutions (238)
TL;DR: In this paper, the authors describe the detailed design and preparation of a construction project for a post-LHC circular energy frontier collider in collaboration with national institutes, laboratories and universities worldwide, and enhanced by a strong participation of industrial partners.
Abstract: Particle physics has arrived at an important moment of its history. The discovery of the Higgs boson, with a mass of 125 GeV, completes the matrix of particles and interactions that has constituted the “Standard Model” for several decades. This model is a consistent and predictive theory, which has so far proven successful at describing all phenomena accessible to collider experiments. However, several experimental facts do require the extension of the Standard Model and explanations are needed for observations such as the abundance of matter over antimatter, the striking evidence for dark matter and the non-zero neutrino masses. Theoretical issues such as the hierarchy problem, and, more in general, the dynamical origin of the Higgs mechanism, do likewise point to the existence of physics beyond the Standard Model. This report contains the description of a novel research infrastructure based on a highest-energy hadron collider with a centre-of-mass collision energy of 100 TeV and an integrated luminosity of at least a factor of 5 larger than the HL-LHC. It will extend the current energy frontier by almost an order of magnitude. The mass reach for direct discovery will reach several tens of TeV, and allow, for example, to produce new particles whose existence could be indirectly exposed by precision measurements during the earlier preceding e+e– collider phase. This collider will also precisely measure the Higgs self-coupling and thoroughly explore the dynamics of electroweak symmetry breaking at the TeV scale, to elucidate the nature of the electroweak phase transition. WIMPs as thermal dark matter candidates will be discovered, or ruled out. As a single project, this particle collider infrastructure will serve the world-wide physics community for about 25 years and, in combination with a lepton collider (see FCC conceptual design report volume 2), will provide a research tool until the end of the 21st century. Collision energies beyond 100 TeV can be considered when using high-temperature superconductors. The European Strategy for Particle Physics (ESPP) update 2013 stated “To stay at the forefront of particle physics, Europe needs to be in a position to propose an ambitious post-LHC accelerator project at CERN by the time of the next Strategy update”. The FCC study has implemented the ESPP recommendation by developing a long-term vision for an “accelerator project in a global context”. This document describes the detailed design and preparation of a construction project for a post-LHC circular energy frontier collider “in collaboration with national institutes, laboratories and universities worldwide”, and enhanced by a strong participation of industrial partners. Now, a coordinated preparation effort can be based on a core of an ever-growing consortium of already more than 135 institutes worldwide. The technology for constructing a high-energy circular hadron collider can be brought to the technology readiness level required for constructing within the coming ten years through a focused R&D programme. The FCC-hh concept comprises in the baseline scenario a power-saving, low-temperature superconducting magnet system based on an evolution of the Nb3Sn technology pioneered at the HL-LHC, an energy-efficient cryogenic refrigeration infrastructure based on a neon-helium (Nelium) light gas mixture, a high-reliability and low loss cryogen distribution infrastructure based on Invar, high-power distributed beam transfer using superconducting elements and local magnet energy recovery and re-use technologies that are already gradually introduced at other CERN accelerators. On a longer timescale, high-temperature superconductors can be developed together with industrial partners to achieve an even more energy efficient particle collider or to reach even higher collision energies.The re-use of the LHC and its injector chain, which also serve for a concurrently running physics programme, is an essential lever to come to an overall sustainable research infrastructure at the energy frontier. Strategic R&D for FCC-hh aims at minimising construction cost and energy consumption, while maximising the socio-economic impact. It will mitigate technology-related risks and ensure that industry can benefit from an acceptable utility. Concerning the implementation, a preparatory phase of about eight years is both necessary and adequate to establish the project governance and organisation structures, to build the international machine and experiment consortia, to develop a territorial implantation plan in agreement with the host-states’ requirements, to optimise the disposal of land and underground volumes, and to prepare the civil engineering project. Such a large-scale, international fundamental research infrastructure, tightly involving industrial partners and providing training at all education levels, will be a strong motor of economic and societal development in all participating nations. The FCC study has implemented a set of actions towards a coherent vision for the world-wide high-energy and particle physics community, providing a collaborative framework for topically complementary and geographically well-balanced contributions. This conceptual design report lays the foundation for a subsequent infrastructure preparatory and technical design phase.

