Showing papers by "University of Kansas published in 2017"
St George's Hospital1, New York University2, McMaster University3, Brown University4, Catholic University of the Sacred Heart5, Hebron University6, University of Manitoba7, Emory University Hospital8, Hebrew University of Jerusalem9, Sunnybrook Health Sciences Centre10, University of Pittsburgh11, Saint Thomas - West Hospital12, University College London13, Vanderbilt University Medical Center14, Keio University15, Memorial Hospital of South Bend16, Cooper University Hospital17, University of Mississippi Medical Center18, Rush University Medical Center19, University of Ulsan20, Federal University of São Paulo21, Regions Hospital22, St. Michael's Hospital23, Washington University in St. Louis24, Ottawa Hospital25, University of Sydney26, Mount Sinai Hospital27, University of New South Wales28, Fujita Health University29, Christiana Care Health System30, Stanford University31, King Abdullah University of Science and Technology32, University of Kansas33, Harvard University34, California Pacific Medical Center35, University of Amsterdam36, Houston Methodist Hospital37
TL;DR: Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
Abstract: To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
4,303 citations
St George’s University Hospitals NHS Foundation Trust1, New York University2, McMaster University3, Brown University4, Catholic University of the Sacred Heart5, Autonomous University of Barcelona6, University of Manitoba7, Emory University8, Hebrew University of Jerusalem9, University of Toronto10, University of Pittsburgh11, St Thomas' Hospital12, University College London13, Vanderbilt University14, Keio University15, Memorial Hospital of South Bend16, Rowan University17, University of Mississippi18, Rush University Medical Center19, University of Ulsan20, Universidade Federal do Rio Grande do Sul21, Federal University of São Paulo22, Regions Hospital23, Washington University in St. Louis24, University of Ottawa25, University of Sydney26, University of New South Wales27, Fujita Health University28, University of Copenhagen29, Sapienza University of Rome30, Christiana Care Health System31, Stanford University32, King Abdullah University of Science and Technology33, University of Kansas34, Harvard University35, California Pacific Medical Center36, University of Amsterdam37, Université libre de Bruxelles38, Houston Methodist Hospital39
TL;DR: A consensus committee of 55 international experts representing 25 international organizations was assembled at key international meetings (forSurviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012 as discussed by the authors ).
Abstract: Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for
2,414 citations
Stony Brook University1, University of Minnesota2, University of Notre Dame3, University of Vermont4, University of Toronto5, Boston University6, University of Maryland, Baltimore7, Duke University8, University of Kansas9, King's College London10, Columbia University11, Broad Institute12, Purdue University13, University of Iowa14, University of Georgia15, Texas A&M University16, Oklahoma State University–Stillwater17, University of Groningen18, Florida State University19, Uniformed Services University of the Health Sciences20, Bryn Mawr College21, University of North Texas22, University of Otago23, University at Buffalo24, University of Arizona25, University of New South Wales26, Northwestern University27, Emory University28, University of Kentucky29, University of Pittsburgh30, Brown University31
TL;DR: The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies and provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response.
Abstract: The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology and were shaped by a variety of other considerations, which may explain the aforementioned shortcomings. The Hierarchical Taxonomy Of Psychopathology (HiTOP) model has emerged as a research effort to address these problems. It constructs psychopathological syndromes and their components/subtypes based on the observed covariation of symptoms, grouping related symptoms together and thus reducing heterogeneity. It also combines co-occurring syndromes into spectra, thereby mapping out comorbidity. Moreover, it characterizes these phenomena dimensionally, which addresses boundary problems and diagnostic instability. Here, we review the development of the HiTOP and the relevant evidence. The new classification already covers most forms of psychopathology. Dimensional measures have been developed to assess many of the identified components, syndromes, and spectra. Several domains of this model are ready for clinical and research applications. The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies. It also provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response. This can greatly improve the utility of the diagnosis of mental disorders. The new classification remains a work in progress. However, it is developing rapidly and is poised to advance mental health research and care significantly as the relevant science matures. (PsycINFO Database Record
1,635 citations
Kyriaki Michailidou1, Kyriaki Michailidou2, Sara Lindström3, Sara Lindström4 +393 more•Institutions (127)
TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
1,014 citations
City of Hope National Medical Center1, American Society of Clinical Oncology2, MedStar Washington Hospital Center3, University of Pennsylvania4, University of Rochester5, University of Ottawa6, Duke University7, Ottawa Hospital8, University of Kansas9, Memorial Sloan Kettering Cancer Center10, Harvard University11, Vanderbilt University12, Mayo Clinic13
TL;DR: Recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers were developed by an expert panel with multidisciplinary representation using a systematic review of meta-analyses, randomized clinical trials, observational studies, and clinical experience.