Journal ArticleDOI
A. Abada1, Marcello Abbrescia2, Marcello Abbrescia3, Shehu S. AbdusSalam4  +1501 moreInstitutions (239)
TL;DR: In this article, the physics opportunities of the Future Circular Collider (FC) were reviewed, covering its e+e-, pp, ep and heavy ion programs, and the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions.
Abstract: We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics.

Journal ArticleDOI
12 Dec 2019-Nature
TL;DR: Measurements from the Parker Solar Probe show that slow solar wind near the Sun’s equator originates in coronal holes, and plasma-wave measurements suggest the existence of electron and ion velocity-space micro-instabilities that are associated with plasma heating and thermalization processes.
Abstract: During the solar minimum, when the Sun is at its least active, the solar wind1,2 is observed at high latitudes as a predominantly fast (more than 500 kilometres per second), highly Alfvenic rarefied stream of plasma originating from deep within coronal holes. Closer to the ecliptic plane, the solar wind is interspersed with a more variable slow wind3 of less than 500 kilometres per second. The precise origins of the slow wind streams are less certain4; theories and observations suggest that they may originate at the tips of helmet streamers5,6, from interchange reconnection near coronal hole boundaries7,8, or within coronal holes with highly diverging magnetic fields9,10. The heating mechanism required to drive the solar wind is also unresolved, although candidate mechanisms include Alfven-wave turbulence11,12, heating by reconnection in nanoflares13, ion cyclotron wave heating14 and acceleration by thermal gradients1. At a distance of one astronomical unit, the wind is mixed and evolved, and therefore much of the diagnostic structure of these sources and processes has been lost. Here we present observations from the Parker Solar Probe15 at 36 to 54 solar radii that show evidence of slow Alfvenic solar wind emerging from a small equatorial coronal hole. The measured magnetic field exhibits patches of large, intermittent reversals that are associated with jets of plasma and enhanced Poynting flux and that are interspersed in a smoother and less turbulent flow with a near-radial magnetic field. Furthermore, plasma-wave measurements suggest the existence of electron and ion velocity-space micro-instabilities10,16 that are associated with plasma heating and thermalization processes. Our measurements suggest that there is an impulsive mechanism associated with solar-wind energization and that micro-instabilities play a part in heating, and we provide evidence that low-latitude coronal holes are a key source of the slow solar wind. Measurements from the Parker Solar Probe show that slow solar wind near the Sun’s equator originates in coronal holes.

Journal ArticleDOI
TL;DR: EC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.
Abstract: Background The emergence of antifungal resistance threatens effective treatment of invasive fungal infection (IFI). Invasive candidiasis is the most common health care-associated IFI. We evaluated the activity of fluconazole (FLU) against 20 788 invasive isolates of Candida (37 species) collected from 135 medical centers in 39 countries (1997-2016). The activity of anidulafungin, caspofungin, and micafungin (MCF) was evaluated against 15 308 isolates worldwide (2006-2016). Methods Species identification was accomplished using phenotypic (1997-2001), genotypic, and proteomic methods (2006-2016). All isolates were tested using reference methods and clinical breakpoints published in the Clinical and Laboratory Standards Institute documents. Results A decrease in the isolation of Candida albicans and an increase in the isolation of Candida glabrata and Candida parapsilosis were observed over time. Candida glabrata was the most common non-C. albicans species detected in all geographic regions except for Latin America, where C. parapsilosis and Candida tropicalis were more common. Six Candida auris isolates were detected: 1 each in 2009, 2013, 2014, and 2015 and 2 in 2016; all were from nosocomial bloodstream infections and were FLU-resistant (R). The highest rates of FLU-R isolates were seen in C. glabrata from North America (NA; 10.6%) and in C. tropicalis from the Asia-Pacific region (9.2%). A steady increase in isolation of C. glabrata and resistance to FLU was detected over 20 years in the United States. Echinocandin-R (EC-R) ranged from 3.5% for C. glabrata to 0.1% for C. albicans and C. parapsilosis. Resistance to MCF was highest among C. glabrata (2.8%) and C. tropicalis (1.3%) from NA. Mutations on FKS hot spot (HS) regions were detected among 70 EC-R isolates (51/70 were C. glabrata). Most isolates harboring FKS HS mutations were resistant to 2 or more ECs. Conclusions EC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.

Journal ArticleDOI
Vassilis Angelopoulos1, P. Cruce1, Alexander Drozdov1, Eric Grimes1, N. Hatzigeorgiu2, D. A. King2, Davin Larson2, James W. Lewis2, J. M. McTiernan2, D. A. Roberts3, C. L. Russell1, Tomoaki Hori4, Yoshiya Kasahara5, Atsushi Kumamoto6, Ayako Matsuoka, Yukinaga Miyashita7, Yoshizumi Miyoshi4, I. Shinohara, Mariko Teramoto4, Jeremy Faden, Alexa Halford8, Matthew D. McCarthy9, Robyn Millan10, John Sample11, David M. Smith12, L. A. Woodger10, Arnaud Masson, A. A. Narock3, Kazushi Asamura, T. F. Chang4, C. Y. Chiang13, Yoichi Kazama14, Kunihiro Keika15, S. Matsuda4, Tomonori Segawa4, Kanako Seki15, Masafumi Shoji4, Sunny W. Y. Tam13, Norio Umemura4, B. J. Wang16, B. J. Wang14, Shiang-Yu Wang14, Robert J. Redmon17, Juan V. Rodriguez17, Juan V. Rodriguez18, Howard J. Singer17, Jon Vandegriff19, S. Abe20, Masahito Nose4, Masahito Nose21, Atsuki Shinbori4, Yoshimasa Tanaka22, S. UeNo21, L. Andersson23, P. Dunn2, Christopher M. Fowler23, Jasper Halekas24, Takuya Hara2, Yuki Harada21, Christina O. Lee2, Robert Lillis2, David L. Mitchell2, Matthew R. Argall25, Kenneth R. Bromund3, James L. Burch26, Ian J. Cohen19, Michael Galloy27, Barbara L. Giles3, Allison Jaynes24, O. Le Contel28, Mitsuo Oka2, T. D. Phan2, Brian Walsh29, Joseph Westlake19, Frederick Wilder23, Stuart D. Bale2, Roberto Livi2, Marc Pulupa2, Phyllis Whittlesey2, A. DeWolfe23, Bryan Harter23, E. Lucas23, U. Auster30, John W. Bonnell2, Christopher Cully31, Eric Donovan31, Robert E. Ergun23, Harald U. Frey2, Brian Jackel31, A. Keiling2, Haje Korth19, J. P. McFadden2, Yukitoshi Nishimura29, Ferdinand Plaschke32, P. Robert28, Drew Turner8, James M. Weygand1, Robert M. Candey3, R. C. Johnson3, T. Kovalick3, M. H. Liu3, R. E. McGuire3, Aaron Breneman33, Kris Kersten33, P. Schroeder2 
TL;DR: The SPEDAS development history, goals, and current implementation are reviewed, and its “modes of use” are explained with examples geared for users and its technical implementation and requirements with software developers in mind are outlined.
Abstract: With the advent of the Heliophysics/Geospace System Observatory (H/GSO), a complement of multi-spacecraft missions and ground-based observatories to study the space environment, data retrieval, analysis, and visualization of space physics data can be daunting. The Space Physics Environment Data Analysis System (SPEDAS), a grass-roots software development platform ( www.spedas.org ), is now officially supported by NASA Heliophysics as part of its data environment infrastructure. It serves more than a dozen space missions and ground observatories and can integrate the full complement of past and upcoming space physics missions with minimal resources, following clear, simple, and well-proven guidelines. Free, modular and configurable to the needs of individual missions, it works in both command-line (ideal for experienced users) and Graphical User Interface (GUI) mode (reducing the learning curve for first-time users). Both options have “crib-sheets,” user-command sequences in ASCII format that can facilitate record-and-repeat actions, especially for complex operations and plotting. Crib-sheets enhance scientific interactions, as users can move rapidly and accurately from exchanges of technical information on data processing to efficient discussions regarding data interpretation and science. SPEDAS can readily query and ingest all International Solar Terrestrial Physics (ISTP)-compatible products from the Space Physics Data Facility (SPDF), enabling access to a vast collection of historic and current mission data. The planned incorporation of Heliophysics Application Programmer’s Interface (HAPI) standards will facilitate data ingestion from distributed datasets that adhere to these standards. Although SPEDAS is currently Interactive Data Language (IDL)-based (and interfaces to Java-based tools such as Autoplot), efforts are under-way to expand it further to work with python (first as an interface tool and potentially even receiving an under-the-hood replacement). We review the SPEDAS development history, goals, and current implementation. We explain its “modes of use” with examples geared for users and outline its technical implementation and requirements with software developers in mind. We also describe SPEDAS personnel and software management, interfaces with other organizations, resources and support structure available to the community, and future development plans.