Abstract: Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.
782 citations
Karolinska University Hospital1, Karolinska Institutet2, Hospital of the University of Pennsylvania3, Great Ormond Street Hospital4, Brigham and Women's Hospital5, University of Kansas6, University of Alabama7, Mayo Clinic8, University of Pittsburgh9, Central Manchester University Hospitals NHS Foundation Trust10, University of Liverpool11, University of Debrecen12, University of Toronto13, University of Guadalajara14, University of Cambridge15, University of Tsukuba16, United States Department of Health and Human Services17, Tokyo Medical and Dental University18, Oregon State University19, Dalhousie University20, Peking University21, Duke University22, Oslo University Hospital23, New Generation University College24, Charles University in Prague25, National Institutes of Health26
TL;DR: New classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups, and have been partially validated and generally perform better than existing criteria.
Abstract: Objective To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. Results Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) ‘probable IIM’, had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to ‘definite IIM’. A probability of Conclusions The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of ‘definite’, ‘probable’ and ‘possible’ IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.
754 citations
TL;DR: Three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease are observed, providing additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's Disease.
Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
730 citations
TL;DR: A fully-fledged particle-flow reconstruction algorithm tuned to the CMS detector was developed and has been consistently used in physics analyses for the first time at a hadron collider as mentioned in this paper.
Abstract: The CMS apparatus was identified, a few years before the start of the LHC operation at CERN, to feature properties well suited to particle-flow (PF) reconstruction: a highly-segmented tracker, a fine-grained electromagnetic calorimeter, a hermetic hadron calorimeter, a strong magnetic field, and an excellent muon spectrometer. A fully-fledged PF reconstruction algorithm tuned to the CMS detector was therefore developed and has been consistently used in physics analyses for the first time at a hadron collider. For each collision, the comprehensive list of final-state particles identified and reconstructed by the algorithm provides a global event description that leads to unprecedented CMS performance for jet and hadronic τ decay reconstruction, missing transverse momentum determination, and electron and muon identification. This approach also allows particles from pileup interactions to be identified and enables efficient pileup mitigation methods. The data collected by CMS at a centre-of-mass energy of 8\TeV show excellent agreement with the simulation and confirm the superior PF performance at least up to an average of 20 pileup interactions.
719 citations
TL;DR: In this paper, the authors study and systematize existing research on CPS security under a unified framework, which consists of three orthogonal coordinates: 1) from the security perspective, they follow the well-known taxonomy of threats, vulnerabilities, attacks and controls; 2) from CPS components, they focus on cyber, physical, and cyber-physical components.
Abstract: With the exponential growth of cyber-physical systems (CPSs), new security challenges have emerged. Various vulnerabilities, threats, attacks, and controls have been introduced for the new generation of CPS. However, there lacks a systematic review of the CPS security literature. In particular, the heterogeneity of CPS components and the diversity of CPS systems have made it difficult to study the problem with one generalized model. In this paper, we study and systematize existing research on CPS security under a unified framework. The framework consists of three orthogonal coordinates: 1) from the security perspective, we follow the well-known taxonomy of threats, vulnerabilities, attacks and controls; 2) from the CPS components perspective, we focus on cyber, physical, and cyber-physical components; and 3) from the CPS systems perspective, we explore general CPS features as well as representative systems (e.g., smart grids, medical CPS, and smart cars). The model can be both abstract to show general interactions of components in a CPS application, and specific to capture any details when needed. By doing so, we aim to build a model that is abstract enough to be applicable to various heterogeneous CPS applications; and to gain a modular view of the tightly coupled CPS components. Such abstract decoupling makes it possible to gain a systematic understanding of CPS security, and to highlight the potential sources of attacks and ways of protection. With this intensive literature review, we attempt to summarize the state-of-the-art on CPS security, provide researchers with a comprehensive list of references, and also encourage the audience to further explore this emerging field.
658 citations
TL;DR: This version of the phylogenetic classification of bony fishes is substantially improved, providing resolution for more taxa than previous versions, based on more densely sampled phylogenetic trees.