Journal ArticleDOI
Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam, Federico Ambrogi  +2298 moreInstitutions (160)
TL;DR: In this article, a search for invisible decays of a Higgs boson via vector boson fusion is performed using proton-proton collision data collected with the CMS detector at the LHC in 2016 at a center-of-mass energy root s = 13 TeV, corresponding to an integrated luminosity of 35.9fb(-1).

Journal ArticleDOI
12 Dec 2019-Nature
TL;DR: Observations of solar-wind plasma at heliocentric distances of about 35 solar radii reveal an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second—considerably above the amplitude of the waves.
Abstract: The prediction of a supersonic solar wind1 was first confirmed by spacecraft near Earth2,3 and later by spacecraft at heliocentric distances as small as 62 solar radii4. These missions showed that plasma accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvenic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy5–7. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams8. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii9–11, well within the distance at which stream interactions become important. We find that Alfven waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second—considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age12–14. Data collected by the Parker Solar Probe in the solar corona are used to determine the organization of Alfven waves, revealing an increasing flow velocity peaking at 35–50 km s−1.

Journal ArticleDOI
TL;DR: An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.
Abstract: Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Journal ArticleDOI
D. S. Aguado, Romina Ahumada1, Andres Almeida2, Scott F. Anderson3  +244 moreInstitutions (78)
TL;DR: The Sloan Digital Sky Survey (SDSS) as discussed by the authors released data taken by the fourth phase of SDSS-IV across its first three years of operation (2014 July-2017 July).
Abstract: Twenty years have passed since first light for the Sloan Digital Sky Survey (SDSS). Here, we release data taken by the fourth phase of SDSS (SDSS-IV) across its first three years of operation (2014 July–2017 July). This is the third data release for SDSS-IV, and the 15th from SDSS (Data Release Fifteen; DR15). New data come from MaNGA—we release 4824 data cubes, as well as the first stellar spectra in the MaNGA Stellar Library (MaStar), the first set of survey-supported analysis products (e.g., stellar and gas kinematics, emission-line and other maps) from the MaNGA Data Analysis Pipeline, and a new data visualization and access tool we call "Marvin." The next data release, DR16, will include new data from both APOGEE-2 and eBOSS; those surveys release no new data here, but we document updates and corrections to their data processing pipelines. The release is cumulative; it also includes the most recent reductions and calibrations of all data taken by SDSS since first light. In this paper, we describe the location and format of the data and tools and cite technical references describing how it was obtained and processed. The SDSS website (www.sdss.org) has also been updated, providing links to data downloads, tutorials, and examples of data use. Although SDSS-IV will continue to collect astronomical data until 2020, and will be followed by SDSS-V (2020–2025), we end this paper by describing plans to ensure the sustainability of the SDSS data archive for many years beyond the collection of data.

Journal ArticleDOI
TL;DR: This article conducted meta-analyses of online panel samples and compared internal reliability estimates for scales and effect size estimates for IV-DV relations commonly found in the field with those based on conventionally sourced data.
Abstract: Samples drawn from commercial online panel data (OPD) are becoming more prevalent in applied psychology research, but they remain controversial due to concerns with data quality. In order to examine the validity of OPD, we conduct meta-analyses of online panel samples and compare internal reliability estimates for scales and effect size estimates for IV–DV relations commonly found in the field with those based on conventionally sourced data. Results based on 90 independent samples and 32,121 participants show OPD has similar psychometric properties and produces criterion validities that generally fall within the credibility intervals of existing meta-analytic results from conventionally sourced data. We suggest that, with appropriate caution, OPD are suitable for many exploratory research questions in the field of applied psychology.