Abstract: Fish classifications, as those of most other taxonomic groups, are being transformed drastically as new molecular phylogenies provide support for natural groups that were unanticipated by previous studies. A brief review of the main criteria used by ichthyologists to define their classifications during the last 50 years, however, reveals slow progress towards using an explicit phylogenetic framework. Instead, the trend has been to rely, in varying degrees, on deep-rooted anatomical concepts and authority, often mixing taxa with explicit phylogenetic support with arbitrary groupings. Two leading sources in ichthyology frequently used for fish classifications (JS Nelson’s volumes of Fishes of the World and W. Eschmeyer’s Catalog of Fishes) fail to adopt a global phylogenetic framework despite much recent progress made towards the resolution of the fish Tree of Life. The first explicit phylogenetic classification of bony fishes was published in 2013, based on a comprehensive molecular phylogeny (
www.deepfin.org
). We here update the first version of that classification by incorporating the most recent phylogenetic results. The updated classification presented here is based on phylogenies inferred using molecular and genomic data for nearly 2000 fishes. A total of 72 orders (and 79 suborders) are recognized in this version, compared with 66 orders in version 1. The phylogeny resolves placement of 410 families, or ~80% of the total of 514 families of bony fishes currently recognized. The ordinal status of 30 percomorph families included in this study, however, remains uncertain (incertae sedis in the series Carangaria, Ovalentaria, or Eupercaria). Comments to support taxonomic decisions and comparisons with conflicting taxonomic groups proposed by others are presented. We also highlight cases were morphological support exist for the groups being classified. This version of the phylogenetic classification of bony fishes is substantially improved, providing resolution for more taxa than previous versions, based on more densely sampled phylogenetic trees. The classification presented in this study represents, unlike any other, the most up-to-date hypothesis of the Tree of Life of fishes.
622 citations
TL;DR: Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.
Abstract: Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.
U. Bhawandeep1, Vardan Khachatryan, Albert M. Sirunyan, Armen Tumasyan +2289 more•Institutions (147)
TL;DR: In this paper, the trigger system consists of two levels designed to select events of potential physics interest from a GHz (MHz) interaction rate of proton-proton (heavy ion) collisions.
Abstract: This paper describes the CMS trigger system and its performance during Run 1 of the LHC. The trigger system consists of two levels designed to select events of potential physics interest from a GHz (MHz) interaction rate of proton-proton (heavy ion) collisions. The first level of the trigger is implemented in hardware, and selects events containing detector signals consistent with an electron, photon, muon, tau lepton, jet, or missing transverse energy. A programmable menu of up to 128 object-based algorithms is used to select events for subsequent processing. The trigger thresholds are adjusted to the LHC instantaneous luminosity during data taking in order to restrict the output rate to 100 kHz, the upper limit imposed by the CMS readout electronics. The second level, implemented in software, further refines the purity of the output stream, selecting an average rate of 400 Hz for offline event storage. The objectives, strategy and performance of the trigger system during the LHC Run 1 are described.
Karolinska University Hospital1, Karolinska Institutet2, Hospital of the University of Pennsylvania3, Great Ormond Street Hospital4, Brigham and Women's Hospital5, University of Kansas6, Mayo Clinic7, University of Pittsburgh8, Central Manchester University Hospitals NHS Foundation Trust9, University of Liverpool10, University of Debrecen11, University of Toronto12, University of Guadalajara13, University of Cambridge14, University of Tsukuba15, National Institutes of Health16, Tokyo Medical and Dental University17, Oregon State University18, Dalhousie University19, Peking University20, Duke University21, Oslo University Hospital22, New Generation University College23, Charles University in Prague24
TL;DR: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.
Abstract: Objective
To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.
Methods
Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria.
Results
Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) “probable IIM,” had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to “definite IIM.” A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50–<55% as “possible IIM.”
Conclusion
The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of “definite,” “probable,” and “possible” IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.
TL;DR: In this paper, an improved jet energy scale corrections, based on a data sample corresponding to an integrated luminosity of 19.7 fb^(-1) collected by the CMS experiment in proton-proton collisions at a center-of-mass energy of 8 TeV, are presented.