Journal ArticleDOI
Iñigo Olalde1, Swapan Mallick2, Swapan Mallick1, Swapan Mallick3, Nick Patterson3, Nadin Rohland1, Vanessa Villalba-Mouco4, Vanessa Villalba-Mouco5, Marina Silva6, Katharina Dulias6, Ceiridwen J. Edwards6, Francesca Gandini6, Maria Pala6, Pedro Soares7, Manuel Ferrando-Bernal8, Nicole Adamski1, Nicole Adamski2, Nasreen Broomandkhoshbacht1, Nasreen Broomandkhoshbacht2, Olivia Cheronet9, Brendan J. Culleton10, Daniel Fernandes9, Daniel Fernandes11, Ann Marie Lawson2, Ann Marie Lawson1, Matthew Mah2, Matthew Mah3, Matthew Mah1, Jonas Oppenheimer1, Jonas Oppenheimer2, Kristin Stewardson1, Kristin Stewardson2, Zhao Zhang1, Juan Manuel Jiménez Arenas12, Juan Manuel Jiménez Arenas13, Isidro Jorge Toro Moyano, Domingo C. Salazar-García14, Pere Castanyer, Marta Santos, Joaquim Tremoleda, Marina Lozano15, Pablo García Borja16, Javier Fernández-Eraso14, José Antonio Mujika-Alustiza14, Cecilio Barroso, Francisco J. Bermúdez, Enrique Viguera Mínguez17, Josep Burch, Neus Coromina, David Vivó, Artur Cebrià18, Josep Maria Fullola18, Oreto García-Puchol19, Juan Ignacio Morales18, F. Xavier Oms18, Tona Majó20, Josep Maria Vergès15, Antonia Díaz-Carvajal18, Imma Ollich-Castanyer18, F. Javier López-Cachero18, Ana Maria Silva21, Ana Maria Silva11, Carmen Alonso-Fernández, Germán Delibes de Castro22, Javier Jiménez Echevarría, Adolfo Moreno-Márquez23, Adolfo Moreno-Márquez24, Guillermo Pascual Berlanga12, Pablo Ramos-García12, José Ramos-Muñoz23, Eduardo Vijande Vila23, Gustau Aguilella Arzo, Ángel Esparza Arroyo25, Katina T. Lillios26, Jennifer E. Mack26, Javier Velasco-Vázquez27, Anna J. Waterman28, Luis Benítez de Lugo Enrich16, Luis Benítez de Lugo Enrich29, María Benito Sánchez30, Bibiana Agustí, Ferran Codina, Gabriel de Prado, Almudena Estalrrich31, Álvaro Fernández Flores, Clive Finlayson, Geraldine Finlayson32, Geraldine Finlayson33, Stewart Finlayson34, Stewart Finlayson32, Francisco Giles-Guzmán32, Antonio Rosas35, Virginia Barciela González22, Gabriel García Atiénzar22, Mauro S. Hernández Pérez22, Armando Llanos, Yolanda Carrión Marco19, Isabel Collado Beneyto, David López-Serrano, Mario Sanz Tormo36, António Carlos Valera, Concepción Blasco29, Corina Liesau29, Patricia Ríos29, Joan Daura18, María Jesús de Pedro Michó, Agustín Diez Castillo19, Raúl Flores Fernández37, Raúl Flores Fernández38, Joan Francès Farré, Rafael Garrido-Pena29, Victor S. Gonçalves21, Elisa Guerra-Doce22, Ana Mercedes Herrero-Corral30, Joaquim Juan-Cabanilles, Daniel López-Reyes, Sarah B. McClure36, Marta Pérez18, Arturo Oliver Foix, Montserrat Sanz Borràs18, Ana Catarina Sousa21, Julio Manuel Vidal Encinas, Douglas J. Kennett36, Douglas J. Kennett10, Martin B. Richards6, Kurt W. Alt38, Kurt W. Alt37, Wolfgang Haak39, Wolfgang Haak5, Ron Pinhasi9, Carles Lalueza-Fox8, David Reich2, David Reich1, David Reich3 
15 Mar 2019-Science
TL;DR: It is revealed that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia, and how the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean is document.
Abstract: J.M.F., F.J.L.-C., J.I.M., F.X.O., J.D., and M.S.B. were supported by HAR2017-86509-P, HAR2017-87695-P, and SGR2017-11 from the Generalitat de Catalunya, AGAUR agency. C.L.-F. was supported by Obra Social La Caixa and by FEDER-MINECO (BFU2015- 64699-P). L.B.d.L.E. was supported by REDISCO-HAR2017-88035-P (Plan Nacional I+D+I, MINECO). C.L., P.R., and C.Bl. were supported by MINECO (HAR2016-77600-P). A.Esp., J.V.-V., G.D., and D.C.S.-G. were supported by MINECO (HAR2009-10105 and HAR2013-43851-P). D.J.K. and B.J.C. were supported by NSF BCS-1460367. K.T.L., A.W., and J.M. were supported by NSF BCS-1153568. J.F.-E. and J.A.M.-A. were supported by IT622-13 Gobierno Vasco, Diputacion Foral de Alava, and Diputacion Foral de Gipuzkoa. We acknowledge support from the Portuguese Foundation for Science and Technology (PTDC/EPH-ARQ/4164/2014) and the FEDER-COMPETE 2020 project 016899. P.S. was supported by the FCT Investigator Program (IF/01641/2013), FCT IP, and ERDF (COMPETE2020 – POCI). M.Si. and K.D. were supported by a Leverhulme Trust Doctoral Scholarship awarded to M.B.R. and M.P. D.R. was supported by an Allen Discovery Center grant from the Paul Allen Foundation, NIH grant GM100233, and the Howard Hughes Medical Institute. V.V.-M. and W.H. were supported by the Max Planck Society.