Abstract: Improved jet energy scale corrections, based on a data sample corresponding to an integrated luminosity of 19.7 fb^(-1) collected by the CMS experiment in proton-proton collisions at a center-of-mass energy of 8 TeV, are presented. The corrections as a function of pseudorapidity η and transverse momentum p_T are extracted from data and simulated events combining several channels and methods. They account successively for the effects of pileup, uniformity of the detector response, and residual data-simulation jet energy scale differences. Further corrections, depending on the jet flavor and distance parameter (jet size) R, are also presented. The jet energy resolution is measured in data and simulated events and is studied as a function of pileup, jet size, and jet flavor. Typical jet energy resolutions at the central rapidities are 15–20% at 30 GeV, about 10% at 100 GeV, and 5% at 1 TeV. The studies exploit events with dijet topology, as well as photon+jet, Z+jet and multijet events. Several new techniques are used to account for the various sources of jet energy scale corrections, and a full set of uncertainties, and their correlations, are provided. The final uncertainties on the jet energy scale are below 3% across the phase space considered by most analyses (p_T > 30 GeV and 0|η| 30 GeV is reached, when excluding the jet flavor uncertainties, which are provided separately for different jet flavors. A new benchmark for jet energy scale determination at hadron colliders is achieved with 0.32% uncertainty for jets with p_T of the order of 165–330 GeV, and |η| < 0.8.
TL;DR: This review considers studies and data that inform this area of AD research and suggests mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of A β deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology.
Abstract: Decades of research indicate mitochondria from Alzheimer's disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.
TL;DR: The design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and the methodology for drilling and deployment are described, including the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis.
Abstract: The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.
TL;DR: The production and tomography of genuinely entangled Greenberger-Horne-Zeilinger states with up to ten qubits connecting to a bus resonator in a superconducting circuit are reported, demonstrating the largest entanglement created so far in solid-state architectures and paving the way to large-scale quantum computation.
Abstract: The largest entangled state created to date is realized in a superconducting circuit, with complete connectivity for and of each qubit.
Karolinska Institutet1, Beth Israel Deaconess Medical Center2, American University of Beirut3, University of Aberdeen4, University of Kansas5, McMaster University6, University of Missouri7, Paris Descartes University8, Mayo Clinic9, University of Ottawa10, University of Glasgow11, Malmö University12, Frederiksberg Hospital13, Research Triangle Park14
TL;DR: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.
TL;DR: A phase 3, randomised, double-blind, placebo-controlled, multicentre study in 76 hospitals and specialised clinics across North America, Latin America, Europe, and Asia to assess the efficacy and safety of eculizumab in patients with refractory myasthenia gravis.
Abstract: Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
TL;DR: A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.
ETH Zurich1, University of Ulm2, Vrije Universiteit Brussel3, Royal Museum for Central Africa4, University of Coimbra5, University of Helsinki6, University of Victoria7, University of Innsbruck8, University of Milan9, Czech University of Life Sciences Prague10, Spanish National Research Council11, Swiss Federal Institute for Forest, Snow and Landscape Research12, Institut national de la recherche agronomique13, Laval University14, University of Ljubljana15, United States Geological Survey16, Ben-Gurion University of the Negev17, Center for International Forestry Research18, Technical University of Berlin19, Dresden University of Technology20, University of Kansas21, University of Arkansas22, Max Planck Society23, National Museum of Natural History24, Desert Botanical Garden25, Humboldt State University26, Sukachev Institute of Forest27, National Scientific and Technical Research Council28, National University of Comahue29, Agricultural Research Organization, Volcani Center30, Wageningen University and Research Centre31, Naturalis32, Pablo de Olavide University33, Autonomous University of Barcelona34, University of Lisbon35, Mediterranean University36, University of Western Sydney37, Technical University of Madrid38, University of Debrecen39, Natural Resources Canada40, American Hotel & Lodging Educational Institute41, University of Patras42, Open University of Cyprus43, University of Cyprus44, University of Colorado Boulder45, Northern Arizona University46, University of Novi Sad47, European Forest Institute48, Estonian University of Life Sciences49, University of Alberta50, University of Minnesota51, University of Forestry, Sofia52
TL;DR: The results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks.
Abstract: Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms
leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-conti-
nental tree-ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living
trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and
those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the
mortality events. The extent and duration of these reductions were highly variable (1–100 years in 96% of events) due
to the complex interactions among study species and the source(s) of mortality. Strong and long-lasting declines were
found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms
and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term
growth reductions. Our analysis did not highlight any universal trade-off between early growth and tree longevity
within a species, although this result may also reflect high variability in sampling design among sites. The intersite
and interspecific variability in growth patterns before mortality provides valuable information on the nature of the
mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality.
Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or
bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be
a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks.
Utrecht University1, United States Department of Energy2, National Autonomous University of Mexico3, National and Kapodistrian University of Athens4, University of Debrecen5, Leiden University6, Commonwealth Scientific and Industrial Research Organisation7, Maynooth University8, University of Göttingen9, University of Natural Resources and Life Sciences, Vienna10, University of Seville11, Broad Institute12, Huazhong Agricultural University13, State University of Campinas14, International Sleep Products Association15, Université libre de Bruxelles16, University of Nottingham17, Aix-Marseille University18, Pasteur Institute19, Institut national de la recherche agronomique20, King Abdulaziz University21, University of Helsinki22, University of Amsterdam23, University of Ioannina24, University of St Andrews25, Saint Petersburg State University26, Spanish National Research Council27, Federal University of São Carlos28, Swedish University of Agricultural Sciences29, Technical University of Berlin30, National Scientific and Technical Research Council31, Concordia University32, Kyungpook National University33, University of the Republic34, Karlsruhe Institute of Technology35, University of Sulaymaniyah36, University of Ljubljana37, Leibniz Association38, Stanford University39, Kansas State University40, Technical University of Denmark41, University of Wisconsin-Madison42, Pacific Northwest National Laboratory43, University of Jena44, University of São Paulo45, University of Kansas46, Imperial College London47, Université Paris-Saclay48, Vienna University of Technology49
TL;DR: In this article, a comparative genomics and experimental study of the aspergilli genus is presented, which allows for the first time a genus-wide view of the biological diversity of the Aspergillus and in many, but not all, cases linked genome differences to phenotype.
Abstract: Background: The fungal genus Aspergillus is of critical importance to humankind. Species include those with industrial applications, important pathogens of humans, animals and crops, a source of potent carcinogenic contaminants of food, and an important genetic model. The genome sequences of eight aspergilli have already been explored to investigate aspects of fungal biology, raising questions about evolution and specialization within this genus. Results: We have generated genome sequences for ten novel, highly diverse Aspergillus species and compared these in detail to sister and more distant genera. Comparative studies of key aspects of fungal biology, including primary and secondary metabolism, stress response, biomass degradation, and signal transduction, revealed both conservation and diversity among the species. Observed genomic differences were validated with experimental studies. This revealed several highlights, such as the potential for sex in asexual species, organic acid production genes being a key feature of black aspergilli, alternative approaches for degrading plant biomass, and indications for the genetic basis of stress response. A genome-wide phylogenetic analysis demonstrated in detail the relationship of the newly genome sequenced species with other aspergilli. Conclusions: Many aspects of biological differences between fungal species cannot be explained by current knowledge obtained from genome sequences. The comparative genomics and experimental study, presented here, allows for the first time a genus-wide view of the biological diversity of the aspergilli and in many, but not all, cases linked genome differences to phenotype. Insights gained could be exploited for biotechnological and medical applications of fungi.
TL;DR: In this paper, a color-blind racial ideology has been conceptualized as an ideology wherein race is immaterial, and efforts not to see race insinuate that recognizing race is problematic.
Abstract: Color-blind racial ideology has historically been conceptualized as an ideology wherein race is immaterial. Efforts not to ‘see’ race insinuate that recognizing race is problematic; therefore, scho...
TL;DR: A facile route to synthesize carbon dots with red emission due to the doping effect of S and N elements, borrowing from the concept of the semiconductor is developed, demonstrating that the S,N-CDs are a potentially excellent bioimaging component in the theranostic field.