Journal ArticleDOI
TL;DR: New described benefits of physical activity include reduced risk of excessive weight gain in children and adults, incidence of 6 types of cancer, and fall-related injuries in older people.
Abstract: Background: The 2018 Physical Activity Guidelines Advisory Committee Scientific Report provides the evidence base for the Physical Activity Guidelines for Americans, 2nd Edition. Methods: The 2018 ...

Journal ArticleDOI
12 Feb 2019-JAMA
TL;DR: It is concluded with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression.
Abstract: Importance Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. Objective To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. Evidence Review The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. Findings The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. Conclusions and Recommendation The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation)

Journal ArticleDOI
TL;DR: Global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable are described and the potential challenges for clinical adoption are discussed.

Journal ArticleDOI
TL;DR: S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period, and MDR-GNB represent the greatest therapeutic challenge among common bacterial BSI pathogens.
Abstract: Bloodstream infection (BSI) organisms were consecutively collected from >200 medical centers in 45 nations between 1997 and 2016. Species identification and susceptibility testing followed Clinical and Laboratory Standards Institute broth microdilution methods at a central laboratory. Clinical data and isolates from 264,901 BSI episodes were collected. The most common pathogen overall was Staphylococcus aureus (20.7%), followed by Escherichia coli (20.5%), Klebsiella pneumoniae (7.7%), Pseudomonas aeruginosa (5.3%), and Enterococcus faecalis (5.2%). S. aureus was the most frequently isolated pathogen overall in the 1997-to-2004 period, but E. coli was the most common after 2005. Pathogen frequency varied by geographic region, hospital-onset or community-onset status, and patient age. The prevalence of S. aureus isolates resistant to oxacillin (ORSA) increased until 2005 to 2008 and then declined among hospital-onset and community-acquired BSI in all regions. The prevalence of vancomycin-resistant enterococci (VRE) was stable after 2012 (16.4% overall). Daptomycin resistance among S. aureus and enterococci (DRE) remained rare (<0.1%). In contrast, the prevalence of multidrug-resistant (MDR) Enterobacteriaceae increased from 6.2% in 1997 to 2000 to 15.8% in 2013 to 2016. MDR rates were highest among nonfermentative Gram-negative bacilli (GNB), and colistin was the only agent with predictable activity against Acinetobacter baumannii-Acinetobacter calcoaceticus complex (97% susceptible). In conclusion, S. aureus and E. coli were the predominant causes of BSI worldwide during this 20-year surveillance period. Important resistant phenotypes among Gram-positive pathogens (MRSA, VRE, or DRE) were stable or declining, whereas the prevalence of MDR-GNB increased continuously during the monitored period. MDR-GNB represent the greatest therapeutic challenge among common bacterial BSI pathogens.

Journal ArticleDOI
TL;DR: Intravascular infusion is the most popular route for therapeutic multipotent mesenchymal stromal/stem cell (MSC) delivery in hundreds of clinical trials and suitable strategies for assessing and controlling hemocompatibility and optimized cell delivery are crucial for the development of safer and more effective MSC therapies.

Journal ArticleDOI
TL;DR: To avoid the risks associated with premature mortality and the development of isChemic heart disease, ischemic stroke, and all-cause heart failure, all adults should strive to reach the 2008 Physical Activity Guidelines for Americans.
Abstract: PurposeConduct a systematic umbrella review to evaluate the relationship of physical activity (PA) with all-cause mortality, cardiovascular mortality, and incident cardiovascular disease (CVD); to evaluate the shape of the dose–response relationships; and to evaluate these relationships rela

Journal ArticleDOI
TL;DR: In this article, the authors provide an overview of the four liquid biofuel generations as well as the latest development efforts in this field and conclude that the current production methods of biofuel in the first and second generations will soon fail to satisfy the increasing demand on biofuel.