Abstract: It is highly desirable and a great challenge for red light emission of carbon dots under long wavelength excitation Here, we developed a facile route to synthesize carbon dots with red emission due to the doping effect of S and N elements, borrowing from the concept of the semiconductor The maximum emission locates at 594 nm under 560 nm excitation The absolute photoluminescence (PL) quantum yield (QY) is as high as 29% and 22% in ethanol and water, respectively XPS and FTIR spectra illustrated that there exist -SCN and -COOH groups on the surface of the carbon dots They endow the carbon dots with high sensitivity for ion detection of Fe3+ The quenched PL emission of Fe3+-S,N-CDs can be recovered by adding ascorbic acid to release the -COOH and -SCN group due to Fe2+ formation in the presence of ascorbic acid High PL QY of red emission is beneficial to application in bioimaging Doxorubicin was loaded onto carbon dots through π–π stacking to form a theranostic agent When the CD-Dox was injected in
Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer2 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam +2333 more•Institutions (195)
TL;DR: In this paper, the authors acknowledge the enduring support for the construction and operation of the LHC and the CMS detector provided by the following funding agencies:======BMWFW and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ,======And FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS======(Colombia); MSES and CSF (Croatia); RPF (
Abstract: we acknowledge the enduring support for the construction and
operation of the LHC and the CMS detector provided by the following funding agencies:
BMWFW and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ,
and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS
(Colombia); MSES and CSF (Croatia); RPF (Cyprus); SENESCYT (Ecuador);
MoER, ERC IUT and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland);
CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece);
OTKA and NIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN
(Italy); MSIP and NRF (Republic of Korea); LAS (Lithuania); MOE and UM (Malaysia);
BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MBIE (New
Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Dubna);
MON, RosAtom, RAS and RFBR (Russia); MESTD (Serbia); SEIDI and CPAN (Spain);
Swiss Funding Agencies (Switzerland); MST (Taipei); ThEPCenter, IPST, STAR and
NSTDA (Thailand); TUBITAK and TAEK (Turkey); NASU and SFFR (Ukraine); STFC
(United Kingdom); DOE and NSF (U.S.A.).
TL;DR: In this paper, the Higgs boson mass was measured in the H → ZZ → 4l (l = e, μ) decay channel and the signal strength modifiers for individual Higgs production modes were also measured.
Abstract: Properties of the Higgs boson are measured in the H → ZZ → 4l (l = e, μ) decay channel. A data sample of proton-proton collisions at $ \sqrt{s}=13 $ TeV, collected with the CMS detector at the LHC and corresponding to an integrated luminosity of 35.9 fb$^{−1}$ is used. The signal strength modifier μ, defined as the ratio of the observed Higgs boson rate in the H → ZZ → 4l decay channel to the standard model expectation, is measured to be μ = 1.05$_{− 0.17}^{+ 0.19}$ at m$_{H}$ = 125.09 GeV, the combined ATLAS and CMS measurement of the Higgs boson mass. The signal strength modifiers for the individual Higgs boson production modes are also measured. The cross section in the fiducial phase space defined by the requirements on lepton kinematics and event topology is measured to be 2. 92$_{− 0.44}^{+ 0.48}$ (stat)$_{− 0.24}^{+ 0.28}$ (syst)fb, which is compatible with the standard model prediction of 2.76 ± 0.14 fb. Differential cross sections are reported as a function of the transverse momentum of the Higgs boson, the number of associated jets, and the transverse momentum of the leading associated jet. The Higgs boson mass is measured to be m$_{H}$ = 125.26 ± 0.21 GeV and the width is constrained using the on-shell invariant mass distribution to be Γ$_{H}$ < 1.10 GeV, at 95% confidence level.
Vardan Khachatryan, Albert M. Sirunyan, Armen Tumasyan, Wolfgang Adam1 +2273 more•Institutions (154)
TL;DR: In this article, the second-order and third-order azimuthal anisotropy harmonics of unidentified charged particles, as well as v2v2 of View the MathML sourceKS0 and ViewTheMathML sourceΛ/Λ ǫ particles, are extracted from long-range two-particle correlations as functions of particle multiplicity and transverse momentum.
TL;DR: In this paper, the origin of high-energy neutrinos has not yet been fully answered and only a small fraction of what is known about this flux comes from a small ev...
Abstract: Since the recent detection of an astrophysical flux of high-energy neutrinos, the question of its origin has not yet fully been answered. Much of what is known about this flux comes from a small ev ...
University of Alabama at Birmingham1, Medical University of Vienna2, University of Bergen3, Haukeland University Hospital4, Federal University of Paraná5, University of Kansas6, The Ohio State University Wexner Medical Center7, University of California, Irvine8, Universidade Federal de Santa Catarina9, Karolinska University Hospital10, Université de Montréal11, Del Rosario University12, Veterans Health Administration13, University of Iowa14, University of California, Los Angeles15, McGill University16, Johns Hopkins University17, University of Virginia18, Queen Mary University of London19, University of Melbourne20, University of Copenhagen21, Merck & Co.22
TL;DR: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV).